JPS6042237B2 - Azetidinone derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION This invention relates to novel azetidinone derivatives having antibacterial activity.

15 This invention is based on the successful elucidation of the chemical structural formula of the antibiotic FR-192.

That is, the antibiotic FR-1923 substance is known as an antibiotic produced by bacteria belonging to the genus Nocardia (
For example, Japanese Patent Application Laid-Open No. 48-33094 (Publication date: ■0 May 1, 1939) does not describe its chemical structural formula. As a result of intensive research, the inventors succeeded in elucidating the chemical structural formula of the antibiotic FR-192 phlegm as shown below.

1-(α-carboxy4-hydroxybenzyl)-3
-[2-(4-(3-amino-3-carboxypropoxy)phenyl)2-hydroxyiminoacetamide]-
2-Azetidinone Based on the success in elucidating the chemical structural formula of the antibiotic FR-192, the inventors conducted further intensive research and succeeded in synthesizing a number of azetidinone derivatives with completely new structures, resulting in the present invention. completed.

The azetidinone derivative of this invention is represented by the following general formula (1).

[In the formula, R1 is an amino group or an acylamino group,
means hydrogen or a group represented by the formula (1) Process 1: (2) Process 2: (wherein R2 means a carboxy group or a lower alkoxycarbonyl group), provided that R1 is a phthalimide group or a formamide group. group, benzyloxycarbonylamino group, 2-(2-nitrophenoxy)acetamido group or 2-(2-nitrophenoxy)-2-methylpropionamide group, A is of the formula (wherein R2 is as defined above). (same meaning), and when R1 is a 2-[4-(3-amino-3-carboxypropoxy)phenyl]-2-hydroxyiminoacetamide group, A is hydrogen. .

The azetidinone derivative (1) of the present invention can be purified by various methods shown in the following formula.

(3) Process 3: (4) Process 4: (5) Professional Heng 5: (6) Process 6: (7) Process 7: (8) Process 8: (9) Process 9: (10) Process 10: Above The definitions of symbols in the general formulas for each process are as follows.

R1 is the same meaning as above A is the same meaning as above A'' is a group from which the hydrogen atom is removed from the definition of symbol A;
is an acylamino group, Y is an alkyl group whose 1-position carbon atom is substituted with either a protected amino group or a protected hydro group, or an oxalo group or an esterified oxalo group, and R2 is an esterified oxalo group. R3 is an amino group or an acylamino group, R″3 is a hydrogen atom or an aralkyl group, R4 is an oxo group or a hydroxyimino group, R5 is an amino group or a hydroxy group, R6 and R7 are together are an oxo group or a hydroxyimino group, or R6 is a hydrogen atom and R7
is an amino group or a hydroxy group, R8 is an acylamino group, R9 and RlO are together an oxo group or a hydroxyimino group, or R9 is a hydrogen atom and RlO is an amino group, a hydroxyl group, or an acylamino group. group or acyloxy group, X1 is an acid residue, A1 is a divalent aliphatic hydrocarbon residue, Rll is a nucleophilic compound residue, Rl2 is a protected amino group, a protected hydroxy group, and R″12 is an acyl group having at least one of a protected carboxy group, R″12 is an acyl group having one of an amino group, a hydroxy group, and a carboxy group from which the protecting group has been removed; Rl3 is an acyl group having at least one of a protected carboxy group; A hydrogen atom, an aralkyl group, an acyl group, or an alkyl group, X2 is a hydrogen atom or a halogen atom, Rl4 is an acyl group, X3 is a hydrogen atom or a halogen atom,
4 is a halogen atom, Rl5 is a hydrogen atom, an alkyl group,
An aryl group, an aralkyl group, an aryloxy group, a heterocyclic group or a heterocyclic-substituted alkyl group, Rl6 is an amino group or an amino-substituted hydrocarbon residue 1, Rl7 is an acylamino group or an acylamino-substituted hydrocarbon residue, Rl8
is a hydrogen atom or an aryl group, Rl9 is an alkyl group, N-arylcarbamoyl, alkyl group or aryl group, R2O is an amino group or acylamino group, R2l is a nitro group and/or
R22 is an aryl group having an esterified carboxy group on its aryl ring; R22 is an acylamino group or an arylamino group having a nitro group and/or an esterified carboxy group on its aryl ring;
represents a mono- or dialkylamino group, R24 represents a nitro-substituted aryl group, R25 represents an amino-substituted aryl group, R26 represents a hydrogen atom, an alkyl group or an aryl group, X
5 is a hydrogen atom or a hydrogen atom, ~ is a divalent aliphatic hydrocarbon residue, R27 is a hydroxy group, alkoxy group, or alkanoylamino group, R28 is an acylamino group, R29 is an acylamino group, R3O and R3l are together an oxo group or a hydroxyimino group, or R3O is a hydrogen atom, R3l is a hydroxy group, R32 and R33 are each a hydrogen atom or an alkyl group, R34 is an acylamino group, R3 , and R36 together represent an oxo group or a hydroxyimino group, or R0 is a hydrogen atom, R0 is an acylamino group or a hydroxy group, R3
7 and R38 are together an oxo group, a hydroxyimino group, an alkoxyimino group, or a substituted alkoxyimino group, or R37 is a hydrogen atom, and R3
8 is an acylamino group, hydroxy group, alkoxy group or substituted alkoxy group, R39 is an alkyl group or substituted alkyl group, R″40 is a hydrogen atom or an acyl group,
R4O is a hydrogen atom, an amino group, or a substituted or unsubstituted alkyl group, R4l is a substituted or unsubstituted alkyl group, R42 is an alkyl group, aryl group, or aralkyl group, I is an alkyreso group, and 8 is a divalent aliphatic group. group hydrocarbon residue, R43 has a nitro group and/or
R44 is an aralkyl group, R45 is an alkyl group, R46 is a hydrogen atom or an alkyl group, R47 is a carboxy group or a derivative thereof, R48 represents a protected amino group or a protected hydroxy group, R
``48 is an amino group or a hydroxy group, R49 is an acylamino group having either a carboxy group or a derivative thereof, and R5O is an acylamino group having any of a carbazol group, an N-(hydroxyalkyl)carbamoyl group, and an N-alkylcarbamoyl group. , R5l is an acylamino group having an amino group, R52 is an acylamino group having an esterified carboxyl-substituted alkylamino group, R53 is an acylamino group having an esterified carboxyl-substituted alkenylamino group,
R54 is an acylamino group having either a nitro group or an azide group, R55 is an acylamino group having a formyl group, an alkanoyl group, or an aroyl group, and R56 is a hydroxyalkyl group or an α-hydroxyaralkyl group. R57 is an aralkylamino group, X6 is a halogen atom, X7 is a hydrogen atom or a halogen atom, R58, R59 and R6O are each an alkyl group,
R6l is an aralkanoylamino group, R62 is an aryl group, ~alkylene group, R63 is an aryl group or a heterocyclic group, R6,, and R65 are both hydrogen atoms or are combined together. hydroxyimino group, R66 and R67 are both hydrogen atoms, or together they form an aroyloxyimino group or an aralkoxycarbonyloxyimino group, and R68 is an aroyl group or an aralkoxycarbonyloxyimino group. , R6O is an aralkyl group, R7O is an alkyl group, a heterocyclic thio group, or the group R7l is an alkyl group having either a carboxy group or an esterified carboxy group, and R72 is hydrogen, an alkyl group, or a substituted or unsubstituted group. R73 is a substituted aryl group, R73 is an esterified carboxy group, A″″ is an alkyl group, alkenyl group or aryl group, R74 is an alkyl group, R75 is a lower alkyl group, R76 is an alkoxy group, carboxy or ester carboxy-substituted alkoxy group, aralkoxy group,
A ureido group, thioureido group or amino group, R77
represents an aralkyl group, R78 represents a protecting group for an amino group, R79 represents an acyl group, and R8O represents a hydrogen atom, an acyl group, an alkyl group, or an aralkyl group, respectively.

Examples of each of the above definitions are as follows.

Regarding compound (1), the acyl moiety in the acylamino group in R1 includes aliphatic acyl, aromatic acyl heterocyclic acyl, and aliphatic acyl in which any carbon atom is substituted with an aromatic group or a heterocyclic group.

Examples of such acyls include: That is, the aliphatic hydrocarbon residue portion in the aliphatic acyl includes a saturated or unsaturated chain or cyclic hydrocarbon residue, and the chain hydrocarbon residue may be branched, and It is also possible to have a partially circular sunset.

Specific examples of such chain or cyclic hydrocarbon residues are as follows. -Alkyl groups (e.g. methyl, ethyl, propyl, butyl, isobutyl, pentylph, neopentyl, octyl, undecyl, tridecyl, pentadecyl, cyclohexylmethyl, cyclohexylethyl, bornylmethyl, bornanyl) groups), -alkenyl groups (e.g., vinyl group, propenyl group, isopropenyl group, 3-methylbutenyl group, butenyl group, 2-methylpropenyl group, pentenyl group, octadecenyl group, 3-cyclohexenylmethyl group, etc.), monoalkynyl group (e.g. ethynyl group,
2-pnolopynyl group, etc.), -cycloalkyl group (e.g., cyclopropyl group, cyclopentyl group, cyclohexyl group, indanyl group, bornyl group, adamantyl group, etc.)
, cycloalkenyl groups (eg, 1-cyclopenten-1-yl group, 2-cyclopenten-1-yl group, 3-cyclohexen-1-yl group, bornenyl group, etc.).

Examples of the aromatic group in the aromatic acyl include aryl groups such as phenyl group, tolyl group, and naphthyl group.

The heterocyclic group in the above-mentioned heterocyclic acyl includes a monocyclic or polycyclic heterocyclic group containing at least one heteroatom such as an oxygen atom, a sulfur atom, or a nitrogen atom.

Specific examples of such heterocyclic groups are as follows. - a monocyclic 3- to 8-membered heterocyclic group containing at least one sulfur atom (e.g., thienyl group, dihydrothiopyranyl group, etc.), a monocyclic group containing at least one oxygen atom; 3- to 8-membered heterocyclic groups (e.g., oxiranyl group, furyl group, dihydrofuryl group, pyranyl group, dihydropyranyl group, tetrahydropyranyl group,
dioxanyl group, etc.), monocyclic 3- to 8-membered heterocyclic groups containing at least one nitrogen atom (e.g., aziridinyl group, azetidinyl group, pyrrolyl group, ?- or pyrrolyl group, 2- or 3-pyrrolinyl group, pyrrolidinyl group, imidazolyl group, imidazolidinyl group, pyrazolyl group, pyridyl group, pyrimidyl group, pyrazinyl group, piperidinyl group, pyridazinyl group, triazolyl group, tetrazolyl group, etc.), - at least one oxygen atom and A monocyclic 3- to 8-membered heterocyclic group containing one nitrogen atom (e.g., oxazolyl group, isoxazolyl group, oxadiazolyl group, cydononyl group, etc.), at least one sulfur atom and one nitrogen atom monocyclic 3- to 8-membered heterocyclic groups containing atoms (e.g., thiazolyl group, isothiazolyl group, thiadiazolyl group, etc.), polycyclic heterocyclic groups containing at least one sulfur atom (e.g., benzodiazolyl group, etc.), thienyl group,
- a benzene-fused heterocyclic group such as a benzothiopyranyl group), - a polycyclic heterocyclic group containing at least one nitrogen atom (e.g. an indolyl group, an isoindolyl group, an isodoridinyl group, a benzimidazolyl group, quinolyl group, isoquinolyl group, dihydroisoquinolyl group, quinazolyl group, 1H- or silicon-isodazolyl group, 1H- or 2H-benzotriazolyl group, purinyl group, carbazolyl group, etc.), at least one oxygen - a polycyclic heterocyclic group containing at least one sulfur atom and one nitrogen atom (e.g. benzoxazolyl group, benzoxadiazolyl group, etc.), - a polycyclic heterocyclic group containing at least one sulfur atom and one nitrogen atom; Examples include ring heterocyclic groups (eg, benzothiazolyl group, penzothiadiazolyl group, etc.).

Examples of the aliphatic hydrocarbon moiety in the above-mentioned "aliphatic acyl in which any carbon atom is substituted with an aromatic group or a heterocyclic group" include examples of aliphatic hydrocarbon residue moieties in the above-mentioned aliphatic acyl. and the examples of the aromatic group and heterocyclic group are the same as the examples of the aromatic group in the aromatic acyl and the heterocyclic group in the heterocyclic acyl, respectively.

Further, any carbon atom of the aliphatic hydrocarbon moiety in the aliphatic acyl and the aliphatic acyl in which any carbon atom is substituted with an aromatic group or a heterocyclic group may be a divalent aromatic group, a divalent aromatic group, or a divalent aromatic group. heterocyclic group, -0-, N=, -S-, -
(and ) may be interrupted.

The aliphatic acid in each of the aliphatic acylamino groups, aromatic acylamino groups, heterocyclic acylamino groups, and aliphatic acylamino groups in which any carbon atom is substituted with an aromatic group or a heterocyclic group as defined above. The group hydrocarbon moieties, aromatic moieties and heterocyclic moieties may be substituted with one or more suitable substituents, such as halogen atoms, nitro groups,
Amino group, carboxy group, esterified carboxy group, hydroxy group, group -N3, -CN, -NlINH2
, =0, =NH, =S, sulfo, =NOH (the hydrogen atom of which may be replaced by an alkyl group or an aralkyl group), and further, the above heterocyclic group is an alkyl group. and/or may be substituted with an aryl group.

A more specific description of the acyl amino group in R1 defined above is as follows.

That is, alkanoylamino groups, alkenoylamino groups, aroylamino groups, heterocyclic carbonylamino groups, aryl groups, and heterocyclic groups substituted with any one of the following groups: an alkenoylamino group substituted by any group, an acanoylamino or alkenoyl group whose carbon chain is interrupted at any position by a divalent aromatic group and/or a divalent heterocyclic group; An alkanoylamino group or an alkenoylamino group substituted with an amino group, an aryl group, and/or a heterocyclic group, in which the carbon chain is a divalent aromatic group at any position of the chain hydrocarbon moiety. acylamino groups, aryl groups and (
or) an alkanoylamino group or an alkenoylamino group substituted by a heterocyclic group, in which the carbon chain is substituted with a group -0-, - at any position of the chain hydrocarbon moiety;
N=, one go one, one S-, 1! ．． Acylamino groups, aryl groups interrupted by one or more groups selected from -SO2- and -NH- (the hydrogen atoms of which may be replaced by alkyl or aryl groups) an alkanoylamino group or alkenoylamino group substituted with a group and/or a heterocyclic group, in which the carbon chain is substituted with a divalent aromatic group and ( Or) 2
valent heterocyclic groups, as well as
1 or 2 groups selected from ``90-, -N=, -S-, -SO2- and -NH- (the hydrogen atom of which may be replaced by an alkyl group or an aryl group) Acylamino group interrupted by the above groups, the carbon chain at any position is the group -0-, -N=, -S-, bundle "-SO2- and -NH- (the hydrogen atom of which is an alkyl group or an alkanoylamino group or an alkenoylamino group interrupted by one or more groups selected from the group (optionally replaced by an aryl group), an aromatic carbon chain in which the carbon chain is divalent at any position; group group and (or) divalent heterocyclic group and group -0-,-
by one or more groups selected from N=, -S-, +7-SO2- and -NH- (the hydrogen atom of which may be replaced by an alkyl group or an aryl group) An interrupted alkanoylamino group, an alkenoylamino group, an aroylamino group, or a heterocyclic carbonylamino group, in which the bond between the ring and the carbonyl is a group -0-, -s-, ↓1-SO2 −
and acylamino or cycloalkyl groups interrupted by one or more groups selected from n-NH- (the hydrogen atom of which may be replaced by an alkyl or aryl group) , an alkanoyl"amino group or an alkenoylamino group substituted by an aryl group and/or a heterocyclic group, in which the bond between the ring and the chain hydrocarbon moiety is a group -0- , −N=, −S−, ↓ ”−SO
cycloalkyl, an acylamino group interrupted by one or more groups selected from 2- and -NH- (the hydrogen atoms of which may be replaced by alkyl or aryl groups); an alkanoylamino group or an alkenoylamino group substituted by a group, an aryl group, and/or a heterocyclic group, and a bond between the ring and a chain hydrocarbon moiety and a chain carbonization. Each of the arbitrary carbon chains of the hydrogen moiety is a divalent aromatic group and/or a divalent heterocyclic group, a group -0-,-
N=, -S-, ↓ ゛1SO2- and -NH-(
1 or 2 of the groups whose hydrogen atoms may be replaced by alkyl or aryl groups.
An acylamino group, an aroylamino group, or a heterocyclic carbonylamino group interrupted by any of the above groups, and a divalent aromatic group in which the bond between the ring and the carbonyl group is one or more, and ( or) an alkanoylamino group or an alkenoylamino group substituted by an acylamino group, an aryl group and/or a heterocyclic group interrupted by a divalent heterocyclic group, which ring and The bond between the chain hydrocarbon moiety is a divalent aromatic group and/or a divalent heterocyclic group and a group -0 10-91, -S-, +. -S
an acylamino group, aryl, interrupted by one or more groups selected from O2- and -NH1, the hydrogen atoms of which may be replaced by alkyl or aryl groups; An alkanoylamino group or an alkenoylamino group substituted with a group and/or a heterocyclic group, in which the bond between the ring and the chain hydrocarbon moiety is one or more divalent aromatic groups. and (or) acylamino groups interrupted by divalent heterocyclic groups, and these acylamino groups may be further substituted with one or more suitable substituents. , such substituents include, for example, a halogen atom, a nitro group, an amino group, a carboxy group, an esterified carboxy group, a hydroxy group, -N3,-
CN, -NHNH2,=0,=NH,=S1 sulfo,=
Examples include NOH (the hydrogen atom of which may be replaced by an alkyl group or an aralkyl group), and the heterocyclic group in the above acylamino group may be substituted by an alkyl group.

More detailed examples of the acylamino group in R1 defined above are as follows.

an alkanoylamino group in which any carbon chain is 1
a phenylalkanoylamino group interrupted by phenylene groups, any carbon atom of which is further substituted by one halogen atom and one oxo group, wherein any carbon atom is By at least one group selected from an amino group, a carboxy group, an esterified carboxy group, a hydroxy group, a halogen atom, a nitro group, a sulfo group, an oxo group, a hydroxyimino group, and a benzyloxyimino group Optionally substituted with any of the following groups: naphthylalkanoylamino group, hydroxy-substituted dihydropyranylalkanoylamino group, morpholinoalkanoylamino group, amino group, hydroxy group, oxo group, and hydroxyimino group. thienylalkanoylamino group, furylalkanoylamino group, tetrazolylalkanoylamino group, amino group-substituted indolylalkanoylamino group, diphenylalkanoylamino group, alkanoylamino group substituted with phenyl group and thienyl group, 3-alkyl-1, 2,5-oxadiazol-4-yl-alkanoylamino group, phenylalkenoylamino group, phenylalkanoylamino group in which any carbon atom of the alkane moiety is interrupted by one phenyl group, It is a phenylalkanoylamino group, and any carbon chain of its alkane moiety is a group -0-, -S-, -NH
It is interrupted by one or more groups selected from -, above, and +, and any carbon atom of the phenylalkanoylamino group is an amino group, a carboxy group, or an esterified group. 1 group selected from carboxy group, halogen atom, oxo group and -NH-
A thienylalkanoylamino group optionally substituted by ~4 groups, in which any carbon chain of the alkane moiety is substituted with one of the groups -0-, -S- and -NH. or interrupted by two groups, and any carbon atom is further substituted by one to four groups selected from amino, carboxy, halogen, and oxo groups, a dihydropyranylalkanoylamino group, in which any carbon chain of the alkane moiety is interrupted by an -NH- group, and any carbon atom thereof is further substituted with a halogen atom, and two phenyl an alkanoylamino group substituted with a group, in which any carbon chain of the alkane moiety is substituted with a group -0-, -N
is interrupted by 1 to 3 groups selected from = and -NH-, and any carbon atoms thereof are interrupted by 1 to 2 groups selected from carboxy, hydroxy, and oxo groups. an alkanoylamino group optionally substituted with a phenyl group and a thienyl group, in which any carbon chain of the alkane moiety is substituted with the groups -0-, -N= and -NH - 1 to 2 of the groups selected from
optional carbon atoms may be further substituted by 1 to 5 groups selected from amino groups, halogen atoms, oxo groups and thiooxo groups, an alkanoylamino group substituted with a phenyl group and an indolyl group, in which any carbon chain of the alkane moiety has one group -0- and one group -
an alkanoylamino group substituted by a phenyl group and a benzo[d]isoxazolyl group, interrupted by NH-, and any carbon atom further substituted by one oxo group, Any carbon chain of the alkane moiety contains one group -0- and one group -NH-
a phenylalkanoylamino group, interrupted by 1 or 2 groups selected from azetidine-1,3-diyl group, 1,3,4-thiadiazole-1,5-diyl group and 1,3-oxazolidine-3,4diyl group, and - 0-,-N
? 1'S4? =, -S-, -NH-
and . It is interrupted by 1 to 4 groups selected from 1, , , and further any carbon atom can be an amino group, a halogen atom, a hydroxy group, an esterified carboxy group, an oxo group, a hydroxy group, etc. 1 to 1 of groups selected from imino group, benzyloxyimino group and hydrazino group
A thienylalkanoylamino group optionally substituted by 6 groups, in which any carbon chain of the alkane moiety is substituted with one phenylene group and the groups -0- and -
benzo[c]pyrrolidinyl, interrupted by two groups selected from NH-, and any carbon atoms further substituted by carboxy, oxo and hydroxyimino groups; an alkanoylamino group,
Any carbon chain of the alkane moiety is interrupted by one phenylene group and one group -0-, and any carbon atom can be an amino group, a carboxy group, a hydroxy group, an esterified carboxy group, An alkanoylamino group substituted with two phenyl groups, which is substituted with four groups selected from an oxo group, a hydroxyimino group, and a methoxyimino group, the alkane moiety thereof Any carbon atom is interrupted by one phenylene group, one group -0-, and one group -NH-, and further any carbon atom can be an amino group, a halogen atom,
an alkanoylamino group substituted with a phenyl group and a furyl group, which is substituted with 2 to 4 groups selected from a nitro group, an oxo group, and a hydroxyimino group; Any carbon chain of the moiety is interrupted by one phenylene group, one group -NH- and one group -0-, and further any carbon atoms are selected from halogen atoms and oxo groups. an alkanoylamino group substituted by three groups, any carbon chain of which is substituted with three groups -0-, -S-, -NH-,
It is interrupted by one or two groups selected from -SO2-, and
An alkenoylamino group optionally substituted with one or two groups selected from oxo group, thiooxo group, and group=NH, any carbon chain of which is 1
an alkanoylamino group interrupted by -S- groups, any carbon of which is interrupted by one or two phenylene groups and the groups -01, -N=, -S-, -NH-
and 1 to 5 groups selected from random groups, and any carbon atom can be an amino group, a carboxy group, a hydroxy group, a halogen atom, an azide group, a sulfo group, or an esterified group. an alkanoylamino group optionally substituted with 1 to 7 groups selected from a carboxy group, an oxo group, a thiooxo group, a hydroxyimino group, and a methoxyimino group; The carbon chain of is one 1,3,4-thiadiazole-2,
interrupted by a 5-diyl group and one or two groups selected from the group -S- and the group -NH-,
Further, an alkenoylamino group in which any carbon atoms are substituted with 1 to 6 groups selected from an amino group, a hydroxy group, and an oxo group, and the arbitrary carbon chain has one phenylene group and groups -0- and -
interrupted by one or two groups selected from NH-, and further optional carbon atoms are selected from carboxy groups, esterified carboxy groups, nitro groups, oxo groups and hydroxyimino groups. A 1,2-oxazolidinylcarbonylamino group substituted with 1 to 3 of the above groups, in which the bond between the 1,2-oxazolidinyl group and the carbonyl group is a bicyclo[2,2,1]pebutylalkanoylamino group interrupted by a group -NH- and any carbon atom further substituted with an oxo group, the bicyclo[2 ，
2,1] The bond between the heptyl group and the alkane moiety is interrupted by the group 10-, and furthermore, the bond between the heptyl group and the alkane moiety is
[2,2,1] Any carbon atom of the heptane ring is a phenylalkanoylamino group substituted with three alkyl groups, and the bond between the phenyl group and the alkane moiety is one group. 0-, -S-, -NH- and -SO
2- interrupted by one or two groups selected from 2-, and further any carbon atom is substituted by one group selected from halogen atoms and nitro groups; or a naphthylalkanoylamino group,
The bond between the naphthyl group and the alkane moiety is 10
a pyridylalkanoylamino group interrupted by - and -NH-, the bond between the pyridine group and the alkane moiety being interrupted by a group 10-, 1,3, 4thiadiazolylalkanoylamino group, in which the bond between the 1,3,4-thiadiazolyl group and the alkane moiety is interrupted by a group -S-, 1H-1,2,3- Pyridyl-1-oxide alkanoyl which is a benzotriazolylalkanoylamino group, in which the bond between the 1H-1,2,3-benzotriazolyl group and the alkane moiety is interrupted by a group -0-. an amino group, the bond between the pisodi-1-oxide group and the alkane moiety is an alkanoylamino group substituted with two phenyl groups, in which the bond between the pisodi-1-oxide group and the alkane moiety is interrupted by a group -S-, and the phenyl The bond between one or two of the groups and the alkane moiety is the group -0-, -S-, -NH
interrupted by one or two groups selected from - and -SO2-, further optional carbon atoms being selected from nitro, carboxy, halogen, hydroxy and oxo groups. an alkanoylamino group substituted by a phenyl group and a naphthyl group, which is substituted by one or two groups of the group, wherein the bond between the naphthyl group and the alkane moiety is a group - an alkanoylamino group substituted by a phenyl group and a pyrimidinyl group, interrupted by 0-,
The bond between the pyrimidinyl group and the alkane moiety is interrupted by a group S-, and any carbon 7 atom is further substituted by one amino group and one hydroxy group, An alkanoylamino group substituted with a bicyclo[2,2,1]heptyl group and a phenyl group, in which the bond between the bicyclo[2,2,1]hebutyl group and the alkane moiety is -0 - and any carbon chain of the alkane moiety is interrupted by a group -NH-, respectively, further any carbon atom of the alkane moiety is an oxo group and bicyclo[2,2,
1] Any carbon atom of the heptane ring is an alkanoylamino group substituted with two phenyl groups, each of which is substituted with three alkyl groups, and one of the phenyl groups and an alkane The bond between the moiety is group-0
-, -NH1, -s-, -Ryo-■SO2- and?ゝ)
] and any carbon chain of the alkane moiety is replaced by the groups -NH1 and -
each is interrupted by one or two groups selected from S-, and any carbon atom is a carboxy group, an esterified carboxy group, a halogen atom,
substituted with 1 to 3 groups selected from nitro and oxo groups, ? - an alkanoylamino group substituted by a purinyl group and a phenyl group, in which the bond between the -purinyl group and the alkane moiety is by the group -S- and any carbon of the alkane moiety; the chains are each interrupted by a group -NH- and any carbon atom is further substituted by one oxo group, an alkanoylamino group substituted by a phenyl group and a thienyl group; Therefore, the bond between the phenyl group and the alkane moiety is the group -0- and the group -NH-
and any carbon chains of the alkane moiety are each interrupted by a group -NH, and further any carbon atom is an esterified carboxy group, a halogen atom, etc. , a phenyl group and a pyridyl-1-oxide group substituted by three groups selected from , a nitro group and an oxo group. is an alkanoylamino group substituted by , and the bond between the pyridyl-1-oxide group and the alkane moiety is
-, and any carbon chain of the alkane moiety is interrupted by a group -NH-, respectively, and further any carbon atom is substituted by an oxo group, naphthyl and phenyl groups. an alkanoylamino group substituted by a group, in which the bond between the phenyl group and the alkane moiety is by one group selected from the groups -S- and -NH-; Any carbon chain of the alkane moiety may include the groups -0-, -S-, -NH-, and +
alkanoyl substituted by phenyl and pyrimidinyl groups, each interrupted by one or two groups selected from an amino group, in which the bond between the pyrimidinyl group and the alkane moiety is interrupted by a group -S-, and any carbon chain of the alkane moiety is interrupted by a group -NH-; Furthermore, any carbon atom is an alkanoylamino group substituted with three phenyl groups, which is substituted with one amino group, one hydroxy group, and one oxo group, and one of the phenyl groups is substituted with three phenyl groups. The bond between the alkane moiety and the alkane moiety is by one group selected from the groups -0S- and -NH-, and any carbon chain of the alkane moiety is NH - a naphthyl group and two groups, each interrupted by a further optional carbon atom being substituted by one or two groups selected from halogen atoms and oxo groups; an alkanoylamino group substituted by a phenyl group, in which the bond between the naphthyl group and the alkane moiety is by the group -0-, and any carbon chain of the alkane moiety is substituted by the group -NH
an alkanoylamino group substituted by two naphthyl groups and one phenyl group, each interrupted by - and any carbon atom further substituted by one oxo group; The bonds between the two naphthyl groups and the alkane moiety are each interrupted by a group -0-, and any carbon chain of the alkane moiety is each interrupted by a group -NH-. is a phenylalkanoylamino group in which any carbon atom is further substituted with an oxo group, and the bond between the phenyl group and the alkane moiety is 10-, -NH- and - by one of the groups selected from S-, and any carbon chain of the alkane moiety is replaced by one phenylene group and one to three groups selected from the groups -0 and -NH-. Thus, each carbon atom is interrupted by one to five groups selected from carboxy groups, esterified carboxy groups, halogen atoms, nitro groups, oxo groups, and hydroxyimino groups. a naphthylalkanoylamino group which is substituted with the naphthyl group and the alkane moiety, wherein the bond between the naphthyl group and the alkane moiety is by a group -NH-, and any carbon chain of the alkane moiety is substituted with one phenylene group. and groups -0- and -NH-, respectively, and any carbon atom is further interrupted by one carboxy group, one oxo group and one thiooxo group. A substituted alkanoylamino group substituted by a pyridyl group and a phenyl group, wherein the bond between the pyridyl group and the alkane moiety is by the group -S-, and the bond between the pyridyl group and the alkane moiety is Any carbon chain has two phenylenes and a group -0-
and -NH-, each of which is interrupted by three groups selected from -NH-, and any carbon atoms are further substituted by four groups selected from halogen atoms and oxo groups, an alkanoylamino group substituted by a phenyl group and a benzo[c]pyrrolidinyl group, wherein the bond between the phenyl group and the alkane moiety is through one group -NH-, and the bond between the phenyl group and the alkane moiety is Any carbon chain of is interrupted by one phenylene group and one group -0-, respectively, and any carbon atom is interrupted by a carboxy group, an esterified carboxy group, a nitro group, and an oxo group. an alkanoylamino group substituted by two phenyl groups, which is substituted by five groups of the selected groups, with a gap between the one or two phenyl groups and the alkane moiety; The bond is formed by one or two groups -NH-, and any carbon chain of the alkane moiety is formed by one phenylene group and one to three groups selected from -0- and -NH-. each of which is interrupted by a group of is an alkanoylamino group substituted by two naphthyl groups, in which the bonds between the two naphthyl groups and the alkane moiety are each a group -NH-
, and any carbon chain of the alkane moiety is 1
each interrupted by three groups selected from phenylene and groups -0- and -NH-,
Further, an alkanoylamino group substituted with a phenyl group and a thienyl group, in which any carbon atom is substituted with three groups selected from a carboxy group and a thiooxo group, and the thienyl group and the alkanoyl group are substituted with an alkanoyl group. The bond between the moieties is interrupted by one tetrazole 1,5-diyl group, and any carbon chain of the alkane moiety is each interrupted by one group -NH-, and further optional is a phenyl-substituted alkanoylamino group in which the carbon atom of is substituted with one oxo group, and the bond between the phenyl group and the alkane moiety is through one group -0-, and the Any carbon chain of the alkane moiety is each interrupted by one group -NH-, and any carbon atom is further interrupted by one halogen atom, one nitro group and one oxo group. A substituted alkanoylamino group substituted by two phenyl groups, wherein the bond between the phenyl group and the alkane moiety is one phenylene group and one group -0-. Then,
And any carbon chain in the alkane part has one group -NH
an alkanoylamino group substituted by two phenyl groups, each interrupted by a -, and any carbon atom further substituted by one oxo group, the phenyl group The bond between and the alkane moiety is an isoxazole-3 substituted with one alkyl group.
, 4-diyl group, and any carbon chain of its alkane moiety is each interrupted by one group -NH-, and further any carbon atom is interrupted by one oxo group. a substituted benzamide group, in which the bond between the phenyl group and the canorbonyl group is interrupted by an isoxazole-3,4-diyl group substituted with one alkyl group, Further, a phenylalkanoylamino group in which any carbon atom is substituted with one halogen atom, and the bond between the phenyl group and the alkane moiety is a phenylene group or a 1,3,5-oxadiazole group. -2,4-diyl group and -0-
, -NH- and -SO2-, and any carbon atom is further interrupted by one carboxy group and one hydroxy group. An optionally substituted phenylalkanoylamino group in which the bond between the phenyl group and the alkane moiety is one 4,5-dihydro-1,2,4-oxadiazole-3,4diyl group. a thienylalkanoylamino group in which the bond between the thienyl group and the alkane moiety is 1 Interrupted by 1H-tetrazole-1,5-diyl groups, and the like.

Regarding compounds (1), (1'') and (■): Preferred examples of the saturated or unsaturated linear (or branched) aliphatic hydrocarbon moiety in the definition of A include linear or branched Chain alkyl groups (e.g. methyl group, ethyl group, propyl group, butyl group, pentyl group, isopropyl group, 1-methylpropyl group, isobutyl group, t-butyl 2 group, methylbutyl group, methylpentyl group, ethylpropyl group, ethylbutyl group, neopentyl group, dimethylbutyl group), linear or branched alkenyl group (e.g. 1-propenyl group, allyl group, 1-butenyl group, 1-pentenyl group, isopenyl group, methylpropenyl group, methylbutenyl group, methylpentenyl group, ethylpropenyl group, ethylbutenyl group, dimethylpropenyl group, dimethylbutenyl group, etc.).

In the definition of A, a saturated or unsaturated linear or branched aliphatic hydrocarbon substituted with at least one group selected from a carboxy group or its derivatives, a cyano group, a hydroxy group, and an amino group. Examples of derivatives of carboxyl groups in residues include esters, acid amides, and salts, and specific examples include the following.

(a) Ester esters include all common hand esters, such as silyl esters, aliphatic esters, and esters containing aromatic or heterocycles.

Preferred examples of silyl esters include tri(lower) alkylsilyl esters (eg, trimethylsilyl, triethylsilyl, etc.).

Preferred examples of aliphatic esters include saturated or unsaturated linear (which may be branched or contain rings) or cyclic aliphatic esters; examples of such aliphatic esters include Alkyl (e.g. methyl, ethyl, propyl, isopropyl, 1-cyclopropylethyl, butyl, t-butyl, octyl, nonyl,
undecyl, etc.) esters, alkenyls (e.g., vinyl, 1-propenyl, allyl, 3-butenyl, etc.) esters, alkynyl (e.g., 3-butynyl, 4-pentynyl, etc.) esters, cycloalkyl (e.g., cyclopentyl, cyclohexyl, cyclo (heptyl, etc.) esters, and such aliphatic esters may also contain at least one heteroatom such as nitrogen, sulfur, or oxygen; examples include lower alkoxyalkyl, (e.g., methoxymethyl, ethoxyethyl, methoxyethyl, etc.) esters, lower alkanoyloxyalkyl (e.g., acetoxymethyl, propionyloxymethyl, pivaloyloxymethyl, etc.) esters, alkylthioalkyl (e.g., methylthiomethyl, ethylthioethyl, methylthio propyl) esters, N,N-dialkylhydroxyamines (e.g. N,
N-dimethylhydroxylamine, N,N-diethylhydroxylamine, N,N-dipropylhydroxylamine, etc.), N-alkyldenehydroxylamine (e.g., N-ethylidenehydroxylamine,
-propylidenehydroxylamine, N-isopropylidenehydroxylamine, etc.) esters, lower alkylsulfinyl (lower) alkyl (eg, methylsulfinylmethyl, ethylsulfinylmethyl, etc.) esters, and the like.

Preferred examples of esters containing aromatic rings include aryl (
For example, phenyl, xylyl, tolyl, naphthyl, indanyl, dihydroanthranyl, etc.) esters, aralkyl (e.g., benzyl, phenethyl, etc.) esters, aryloxyalkyl (e.g., phenoxymethyl, phenoxyethyl, phenoxypropyl, etc.) esters, arylthioalkyl (e.g. phenylthiomethyl, phenylthioethyl, phenylthiopropyl, etc.) esters,
Arylsulfinyl alkyl (e.g., phenylsulfinyl 1-methyl, phenylsulfinylethyl, etc.) ester, aryloxyalkyl (e.g., benzoylmethyl, toluoyl ethyl, etc.) ester, N-hydroxyarylimide (e.g., N-hydroxyphthalimide, etc.) The ester answer is:

Preferred examples of esters containing heterocycles include heterocyclic esters and heterocyclic alkyl esters, and preferred examples of such heterocyclic esters include heterocyclic esters such as oxygen atoms, sulfur atoms, and nitrogen atoms. saturated or unsaturated monocyclic or fused 3- to 10-membered heterocycles containing 1 to 4 atoms (e.g., pyridyl, piperidino, 2-pyridon-1-yl, tetrahydropyralyl,
Preferred examples of heterocyclic alkyl esters include saturated or unsaturated monocyclic or fused polycyclic rings containing 1 to 4 heteroatoms such as oxygen, sulfur, and nitrogen atoms. 3- to 10-membered heterocycle (e.g. pyridyl, piperidino, 2-pyridone-4-1-
yl, tetrahydropyranyl, quinoline, pyrazolyl, etc.) substituted alkyl (eg, methyl, ethyl, propyl, etc.) esters.

The above silyl esters, aliphatic carbon esters and esters containing aromatic or heterocycles may have 1 to 10 suitable substituents, examples of such substituents include, for example, alkyl groups (e.g. methyl group, ethyl group, propyl group, isopropyl group, butyl group, t-butyl group, etc.)
, lower cycloalkyl group (e.g. cyclopropyl group,
cyclohexyl group, etc.), lower alkoxy group (e.g.
methoxy group, ethoxy group, propoxy group, isofukomapoxy group, butoxy group, t-butoxy group, etc.), lower alkylthio group (e.g., methylthio group, ethyleo group, propylthio group, etc.), lower alkylsulfinyl group (e.g., methyl Sulfinyl groups (e.g., methylsulfinyl, ethylsulfinyl, propylsulfinyl, etc.), lower alkanesulfonyl groups (e.g., methanesulfonyl, ethanesulfonyl, etc.), phenylazo groups, halogen atoms (e.g., chlorine, bromine, fluorine, etc.) etc.) cyano group, nitro group, etc. Specific examples of esters having such substituents include mono (or di or tri) halo (lower) alkyl (e.g. chloromethyl, bromoethyl, dichloromethyl, 2,2,2-trichloroethyl, 2,2,2-tribromoethyl, etc.) esters, cyano(lower)alkyl (e.g. cyanomethyl, cyanoethyl, etc.) esters, mono(or di- or tri- or tetra- or petane) halofenyl , (e.g. 4-chlorophenyl, 3,5-dibromophenyl, 2,4,5-trichlorophenyl, 2,4,6
- trichlorophenyl, pentachlorophenyl, etc.) esters, lower alkanesulfonylphenyl (e.g. 4
-methanesulfonylphenyl, 2-ethanesulfonylphenyl, etc. ester, 2-(or 3 or 4)-
Phenylazophenyl ester, mono (or di or tri) nitrophenyl (e.g. 4-nitrophenyl, 2,4-dinitrophenyl, 2,4,6-trinitrophenyl, etc.) ester, mono (or di or tri or tetra) or penta)halophenyl (lower) alkyl (e.g., 2-chlorobenzyl, 2,4-dibromobenzyl, 2,4,5-trichlorobenzyl, pentachlorobenzyl, etc.) ester, mono(or di- or tri)nitrophenyl (lower) ) alkyl (e.g. 2-nitrobenzyl, 2,4 dinitrobenzyl, 2,
(4,6-trinitrobenzyl, etc.) esters, mono (or di or tri) (lower) alkoxyphenyl (lower) alkyl (e.g. 2-methoxybenzyl, 3,4
-dimethoxybenzyl, 3,4,5-trimethoxybenzyl, etc.) esters, hydroxy- and di(lower)alkylphenyl-substituted alkyls (e.g., 3,5-dimethyl-4-hydroxybenzyl, 3,5-di-t-butyl-4)
-hydroxybenzyl, etc.) esters.

(b) Suitable examples of acid amide diamide include N-substituted acid amide, N-lower alkyl acid amide (for example, N-methyl acid amide, N-ethylic acid amide, etc.), N,N-di(lower ) Alkyl acid amide (e.g. N,N-dimethyl acid amide,,
N-diethylamide, N-methyl-N-ethylamide, etc.), N-phenylamide, such as pyrazole, imidazole, 4-(lower) alkylimidazole (e.g., 4-methylimidazole, 4-ethylimidazole, etc.), etc. and acid amides.

(c) Salt: Suitable examples of salts include salts with inorganic bases (e.g., sodium salts, potassium salts, magnesium salts, ammonium salts, etc.) and salts with organic bases (e.g., dicyclohexylamine salts, pyridine salts, etc.). , ethanolamine salt, etc.).

Regarding compound (■): Suitable examples of the alkyl group in the definition of Y include the above A
Examples of the straight chain or branched alkyl group given in the explanation of the definition are exemplified as they are.

In the definition of Y, preferred examples of protecting groups for the protected amino group and the protected hydroxy group include ordinary acyl, ordinary alkanoyl (for example, formyl, acetyl, etc.), ordinary haloalkanoyl (for example, dichloro acetyl, trifluoroacetyl, etc.), normal aroyl (e.g., benzoyl, etc.), normal alkoxyl carbonyl (e.g., ethoxycarbonyl, t-butoxycarbonyl, adamantyloxycarbonyl, etc.),
Usual haloalkoxycarbonyl (eg, trichloroethoxycarbonyl, etc.), usual substituted or unsubstituted alkoxycarbonyl (eg, benzyloxycarbonyl, P-nitrobenzyloxycarbonyl, etc.), and the like.

Compound (V), (XXXXX■), (XXXXX■),
(XXXXXX), (XXXXXX[), (XXXXXX
xn) and (XXXXXX■): Preferred examples of the acyl moiety of the acylamino group in R1 are the same as the example of the acyl moiety of the acylamino group in R1 of the above compound (1). Regarding the compound (pi): As mentioned above, the symbol A'' means a group obtained by removing a hydrogen atom from the definition of A, and its preferable example is the same as the example of A above.

Compound (V), (■), (■), (X), (XXI),
(XX■), (XXX), (XXX■) and (XXX
■) Regarding: R29R39R89RlO9R2O9R
229R239R299The acyl moiety of the acylamino group in the definitions of R34, R36 and R38 and Rl
Suitable examples of the acyl moiety in the acyloxy group in the definition of O include aliphatic acyl, aromatic acyl, heterocyclic acyl, and aromatic ring or heterocyclic acyl as shown in the explanation of the acyl moiety in the acylamino group in R1 above. ``Aliphatic acyl substituted with a cyclic group.

More suitable examples of the above acyl include, for example, alkanoyl or cycloalkanoyl (e.g. formyl,
acetyl, propionyl, purityl, isobutyl, pivaloyl, cyclohexanecarbonyl, etc.), aralkanoyl (e.g., phenylacetyl, phenylpropionyl, naphthylacetyl, etc.), heterocyclic-substituted alkanoyl (e.g., thienyl acetyl, tetrazolylacetyl, etc.)
freelacetyl, thiadiazolyl acetyl, thiazolyl acetyl, monophorinoacetyl, piperazinoacetyl, benzothiazolylacetyl, thienylpropionyl, etc.), aroyl (e.g. benzoyl, toluoyl, xyloyl, naphthoyl, phthaloyl, etc.) , heterocyclic carbonyl (eg, thenoyl, furoyl, prolyl, nicotinoyl, isonicotinoyl, benzodioxanecarbonyl, etc.), and cycloalkylalkanoyl (eg, cyclopentylacetyl, cyclohexylacetyl, etc.). In the above examples, the bond between the carbonyl group and the aliphatic group, aromatic group, or heterocyclic group and the bond between the alkylene and the cycloalkyl, aryl, or heterocyclic group are the same as the divalent group. It may be interrupted by 0-, -S- or -NH-.

Preferred examples of such acyl include alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, t-butoxycarbonyl, etc.), cycloalkoxycarbonyl (e.g., cyclopropoxycarbonyl, cyclohexyloxycarbonyl, bornanyloxycarbonyl, adamantyloxycarbonyl, etc.), aralkoxycarbonyl (e.g., benzyloxycarbonyl, phenethyloxycarbonyl, etc.), heterocyclic-substituted alkoxycarbonyl (e.g., furfuryloxycarbonyl, pyrrolidinyloxycarbonyl, pyridylmethoxycarbonyl, etc.), aryloxy Carbonyl (e.g., phenoxycarbonyl, naphthoxycarbonyl, etc.), alkoxythiocarbonyl (e.g., methoxythiocarbonyl, ethoxythiocarbonyl, propoxythiocarbonyl, etc.), alkoxyalkanoyl (e.g., methoxyacetyl, ethoxypropionyl, etc.), cycloalkoxy Alkanoyl (e.g. cyclohexyloxyacetyl, porunyloxyacetyl, adamantyloxyacetyl, etc.), alkylthioalkanoyl (e.g. methylthioacetyl, ethylthioacetyl, isopropylthioacetylbutyl, thioacetyl, etc.), arylthioalkanoyl (e.g. phenylthioacetyl) ), heterocyclic thioalkanoyl (e.g., thienylthioacetyl, thienylthiopropionyl,
thiazolylthioacetyl, thiadiazolylthioacetyl, oxazoylthioacetyl, oxadiazolylthioacetyl, triazolylthioacetyl, tetrazolylthioacetyl, benzothiazolyl-2-thioacetyl, etc.),
N-alkylcarbamoyl (e.g., N-methylcarbamoyl, N-ethylcarbamoyl, etc.), N-arylcarbamoyl (e.g., N-phenylcarbamoyl, N-
naphthylcarbamoyl, etc.), N-alkylthiocarbamoyl (eg, N-methylthiocarbamoyl, N-ethylthiocarbamoyl, etc.), N-arylthiocarbamoyl (eg, N-phenylthiocarbamoyl, etc.), and the like. Any carbon atom of the above acyl may be substituted with one or more suitable substituents, such as halogen atoms (e.g. chlorine,
(bromine, etc.), nitro group, formyl group, etc.

Examples of the aralkyl group in R″3 include benzyl group and phenethyl group. Regarding compound (XI): Preferred examples of the acid residue in X1 include inorganic acids (e.g., hydrochloric acid, hydrobromic acid, iodide acid, Examples include residues of organic sulfonic acids (e.g., methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, etc.), and organic carbamic acids (e.g., dimethylcarbamate, diethylcarbamate, etc.). It will be done.

Suitable examples of divalent aliphatic hydrocarbon residues in the definition of A1 include alkylene groups or alkylidene groups (e.g. methylene, ethylene, trimethylene, propylene,
Benchilidene, hexamethylene, etc.), and any carbon chain thereof may be interrupted by at least one group -NH- or -0-, and any carbon atom thereof may be interrupted by at least one group -NH- or -0-. is an oxo group, an aryl group (e.g.
phenyl group, naphthyl group, etc.) or a heterocyclic group (eg, thienyl group, etc.).

Regarding compound (■): Preferred examples of nucleophilic compound residues in the definition of Rll include substituted or unsubstituted alkylthio groups (e.g., methylthio group, ethylthio group, propylthio group, isopropylthio group, etc.), alkenylthio group (e.g., vinylthio group, propenylthio group, isopropenylthio group, butenylthio group, etc.), alkynylthio group (e.g.,
2-provinylthio group, etc.), arylthio group (e.g.,
phenylthio group, naphthylthio group, etc.), substituted or unsubstituted aralkylthio group (e.g., benzylthio group, phenethylthio group, phenylpropylthio group, phenylbutylthio group, etc.) Any carbon atom in the alkyl part of the group -
0- or -NH-, and any carbon atom may be further substituted by an oxo group), substituted or unsubstituted hetero Ring thio groups (e.g. morpholinylthio group, thiadiazolylthio group, oxadiazolylthio group, triazolylthio group, pyrimidinylthio group, oxazolylthio group, tetrazolylthio group, purinylthio group, pyridine-1
-oxide-2-ylthio group, 5-methyl-1,3,
4-thiadiazolylthio group, 5-isopropyl-1,3
, 4-thiadiazolylthio group, 1-methyltetrazolylthio group, 2-aminothiazolylthio group, 1-methyltriazolylthio group, etc.), substituted or unsubstituted allyloxy groups (e.g. phenoxy group, tolyloxy group, chloro phenoxy group, biphenyloxy group, naphthoxy group, methoxyphenoxy group, phenoxyphenoxy group, vinylphenoxy group, propenylphenoxy group, acetoxyphenoxy group, benzoylphenoxy group, benzoylnaphthoxy group), substituted or unsubstituted arylamino group (for example, anilino group, N-methylanilino group, naphthylamino group, etc.), substituted or unsubstituted aralkylamino group (for example, benzylamino group, N-methylbenzylamino group, phenethylamino group, naphthylmethylamino group, etc.), etc. Can be mentioned.

The above-mentioned nucleophilic compound residue may be substituted with a suitable substituent, and such substituents include a carboxy group, an esterified carboxy group (e.g., methoxycarbonyl group, ethoxycarboxy group, propoxycarbonyl group, etc.). carbonyl group, etc.), halogen atoms (e.g. fluorine, bromine, chlorine, etc.), nitro group, formyl group, amino group, hydroxy group, as well as protected amino groups similar to those exemplified for Y in compound (■) group, protected hydroxy group, and the like.

Regarding compounds (X■) and (X■): Rl.

The protected amino group, protected hydroxy group, and protected carboxy group moiety in the definition are groups bonded to the terminal amino group, hydroxy group, and carboxy group, respectively, in the acylamino group defined in R1 above. A. corresponding to a. It means a group that converts a amino group, a hydroxy group, and a carboxy group, and specific examples of protecting groups for such protected amino groups and protected hydroxy groups include the protecting groups exemplified in the definition of Y above. As an example of the protecting group for the protected carboxy group, the example of the ester in the definition of A above is directly exemplified. Further, as examples of the acyl moiety in the definition of Rl2, the acyl moiety in the acylamino group in the previous example is directly exemplified. Preferred examples of the acyl moiety in the acyl group having an amino group, hydroxy group or carboxy group from which the protecting group has been removed in R''12 include the free amino group, hydroxy group or carboxy group in the acylamino group in R1. An example of an acyl moiety having the following is directly exemplified.

Preferred examples of the alkyl group for Rl3 include, for example, a methyl group, an ethyl group, a propyl group, and the like.
Examples of the acyl group in Rl3 include the acyl moiety in the acylamino group in R1, and examples of the aralkyl group include benzyl group and phenethyl group. Preferred examples of the halogen atom for X2 include bromine, chlorine, and the like.

Regarding compounds (X■) and (X■): Preferred examples of the acyl group in Rl4 include the acyl moiety in the acylamino group in R1, but
More preferred examples include aroyl (e.g., benzoyl group, naphthoyl group, etc.), aralkanoyl group (e.g., phenylacetyl group, phenylpropionyl group, etc.),
Heterocyclic-substituted alkanoyl, for example, thienylalkanoyl groups (e.g., thienyl acetyl, thienylpropionyl, thienylbutyryl, etc.), alkoxyararalkanoyl groups (any carbon atom of which can be substituted with hydroxyimino, carboxy, amino and protected (substituted by at least one amino group) e.g. 2-
[4-(3-carboxy 3-acetamidopropoxy)phenyl]-2-hydroxyiminoacetyl group, 2-[4-(3-carboxy 3-(3-phenylureido)propoxy)phenyl]-2-hydroxyiminoacetyl group , 2-[4-(3-(2,2,2-trifluoroacetamido)-3-carboxypropoxy)phenyl]-2-hydroxyiminoacetyl group, and the like.

Suitable examples of the halogen atoms in X3 and X4 include the halogens mentioned above.

Regarding compounds (X■) and (X■): Preferred examples of the aryl group in the definition of Rl5 include phenyl group, naphthyl group, etc., and examples of the alkyl group include methyl group, ethyl group, propyl group. etc. are mentioned,
Examples of aralkyl groups include benzyl and phenylpropyl groups, examples of aryloxy groups include phenoxy and naphthoxy groups, and examples of heterocyclic groups include thienyl, pyranyl, and 5,6-dihydro?
-Pyranyl group, isobenzofuranyl group, indolyl group, etc., and examples of the heterocyclic-substituted alkyl group include thienylmethyl group, thienylpropyl group, furylmethyl group,
Examples include furylethyl group, furylpropyl group, indolylethyl group, thiazolylmethyl group, thiadiazolylmethyl group, thiadiazolylethyl group, and oxazolylmethyl group.

Preferred examples of amino-substituted hydrocarbon residues in the definition of Rl6 include aminoalkyl groups (e.g., aminomethyl group, aminoethyl group, aminopropyl group, etc.),
Aminoaryl groups (eg, aminophenyl group, aminonaphthyl group, etc.).

Preferred examples of the hydrocarbon moiety of the acylamino-substituted hydrocarbon residue in the definition of Rl7 include alkyl groups (e.g., methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group, etc.), alkenyl groups (e.g., vinyl group, propenyl group, isopropenyl group, etc.), aryl group (e.g., phenyl group, naphthyl group, etc.), aralkyl group (e.g., benzyl group, phenethyl group, phenylpropyl group, phenylbutyl group, etc.), Any carbon atom of such a hydrocarbon residue may have at least one suitable substituent, and examples of such a substituent include, for example, a halogen atom (e.g., fluorine,
bromine, chlorine, etc.), hydroxy group, carboxy group, etc. Furthermore, any carbon atom of the above hydrocarbon residue may be an oxygen atom, nitrogen atom, sulfur atom, imino group, carbonyl group,
It may be replaced by at least one group selected from thiocarbonyl and carbamoyl groups.

Preferred examples of the acyl moiety in the acylamino group and the acyl moiety in the acylamino-substituted hydrocarbon residue in the definition of Rl7 include the acyl moiety in the acylamino group of R1.

Regarding compounds (X■ and (XX)): Preferred examples of the aryl group in the definition of Rl8 include phenyl group, naphthyl group, and the like.

Preferred examples of the alkyl group in the definition of Rl9 include methyl group, ethyl group, propyl group, isopropyl group, etc., and examples of the aryl group include phenyl group, naphthyl group, etc., and N-arylcarbamoylalkyl Preferred examples of the group include N-phenylcarbomoylmethyl group, N-phenylcarbamoylethyl group, N-naphthylcarbamoylethyl group, N-
Examples include naphthylcarbamoylethyl group.

Regarding compound (XXIl): Preferred examples of the aryl group '5 having a nitro group or an esterified carboxy group on its aryl ring in R2l include, for example, P-nitrophenyl group, 24-dinitrophenyl group, 24-dinitrophenyl group, -Nitro-4-methoxycarbonylphenyl group, etc., and R2.

Preferred examples of the aryl moiety in the "arylamino group having a nitro group or esterified carboxy group on its aryl ring" can be directly exemplified by the example in R2l above.Also, preferred examples of the aryl moiety in the acylamino group in R22 As an example, the example of the acyl moiety in the acylamino group of R1 is directly exemplified.Regarding compound (XX■): Preferred examples of the mono- or dialkylamino group in R23 include methylamino group, ethylamino group, propylamino group, etc. monoalkylamino groups such as isopropylamino, butylamino, etc., dialkylamino groups such as dimethylamino, diethylamino, etc., and any carbon atom of such mono- or dialkylamino groups may be e.g. Alkoxycarbonyl group (e.g. methoxycarbonyl group,
It may be substituted with a substituent such as an esterified carboxy group such as ethoxycarbonyl group, etc.

Regarding compound (XX■): Preferred examples of the nitroaryl group for R24 include a mono- or dinitrophenyl group, a mono- or dinitronaphthyl group, and the like.

Regarding compound (XX■): Preferred examples of the aminoaryl group in R28 include mono- or diaminophenyl group, mono- or diamino-naphthyl group, etc.
An aminoaryl group corresponding to the nitroaryl group in 4 is mentioned.

Regarding compounds (XX■) and (XX■): Preferred examples of the aryl group in R26 include phenyl group,
Examples include naphthyl group.

As a preferable example of the divalent aliphatic hydrocarbon residue in A2, the example in A1 above is directly exemplified. X
Preferred examples of the halogen atom in 5 include, for example,
Examples include bromine and chlorine.

Suitable examples of the alkoxy group in R27 include a methoxy group, an ethoxy group, etc., and the alkyl portion thereof may be substituted with a suitable substituent, and examples of such substituents include For example, a carboxy group, an esterified carboxy group, etc. may be mentioned, and preferable examples of an alkoxy group having such a substituent include a carboxymethoxy group, a methoxycarbonylmethoxy group, etc.

Suitable examples of the alkanoylamino group in R27 include formamide, acetamide, propionamide, etc., and the alkyl portion thereof is an ammonio group (e.g., N,N,N-trimethylammonio group, N,N, N-triethylammonio group, pyridinio group, etc.), and the ammonio group is substituted with negative groups such as chloro, bromo, iodo, sulfoxy, methanesulfonyloxy, ethasulfonyloxy, formyloxy, P-toluenesulfonyloxy, etc. Assume that it is accompanied by an ionic group. Regarding compound (XXX■): Preferred examples of the alkyl group for R32 and R33 include the alkyl group for Rl3.

Regarding compounds (XXX■) and (XXX■): R3
Preferred examples of the alkyl group in 9, R4O, and R41 and preferred examples of the alkoxy group or alkyl moiety in the alkoxy moiety in the definition of R38 include the alkyl group in R13.

Preferred examples of the substituent in substituted alkoxy in the definition of R38 include the acyl exemplified in the explanation of the protecting group in the definition of Y above.

Preferred examples of substituted alkyl groups in the definitions of R39, R4O and R4l include alkanoyloxyalkyl groups (e.g. acetoxymethyl group, acetoxyethyl group, acetoxypropyl group, propionyloxymethyl group, propinyloxyethyl group, butyryloxymethyl group). acyloxyalkyl groups, such as pivaloyloxymethyl groups, monohaloalkyl groups (e.g., fluoromethyl groups, chloromethyl groups, bromomethyl groups, chloroethyl groups, bromoethyl groups, chloropropyl groups, bromopropyl groups, etc.), Examples include halogen-substituted alkyl groups such as dihaloalkyl groups (eg, dichloroethyl group, 2,3-dichloropropyl group, etc.) and trihaloalkyl groups (eg, trichloromethyl group, etc.).

Preferred examples of the acyl group in R4O and R4O'' include the acyl in the acylamino group in R1 above.

Regarding compounds (XXXV) and (XXX■): R4
The aryl group in the definition of 2 may be substituted with a suitable substituent (for example, a carboxy group, etc.), and preferable examples of such an aryl group include a phenyl group, a carboxyphenyl group, a tolyl group, a naphthyl group, etc. can be mentioned.

Moreover, as a preferable example of the alkyl group and aralkyl group in R42, the example in Rl5 above is directly exemplified. Furthermore, preferable examples of the alkylene group in A3 include a methylene group, an ethylene group, a propylene group, and the like. Compound (XXX■) and (XXX
Regarding X): In the definition of R43, preferable examples of the aryl group 2 having a nitro group or an esterified carboxy group on the aryl ring include
The example in is exemplified as is.

In addition, as a preferable example of the aromatic heterocyclic group in the definition of R43, the example of the aromatic heterocyclic group in the illustration of the heterocyclic group given in the explanation of the definition of R1 above is exemplified as is, Particularly preferred examples include pyridyl group, pyridyl-1-oxide group, pyrimidinyl group,
Examples thereof include an oxadiazolyl group, and these groups may be substituted with an aryl group such as a phenyl group, tolyl group, or naphthyl group. As a preferable example of the divalent aliphatic hydrocarbon group residue in the definition of A4, the example in A1 is directly exemplified.

Regarding compounds (XXXXI) and (XXXX■):
A preferable example of the aralkyl group in R44 is ? The example of the aralkyl group in 15 is directly exemplified. Preferred examples of the alkyl group for R45 and R46 include the alkyl group for Rl3 above.

Regarding compounds (XXXX■) and (XXXX■):
Preferred examples of the derivative of the carboxy group in R47 include the examples exemplified in the explanation of the carboxy derivative in the definition of A above.

Preferred examples of the protected amino group and protected hydroxy group in R48 include the same examples as the protected amino group and protected hydroxy group in the definition of Y above. Compound (XXXX■), (X
XXX■), (XXXX■), (XXXX■), (XX
Regarding XX■), (XXXXXXII), (XXXXX■) and (XXXXX■): R499R5O9R5l
9R529R539R549 Preferred examples of the acyl moiety in each definition of R55 and R56 include the acyl moiety in the acylamino group in R1 above. Preferred examples of carboxy or its reactive derivative moiety in the definition of R49 include carboxy or its derivative in the definition of A above. Preferred examples of the N-hydroxyalkyl)carbaloyl moiety in the definition of R5O include N-(hydroxymethyl)carbamoyl, N-(hydroxyethyl)carbamoyl, N-(hydroxypropyl)carbamoyl, etc., and N-aralkylcarbamoyl Preferred examples of the moiety include N-benzylcarbamoyl, N-phenethylcarbamoyl, etc., and the aryl portion thereof may be substituted with a suitable substituent. R5.

Preferred examples of the ester moiety in the definition include those exemplified in the explanation of the definition of A above, and preferred examples of the alkylamino moiety include methylamylamino, isopropylamino, and the like.

Preferred examples of the ester moiety in the definition of R53 include those exemplified in the explanation of the definition of A above, and preferred examples of the alkenylamino moiety include vinylamino, propenylamino, 1-methylvinylamino,
Examples include 2-propenylamino. Preferred examples of the alkanoyl moiety in the definition of R55 include the above R
The examples of alkanoyl given in the explanation of the acyl moiety in the acylamino group in 1 are exemplified as they are, and as preferred examples of the aroyl moiety in the definition of R55, in the explanation of the acyl moiety in the acylamino group in 1. The examples of aroyl made are exemplified as they are.

Preferred examples of the alkyl moiety in the definition of R56 include the examples of alkyl given in the explanation of the definition of Rl3 above.

Preferred examples of the α-hydroxyaralkyl moiety defined in R56 include α-hydroxybenzyl, hydroxy(1-naphthyl)methyl, and the like. Regarding compound (XXXXXX): Preferred examples of the aralkyl moiety in the aralkylamino group in R57 include the examples of aralkyl given in the explanation of Rl5 above.

Regarding compound (XXXX■): Preferred examples of the halogen atom in X7 and X7 are the same as those of X2 above.

Preferable examples of the alkyl group in R58, R59 and R6O include the above-mentioned alkyl group. The examples of alkyl groups given in the explanation of No. 13 are exemplified as they are.

Regarding Compound (XXXXI): Preferred examples of the aralkanoyl moiety in the aralkanoylamino group in δR6l include the examples of the aralkanoyl moiety given in the explanation of the acyl moiety in the acylamino group in R1 above.

Regarding compounds (XXXXX■) and (XXXXX■): Preferred examples of the aryl group in the definition of R62 include the example of the aryl group in R15 above, and preferred examples of the alkylene group in the definition of A5 include the aryl group in A3 above. Examples of alkylene groups are directly exemplified.

Regarding compounds (XXXXX■) and (XXXXX■): Preferred examples of the aryl group and heterocyclic group in the definition of R63 include the aryl group and heterocyclic group in Rl5 above.

Preferred examples of the aroyl moiety and aroyl group in the definitions of R66 and R67 and R68 include benzoyl, toluoyl, xyloyl, etc.
Preferred examples of the aralkoxy moiety include benzyloxy, phenethyloxy, phenylpropionyloxy, tolylmethoxy, and the like.

Regarding compound (XXXXXX): Preferred examples of the aralkyl group in the definition of R69 include the aralkyl group of Rl5 above.

Regarding the compound (XXXX
Preferred examples of the heterocyclic moiety in the definition of R
The example of the heterocyclic group in l5 is directly exemplified.

Regarding the compounds (XXXXXX) and (XXXXXXI■): Preferred examples of the ester moiety in the definition of R7l include the ester examples exemplified in the explanation of the definition of A above, and preferred examples of the alkyl moiety include the alkyl of Rl3 above. Examples of the groups are directly illustrated.

Regarding the compounds (XXXXXX■) and (XXXXXX■): Preferred examples of the aryl group in the definition of R72 include the aryl group of Rl5 above, and preferred examples of the alkyl group in the definition of R72 include the alkyl group of Rl3 above. The example of the group is directly exemplified,
Examples of the ester moiety in the definition of R73 include the above A
The examples of esters exemplified in the explanation of the definition of are exemplified as they are.

Compound (XXXXXX■), (XXXXXX■■), (
XXXXXXX■) and (XXXXXX■): In the definitions of A'' and R74: Examples of the alkyl group are the above-mentioned groups, respectively.

Examples of the alkyl group are exemplified as they are, examples of the alkenyl group are exemplified as are the examples of the alkenyl group exemplified in the explanation of the definition of R1 above, and examples of the aryl group are the aryl group in the definition of Rl5 above. The example is directly illustrated. Regarding the compound (XXXXXX■): Examples of the lower alkyl group in the definition of R75 include a methyl group, an ethyl group, a propyl group, and the like.

Regarding compound (XXXXXX■): Examples of the alkoxy group in the definition of R76 include methoxy group, ethoxy group, propoxy group, budoxy group, etc., and examples of the aralkyl group in the aralkoxy group include the aralkyl group in the definition of Rl5 above. It is exemplified as is.

Examples of the alkyl group, acyl group and aralkyl group in R8O are the same as those in the definition of Rl3C above. Regarding compound (XXXXXXXX): As the aralkyl group in the definition of R77, the above Rl5
Examples of the aralkyl group in the definition are exemplified as they are.

Compounds (XXXXXXXXI) and (XXXXXXXX■
): Examples of the protecting group for the amino group in the definition of R78 include the same examples of the protecting group for the amino group exemplified in the definition of Y above.

The acyl group in the definition of R79 is directly exemplified by the acyl moiety in the acylamino group of R2.
Next, each of the above-mentioned methods for producing the azetidinone derivative (1) of the present invention will be described in detail below.

In each of the following methods, Process 1 and Process 2 are the basic processes for producing the azetidinone derivative (1) of the present invention, and the other processes include, for example, adding a special acylamino group to the 3-position of the azetidinone derivative (1). The present invention relates to a more advantageous synthetic method for producing compounds having the following properties. The important starting materials used in this method include: FR-192 aerosol, 3-amino-1-(α-carboxy-4-hydroxybenzyl)-2-azetidinone (a), 1-monosubstituted-3 -amino-2-azetidinone (b), and 3-amino-2
-Azetidinone (c), and these compounds can be produced, for example, by the method shown in the following figure.

(In the formula, X represents an acid residue and A″ is as described above.

) (1) Process 1: Compound (■)→Compound (1) This process is one of the basic methods for producing the target compound (1) of the present invention.

This process is carried out by allowing an acylating agent to act on the compound (■) or the reacted derivative at the amino group of the compound. Acylating agents used in this reaction include organic carboxylic acids, organic sulfonic acids or their thio or imide acids, more particularly aliphatic carboxylic acids, aromatic carboxylic acids and their sulfonic, carbamic, carbonic or They may be thioacids or reactive derivatives of these acids.

Here, examples of the reactive derivatives of the organic acids mentioned above include acid anhydrides, active amides, active esters, acid azides, isocyanates, isothiocyanates, etc., and these reactive derivatives of organic acids will be specifically described. and as follows.

(a) Acid anhydride: Here, examples of the acid anhydride include dialkyl phosphoric acid mixed acid anhydride, phenyl phosphoric acid mixed acid anhydride, diphenyl phosphoric acid mixed acid anhydride, dibenzyl phosphoric acid mixed acid anhydride, and halophosphoric acid mixed acid anhydride. Acid mixed acid anhydride, dialkyl phosphorous acid mixed acid anhydride, sulfite mixed acid anhydride, thiosulfuric acid mixed acid anhydride, hydrohalic acid (e.g., hydrochloric acid, hydrobromic acid, etc.) mixed acid anhydride, sulfuric acid mixture Acid anhydrides, monoalkyl carbonic acid mixed acid anhydrides, aliphatic carboxylic acids (e.g. acetic acid, pivalic acid, valeric acid, isopentanoic acid, 2-ethylbutanoic acid, trichloroacetic acid, etc.) mixed acid anhydrides, aromatic carboxylic acids (e.g. , benzoic acid, etc.), mixed acid anhydrides, and symmetrical anhydrides.

(b) Active amide Examples of the active amide include pyrazole, imiguzole, 4-monosubstituted imidazole, dimethyl group pyrazole,
Examples include triazole, tetrazole, etc. and amides.

(c) Active ester Here, examples of the active ester include methyl ester,
Ethyl ester, cyanomethyl ester, methoxymethyl ester, vinyl ester, propargyl ester,
4-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesyl phenyl ester, phenylazophenyl ester, phenylthio ester, 4-
Nitrophenyl thioester, P-cresyl thioester, carboxymethyl thioester, pyranyl ester,
In addition to esters such as pyridyl ester, piperidyl ester, and quinolyl thioester, N,N-dimethylhydroxylamine, 1-hydroxy-1H-2-pyridone, N
-Hydroxysuccinimide, N-hydroxyphthalimide and other carboxylic acids, and esters with acids such as sulfonic acid.

Such reactive derivatives of organic acids are appropriately selected depending on the type of acid used. Furthermore, when using a free acid as an acylating agent, it is preferable to carry out the reaction in the presence of a condensing agent. Examples of such condensing agents include N, N''
-dicyclohexylcarbodiimide, N-cyclohexyl-N''-morpholinoethylcarbodiimide, N-cyclohexyl-N''-(4-diethylaminocyclohexyl)carboimide, N,N''-diethylcarbodiimide, N,N''-diisopropylcarbodiimide, N-ethyl-N "-(3-dimethylaminopropyl)carbodiimide, N,N-1carbonylbis(2-methylimidazole), pentamethyleneketene-N-cyclohexylimine, diphenylketene-N-cyclohexylimine,
Alkoxyacetylene, 1-alkoxy 1-chloroethylene, trialkyl phosphite, ethyl polyphosphate, isopropyl polyphosphate, phosphorus oxychloride, phosphorus trichloride,
Thionyl chloride, oxalyl chloride, triphenylphosphine, 2-ethyl-7-hydroxybenzisoxazolium salt, 2-ethyl-5-(3-sulfophenyl)isoxazolium hydroxide, (chloromethylene)dimethylammonium chloride, 2 ,2,4,
4,6,6-hexachloro 2,2,4,4,6,6-
Condensation by combining hexahydro-1,3,5,2,4,6-triazatriphosphine, triphenylphosphine with carbon tetrahalides such as carbon tetrachloride and carbon tetrabromide, or halogens such as chlorine, bromine, and iodine. Examples include agents.

Here, the acyl group introduced into the amino group of compound (■) is the aliphatic carboxylic acid, a carboxylic acid containing an aromatic ring, a carboxylic acid containing a heterocycle, their sulfonic acid, carbonic acid, carbamic acid or their thio acid. is the acyl part of
Preferred examples of those acyl moieties are R as defined above.
Examples of the acyl group in 1 are as follows.

In this reaction, 3 of the azetidinone ring of compound (■)
A case in which the amino group at the position is converted into a reactive derivative can also be used as a starting material for this reaction, and such a reactive derivative at the amino group is, for example, a compound formed by dehydration condensation of a carbonyl compound and an amino group. Examples include imine derivatives or enamine derivatives such as Schiff's base, salts with acids such as hydrochloric acid, and other usual groups that activate amino groups. For the acylation of compound (■) in this reaction, for example, a method commonly used in the acylation of 6-aminopenicillanic acid and 7-aminosephalosboranic acid can be applied.

In addition, good results are usually obtained when this reaction is carried out in the presence of a base, and such bases include, for example, alkali metal hydrogen carbonate, alkali earth metal carbonate, alkali metal carbonate, and alkaline earth metal carbonate. metals, inorganic bases such as alkali metal hydroxides and alkaline earth metal hydroxides, trialkylamino (e.g., trimethylamine, triethylamine, tributylamine, etc.), 4-methylmo, luforin, N
-Methylpiperidine, N,N-dialkylaniline (e.g., N,N-dimethylaniline, N,N-diethylaniline, etc.), N,N-dialkylbenzylamine (e.g., N,N-dimethylbenzylamine, N,N -di.ethylbenzylamine, etc.), pyridine, picoline, lutidine, 1,5-diazabicyclo[4,3,0]-5-nonene, 1,4-diazabicyclo[2,2,2]octane,
An organic base such as 1,8-diazabicyclo[5,4,0]-7-undecene is used.

This reaction is usually carried out in a solvent such as water, acetone, methanol, ethanol, dioxane, tetrahydrofuran, N,N-dimethylformamide, pyridine, chloroform, methylene chloride, carbon tetrachloride, ethyl acetate, and mixed solvents thereof. However, other general organic solvents that do not adversely affect this reaction can also be used, and among these, hydrophilic ones can also be used in combination with water.

Further, when the above-mentioned condensing agent or base is a liquid, it can also be used as a solvent. The reaction temperature in this reaction is not particularly limited, but it is usually carried out under mild conditions such as cooling or heating.

In this reaction, if group A contains a hydroxy group,
This may be acylated at the same time depending on the type of acylating agent, reaction conditions, etc.

)) Process 2: Compound (■) One compound (Pi) This process converts the compound shown in general formula (■) into general formula A5-X
5 (wherein A'' has the same meaning as above and X'' means an acid residue).

In addition, examples of the acid residue defined by X'' in the N-substituting agent include acid residues of inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, and sulfuric acid.

Organic sulfuric acids (e.g. methyl sulfuric acid, ethyl sulfuric acid, etc.) Organic sulfonic acids (e.g. methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, etc.) Organic carbamic acids (e.g. dimethylcarbamic acid, diethylcarbamic acid)
Examples include acid residues of organic acids such as. This reaction is usually carried out in a solvent, and water, acetone, dioxane, acetonitrile, methylene chloride, chloroform, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine, and mixed solvents thereof are frequently used, but other solvents are also used. General organic solvents that do not adversely affect this reaction can also be used.
Among them, hydrophilic ones are used by mixing with water.

Good results are usually obtained when this reaction is carried out in the presence of a base, and as such a base, the bases exemplified in Process 1 above can be used as they are, but in addition, hydrogen hydride such as sodium hydride and potassium hydride can be used. Alkali metal hydride, alkaline earth metal hydride such as calcium hydride, magnesium hydride, sodium bis(trimethylsilyl)amino, sodium methanesulfinylmethyl, lithium dicyclohexylamino, silver boron fluoride, thallium ethoxide, butyllithium, bases Polymer ion exchange resins and the like can also be used. The reaction temperature for this reaction is not particularly limited, but it is usually carried out under cooling or at room temperature.
5 If the carboxy group in the compound (pi) obtained in this way is protected with its derivative or an appropriate protecting group, the carboxy group derivative or protecting group may be subjected to an elimination reaction as necessary. good.

1 (Here, the method for removing the protecting group of the carboxy group is usually carried out by a conventional method such as solvolysis or reduction, which will be described in Process 3 below. 3) Process 3: Compound (1″) → Compound (■ ) This process is a reed 1 in the compound (1″)! This is carried out by subjecting the group to an elimination reaction.

The elimination method in this reaction can be the elimination method of the acyl group for purification, for example, solvolysis such as hydrolysis using an acid or base, a method using hydrazine, or 2 (reduction reaction) such as chemical reduction or catalytic reduction. , iminohalogenating agent,
Examples include a method in which an imino etherification agent is then applied, followed by solvolysis as necessary, and these methods are appropriately selected depending on the type of acyl group in the acylamino group. 2. Here, the method for eliminating the acyl group used in this reaction will be described in detail as follows. (a) Solvolysis: Acids used in solvolysis include, for example, inorganic acids such as hydrochloric acid and sulfuric acid, acidic acid, acetic acid, trifluoroacetic acid, propionic acid, benzenesulfonic acid, and P-toluenesulfone. In addition to organic acids such as acids, acidic ion exchange resins, etc. can be mentioned, and examples of bases include the bases exemplified in Step 3 of Process 1 above, as well as alkali metal alkoxides such as sodium alkoxide and potassium alkoxide, Basic ion exchange resins and the like can also be mentioned.

This solvolysis reaction is usually carried out in a solvent, and affinity solvents such as water, alcohol, acetone, or mixed solvents thereof are often used, but other general organic solvents that do not have an adverse effect on this reaction can also be used. Furthermore, when the above acid or base is liquid, it can also be used as a solvent.

1) Reduction: Examples of chemical reduction used as a reduction method include metals such as zinc, tin, and iron, or zinc chloride, ferrous chloride,
Metal compounds such as ferric chloride, chloro chloride, and chlor acetate with water, inorganic or organic acids (e.g. hydrochloric acid, hydrobromic acid,
Sulfuric acid, acidic acid, acetic acid, trifluoroacetic acid, propionic acid,
P-toluenesulfonic acid, etc.).

Examples of catalysts used for catalytic reduction include platinum plates, platinum sponges, platinum black, platinum colloids,
Platinum catalysts such as platinum oxide and platinum wire, palladium catalysts such as palladium sponge, palladium black, palladium oxide, palladium carbon palladium colloid, palladium barium sulfate, palladium barium carbonate, nickel catalysts such as reduced nickel, nickel oxide, Raney nickel, Urushihara nickel, etc. Cobalt catalysts such as reduced cobalt and Raney cobalt, and other conventional catalysts used in catalytic reduction can also be used. Here, the chemical reduction method is usually carried out in a solvent, and water, methanol, ethanol, acetone, etc. are often used, but other general organic solvents that do not have an adverse effect on this reaction can also be used, and inorganic Alternatively, if the organic acid is in liquid form, it can also be used as a solvent.

In addition, the catalytic reduction method is usually carried out under normal pressure in a solvent such as methanol, ethanol, propanol, isopropyl alcohol, dioxane, diethyl ether, etc., or other general organic solvents that do not have an adverse effect on the reaction. .

・→ A method in which the iminohalogenating agent is then treated with the iminoetherifying agent, followed by solvolysis if necessary: In this method, the iminohalogenating agent, iminoetherifying agent, and reagents used for solvolysis are all available. Such iminohalogenating agents include, for example, phosphorus compounds such as phosphorus trichloride, phosphorus pentachloride, phosphorus tribromide, phosphorus pentabromide, phosphorus oxychloride, and reactive equivalents of these compounds. Examples include thionyl chloride and phosgene.

Examples of the iminoetherification agent that acts on the reaction product thus obtained include alkanols such as methanol, ethanol, propanol, isopropyl alcohol, tertiary butyl alcohol, methoxy, ethoxy, propoxy, isopropoxy, butoxy, etc. Examples include alkanols having an alkoxy group as a substituent and alkali metal or alkaline earth metal salts of these alcohols.

Further, the solvolysis can be carried out by simply treating the reaction solution with water after the action of the iminoetherifying agent, or by the same method as shown in (a) above. Thus, the method for eliminating the acyl group is carried out under conditions similar to those used for penicillin or self-allosporin compounds, for example, iminohalogenation and iminoetherification are usually carried out under cooling or at room temperature; Solvolysis may proceed by simply adding water or a mixed solvent of water and a hydrophilic solvent (e.g., methanol, ethanol, etc.) to the reaction mixture, or by adding an acid or base if necessary. Na2. (4) Process 4: Compound (■) → Compound (■) This process is carried out by one of the azetidine rings of compound (■).
This is carried out by subjecting the substituted alkyl group at the position to an elimination reaction.

5 As for the elimination method used in this reaction, conventional methods such as the method using solvolysis such as hydrolysis described in Process 3 above can be applied as is, and the starting compound (
(2) is selected as appropriate depending on the type.
3 (5) Process 5: Compound (■) → Compound (■) This process is compound (■)
Alternatively, it is carried out by hydrolyzing the oximino group of the derivative in the carboxy group of the compound. Preferred examples of derivatives in the carboxy group of the starting compound (■) include the derivatives in the carboxy group mentioned in the definition of A in compound (1). Hydrolysis in this reaction includes methods carried out in the presence of acids or bases, methods carried out in the presence of metal compounds, etc. Examples include hydrochloric acid, sulfuric acid, sulfite, sodium sulfite, sodium hydrogen sulfite, zinc sulfate, ferric sulfate, etc. , hydrolysis in the presence of acids such as inorganic acids or their salts such as hydrobromic acid, organic acids such as diric acid, acetic acid, trifluoroacetic acid, trichloroacetic acid, propionic acid, benzenesulfonic acid, P-toluenesulfonic acid, etc. , for example, hydroxides of alkali metals such as sodium and potassium, or alkaline earth metals such as calcium and magnesium, inorganic bases such as carbonates, metal alkoxides, organic amines, organic bases such as quaternary ammonium salts, and bases. Hydrolysis in the presence of bases such as ion exchange resins, boron trihalides such as boron trichloride, boron tribromide, boron trifluoride, titanium trichloride,
Titanium halides such as titanium tetrachloride and titanium tetrabromide, zirconium tetrahalides such as zirconium tetrachloride and zirconium tetrabromide, tin tetrahalides such as tin tetrachloride and tin tetrabromide, antimony trichloride, and pentachloride. Decomposition using metal compounds such as antimony halides such as antimony, aluminum trihalides such as bismuth trichloride, aluminum trichloride, and aluminum tribromide, aluminum isopropoxide, zinc dichloride, and iron trichloride, formalin, and pentacarbonyl iron. By exchanging the oximino group with a catalytic amount of boron trifluoride, etherate, etc., the group=NOH is converted into the group=
A method such as one that can be converted to O is applied.

This reaction is usually carried out in a solvent, often using water or a mixed solvent of water and a hydrophilic solvent, and if the acid or base used is liquid, it can also be used itself as a solvent. .

The reaction temperature is not particularly limited and is appropriately selected depending on the hydrolysis method, but the reaction is usually carried out under mild conditions ranging from room temperature to elevated temperatures.

:) Process 6: Compound (■) → Compound (■) This process is carried out by reducing the compound (■) or its derivative at the carboxy group.

In this reaction, examples of derivatives of the carboxy group of the starting compound (■) include the same examples of the derivatives of the carboxy group mentioned in the definition of A in compound (1).

For the reduction in this reaction, for example, the catalytic reduction method or chemical reduction method described in Process 3 above can be used, and also amalgams such as sodium amalgam, aluminum amalgam, zinc, tin, iron, etc. A reduction method using a combination of a metal or a metal compound such as zinc chloride, soot chloride, ferrous chloride, etc., and water, an aqueous alkali solution, or an alcohol such as methanol or ethanol, or a hydrazine compound such as hydrazine such as hydrazine or phenylhydrazine. In addition to reduction methods, such as reduction methods using alkali metal borohydrides such as sodium borohydride and potassium borohydride, siborane, etc., electrolytic reduction methods can also be used.

This reaction is usually carried out in a solvent, and water, alcohols such as methanol, ethanol, propanol, isopropyl alcohol, dioxane, acetonitrile, tetrahydrofuran, N,N-dimethylformamide, pyridine, etc. are often used, but other solvents are also used for the reaction. General organic solvents and mixed solvents of such solvents that do not have any adverse effects can also be used, and these solvents are appropriately selected depending on the raw material compound, reducing agent, method, etc. to be used.

Furthermore, if the acid used in the chemical reduction is a liquid, it can also be used as a solvent. Although the reaction temperature is not particularly limited, it is usually carried out under mild conditions such as cooling or heating.

(7) Process 7: Compound (■)→Compound (X) This process is carried out by allowing an acylating agent to act on compound (■) or a derivative at the carboxy group of the compound. Examples of derivatives of the carboxy group of the starting compound (■) include the same examples of the derivatives of the carboxy group mentioned in the definition of A in compound (1).

Examples of the acylating agent used in this reaction include the acylating agents exemplified in Process 1 above.

Further, the amino group of the starting compound (■) may be converted into the reactive derivative of the amino group exemplified in Process 1 above, for example.

This reaction is usually carried out in a solvent, and examples of such a solvent include the solvents mentioned in Process 1 above.

Although the reaction temperature is not particularly limited, it is usually carried out under mild conditions such as cooling or heating.

In this reaction, hydroxy groups and hydroxyimino groups may be acylated depending on the type of acylating agent and reaction conditions. )) Process 8: Compound (■) →
Compound (■) This process is applied to compound (■) or a derivative at the carboxy group of the compound with the general formula Rll-
This is carried out by the action of a nucleophilic compound represented by H (in the formula, Rll means a residue of a nucleophilic compound) or a salt thereof.

Examples of derivatives of the carboxy group of the starting compound (XI) include the same examples of the derivatives of the carboxy group described in A of compound (1) above.

In this reaction, examples of the nucleophilic compound represented by the general formula: Rll-H include primary amines, secondary amines, etc. having the residue moiety of the nucleophilic compound exemplified for Rll in the above compound (■). Examples include amines, thiol compounds, and phenolic hydroxy compounds.

Nucleophilic compounds such as amines, thiol compounds, and phenolic hydroxy compounds represented by the above general formula used in this reaction are salts with alkali metals such as sodium and potassium, and salts with alkaline earth metals such as calcium and magnesium. Furthermore, in cases where the thiol compound (1) has a free amino group as a substituent, the amino group may be converted into an inorganic salt such as hydrochloric acid or hydrobromic acid. It may be converted into a salt with an acid, a salt with an organic acid such as acetic acid, acetic acid, and p-toluenesulfonic acid.

This reaction is usually carried out in a solvent, and commonly used solvents include water, methanol, ethanol, acetone, tetrahydrofuran, dioxane, N,N-dimethylformamide, methylene chloride, chloroform, carbon tetrachloride, or a mixed solvent thereof. However, other general organic solvents that do not adversely affect this reaction can also be used, and if the nucleophilic compound is a liquid, it can also be used as a solvent.

This reaction usually gives good results when carried out in the presence of a base.

Examples of such bases include the inorganic bases and organic bases mentioned in Process 1 above, as well as basic ion exchange resins.
Although the reaction temperature is not particularly limited, it is usually carried out under mild conditions such as cooling or heating.

(9) Process 9: Compound (X■) → Compound (X■) This process
This is carried out by subjecting the protecting group at the amino group, hydroxyl group or carboxy group in the acylamino group at the position to an elimination reaction.

As the method for removing the protecting group in this reaction, for example, the solvolysis method described in Process 3 above, the reduction method such as chemical reduction, catalytic reduction, etc. can be applied as is, and methods such as methods using heavy metals can also be used. It is done using
Such a method of elimination is appropriately selected depending on the type of the raw material compound (X).

Further, examples of heavy metals in the method using heavy metals include copper and zinc.

In this reaction, if there are two or more protecting groups on the amino group, hydroxyl group or carboxy group of the acylamino group of compound (X), only one of these protecting groups may be eliminated.

(10) Process 10: Compound (XV): -Compound (X
(2) This process is carried out by allowing a halogenating agent to act on the compound (XV) or its derivative at the carboxy group.

Examples of the derivatives at the carboxy group of the starting compound (XV) include the same examples as the derivatives at the carboxy group mentioned in the definition of A in compound (I). As the halogenating agent used in this reaction, all of the halogenating agents commonly used in halogenating aromatic compounds can be used.

Such halogenating agents include, for example, chlorine, bromine,
Halogen of iodine, bromine trichloride, Ξ halogen monochloride of iodine chloride, hypohalous acid and its alkyl esters such as hypochlorous acid, tertiary butyl hypochlorous acid ester, N-bromoacetic acid amide, N-iodoacetamide, N
- N-halogenamides such as promosuccinimide and N-chlorosuccinimide, cupric halides such as cupric chloride and cupric bromide, pyridinium hydropromide, dioxane dipromide, etc. can be given. Further, this halogenation reaction is usually carried out in a solvent. Water, methanol, ethanol, etc. are often used as solvents, but general organic solvents that do not adversely affect the reaction, such as acetic acid, chloroform, methylene chloride, carbon tetrachloride, dioxane, acetonitrile, tetrahydrofuran, dimethylformamide, and pyridine, are also used. They can be appropriately selected depending on the halogenating agent used, and used alone or in combination. Although the reaction temperature is not particularly limited, it is usually preferable to carry out the reaction under mild conditions such as cooling or heating.

(11) Process 11: Compound (X■) One compound (X■
) This process is carried out by reacting the compound (X■) or its derivative at the carboxy group with an acylating agent.

Examples of the derivatives at the carboxy group of the starting compound (X) include the same examples as the derivatives at the carboxy group mentioned in the definition of A in compound (I) above.

Examples of the acylating agent used in this reaction include those exemplified in the acylating agent in Process 1 above.

The conditions for this reaction (reaction solvent, reaction temperature, base, condensing agent, etc.) are the same as those described in Process 1 above.

(12) Process 12: Compound (X■) → Compound (XX
) This process is carried out by subjecting the compound (X■) or its derivative at the carboxy group to an oxidation reaction.

Examples of the derivatives at the carboxy group of the starting compound (X) include the same examples as the derivatives at the carboxy group mentioned in the definition of A in compound (I) above.

The oxidizing agents used in this reaction include all those capable of converting thio groups into sulfinyl groups, such as inorganic peracids such as periodic acid and persulfuric acid;
Perbenzoic acid, 3-chloroperbenzoic acid, periodic acid, peracetic acid,
Examples include organic peracids such as chloroperacetic acid and trifluoroperacetic acid, or their salts, ozone, and hydrogen peroxide.

This reaction also applies to compounds containing metals included in Group Ⅰ b or Ⅲ b of the periodic table, such as tungstic acid,
In the presence of molybdic acid, vanadate, and salts of these acids with alkali metal salts such as sodium and potassium, alkaline earth metal salts such as calcium and magnesium, ammonium salts, and organic bases such as pyridine, and other vanadium pentoxide, etc. In many cases, the reaction proceeds favorably.
This reaction is usually carried out in a solvent. As the solvent, for example, chloroform, methylene chloride, pyridine, water, acetone, tetrahydrofuran, dithylformamide, dioxane, acetic acid, or a mixed solvent thereof are often used, but other general organic solvents that do not have an adverse effect on this reaction may also be used. All can be used. The temperature of the reaction is not particularly limited, but it is usually carried out under heating or cooling.

(13) Process 13: Compound (XX[) one compound (X
,
X'' (wherein R'' is an aryl group having at least one of a nitro group and an esterified carboxy group, and x'' means a halogen). .

In this reaction, the derivatives at the 3-lupoxy group of the starting compound (XX[) include the same examples as the derivatives at the carboxy group mentioned in the definition of A in compound (1).

In the above formula, the 4-aryl group having at least one of a nitro group and an esterified group as defined by R'' is the same as the group exemplified for R2l and Rl in the above formula (XXII). Furthermore, examples of the esterified carboxy group include the esters listed in the explanation of the derivatives of the carboxy group mentioned in A of compound (1). Examples of the halogen defined by X'' in the agent include fluoro, chlorine, and bromine.

This reaction is usually carried out in a solvent, such as water,
Methanol, ethanol, propanol, tetrahydrofuran, acetone, N,N-dimethylformamide, dioxane, etc. are often used, but other general organic solvents that do not adversely affect the reaction, such as methylene chloride, chloroform, and carbon tetrachloride, are also used. Among these, hydrophilic solvents can also be used in combination with water. Further, good results are often obtained when this reaction is carried out in the presence of the same base as mentioned in Process 1 above. It is preferable that the reaction temperature is generally moderate, such as cooling or heating.

[14) Process 14: Compound (XX■) One compound (X
X■) This process applies the general formula (wherein R
""" and R""7 are the same or different and mean hydrogen or an alkyl group, respectively.

This is carried out by reacting a carbonyl compound represented by or a reactive equivalent thereof, and then reducing the resulting product. Examples of the derivatives at the carboxy group of the starting compound (XX■) include the derivatives at the carboxy group mentioned in the definition of A of the compound (1).

R--C-R''7 In the above general formula: 11, examples of the alkyl group defined by R'''' and R'''' include zothyl, ethyl,
Examples include propyl, isopropyl, butyisobutyl, pentyl, etc., and groups such as - can be placed at any position of 1
It may have one or more suitable substituents, and examples of such substituents include carboxy groups, alkoxycarbonyl groups, and halogens such as chloro and brome.

Specific examples of carbonyl compounds defined in this way include formaldehyde, acetaldehyde, propionaldehyde, aliphatic aldehydes such as butyraldehyde, isobutyraldehyde, valeraldehyde, and methoxycarbonylacetaldehyde, aromatic aldehydes such as benzaldehyde, acetone, Examples include aliphatic and aromatic ketones such as methyl ethyl ketone, diethyl ketone, methyl propyl ketone, acetophenone, and 1, methyl tolyl ketone.

The product obtained by the reaction of the rubonyl compound with the compound (XX) or a derivative of the carboxy group of the compound as described above can be subjected to the next reduction reaction with or without separation.

Here, as the reduction method, the reduction method described in Process 3 above can be applied as is.

This reaction is usually carried out in a solvent, and the two solvents used are, for example, water, dioxane, N,N-dimethylformamide, methanol, ethanol, propanol, isopropyl alcohol, and mixtures thereof. However, general organic solvents that do not adversely affect this reaction can also be used, and when the carbonyl compound is liquid, it can also be used as a solvent.

The reaction temperature is not particularly limited and is appropriately selected depending on the type of carbonyl compound and reducing agent, but it is preferable to carry out the reaction under mild conditions such as cooling or heating.

In this reaction, depending on the type of reducing agent used, reaction conditions, etc., the oximino group in compound (XX There is a yang combination that separates and converts into hydrogen.

(15) Process 15: Compound (XXV) → Compound (X
X■■) This process uses compound (XXV) or its
This is carried out by subjecting a derivative of the carboxy group of the compound to a reduction reaction.

Examples of the derivatives at the carboxy group of the starting compound (XXV) include the same examples as the derivatives at the carboxy group mentioned in the definition of A in compound (1).

As the reduction method in this reaction, any reduction method capable of converting a nitro group into an amino group can be used, and as such a reduction method, the reduction method exemplified in Process 3 above can be applied as is.

This reaction is usually carried out in a solvent, and water, acetone, methanol, ethanol, propanol, etc. are often used.
Other general organic solvents that do not have a negative effect on this reaction can also be used, and in the case of chemical reduction methods, if the acid used is liquid, it can also be used as a solvent.
Furthermore, these solvents are appropriately selected depending on the reduction method used.

The temperature and pressure of this reaction are not particularly limited, but it is usually carried out at room temperature and under normal pressure.

16) Process 16: Compound (XX■■) → Compound (X
XV■) This process is carried out by reacting the compound (XXVH) or a derivative of the compound at the carboxy group with an amine represented by the general formula (wherein R27 has the same meaning as above).

Examples of the derivatives at the carboxy group of the starting compound (XX■■) include the derivatives at the carboxy group mentioned in the definition of A of the compound (1).
In this reaction, the formula is simple. The amine represented by 7-NH2 can also be used in its salt form, and examples of such salts include salts with inorganic acids such as hydrochloric acid and sulfuric acid, and salts with organic acids such as acidic acid and acetic acid. .

When such compounds are used as raw material compounds, the reaction is usually carried out by adding alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkaline earth metal hydroxides such as calcium hydroxide and magnesium hydroxide, etc. I often get good results. This reaction is usually carried out in a solvent,
Water, methanol, ethanol, propanol, N9N-
Hydrophilic solvents such as dimethylformamide and mixed solvents thereof are often used, but other general organic solvents that do not have an adverse effect on this reaction can also be used.The reaction temperature is not particularly limited, but is usually under cooling or heating. It is carried out under mild conditions.

(17) Process 17: Compound (XX■) → Compound (X
XX) This process is carried out by reacting the compound (XX■) or its derivative at the carboxy group with an acylating agent.

As the derivative of the carboxy group of the starting compound (XX■), the examples of the derivative of the carboxy group mentioned in the definition of A of the compound (1) can be used as is. Further, as the acylating agent, the examples of the acylating agent mentioned in Process 1 above can be mentioned as they are. This reaction is usually carried out in a solvent, and examples of the solvent include those mentioned in Process 1 above.

Although the reaction temperature is not particularly limited, it is usually carried out under mild conditions such as cooling or heating.

This reaction is usually carried out in the presence of a base, and examples of such bases include those mentioned in Process 1 above.
〉Also, when using free carbonic acid as the acylating agent in this reaction, good results are often obtained when the reaction is carried out in the presence of a condensing agent.
Examples of such a condensing agent include the same three examples of the condensing agent mentioned in Process 1 above. (18
) Process 18: Compound (XXX[) One compound (XXX
■) This process is applied to a compound (XXX[) or a derivative at the carboxy group of the compound with the general formula 3 (in the formula R
3. and R33 have the same meanings as above).

In this reaction, the derivatives at the carboxy group of the starting compound (XXXI) include the same examples as the derivatives at the carboxy group mentioned in the definition of A in compound (1).

Examples of the salts of the hydroxyalkanesulfonic acids include salts with alkali metals such as sodium and potassium, salts with alkaline earth metals such as calcium and magnesium, and the like. The hydroxyalkanesulfonic acids used in this reaction usually have the general formula (wherein R32
and R33 have the same meanings as above) can be produced by reacting sulfite or its salts with sulfite or its salts, and the reaction in this process is a modified method in which the above carbonyl compound and sulfite or its salts are added to the raw material compound (XXX[). This can also be done by applying

Furthermore, in this reaction, when the hydroxyalkanesulfonic acids are used in their free state, the presence of alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, alkaline earth metal hydroxides, etc. It is preferable to do this below.

This reaction is usually carried out in a solvent, and hydrophilic solvents such as water, methanol, ethanol, propanol, tetrahydrofuran, dioxane, N,N-dimethylformamide, and mixed solvents thereof are frequently used, but other solvents that have an adverse effect on the reaction are frequently used. A general organic solvent that does not give the carbonyl compound may also be used, and if the carbonyl compound is a liquid, it can also be used as a solvent.

The temperature of this reaction is not particularly limited and is appropriately selected depending on the type of sulfonic acid, but it is preferable to carry out the reaction under mild conditions such as cooling or heating.

Depending on the type of sulfonic acid, the amount used, reaction conditions, etc., the amino group of the starting compound (XXXI) may react with the sulfonic acid to form a di-substituted a[---N(-4-.
-5υ3t1ノ2'mino group g wa or its salt may be formed.

(19) Process 19: Compound (XXX■) → Compound!
(XXX■) This process is carried out by reacting the compound (XXX■) with an esterifying agent.

The esterifying agent used in this reaction means any usable esterifying agent that esterifies a carboxy group, and examples of such esterifying agents include the following. (a) Halides: Typical examples of halides include iodomethane, bromoethane, iodoethane, bromoethane,
Halogenated alkanes such as iodoethane, bromopropane, iodopropane, bromobutane, 2-bromo-2-methylpropane, 2-chloro-1-iodoethane, 3-chloro-1-iodoethane, halogenated alkenes such as chloroethylene and bromopropene, chloroacetylene , halogenated algines such as bromopropine, chloromethyl acetate, chloroethyl acetate, dichloropropyl acetate, chloromethyl valerate, chloroethyl valerate, chloromethyl isovalerate, chloromethyl pivalate, etc. Examples include halogenated alkanes substituted with alkanoyloxy, halogenated alkanes substituted with aroyl such as feu-3-nasyl bromide, and halogenated alkanes substituted with aryl groups such as benzyl bromide.

(b) Sulfonic acid esters: Here, sulfonic acid esters include compounds in which the halogen atom corresponding to the halides exemplified in (a) above is replaced with a sulfonic acid residue; typical examples thereof include: Examples include methyl benzenesulfonate, methyl P-toluenesulfonate, ethyl 4-bromobenzenesulfonate, and ethyl methanesulfonate.

(c) Sulfuric acid derivatives Examples of the sulfuric acid derivatives include dimethyl sulfate, diethyl sulfate, dipropyl sulfate, and the like.

→ Halogenated acid esters Typical examples of the halogenated esters include alkyl chlorinated esters such as methyl chlorinated acid, ethyl chlorinated acid, propyl chlorinated acid, and allyl chlorinated esters. Examples include chloroformic acid alkenyl esters such as chloroformic acid alkenyl esters, and chloroformic acid alkynyl esters such as chloroformic acid provinyl.

e) Diazoalkanes Representative examples of diazoalkanes include diazomethane, diazoethane, and the like.

(f) Hydroxy compound and condensing agent Here, examples of the hydroxy compound include methanol,
Alkanols such as ethanol, 2-chloroethanol, 2,2,2-trichloroethanol, propanol, 3-chloropropanol, isopropyl alcohol, butanol, tertiary butyl alcohol, alkenols such as allyl alcohol, alkynols such as propargyl alcohol, cyclo Examples include cycloalkanols such as propanol, cyclopentanol, cyclohexanol, borneol and adamantanol, and aralkanols such as benzyl alcohol, diphenylmethanol and phenethyl alcohol.

Further, examples of the condensing agent include those mentioned in Process 1 above.

The reaction of this invention is usually carried out in a solvent.

The solvent to be used is appropriately selected depending on the esterifying agent used, but water, dioxane, acetone, pyridine,
Organic solvents such as N,N-dimethylformamide and diethyl ether, and mixed solvents thereof are often used, but other general organic solvents that do not adversely affect this reaction can also be used. The temperature of this reaction is not particularly limited and is appropriately selected depending on the type of esterifying agent, but generally cooling to heating conditions are preferred.

In this reaction, a halide as an esterifying agent,
When using sulfonic acid esters, sulfuric acid derivatives, and halogen acid esters, good results are often obtained when the reaction is usually carried out in the presence of a base. Examples of such bases include the bases mentioned in Process 1 above. Examples can be given directly. In this reaction, the starting compound (XXX
The hydroxy group or hydroxyimino group in (2) may be alkylated or aralkenylated using an esterifying agent, for example.

(20) Process 20: Compound (XXXV) One compound (
XXX■) This process is carried out by subjecting the compound (XXX■) or its derivative at the carboxy group to an oxidation reaction.

Examples of the derivatives at the carboxy group of the starting compound (XXXV) include the same examples as the derivatives at the carboxy group mentioned in the definition of A in compound (1).

The oxidizing agent used in this reaction includes all those capable of converting the thio group 2 into a sulfinyl group, and such oxidizing agents include the oxidizing agents mentioned in Process 12 above.

Also, the conditions for this reaction (reaction solvent, reaction temperature 2, etc.) can be the same as in Process 12 above.

(21) Process 21: Compound (XXX■) → Compound (
XXX■) This process is carried out by subjecting the compound (XXX■) or its derivative at the carboxy group to a diazotization reaction.

The derivatives at the carboxy group of the starting compound (XXX■) include the derivatives at the carboxy group described in the definition of A of the compound (1) 3. An example of the body can be given.

The diazotizing agent used in this diazotization reaction can be any diazotizing agent used in a normal diazotization reaction, and typical examples include dinitrogen trioxide, nitrous acid, nitrous acid derivatives, and diazotizing agents. (Trosyl compounds etc. are mentioned.

Specific examples of nitrite derivatives include nitrite alkyl esters such as methyl nitrite, ethyl nitrite, and aluminum nitrite, sodium nitrite, potassium nitrite, calcium nitrite, magnesium nitrite, and silver nitrite. Examples include salts of nitrous acid and alkali metals, alkaline earth metals, or other metals. Further, examples of the nitrosyl compound include nitrosyl chloride, nitrosyl butenamide, nitrosyl sulfate, and nitrosyl acetic acid.
When nitrous acid or dinitrogen trioxide is used as the diazotizing agent, the reaction can also be carried out by passing nitrous acid gas or dinitrogen trioxide gas into the reaction solution. This reaction is usually carried out using inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, acidic acid, acetic acid, etc.
Favorable results are obtained when the reaction is carried out in the presence of an organic acid such as propionic acid, butyric acid, p-toluenesulfonic acid, etc. However, compounds in which the amino group in formula (XXX■) is derived from the above-mentioned salts are used as starting materials. When using the above-mentioned acid, the same purpose can be achieved without adding the above-mentioned acid. This reaction is usually carried out in a solvent such as water, methanol, N,N-
Solvents such as dimethylformamide, dimethyl sulfoxide, and mixed solvents thereof are often used, but other general organic solvents that do not have a negative effect on this reaction are also used, and when the above inorganic acids or organic acids are used. , these acids can also be used as a solvent.

In this reaction, the target compound (XXX■) is obtained by diazotizing the starting compound (XXX■) and decomposing the diazonium compound once formed with water. When a mixed solvent of
) can be obtained. The temperature of this reaction is not particularly limited, but it is usually preferable to carry out the reaction under mild conditions such as cooling or heating.

22) Process 22: Compound (XXX■) → Compound (X
XXX) This process converts the compound (XXX■) or its derivative at the carboxy group into the general formula R43
．． This is carried out by the action of an N-substituent represented by X'' (in the Y formula, R43 has the same meaning as above, and X'''' means a halogen).

Examples of the derivatives at the carboxy group of the starting compound (XXX) include the same examples as the derivatives at the carboxy group mentioned in the definition of A in compound (1).

Preferred examples of the halogen atom in x'''' in the above formula include chloro, brome, and iodo.

The conditions for this reaction (reaction solvent, reaction temperature, base, etc.) can also be applied as they are in the process 13 above.

(23) Process 23: Compound (XXXXI) → Compound (XXXXII) This process is compound (XXXXI)
This is done by applying an alkylating agent to the alkylating agent.

Examples of the alkylating agent used in this reaction include alkanols such as methanol, ethanol, propanol, isopropyl alcohol, and butal; diazoalkanes such as diazomethane and diazoethane; dialkyl sulfates such as dimethyl sulfate, diethyl sulfate, and dipropyl sulfate;
Examples include sulfonic acid alkyl esters such as methyl toluenesulfonate, ethyl toluenesulfonate, and ethyl methanesulfonate. This reaction is usually carried out in a solvent such as methanol, ethanol, propanol, acetone,
Diethyl ether, N,N-dimethylformamide, and the like are often used, but other general organic solvents that do not adversely affect this reaction can also be used.

In this reaction, when a diazoalkane or a toluenesulfonic acid alkyl ester is used as an alkylating agent, not only the carboxy group but also the hydroxy group of the starting compound (XXXX[) may be alkylated.

Furthermore, when dialkyl sulfuric acid or toluene sulfonic acid alkyl ester is used as an alkylating agent, good results are often obtained when the reaction is carried out in the presence of a base. and organic solvents are directly exemplified.

Furthermore, when alkanol is used as the alkylating agent, good results are often obtained when the reaction is carried out in the presence of a condensing agent. Specific examples of such a condensing agent include the condensing agents mentioned in Process 1 above. You can give it as is.

The temperature of this reaction is not particularly limited and is appropriately selected depending on the type of raw material compound (XXXX[) and alkylating agent used, etc., but it is usually carried out under mild conditions of cooling or room temperature. 20 Process 24: Compound (XXXX
■) → Compound (XXXX■) This process starts with compound (X
This is carried out by subjecting XXX■) to an elimination reaction of the protecting group at the amino group or hydroxyl group.

In this process, the elimination reaction of the protecting group at the amino group or hydroxyl group is carried out using methods such as solvolysis, chemical reduction, reduction methods such as catalytic reduction, and methods using heavy metals. The method for removing the protecting group on the amino group or the hydroxyl group can be the same as the method for removing the protecting group on the amino group of compound (X) described in Process 9 above.

As for the conditions for this reaction (reaction solvent, reaction temperature, etc.), the reaction conditions described in Process 9 above can be applied as they are.

In this reaction, a protecting group for the amino group in the acylamino group defined as R1 in the starting compound (XXXX■),
Depending on the elimination method used, reaction conditions, etc., the hydroxy-protecting group and the carboxy-protecting group may be converted to the corresponding amino group, hydroxy group, and carboxy group, respectively.

25) Process 25: Compound (XXXX■) → Compound (
XXXX■) This process is carried out by reacting compound (XXXX■) with hydrazine, N-(hydroxyalkyl)amine or aralkylamine.

Representative examples of N-(hydroxyalkyl)amines used in this reaction include 2-aminoethanol, 3-aminoethanol,
-aminopropanol, etc., and representative examples of aralkylamines include benzylane, phenethylamine, (naphthylmethyl)amine, etc.

Such hydrazine, N-(hydroxyalkylamines and aralkylamines) may be salted with acids, such as hydrochloric acid,
Salts with inorganic acids such as sulfuric acid and phosphoric acid, salts with organic acids such as acid, acetic acid, trifluoroacetic acid, malonic acid, tartaric acid, benzenesulfonic acid, toluenesulfonic acid, etc. can also be used as reagents for this reaction. I'll come.

This reaction is usually carried out in a solvent, and water, methanol, ethanol, propanol, isopropyl alcohol, acetonitrile, and mixed solvents thereof are frequently used.
In addition, general organic solvents that do not adversely affect this reaction can also be used.

Although the reaction temperature is not particularly limited, it is usually carried out under mild conditions such as cooling or heating. Further, good results are often obtained in this reaction when the reaction is carried out in the presence of a base, and examples of such bases are directly exemplified in Process 1 above. (26) Process 26: Compound (
XXXX■)→Compound (XXXX■) This process is carried out by reacting compound (XXXX■) with an alkene having an esterified carboxyl group.

Representative examples of alkenes having an esterified carboxy group used in this reaction include ethylene, propene, butene, pentene,
Examples include 2-methyl-propene and 2-methylbutene.

Examples of the esterified carboxy group include the esters of the carboxy group mentioned in the definition of A in compound (1). This reaction is usually carried out in a solvent, and water, methanol, ethanol, acetone, chloroform, N,N-dimethylformamide, and a mixed solvent thereof are often used, but other common solvents that do not have an adverse effect on the reaction are also used. Organic solvents can also be used.

Good results are often obtained when this reaction is carried out in the presence of a base, and examples of such bases include the bases mentioned in Process 1 above.

The temperature of this reaction is not particularly limited, but it is usually carried out under mild conditions such as cooling or heating.

(27) Process 27: Compound (XXXX■)→Compound (XXXX■) This process is carried out by reacting compound (XXXX■) with an acetate substituted with an aliphatic acyl.

In this reaction, the amino group of the starting compound (XXXX■) may be converted into its salts, and examples of such salts include diric acid, acetic acid, malonic acid, tartaric acid, benzenesulfonic acid, toluenesulfonic acid, etc. Examples include salts with organic acids, and salts with inorganic acids such as hydrochloric acid, sulfuric acid, and phosphoric acid.

In the acetic ester substituted with an aliphatic acyl used in this reaction, examples of the aliphatic acyl include the aliphatic acyl in the acyl group described in the above compound (1).

The ester moiety is directly exemplified by the example of ertel in the derivative of the carboxy group mentioned in the definition of A in compound (1). Specific representative examples of acetate esters substituted with aliphatic acyl thus defined include, for example, methyl acetoacetate, ethyl acetoacetate, propyl acetoacetate, ethyl propionyl acetate, ethyl propionyl acetate, methyl butyryl acetate, isobutyryl acetate. Examples include methyl. This reaction can be carried out without a solvent or using a solvent. Examples of solvents used include methanol, ethanol, propanol,
N,N-dimethylformamide and the like are often used, but general organic solvents that do not adversely affect this reaction can also be used.

Furthermore, the above aliphatic acyl-substituted acetate, which is a reaction reagent, can also be used as a solvent. Good results are often obtained when this reaction is carried out in the presence of a base, and examples of such bases include the bases mentioned in Process 1 above.

The temperature of this reaction is not particularly limited, but it is usually carried out under heating conditions.

In this reaction, the target compound (XXXX■) is its tautomer.

It is sometimes obtained as a compound having an alkylidene amino group substituted with an esterified carboxy group.
(28) Process 28: Compound (XXXXX■) → Compound (XXXX■) This process
) by reducing b.

The reduction method in this reaction includes all methods that can reduce a nitro group or an azide group to an amino group, and as such a reduction method, the reduction method described in Process 6 above can be applied as is.1. can.

This reduction reaction is usually carried out in a solvent, which is appropriately selected depending on the reduction method used. Typical examples include water, methanol, ethanol, propanol, iso-1 propanol, etc. Water, acetone, etc. are often used for chemical reduction, but if the acid used is a liquid, a solvent can also be used.

The temperature of this reaction is not particularly limited, and starting compound 2 (XXX
Although the reaction is appropriately selected depending on the type of reduction method and the reduction method used, it is usually carried out at room temperature.

(29)-(a) Process 29-(a): Compound (XX
XXX■)→Compound (XXXX■)
This process is carried out by reducing the compound (XXXXXX).

Reduction methods in this reaction include all methods of reducing an oxo group to a hydroxy group, and examples of preferred representative examples of such reduction methods include: For example, there is a method using a reducing agent such as an alkali metal borohydride such as sodium borohydride, potassium borohydride, lithium borohydride, and the like.

This reaction is usually carried out in a solvent such as water, meth. Knoll,
Ethanol, chloroform, benzene, toluene, etc. are often used, but other general organic solvents that do not have an adverse effect on this reaction can also be used, and among these, hydrophilic ones can also be used in combination with water.

The temperature of this reaction is not particularly limited, and the starting compound (XXX
XX■) and the reduction method, but it is usually carried out under mild conditions, such as under cooling or around room temperature.

! 9)-(b) Process 29-(b): Compound (XXX
XX■)→Compound (XXXXX■) This process is carried out by treating the compound (XXXXX■) or its derivative at the carboxy group with an aralkylamine under reducing conditions.

Examples of the derivatives at the carboxy group of the starting compound (XXXXXXV) include the same examples as the derivatives at the carboxy group mentioned in the definition of A in compound (1) above.

This reaction is carried out under reducing conditions, as described in Process 3.
The starting compound (XXXXXX■) and the aralkylamine may be reacted in the presence of a reducing agent similar to that described in , or the above reducing agent may be reacted with the starting compound (XXXXXX■) after reacting the aralkylamine. In addition, a reduction reaction may be performed.

In this reaction, good results are often obtained when the starting compound (XXXXX) is reacted with an aralkylamine in the presence of an inorganic base or an organic base as exemplified in Process 1 above.

This reaction is usually carried out in a solvent, and water, methanol, ethanol, propanol, benzene, toluene, and mixed solvents thereof are often used, but other common organic solvents that do not have a negative effect on this reaction can also be used. .

The temperature of this reaction is not particularly limited, and the starting compound (XXX
XX■) is appropriately selected depending on the type of aralkylamine and reducing agent, but is usually carried out under mild conditions such as cooling or room temperature.

(30) Process 30: Compound (XXXXXX■) → Compound (XXXXXX■) This process
(2) or by reacting a derivative at the carboxy group of the compound with a trialkylamine.

As the derivative of the carboxyl group of the starting compound (XXXXXX), the derivatives of the carboxyl group mentioned in the definition of A of the compound (1) can be mentioned as they are.

This reaction is usually carried out in a solvent, and methanol, ethanol, acetone, diethyl ether, N,N-dimethylformamide, etc. are often used, but other general organic solvents that do not have a negative effect on this reaction may also be used. I can do it.

The temperature of this reaction is not particularly limited, but it is usually carried out at room temperature or at elevated temperatures.

(31) Process 31: Compound (XXXXX) → Compound (XXXXXI) This process is a compound (XXXXXX)
Alternatively, it can be carried out by allowing an acylating agent to act on the derivative at the carboxy group.

Examples of the derivatives at the carboxy group of the starting compound (XXXXX) include the derivatives at the carboxy group mentioned in the definition of A in compound (1).

In addition, the acylating agents used in this reaction include those exemplified in Process 1 above, and the reaction conditions (reaction solvent, reaction temperature, base condensing agent, etc.) are also the same as those in Process 1. can be applied as is.

(32) Process 32: Compound (XXXXXX■) → Compound (XXXXXX■) This process
(2) or by subjecting a derivative of the carboxy group of the compound to a reduction reaction.

As the derivative of the carboxy group of the starting compound (XXXXXX), the derivatives of the carboxy group mentioned in the definition of A of the compound (1) can be mentioned as they are.

As for the reduction method in this reaction, the reduction methods such as chemical reduction and catalytic reduction described in Process 3 above can be applied as they are. One example is a method in which catalytic reduction is carried out using This reaction is usually carried out in a solvent, such as water, methanol, ethanol, propanol, dioxawa, or a mixture thereof. etc. are often used, but other general organic solvents that do not adversely affect this reaction can also be used.

This reaction is usually carried out at normal pressure to medium pressure, and although the reaction temperature is not particularly limited, it is usually carried out at room temperature.

[33) Process 33: Compound (XXXXXX■) → Compound (XXXXXX■) This process
(2) or by allowing an acylating agent to act on a derivative of the carboxy group of the compound.

As the derivative of the carboxy group of the starting compound (XXXXXX), the examples of derivatives of the carboxy group mentioned in the definition of A of the compound (1) can be mentioned as they are.

Further, as the acylating agent used in this reaction, the ethylating agent exemplified in Process 1 above can be used as is. Reaction conditions (reaction solvent, reaction temperature, base, etc.)
The reaction conditions in Process 1 above can be applied as they are. ]34) Process 34: Compound (XXXXX■)→
Compound (XXXXX■) This process
XX■) or a derivative at the carboxy group of the compound having the general formula R69-XH (wherein, RO has the same meaning as above and X″″″″ means an acid residue) and is treated with an aralkylating agent. This is done by

Examples of the derivatives at the carboxy group of the starting compound (XXXXXX~]) include the same examples as the derivatives at the carboxy group mentioned in the definition of A in compound (1).

In the definition of the alkylating agent used in this reaction, the acid residue at X''''7 is the same as the acid residue defined as X1 of the compound (XI).

This reaction is usually carried out in a solvent, and methylene chloride, chloroform, dichloroethane, N,N dimethylformamide, etc. are often used, but other general organic solvents that do not have an adverse effect on this reaction can also be used.

The temperature of this reaction is not particularly limited, but it is often carried out under mild conditions, usually under cooling or around room temperature.

Good results are often obtained when this reaction is carried out in the presence of the base exemplified in Process 1 above.

(35) Process 35: Compound (XXXXX■)→Compound (1) This process is carried out by subjecting the compound (XXXXX■) to a reductive desulfurization reaction.

Reductive desulfurization agent used in this reaction. Examples include Raney nickel and Raney cobalt.

This reaction is usually carried out in a solvent, and ether, dioxane, methanol, ethanol, propanol, tetrahydrofuran, ethyl acetate, and water are frequently used, but other common organic solvents that do not adversely affect the reaction can also be used. .

The temperature of this reaction is not particularly limited, but it is usually carried out under conditions of heating or heating.

(36) Process 36: Compound (XXXXXX■) → Compound (XXXXXX) This process
(2) or by subjecting a reactive 1 derivative at the carboxy group of the compound to an intramolecular ring-closing reaction.

Examples of reactive derivatives at the carboxy group of the raw material compound (XXXX Specific examples of reactive derivatives may also be mentioned.

In addition, the imino group (-NH-
) may be converted into a salt with an acid. Examples of salts with such acids include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, acidic acid, acetic acid, trifluoroacetic acid,
Examples include salts with organic acids such as benzenesulfonic acid.

This reaction is usually carried out in a solvent such as methylene chloride, chloroform, diethyl ether, ethyl acetate, N,N-
Dimethylformamide and the like are often used, but other general organic solvents that do not adversely affect this reaction can also be used. In addition, good results are often obtained in this reaction when the reaction is carried out in the presence of a base and/or a condensing agent, and examples of such a base and condensing agent include the base and condensing agent mentioned in Process 1 above. It can be given as is,
Furthermore, examples of the condensing agent include Grignard reagents such as acetic anhydride, methylmagnesium chloride, and ethylmagnesium chloride.

The temperature of this reaction is not particularly limited, but it is usually carried out under mild conditions such as cooling or room temperature.

(7) Process 37: Compound (XXXXXX[) → Compound (XXXXXX■) This process
This is carried out by an elimination reaction of a protecting group on the carboxy group of X[).

Examples of the method for removing the protective group from a carboxyl group include the methods such as solvolysis and reduction used as the method for removing the acyl group described in Process 3 above, and the reaction conditions are also the same as those in Process 3 above. The reaction conditions in can be applied as is.

38) Process 38: Compound (XXXXX , a metal salt such as potassium azide or calcium azide, or an azidating agent such as diphenyl phosphate azide.

The reaction temperature is usually carried out under cooling or at room temperature.

39) Process 39: Compound (XXXXX
XXXX■) and the compound thus obtained (X
XXXXX■) with or without isolation of formula R74-
This is done by reacting with an alcohol represented by 0H.

The reaction of reacting the above alcohol with compound (XXXXXX■) to obtain compound (XXXXXX■) is usually carried out in a general organic solvent that does not participate in the reaction, such as tetrahydrofuran, methylene chloride, or ether, under cooling or heating. . Moreover, the alcohol used may also serve as a solvent. Moreover, the reaction can be carried out continuously using the process feather and this process 39, in which case the compound (XXX
Compound (XXXXXX■) can also be obtained by reacting XXXXX■) with an azidating agent and alcohol.

(40) Process 40: Compound (XXXXXX■) → Compound (XXXXXX■) This process
XXX■) is reacted with a compound represented by the formula Pb(0C0R75)4.

This reaction is usually carried out in a solvent, and examples of the solvent include common organic solvents that do not adversely affect the reaction, such as benzene, acetic acid, ethyl acetate, methylene chloride, chloroform, and ether.

In addition, good results are often obtained in this reaction if the reaction is carried out in the presence of a radical reaction initiator such as copper acetate, or if the reaction is carried out under photochemical reaction conditions such as under ultraviolet irradiation. The reaction temperature is generally heated.

(41) Process 41: Compound (V) → Compound (XXX
XXX■) The reaction in this process is carried out by reacting the compound (V) or its derivative at the carboxy group with a compound represented by the formula R76NH2 under substantially the same conditions as in Process 16 above.

Examples of derivatives of the carboxyl group of compound (■) include the derivatives of the carboxyl group mentioned in the definition of A of compound (1). (42) Process 42: Compound (X■) → Compound (XXXXXXXX)
This reaction converts the compound (X) or its derivative at the carboxy group into a compound represented by the formula R77-X'''''' (wherein R77 is the same as above and x means an acid residue) using the process 34 above. It is carried out by operating under substantially similar conditions.

Examples of the derivatives at the carboxy group of compound (X) are the same as the derivatives at the carboxy group mentioned in the definition of A in compound (1). Also X″
Acid residue in "" is the same as the acid residue defined in X1 of the above compound (■).

(43) Process 43: Compound (XXXXXXXXI) →
Compound (XXXXXXXX) The reaction in this process is carried out by reacting the compound (XXXXXXX) or its derivative at the carboxy group with an acylating agent under substantially the same conditions as in Process 1 above.

Examples of the derivatives at the carboxy group of compound (XXXXXXXXI) include the same examples as the derivatives at the carboxy group mentioned in the definition of A in compound (1). As the acylating agent used in this reaction, the same examples as those exemplified in Process 1 above can be used.

In addition, in each process mentioned above, the raw materials used,
Depending on the reagents, other reaction conditions, etc., side reactions in each process may occur during the reaction or post-treatment of the reaction.
For example, a carboxyl group may be converted to its derivative, a derivative of a carboxyl group may be converted to a free carboxy group, or a protective group such as an amino group, hydroxy group, meltcapto group, or carboxy group may be removed. be.

The azetidinone derivative of the present invention is represented by the general formula (1) above, but it can also be represented by the following formula.

In the formula, (1) Ra and Rb both represent hydrogen atoms, (2) Ra
is a hydrogen atom and Rb is an allenesulfonyl group, (3)
Ra and Rb together represent an imide group derived from dicarboxylic acid, (4) Ra represents a hydrogen atom, and Rb represents an acyl group selected from the following groups, where n is 0 to 4. An integer, Rt is a hydrogen atom or carboxy or its sister DG
ζR? is a hydroxy group, halogen atom, azide group, amino group, alkylamino group or dialkylamino group, alkenylamino group, cycloalkylamino group, arylamino group, aralkylamino group, alkanoylamino group, alkoxycarbonylamino group, alkoxy (thio carbonyl) amino group, aryloxyalkanoylamino group, alkanoylamino group, heterocyclic-substituted alkanoylamino group, aroylamino group, N″-
Arylureido group, N″-arylthioureido group,
Or an arylthio group, R? is a hydrogen atom, hydroxy group, amino group, arylamino group, alkanoylamino group, alkoxycarbonylamino group, alkoxy(thiocarbonyl)amino group, aroylamino group, aralkanoylamino group, N″-arylureido group, or N″
-Arylthioureido group, where R is a hydrogen atom or Re and R? together form an oxo group, hydro
It means a xiimino group, an alkanoyloxyimino group or an alkoxyimino group, respectively, and in the group defined above, the alkane part and the alkene part are a carboxy group or a derivative thereof, a halogen atom,
and a sulfo group as a substituent, and the aromatic ring and heterocycle are selected from a hydroxy group, an amino group, a nitro group, a halogen atom, a carboxy group, or a derivative thereof. In the formula, Ru is a hydroxyimino group, an oxo group, an alkoxyimino group, an aroyloxyimino group, or an aralkoxyimino group. a shiimino group, R2 means a cyano group, an alkyl group, an aryl group, an alkylamino group, an alkoxyaryl group, an alkenyloxyaryl group, an alkylamino group, an aralkoxyaryl group, an alkoxy group or a heterocyclic group; The alkane moiety, aromatic ring, and heterocycle in the above groups may have a hydroxy group or (and) a carboxy group or a derivative thereof as a substituent, where RZ is an aryl group, an alkoxyaryl group, Aryloxy group, alkenyl group, 1,1-dialkyl-1-arylaminoalkyl-aryloxyalkyl group, aralkyloxy group, aralkenyl group, alkylthioalken-1-yl group, arylamino group, alkyl group and/or aryl group substitution means a heterocyclic group, a heterocyclic amino group, an aryloxyalkanoylamino group, a guanidino group, or a 3-aralkanoylguanidino group, and in the above groups, aromatic rings and heterocycles are carboxy groups or derivatives thereof, nitro groups. , halogen atom, oxo group,
may be substituted with an amino group and (or) a protected amino group, where m and 1 each represent an integer of O to 4, Re represents a hydrogen atom, an alkyl group, an aryl group, Aryloxy group, heterocyclic group, N- (aralkanoylaminoalkyl) group means a rubamoyl group or N-arylcarbamoyl group, and in the above groups, aromatic rings and heterocycles are hydroxy groups or protected or hydroxy groups. It may be substituted with a group.

Re means a hydrogen atom or an alkyl group, and Rr represents a hydrogen atom, an amino group, a protected amino group, an azide group, a halogen atom, a hydroxy group, a protected hydroxy group, a carboxy group or its derivative, a sulfo group, or its salts, ansulfonyloxy group, alkyl group or alkyl group;
105nyl group, (this alkyl group or alkenyl group is an amino group, N-alkyl-N-arylamino group, protected amino group, azido group, halogen atom, hydroxy group, carboxy group or a derivative thereof,
sulfo group, aroyl group, substituted or unsubstituted aryl group, and substituted or unsubstituted heterocyclic group), the aryl group in the aryl group is by at least one group selected from a hydroxy group, a protected hydroxy group, a nitro group, a protected carboxy group, a halogen atom, an alkanoyl group, and a carboxy group or a hydroxy-substituted or unsubstituted sulfonamido group (optionally substituted), heterocyclic group, heterocycle-substituted heterocyclic group, oxo-substituted or unsubstituted aryl-substituted heterocyclic group, oxo- and aracoxycarbonyl-substituted heterocyclic group, heterocycle a heterocyclic group substituted with the formula group alkanoylamino,
Oxo-substituted or unsubstituted aralkanoylamino-substituted heterocyclic group, aroyl group, heterocyclic-substituted alkanoyl group (
This group may be substituted with an alkyl group, a halo-substituted or unsubstituted aryl group, a heterocyclic group, a halogen atom, an amino group, etc.), an alkoxy group, a cycloalkoxy group, an aryloxo group, The aryl moiety may be substituted with one or more suitable substituents,
Such substituents include nitro group, halogen atom,
formyl group, alkanoyl group, alkanoylamino group,
Aralkylamino group, aryl group, halogen atom and nitro group substituted or aryloxy group, alkyl group or alkenyl group (this alkyl or alkenyl group is a carboxy group or its derivative, amino group, protected amino group, hydroxy group, nitro group) group, hydroxyimino group, carboxy-substituted or unsubstituted alkoxyimino group, N-halo N,N,N-trialkylammonioalkanoylhydrazono group, alkylthio optionally having carboxy and/or amino groups (which may have an appropriate substituent such as a substituted alkanoylamino group), and the like.

), aralkylaminoalkyl group (this group is a carboxyalkoxy group or derivative of a carboxyalkoxy group)
), heterocyclic oxy group, alkylthio group, alkenylthio group, aroyloxyalkanoylaminoalkylthio group, aroylalkylthio group or N-arylcarbamoylalkylthio group (these groups may be substituted on the 106 conductor) group, carboxy group, nitro group, halogen atom, etc.)
, alkylsulfinyl group, N-arylcarbamoylalkylsulfinyl group, carboxy-substituted or unsubstituted arylthio group, heterocyclicthio group, aminoalkyl-substituted heterocyclicthio group, alkanoylalkyl-substituted heterocyclicthio group substituted with or not substituted with hydroxy group , a substituted or unsubstituted arylamino group, a heterocyclic amino group substituted or unsubstituted with an oxo group or an aryl group, an alkylamino group, an aralkylamino group substituted or unsubstituted with an imino group, an N-alkyl-N-aralkyl amino group, N-alkyl-N-protected alkylamino group, N-alkanoyl-N-arylamino group, N-alkyl-N-arylamino group (the alkyl portion thereof may be substituted with an azido group, a carboxy group, etc.), N -Alkanesulfonyl-N-arylamino group, alkanoylamino group (the alkanoyl portion of this group may have a halogen atom, an amino group, a protected amino group, an azido group, etc.), substituted or unsubstituted cycloalkoxyalkanoyl Amino group, alkylthioalkanoylamino group (the alkane portion thereof may be substituted with an amino group, halogen atom, carboxy, etc.), aralkanoylamino group, alkoxy-substituted aralkanoylamino group, or aryloxy-substituted aralkanoylamino group groups (these groups include halogen atoms, aralkoxyimino groups,
Arylamino-substituted alkanoylamino group (which may be substituted with an arylamino group, an amino group, a protected amino group, a hydroxy group, etc.) (this group can be substituted with a halogen atom, a carboxy group, a protected carboxy group, a nitro group, an alkyl-substituted aryloxyalkanoylamino group that may be substituted with a group, etc. (this group may be substituted with a hydroxy group, etc.), an aryl-substituted aryloxyalkanoylamino group (this group may be substituted with a nitro group, etc.) ), aryloxy-substituted alkanoylamino group (this group may be substituted with a halogen atom, nitro group, carboxy or its derivatives, formyl group, carbazol group, etc.), alkyl-substituted aryloxyalkanoylamino group (this group may be substituted with a hydroxyimino group, a halogen atom), an alkylaminoalkyl-substituted aryloxyalkanoylamino group may be substituted with a carboxymethoxy group, a carboxy derivative), an alkanoyl-substituted aryloxy Alkanoylamino group, aroyl-substituted aryloxyalkanoylamino group (this group includes nitro group, amino group,
may be substituted with a halogen atom, etc.), an alkylthioalkanoylaminoaroyl-substituted aryloxyalkanoylamino group (this group may be substituted with a halogen atom, an amino group,
), alkylthioalkylaminoaroyl-substituted aryloxyalkanoylamino group (this group may be substituted with an amino group or halogen atom), alkanoylaminoaroyl-substituted aryloxyalkanoylamino group (this group may be substituted with a halogen atom), (N-halo N,
N,N-trialkylammonio)alkanoylaminoaroyl substituted aryloxyalkanoylamino group (
This group may be substituted with a halogen atom, etc.), heterocyclic carbonyl-substituted aryloxyalkanoylamino group (this group may be substituted with a halogen atom, etc.), aralkylaminoargyl-substituted aryloxyalkanoylamino group (this group may be substituted with an alkoxy group, a carboxyalkyl group, a carboxy group or a derivative thereof, etc.), heterocyclic thioalkanoylaminoaroyl. Substituted aryloxyalkanoylamino group, heterocyclic substituted aryloxyalkanoylamino group (this group may be substituted with an alkyl group, aryl group, haloaryl group, halogen atom, amino group, etc.), di(aryloxy)alkanoylamino group group (this group may be substituted with a halogen atom, amino group, nitro group, etc.), arylthioalkanoylamino group (this group may be substituted with a carboxy group, etc.), heterocyclic substituted heterocyclic group an alkanoylamino group substituted with a group, a heterocyclic thioalkanoylamino group (this group is a hydroxy group, an amino group,
(may be substituted with amino-substituted or unsubstituted alkyl group, etc.), alkanoylaminoalkanoylamino group (this group may be substituted with amino group, halogen atom, carboxy group, etc.), arylsulfinylalkanoylamino group (this group may be substituted with a carboxy group, etc.), an arylsulfonyloxyalkanoylamino group, an (N-arylarenesulfonamido)alkanoylamino group, a heterocyclic carbonylamino group (this group is a halogen-substituted aryl group) ), arylglyoxyloylamino group, alkoxarylamino group, aralkylaminooxarylamino group, arylaminooxarylamino group (this group may be substituted with a nitro group), N-aryl carbamoylamino group, guanidinocarbonylamino group, arenesulfonamide group or anolecanesulfonamide group (
These groups may be substituted with an aryl group, a hydroxy group, a carboxy group, a halogen atom, etc.), an N-alloythioureido group, an aryloxyalkanoylaminooxy group, or an N-alkylidene, an aralkylidene,
or a heterocyclic-substituted alkylidene aminooxy group (these groups may be substituted with a carboxy group or a derivative thereof, alkoxy, etc.).

Above R8, R? ,Rg,Ra,Rdo,Rg,R≦,R?
and RI,.

In each definition of A, preferred examples of the halogen moiety include the halogen in X2, preferred examples of the alkyl group or alkyl moiety include the alkyl in the definition of A above, and preferred examples of the dialkyl moiety. includes dimethyl, diethyl, dipropyl, etc. Preferred examples of the alkenyl group or alkenyl moiety include alkenyl in the definition of A above, and preferred examples of the cycloalkyl group or cycloalkyl moiety include the alkenyl group in the definition of R1 above. Examples of cycloalkyl in the explanation include the aryl group or the aryl group in the definition of R,5 above as a preferable example of the aryl moiety, and the aralkyl group in the explanation of the definition of Rl7 as a preferable example of the aralkyl group or aralkyl moiety. Preferred examples of the alkanoyl group or alkanoyl moiety include the examples of alkanoyl in the explanation of the definition of R2 above.
Preferred examples of the alkoxy group or alkoxy moiety include the following. Preferred examples of the aralkoxy group or aralkoxy moiety include benzyloxy, phenethyloxy, phenylpropoxy, phenylbutoxy, etc., and preferred examples of the aralkanoyl group or aralkanoyl moiety include the aforementioned 4. The example of aralkanoyl in the explanation of the definition of R2 is an aroyl group or a preferable example of the aroyl moiety, and the example of aroyl in the explanation of the definition of R2 is a preferable example of a t-alkyl group, such as t-butyl, t-pentyl. , t-hexyl, etc. Preferred examples of the heterocyclic group or heterocyclic moiety include a protected amino group, a protected hydroxy group, etc. Preferred examples of the protecting group for the protected carboxy group include the protecting group for Rl2, and preferred examples of the carboxy group derivatives include the carboxy group derivatives in the definition of A above. Azetidinone derivatives of this invention (
1) has antibacterial activity and is useful as a medicine, and is also useful as a synthetic intermediate for producing other substances with antibacterial activity.

Here, the azetidinone derivative (1) of the present invention. The antibacterial activity (minimum inhibitory concentration) of representative examples of is shown below.

Test method: Inoculate one platinum loopful of the test bacteria into a medium-sized test tube containing 5ml of broth and leave it at 30°C overnight! Add 1% of the cultured bacteria to Mueller-Hinton medium (1% agar) and add 8
10 m. Dispense 1 at a time.

The substance of the present invention shown below is dissolved and diluted in water, 2% aqueous sodium bicarbonate solution, or methanol to a concentration of 10 m9/ml. This was tested by attaching it to a 8CTn major axis PAP, and the minimum concentration showing the inhibition circle was determined. I. C.
(minimum inhibitory concentration). M. I. C. Example 39
Compound of: Pseudomonas. 30 against Erginosa
γ/Mtl Compound of Example 51: 125 γ/Ml against Bacillus subtilis Compound of Example 112: 600 γ/ml against Escherichia coli;
30 γ/ml against Staphylococcus aureus 600 γ/ml Example 157
Compound: 75γ/Ml against Bacillus subtilis
Compound of Example 158: 800 γ/ml against Bacillus subtilis, <800 γ/ml against Staphylococcus aureus, Compound of Example 161: 160 γ/ml against Escherichia coli, 160 γ/ml against Proteus vulgaris 80γ/MLl 80γ/ml against Staphylococcus aureus, compound of Example 304: 16γ/Mll against Escherichia coli Proteus 250γ/Mll against E. vulgaris Example 313
Compound of: Pseudomonas. 15 against Erginosa
0γ/77! 600γ for L1 E. coli
/Mll Compound of Example 352: Pseudomonas. 75 γ/Mll for Pseudomonas aeruginosa 10 γ/Mll for E. coli Staphylococcus 20 γ/Mll for Pseudomonas aureus Compound of Example 410: Pseudomonas. 320 γ/Mtl against E. aeruginosa ● 160 γ/Mll against E. coli Compound of Example 419: 600 γ/77 against E. coli!
11 against Proteus vulgaris〈30γ/Mll
600γ/Tr for Stachylococcus aureus
Compound of Ltl Example 456: 7.5 γ/WLI against E. coli Compound of Example 457: 40 γ/Mll against E. coli Compound of Example 478: 600 γ/Mll against Bacillus subtilis
40γ/Mll against E. coli Stahylococcus 40γ/Mll against E. aureus Example 49
Compound 8: Pseudomonas. 1 against Erginosa
39γ/M against 50γ/Mll E. coli
600γ/MLl against Proteus vulgaris
Compound of Example 516: Pseudomonas. 63γ/Tntl against Pseudomonas aeruginosa ●250γ/Mll against Pseudomonas vulgaris Compound of Example 517: Pseudomonas. 63γ/Mll against Proteus vulgaris 250γ/Mll Stahylococcus against Aeruginosa *16γ/Mll against Aureus Example 520
Compound: 60γ/ml for Bacillus subtilis
, 300 γ/ml against E. coli, 600 γ/Mtl against Staphylococcus aureus Compound of Example 545: 40 γ/ml against S. aureus 40 γ/ml against E. coli
/Tnll Compound of Example 549: 80 γ/Mll against E. coli Compound of Example 573: 40 γ/ml against E. coli, 40 γ/ml against Staphylococcus aureus, then this invention was applied to Examples This is explained by:

Next, examples of this invention will be shown.

Example 1 3-amino-1-(α-carboxy-4-hydroxybenzyl)-2-azetidinone (hereinafter abbreviated as 3-aminolactasilanic acid) 0. Suspend the suspension in 10 ml of water, and add and dissolve 0.80 g of sodium bicarbonate.

Add 10 ml of acetone to this solution, cool it to -7°C,
Add a solution of 0.80y of 2-phenylacetyl chloride in 5ml of acetone. After stirring the reaction solution at the same temperature for 2 hours, acetone was distilled off under reduced pressure, and the remaining aqueous layer was washed with diethyl ether, adjusted to pH 2 with 10% hydrochloric acid, and then extracted twice with 15 ml each of ethyl acetate. . The ethyl acetate extracts are combined, washed with water and then with saturated brine, and then dried over magnesium sulfate. After evaporation of the solvent, the resulting residue is treated with a small amount of a mixture of ethyl acetate and diethyl ether to obtain 0.53y of 3-(2-phenylacetamido)lactasilanic acid. Mpl34~141℃
. The compound shown below is obtained in the same manner as above.

Example 57 492 mg of N-phenylglycyl chloride hydrochloride is suspended in 10 ml of methylene chloride and cooled to -15°C.

3-aminolactasilanic acid 472 was then added to this suspension.
mg and bis(trimethylsilyl)aceamide 2.0
A solution of 3y in 17 mt of methylene chloride is added all at once. The temperature of the reaction solution was maintained at 0 to -10'C for 1 hour, then cooling was removed and 1. Stir for a while. Methylene chloride is distilled off from the reaction mixture and the residue is dissolved in ethyl acetate. This solution is washed successively with water and a saturated aqueous sodium chloride solution, dried, and then the solvent is distilled off. A small amount of acetone is added to the residue and the crystals are collected to obtain 116 mg of 3-(N-phenylglycinamidodo)lactasilanic acid. Mpl94-19
4.5℃. The resin solution is left to cool, and the precipitated crystals are separated and washed with a small amount of ethyl acetate to recover 60 m9 of the same desired product. Mpl93-194.5°C. Total yield 176m
g. The compound shown below is obtained in the same manner as above. Example 8
3 After heating a mixture of 320 m9 of N,N-dimethylformamide and 780 mg of thionyl chloride to 40-50° C. for 30 minutes, the excess thionyl chloride is distilled off and the residue is suspended in 10 ml of methylene chloride.

To this suspension, 370 m9 of 4-hydroxyphenylglyoxylic acid was added while cooling at -15 to -20°C, and the mixture was stirred. Further, the reaction temperature is raised to -5 to 10 DEG C. and the mixture is stirred once to obtain a clear solution containing 4-hydroxyphenylglyoxychloride. This solution was then heated to -45~
The mixture was cooled to −50° C., and a solution of 440 ml of triethylamine and 2 ml of methylene chloride was added over a period of 5 minutes, followed by stirring for 3 times. Add 470 m9 of 3-aminolactasilanic acid to this solution in advance while keeping it cooled at -45 to -50°C.
and bis(trimethylsilyl)acetamide 1.2y
A solution prepared by stirring the mixture in 10 ml of dry methylene chloride at room temperature for 1 hour was added at once and stirred for 3 minutes, then the cooling solution was removed and stirring was continued for 1.5 hours while gradually raising the reaction temperature to room temperature. Methylene chloride is distilled off from the reaction mixture, and the residue is dissolved in 20 ml of 5% aqueous sodium hydrogen carbonate solution. After washing this solution twice with 10 TrL of ethyl acetate, 50 mL of ethyl acetate was layered on top of the solution, and while shaking well,
% hydrochloric acid to adjust the liquidity of the aqueous layer to PHL. The ethyl acetate layer is separated, and the aqueous layer is extracted twice with 20 ml of ethyl acetate. The ethyl acetate layers were combined, washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, and then the solvent was distilled off to obtain 460 m9 of crude 3-(4-hydroxyphenylglyoxyroylamino)lactasilanic acid. Dissolve 720 ml of the product thus prepared in 3 ml of ethyl acetate, apply column chromatography using silica gel, elute with ethyl acetate, and collect fractions containing the target product. The residue obtained by distilling off the solvent was dissolved in acetone, and 2
- Add an acetone solution of sodium ethylhexanoate to obtain a sodium salt solution of the target product, and then distill off the acetone. The residue was powdered by adding ether, washed with acetone, and the sodium salt of 3-(4-hibiloxyphenylglyoxyroylamino)lactasilanic acid 1 was obtained.
Obtain 70m9. Mp22O~225°C The compound shown below is obtained in the same manner as above.

Example 89 0.453y of sodium hydrogen carbonate is dissolved in 10T1Lt of water and cooled to 5°C.

Add and dissolve 0.427y of 3-aminolactasilanic acid. After further adding 10 ml of acetone to this solution, a solution of 0.38 f of butyric anhydride in 5 ml of acetone was added over a period of about 5 minutes. After the addition, 0.04V of sodium hydrogen carbonate was added, and the mixture was further stirred at the same temperature for 1 hour. Acetone is distilled off from the reaction solution, and the residual aqueous layer is washed with diethyl ether, cooled, and adjusted to pH 1~2 with 10% hydrochloric acid. This aqueous layer is extracted twice with 30 ml portions of ethyl acetate. The ethyl acetate extracts were combined, washed with 50 ml of water, then with saturated saline, and dried over magnesium sulfate. Concentration of the solvent yields 112m9 of crystals of 3-butylamidolactasilanic acid. Mpl78~178.5℃(
Decomposition) Example 90 0.350 y of pivalic acid chloride was dissolved in methylene chloride, and while cooling to -10 to -15°C, 0.520 y of 4-methoxyphenylglyoxylic acid and 0.0 y of triethylamine were dissolved.
A solution of 290y dissolved in methylene chloride (10 ml) was added and reacted for 1 hour to prepare a solution of mixed acid anhydride of 4-methoxyphenylglyoxylic acid and pivalic acid.

On the other hand, 2.3y of bis(triaminosilyl)acetamide was added to a solution of 0.680f of 3-aminolactasilanic acid suspended in 10ml of methylene chloride, and the mixture was stirred at room temperature for 1 hour. The mixed acid anhydride solution prepared above is added to this reaction solution, and the mixture is reacted for 2 hours while being maintained at -10 to -15°C. Methylene chloride is distilled off from the reaction solution, and the resulting residue is dissolved in ethyl acetate, washed with 5% hydrochloric acid and then with saturated saline, and then dried over magnesium sulfate. The solvent was distilled off, about 30 mt of diisopropyl ether was added to the residue, stirred for 1 hour, and taken out to obtain a powder of 1.14 f. Dissolve this product in 30 ml of ethyl acetate, treat with 0.11 J of activated carbon, and filter. After concentrating the liquor to about 2 ml, if you rub the container wall, crystals will precipitate out. This is taken in a furnace and recrystallized from a small amount of ethyl acetate to obtain 0.16y of 3-(4-methoxyphenylglyoxyroylamino)lactasilanic acid. Mpl 78-181°C (decomposed). The following compound is obtained in the same manner as above.

Example 109 0.44y of 3-aminolactasilanic acid was suspended in 60ml of dry methylene chloride, and bis(trimethylsilyl)
Acetamide 7.0y and dimethylformamide 0.0y.
Add 7rn1 and stir at room temperature for 2 hours to dissolve.

Separately, in a solution of 0.523 q of ethyl chloroformate in 30 mL of dry methylene chloride, 1 mL of N-benzyloxycarbonyl-2-(2-thienyl)glycine was added under cooling at -5 to -10°C.
．． A solution of 40y and 0.485 da of triethylamine in 30 ml of dry methylene chloride was added dropwise over 7 minutes, and the mixture was further stirred for 2 minutes at the same temperature to prepare a solution of mixed acid anhydride. The solution obtained above was added dropwise to this solution over 20 minutes, and the mixture was stirred at the same temperature for 3 hours. Stirring was continued while the reaction temperature was gradually raised to room temperature over about 2 hours. The reaction solution was washed with dilute hydrochloric acid and water, dried, and concentrated to give 3-[2-(2-
1.40 V of lactasilanic acid (thienyl)-N-benzyloxycarbonylglycinamide] is obtained. Infrared absorption spectrum (liquid film) να-1: 1730, 1710, 1650 The following compound was obtained in the same manner as above.

Example 111 500 mg of 2-(4-methoxyphenyl)-2-methoxyiminoacetic acid and 495 mg of N,N''-dicyclohexylcarbosiimide are dissolved in a mixture of 9 mL of chloroform and 3 mL of dioxane, and stirred for 1 hour under ice cooling. .

A solution prepared by dissolving 472 mg of 3-aminolactasilanic acid and 1.22 y of bis(trimethylsilyl)acetamide in 10 mt of chloroform is added at once to this solution, and the mixture is stirred at room temperature for 4 hours. The solvent was distilled off from the reaction mixture, sodium hydrogen carbonate solution and ethyl acetate were added to the residue, and after shaking, the aqueous layer was separated, the pH was adjusted to ~2 with 10% hydrochloric acid, and the mixture was extracted with ethyl acetate. After washing the ethyl acetate extract with water and drying, the solvent was distilled off, and diethyl ether was added to the residue, which was collected and washed with diethyl ether to give 3-[2-(4
-methoxyphenyl)-2-methoxyiminoacetamide]lactasilanic acid 150TfL9 is obtained. Mpl57
~161 acid C (decomposition). The following compound is obtained in the same manner as above. Example 113 0.472 g of 3-aminolactasilanic acid is suspended in 10 mL of methylene chloride, and 1.22 y of bis(trimethylsilyl)acetamide is added at room temperature, followed by cooling to -15°C.

Next, a solution of 935 Tng (0.0024 mol) of triethylammonium salt of a mixed acid anhydride prepared from 2-phenyl-2-sulfoacetic acid and ethyl chloroformate in methylene chloride (10 ml) was added in two drops. 1 at the same temperature
Stir for 1 hour and then at room temperature for 1 hour. Approximately 5 liters of water is added to the reaction solution.
0ml was added (PH becomes 3.0), the aqueous layer was separated and washed with ethyl acetate, and the pH was adjusted with an aqueous sodium bicarbonate solution.
Adjust to 5-6 and pass. Adsorption resin Amber*Lite
(Trademark, manufactured by Rohm & Haas) After adsorption onto a column packed with 20 mL, desorption and elution are performed with water. The eluate is concentrated under reduced pressure, ethanol is further added, and the solvent is distilled off under reduced pressure. When ethanol is added to the resulting residue, crystals are precipitated. This was filtered to obtain 120 m9 of 3-(2-phenylsulfoacetamido)lactasilanic acid.
After collecting the crystals, the Oki liquid is concentrated and the resulting oil is treated with acetone to obtain 0.45% of the disodium salt of 3-(2-phenyl-2-sulfoacetamido)lactasilanic acid in the form of powder. Mpl44-157C The following compound is obtained in the same manner as above.

Example 116 N-benzyloxycarbonyl-2-(benzo[d]isoxol-3-yl)glycine 625m
9 o. and trimethylamine (202 mg) were dissolved in 8 mL of dry tetrahydrofuran, and 6-chloro 1 was dissolved under stirring under ice cooling.
690 mg of 1-(4-chlorobenzenesulfonyloxy)-1H-benzotriazole was added and stirred at the same temperature for 3 hours.

Next, while stirring under ice cooling, a solution of 472 mg of 3-aminolactasilanic acid and 202 m9 of trimethylamine dissolved in 10 ml of acetone/water (1:1) was added, and after further stirring for 1 hour, the solvent was distilled off. Add 20 mL of water to the residue to make a solution, layer the ethyl acetate group, add 1N monohydrochloric acid dropwise while shaking to make the liquid acidic, and then separate the ethyl acetate layer. The aqueous layer is extracted with ethyl acetate, combined with the previously separated ethyl acetate layer, washed with water, dried over magnesium sulfate, and the solvent is distilled off to obtain a residue 1.2y. This residue was subjected to column chromatography using silica gel with 500% ethyl acetate containing 10% methanol.
Develop and elute with wL1 to obtain a fraction containing the target product,
The resulting residue is pulverized by treatment with diethyl ether to obtain 180 m9 of 3-[N-benzyloxycarbonyl-2-benzisoxazol-3-yl)glycinamido]lactasilanic acid. Mpl59
~168℃. Do the same as above to obtain the following. Example 118 0.472y of 3-aminolactasilanic acid is suspended in 20ml of water, and 420y of sodium bicarbonate is added and dissolved.

Add 20 mt of acetone to this solution, cool it to 0 to 50°C, and add 20 mt of acetone to this solution.
Add m1 solution dropwise and stir at the same temperature for 2.5 hours. Insoluble matter is removed from the aqueous solution obtained by distilling off acetone from the reaction mixture.
After removing the water and washing the liquid with ethyl acetate, pH was adjusted with 10% hydrochloric acid.
Adjust to l. This aqueous solution is extracted with ethyl acetate, and the ethyl acetate layer is washed with water, dried over magnesium sulfate, and then the solvent is distilled off to obtain a crystalline residue. When this residue is washed with diisopropyl ether and filtered off, 470 g of 3-(3-phenyl aleide (lactasilanic acid 0)) is obtained. Mp
l67~172'CO Example 119 Dissolve 0.38y of dihydrochloride of guanidinocarbohydrazide in 2nLt of water, add 0.14d of sodium nitrite while cooling to 0~5°C, stir once, and dissolve guanidinocarbonyl. Prepare the azide solution.

On the other hand, add 0.240 f of 3-aminolactasilanic acid to 7 m of water.
After suspending in t, 0.170 g of sodium carbonate is added and dissolved. This aqueous solution is cooled to 0 to 5°C, and the solution prepared above is added over a period of about 1 minute, followed by stirring for 2 hours. After washing the reaction mixture with 10 TrLt of ethyl acetate, it was concentrated to a clear solution to completely remove the ethyl acetate saturated in the aqueous layer, and crystals were precipitated. After standing for a while, the crystals are peeled off to obtain 0.15 g of 3-(guanidinocarbonamido)lactasilanic acid. Mp2O6~2
10℃. Example 1202-Phenyl-N-(2,2,2
, monotrichloroethoxycarbonyl) glycine 1.42
A solution consisting of y and 15 ml of thionyl chloride is refluxed for 1 hour.

Excess thionyl chloride is distilled off from this solution under reduced pressure and the residue is dissolved in acetone. To this solution, add 1.0f1 of 3-aminolactasilanic acid, 0.9y1 of sodium bicarbonate, 44ml of water.
A solution consisting of 0mt and acetone 40WLt was added to
Suitable while cooling to ℃. Acetone is distilled off from the reaction solution under reduced pressure, and the residue is washed with ethyl acetate. The resulting residue is adjusted to pH1~2 with 10% hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer is separated and dried over magnesium sulfate. The solvent is distilled off from the ethyl acetate solution, and the resulting residue 2.1y is dissolved in diethyl ether. The solution was concentrated in diethyl ether and the residue was washed with diisopropyl ether to give 3-[2-phenyl-N-(2,"2,2-
1.69y of trichloroethoxycarbonyl)glycinamide]lactasilanic acid is obtained. Mpl3O~137C(
Decomposition) The following compound is obtained by treatment in the same manner as above.

Example 13 After 700 mg of 1-3-aminolactasilanic acid was suspended in 15 mt of dry methylene chloride, 3.6 y of bis(trimethylsilyl)acetamide was added and stirred for 3 hours.

This solution was cooled to -50 to -40°C, 630 m9 of 2-(2-pyridyloxy)acetylchloride hydrochloride was added at once, and the reaction temperature was kept at the same temperature for 2 min. Then, the reaction temperature was gradually increased to about 4 Cy! The mixture was heated to -10° C. for 2 hours, and then stirred at the same temperature for 1 hour and then for 1 hour under ice-cooling. Methylene chloride was distilled off from the reaction solution, and 25% of a 5% aqueous sodium hydrogen carbonate solution was added to the residue.
mL and 30 ml of ethyl acetate is added. Separate the aqueous layer and wash with ethyl acetate. The separated aqueous layer was adjusted to pH 3 with 10% hydrochloric acid under ice cooling, and extracted with ethyl acetate. Separate the ethyl acetate layer, and add 10% of the remaining aqueous layer.
% hydrochloric acid to adjust the pH to ~2, and further extracted several times with ethyl acetate. The ethyl acetate layers obtained above are combined, washed with saturated aqueous sodium chloride solution, and dried over magnesium sulfate. The solvent is distilled off from the ethyl acetate solution, and the resulting residue (330 m9) is powdered with diethyl ether. Washing this powder with acetate gives 130 mg of 3-[2-2-pyridyloxy)acetamio]lactasilanic acid. Mp
192.5-193°C (decomposition). Example 132N,N-
Dimethylformamide 292m9 and thionyl chloride 7
Heat 10 m9 of the mixture at 50° C. for 30 minutes.

Excess thionyl chloride is distilled off from this mixture, and the residue is washed with diethyl ether. 7 ml of methylene chloride is added to this residue, and the mixture is cooled to 0 to 5° C., and a solution of 455 ml of 2-(5,6-dihydro?-pyran-3-yl)glycolic acid dissolved in 5 ml of methylene chloride is added dropwise. Next, triethylamine 600% was added to this reaction solution while cooling at -50°C.
A solution of 5 ml of methylene chloride containing mg of chloride was added dropwise over a period of 1 hour, and the mixture was stirred for three times at the same temperature. This solution was added all at once to a solution prepared by stirring a mixture of 472 mg of 3-aminolactasilanic acid, 1.22 V of bis(trimethylsilyl)acetamide, and 10 mt of methylene chloride at room temperature for 2 hours, and the mixture was further reacted at -50°C for 2 hours. Stir for 2 hours while gradually raising the temperature to 0°C. The solvent is distilled off from the reaction mixture, and an aqueous sodium hydrogen carbonate solution and ethyl acetate are added to the residual liquid. The aqueous layer is separated, 10% hydrochloric acid is added to adjust the pH to ~2, and the mixture is extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, and the solvent was distilled off to obtain 80 m9 of 3-[2-(5,6-dihydro?-pyran-3-yl))glycolamido]lactasilanic acid. Infrared absorption spectrum νCm-1 (nudicol):
1740, 1685, 1660 Example 133 In a solution of 10 ml of methylene chloride containing 216 mg of ethyl chloroformate,
2-(2-bromoacetamido)-2-phenylacetic acid 5
A mixed solution consisting of 76 mg of triethylamine, 200 m9 of triethylamine, 1 drop of N,N-dimethylbenzylamine, and 8 mL of methylene chloride was added dropwise under cooling to -30°C, and the mixture was stirred at the same temperature.

This reaction solution was kept at -30°C, and 472 m9 of 3-amino group lactasilanic acid, bis(trimethylsilyl)
Acetamide 1.2y1 Methylene chloride 10ml and N
, N-dimethylformamide 17rL1 was briefly stirred at room temperature, then the solution cooled to 0°C was added all at once, and the mixture was heated at about -25°C for 2 hours, and the reaction temperature was gradually raised to 0°C for 1 hour. Stir for an hour. The reaction solution was concentrated, ethyl acetate and water were added to the residue, and then PHL~ was added with 10% hydrochloric acid.
Adjust to 2. The ethyl acetate layer is separated, washed with water, dried over magnesium sulfate, and concentrated. The resulting residue was washed with diisopropyl ether and then powdered with ethyl acetate to obtain 400 m9 of 3-[2-(2-bromoacetamide)-2-phenylacetamide]lactasilanic acid. Furthermore, 188 m9 of this product was recovered from the mother liquor. Total yield 5887
! 9. mp 156-161°C (decomposed). The following compound is obtained by treatment in the same manner as above.

Example 141 N-phenyliminodiacetic acid 537 mg, N,N''-cyclohexylcarbodiimide 495 m9, chloroform 9
ml and dioxane 3ml under ice cooling.
? Stir for a while.

After removing insoluble matter from this mixed solution, a mixed solution consisting of 472 mg of 3-aminolactasilanic acid, 10 ml of methylene chloride, and 1.2 y of bis(trimethylsilyl)acetamide was added at once under ice cooling, and the mixture was stirred at room temperature for 4 hours. After distilling off the solvent from the reaction solution, the residue is dissolved in ethyl acetate, and an aqueous sodium hydrogen carbonate solution is added. Add this mixture to 10% hydrochloric acid to pH 4. After reducing the temperature to
-carboxy group methyl-N-phenylglycinamide)
260 mg of lactasilanic acid are obtained. Mpl42.5~1
45°C (decomposition). Example 142 2-[4(3-promopropoxy)phenyl]acetic acid 30
A solution of 0 mg and 30 mg of thiol chloride dissolved in 2 mt of chloroform is heated under reflux for 2 hours.

The solvent and excess thionyl chloride were distilled off from this solution,
Dissolve the residue in 1 Tnt of dry acetone. Add this acetone solution to 240ml of 3-aminolactasilanic acid in advance.
9 and 210 m9 of sodium hydrogen carbonate were dissolved in a mixture of 10 ml of water and 10 mL of acetone.
Add dropwise while stirring while cooling to 5°C, and stir at the same temperature for 4 times. After distilling off the acetone from the reaction solution, 30 ml of ethyl acetate was layered on the remaining aqueous layer, and the pH was adjusted to PHL with 10% hydrochloric acid. After separating the ethyl acetate layer, the aqueous layer is further extracted with ethyl acetate group 207TLt. The ethyl acetate layers were combined, washed with a saturated aqueous solution of sodium chloride, and then dried over magnesium sulfate. The solvent was distilled off from this solution, and 510 mg of the resulting residue was washed with diethyl ether.
420 mg of 2-(4-(3-promopropoxy)phenyl)acetamido]lactasilanic acid are obtained. Mpl2O
~123 Acid C (decomposition). The following compound is obtained by treatment in the same manner as above.

Example 148 472 mg of 3-aminolactasilanic acid, 1.2 y of bis(trimethylsilyl)acetamide, 10 ml of methylene chloride, and 1 ml of N,N-dimethylformamide.
The mixture consisting of m1 is stirred at room temperature for 1 hour.

Next, this solution was cooled to 0 to 5°C, and a solution of 3 ml of methylene chloride containing 548 ml of hexadecanoyl chloride was added dropwise, followed by 1. Allow to react for 30 minutes at room temperature. The reaction solution was concentrated, ethyl acetate and water were added to the residual solution, and the pH was adjusted to 2 with 10% hydrochloric acid. The ethyl acetate layer is separated, washed with water, dried over magnesium sulfate, and concentrated to obtain 0.95 q of crude 3-hexadecanoylaminolactasilanic acid. Further, 60 mg of this product was subjected to column chromatography using silica gel, eluted with ethyl acetate, and ethyl acetate was distilled off from the eluate to obtain 10 m9 of a purified product of this product. Mpl57-161 C (decomposition).
Example 149 2-[N-(2-tenylidene)aminooxy]-12-phenylacetic acid 400 m9, triethylamine 155 TrL
9 and 10 ml of tetrahydrofuran,
A solution of 184 m9 of pivalic acid dissolved in 3 ml of tetrahydrofuran was added dropwise over 5 minutes while cooling to -2 to 0°C, and the mixture was stirred for three times.

This solution was added all at once to a mixture of 320 m9 of 3-aminolactasilanic acid, 825 mg of bis(trimethylsilyl)acetamide, and 10 m1 of methylene chloride while cooling at -30°C, and the reaction temperature was gradually raised to 10°C while adding 2. React for .5A. The solvent is distilled off from the reaction solution, and an aqueous sodium hydrogen carbonate solution and ethyl acetate are added to the remaining solution. The aqueous layer was separated, adjusted to pH1~2 with 10% hydrochloric acid, and extracted with ethyl acetate. After washing the extract with water and drying, the solvent is distilled off to obtain a foamy residue 300TfL9.
After dissolving this residue in acetone and converting sodium 2-ethylhexanoate into sodium salt by a conventional method, 3-
[2-(N-(2-tenylidene)aminooxy)-2-
160 m9 of the sodium salt of phenylacetamide]lactasilanic acid is obtained. Infrared absorption spectrum νC77! -1 (Nuzir): 1730, 1650, 1
600 Example 150 3-Aminolactasilanic acid 355m
g, bis(trimethylsilyl)acetamide 0.92f
Add 0.23 ml of N,N-dimethylformamide to 7 TnL of methylene chloride, and stir at room temperature for 2 hours.

Separately, 380 mg of 2-(2-nitrophenoxy)-2-phenoxyacetic acid, 132 mg of trimethylamine, and 2 drops of N,N-dimethylbenzylamine were dissolved in 101 rL1 of methylene chloride, cooled to -30'C, and chloride added to this solution. Add 141mg of ethyl chloride dropwise at the same temperature
Stir for a while. Immediately add the solution prepared above to this solution and heat at -40 to -20°C for 5. Stir for an hour. The solvent was distilled off from the reaction solution under reduced pressure, and ethyl acetate and an aqueous sodium hydrogen carbonate solution were added to the residue. Separate the aqueous layer and
The pH was adjusted to ~2 with 0% hydrochloric acid, and then extracted with ethyl acetate. The extract is washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, and then the solvent is distilled off. After dissolving 540 m9 of the obtained residue in a small amount of acetone, sodium 2-ethylhexanoate was added thereto and converted to a sodium salt by a conventional method. Diethyl ether is added to this solution, and the crystals precipitated in the solution are collected and washed with a mixed solvent of diethyl ether and acetone to produce 3-[2-(2-nitrophenoxy)-2-phenoxyacetoade]lactasilane. 380 mg of the sodium salt of the acid are obtained. Mpl69~172'C (
Disassembly). The following compound is obtained by treatment in the same manner as above.

Example 175 2-[4-(3-(4-nitrophenylthio)propoxy)phenyl]acetic acid 260 mg and thionyl chloride 300 mg dissolved in chloroform 10 ml, 2
Heat to reflux for an hour.

Chloroform and excess thionyl chloride are distilled off from the reaction solution under reduced pressure, and the residue is dissolved in 1 ml of acetone. This acetone solution was added dropwise to a solution consisting of 180 m9 of 3-aminolactasilanic acid, 160 m9 of sodium hydrogen carbonate, 5 ml of water, and 5 ml of acetone while cooling to 0 to 5°C, and the mixture was stirred at the same temperature. Acetone was distilled off from the reaction solution under reduced pressure, and 40 mt of ethyl acetate was added to the remaining solution, and then 10%
Adjust to PHL with hydrochloric acid. The ethyl acetate layer is separated, and the remaining aqueous layer is further extracted with 20 ml of ethyl acetate. The ethyl acetate layer is combined, washed with an aqueous sodium chloride solution, and then dried over magnesium sulfate. The solvent was distilled off from the ethyl acetate solution to obtain 400 mg of 3-[2-[4-(3-(4-nitrophenylthio)propoxy)phenyl]acetamido]lactasilanic acid. Mpl42~146taC
(Disassembly). Example 176 2-[2-(2naphthoxy)acetamidoxy]-
2-phenylacetic acid 351m9 and triethylamine 1
110 ml of dry tetrahydrofuran containing 0.01 mg -
The mixture was cooled to 10'C, and a solution of 5 ml of dry tetrahydrofuran containing 20 ml of pivalic acid chloride was added dropwise, followed by stirring at the same temperature for 1 hour.

The solution was cooled to -30'C, and a solution of 236 m9 of 3-aminolactasilanic acid and 600 m9 of bis(trimethylsilyl)acetamide in 5 ml of dry methylene chloride was added at once at -10'C for 1 hour and at 0°C for 1 hour. Stir for an hour. The solvent was distilled off from the reaction solution under reduced pressure, and a saturated aqueous solution of sodium hydrogen carbonate was added to the residue. After washing this aqueous solution with ethyl acetate, the pH was adjusted to ~2 with 10% hydrochloric acid,
Extract with ethyl acetate. The extract is washed with water and a saturated aqueous solution of sodium chloride, and then dried over magnesium sulfate. The solvent is distilled off from the ethyl acetate solution, and the resulting residue is powdered with diethyl ether to obtain 340 m9 of 3-[2-(2-(2-naphthoxy)acetamidooxy)-2-phenylacetamido]lactasilanic acid. MplO
9-112 solutions). Example 177 2-[2-oxy-3-(2-phenylacetamide)
-1-Azetidinyl)-3-methylbutanoic acid 455m9
, 151 m9 of triethylamine and 2 drops of N,N-dimethylbenzylamine were added to 10 mL of methylene chloride, -
Cooled to 30°C, 577 methylene chloride containing 163 m9 of ethyl chloroformate! Add the solution dropwise.

This solution was cooled to -40°C, and 389 mg of 3-aminolactasilanic acid, 1.0 y of bis(trimethylsilyl)acetamide and 0.25 ml of N,N-dimethylformamide were added in advance to 10 ml of methylene chloride, and the mixture was heated at room temperature. The solution stirred for 3 hours is added all at once and stirred for 1.5 hours to react. The solvent is distilled off from the reaction solution, ethyl acetate and an aqueous sodium hydrogen carbonate solution are added to the residue, and the aqueous layer is separated. The aqueous layer was adjusted to pH1~2 with 1N monohydrochloric acid, and then extracted with ethyl acetate. The ethyl acetate layer is separated, and the remaining aqueous layer is further extracted with ethyl acetate. The extracts are combined, washed with a saturated aqueous solution of methylene chloride, and then dried over magnesium sulfate. The solvent was distilled off from the ethyl acetate solution, and 480 m9 of the resulting powder was washed with diethyl ether to give 3
-[2-oxy-3-(2-phenylacetamide)-
1-Azetidinyl)-3-methylbutanamide]lactasilanic acid 359TrL9 is obtained.゛Mpl6O~164
TaC (decomposition). The following compound is obtained by treatment in the same manner as above. Example 1882-Methyl-5,6-dihydro 1
, 0.320y of 4-oxathiine-3-carboxylic acid is dissolved in 10mt of chloroform.

To the solution was added 5 ml of a dry methylene chloride solution containing 7 ml of thionyl chloride, and the mixture was heated under reflux for 4 hours. This solution is concentrated to prepare the acid chloride of the above carboxylic acid. on the other hand,
0.236y of 3-aminolactasilanic acid is suspended in 20ml of dry methylene chloride. 1.50 y of bis(trimethylsilyl)acetamide is added to this suspension, and the mixture is stirred at room temperature for 4 hours to dissolve. The solution prepared above was added dropwise to this solution while cooling at 0 to 5°C, and the mixture was stirred at the same temperature for 2 hours and then at room temperature for 5 hours. The reaction solution is concentrated under reduced pressure, and ethyl acetate and an aqueous sodium hydrogen carbonate solution are added to the residue.
After stirring this mixture thoroughly, the aqueous layer is separated. After washing the aqueous layer with diethyl ether, the pH was adjusted to ~2 with dilute hydrochloric acid, and extracted with ethyl acetate. The extract is washed with water and dried over magnesium sulfate. The solvent is distilled off from this solution and the powder is separated. After adding 5 ml of hot ethyl acetate to this powder, what about the insoluble matter? When taken, 3-(2-methyl-5,6-dihydro 1
, 240 mg of 4-oxathiine-3-carbonylamino)lactasilanic acid are obtained. Recrystallizing this product from acetone yields 172 mg of purified product. Mpl72.5~
175.0'C (decomposition). Example 189 0.708y of 3-aminolactasilanic acid was dried in 20ml of methylene chloride.
C. Suspend.

Add bis(trimethylsilyl)acetamide 2 to this suspension.
．． Add 0y and dissolve. On the other hand, N-[4-(3-benzyloxycarbonyl-5-oxo-1,3-oxazolidin-4-yl)butyryl]succinimide 1.21
2 Da is dissolved in 15 ml of dioxane and cooled to 0~51C. The solution obtained above was added dropwise to this solution, and at the same temperature
Stir for an hour. The reaction solution is concentrated under reduced pressure, and a 5% aqueous sodium hydrogen carbonate solution and ethyl acetate are added to the residue. The aqueous layer is separated and washed twice with ethyl acetate. The aqueous solution was adjusted to pH1~2 with dilute hydrochloric acid and extracted with ethyl acetate. The extract is washed with water and dried over magnesium sulfate. The solvent was distilled off from the solution, and 0.470y of the obtained substance was transferred to silica gel 1.
Subjected to column chromatography using 0 da. Elute with a mixture of ethyl acetate and methanol (volume ratio 50:1), and collect fractions containing the target compound. When these fractions were combined and the solvent was distilled off, 3-[4-(3-benzyloxycarbonyl-5-oxo-1,3-oxazolidine-4-
0.100q of butanamide]lactasilanic acid is obtained. Infrared absorption spectrum νo-1 (nujiol): 1730, 1720, 170
0 to 1680,1650 Example 190 472 mg of 3-aminolactasilanic acid, 4588 m9 of 2-(2-propionylphenoxy)acetic acid and 238 mg of ethyl chloroformate were treated in the same manner as in Example 109 to obtain 3
-40 m9 of [2-(2-propionylphenoxy)acetamide]lactasilanic acid are obtained.

Mpll 4-118°C (decomposition). Example 191 3-aminolactasilanic acid 0.236y12-[4-(
4-chloroN-(2,2,2-trifluoroethoxycarbonyl)anilinoamino)phenoxy]-2-methylpropionic acid 0.610q and thionyl chloride 7
m1 was treated in the same manner as in Example 120 to obtain 3-[2-[4-
450 mg of (4-clo N-(2,2,2-trichloroethoxycarbonyl)anilinomethyl)phenoxy)-2-methylpropionamido)lactasilanic acid are obtained.

Mp 76-82°C (decomposed). Example 192 After suspending 944 m9 of 3-aminolactasilanic acid in 30 TrL1 of dry methylene chloride, 3.50 q of bis(trimethylsilyl)acetamide and 0.2 ml of N,N-dimethylformamide were added, and the mixture was stirred at room temperature for 4 and a half hours. .

Add triethylamine 404 to this solution under cooling at -101C.
After adding mg phenylglyoxyloyl chloride 67
10 ml of dry methylene chloride containing 2 mg was added dropwise over 20 minutes, and the mixture was stirred at the same temperature for 2 and a half hours. The reaction solution was washed with dilute hydrochloric acid and water and dried over magnesium sulfate. The solvent is distilled off from this solution under reduced pressure to obtain an oily residue.1.
57y was subjected to column chromatography using silica gel. Elute with ethyl acetate and collect fractions containing the target product. These fractions were combined, the solvent was distilled off under reduced pressure, and the resulting residue was powdered with ethyl acetate to obtain 404 mg of 3-phenylglyoxyloylaminolactasilanic acid.
Mpl9O. 5-197C (decomposition). The compounds shown in the following table are obtained by treatment in the same manner as in Example 192. Example 196 Vilsmeier reagent is prepared from 292 mg of N,N-dimethylformamide and 710 mg of thionyl chloride by a conventional method.

After adding 10 ml of methylene chloride to this reagent, 34% of 2-(2-furyl)glycolic acid was cooled to -50°C in a nitrogen stream.
A solution of 1 mg and 500 ml of triethylamine dissolved in 10 ml of methylene chloride was added dropwise over 10 minutes.
Stir one powder at the same temperature. Add 3-
472m9 of aminolactasilanic acid, 1.2y of bis(trimethylsilyl)acetamide and 10m of methylene chloride
Add a solution of slightly stirred mixture consisting of 1 at once to -50
Stir at ~-30°C for 2 hours and then at -30~0°C for 1.5 hours. Methylene chloride was distilled off from the reaction solution under reduced pressure, and ethyl acetate and an aqueous sodium hydrogen carbonate solution were added to the residue, followed by stirring for three times. Remove the insoluble matter and separate the aqueous layer from the liquor. The aqueous layer was adjusted to pH1~2 with 10% hydrochloric acid, and 30 ml of ethyl acetate and a small amount of sodium ethyl chloride were added and stirred. The ethyl acetate layer is separated, washed with water, and then dried over magnesium sulfate. The solvent is distilled off from this solution under reduced pressure to obtain 35 m9 of 3-[2-(2-furyl)glycolamido]lactasilanic acid. This target product is dissolved in a small amount of acetone, sodium hexanoate is added, and the solution is treated in a conventional manner to obtain the sodium salt of the target product. Infrared absorption spectrum Example 197 2-(2-azidoacetamido)-2-(2-thienyl)acetic acid 0.53V1 Triethylamine 0.221 da,N
, 0.238y of ethyl chloroformate in a solution consisting of 1 drop of N-dimethylbenzylamine and 10ml of methylene chloride.
5 mt of methylene chloride containing the above was added dropwise at -30°C, and the mixture was stirred at the same temperature.

Add 0.0% of 3-aminolactasilanic acid to this solution in advance.
472V and 1.22y of bis(trimethylsilyl)acetamide were added to 10Tnt of methylene chloride, and the slightly stirred solution was added all at once at -40°C and stirred at the same temperature for 3 hours. Methylene chloride is distilled off from the reaction solution under reduced pressure, and a saturated aqueous sodium bicarbonate solution is added to the residue, which is then washed with diethyl ether. This aqueous solution was adjusted to PHL with 10 ml of hydrochloric acid under ice-water cooling, and extracted with ethyl acetate. The extract is washed with water and dried with magnesium sulfate. The solvent was distilled off from this solution, and the residue was powdered with diisopropyl ether and collected to give 3-[2-(2-azidoacetamide)]
550 m9 of -2-(2-thienyl)acetamide]lactasilanic acid are obtained. Further, 100 m9 of the target product was recovered from the mother liquor. Total yield 650m9, Mpl2O ~ 125℃ (
Disassembly). Example 1982-benzyloxyimino 2-
(4-methoxyphenyl)acetic acid 695m9 and N,N
``495 ml of dicyclohexylcarbodiimide was added to a solution consisting of 6 ml of chloroform and 4 ml of dioxane, stirred for 1 hour under ice cooling, and then filtered.

Add 3-aminolactasilanic acid 472 to the lacquer solution in advance.
m9 and bis(trimethylsilyl)acetamide 1.
A solution of 22q dissolved in 10 mt of chloroform was added dropwise with stirring under ice cooling, and the mixture was stirred at the same temperature for 2.5 hours. The solvent was distilled off from the reaction solution under reduced pressure, and a saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added to the residue, followed by stirring for a while.
The aqueous layer was separated, adjusted to pH 2 with 10% hydrochloric acid under ice cooling, and then extracted with ethyl acetate. After washing the extract with water and drying over magnesium sulfate, the solvent was distilled off under reduced pressure. The resulting residue was subjected to column chromatography using silica gel, and a mixture of chloroform and methanol (volume ratio,
99:1). Fractions containing the desired product were collected and the solvent was distilled off under reduced pressure to obtain 20 m9 of 3-[2-benzyloxyimino-2-(4-methoxyphenyl)acetamide]lactasilanic acid. Mpl38-148 solution). The compounds shown in the following table are obtained by treatment in the same manner as in Example 13.

Example 203 1-(1-methoxycarbonyl-2-methyl-1-propenyl)-3-(2-phenoxyacetamide)-2-
Dissolve 1.0y of azetidinone in 40ml of methylene chloride.

0.55f of N,N-dimethylaniline was added to this solution, and after cooling to -35 to -30°C, 0.5f of phosphorus pentachloride was added to the solution with stirring.
Add 94y at once. After stirring the reaction solution for 13 minutes at the same temperature, 0.9y of methanol was added, and the mixture was further stirred at the same temperature for 1 hour.
Stir for an hour. Next, the reaction temperature was raised to 05°C, and water was added to 0.
．． Add 6ml and stir for 1 hour. Dilute the reaction mixture with water 3
Extract twice (total volume: 10 mL), combine the aqueous extract layers, adjust the pH to around 7 with sodium bicarbonate, and wash once with 10 ml of ethyl acetate and once with 5 ml of ethyl acetate. The aqueous layer is then salted out with sodium chloride and extracted seven times with 8 ml portions of chloroform.

The chloroform extracts were combined, dried over magnesium sulfate, and the solvent was distilled off to obtain 0.34y of 3-amino-1-(1-methoxycarbonyl-2-methyl-1-propenyl)-2-azetidinone. Take some of this,
When p-toluenesulfonate is derived using ethyl acetate as a solvent according to a conventional method, p-
Toluenesulfonate is obtained. Example 204 1-(1-carboxy2-methylpropyl)-3-(
2-phenylacetamido)-2-azetidinone 1.5
2y and 2.15y of N,N-dimethylaniline were suspended in 12ml of methylene chloride, and 0.8ml of trimethylsilane chloride was added.
Add 8q and dissolve.

This solution was stirred at room temperature for 3 minutes, then cooled to -50°C, 1.1y of phosphorus pentachloride was added, and stirred for 2 hours (during which time the reaction temperature rose to about -30°C). It was further cooled to -50°C, 1.85q of n-butyl alcohol was added, and stirred for 2 hours (during which time the reaction temperature rose to about -30'C).
After cooling to -50°C again, sodium hydrogen carbonate 1.
A solution of 3q dissolved in 15 mL of water is added (the temperature of the reaction solution rises to about -25°C and the pH becomes about 3). Further, sodium bicarbonate was added to adjust the pH to around 4, and then the aqueous layer was separated, washed with diethyl ether, and then dried under reduced pressure while keeping the temperature below 25°C. 15Tf1.1 of isopropyl alcohol is added to the residue to remove the insoluble portion, and the isopropyl alcohol solution is dried under reduced pressure. By repeating this operation twice, 0.3y of 3-amino(1-carboxy-2-methylpropyl)-2azetidinone is obtained as a colorless powder. The above isopropyl alcohol-insoluble parts were combined and dissolved in a small amount of water, and the pH was adjusted to 2.5 with IN hydrochloric acid.
The desired product is obtained by drying under reduced pressure at temperatures below ℃ and treating the resulting residue with isopropyl alcohol in the same manner as above.
Collect 3y. Total yield: 0.43y0 This was converted into D-camphor 10-sulfonate according to a conventional method, and recrystallized from an acetone-ether mixture to obtain the D-camphor 10-sulfonate of this product. Mpl78~18JC (
Disassembly). Example 205 7.2 of 3-[2-(4-3-benzamido-3-carboxypropoxy)phenyl)-2-(3-phenylthioureido)acetamide]lactasilanic acid was dissolved in 20 m of acetic acid.
2 ml of concentrated hydrochloric acid was added dropwise while cooling and stirring.

After stirring the reaction solution for 1.5 hours, it was poured into a mixture of 50 ml of ice water and 50 ml of ethyl acetate. The ethyl acetate layer was separated and extracted with 20 ml of ice water. This aqueous layer and the above water layer were combined and backwashed with 20 ml of ethyl acetate. Add 60 ml of mold) (trademark, manufactured by Rohm & Haas) and stir under ice cooling. Remove the resin from the water layer and add approximately 10ml of ice water.
After washing with water, the washings are combined and concentrated under reduced pressure. Methanol is added to the precipitated solid residue, which is then washed with acetone to obtain 0.59y of 3-aminolactasilanic acid. Mp2O3-206°C (decomposed). Infrared absorption spectrum νG-1 (nujiol): 1763, 1742 Nuclear magnetic resonance absorption spectrum l◆LIOV'J'
909Jυ51b Example 206 3-(2-Phenylacetamido)lactasilanic acid is treated in the same manner as in Example 204 to obtain 3-aminolactasilanic acid.

This product was confirmed to be a 3-amino acid because the absorption in the infrared absorption spectrum and the absorption in the nuclear magnetic resonance absorption spectrum matched those of the specimen obtained in Example 205, and as a result of the mixed melting point measurement, no decrease in the melting point was observed. It was identified as lactasilanic acid. Example 207 3-[2-[4-(3-(3-phenylthioureido)
-3-carboxypropoxy)phenyl]-2-(3-
1.44 y of phenylthioureido)acetamide]lactasilanic acid was suspended in 10 ml of water, and 0.0 ml of anhydrous potassium carbonate was added.
．． Add 56y and dissolve (pH will be approximately 9).

This solution was heated to 2'nl at 30°C. After stirring for a while, the mixture was filtered, diluted with 50 ml of ethanol, and left to cool on ice to form a precipitate. After removing the precipitate, the Oki liquid is concentrated under reduced pressure and ethanol is distilled off. The residue was adjusted to pH 2 by adding 5% hydrochloric acid, washed with ethyl acetate, adjusted to pH 7.5 with sodium carbonate, and then the aqueous layer was dried under reduced pressure to obtain a powder of 0.75'. Add 7ml of water to this powder.
was added, and the insoluble portion was taken off and washed with water to obtain 40 m9 of 3-aminolactasilanic acid. Also, combine Oki washing liquid and activate carbon 3
After injecting into a column packed with 0 mt and adsorbing it, 123 m9 of 3-aminolactasilanic acid was recovered. These target compounds were combined, suspended in 30% aqueous methanol, stirred for 1 hour, and then collected to obtain 133 mg of purified crystals of 3-aminolactasilanic acid. This product was identified as the standard product based on its infrared absorption spectrum, nuclear magnetic resonance absorption spectrum, and melting point. Example 208 3-[2-[4-(3-(3-phenylthioureido)
-3-carboxypropoxy)phenyl]-2-(3-
Dissolve 0.36q of phenylthioureido)acetamide]lactasilanic acid in 3ml of menol, and add 0.0ml of concentrated hydrochloric acid under ice cooling.
．． Add 1 ml and stir for 30 minutes.

After adding 0.08y of sodium hydrogen carbonate to the reaction solution and stirring once, 10ml of ice water was added to the reaction solution to remove the precipitated crystals. Next, the aqueous layer of the bottom liquid was washed with 10 ml of ethyl acetate, dried under reduced pressure, and methanol was added to the residue to crystallize it.
Obtain 0m9. Concentrate this mother liquor and collect 80ml of this product. This product was identified as the standard product based on its infrared absorption spectrum, nuclear magnetic resonance absorption spectrum, and melting point. Example 20
9 3-[2-[4-(3-(3-phenylthioureido)
-3-carboxypropoxy)phenyl]-2-(3-
0.50 f of phenylthioureido)acetamide]lactasilanic acid is dissolved in 4 mt of 2,2,2-trifluoroacetic acid and stirred for 1 hour under ice cooling.

The reaction solution was poured into approximately 10 ml of ice water, washed twice with 1 nL of ethyl acetate, and then washed with a weakly basic anion exchange resin, Amperlite IR-45 (0H type) (trademark, Rohm and Haas) under ice cooling. The pH was adjusted to 4 by adding 9.5 ml of the solution (manufactured by Kawasaki, Ltd.), the resin was removed, and the water was distilled off under reduced pressure. Methanol is added to the residue to crystallize it, and the residue is filtered to obtain 30 m9 of 3-aminolactasilanic acid. This product was identified as the standard product based on its infrared absorption spectrum. Example 210 0.67 g of 3-[2-[4-(3-acetamido-3-carboxypropoxy)phenyl)-2-(3-phenylthioureido)acetamido]lactasilanic acid was dissolved in 6.7 ml of acetic acid and cooled on ice. Under stirring, concentrated hydrochloric acid 0.15
Add mt all at once and stir for 1 hour.

When the reaction solution was treated in the same manner as in Example 209,
90 mg of 3-aminolactasilanic acid are obtained. This product was identified as the standard product based on its infrared absorption spectrum and nuclear magnetic resonance absorption spectrum. 7 Example 2113-[2-[4-(3
- Carboxy 3-(N-ethoxythiocarbonylamino)propoxy)phenyl)-2-(N-ethoxythiocarbonylamino)acetamide]lactasilanic acid is treated in the same manner as in Example 7210 to obtain 3-aminolactasilanic acid. Example 212 3-[2-[4-(3-(3-phenylthioureido)
-3-carboxypropoxy)pheni
Dissolve 2.28y of [10J]-2-(3-phenylthioureido)acetamido]lactasilanic acid in 6mt of acetic acid, add 1 powder of a solution of 0.45ml of concentrated hydrochloric acid in 6ml of acetic acid under stirring under water cooling, and then add acetic acid. Add 25 mt of ethyl and 25 ml of water, shake, separate the ethyl acetate layer, extract the ethyl acetate layer with 10 ml of water, combine with the previous water layer, backwash once with ethyl acetate, and then exchange with weakly basic anion. resin,
Amperlite IR-45 (0H type) (trademark, ROHM
Add 15ml of (manufactured by And Haas) and adjust the pH to 3.4.

After removing the resin, the water is distilled off under reduced pressure, and methanol is added to the resulting residue to crystallize it. When the residue is removed, 0.25% of 3-aminolactasilanic acid is obtained. This product was identified as the standard product based on its infrared absorption spectrum and nuclear magnetic resonance absorption spectrum. Example 2133-[2-(4-(3-benzamido-3-carboxypropoxy)phenyl)-2-(2
-Nitro-4-methoxycarbonylanilino)acetamide] After dissolving 1.4y of lactasilanic acid in a mixed solvent of 10ml of water and 20ml of methanol,
Add 500 m9 of 0% palladium and carbon, and shake under pressure at room temperature for 2 hours in a hydrogen atmosphere using a medium pressure reduction apparatus.

After the reaction is completed, the catalyst is removed and methanol is distilled off from the bottom liquid under reduced pressure. The residual liquid was washed with ethyl acetate and then cooled.
When acetone is added and the precipitated crystals are collected in a furnace, 83 m9 of 3-aminolactasilanic acid is obtained. Further, the mother liquor was dried under reduced pressure, the residue was washed with methanol, and the crystals were filtered off to obtain 50 m9 of this product. Total yield 123m9. This product is
It was identified as the standard product based on infrared absorption spectrum and nuclear magnetic resonance absorption spectrum. Example 214 3-[2-[4-(3-(2-nitro-4-methoxycarbonylanilino)-3-carboxypropoxy)phenyl]-2-(2-nitro-4-methoxycarbonylanilino)acetamide]lactasilane Example 213
3-aminolactasilanic acid is obtained by treatment in the same manner as above.

Example 215 3-[2-[4-(3-acetamido-3-carboxypropoxy)phenyl)-2-(3-(1-naphthyl)
thiourido)acetamide]lactasilanic acid 2.5y
was dissolved in 10ml of acetic acid, and added with concentrated hydrochloric acid while stirring under water cooling.
．． Add 56ml and stir for 3C@.

The reaction solution was poured into a mixture of 10 ml of ice water and 20 ml of ethyl acetate, the aqueous layer was separated, and the ethyl acetate layer was poured into a mixture of 10 ml of ice water and 20 ml of ethyl acetate.
Extract with 0ml. Combine the aqueous layers and add 10ml of ethyl acetate.
After washing with water, add 15 ml of a weakly basic anion exchange resin, Amperlite IR-45 (0H type) (trademark, manufactured by Rohm and Haas) under ice-cooling, and stir for 5 minutes (liquid pH 3.4). ). The ion exchange resin was filtered off from the reaction solution, and further washed with 5 ml of ice water. The washings were combined and concentrated, the residue was washed with methanol, and the crystals were collected to obtain 149 mg of 3-aminolactasilanic acid. Further, the mother liquor is concentrated, and the residue is washed with methanol to recover 80 mg of this product. Total yield 229mg, this product is
It was identified as the standard product based on infrared absorption spectrum and nuclear magnetic resonance absorption spectrum. Example 216 3-[2-[4-(3-carboxy 3-(3-(1-
naphthyl)thioureido)propoxy]phenyl]-2
2.6y of -(3-(1-naphthyl)thioureido)acetamido)lactasilanic acid was reacted and post-treated in the same manner as in Example 215 to yield 190m of 3-aminolactasilanic acid.
get g.

This product was identified as the standard product based on its infrared absorption spectrum and melting point. Example 217 770 m9 of 3-benzyloxycarbonylamino-2-azetidinone and 250 m9 of acetic acid were added to 70 m9 of ethanol.
Dissolve in 1.

Add 350 m9 of 10% palladium carbon to this solution as a catalyst.
was added, and catalytic reduction was carried out in a hydrogen stream to absorb 82 ml of hydrogen gas. The catalyst is removed from the reaction solution and washed with ethanol. This washing solution was combined with the solution obtained above and concentrated to dryness under reduced pressure. 490 mg of the resulting residue was washed with diethyl ether and then dissolved in 60 ml of ethyl acetate while hot. Next, the solution was concentrated until the total volume was 3 mt, and the precipitated crystals were collected to obtain 286 m9 of 3-amino-2-azetidinone acetate. Mpl3O~131
．． 5°C (decomposition). Example 218 816 mg of 3-(2-phenylacetamido)-2-azetidinone and 1.22' of benzyl 2-bromo-2-phenylacetate were dissolved in 20 ml of N,N-dimethylformamide.
210 m9 of sodium hydride (50% oil base) was added to the mixture under ice-water cooling and stirring in a nitrogen atmosphere, and the mixture was stirred at the same temperature for 1 hour.

After adding 150 ml of ethyl acetate to the reaction solution, the mixture was washed with water, successively washed with a saturated aqueous sodium bicarbonate solution and then with water, dried over magnesium sulfate, and then evaporated to dryness under reduced pressure to obtain 1.7y of a yellow oil. This oil was purified using column chromatography using silica gel (developing solvent: chloroform).
26 mg and 65 mg of two isomers of 1-(α-benzyloxycarbonylbenzyl)-3-(2-phenylacetamido)-2-azetidinone are obtained. Isomer oil mass spectrometry: m/e = 428 (M infrared absorption spectrum
hno7 Av●ν Nuclear magnetic resonance absorption spectrum Isomer mass spectrometry: m/e=428 (M+) Infrared absorption spectrum Nuclear magnetic resonance absorption spectrum The following compound was obtained by treatment in the same manner as above.

Example 229 3-(2-
(Phenylacetamido)-2-azethione 610m9
, 900 m9 of methyl 2-(3-nitrophenyl)acetate and 460 m9 of anhydrous potassium carbonate were added,
Heat to reflux for 8 hours while stirring.

After cooling the reaction mixture, it was poured into ice water, extracted with ethyl acetate, washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, and the solvent was dried under reduced pressure. The resulting oily residue was column chromatographed using silica gel. Attach to fee. The fraction obtained by elution with a mixed solvent of chloroform and methanol (100:1) was further fractionated by thin layer chromatography using silica gel (developing solvent: a mixed solvent of chloroform and methanol (40:1)). (α−
methoxycarbonyl-3-nitrobenzyl)-3-2-
7.5 m9 of a mixture of two isomers of phenylacetamido-2-azetidinone are obtained. Infrared absorption spectrum νCrft-1 (CHCl3): 1765, 1745,
1680 Example 230 3-(2-phenylacetamido)-2-azetidinone 612m9 and 2-bromo2
-(4-methylthiophenyl)methyl acetate 825 immediately N
Dissolve in 20ml of 9N-dimethylformamide.

N9N-bis(trimethylsilyl)aminosodium 546T! while stirring and maintaining this solution at 20-30°C in a nitrogen atmosphere. A solution of Lg in 20 ml of benzene was added dropwise over a period of 1 hour, and the mixture was further stirred at the same temperature. 150 ml of ethyl acetate was added to the reaction solution, which was washed successively with water, a saturated aqueous sodium bicarbonate solution, and then water, dried over magnesium sulfate, and the solvent was distilled off to obtain 1.2 ml of oily residue. When this residue was subjected to column chromatography using silica gel (developing solvent: chloroform), 1-(α-
methoxycarbonyl-4-methylthiobenzyl)-3-
(2-phenylacetamido)-2-azetidinone 2
Species isomer a) 10Tn9 (Mpl5-11TC (decomposition)) and mouth) 443.5m9, (Mpl57-15
9°C (decomposition)). Example 23 408 mg of 3-(2-phenylacetamido)-2-azetidinone and 152 mg of chloroacetonitrile were dissolved in 15 ml of N,N-dimethylformamide. While stirring at room temperature, add 105 mg of sodium hydride (50% oil base) and add 1.
Stir at room temperature for an hour.

After adding 100 ml of ethyl acetate, washing with water and drying over magnesium sulfate, the solvent was distilled off under reduced pressure. 0.25 q of the resulting oily residue is subjected to column chromatography using silica gel. 1 from the fraction eluted with chloroform
-Cyanomethyl-3-(2-phenylacetamide)-
56.3 m9 of 2-azetidinone are obtained. RllplO8
~109°C (decomposed). Example 232 154 m9 of 3-(2-phenoxyacetamido)-2-azetidinone was added to N. N-dimethylformamide 1.75
Thallium ethoxide 174.6TL9 dissolved in mL
Add 1 powder at a time and stir at room temperature, then add 2 to this mixture.
A solution of 232 m9 of ethyl bromo-2-(4-ethoxycarbonyloxy)phenylacetate dissolved in 0.6 m1 of N,N-dimethylformamide was added dropwise, and the mixture was stirred at room temperature for 2 hours.

Insoluble matter) is filtered from the reaction mixture, and the filtered residue is washed with ethyl acetate. Combined with the furnace washing solution, diluted with ethyl acetate, washed with water, dried over magnesium sulfate, concentrated under reduced pressure, and the resulting yellow oily residue was subjected to column chromatography using silica gel. From the fraction obtained by elution with benzene, oily 1-(α-ethoxycarbonyl-4-ethoxycarbonyloxybenzyl)-3-(2-
phenoxyacetamido)-2-azetidinone is obtained.
Infrared absorption spectrum ν-1 (liquid film): 1760, 1740 (shoulder), 167
5 Example 233 63 m9 of 1-(α-benzyloxycarbonylbenzyl)-3-(2-phenylacetamido)azetidinone isomer) obtained in Example 218 was dissolved in 12 ml of isopropyl alcohol, and 10 m9 of 10% palladium on carbon was added. The reaction is carried out at room temperature and normal pressure in a hydrogen stream until the absorption of hydrogen gas is completed, and after the catalyst is removed from the reaction solution, the solvent is distilled off from the solution, and diethyl ether is added to the resulting residue to crystallize it. , 1-(α-carboxybenzyl)-3-(2-phenylacetamide)-2-
27m9 of azetidinone is obtained.

Recrystallization from a mixed solvent of methanol and diethyl ether yields a purified product with an Mpl of 74-175°C (decomposition). Example 234 1-benzyloxycarbonylmethyl-3-(2-phenylacetamido)-2-azetidinone Example 233
1-carboxymethyl-3-(2-phenylacetamido)-2-azetidinone is obtained in the same manner as above.

Mpl44-145-C Example 235 750 m9 of 3-(2-phenylacetamido)-2-azetidinone and 1.51 g of benzyl 2-bromo 2-(4-benzyloxy)phenylacetate were added to 101 nt of anhydrous N,N-dimethylformamide, Heat and stir briefly to dissolve.

After cooling this solution on ice, 178 m9 of sodium hydride (5% oil) was added at once while stirring. After leaving the cooling bath and stirring for an additional 30 minutes, ethyl acetate was added to remove insoluble matter. The Oki liquid is washed successively with water, 2% hydrochloric acid, and then water, dried over magnesium sulfate, and concentrated under reduced pressure to obtain 1.98 q of an oil. Add this to silica gel (40
Subject to column chromatography using q). benzene. The fraction obtained by elution with a mixed solvent of chloroform was subjected to thin layer chromatography using silica gel, and further fractionated by extension using a mixed solvent of chloroform and acetone. 4-benzyloxybenzyl)-3-(2-phenylacetamide)
- Two isomers of 2-azetidinone a) Mpl29-1
30zeC (decomposition) (recrystallized from chloroform/ether mixture) yield 90 mg) and oil (yield 120 m
g) is obtained. Dissolve 90 mg of the isomer a) obtained above in 7 ml of methanol, add 30 ml of 10% palladium on carbon, and carry out the reaction in a hydrogen stream at room temperature and pressure until absorption of hydrogen gas is completed. and concentrate the p solution under reduced pressure.

The resulting residue was crystallized from a mixed solvent of ethyl acetate and diethyl ether and separated. The infrared absorption spectrum and nuclear magnetic resonance spectrum of this product matched those of a specimen synthesized separately from 3-aminolactasilanic acid, and furthermore, no drop in melting point was observed in the measurement of the mixed melting point with the specimen. It was identified as -(2-phenylacetamido)lactasilanic acid. Example 236 300 m9 of 3-(2-phenylacetamido)-2-azetidinone and 604 mg of benzyl 2-bromo 2-(4-benzyloxyphenyl)acetate are dissolved in 4 ml of anhydrous N,N-dimethylformamide by heating.

After cooling this solution on ice, sodium hydride (50% oil) 71Tn9 was added all at once while stirring, and after stirring for a while, the cooling was removed and the solution was further stirred for three times. Ethyl acetate is added to the reaction mixture to remove insoluble materials, and the filtrate is washed successively with water, 2% hydrochloric acid, and then water, dried over magnesium sulfate, and concentrated under reduced pressure. 727 m9 of the resulting oily residue was subjected to column chromatography using silica gel (15y),
Elution with benzene-chloroform gives 255 mg of an oil. Dissolve 200 m9 of this in 14 m1 of methanol, add 60 m9 of 10% palladium and carbon, and carry out the reaction in a hydrogen stream at room temperature and pressure until the absorption of hydrogen gas is completed.The catalyst is removed from the reaction solution. Concentrate the liquid under reduced pressure.
A mixed solvent of ethyl acetate and diethyl ether is added to the resulting residue for crystallization to obtain 3-(2-phenylacetamido)lactasilanic acid. Infrared absorption spectrum νCm'-1 (nujiol): 1745, 1690, 1
650 Treat as above to obtain the following compound.

Example 251 157 m9 of crude product obtained by reacting and post-treating 3-(2-phenoxyacetamido)-2-azetidinone and 2-bromo 2-(4-ethoxycarbonyloxyphenyl)ethyl acetate in the same manner as in Example 232 Without separation and purification, dissolve in 3 ml of ethanol, add 1.0 ml of 1N sodium hydroxide solution while stirring under ice-cooling, remove the cooling bath, and stir for three more times.

The reaction solution was concentrated under reduced pressure, and the resulting residue was dissolved in water and washed with ethyl acetate. PHL the aqueous layer with 1N hydrochloric acid.
After adjusting to ~2, extract with ethyl acetate. The ethyl acetate extract was washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was washed with diethyl ether to obtain crude 3-(2-
phenoxyacetamido)lactasilanic acid is obtained. Infrared absorption spectrum νCm-1 (nujiol): 1745, 1690, 16
3-acylamino-2-a corresponding to 601
Treat zetidinone as above
The following compound is obtained.

Compound (■) in the following table is treated in the same manner as in Example 236 to obtain compound (■4) in the following table. The compound (■) in the following table is treated in the same manner as in Example 251 to obtain the compound (1'') shown in the following table.

Example 299 3-[2-(2-oxo3-(2-phenylacetamide)1-azetidinyl)-3-methylbutanamide]
-2-azetidinone and 2-bromo-2-(4-benzyloxyphenyl)benzyl acetate were treated in the same manner as in Example 236 to obtain 3-[2-(2-oxo-3-(2-phenylacetamido)-1-azetidinyl) )-3-methylbutanamide]lactasilanic acid is obtained.

Mpl6O~164°C (decomposed). The 3-acylamino-2-azetidinone (1) shown in the following table was treated in the same manner as in Example 251 to obtain the compound shown in the following table.

Example 3043-[2-(4-(3-amino-3-carboxypropoxy)phenyl)-2. -Hydroxyiminoacetamide] 1.0 y of lactasilanic acid is dissolved in 20 ml of a 1.5% aqueous sodium bicarbonate solution, 1.0 y of sodium hydrogen sulfite is added, and the mixture is heated at 80° C. for 3 hours.

The reaction solution was brought to pH 3 with 10% hydrochloric acid, concentrated to about 10 ml, and then adjusted to pH 3 again with 10% hydrochloric acid. When the precipitated crystals are removed, 3-[4-(3-amino-3-carboxypropoxy)phenylglyoxyroylamino]
0.57y of lactasilanic acid is obtained. Mp2l6°C (decomposition). Example 305 3-[2-(4-(3-acetamido-3-carboxypropoxy)phenyl)-2-hydroxyiminoacetamido]lactasilanic acid was treated in the same manner as in Example 304 to give 3-[4-(3- Acetamido-3-carboxypropoxy)phenylglyoxyroylamino]lactasilanic acid is obtained.

Mp 96-102°C (decomposed). Example 306 3-[2-(4-(3-carboxy3-phthalimidopropoxy)phenyl)-2-hydroxyiminoacetamide]lactasilanic acid 42y in methanol 40Tn1
dissolve in

Add 42y of sodium bisulfite to this solution and 80mL of water.
Add the solution dissolved in 3. ? Heat to reflux for a while. Next, the reaction solution was concentrated to about 30 ml, and the pH was adjusted with 10% hydrochloric acid under ice cooling.
2. After adjusting to O, the mixture is extracted with ethyl acetate. After washing the extract with water and drying, the solvent is distilled off to obtain 3-[4-(3-carboxy-3-phthalimidopropoxy)phenylglyoxyroylamino]lactasilanic acid 2.1f1. Mpll5-120°C (decomposition). Example 307 3-[2-[4-(3-carboxy3-(3-phenylureido)propoxy)phenyl]12-hydroxyiminoacetamide]lactasilanic acid was treated in the same manner as in Example 306 to give 3-[ 4-(3-carboxy 3-(
3-Phenylureido)propoxy)phenylglyoxyroylamino]lactasilanic acid is obtained.

MplOO~106°C (decomposed). Example 308 10 ml of an aqueous solution containing 1.93 g of ammonium acetate
0.5 y of 3-[2-(4-(3-amino-3-carboxypropoxy)phenyl)-2-hydroxyiminoacetamido]lactasilanic acid was suspended in the solution, and 0.3 ml of 28% ammonia water and 0.4359 ml of zinc powder were added to the suspension. After adding
Stir at room temperature for 24 hours.

The reaction solution was adjusted to pH 4 with 1N monohydrochloric acid, hydrogen sulfide gas was introduced thereto, and insoluble matter was removed. After concentrating the Oki liquid under reduced pressure and dissolving the residue in 10 ml of water, 200 ml of ethanol was added.
Add 1. When the resulting precipitate is collected and dried, 3-
[2-(4-(3-amino-3-carboxypropoxy)phenyl)glycinamide]lactasilanic acid 4207
7! Get 9. Mp2O6~2085C (decomposed). Example 309 3-[2-(4-(3-phthalimido-3-carboxypropoxy)phenyl)-2-hydroxyiminoacetamide]lactasilanic acid 1.00y N,N-dimethylformamide was added to a solution consisting of 8ml of methanol and 2ml of water. 0.5mL 1 chlorine acid 0.57TLL and zinc powder 1
．． After adding Oy, stir for 4 hours.

After removing zinc dust from the reaction solution and introducing hydrogen sulfide into the bottom solution, the precipitate is removed. The liquor solution is concentrated under reduced pressure and the residue is powdered with acetone to obtain 0.68y of 3-[2-(4-(3-phthalimido-3-carboxypropoxy)phenyl)glycinamide]lactasilanic acid. Mp2l5~
219°C (decomposition). Example 3103-[2-(4-(3
-Acetamide (3-carboxypropoxy)phenyl)-2-hydroxyquinoshiiminoacetamide]lactasilanic acid 1.85y1 10% palladium on carbon 0.6 in a solution consisting of 0.42 da of sodium bicarbonate and 20 mt of water
y is added to absorb a theoretical amount of hydrogen gas at room temperature and pressure.

Catalyst from reaction solution? The Oki liquid was diluted with 10% hydrochloric acid and cooled on ice.
After adjusting the pH to 3j and treating with L1 activated carbon, 150 ml of acetone was added thereto and crystallized under ice cooling. The crystals were removed and washed with 10 mL of water and acetone to give 3-[2-(
4-(3-acetamido-3-carboxypropoxy)
phenyl)glycinamide]lactasi)lanic acid 0.38
Get y. Further, 10 ml of acetone was added to the above washing solution under ice cooling to crystallize it, and the product was then washed with acetone and taken off the coast to recover 0.32 q of this product. Total yield 0.70y. ．． m
p198-204°C (decomposition). Example 3113-[2-
(4-(3-Benzamido-3-carboxypropoxy)phenyl)-2-hydroxyiminoacetamide]lactasilanic acid 10.0f and sodium bicarbonate 2.
79f1 and water 7077! In a solution consisting of l, 10%
Add 3 g of palladium on carbon, shake well at room temperature under 3 atm, and perform catalytic reduction for 5 hours.

After the reaction was completed, the catalyst was removed and the resulting solution was purified with 10% hydrochloric acid under ice cooling.
H3. Adjust to O. When the precipitated crystals are removed, 3-
[2-(4-(3-benzamido-3-carboxypropoxy)phenyl)glycinamide]lactasilanic acid 7
．． Get 8y. Furthermore, 0.4y of this product was recovered from the mother liquor. Total yield 8.2 Da. Mpl7l~176°C (decomposed). Example 312 1.10 y of 3-[4-(3-carboxy-3-phthalimidopropoxy)phenylglyoxyroylamino]lactasilanic acid was suspended in 11 ml of water, and 0.40 y of sodium bicarbonate was added to dissolve it. After adding 0.08y of sodium borohydride while cooling with ice, the mixture was stirred at the same temperature for 4 hours.

After adjusting the reaction solution to pH 2 with 10% hydrochloric acid, the precipitated crystals were collected and washed with water to give 3-[2-(4-(3-carboxy-3-phthalimidopropoxy)phenyl)-2-hydroxyacetamide]lactasilane. 0.91y of acid is obtained. Mpl6O~163°C (decomposed). Example 3133-
[2-(4-(3-amino-3-carboxypropoxy)phenyl)-2-hydroxyiminoacetamide]
Add 20 ml of acetic anhydride to 150 ml of a methanol suspension of 10 y of lactasilanic acid; 4. Ichima stirring. Stir.

The reaction solution was concentrated under reduced pressure, toluene was added to the residue, evaporation was again carried out under reduced pressure, and ethyl acetate was added to the residue to form a powder, yielding 3-[2-(4-(3-acetamido-3-carboxypropoxy)phenyl). )-2-hydroxyiminoacetamide] La. 10.3y of cutasilanic acid is obtained. Mp9
O~93. C (decomposition). Example 314 3-[4-(3-amino-3-carboxypropoxy)
Phenylglyoxyroylamino]lag tasilanic acid 3
．． To 60 mL of methanol suspension of 0y, add 6 mL of acetic anhydride.
was added under ice-cooling, and the mixture was stirred at the same temperature for 1 hour and then at room temperature for 4 hours.

The reaction solution was concentrated under reduced pressure, and the residue was triturated with diethyl ether.
2.26 g of 3-acetamido-3-carboxypropoxy)phenylglyoxyroylaminolactasilanic acid
get.

96-102°C (decomposition).

Example 315 3-[2-(4-(3-amino-3-carboxypropoxy)phenyl)glycinamide]lactasilanic acid was treated in the same manner as in Example 314 to form 3-[2-(4-(3-
Acetamide (3-carboquinocypropoxy)phenyl)-N-acetylglycinamide]lactasilanic acid is obtained.

Infrared absorption vector niνd-1 (nujiol): 1735, 1650 Example 3
163-[2-(4-(3-amino-3-carbo semi-cypropoxy)phenyl)-2-hydroxyiminoacetamide] 0.50 y of lactasilanic acid was dried in methylene chloride 2
Suspend in 0ml.

1.5 bis(trimethylsilyl)acetamide in suspension
After adding 0y and stirring at room temperature for 2 hours, the mixture was heated to reflux for about 1 minute. The reaction solution was ice-cooled to 0 to 5°C, and triethylamine was added to 0.
After adding 12y1 and 0.27q of trifluoroacetic anhydride, the reaction solution was stirred for 1 hour. Methylene chloride is distilled off from the reaction solution, and 20 ml of ethyl acetate is added to the residue to dissolve it. This solution is washed five times with 2% hydrochloric acid, twice with water, and once with a saturated aqueous solution of sodium chloride, and then dried over magnesium sulfate. When the solvent is distilled off from the solution and benzene is added to the residue to powder it, 3-[2-(4-(3
-Carboxy 3-(2,2,2-trifluoroacetamidopropoxy)phenyl)-2-hydroxyiminoacetamido]lactasilazoic acid 0.41y is obtained. M
pl43-14rC (degraded). Example 317 3-[4-(3-amino-3-carboxypropoxy)
Phenylglyoxyroylamino]lactasilanic acid 4.
Add 15 mL of bis(trimethylsilyl)acetamide to a solution of 0 V suspended in 80 jLt of dry methylene chloride.
Stir for an hour to completely dissolve the ingredients.

To this solution, add 0.88 f of triethylamine under ice-cooling, and then add dropwise a solution of 1.9 y of trifluoroacetic anhydride dissolved in 5 ml of methylene chloride, and stir at the same temperature for 1 hour. . Methylene chloride was distilled off from the reaction solution under reduced pressure, and the residue was mixed with 50 ml of ice water and 10 ml of ethyl acetate.
Pour into a mixture consisting of 0ml. The ethyl acetate layer is separated, dried over magnesium sulfate, and then the solvent is distilled off. When the resulting residue is powdered with benzene, 3-[4-(3
3.0 q of -carboxy 3-(2,2,2-trifluoroacetamido)propoxy)phenylglyoxyroylamino]lactasilanic acid are obtained. Infrared absorption Svector Ni νCm-1 (Nudiol): 1730,1680 Example 3183-[2-(4-(3-Amino-3-carboxypropoxy)phenyl)-2-hydroxyiminoacetamide] 20.0y of lactasilanic acid was added to 200ml of water and Suspend in a mixture of 200 ml of acetone.

Add 6.8y of sodium hydrogen carbonate to the suspension and dissolve.
Furthermore, 6.7 y of benzoyl chloride is added dropwise to this solution under ice cooling. (Keep the reaction solution at pH 8.0)
After stirring for an hour, acetone is distilled off, the residue is washed with ethyl acetate, and 400 ml of ethyl acetate is added. Add 10% hydrochloric acid to this solution under cooling to pH 2. Adjust to O.
The ethyl acetate layer is separated, washed with water and a saturated aqueous solution of sodium chloride, and then dried. Ethyl acetate was distilled off from the solution, and 200ml of water was added to the residue. Add L and suspend.
Add 160 ml of 1N aqueous sodium monohydroxide solution to the suspension and stir for 2 hours. 400 mt of ethyl acetate was added to the reaction solution, and the pH was adjusted to 2.0 with 10% hydrochloric acid while cooling. Adjust to O. The ethyl acetate layer is separated, washed with water, dried, and then the solvent is distilled off to obtain powder 21.6y. When a mixed solvent of acetone and benzene is added to this powder and crystallized, 3-
10.4 q of [2-(4-(3-benzamido-3-carboxypropoxy)phenyl)-2-hydroxyiminoacetamide]lactasilanic acid are obtained. Mpl7O~1
72C (decomposition). Example 3 970 ml of 193-[4-(3-amino-3-carboxypropoxy)phenylglyoxyroylamino]lactasilanic acid was suspended in 10 ml of water, and the pH was adjusted to 8 to 9 using 1N aqueous sodium hydroxide solution under ice cooling. After that, phenyl isocyanate 36
Add 10 mt of an acetone solution in which 0 mg is dissolved (keep the dropping liquid at pH 8-9).

This solution is stirred for 1 hour, by-product diphenyl urea is removed, and the solution is adjusted to pH1~2 with 10% hydrochloric acid, and then extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and the solvent was distilled off to give 3-[4-3-carboxy-3-(3-phenylureido)propoxy)phenylglyoxyloylamino]lactasilane. 1.33f1 of acid is obtained. MplOO
~106°C (decomposition). Example 320 3-[2-(4-(3-amino-3-carboxypropoxy)phenyl)glycinamide]lactasilanic acid 25
0 m9 is suspended in 5 mt of water, and while cooling, the pH is adjusted to 8 using 1N aqueous sodium monohydroxide solution and dissolved.

To this solution, 2 ml of a dry acetone solution containing 150 mg of phenyl isocyanate was added while cooling (while keeping the liquid property at pH 8 to 9), and after stirring for 1 hour under ice cooling, the reaction solution was adjusted to pH 2 with 10% hydrochloric acid. do. After the precipitate was offshored and washed with water, it was dissolved in an aqueous sodium bicarbonate solution and the insoluble materials were removed.
Adjust to. The precipitate was filtered out, washed with water, and then dried over phosphorus pentoxide to form 3-[2-[4-(3-carboxy 3
-(phenylureido)propoxy)phenyl]-2-
0.35f of (3-phenylureido)acetamide]lactasilanic acid is obtained. Mpl7O~172°C (decomposed).
Example 321 3-[2-(4-(3-amino-3-carboxypropoxy)phenyl)2-hydroxyiminoacetamide]
Lactasilanic acid 10y1 water 100ml and acetone 3
After adjusting the pH to 8 to 9 by adding 1N aqueous sodium monohydroxide solution to 0 mL of the suspension under ice cooling, 5 ml of an acetone solution of 2.9 y of phenyl isocyanate was added dropwise at the same temperature.
Stir for 1 hour.

Acetone was distilled off from the reaction solution under reduced pressure, and the remaining solution was reduced to 10%.
Adjust the pH to 2 with hydrochloric acid and extract with 200 ml of ethyl acetate.
After washing the 7 extracts with dilute hydrochloric acid and water and drying them, ethyl acetate was distilled off, and the residue was diluted with 100% diethyl ether.
When adding m1 and filtering out the powder, 3-[2-[4-(3-
10.3y of carboxy 3-(3-phenylureido)propoxy)phenyl]2-hydroxyiminoacetamide]lactasilanic acid is obtained. Mpl35~139kuC
(Disassembly). Example 322 Sodium salt of 3-[2-(4-(3-amino-3-carboxypropoxy)phenyl)-2-hydroxyiminoacetamide]lactasilanic acid 0.94y110% dipotassium hydrogen phosphate aqueous solution 20ml and acetone 10
0.60y of ethyl phthalimide acid in a solution consisting of mL
5ml of acetone solution was added dropwise with stirring to bring the liquid property to P.
Stir for 2 hours while maintaining the temperature at H8.

Acetone was distilled off from the reaction solution under reduced pressure, and the remaining solution was PHified with hydrochloric acid.
2 and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, ethyl acetate was distilled off, and the residue was crystallized from an aqueous ethanol solution.
0.69y of -[2-(4-(3-carboxy3-phthalimidopropoxy)phenyl)-2-hydroxyiminoacetamide]lactasilanic acid is obtained. Mpl6O~
165°C (decomposition). Example 3233-[2-(4-(3
-amino-3-carboxypropoxy)phenyl)glycolamide]lactasilanic acid was treated in the same manner as in Example 322 to produce 3-[2-(4-(3-carboxy3-phthalimidopropoxy)phenyl)glycolamide]
Lactasilanic acid is obtained.

Mp6O~163°C (decomposed). Example 3243-[4-
(3-Amino-3-carboxypropoxy)phenylglyoxyroylamino]lactasilanic acid Example 322
Treat in the same manner as 3-[4-(3-carboxy 3
-phthalimidopropoxy)phenylglyoxyroylamino]lactasilanic acid is obtained.

Mp2l6°C (decomposition). Example 3253-[2-(4
-(3-Amino-3-carboxypropoxy)phenyl)glycinamide]To 6 ml of a 50% aqueous pyridine solution containing 250 mg of lactasilanic acid, 320 ml of phenylisothiocyanate was added with stirring at 40°C, and then added with a saturated aqueous sodium bicarbonate solution. Stir for 1 hour while maintaining pH 8-9.

After washing the reaction solution with diethyl ether, the aqueous layer was separated and the pH was adjusted to ~2 with 10% hydrochloric acid when cold, and the precipitated crystals were collected and dried to give 3-[2-[4-( 3-carboxy3-(3-phenylthioureido)propoxy)
250 mg of phenyl]-2-(3-phenylthioureido)acetamido]lactasilanic acid are obtained. Mpl9
O~195°C (decomposition). Example 3263-[2-(4
-(3-amino-3-carboxy Otsu 1
2.0 f of rtcypropoxy)phenyl)glycinamide]lactasilanic acid is suspended in 20 ml of aqueous pyridine.

This suspension was diluted with 1N aqueous sodium monohydroxide solution under ice-cooling.
After adjusting to H8.6 and dissolving, 1.94 f of 1-naphthyl isothiocyanate was added and stirred for 4 hours. After washing the reaction solution with diethyl ether, 10%
pH2 with hydrochloric acid. The precipitated solids are filtered out and washed with water. After dissolving this solid in a saturated aqueous solution of sodium bicarbonate and adding 10% hydrochloric acid to collect the precipitated crystals, 3-[2-4-[3-carboxy 3-(3-(1-
naphthyl)thioureido)propoxy]phenyl]-(
2.7y of 3-(1-naphthyl)thioureido)acetamide]lactasilanic acid is obtained. Mpl69~173℃(
Disassembly). Example 327 3-[2-(4-(3-amino-3-carboxypropoxy)phenyl)glycinamide]lactasilanic acid 48
0 ml is suspended in 10 ml of water, and 5 ml of 1N potassium hydroxide aqueous solution is added under ice cooling with stirring.

o-ethyl-s-methyldithiocarbonate 0.72y
After adding 5 ml of acetone solution, the mixture was stirred at room temperature for 5 hours. After washing the reaction solution with diethyl ether, the aqueous layer was separated and adjusted to pH1~2 with 10% hydrochloric acid. The resulting precipitate was extracted with ethyl acetate, washed with water, dried, and the solvent was distilled off under reduced pressure to give 3-[2-(4-(3-carboxy 3-ethoxythiocarbonylaminopropoxy)phenyl)-2 -Ethoxythiocarbonylaminoacetamide] 230 mg of lactasilanic acid are obtained. Mpll2~1
19 (decomposition). Example 328 1.0q of 3-[2-(4-(3-amino-3-carboxypropoxy)phenyl)-2-hydroxyiminoacetamide]lactasilanic acid was added to a mixed solution of 40ml of 0.1N aqueous sodium hydroxide solution and 15mt of acetone. After dissolving, add 2-(4-chloro2) while stirring under ice-cooling.
- 5 ml of acetone solution containing 550 ml of (nitrophenoxy)acetyl chloride and 40 ml of 0.1N sodium monohydroxide aqueous solution are simultaneously added dropwise (liquidity of the reaction solution is P
H9.2 to H9.4).

The reaction solution was mixed with 4 powders at the same temperature and further stirred at room temperature for 40 minutes.
After washing the reaction solution with ethyl acetate, ethyl acetate was added to the aqueous layer, and the pH was adjusted to 2 with 10% hydrochloric acid. vinegar
The ethyl TvhJ acid layer is separated, washed with water, and then dried over magnesium sulfate.

The solvent is then distilled off from the solution and the resulting residue is washed several times with diethyl ether. The residue was dissolved in ethyl acetate while hot, and after removing insoluble materials, chloroform was added, powdered, and sifted to obtain 3-[2-[4-[3-(2-(4-chloro-2-nitrophenoxy)acetamide)]. 150 mg of )-3-carboxypropoxy[phenyl]-2-hydroxyiminoacetamido]lactasilanic acid are obtained. Furthermore, 30 m9 of this product was obtained from the mother liquor, with a total yield of 180 m9. mp
145-150°C (decomposition). Example 3293-[2-(
4-(3-amino-3-carboxypropoxy)phenyl)-2-hydroxyiminoacetamide]. Lactasilanic acid 1.0q1 Sodium hydrogen carbonate 504mg, Water 3
0 ml of acetone and 10 ml of acetone while stirring under ice cooling while maintaining the liquidity of the reaction solution at pH 8.
A solution of 4 ml of acetone containing 352 mg of -(2-thienyl)acetyl chloride is added dropwise.

After stirring the reaction solution for 4 minutes at the same temperature and a further 3 minutes at room temperature,
Wash with ethyl acetate, then add ethyl acetate to the aqueous layer and adjust the pH to 2 with 10% hydrochloric acid. The ethyl acetate layer is separated, and the remaining aqueous layer is further extracted with ethyl acetate. The ethyl acetate layers are combined, washed with a saturated aqueous sodium chloride solution, and then dried over magnesium sulfate. The solvent was distilled off, and 740 mg of the resulting residue was added to 30 TI1 of a 0.1N aqueous sodium monohydroxide solution (the pH of the reaction solution was 9.4), and the mixture was stirred at room temperature for 1 hour. After washing the reaction solution with ethyl acetate, ethyl acetate was layered on the aqueous layer, 10% hydrochloric acid was added, and P[]2 was treated in the same manner as above, resulting in a residue 4507.
Get 19. This product was dissolved in a mixed solvent of acetone and n-hexane, treated with activated carbon, and the resulting solution was concentrated. The resulting residue was washed several times with diethyl ether and then with n-hexane. [2-[4-[3-carboxy 3-(2-(2-thienyl)acetamide)]
400 mg of propoxy[phenyl]-2-hydroxyiminoacetamido]lactasilanic acid are obtained. Mpl45
~1500C (decomposition). Example 330 3-[2-(4-(3-amino-3-carboxypropoxy)phenyl)-2-hydroxyiminoacetamide]lactasilanic acid 2.0 g, sodium bicarbonate 756
Triethylamine salt 3.1 of α-ethoxycarbonyloxycarbonyl-α-1 toluenesulfonic acid was added to a solution consisting of Tn9, 35 μl of water, and 15 ml of acetone under ice cooling.
A solution of 25 ml of acetone containing y and 101 rL of an aqueous solution containing 756 m9 of sodium hydrogen carbonate are simultaneously added dropwise (the liquid property of the reaction liquid is pH 7.6).

The reaction solution was stirred at the same temperature for 30 minutes, and then at room temperature for three times. After acetone is distilled off from the reaction solution, the remaining solution is adjusted to pH 3 with 10% hydrochloric acid and washed with ethyl acetate. After separating the ethyl acetate layer, the aqueous layer was adjusted to PHL with 10% hydrochloric acid and extracted with n-butyl alcohol. The n-butyl alcohol layer was washed once with 5% hydrochloric acid and once with saturated aqueous sodium chloride solution, and then dried over magnesium sulfate. Add 11 m of sodium 2-ethylhexanoate to this solution.
Add 21 ml of acetone solution containing g to adjust the pH to 6,
Collect the precipitated powder overnight. Washing this powder with acetone gives 2.3 g of colorless powder. Add 1.0 y of this powder to 3 y of water.
After dissolving in mt and adjusting the pH to 3 with 10% hydrochloric acid, the solution is washed with ethyl acetate. The remaining aqueous layer was subjected to column chromatography using adsorption resin Amperlite XA-2 (trademark, manufactured by Rohm and Haas), and the compound eluted with water was lyophilized to yield 3-[2-[4 350 mg of the sodium salt of -(3-carboxy3-(2-phenyl-2-sulfoacetamide)propoxy)phenyl]2-hydroxyiminoacetamide]lactasilanic acid is obtained. Furthermore, this product 4 was extracted from the fraction eluted from water containing 20% methanol and the fraction eluted with methanol.
Collect 80 mg. Total yield 830m9. mp244~
250°C (decomposition). Example 331N-methylaniline 0
．． 0.127y of potassium carbonate and 3mt of water are added to 3mt of acetone solution containing 200y and stirred at 25-28°C.

To this solution was added 0.321y of 3-(2-bromoacetamido)lactasilanic acid and 0.06y of sodium bicarbonate.
Acetone/water (1:1) mixed solution (4ml) containing 7q
) was added dropwise and allowed to react for one hour at the same temperature. After acetone is distilled off from the reaction solution under reduced pressure, the remaining aqueous layer is washed with ethyl acetate. The aqueous layer was adjusted to pH 3 with diluted hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried, and concentrated.
When methanol is added to the resulting residue and crystallized, 3-
0.208f of (N-methyl-N-phenylglycinamide)lactasilanic acid is obtained. Mpl98-2199 LaC
(Disassembly). The compounds shown in the table below are obtained by treatment in the same manner as above.

．． Example 33 0.262y of morpholine was dissolved in a mixed solution (5ml) of acetone/water (1:1), and then 0.180g of potassium carbonate was added.

This solution was cooled to 10°C, and while stirring, acetone/water (1:
Add the mixed solution (5 ml) of 1) dropwise. The temperature of the reaction solution is maintained at 10 to 20°C and the reaction is allowed to proceed for 5 hours. Acetone is distilled off from the reaction mixture under reduced pressure, and the remaining aqueous layer is washed with ethyl acetate. The aqueous layer was adjusted to pH1~2 with dilute hydrochloric acid and then washed with ethyl acetate. Next, the aqueous layer is adjusted to pH 4.5 to 4.8 with sodium hydrogen carbonate, concentrated under reduced pressure, and the residue is extracted with methanol. Concentrate the methanol solution, dissolve the remaining extract in a small amount of methanol, and then add acetone. The precipitated inorganic substances are removed and the p liquid is concentrated.
0.38y of the obtained extract was adsorbed using resin Amperlite
AD-2 (trademark, manufactured by Kuchum & Haas) 35m
1 and subjected to column chromatography for isolation and purification. Fractions obtained by elution with water are collected and water is distilled off to obtain 0.38 V of 3-(2-morpholinoacetamido)lactasilanic acid. Mp2Ol ~ 203℃ (decomposition)
. Example 3373-[2-(2-bromoacetamide)
-2-phenylacetamide]lactasilanic acid 196m
9,2-Mercaptobenzoic acid 62WL9 and 0.1N
A mixture of 12 ml of sodium monohydroxide aqueous solution is stirred at room temperature for 1 hour (the reaction liquid has a pH of 6.8 to 7.0).
).

Add 0.4 ml of 1N monohydrochloric acid to the reaction solution to adjust the pH to 3, and then wash with diethyl ether. The aqueous layer was adjusted to pH1~2 with 1N monohydrochloric acid, and then extracted with ethyl acetate.
After washing the extract with water and drying with magnesium sulfate, about 4 m
Concentrate under reduced pressure until 1. When the precipitated crystals are collected and washed with diethyl ether, 3-[2-(2-(
125 m9 of 2-carboxyphenylthio]acetamido)-2-phenylacetamido]lactasilanic acid are obtained. Furthermore, 50m9 of this product was recovered from the liquid. Total yield 17
5mg. mp 143-146°C (decomposed). Example 353 86 m9 of 3-(2-bromo-2-phenylacetamido)lactasilanic acid and 35 m9 of cysteine hydrochloride (monohydrate) were suspended in 3 ml of water, and 1 was added with stirring under ice cooling.
Add 0.4 ml of N aqueous sodium monohydroxide solution and allow to react for about 3 hours.

After adjusting the pH of the reaction solution to 8, the reaction was continued for another 2 hours. The reaction solution was adjusted to pH 2 with 1N monohydrochloric acid, and then filtered. The solution is adjusted to pH 8-9 with an aqueous sodium bicarbonate solution and then concentrated. The residue is isolated and purified by column chromatography using 20 ml of adsorption resin Amperlite X7V-2 (trademark, manufactured by Rohm & Haas) which has been washed with methanol and water in advance. After collecting the fractions obtained by elution with water and distilling off the water, 3-[
20 m9 of the disodium salt of the carboxy group of 2-(2-amino-2-carboxyethylthio)2-phenylacetamide]lactasilanic acid is obtained. Mp2ll~2
16°C (decomposition). Example 3543-(2-bromo2
Example 353: 150 m9 of -phenylacetamido)lactasilanic acid and 35 m9 of 2-aminoethanethiol
The sodium salt of 3-[2-(2-aminoethylthio)-2-phenylacetamido]lactasilanic acid was treated in the same manner as 54m! Get 9.

Mpl7l~173liC (decomposition). Example 355 To a solution consisting of 38 ml of cysteine hydrochloride, 3 ml of water and 0.9 ml of IN potassium monohydroxide aqueous solution was added 107 3-(2-bromoacetamido)lactasilanic acid and 3 ml of water.
A solution consisting of 0.6 mt of 1N aqueous potassium monohydroxide solution was added dropwise with stirring under ice cooling, and the mixture was allowed to react at the same temperature for 1 hour.

The reaction solution was adjusted to pH approximately 4 with 0.9 ml of 1N monohydrochloric acid, and then concentrated under reduced pressure. The residue was dissolved in methanol and subjected to column chromatography using adsorption resin Amperlite XAD-2 (trademark, manufactured by Rohm and Haas) for isolation and purification. The fractions eluted with water were collected and the water was distilled off to obtain 95 m9 of 3-[2-(2-amino-2-carboxyethylthio)acetamido]lactasilanic acid. MplO5~110taC (decomposition). The compounds shown in the table below are obtained by treatment in the same manner as above. Example 3613-[2-
(2-Bromoacetamide)-2-phenylacetamide] To a solution consisting of 200 m9 of lactasilanic acid and 4 TfLL of 0.1N aqueous sodium monohydroxide solution was added 60 mg of sodium pyridine-1-oxide-2-thiolate under ice cooling, and 3 powders were added at room temperature. Stir for a while.

After adding ethyl acetate to the reaction solution, add 10% hydrochloric acid to PHL~2
Adjust to. The precipitate was collected by decantation, dried, and washed with acetone to give 3-[2-
82 mg of (2-(pyridyl-1-oxide-2-thio)acetamide)-2-phenylacetamide]lactasilanic acid are obtained. Further, when the acetone washing solution is concentrated and the resulting residue is washed with diisopropyl ether, this product 3 is obtained.
Collect 3 mg. Total yield 115mg. mp160~1
64°C (decomposition). Example 362 3-(2-bromoacetamido)lactasilanic acid 285
mg and sodium pyridine-1-oxide-2-
Thiolate 120m9 is treated as in Example 361 to yield 250 mg of 3-[2-(pyridyl-1-oxaido-2-thio)acetamido]lactasilanic acid.

Mp22l~225°C (decomposed). Example 3633-[2
-Phenyl-2-(2-phenylsulfoacetamide)
Acetamide] lactasilanic acid 285m9, and 0
．． To a solution consisting of 10 ml of 1N aqueous sodium monohydroxide solution was added 76 ml of 8-mercapto-contaminated purine under ice cooling, the reaction temperature was raised to room temperature, and the mixture was stirred for 3 hours.

Add 0.5 mL of 1N monohydrochloric acid to the reaction solution and scrape off the precipitate. When the precipitate is washed with water and dried, 3-[
2-phenyl-2-(2(9H-purinyl-8-thio)
Acetamide) Acetamide] Lactasilanic acid 120m
Get 9. Mpl92-19rC (degraded). l Example 3
64 Add 9.6 mg of sodium hydride (50% oily) and 19 mg of phenol to 2 mt of anhydrous dimethylformamide,
3. Cool the stirred solution on ice.

To this solution, 50 m9 of 3-[2-phenyl-2-(2-bromoacetamido)acetamido]lactasilanic acid was added at once, and the mixture was stirred at the same temperature for 1 hour and at room temperature for 1 hour. After adding 10 ml of diethyl ether to the reaction solution, the precipitate was washed off. This precipitate was dissolved in a small amount of water, adjusted to approximately PHL with 10% hydrochloric acid, and extracted with ethyl acetate. The extract is washed with water, dried over magnesium sulfate, and then the solvent is distilled off. The residue was pulverized with diethyl ether and then washed thoroughly with diethyl ether to form 3-[phenyl-2-
10 m9 of (2-phenoxyacetamide)acetamide]lactasilanic acid are obtained. This product was identified because it matched a separately synthesized specimen. Infrared absorption spectrum νd-1 (nujiol): 1740, 1020, 165
0 Treat in the same manner as above to obtain the compounds shown in the table below.

Example 375 25 m9 of 10% palladium/carbon was added to 10 ml of a solution consisting of 220 mg of 3-(6-benzyloxycarbonylaminohexanamide)lactasilanic acid and methanol, and a theoretical amount of hydrogen gas was introduced over a period of 2 hours at room temperature and normal pressure. do.

After filtering the reaction liquid and concentrating the bottom liquid under reduced pressure under No. 8, the residue was powdered with acetone, washed with acetone, and collected.
(6-aminohexanamide)lactasilanic acid 100m
Get 9. Mpll8-127C (degraded). The compounds shown in the following table are obtained by treatment in the same manner as above. Example 3933-[2
-(2-thienyl)-N-(2,2,2-trichloroexycarbonyl)glycinamide]lactasilanic acid 0.
Dissolve 250 ml of 90% acetic acid in 13 ml of 90% acetic acid and cool to 10°C.

1.20 y of zinc powder was gradually added to this solution, and the mixture was allowed to react at the same temperature for 1 hour. Add 0.50 y of zinc powder to the reaction solution, and react for an additional 2 hours. After removing the zinc powder from the reaction solution, hydrogen sulfide gas is passed through the solution to remove the resulting precipitate. After washing the sake liquor with ethyl acetate, the remaining aqueous layer is concentrated, and the resulting residue is crystallized with a mixed solvent of methanol and diethyl ether to form 3-[2-
(2-thienyl)glycinamide]lactasilanic acid 35
Get m9. Further, the ethyl acetate layer is extracted with water, and the aqueous layer is concentrated to recover 15 Tng of this product. Total yield 50m9
. mp184-189°C (decomposition). Example 3961-
(αcarboxy3,5-dibromo4-hydroxybenzyl)-3-[2-[4-(3-carboxy3-(
2,2,2-trifluoroa! cetamido)propoxy)phenyl]2-hydroxyiminoacetamide]-2
- 1N after suspending 0.50y of azetidinone in 3ml of water
Add 3n1 of sodium monohydroxide aqueous solution and stir.

Add 10% hydrochloric acid to the reaction solution under ice cooling to adjust the pH to 3.
The precipitated crystals are filtered out, dissolved in a small amount of sodium bicarbonate aqueous solution, and then treated with activated carbon. After adjusting the pH of the treated solution to 4 with 10% hydrochloric acid under ice-cooling, the precipitate was collected and treated in the same manner as above to obtain 3.5-dibromo-4-hydroxy. Benzyl)-3-[2-(4-(3-amino-3-carboxypropoxy)phenyl)-2-hydroxyiminoacetamide]2-azetidinone 40Tn9 is obtained.

Furthermore, 60 m9 of this product was recovered from the mother liquor. Total yield 100
mg. mp190-194mC (degraded). Example 397 3-[2-benzyloxycarbonyloxyphenyl)
Acetamide] 10% palladium on carbon 2 in 35 ml of a solution consisting of 230 ml of lactasilanic acid and methanol
5 mg was added, and the theoretical amount of hydrogen gas was introduced over a period of 2 hours under conditions of room temperature and pressure.

The reaction mixture is filtered, the filtrate is concentrated under reduced pressure, and the residue is crystallized from a small amount of a mixed solvent of acetone and ethyl acetate. After collecting these crystals and washing them with ethyl acetate,
3-[2-(4-hydroxyphenyl)acetamide]
90 mg of lactasilanic acid are obtained. Mpl7l~176℃
(Disassembly). Example 398 A solution consisting of 213 mg of 3-(2-ethoxycarbonyl-2-phenylacetamido)lactasilanic acid, 5 ml of ethanol, and 1.4 ml of 1N aqueous sodium monohydroxide solution is reacted at room temperature for 1.2 hours.

After the reaction is completed, the reaction solution is cooled and adjusted to PHL by adding 1.4 mt of 1N monohydrochloric acid. Furthermore, a 1N aqueous sodium monohydroxide solution is added to this mixed solution to adjust the pH to 6 to 7, and then the mixture is concentrated. After the resulting residue is dissolved in water, the liquidity of the solution is adjusted to pH1~2 with 1N monohydrochloric acid and washed with ethyl acetate. The remaining aqueous layer was adjusted to pH 6 with a 1N aqueous sodium monohydroxide solution, concentrated, and the residue was washed with methanol and water in advance using 30 ml of adsorption resin Amperlite XAD-2 (trademark, manufactured by Rohm and Haas). It is isolated and purified by column chromatography. Fractions eluted with water are collected and water is distilled off from the eluate to obtain 159m9 of the disodium salt of 3-(2-carboxy-2-phenylacetamido)lactasilanic acid at the carboxy group. Mp2O9-214°C (decomposed). The compounds shown in the following table are obtained by treatment in the same manner as above. Example 4013-[2-(2-
(2-ethoxycarbonylphenoxy)acetamide)
-2-phenylacetamide]lactasilanic acid 170m
9 was dissolved in 0.9 ml of 1N aqueous sodium monohydroxide solution and stirred at room temperature for 3 hours.

Approximately 10 ml of water was added to the reaction solution, the pH was adjusted to PHL with 10% hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract is washed twice with an aqueous sodium chloride solution and then dried over magnesium sulfate. When the solvent is distilled off from the ethyl acetate solution and the resulting residue is crystallized with diisopropyl ether, 3-[2-
(2-(2-carboxyphenoxy)acetamide)-
2-phenylacetamide]lactasilanic acid 120Tn
Get 9. Mpl3O~135kC (decomposition). The compounds shown in the following table are obtained by treatment in the same manner as above.

Example 4201-(α-Methoxycarboxy-4-methoxybenzyl)3-[2-[4-(3-methoxycarbonyl-3-(2,2,2-trifluoroacetamide))
Dissolve 0.19 y of propoxy)phenyl 2-methoxyiminoacetamide 2-azetidinone in 2 ml of acetone.

Add 0.9 1N sodium monohydroxide aqueous solution to this solution at room temperature.
Add m1 and stir for 5 minutes. Acetone was distilled off from the reaction solution, and the remaining solution was adjusted to pH 3 with 10% hydrochloric acid. The oil that separates is separated by decantation and the residue is washed with acetone and water. Powdering this residue with acetonitrile yields 1-(α-carboxy4-methoxybenzyl)-3-[2-(4-(3-amino-3-carboxypropoxy)phenyl)-2-methoxyiminoacetamide]-2-azetidinone. Obtain 0.02y. Mpl7
O~176°C (decomposed). Example 4 15 ml of sodium methylate and 20 ml of anhydrous methanol are added to 1.11 liters of 1-methoxalyl-3-(2-phenoxyacetamido)-2-azetidinone, and the mixture is heated under reflux.

Next, the solvent is distilled off from the reaction solution under reduced pressure, the residue is dissolved in acetone, and the insoluble materials are removed in an oven. After concentrating the liquid, it is allowed to cool and the precipitated crystals are removed. The crystals were washed with acetone and dried to obtain 456 mg of 3-(2-phenoxyacetamido)-2-azetidinone. Furthermore, 109 mg of this product was recovered from the mother liquor. Total yield 565m9, M
pl53-155°C. Example 422 240 m9 of 1-methoxalyl-3-benzyloxycarbonylamino-2-azetidinone was dissolved in 10 mL of methanol.
After dissolving 6 mg of sodium methylate, the mixture was heated to reflux.

Methanol is distilled off from the reaction solution, and the resulting residue is washed with diethyl ether to obtain 126 mg of crude 3-benzyloxycarbonylamino-2-azetidinone.
Further, this product is recrystallized from acetone to obtain 50m9 of purified product. In addition, 54 mg of purified product of this product was recovered from the mother liquor. Total yield 104m9. mp164-165mC
Example 42 13.8y of 1-(1-acetoxy2-methylpropyl)-3-(2-phenylacetamido)-2-azetidinone was added to 100ml of methanol and 10ml of water.
Dissolve in a solution consisting of 0 ml.

To this solution were added 6 y of potassium carbonate and 1.65 y of sodium borohydride under ice cooling, and the mixture was allowed to react at 20° C. for 1 hour. Next, the crystals precipitated in the reaction solution were filtered out, washed with water, and dried to give 3-(2-phenylacetamide)-2.
- 5.15 g of azetidinone are obtained. Furthermore, 1.35 y of this product was recovered from the liquor liquor. Total yield 6.5ymp191-1
93℃. Example 42 1.13V of 1-[1-(2,2,2-trichloroethoxy"carbonylamino)-2-methylpropyl]-3-(2-phenylacetamido)-2-azetidinone was dissolved in 20 ml of 90% acetic acid, 5℃
Cool to

To this solution, 1.62 y of zinc powder was added dropwise over 5 minutes while stirring, and the powder was stirred for three times. Furthermore, 1.0% zinc powder was added to this reaction solution.
Add 62V and stir for 2 days. The reaction solution is then neutralized with an aqueous sodium bicarbonate solution and extracted with methylene chloride.
After washing the extract with water and drying over anhydrous magnesium sulfate, the solvent was distilled off, and the resulting residue (0.65y) was subjected to preparative thin layer chromatography using silica gel (developing solvent:
Ethyl acetate, methyl ethyl ketone, water, and acidic acid mixed solvent (
When isolated and purified at a volume ratio of 5:3:11), 3-
(2-phenylacetamido)-2-azetidinone 0.
Get 3y. Mpl9O-192'CO Example 4251
-(α-methoxycarbonyl-4-hydroxybenzyl)-3-[2-(2-thienyl)acetamide]-2-
0.18y of azetidinone was added to sodium borate buffer (P
H7.8) 3ml, methanol 5ml and acetone 3
After dissolving in a solution consisting of m1 and cooling to -5°C, methanol containing 0.10y of tertiary butyl hypochlorous acid ester was added.
．． Add 5 ml of solution three times every 15 minutes and stir three times.

After distilling off the solvent from the reaction solution, the remaining solution was PH'd with 10% hydrochloric acid.
2 and extracted with ethyl acetate. The extract is separated, washed with water and a saturated aqueous solution of sodium chloride, and dried over magnesium sulfate. The solvent was distilled off from the ethyl acetate solution, the resulting residue (0.22y) was subjected to column chromatography using 10y of silica gel, the fractions eluted with chloroform were collected, and when chloroform was distilled off from the eluate, 1-( 50 mg of α-methoxycarbonyl-3,5-dichloro-4-hydroxybenzyl)-3-[2-(2-thienyl)acetamido]-2-azetidinone is obtained. Infrared absorption spectrum νc! n-1 (liquid film): 3270, 1760, 1755
, 1665 Example 426] -(α-Methoxycarbonyl-4-hydroxybenzyl)-3-(2-phenylacetamido)-2-azetidinone (184 mg) dissolved in dioxane (2 mt) was added with 1.5 ml of chloroform, and then 104 TrLg of bromine was added. 0.5ml of chloroform containing
The solution is added dropwise over 5 minutes while stirring under ice-cooling.

After adding 80 ml of ethyl acetate to the reaction solution, the ethyl acetate layer was washed with water and dried over magnesium sulfate. Concentrate this solution, dissolve the residue in a small amount of acetone, and then perform preparative thin layer chromatography using silica gel (developing solvent: chloroform/methanol mixed solvent (5:0.3)).
The resulting compound was recrystallized from a mixed solvent of ethyl acetate and acetone to give 1-(α-methoxycarbonyl-3-bromo-4-hydroxybenzyl)-3.
-(2-phenylacetamido)-2-azetidinone 1
Obtain 8m9. Mpl5l~153-C (decomposition). Example 427 3-(2-phenylacetamido)lactasilanic acid 35
Rml of a methanol solution containing 352 mg of bromine was rapidly added dropwise to 5 ml of a solution of 4 m9 and 246 mg of sodium acetate dissolved in anhydrous methanol while stirring under ice cooling.

Methanol is distilled off from the reaction solution under reduced pressure, a mixture of ethyl acetate and water is added to the residue, and the ethyl acetate layer is separated. The ethyl acetate layer was washed with water, dried over magnesium sulfate, and then the solvent was distilled off. The resulting residue, 590 m9 of a yellow-orange oil, was dissolved in a small amount of ethyl acetate and subjected to column chromatography using 7 ml of silica gel. Fractions eluted from a mixed solvent consisting of ethyl acetate and acetone are collected, and the solvent is distilled off from the eluate. The resulting residue is further isolated and purified by preparative thin layer chromatography using silica gel. Fractions eluted from a mixed solvent of ethyl acetate and acetic acid (5:1) are collected, the solvent is distilled off from the eluate, and the resulting residue is powdered with chloroform. When this powder is recrystallized from a mixed solvent of chloroform and acetone, 1-(α-carboxy 3,5-dibromo 4-
Hydroxybenzyl)-3-(2-phenylacetamido)-2-azetidinone 157TrL9 is obtained. Furthermore, 26 mg of this product was recovered from the mother liquor. Total yield 183m9.
mp161-167C (degraded). Example 4283-[2
-[4-(3-carboxy3-2,2,2-trifluoroacetamido)propoxy)phenyl]-2-hydroxyiminoacetamido]lactasilanic acid 1.77f
Dissolve in 20ml of methanol.

After adding 1.03y of sodium acetate to this solution -5℃
5ml of methanol solution containing 1.06y of bromine
Drip in one drop. After reacting the reaction mixture for 1 hour, methanol was distilled off from the reaction mixture, and the residue was diluted with ethyl acetate for 20 minutes.
ml and 20 ml of water. After adjusting the pH of this mixture to 2 with 2% hydrochloric acid, the ethyl acetate layer was separated, washed successively with an aqueous sodium thiosulfate solution, water, and a saturated aqueous solution of sodium chloride, and dried over magnesium sulfate. When the ethyl acetate solution was concentrated and the resulting residue (2.56q) was reprecipitated twice with a benzene/acetone mixture, 1-(α
-carboxy3,5-dibromo4-hydroxybenzyl)-3-[2-(4-(3-carboxy3-(2
,2,2-trifluoroacetamide)propoxy)phenyl]-2-hydroxyiminoacetamide]-2-
1.16y of azetidinone is obtained. Infrared absorption spectrum νo-1 (liquid film): 1720 (BrOad), 1650
Example 4293-Glycinamidlactasilanic acid 100
mg of sodium bicarbonate suspended in 5 ml of water.
Add 0m9 and dissolve.

The solution was cooled to 0-5°C and 2-(4-chloro2-
A solution of 100 m9 of (nitrophenoxy)acetyl chloride dissolved in 5 m1 of acetone was added dropwise, and the mixture was allowed to react at the same temperature for 2 hours. Acetone was distilled off from the reaction solution under reduced pressure, and dilute hydrochloric acid was added to the remaining solution to adjust the pH to 2. The resulting solution was extracted with ethyl acetate. The extract is washed with water, dried, and then the solvent is distilled off. The resulting oil is washed with diethyl ether, dissolved in a small amount of methanol and diethyl ether is added. After collecting the precipitated powder and drying it, 3-[2-(2
82 m9 of -(4-chloro2-nitrophenoxy)acetamido)acetamido]lactasilanic acid are obtained. Mp
l49-153 molten C (decomposition). Example 478 3-(2-phenylglycinamido)lactasilanic acid as a raw material, 2-[4-chloro 2-(
Using α-acetoxyiminobenzyl)phenoxy]acetyl chloride, the 3-[2-[
2-(4-chloro2-(α-hydroxyiminobenzyl)phenoxy)acetamide]2-phenylacetamide]lactasilanic acid is obtained.

Mpl7l~176 (degraded).

Example 479 200 mg of 3-(2-phenylglycinamido)lactasilanic acid was added to 10 ml of methylene chloride. ．． N,
Suspended in a solution consisting of 1 ml of N-dimethylformamide and 1 ml of bis(trimethylsilyl)acetamide,
Stir for 1 hour at room temperature.

To this solution was added 140 m9 of hydrochloride of 2-aniline-2-phenylacetyl chloride under ice cooling, and the mixture was stirred at the same temperature for 1 hour to dissolve. The reaction solution was further stirred at room temperature for 1 hour, and then concentrated under reduced pressure. After adding ethyl acetate and water to the residual liquid, the ethyl acetate layer is separated. The ethyl acetate layer is extracted with an aqueous sodium bicarbonate solution, and the resulting aqueous layer is adjusted to pH1~2 with 1N monohydrochloric acid, and then extracted with ethyl acetate.
The ethyl acetate layer was washed with water, dried over magnesium sulfate, and then the solvent was distilled off. Diethyl ether was added to the resulting residue, stirred for 1 hour, and then the powder was collected, yielding 89 mg of 3-[2-phenyl-2-(2-anilino-2-phenylacetamido)acetamido]lactasilanic acid. Mp
l58-16rC (decomposition). Example 480 A mixed solution of 50 m9 of N,N-dimethylformamide and 200 m9 of thionyl chloride is stirred at 40 to 50°C for three times.

Excess thionyl chloride is distilled off from this mixture, and the residue is dissolved in 5 mt of methylene chloride and cooled to -10 to -5°C.
After adding 114 m9 of 2-[5-(2-thienyl)1H-tetrazol-1-yl]acetic acid at once to this solution, N
, 2 drops of N-dimethylformamide are added and dissolved, and the mixture is stirred. Then, after cooling this solution to -60 to -50°C, methylene chloride 2 containing 65 mg of triethylamine was added.
Add the rrL1 solution dropwise and stir at the same temperature for 3 times. Add 3-(
2-phenylglycinamide) lactasilanic acid 200T
ng, bis(trimethylsilyl)acetamide 430m
9. A suspension consisting of 10 ml of methylene chloride and 1 TrL of N,N-dimethylformamide was stirred at room temperature for 1 hour, and a solution obtained was added at once, and the mixture was mixed at the same temperature for 3 times, from -20 to
Stir at -10°C for 1 hour and then at -10 to 0°C for 1 hour. The solvent was distilled off from the reaction solution, and ethyl acetate and an aqueous sodium hydrogen carbonate solution were added to the residue. Separate the aqueous layer,
The pH was adjusted to 4 with 10% hydrochloric acid, and then extracted with ethyl acetate. The ethyl acetate layer is separated, washed with water, dried over magnesium sulfate, and then the solvent is distilled off. The resulting residue (70 m9) is washed with diethyl ether to obtain 60 mg of crude 3-[2-phenyl-2-[2-(5-(2-thienyl)-1Htetrazol-1-yl)acetamido]acetamido]lactasilanic acid. Furthermore, after dissolving this product in ethyl acetate, diethyl ether is added and the precipitated crystals are collected to obtain 30 Tng of a purified product of this product. Mpl7O~17
4°C (decomposition). Example 481 2-[5-(2-thienyl)-1H-tetrazole-1
-yl] using 2-phenylglycolic acid instead of acetic acid, and proceeding substantially in the same manner as in Example 480 to obtain 3
-[2-(Hydroxy-2-phenylacetamide)2
-phenylacetamide]lactasilanic acid is obtained.

Mp9O-93°C (decomposed). Example 482 3-[2-(2-thienyl)glycinamide])lactasilanic acid 0.358y and sodium bicarbonate 0.1
Add 5 ml of acetone to 5 ml of an aqueous solution consisting of 85y,
Cool to 0-5°C.

Add 2-(4-chloro-2-nitrophenoxy) to this solution.
5 m of dry acetone containing 0.230 V of acetyl chloride
t solution was added dropwise 7 and allowed to react at the same temperature for 2 hours. Methanol is distilled off from the reaction solution under reduced pressure, and the remaining aqueous layer is washed with ethyl acetate. The aqueous layer is then adjusted to pH1~2 with dilute hydrochloric acid and extracted with ethyl acetate. After washing the extract with water and drying, the solvent was distilled off to obtain a residue of 0.34y. Dissolve this residue in 2 ml of methanol, add 1 ml of acetone solution containing 0.88 y of sodium 2-ethylhexanoate, and then add 15 ml of diethyl ether. The precipitated powder was collected and washed three times with diethyl ether, resulting in 3-[
0.140 q of the sodium salt of 2-(2-(4-chloro-2-nitrophenoxy)acetamide)-2-(2-thienyl)acetamide]lactasilanic acid is obtained. Mpl
87-1900C (decomposition). The compounds shown in the following table are obtained by treatment in the same manner as above.

0UJ Example 490 To a solution of 380 m9 of dihydrochloride of guanidinocarbohydrazide dissolved in 3 nt of water, 140 Tng of sodium nitrite was gradually added while cooling to 0 to 5°C and stirred for 10 minutes to prepare a solution of guanidinocarbonyl azide. do.

On the other hand, 220 mg of 3-(2-phenylglycinamido)lactasilanic acid and 150 mg of sodium bicarbonate are dissolved in a solution consisting of 8 Tn1 of water and 4 ml of acetone, and one powder is stirred at 0 to 5°C. After removing insoluble matter from this solution, the solution prepared above was added dropwise to the bottom liquid over about 5 minutes, and the mixture was stirred at 0 to 5°C for 2 hours. During this time, the pH of the reaction solution was adjusted to pH 7.5-8 with 5% aqueous sodium hydrogen carbonate solution.
Keep it at 0. When the crystals precipitated in the reaction solution are filtered, 3-
20 m9 of (2-guanidinocarbonylamino-2-phenylacetamido)lactasilanic acid are obtained. Further, the liquid is concentrated to about 5 mt, and the precipitated crystals are collected to recover 60 mg of this product. Total yield 80mg. mp198~2
02°C (decomposition). Example 491 375 mg of 3-[2-(2-thienyl)glycinamide]lactasilanic acid is suspended in 5 ml of water, and then 104 ml of potassium carbonate is added and dissolved (the pH of the solution is about 9).

Add to this solution 1 a solution of acetone and water (1:1).
After adding 0 mt, 5 ml of dry acetone solution containing 163 mg of benzoyl isothiocyanate was added dropwise while stirring at room temperature, and stirred for 3 hours (during this time, a solution of 104 mg of potassium carbonate dissolved in 7j1.t of water was added to the reaction solution,
(maintain the liquid at approximately pH 8.5). Acetone is distilled off from the reaction solution under reduced pressure, and the remaining aqueous layer is washed with ethyl acetate. The aqueous layer was adjusted to pH1~2 with dilute hydrochloric acid and extracted with ethyl acetate. After washing the extract with water and drying, the solvent is distilled off.
496 mg of the remaining oil was subjected to column chromatography using silica gel 7y and eluted with a mixture of 3-methyl acetate and methanol to obtain 3-[2-(3-benzoylthioureido)-2-(2-thienyl). ) Acetamide]lactasilanic acid (97 mg) was obtained. Mpl24~129℃(
Disassembly). Example 49 To a solution of 100 mg of 3-(2-methylthio-2-phenylacetoa-4mido)lactasilanic acid dissolved in 5 nL of methanol solution, 85% 3
- Add chloroperbenzoic acid and stir for 1 hour at the same temperature to react. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in chloroform.
Washing with water gives 86 m9 of 3-(2-methanesulfinyl-2-phenylacetamido)lactasilanic acid.

Infrared absorption spectrum νCm-1 (nujiol): 17
40,1720,1665, Example 4933-[2:(
To a solution of N-(2-naphthyl)carbamoylmethylthio)2-phenylacetamide]ragtasilanic acid 171WL9 dissolved in 7ml of acetone, 61ml of 85% 3-chloroperbenzoic acid was added under ice cooling, and the reaction was stirred for 1 hour at the same temperature. let

When the reaction solution is concentrated and the resulting residue is crystallized from chloroform, 3-[2-(N-(2-naphthyl)carbamoylmethanesulfinyl)-2-phenylacetamide]
134 mg of lactasilanic acid are obtained. Mpl5l~155
°C (decomposition) Example 494 3-[2-(4-(3-amino-3-carboxypropoxy)phenyl)glycinamide]lactasilanic acid 1
．． 00V to water containing 0.66V of sodium hydrogen carbonate20
After dissolving in 10ml of acetone, add 10ml of acetone.

This solution is cooled with ice, and 5 ml of acetone solution containing 0.75 f of 2,4-dinitro-1-fluorobenzene is added dropwise with stirring, and stirred for 3 times at the same temperature and further stirred at room temperature for 5 hours. Wash the reaction solution with ethyl acetate. 10% residual liquid
Adjust the pH to 2 with hydrochloric acid and extract with ethyl acetate. The ethyl acetate layer was separated and the solvent was distilled off under reduced pressure. The resulting residue was powdered with diethyl ether to give 3-[2-[4-
(3-carboxy3-(2,4-dinitroanilino)
1.50 y of propoxy)phenyl]2-(2,4-dinitroanilino)acetamido]lactasilanic acid is obtained.
Infrared absorption spectrum νCrft-1 (nujiol): 1735, 1700 (
Shoulder), 1520, 1340 Example 495 3-[2-(4-(3-amino-3-carboxypropoxy)phenyl)glycinamide]lactasilanic acid 0
．． 49y and 0.49y of sodium hydrogen carbonate to 10% of water
ml and then add 5ml of methanol.

To this solution, 7 ml of methanol solution containing 0.08y of 4-fluoro-3-nitrobenzoic acid methyl ester was added dropwise, and the mixture was reacted at room temperature for 1'7 VIf and then at 50'C for 4 hours. After the reaction solution is allowed to cool for a while, the precipitate in the reaction solution is removed. (2) Methanol is distilled off from the liquid under reduced pressure, and the remaining aqueous solution is washed with diethyl ether. The aqueous solution is then adjusted to pH 3 with 1N monohydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer is separated and dried over magnesium sulfate.
The solvent was distilled off from the ethyl acetate solution under reduced pressure, and the resulting residue was powdered with benzene to give 3-[2-[4-(3-carboxy3-(4-methoxycarbonyl-52-nitroanilino)propoxy)phenyl]. 0.86y of -2-(4-methoxycarbonyl-2-nitroanilino)acetamide]lactasilanic acid is obtained. Mpl5O~15
5k C (decomposition). Example 496 8.9 y of 3-[2-(4-(3-benzamido-3-carboxypropoxy)phenyl)glycinamide]lactasilanic acid and 5.4 q of sodium bicarbonate were dissolved in 10 ml of water.
Dissolve in 0ml.

To this solution was added 100ml of methanol and 4.5y of 4-fluoro-3-nitrobenzoic acid methyl ester.
React at ~50°C for 4 hours with stirring. Methanol is distilled off from the reaction solution under reduced pressure, and the remaining solution is washed with ethyl acetate. This residual solution was adjusted to pH 2 with 10% hydrochloric acid and extracted with ethyl acetate. The extract is washed with dilute hydrochloric acid and water and then dried. The solvent was distilled off from the ethyl acetate solution under reduced pressure, and the resulting residue was powdered with diethyl ether and filtered to give 3-[2-(4-(3-benzamido-3-carboxypropoxy)phenyl)- 9.23y of 2-(4-methoxycarbonyl-2-nitroanilino)acetamido]lactasilanic acid is obtained. Infrared absorption spectrum ν-1 (nujiol): 1730, 1620, 1
528, Example 4973-[2-(4-(3-Carboxy3-phthalimidopropoxy)phenyl)glycinamide] 0.68 y of lactasilanic acid is dissolved in 10 ml of water containing 0.40 y of sodium bicarbonate.

After adding 10 nt of methanol to this solution, 0.30 y of 4-fluoro-3-nitrobenzoic acid methyl ester was added, and the mixture was reacted with stirring at 50° C. for 3 hours. Methanol is distilled off from the reaction solution, and the remaining aqueous solution is washed with ethyl acetate. The aqueous solution was adjusted to pH 2 with 10% hydrochloric acid, and then extracted with ethyl acetate. The ethyl acetate layer is separated and dried over magnesium sulfate. The solvent was distilled off from the ethyl acetate solution under reduced pressure, and the resulting residue was powdered with diethyl ether to give 3-[2-(4-(3-carboxy3-phthalimidopropoxy)phenyl)-2-(4- 0.53y of methoxybonyl-2-nitroanilino)acetamido]lactasilanic acid is obtained. 1mp155-160〕C(
Disassembly).

Example 498 0.50 g of the monosodium salt of 3-[2-(4-(3-amino-3-carboxypropoxy)phenyl)-2-hydroxyiminoacetamide]lactasilanic acid was added to 1 part of water.
Dissolve in 0 mL.

2 mt of acetone is added to this solution, and after stirring for a while, 0.30 y of sodium borohydride is gradually added and stirred for 3 hours. After adding 2Tnt of acetone to the reaction solution, the liquid property was reduced to 1
Adjust the pH to 3 with 0% hydrochloric acid. The precipitated crystals are collected in a furnace to obtain 0.05y of 3-[2-[4-(3-carboxy-3-(N-isopropylamihapropoxy)phenyl]-2-hydroxyiminoacetamide]lactasilanic acid. Furthermore, the mother liquor is Concentrate to about half the volume and collect the precipitated crystals overnight to recover 0.17y of the same target product (total yield: 0.17y).
622g). Mpl 93-194°C (decomposition). Example 4
99 3-[2-(4-(3-amino-3-
Example 49 using methyl 2-formylacetate as carboxypropoxy)phenyl)-2-hydroxyiminoacetamide]lactasilanic acid and the carbonyl compound
8, 3-[2-[4-[3-carboxy-3-(N-(2-methoxycarbonylethyl)amino)pro5-poxy]phenyl]-2-hydroxyiminoacetamido]lactasilanic acid is obtained.

Mpl 75-179°C (decomposed). Example 500 0.50 Da of the monosodium salt of 3-[2-(4-(3-amino-3-carboxy″θcypropoxy)phenyl)-2-hydroxyiminoacetamide]lactasilanic acid was dissolved in 10 mt of water and cooled on ice. Add 1 ml of 30% formaldehyde aqueous solution to the bottom and stir briefly.

Next, 0.15y of sodium borohydride was added to this reaction solution.
Gradually add and stir for 3 minutes. The reaction solution was cooled on ice at 10%
Adjust the pH to 3 with hydrochloric acid. The precipitated crystals were collected, washed with water and acetone, and then dried under reduced pressure at 40°C.
-[2-[4-(3-carboxy3-(N,N-dimethylamino)propoxy)phenyl]-2-2-hydroxyiminoacetamide]lactasilanic acid 0.281 is obtained. Mpl 93-194°C (decomposition). Example 501 3-(4-nitrobenzamido)lactasilanic acid 235
m9 was dissolved in 20 mt of methanol, 40 m9 of palladium/carbon catalyst was added thereto, and the mixture was shaken in a hydrogen stream at room temperature and normal pressure.

The calculated amount (44 ml) of hydrogen is absorbed in about 1 hour. The catalyst was removed from the reaction solution, and the Oki solution was concentrated to dryness under reduced pressure. The resulting residue is treated with diethyl ether and taken off, resulting in 3
-(4-aminobenzamido)lactasilanic acid 200m
get g. Mpl9O~194°C (decomposed). Example 50
2 210 mg of 3-(3,5-dinitrobenzamido)lactasilanic acid is dissolved in 20 ml of methanol, 40 ml of palladium/carbon catalyst is added thereto, and the mixture is shaken at room temperature and under normal pressure in a hydrogen stream.

A calculated amount (70TrL1) of hydrogen gas is absorbed in about 2 hours. The catalyst was removed from the reaction solution, and the resulting solution was concentrated to dryness under reduced pressure. The residue is washed with diethyl ether and then dissolved in acetone. Filter this acetone solution? Add ethyl acetate to the solution and concentrate. The concentrated solution is filtered, and the concentrated solution is concentrated to dryness under reduced pressure. The resulting residue is treated with diethyl ether and filtered to obtain 60 mg of 3-(3,5-diaminobenzamido)lactasilanic acid. Mpll6~121
Ku C (decomposition). Example 503 200 mg of 3-[2-(4-formylphenoxy)acetamido]lactasilanic acid was added to a solution of 1 ml of water containing 70 ml of hydroxylamine hydrochloride and 1.5 ml of 1N aqueous sodium monohydroxide solution at room temperature. Stir in between.

Ethyl acetate was layered on the reaction solution, 1.5 ml of 1N monohydrochloric acid was added, and the mixture was shaken, and then the ethyl acetate layer was separated. After washing the ethyl acetate with water and drying over magnesium sulfate, the solvent was distilled off. A mixed solvent of ethyl acetate◆chloroform (1:1) was added to 190 mg of the obtained residue to crystallize it, and then 190 mg was added at room temperature.
Stir for an hour. When this crystal is cut off, 3-[2-(4
-Hydroxyiminomethylphenoxy)acetamide]
130 m9 of lactasilanic acid are obtained. Mpl5O~155
°C (decomposition) Example 504 3-[2-(4-formylphenoxy)acetamide]
200 mg of lactasilanic acid to 1 part of 2-aminooxyacetic acid
h Add to a solution consisting of 66 mg of hydrochloride and 1.5 ml of 1N aqueous sodium monohydroxide solution and stir at room temperature for 2 hours.

The reaction solution was adjusted to pH 2 with 1N monohydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer is separated, washed with water, and then dried over magnesium sulfate. The solvent was distilled off from the extract, diethyl ether was added to the residue, and the mixture was stirred at room temperature for 2 hours. The crystals precipitated in the solution are harvested, and 150 m9 of the resulting crystals are washed with ethyl acetate for 7 times to obtain 110 m9 of 3-[2-(4-carboxymethoxyiminomethylphenoxy)acetamido]lactasilanic acid. Mpl44-14TC (degraded). Example 5053-[2-(4-formylphenoxy)-2-a phenylacetamide]lactasilanic acid 2
37 mg of 2-aminooxyacetic acid 112 hydrochloride 106
mg and 1.8 TfL of 1N sodium monohydroxide aqueous solution
Add to the solution consisting of t and stir at room temperature for 2 hours.

The reaction solution was adjusted to pH1~2 with 10% hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer is separated, washed with water, and then dried over magnesium sulfate. The solvent was distilled off from the extract, the residue was washed with diisopropyl ether, and the residue was washed with diisopropyl ether to give 3-[2
-(4-carboxymethoxyiminomethylphenoxy)
-2-phenylacetamide]lactasilanic acid 190m
Get 9. Mpll7-121 solution). Example 506 3-[2-(4-formylphenoxy)acetamide]
200 m9 of lactasilanic acid, 5 m1 of 0.1N aqueous sodium monohydroxide solution and N-(carbazoylmethyl)-N
, N,N-Trimethylammonium chloride (90 mg) and stirred at room temperature for 2 hours.

Add N-(carbazoylmethyl)-N,N to this solution.
, 90 mg of N-trimethylammonium chloride was added and left overnight. Add 0.5 m of 1N monohydrochloric acid to the reaction solution. After adding t and 100Tn9 of acetic acid, the mixture is washed with ethyl acetate and diethyl ether. The aqueous layer is taken, and the organic solvent saturated therein is completely distilled off under reduced pressure, and then subjected to column chromatography using 50ml of adsorption resin Amperlite XAD-2 (trademark, manufactured by Rohm and Haas). . Elute with water and then methanol, and collect the fractions containing the target product eluted with methanol. These fractions were combined and concentrated, and the resulting residue was washed with ethanol and filtered to give N-
(3-[4-[N-(1-(α-carboxy4-hydroxybenzyl)-2-oxo-3-azetidinyl)carbamoylmethoxy]benzylidene]carbazoylmethyl]-N,N,N-trimethylammonium chloride 1
Obtain 88 mg. Mpl99-205UC (degraded). Example 507 3-[2-(2=(2-benzoyl-4-chlorophenoxy)acetamide)2-phenylacetamide] Hydrochloride of hydroxylamine (35 m9) in 5 m1 of 0.1N aqueous sodium monohydroxide solution containing 160 mg of lactasilanic acid
Add 0.5 ml of water containing

Add a small amount of hydroxyamine hydrochloride to this solution and adjust the pH.
6. After adjusting the temperature to 0~6.2, stir for 10 minutes. Add 5 mt of methanol to the reaction solution, stir at room temperature for 3 hours, and then leave in the refrigerator overnight. When the crystals precipitated in the reaction solution are removed, 3-[2-[2-(4-chloro2-(α-hydroxyiminobenzyl)phenoxy)acetamide]-
2-phenylacetamide]lactasilanic acid 100mg
get. Mpl7l~176°C (decomposition). Example 508 3-[2-(4-(3-acetamido-3-carboxypropoxy)phenyl)glycinamide]lactasilanic acid 1.3' was dissolved in 50% hydrated pyridine 267n1,
Add 1N aqueous sodium monohydroxide solution to adjust the pH to 8.
Adjust to 4.

Next, 0.40 g of phenyl isothiocyanate was added to this solution under ice cooling, and the mixture was stirred for 4.5 hours. The reaction solution was washed with diethyl ether, the aqueous layer was adjusted to pH 2 with 10% hydrochloric acid, and the precipitated solid was washed off. After dissolving the obtained solid in an aqueous sodium hydrogen carbonate solution, the pH was adjusted to 2 with 10% hydrochloric acid.
When the precipitated crystals are collected, 3-[2-(4
-(3-acetamido-3-carboxypropoxy)phenyl)-2-(3-phenylthioureido)acetamido]lactasilanic acid 0.92f is obtained. Mpl5O~
156kuC (decomposition). Example 5093-[2-(4-(
50% of 2.0y of 3-acetamido-3-carboxypropoxy)phenyl)glycinamide]lactasilanic acid
Dissolve in 20 ml of water-containing pyridine, and adjust the pH to 8.6 by adding 1N aqueous sodium monohydroxide solution under ice cooling.

Next, 0.74 fI of 1-naphthyl isothiocyanate was added to this solution at the same temperature, and the mixture was stirred at room temperature for 4 hours. The reaction solution was washed with diethyl ether, and the aqueous layer was diluted to 10% under ice cooling.
After adjusting the pH to 2 with phosphoric acid, the precipitated solid is taken off and washed with water. The resulting solid was dissolved in a saturated aqueous solution of sodium bicarbonate, the pH was adjusted to 2 with 10% phosphoric acid, and the precipitated crystals were collected.3-[2-(4-(3-acetamido-3-carboxypropoxy)phenyl) )-2-(3-
(1-Naphthyl)thioureido)acetamide]lactasilanic acid 2.5y is obtained. MPl42-14rC (decomposed). Example 5103-[2-(4-(3-acetamido-3-carboxypropoxy)phenyl)glycinamide] Using lactasilanic acid as the raw material and acetyl chloride as the acylating agent, the same treatment as in Example 509 was carried out, and 3 -[2-(4-(3-acetamido-3-carboxypropoxy)phenyl)-2-acetamido]lactasilanic acid is obtained.

Infrared absorption spectrum νCm-1 (nujiol): 17
35,1650.

Example 5113-[2-(4-(3-benzamide 3)
-carboxypropoxy)phenyl)glycinamide]
50% hydrated pyridine containing 7.8f of lactasilanic acid (160)
ml, and adjust the pH to 8.6 by adding 1N aqueous sodium monohydroxide solution.

Next, 2.64 y of phenyl isothiocyanate was added to this solution at the same temperature and stirred for 3 hours. The reaction solution was washed with diethyl ether, and the aqueous layer was adjusted to pH 2 with 10% phosphoric acid under ice. 5. Take the oily substance separated into the aqueous solution and dissolve it in a saturated aqueous solution of sodium bicarbonate.

After adjusting the pH of this aqueous solution to 2 with 10% phosphoric acid, the precipitated crystals were collected and 3-[2-(4-(3-benzamido-3-carboxypropoxy)phenyl)-2-(3-
9.6f of fe-O-nylthioureido)acetamide]lactasilanic acid is obtained. Mpl33-138°C (decomposed). The following compound is obtained by treatment in the same manner as in Example 511.
317 Example 516 2.0 y of 3-[2-(4-(3-amino-3-carboxypropoxy)phenyl)-2-hydroxyiminoacetamide]lactasilanic acid are suspended in 20 ml of water.

Add 4.5 ml of 1N sodium monohydroxide aqueous solution to this suspension.
After adding and dissolving 0.66y of sodium hydroxymethanesulfonate (monohydrate), the mixture was stirred at room temperature for 2 hours. Filter the reaction solution and reduce the volume of the solution under reduced pressure to approximately 213.
Concentrate until. Add 40ml of acetone to the residual solution, scrape off the powder that precipitates in the solution, and add 3-[2-[4-(
1.85 Da of the disodium salt of 3-carboxy 3-(N-sulfomethylamino)propoxy)phenyl]-2-hydroxyiminoacetamido]lactasilanic acid is obtained. Infrared absorption spectrum να-1 (nujiol): 17
30,1600,1240 Example 5173-[4-(3
-Amino-3-carboxypropoxy)phenylglyoxyroylamino]lactasilanic acid 0.50y in water 10
Suspend in mt.

Add 1.1 ml of 1N sodium monohydroxide aqueous solution to this suspension.
After adding and dissolving 0.152y of sodium hydroxymethanesulfonate (monohydrate), the mixture was stirred at room temperature for 4 hours. Water is distilled off from the reaction solution under reduced pressure, and the residue is pulverized with acetone. After dissolving 0.49y of the resulting powder in a small amount of water, acetone was gradually added and the precipitated crystals were distilled to give 3-[4-(3-carboxy 3-(N-sulfomethylamino)propoxy) phenylglyceride. 63 mg of the disodium salt of oxyroylamino]lactasilanic acid is obtained. Infrared absorption spectrum νCm-1 (nujiol): 1720, 1650, 12
60 Example 5183-[2-(4-(3-amino-3-
Carboki. Cypropoxy)phenyl)-2-hydroxyiminoacetamide] To a mixture of 500 mg of lactasilanic acid and 6 ml of water was added 1.2 ml of a 1N aqueous sodium monohydroxide solution under cooling and dissolved. Add a solution of
Stir at ℃ for 1 hour.

The reaction solution was concentrated under reduced pressure until the volume was about 113. After adding 10 ml of ethanol to the residual solution, the precipitated crystals were collected in a furnace to obtain 3-[2-[4-[3-carboxy 3-(
Disodium salt 0.3y of N-(1-sulfoethyl)amino)propoxy[phenyl]-2-hydroxyiminoacetamide]lactasilanic acid is obtained.

Mp224.5-22 RyoC (decomposition). Example 519 169m9 of 3-[2-(2-(2-carboxyphenylthio)acetamide)-2-phenylacetamide]lactasilanic acid was dissolved in 6Tn1 of acetone, and 85% 3-chloroperbenzoic acid was prepared under ice cooling. Add 61m9 and 1 at the same temperature.
Stir for an hour.

The reaction solution was concentrated under reduced pressure, and about 3 mt of ethyl acetate was added to the residue, followed by stirring for 2 hours. The crystals precipitated in the ethyl acetate solution were collected, washed with ethyl acetate, and dried, resulting in 3
120 m9 of -.[2-(2-(2-carboxybenzenesulfinyl)acetamide)-2-phenylacetamide]lactasilanic acid are obtained. MPl75~18rc(
Disassembly). Example 520 3-[2-[4-(3-carboxy 3-(2,2,2
-trifluoroacetamido)propoxy)phenyl]
-2-Hydroxyiminoacetamide] In a solution of 0.59 y of lactasilanic acid dissolved in 10 ml of acetone and 2 ml of water, 0.34 J of sodium bicarbonate and 0.15 J of sodium iodide were added and allowed to stand for a while.

Add 0.60q of pivalic acid chloromethyl ester to this solution.
was added and heated under reflux for 4 hours. Acetone was distilled off from the reaction solution under reduced pressure, and the remaining solution was mixed with 20 ml of ethyl acetate and 2 ml of water.
0071. The ethyl acetate layer is washed successively with an aqueous sodium bicarbonate solution, water, and a saturated aqueous sodium chloride solution, and then dried over magnesium sulfate.
The solvent is distilled off from the ethyl acetate solution under reduced pressure and the residue is triturated with benzene. 0.19y of the resulting powder is subjected to column chromatography using 10y of silica gel. Elute with a mixed solution of chloroform and methanol (99:1), collect fractions containing the target product, and distill off the solvent from the eluate. When the residue was recrystallized from a mixed solvent of diethyl ether and diisopropyl ether, 1-(α-pivaloyloxymethoxycarbonyl-4-hydroxybenzyl) was obtained.
-3-[2-[4-(3-pivaloyloxymethoxycarbonyl-3-(2,2,2-trifluoroacetamido)propoxy)phenyl]-2-hydroxyiminoacetamide]-2-azetidinone 0.12y get. M
pl35-1400C (decomposition). Example 5213-[2
-[4-(3-carboxy3-(3-phenylthioureido)propoxy)phenyl]-2-(3-phenylthioureido)acetamide]lactasilanic acid 3.04
A solution of y dissolved in 30 ml of dry acetone was added with 1.0 f of triethylamine and 6.4 da of pyridine, and stirred for a while.

This mixed solution was cooled to -20 to -500C, and a solution of 2.1y of chloroformic acid 2,2,2-trichloroethyl ester dissolved in 20ml of dry acetone was added dropwise to it, and at the same temperature. Stir for 2 hours. Acetone is distilled off from the reaction solution under reduced pressure, and the residue is poured into a mixed solution consisting of 200 ml of water and 200 ml of ethyl acetate. The ethyl acetate layer is separated, washed with an aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, and then dried over magnesium sulfate. The solvent is distilled off from the ethyl acetate solution and the residue is triturated with diethyl ether. The resulting powder 1.2y is subjected to column chromatography using silica gel 50q. Elute with a mixed solvent of chloroform and methanol (99:1). Fractions containing the target product were collected and the solvent was distilled off from the eluate to obtain 1-[α-2,2,2-trichloroethoxycarbonyl)-4-hydroxybenzyl]-3-[2-[4-
(3-(3-phenylthioureido)-3-(2,2,
0.16 q of 2-trichloroethoxycarbonyl)propoxy)phenyl]-2-(3-phenylthioureido)acetamide]-2-azetidinone is obtained. Infrared absorption spectrum νCm-1 (nujiol): 1750, 1680, 12
20 Example 52223-[2-(4-(3-acetamido-3-carboxypropoxy)phenyl)-2-hydroxyiminoacetamide] A diethyl ether solution containing diazomethane was added to a solution of 5.5 g of lactasilanic acid dissolved in 150 ml of methanol. Add diazomethane until the color does not disappear and leave it in the refrigerator overnight.

The solvent is distilled off from the reaction solution, and the residue is subjected to column ◆ chromatography using silica gel. Elute with a mixed solvent of chloroform and methanol (98:2) and collect fractions containing the target product. When the solvent is distilled off from the eluate, 1-(''
α-methoxycarbonyl-4-methoxybenzyl)-3
3.50 g of -[2-(4-(3-acetamido-3-methoxycarbonylpropoxy)phenyl)-2-methoxyiminoacetamide]-2-azetidinone are obtained. Nuclear magnetic resonance absorption spectrum δPpm (CDCl3): 1.
95 (311, s), 2.25 (2H, m), 3.15
(1H, 1, d, J = 3Hz, 6Hz), 3.70 (3
H, c), 3.74 (3H, s), 3.78 (3H, s
), 3.89 (311, s), 3.96 (2H, t, J
=6Hz), 4.70 (1H, q, J=8Hz), 4.
92 (1H, m), 5.52 (1H, s), 6.75 (
2H, d, J = 9Hz), 6.86 (211, d, J =
9Hz), 7.20 (2H, d, J=9Hz), 7.4
5(21(,D,J=9Hz) Example 523 3-[2-[4-(3-carboxy 3-(2,2,2
-trifluoroacetamido)propoxy)phenyl]
-2-Hydroxyiminoacetamide] 2.0 y of lactasilanic acid is dissolved in a solution consisting of 20 ml of diethyl ether and 15 ml of methanol and cooled on ice.

A diethyl ether solution containing diazomethane is added dropwise to this solution until the color of diazomethane no longer disappears, and the mixture is stirred at the same temperature for 4 hours and then at room temperature for 2 hours. The solvent was distilled off from the reaction solution, and the resulting residue (2.10y) was poured into 50q of silica gel.
The sample is subjected to column chromatography using chloroform and eluted with chloroform. Fractions containing the target product were collected and chloroform was distilled off from the eluate to obtain 1-(α-methoxycarbonyl-4-methoxybenzyl)-3-[2-[4-(3
-Methoxycarbonyl-3-(2,2,2-trifluoroacetamido)propoxy)phenyl]-2-methoxyiminoacetamido]-2-azetidinone 1.2y is obtained. Infrared absorption spectrum νCm-1 (liquid film): 1730, 1700, 1650 Example 5 3.50y of 3-[2-(4-(3-carboxy-3-phthalimidopropoxy)phenyl)-2-hydroxyiminoacetamide]lactasilanic acid A solution dissolved in 30TrL1 of methanol is ice-cooled, and a diethyl ether solution containing diazomethane is added dropwise until the color of diazomethane no longer disappears, stirred at the same temperature for 5 hours, and left in the refrigerator overnight.

The solvent was distilled off from the reaction solution, and the resulting residue was purified with silica gel 8.
0y was subjected to column chromatography using JZI.

Elute with chloroform and then with a mixed solvent of chloroform◆methanol (98:2). Chloroform/
Fractions containing the target product eluted with a methanol mixed solvent are collected, and the solvent is distilled off from the eluate to obtain 1-(α-methoxycarbonyl-4-methoxybenzyl)-3-[2-(4
-(3-phthalimido 3-methoxycarbonylpropoxy)phenyl)-2-methoxyiminoacetamide]
-2-azetidinone 1.20f is obtained. Nuclear magnetic resonance absorption spectrum Ppm (CDCl3): 2.70 (211, s), 3.
15 (1H, dd, J = 3Hz, 6Hz), 3.70 (
1H, m), 3.75 (6H, s), 3.78 (Aim, s
), 3.88 (3H, s), 3.94 (2H, m), 5
．． 05 (1H, m), 5.16 (1H, t, J=6Hz
), 5.56 (1H, s), 6.62 (211, d, J
=9Hz), 6.84 (2H, d, J = 9Hz), 7.
20 (2H, d, J = 9Hz), 7.38 (211, d
, J=9Hz), 7.74 (4H, m) Example 525 0.70y of 3-[2-(4-(3-acetamido-3-carboxypropoxy)phenyl)-2-acetamidoacetamido]lactasilazoic acid in 20ml of methanol A diethyl ether solution containing diazomethane is added dropwise to the solution in which the diazomethane is dissolved until the color of the diazomethane no longer disappears, and the solution is left in the refrigerator overnight.

The solvent was distilled off from the reaction solution, and the resulting residue was purified using silica gel 2.
Subjected to column chromatography using 5y. Chloroform, then chloroform◆methanol mixed solvent (
Elute by increasing the amount of methanol (1%, 2%, 3%). Collect fractions containing the target product. When the solvent was distilled off from the eluate, 1-(α-methoxycarbonyl-4-methoxybenzyl)-3-[2-(4-(3-acetamido-3-methoxycarbonylproboxy)phenyl)-2-
Acetamide Acetamide]-2-azetidinone 0.3
Get 0y. Infrared absorption spectrum νCwl-1 (CDCl3): 1745, 1667, 1
195 Example 52 2.50 da of 3-[4-(3-amino-3-carboxypropoxy)phenylglyoxyroylamino]lactasilanic acid was dissolved in 17.5 ml of dimethyl sulfoxide, and 12.5 ml of acetic acid and 12.5 ml of acetic acid were dissolved under ice-cooling. Add 12.5ml of water and stir briefly.

21n of water containing 0.50y of sodium nitrite in this solution
1 solution and stirred at room temperature for 2 hours. Pour the reaction solution into ice water for 50 minutes.
m1 and extracted three times with acetic acid 507n1. The ethyl acetate layer is separated, washed twice with 20 ml of water and once with a saturated aqueous solution of sodium chloride, and then dried over magnesium sulfate. The solvent was distilled off from the ethyl acetate solution under reduced pressure, and the residue was crystallized from a mixed solvent of ethyl acetate and diethyl ether, and then filtered to give 3-[4-(3-carboxy 3-hydroxypropoxy) phenylglyoxy. 0.49' of roylamino]lactasilanic acid is obtained. Further, 0.21y of the same target product was recovered from the mother liquor. Total yield 0.70y0m
p196-201 C (decomposition).

Example 527 Using 3-[2-(4-(3-carboxy3-phthalimidopropoxy)phenyl)glycinamide]lactasilanic acid as a raw material and treating in the same manner as in Example 526, 3-[2-(4-( 3″-1-carboxy-3-phthalimidopropoxy)phenyl)-2-hydroxyacetamide]lactasilanic acid is obtained.

Mpl6O~163°C (decomposition). Example 5283-[
2-Glycinamide 2-(2-thienyl)acetamide] 200 m9 of lactasilanic acid was dissolved in 1 ml of sodium bicarbonate.
Dissolve in 5ml of water containing 68m9.

After adding 5 ml of methanol to this solution, 80 mg of 4-fluoro-3-nitrobenzoic acid methyl ester was added,
Stir at 50°C for 3 hours. Methanol is distilled off from the reaction solution under reduced pressure, and the remaining aqueous solution is washed with ethyl acetate. While cooling the aqueous layer, adjust the pH to 2-3 with 10% hydrochloric acid, and then extract twice with ethyl acetate. After combining the ethyl acetate extracts and washing with water, drying with magnesium sulfate,
Concentrate to dryness under reduced pressure. 90 m9 of the resulting residue was crystallized by treatment with diethyl ether to give crude 3-[2
70 m9 of -(N-(4-methoxycarbonyl-2-nitrophenyl)glycinamide)-2-(2-thienyl)acetamide]lactasilanic acid is obtained. Further, this product was subjected to column chromatography using silica gel (2J), the fractions eluted with ethyl acetate were collected, and the solvent was distilled off from the eluate to obtain 11 mg of a purified product of this product.
Mpl6O~164°C (decomposition). Example 529 369 m9 of 3-(2-phenylglycinamido)lactasilanic acid is dissolved in a solution of 8T91 water containing 572 m9 of sodium carbonate.

To this solution, 7 ml of acetone solution containing 180 ml of 5-chloro-3-phenyl-1,2,4-oxadiazole was added dropwise, and the mixture was allowed to react at room temperature for 5 hours. The reaction solution was adjusted to pH 7. with sodium hydrogen carbonate. O and wash with ethyl acetate. The remaining aqueous solution was adjusted to pH approximately 3 with dilute hydrochloric acid and then extracted with ethyl acetate. The ethyl acetate layer is separated, washed with water, and dried over magnesium sulfate. The solvent was distilled off from the acetic acid tail solution, and 270 m9 of the resulting oily residue was immersed in silica gel (7 f
) for column chromatography. The fractions eluted with a mixed solvent of ethyl acetate and methanol (97:3) were collected, and the solvent was distilled off from the eluate to form a powdery 3-[
95 m9 of 2-phenyl-N-(3-phenyl-1,2,4-oxadiazol-5-yl)glycinamide]lactasilanic acid is obtained. Infrared absorption spectrum νCm-1
(Nudiyol): 1738, 1680, 1618 Example 530 0.19 g of 3-(2-phenylacetamido)lactasilanic acid is suspended in 5 mL of methanol.

A diethyl ether solution of diazomethane is added to this suspension under ice cooling until the color of diazomethane no longer disappears, and the mixture is stirred at the same temperature for 2 hours. The solvent is distilled off from the reaction solution under reduced pressure, and the resulting residue is dissolved in chloroform. This solution was washed successively with an aqueous sodium bicarbonate solution, water and a saturated aqueous sodium chloride solution, and then dried over magnesium sulfate.
Chloroform was distilled off from this solution, and the residue was crystallized with diethyl ether to obtain 0.12y of crude crystals of 1-(α-methoxycarbonyl-4-methoxybenzyl)-3-(2-phenylacetamido)-2-azetidinone. obtain.
The crude crystals are recrystallized from diethyl ether to obtain 0.06y of the same objective compound. Mpl 45-146°C (decomposed). Example 531 14 mg of 3-(2-phenylacetamido)-1-(α-methoxycarbonyl-3-benzyloxycarbonylaminobenzyl)-2-azetidinone is dissolved in 4 ml of isopropyl alcohol.

Add 10% palladium/carbon 10m9 to this solution as a catalyst.
After adding 10% of
Shake for a time to absorb the calculated amount of hydrogen and perform catalytic reduction. When the catalyst is removed from the reaction solution and the Oki solution is concentrated, 3-(
2-phenylacetamido)-1-(α-methoxycarbonyl-3-aminobenzyl)-2-azetidinone 7m
Get 9. Infrared absorption spectrum νo-1 (CHCl3): 3425, 1755, 174
5,1675,1620, nuclear magnetic resonance absorption spectrum δPpm (CDCI3): 3.1 (1H, d, d, J'
-3Hz) 3.2 (2H, m) 3.5 (2
H, s) 3.7 (3H, s) 3.9 (1H, d, d-J half 5Hz) 4.
9 (1H, d, d, d, J: d3Hz) 5.5 (
1H, s) 6.2 (1H, d, J-8Hz) 6.6-7.7 (9FI, m) Example 532 3-[2-(2-(2-phenoxycarbonylphenoxy)acetamide)-2 -Phenylacetamide] 190 ml of lactasilanic acid is dissolved in 6 ml of methanol.

To this solution was added 60 m9 of an 80% aqueous hydrazine solution, and the mixture was stirred at room temperature for 3 hours. Methanol is distilled off from the reaction solution under reduced pressure, and the residue is pulverized with diethyl ether. Add a small amount of ethanol to 180 m9 of the resulting powder and mix at room temperature.
After stirring for an hour and removing the insoluble matter, 3-[2-(2-(2-(2)
100 m9 of -carbazoylphenoxy)acetamide)-2-phenylacetamide]lactasilanic acid are obtained.
Mpl78-182 C (decomposition). Example 533 200 m9 of 3-ethoxarylaminolactasilanic acid are suspended in 2 Tn1 ethanol.

Water containing 110 m9 of ethanolamine in this suspension 1.
Add 8q and stir at room temperature for 5 hours. Ethanol was distilled off from the reaction solution under reduced pressure, and 20 mt of ethyl acetate was added to the residue, followed by 1.2 Tn1 of 1N hydrochloric acid and stirred briefly. The ethyl acetate layer was separated and washed with 3 m1 of a saturated aqueous sodium chloride solution. The solvent is distilled off from this solution under reduced pressure, and 100 m9 of the resulting residue is powdered with diisopropyl ether to give 3-[N-(N-(
87 mg of 2-hydroxyethyl)oxamoyl)amino]lactasilanic acid are obtained. 325 Infrared absorption spectrum να-1 (KBr): 3300, 1735, 1660,
15100 Example 5 100 ml of 3-ethoxarylaminolactasilanic acid are suspended in 2 ml of ethanol.

To this suspension was added 3.5 ml of ethanol containing 96 ml of benzylamine, and the mixture was stirred at room temperature for 6 hours. Further, 2 ml of ethanol was added to this reaction solution, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated to dryness under reduced pressure, and 20% of ethyl acetate was added to the residue.
After adding m1 and 0.7Tn1 of 1N hydrochloric acid, the mixture is stirred. The ethyl acetate layer is separated, washed successively with 1-2% hydrochloric acid, water and aqueous sodium chloride solution, and then dried over magnesium sulfate. The solvent is distilled off from this solution under reduced pressure, and ethyl acetate is added to the resulting residue for crystallization. When this crystal is treated with diisopropyl ether, 3-[N-(N-
Benzyloxamoyl)amino]lactasilanic acid 90m
get g. Mpl25-129°C (decomposition). Example 5
35 200 ml of 3-(2-ethoxarylamino-2-phenylacetamido)lactasilanic acid are dissolved in 6 ml of ethanol.

To this solution was added 1.5 y of ethanol containing 137 mg of benzylamine, and the mixture was stirred at room temperature for 6 and a half hours. After concentrating the reaction solution under reduced pressure and adding water and ethyl acetate to the residue, 1
Add 1 ml of N hydrochloric acid. Separate the ethyl acetate layer and add 1%
After washing with hydrochloric acid and water, drying with magnesium sulfate. Ethyl acetate was distilled off from this solution under reduced pressure, and the resulting residue was washed with diisopropyl ether to obtain 3-[2-(N-benzinoleoxamoinole)amino] of the roving Yoshi crystal.
-2-phenylacetamide]lactasilanic acid 160m
get g. The crude crystals are recrystallized from a mixture of acetone and ethyl acetate to obtain 70m9 of the desired product. Mpl4
9-154°C (decomposition). Example 5363-[2-(4
-(3-Amino-3-carboxypropoxy)phenyl)-2-hydroxyiminoacetamide] 1.0 y of lactasilanic acid is dissolved in an aqueous solution consisting of 4 ml of 1N aqueous sodium hydroxide solution and 20 ml of water.

Add 0.17 methyl acrylate to this solution under ice cooling.
Gradually drop a solution of Da dissolved in 2 ml of methanol,
Stir for 3 minutes. Add 0.0% methyl acrylate to the reaction solution.
A solution of 17V dissolved in 2 mL of methanol was added dropwise, and the mixture was stirred at the same temperature for 4 and a half hours.

Add 10% hydrochloric acid to the reaction solution to adjust the pH to 3, and collect the precipitated crystals. The obtained crystals (0.87V) were dissolved in an aqueous sodium bicarbonate solution, the pH was adjusted to 3 with 10% hydrochloric acid, and the precipitated crystals were collected to give 3-[2-[4-(3-carboxy 3-(2-methoxycarbonylethyl) 0.57y of amino)propoxy)phenyl]-2-hydroxyiminoacetamido]lactasilanic acid is obtained. Mpl75～
179°C (decomposition). Example 5373-[2-(4-(3
-amino-3-carboxypropoxy)phenyl)-2
-Hydroxyiminoacetamide]lactasilanic acid 3.
0y to methanol 6 containing 480mg of sodium hydroxide
Dissolve in 0ml.

20 mL of methanol containing 835 mg of methyl acetoacetate is added to this solution, and the mixture is stirred at 74° C. for 6 hours.
Methanol is distilled off from the reaction mixture under reduced pressure, and the residue is suspended in 300 ml of ethanol. This suspension was stirred at room temperature for 1 hour, and the insoluble materials were removed and washed with diethyl ether. -carboxypropoxy)phenyl]-2-hydroxyiminoacetamide]
1.2y of lactasilanic acid disodium salt is obtained. Concentrate the mother liquor, add diethyl ether, and remove the precipitated material to recover 2.4y of the same desired product. Total yield 3
．． 6 da. Nuclear magnetic resonance absorption spectrum δPpmcD2O] 1.8 (31(,s) 2.2(2H,m) 3.1(1H,m) 3.8(2H,m) 3.56(311,s) 4. 1(2H,br0ads) 5.0(1H,m) 5.3(1H,s) 6.7-7.5(8H,m) Example 538 3-[2-(4-(3-azidopropoxy) ) phenyl)
Acetamide] Lactasilanic acid 52m9 methanol 1
Dissolve in 0ml.

To this solution, 30 m9 of 10% palladium on carbon was added as a catalyst, and catalytic reduction was carried out in a hydrogen stream at room temperature and pressure for 1.5 hours to absorb the calculated amount of hydrogen gas. The catalyst was removed from the reaction mixture, concentrated to dryness under reduced pressure, and the residue was treated with acetone to obtain 3-[2-(
38 m9 of 4-(3-aminopropoxy)phenyl)acetamide]lactasilanic acid are obtained. Infrared absorption spectrum νCm-1 (nujiol): 1730, 1660, 16
100 Example 5 200 ml of 393-[2-(2-azidoacetamide)-2-(2-thienyl)acetamide]lactasilanic acid are dissolved in 10 ml of methanol.

In this solution, 150 m of 10% palladium carbon was added as a catalyst.
9 was added and catalytic reduction was carried out under conditions of normal temperature and pressure in a hydrogen stream for 3 days to absorb the calculated amount of hydrogen gas. Catalyst from reaction mixture? The extract was concentrated to dryness under reduced pressure. The resulting residue was powdered with diethyl ether to give 3-[2-(
40 mg of lactasilanic acid (2-aminoacetamido)-2-(2-thienyl)acetamido] is obtained. Mpl95
~198°C (decomposition). Example 5403-[2-[2-(
103 m9 of 4-chloro2-(4-nitrobenzoyl)phenoxy)acetamide]-2-phenylacetamide]lactasilanic acid are dissolved in 15771 L of methanol.

To this solution, 45 mg of 10% palladium on carbon is added as a catalyst, and catalytic reduction is carried out for 1.5 hours under normal temperature and normal pressure conditions in a hydrogen stream to absorb the calculated amount of hydrogen gas. The catalyst is removed from the reaction solution, and the liquid is concentrated to dryness under reduced pressure. When 80 mg of the resulting residue was treated with diethyl ether, 3-[2-[
2-(4-chloro2-(4-aminobenzoyl)phenoxy)acetamide]-2-phenylacetamide]
70 m9 of lactasilanic acid are obtained. Mpl5O~153°C (decomposition). Example 541 3-[2-(4-formylphenoxy)acetamide]
200 m9 of lactasilanic acid is dissolved in 5 mL of 0.1N aqueous sodium hydroxide solution.

To this solution was added 20 mg of sodium borohydride under ice cooling, and the mixture was stirred at the same temperature for 5 minutes. There is no acetone in this reaction solution.
．． After adding 5 ml and 10 ml of ethyl acetate, the pH was adjusted to ~2 with 1N hydrochloric acid. The ethyl acetate layer is separated, washed with water and an aqueous solution of sodium chloride, and then dried over magnesium sulfate. This solution is concentrated under reduced pressure, and the precipitated solid is collected. When this solid was crystallized from ethyl acetate, 3-[2-(4-hydroxymethylene)
(1 chlorophenoxy)acetamide]lactasilanic acid 110ff19 is obtained.

Mpl 82-185°C (decomposition). Example 5423-[2
-(2-(2-formylphenoxy)acetamide)-
2-phenylacetamide]lactasilanic acid 200Tn
9 is ice cold sewage 1077! Suspend in l.

After adding 175 m9 of 30% ammonia water to this suspension at the same temperature and dissolving it, 28.4 m of sodium borohydride was added.
Add mg and stir for 2 hours at 1C. Add 1N hydrochloric acid to the reaction solution to adjust the pH to 3-4, and extract with ethyl acetate. The extract is washed with water, dried over magnesium sulfate, and then concentrated to dryness under reduced pressure. The resulting residue is treated with diisopropyl ether to obtain 130 mg of 3-[2-(2-(2-hydroxymethylphenoxy)acetamide)-2-phenylacetamido]lactasilanic acid. Mp95-101℃ (
Disassembly). Example 543-(2-phenyl-2-phenylglyoxyloylaminoacetamide)lactasilanic acid 170 was added to 3.5 m of 0.1N aqueous sodium hydroxide solution.
Dissolve in 1.

Add 13 m of sodium borohydride to this solution while stirring.
Gradually drop 1 TI 1 of water containing 10 g of water into the mixture, and stir at room temperature for 4 minutes. After adding 30 ml of ethyl acetate to the reaction solution, the mixture was adjusted to PHL with 10% hydrochloric acid and stirred for a while. After separating the ethyl acetate layer, the remaining aqueous layer was extracted with 20 ml of ethyl acetate. This extract and the previously obtained ethyl acetate layer are combined, washed with an aqueous sodium chloride solution, and then dried over magnesium sulfate. Ethyl acetate was distilled off from this solution under reduced pressure, and 1707 mg of the resulting residue was crystallized with diethyl ether to produce 3-[2-(2-hydroxy-2-phenylacetamide)-2-phenylacetamide]lactasilanic acid 14.
Obtain 0m9. Mp9O-93°C (decomposed). Example 54
43-[2-(4-formylphenoxy)acetamide]lactasilanic acid 200mg, benzylamine 106m
9. Add 40 TTLL of sodium borohydride to a mixed solution consisting of 2 ml of ethanol and 5 ml of 0.1N aqueous sodium hydroxide solution under ice cooling, and stir at the same temperature for 3 times.

The reaction solution was washed twice with diethyl ether, and the resulting aqueous layer was adjusted to pH 4 with 10% hydrochloric acid. The separated oil was collected by decantation, pulverized with acetone, and then treated to give 105 m9 of 3-[2-(4-benzylaminomethylphenoxy)acetamio]lactasilanic acid, Mpl 72-177°C (decomposition). .

Example 545 3-[2-[2-[4-chloro-2-(4-(2-chloroacetamido)benzoyl)phenoxy]acetamido]-2-phenylacetamido]lactasilanic acid 15
160 mg of a 30% trimethylamine aqueous solution was added to a solution of 0 mg dissolved in 4 ml of methanol, and the mixture was stirred at 50°C for 1.5 hours.

Add 160ml of 30% trimethylamine aqueous solution to the reaction solution.
9 was added 4 times every hour (total 640 m9) to react. The solvent is distilled off from the reaction solution, and the residue is washed with acetone. Add 5 ml of water to 150 ml of the resulting residue, stir for 3 minutes, and filter out the crystals. After adding 10 mL of acetone to the crystals and stirring for 30 minutes, the crystals were taken out and N-[N-[4
-[5-chloro2-[N-[1-[N-(1-(α-carboxy4-hydroxybenzyl)-2-oxo-3-azetidinyl)carbamoyl]-1-phenylmethyl]carbamoylmethoxy]benzoyl]phenyl 120 mg of [carbamoylmethyl]-1N,N,N-trimethylammonium chloride is obtained. Mp2l4~2200
C (decomposition). Example 54 160 m9 of 3-(guanidinocarbonylamino)lactasilanic acid and 130 m9 of sodium bicarbonate were mixed with 10 m9 of 0.1N potassium hydroxide aqueous solution.
TLL1 is dissolved in a solution consisting of 5 ml of water and 10 ml of acetone.

2 mL of acetone containing 240 m9 of 2-phenylacetyl chloride was added dropwise to this solution, and the mixture was stirred for 3 hours under ice cooling. When the crystals precipitated in the reaction solution are collected, 3-, [
120 m9 of 3-(2-phenylacetyl)guanidinocarbonylamino]lactasilanic acid are obtained. Mpl59～
1610C (decomposition). Example 547 2-(2,2-dichloroacetoxyimino)-. 552 m9 of 2-phenylacetic acid was diluted with 10 m of diethyl ether under ice cooling.
Dissolve in m1.

After adding 416 m9 of phosphorus pentachloride to this solution, 1
Stir for an hour. Separately, 472 m9 of 3-aminolactasilanic acid, 1.2 y of N,O-bis(trimethylsilyl)acetamide and 1 ml of N,N-dimethylformamide are dissolved in 10 ml of methylene chloride and stirred at room temperature for 1 hour. The acid chloride solution obtained above was added dropwise to this solution while cooling at -30°C, and the mixture was heated at -30 to -20°C for 1 hour.
The mixture was stirred for 1 hour while the reaction temperature was gradually raised to room temperature.

The reaction solution is concentrated to dryness under reduced pressure, and ethyl acetate and water are added to the resulting residue. The ethyl acetate layer is separated, washed with water, and then dried over magnesium sulfate. The solution is concentrated to dryness under reduced pressure, and the residue 0.9y is triturated with diisopropyl ether. After adding an aqueous sodium hydrogen carbonate solution and ethyl acetate to 500 m9 of the resulting powder, the aqueous layer was separated.
Add 10% hydrochloric acid to the aqueous layer to adjust the pH to ~2, and extract with ethyl acetate. Wash the extract with water and dry with magnesium sulfate. The solvent is distilled off from this solution under reduced pressure, and the resulting residue is recrystallized from ethyl acetate to obtain 200 mg of 3-(2-hydroxyimino-2-phenylacetamidolactasilanic acid) Mpl 97-199°C (decomposition)
. Example 548 After heating 472 m9 of thionyl chloride and 292 mg of N,N-dimethylformamide at 50 to 60°C for three times, unreacted thionyl chloride was distilled off under reduced pressure.

The residue) was suspended in 10 ml of dry methylene chloride, and
At -20'C, 584 mg of 2-(2,2-dichloroacetoxyimino)-2-(4-hydroxyphenyl)acetic acid was added, and the mixture was stirred three times at the same temperature. This mixture contains 277 methylene chloride containing 400 mg of triethylamine at -45 to -40°C! 1 solution was added dropwise and stirred at the same temperature for 1 min. Separately, 472m9 of 3-aminolactasilanic acid, N
, C-bis(trimethylsilyl)acetamide 1.2y
and 1 ml of N,N-dimethylformamide was added to 10 mL of methylene chloride, stirred at room temperature for 3 minutes, and then heated to -40°C.
Cool to This solution is added all at once to the acid chloride solution obtained above at the same temperature, then the cooling bath is removed and the mixture is stirred until the reaction temperature rises to room temperature. Concentrate the reaction solution under reduced pressure,
After adding 100 ml of ethyl acetate and 30 ml of water to the residue, the mixture was stirred for 3 minutes. The ethyl acetate layer was separated, washed with 2% hydrochloric acid and water, and then an aqueous sodium bicarbonate solution was added. The aqueous layer was separated, adjusted to pH1~2 with 10% hydrochloric acid, and extracted with ethyl acetate. The extract is washed with water and then dried with magnesium sulfate. The solvent is distilled off from this solution under reduced pressure, and the residue is triturated with diisopropyl ether. 240 m9 of the resulting powder was subjected to column chromatography using 10f of silica gel and eluted with ethyl acetate. Fractions containing the target product were collected, the solvent was distilled off under reduced pressure, and the resulting residue was powdered with diisopropyl ether to obtain 47 m9 of 3-[2-hydroxyimino-2-(4-hydroxyphenyl)acetamido]lactasilanic acid. . Infrared absorption spectrum ν-1 (nudyl): 1740, 16950 Example 5492-(4-benzyloxyphenyl)-2-(2
, 2-dichloroacetoxyimino)acetic acid is suspended in 7 ml of benzene.

Add 0.250q of phosphorus pentachloride to this suspension under cooling at 0 to 5℃.
Add at once and stir at the same temperature for 1 hour. Benzene was distilled off from this mixture under reduced pressure, and 7% of benzene was added to the resulting residue.
Add m1. Benzene is distilled off from this solution under reduced pressure, and after adding 7 ml of benzene to the resulting residue, the solvent is distilled off under reduced pressure. This operation is repeated three times and the resulting residue is dissolved in 10 ml of dry methylene chloride. Separately, 0.236 q of 3-aminolactasilanic acid is suspended in 20 ml of dry methylene chloride. 0.87y of N,O-bis(trimethylsilyl)acetamide is added to this suspension and dissolved by stirring at room temperature. The acid chloride solution obtained above was added dropwise to this solution over a period of 3 minutes while cooling at 0 to 5°C, and the mixture was stirred at the same temperature for 1 hour. After washing the reaction solution with water, the remaining solution is concentrated under reduced pressure. Ethyl acetate and a 5% aqueous sodium hydrogen carbonate solution were added to the resulting residue, stirred briefly, and then the aqueous layer was separated. PHL~ of aqueous solution with dilute hydrochloric acid
2 and then extracted with ethyl acetate. The extract is concentrated under reduced pressure and the resulting oily residue is washed with diethyl ether. After adding chloroform to the residue and pulverizing it, 108 m9 of the resulting powder was dissolved in 2 mL of acetone. After adding 1.2 mt of an acetone solution containing 598 mg of sodium 2-ethylhexanoate to this solution, 3 m of diethyl ether was added.
Add L. The solid that precipitates! Wash with cold diethyl ether. Dissolve this solid in water and pH it with dilute hydrochloric acid.
The volume was adjusted to 1 to 2 liters and extracted with ethyl acetate. The extract is washed with water and then dried with magnesium sulfate. The solvent was distilled off from this solution, and the resulting residue was powdered with chloroform to obtain 95 mg of 3-[2-(4-benzyloxyphenyl)-2-hydroxyiminoacetamide]lactasilanic acid. Mpl 37-140°C (decomposition). Example 550 2-acetoxyimino 2-(2-thienyl)acetic acid 42
6 mg is suspended in 10 mt of methylene chloride.

417 Tng of phosphorus pentachloride was added to this suspension and stirred at room temperature for 1 hour. A small amount of benzene is added to this mixture, concentrated under reduced pressure, and the residue is dissolved in 5 mt of ethyl acetate. Separately, 472 mg of 3-aminolactasilanic acid, N,O
Add 1.2 q of -bis(trimethylsilylacetamide and 1 ml of N,N-dimethylformamide to 10 ml of dry methylene chloride and stir at room temperature for 1 hour. Add the acid chloride solution obtained above dropwise to this solution at -30 to -20°C. 3 times at the same temperature, then remove the cooling bath and stir until the reaction temperature rises to room temperature.The reaction solution is concentrated to dryness under reduced pressure.
Dissolve the residue in ethyl acetate. After washing this solution with water, an aqueous sodium hydrogen carbonate solution is added and stirred for a while. The aqueous sodium hydrogen carbonate solution is separated, adjusted to pH 3 with dilute hydrochloric acid, and then extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 3-
390 mg of [2-hydroxyimino 2-(2-thienyl)acetamide]lactasilanic acid is obtained. After further extraction with ethyl acetate, the remaining aqueous solution was diluted with dilute hydrochloric acid to PHL~
2 and extracted with ethyl acetate. Wash the extract with water,
After drying with magnesium sulfate, the solvent was distilled off under reduced pressure to recover 300 m9 of the same target product. Total yield 690mg
. Nuclear magnetic resonance absorption spectrum δPpm (CD3OD):
3.25 (1H, m) 3.90 (1H, m)
5.10 (1H, m) 5.50 (1H, s) J6.85 (2H, d, J=9Hz) 7.25 (2H, d, J=9Hz) 7.2
(1H, m) 7.65 (1H, d, J=5Hz) 7.9
5 (1H, d, J = 4Hz) 7 Infrared absorption spectrum να-1 (nujiol): 1730, 1700 (shoulder),
Example 5512-acetoxyimino 2-cyanoacetic acid 4
After dissolving 9 pieces of 30ml in 8Tn1 of methylene chloride, 0.85v of phosphorus pentachloride was added, and the mixture was stirred at room temperature.

The solvent was distilled off from this solution under reduced pressure, and 20 mt of anhydrous benzene was added to the resulting residue, and then the benzene was distilled off under reduced pressure. This operation is repeated once more, and the resulting residue is dissolved in 5 ml of anhydrous ethyl acetate. Apart from this, 3
-Aminolactasilanic acid 708m9, N,O-bis(trimethylsilyl)acetamide 1.83y and N,N
-1.5 ml of dimethylformamide to 15 ml of methylene chloride
ml and stirred for 1 hour at room temperature. Add N to this mixture
After adding 1 ml of O-bis(trimethylsilyl)acetamide, the solution of acid chloride obtained above was added under ice cooling, and the mixture was stirred at the same temperature for 2 hours. The reaction mixture is concentrated to dryness under reduced pressure, and ethyl acetate and water are added to the resulting residue.
After separating the ethyl acetate layer, an aqueous sodium hydrogen carbonate solution was added, and the mixture was stirred for a while. After separating the aqueous layer and adding ethyl acetate, the aqueous layer was adjusted to pH1~2 with 10% hydrochloric acid. The ethyl acetate layer is separated, washed with an aqueous sodium chloride solution, and then dried over magnesium sulfate. The solvent was distilled off from this solution under reduced pressure, and 10 m of chloroform was added to 730 m9 of the resulting residue.
1 was added and stirred for 2 hours, then taken out, powdered 3-(2
- 630 m9 of cyano-2-hydroxyiminoacetamidolactasilanic acid are obtained. 3 out of 630mg of this powder
Dissolve 327719 in 5 ml of dry acetone. To this solution, 3.3Tn1 of an acetone solution containing 1.65y of sodium 2-ethylhexanoate is added dropwise. The powder precipitated in the solution is taken off and washed with acetone and diethyl ether to obtain 180 mg of the sodium salt of the target product. Mp2
4O~2451C- (decomposition). Example 552 3-[2-(4-(1-benzyloxycarbonylamino-1-methoxycarbonylmethyl)phenoxy)acetamido]lactasilanic acid 200 m9. methanol 1
Dissolve in 5ml.

Add 35 mg of 10% palladium and carbon to this solution as a catalyst.
is added, and the calculated amount of hydrogen gas is absorbed in a hydrogen stream at room temperature and pressure for about 2 hours. What remains after removing the catalyst from the reaction solution and distilling off methanol from the Oki solution under reduced pressure! Powder the residue with acetone. When this powder is taken off and washed with acetone, 3-[2-(4-(1-amino-1-methoxycarbonylmethyl)phenoxy)acetamide]
90 mg of lactasilanic acid are obtained. Mpl9O~194°C (decomposition). Example 553 1.35 q of 3-[2-(4-(2-benzyloxycarbonylamino-2-methoxycarbonylethyl)phenoxy)acetamido]lactasilanic acid was dissolved in 6.7 mt of 1N aqueous sodium hydroxide solution, and 1.35 q of 1N aqueous sodium hydroxide solution was dissolved at room temperature. Let stir for an hour.

After adding a small amount of water to the reaction solution, it is washed with ethyl acetate. The aqueous solution was adjusted to PHL with 1N hydrochloric acid and extracted with ethyl acetate. The extract is washed with water and then dried with magnesium sulfate.
The solvent is distilled off from the solution and the resulting residue is treated with chloroform to obtain 1.07y of 3-[2-(4-(2-benzyloxycarbonylamino-2-carboxyethyl)phenoxy)acetamido]lactasilanic acid. Mpl
25-130°C (decomposition). Example 5543-[2-(4
1.18 ml of -(1-benzyloxycarbonylamino-1-methoxycarbonylmethyl)phenoxy)acetamido]lactasilanic acid is dissolved in 4 ml of 1.1N aqueous sodium hydroxide solution and stirred at room temperature for 2 hours.

Add 4 ml of 0.1N hydrochloric acid to the reaction solution, extract with ethyl acetate, wash the extract with water, and then dry over magnesium sulfate. Ethyl acetate is distilled off from this solution under reduced pressure, and a small amount of acetone is added to the resulting residue for crystallization. The crystals are washed with ethyl acetate to obtain 30 m9 of 3-[2-(4-(1-benzyloxycarbonylamino-1-carboxymethyl)phenoxy)acetamido]lactasilanic acid.
Mpl34-138'C (decomposition). Example 5553-[
4-(3-benzyloxycarbonyl-5-oxo 1
,3-oxazolidin-4-・yl)butyrylamino]
Dissolve 200 m9 of lactasilanic acid in 15 mL of methanol.

Add 50m9 of 1.0% palladium carbon to this solution as a catalyst.
is added to carry out catalytic reduction at room temperature and pressure, and it takes about 4 hours to absorb the calculated amount of hydrogen gas. Scrape the catalyst from the reaction mixture and wash with methanol. This washing liquid and liquor liquor are combined, and methanol is distilled off under reduced pressure. The resulting residue was powdered with acetone to give 3-(5-amino-5-
97m9 of carboxypentanamide lactasilanic acid is obtained. Infrared absorption spectrum νo-1 (KBr): 1735, 1650, 16100
Nuclear magnetic resonance absorption spectrum δPPm (D2O+NaHC
O3): 1.64-1.90 (4H, m) 2.24 (2H, t, J = 4Hz) 2.90, 2.94 (1H, d, d, J = 2Hz,
6Hz) 3.67 (1H, t, J = 6Hz) 5.19 (1H, s) 6.79 (2H, d, J = 8Hz) 7.12 (2H, d, J = 8Hz) Example 556 3 - [2-(5-oxo-3-phenyl-4,5-dihydro-1,2,4-oxadiazol-4-yl)acetamide] 400 mg of lactasilanic acid was dissolved in 20 ml of water containing 84 mg of sodium bicarbonate.

0.8 mL of Raney nickel was added to this solution, and catalytic reduction was carried out under conditions of room temperature and 3 atm in a hydrogen stream. The calculated amount of hydrogen is absorbed in about 2 hours. The catalyst was removed from the reaction solution, and the bottom solution was adjusted to pH 6.0 with dilute hydrochloric acid. After adjusting to O, reduce the liquid volume to about 5m.
Concentrate under reduced pressure to 1. The concentrated liquid is treated with a nonionic adsorption resin, Amperlite XAD-2 (trademark, ROHM ●&●
The sample was subjected to column chromatography using a 30ml column (manufactured by Haas). Elute with 50% aqueous methanol solution and collect fractions containing the target product.

These fractions were combined and the solvent was distilled off under reduced pressure, resulting in 3-
70 mg of [2-(α-iminobenzylamino)acetamide]lactasilanic acid is obtained. Mpl75-178.5
°C (decomposition). Example 5573-(2-Hydroxyimino-2-phenylacetamido)lactasilanic acid 383
mg is suspended in 10 mt of water.

Add 1 1 N aqueous sodium hydroxide solution to this suspension at 0 to 5°C.
After mt is added and dissolved, acetone 107711 is added. To this solution, 10 ml of dry acetone containing 335 mg of benzoyl chloride was added dropwise over 30 minutes. During this time, 2.2 TL of a 1N aqueous sodium hydroxide solution was gradually added dropwise to the reaction solution to maintain the pH of the reaction solution at 7.5 to 8.0. After stirring the reaction solution at the same temperature for 1.5 hours, acetone was distilled off under reduced pressure. The remaining aqueous solution was washed with ethyl acetate,
After adjusting the pH to ~2 with dilute hydrochloric acid, extract with ethyl acetate. The extract is washed with water and dried over magnesium sulfate. The solvent is distilled off from this solution under reduced pressure, and the resulting oil is dissolved in a small amount of diethyl ether, and then cyclohexane is added. Crystals precipitated in solution? When treated with cyclohexane, 1-(4-benzoyloxy-α-carboxybenzyl)-3-(2-benzoyloxyimino 2-
(phenylacetamido)-2-azetidinone 430mg
get. Mpll 9-123°C. Example 5583-[2
-(2-thienyl)acetamide]lactasilanic acid 48
0 m9 is suspended in 10 mt of water.

Sodium hydrogen carbonate 5207 in this suspension? ! After adding and dissolving 9, add 10 ml of acetone. To this solution, 5 ml of dry acetone containing benzoyl chloride 560Tn9 was added dropwise under ice cooling, and the mixture was stirred at the same temperature for 4 hours and then at room temperature for 5 hours. Acetone is distilled off from the reaction solution under reduced pressure, and the remaining aqueous solution is washed with ethyl acetate. This aqueous solution was adjusted to pH1~2 with dilute hydrochloric acid and then extracted with ethyl acetate, and the resulting extract was washed with water and dried over magnesium sulfate. The solvent was distilled off from this solution under reduced pressure, and the resulting powdery residue was subjected to column chromatography using silica gel 20y. Elute with ethyl acetate and collect fractions containing the target product. After combining these fractions, the solvent was distilled off under reduced pressure, and the resulting residue was crystallized from ethyl acetate to give 1-(4-benzoyloxy-α-carboxylbenzyl)-3-[2-(2-thienyl). ) acetamide]-2
- Obtain 240 mg of azetidinone. Mpl29-131
℃. Example 559 0.360 f of 3-[2-(2-thienyl)acetamido]lactasilanic acid is suspended in 10 TLL of water.

Add 1 ml of 1N aqueous sodium hydroxide solution to this suspension under ice-cooling.
After adding and dissolving t, add 10 ml of acetone. This solution contains 5 ml of dry acetone solution containing 0.221 y of benzyl chloroformate and 1 ml of 1N aqueous sodium hydroxide solution.
．． Alternately drop 3 ml of the liquid in small quantities to bring the liquidity of the reaction liquid to P.
While maintaining H7.5 to 8.5, stir at the same temperature for 2 and a half hours. Acetone is distilled off from the reaction solution under reduced pressure, and the remaining aqueous solution is washed with ethyl acetate. Dilute the aqueous solution with diluted hydrochloric acid to PHL.
-2 and extracted with ethyl acetate. Wash the extract with water and dry. The solvent is distilled off from this solution under reduced pressure, and the resulting residue is dissolved in 5 mt of ethyl acetate. Add 2 to this solution
- 3 ml of acetone containing 165 ml of sodium ethylhexanoate are added followed by diethyl ether. The precipitate was collected by decantation, dissolved in 5 ml of acetate, and left to cool on ice to give 1-(4
-benzyloxycarbonyloxy-α-carboxybenzyl)-3-[2-(2-thienyl)acetamide]
310 m9 of the sodium salt of -2-azetidinone are obtained.
Mpl28-130°C. Example 5603-[2-(4-
(3-amino-3-carboxypropoxy)phenyl)
-2-Hydroxyiminoacetamide] 2.0 Da of lactasilanic acid is suspended in 40 ml of dry methylene chloride.

After adding 5.6 V of N,-bis(trimethylsilyl)acetamide to this suspension, the mixture was stirred at room temperature for 1.5 hours and then for 5 minutes under reflux. After adding 0.6 y of triethylamine to this solution under ice cooling, 1.68 d of trityl chloride was added at about 1 C@, and the mixture was stirred at the same temperature for 4 hours at room temperature. Methylene chloride was distilled off from the reaction solution under reduced pressure, and ethyl acetate and water were added to the residue, followed by stirring for a while. The ethyl acetate layer is separated, and an aqueous sodium hydrogen carbonate solution is added to this solution, followed by stirring for a while. The aqueous layer is separated, adjusted to pH 3 with 5% phosphoric acid under ice cooling, and extracted with ethyl acetate. Separate the extract and dry with magnesium sulfate.
The solvent was distilled off from this solution under reduced pressure, and the resulting residue was reprecipitated with acetone and benzene to give 3-[2-(4
-(3-carboxy 3-tritylaminopropoxy)
1.70f of phenyl)-2-hydroxyiminoacetamide]lactasilanic acid is obtained. Mp: 163-170℃
. Infrared absorption spectrum ν-1 (nujiol): 3250, 1735, 172
0,1650.

Example 561 1-(α-methoxycarbonylbenzyl)-4-methylthio 3-(2-phenylacetamido)-2-azetidinone (mixture of two trans isomers at the 3 and 4 positions of the azetidine ring) 0. 50y is dissolved in 10 ml of dry dioxane.

10 ml of a dioxane solution containing 5 ml of Raney nickel is added to this solution, and the mixture is stirred at 60° C. for 2 hours. Raney nickel is filtered out from the reaction solution and washed with dioxane. After combining this washing solution and the bottom solution, the solvent was distilled off under reduced pressure, and the resulting residue was transferred to a column using Shimano Gel 10y.
Subject to chromatography. Elute with chloroform and collect fractions containing the target product. When the solvent was distilled off from this solution under reduced pressure, 1-(α-4, methoxycarbonylbenzyl) was obtained.
320 mg of a mixture of two isomers at the 3-position of the azetidine ring of -3-(2-phenylacetamido)-2-azetidinone) are obtained. This mixture was further subjected to column chromatography using silica gel and eluted with chloroform. When this eluate was treated in a conventional manner, two types of isomers at the 3-position of the azetidine ring of the same target product were obtained.
0 mg and 140 mg, respectively. Physical constant Mp of isomer A: 138-140mC Infrared absorption spectrum νd-1 (Nujiol): 3260, 1750, 173
0,1680.

Nuclear magnetic resonance absorption spectrum δPpm (CDCl3): 3.06 (1H, q, J = 3
Hz, 5Hz) 3.50 (2H, s) 3.73 (3H, s) 3.86 (1H, t, J=5Hz) 4
．． 88 (1H, m) 5.56 (1H, s) 6.46 (1H, d, J=7Hz) 7
．． 08-7.28 (10H, m) Physical constant infrared absorption spectrum of isomer νo-1 (liquid film): 3290, 1760, 1740, 1
6600 nuclear magnetic resonance absorption spectrum δPpm (CDCl
3): 3.32-3.60 (2H, m) 3.5
0 (2H, s) 3.71 (311, s) 4.94 (1H, m) 5.55 (1H, s) 6.74 (1H, d, J=7Hz) 7
．． 08-7.28 (10H, m) Example 5621-(α
-methoxycarbonyl-4-benzyloxybenzyl)
-4-methylthio 3-(2-phenylacetamide)
0.73 f of -2-azetidinone (two trans isomers in the 3 and 4 positions of the azetidine ring) are dissolved in 10 ml of dry dioxane.

Add 0 ml of dry dioxane containing 7.3 ml of Raney nickel to this solution and stir at 50° C. for 1.5 hours.
Raney nickel is removed from the reaction solution and washed with dioxane. With this cleaning liquid? After combining the liquid and distilling off the solvent,
The resulting residue was subjected to column chromatography using silica gel 20f. Elute with chloroform and collect fractions containing the target product. When these fractions were combined and the solvent was distilled off under reduced pressure, two species at the 3-position of the azetidine ring of 1-(α-methoxycarbonyl-4-benzyloxybenzyl)-3-(2-phenylacetamido)-2-azetidinone were obtained. A mixture of isomers 1 and 130Tn9 is obtained.
Further, this mixture was subjected to column chromatography using silica gel and eluted with chloroform. This eluate is treated in a conventional manner to obtain 70mg and 30mg of two isomers at the 3-position of the azetidine ring, respectively. Physical constant Mp of isomer A: 150.5-1
54.50C Infrared absorption spectrum ν-1 (nujiol): 3280, 1755, 173
0, Nuclear magnetic resonance absorption spectrum δPpm (CDCl3)
:3.02 (1H, q, J=3Hz, 6Hz) 3
．． 49 (2H, s) 3.72 (3H, s) 3.82 (1H, t, J=6Hz) 4.9
0 (1H, m) 5.05 (2H, s) 5.53 (1H, s) 6.69 (1H, d, J=7Hz) 6.8
4-7.65 (14H, m) Physical constant infrared absorption spectrum of isomer νCm-1 (chloroform): 1760,1745,1
675.

Nuclear magnetic resonance absorption spectrum δPpm (CDCl3): 3
．． 25-3.63 (2H, m) 3.57 (2H,
s) 3.70 (311, s) 4.95 (1H, m) 5.05 (2H, s) 5.49 (1H, s) 6.68 (1H, d, J=8Hz) 6.6
8-7.75 (14H, m) Example 563 4-(1,3-benzo[d]thiazol-2-yldithio)-3-phthalimido 1-(1-methoxycarbonyl-2-methyl-1-propenyl) -2-Azetidinone 47y is dissolved in 500 ml of dioxane.

Add Raney nickel 47Cmt to this solution and
Stir the two powders at 70'C. Raney nickel is collected from the reaction solution and washed with chloroform. After combining the washing solution and the ash solution, the solvent is distilled off. After adding chloroform to the residue, it was washed twice with 5% hydrochloric acid and dried over anhydrous magnesium sulfate. The solvent was distilled off from this solution under reduced pressure, and the resulting residue (30.3y) was left in a refrigerator for 2 days. This residue is subjected to column chromatography using 900 g of silica gel. Elute with chloroform and collect fractions containing the target substance. These fractions are combined and concentrated to dryness under reduced pressure to obtain 238V of crude 1-(1-methoxycarbonyl-2-methyl-1-propenyl)-3-phthalimido-2-azetidinone. When this crude product was recrystallized once from ethanol and diisopropyl ale (volume ratio 3:14) and once from ethanol, the purified target compound 14 was obtained.
．． Get 6y. Mpl27-128℃ Infrared absorption spectrum νd-1 (Nujiol): 1767, 1758, 173
0,1715.

Nuclear magnetic resonance absorption spectrum δPpm (CD3OD): 2.14 (3H, s)
2.24 (3FI, s) 53.8 (31 (, s) 3.96 (2H, d, J=5Hz) 5.6
4 (1H, t, J=6Hz) 7.86 (4H, s
) Example 564 H As a raw material compound 4-(1,3-benzo[d]thiazol-2-yldithio)-3-(2-phenoxyacetamide)-1-(1-methoxycarbonyl-2-methyl-1-propenyl )-2-Azetidinone 13q and Raney Nickel 7.5q5 Example 563
3-(2-
3.09q of phenoxyacetamido)-1-(1-methoxycarbonyl-2-methyl-1-propenyl)-2-azetidinone are obtained.

″θMp: 154-155°C Infrared absorption spectrum νCm-1 (nujiol): 3320, 1745, 17
10, Nuclear magnetic resonance absorption spectrum δPpm (CDCl3
):2.02(3H,s) 2.23(3H,s)
3.57 (1H, d, d, J=3Hz, 5Hz)
3.85 (1H, t, J=5Hz, 5Hz) 4.5
4(?,s) 5.07(1H,m) 6.86-7.42(51(,m) Example 565 1-(1-methoxycarbonyl-2-methyl-1-propenyl)-3-(2 -phenoxyacetamide)-4-
[1-(1-Methoxycarbonyl-2-methyl-1-propenyl)-2-oxo-3-(2-phenoxyacetamide)-4-azetidinyldithio 50 mg of 2-azetidinone and 1 ml of Raney nickel in dioxane 5
Add to m1 and stir at 60°C for 3 times.

Raney nickel is removed from the reaction solution and washed with dioxane. With this cleaning liquid? The liquids were combined and concentrated to dryness under reduced pressure to obtain 45 mg of crude 1-(methoxycarbonyl-2-methyl-1-propenyl)-3-(2-phenoxyacetamido)-2-azetidinone. Infrared absorption spectrum ν-1 (nujiol): 3320, 1745, 171
0,1685.

Example 566 4-(1,3-benzo[d]thiazol-2-yldithio)-3-phthalimido 1-(1-carboxy2-
2.0 da of the sodium salt of methyl-1-propenyl-2-azetidinone was added to 20 ml of dioxane. Dissolve in 1.

Add 20TrLL of Raney◆nickel to this solution and add 50 ~
Stir 3 times at 55°C. Remove Raney nickel from the reaction mixture and wash with dioxane. The washing solution and the bottom solution are combined and concentrated to dryness under reduced pressure. Dissolve the resulting residue in aqueous sodium hydrogen carbonate. After dissolving in the solution, wash with ethyl acetate. This aqueous solution was adjusted to pH 2 with diluted hydrochloric acid and then extracted twice with ethyl acetate. The extract is washed with a saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was distilled off from this solution under reduced pressure, and the residue 1.1f was subjected to column chromatography using Silica gel 40y.
Elute with ethyl acetate and collect fractions containing the target product. When the solvent was distilled off from this solution under reduced pressure, 3-phthalimide 1 was obtained.
-(1-carboxy2-methyl-1-propenyl)-
240 mg of 2-azetidinone are obtained. Infrared absorption spectrum νd-1 (nujiol): 1780, 1770, 176
0, Nuclear magnetic resonance absorption spectrum δPpm (CD3OD)
:2.40(S,s) 2.80(3H,s)
4.00-4.18 (2H, m) 75.67, 5.83 (1H, d, d, J=7Hz)
8.13 (4H,s) Example 567 0.92y of 3-(1-methoxycarbonyl-2-methylpropylamino)-2-(2-phenylacetamido)propionic acid is dissolved in 100ml of ethyl acetate.

After adding 0.66f of 4-methylmorpholine to this solution, 1-(4-chlorobenzenesulfonyloxy) was added under ice cooling.
-6-chloro 1H-benzotriazole 1.11 (l
and stirred at the same temperature for a specific time. Insoluble materials generated in the reaction solution were removed, and the Oki solution was poured into 30 ml of ice water and thoroughly stirred. The ethyl acetate layer is separated, washed three times with an aqueous sodium bicarbonate solution and once, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was 0.
47 g was purified by column chromatography using silica gel 15y. Elution was carried out with chloroform, fractions containing the target product were collected, and the solvent was distilled off under reduced pressure to obtain 1-(
1-methoxycarbonyl-2-methylpropyl)-3-
(2-phenylacetamide)”-2-azetidinone 1
Obtain 0T,g. MplO5~107°C0 Example 56
8 Dissolve 70 mL of 3-(2-phenylacetamido)-1-(α-methoxycarbonyl-4-benzyloxybenzyl)-2-azetidinone in 10 mL of anhydrous Equinol.

Add 30m9 of 10% palladium/carbon as a catalyst to this solution.
was added and shaken for 3 hours under conditions of room temperature and pressure in a hydrogen stream to absorb the calculated amount of hydrogen and perform catalytic reduction. The catalyst is removed from the reaction solution, and the bottom solution is concentrated to dryness under reduced pressure. The resulting residue was treated with diethyl ether and then filtered to give 3
40 m9 of crystals of -(2-phenylacetamido)-1-(α-methoxybenzyl-4-hydroxybenzyl)-2-azetidinone are obtained. Mpl7l. 5-175℃.
Infrared absorption spectrum ν-1 (nujiol): 3250, 1750, 173
0,1670.

Nuclear magnetic resonance absorption spectrum δPpm (CD3OD): 3.05 (1H, q, J=3
Hz, 6Hz) 3.50 (2H, s) 3.75 (3H, s) 3.83 (1H, t, J=6Hz) 4.9
0 (1H, m) 5.52 (1H, s) 6.87, 7.23 (4H,,AB-Q,J=1
0 Hz) 7.28 (5FI, s) Example 569 40 mg of 3-(2-phenylacetamido)-1-(α-methoxycarbonyl-4-hydroxybenzyl)-2-azetidinone was dissolved in 5 ml of acetone, and the solution was cooled on ice. 0
．． After adding 1N sodium hydroxide aqueous solution 3TrL1
Stir in between.

Acetone is distilled off from the reaction solution under reduced pressure, and the remaining aqueous solution is washed with ethyl acetate. pH this aqueous solution with 1N hydrochloric acid.
2 and then extracted with ethyl acetate. The extract is washed with water and then dried with magnesium sulfate. The solvent was distilled off from this solution under reduced pressure, the residue was crystallized from acetone, and then taken at home to obtain 20 mg of 3-(2-phenylacetamido)lactasilanic acid. Mpl34-141°C0 Example 570 2-[2-(2,2,2-trichloroethoxycarbonylaminomethyl)phenoxy]acetyl chloride 0.3
93y with anhydrous benzene 7T! 11, then N,
1 drop of N-dimethylformamide and 3T thionyl chloride
Add rlt and heat under reflux for 3 hours.

Unreacted thionyl chloride is distilled off from the reaction solution under reduced pressure, and the residue is dissolved in 5Tnt of dry acetone. Apart from this, 3-
After suspending 0.236V of aminolactasilanic acid in 10mt of water, 0.184q of sodium hydrogen carbonate is added and dissolved. After adding 5 mL of acetone to this solution, the acetone solution prepared above was added dropwise at 0 to 5°C for about 3 minutes.
Stir at the same temperature for 2 hours. Concentrate the reaction mixture under reduced pressure. After washing the remaining aqueous layer with ethyl acetate, pH was adjusted with dilute hydrochloric acid.
The volume was adjusted to 1-2 and extracted with ethyl acetate. The extract is washed with water and dried over magnesium sulfate. The solvent was distilled off from this solution under reduced pressure, and the residue was powdered with diethyl ether, and when p was removed, 3-[2-(2-(2,2,2-trichloroethoxycarbonylaminomethyl)phenoxy)acetamide]lactasilanic acid was obtained. Obtain 0.49V. Infrared absorption spectrum ν-1 (KBr): 3275, 1740, 1715,
1660.

Example 57 7.9 da of benzyl chloroformic acid ester is dissolved in 50 ml of methylene chloride.

Add 3-amino-1-(methoxycarbonyl-2-methyl-1-propenyl)-2- to this solution at -15 to -10°C.
Azetidinone 2.42y and triethylamine 3.
1 while stirring 20 ml of methylene chloride solution containing 7y.
The mixture was added dropwise over a period of 2 hours, and the mixture was stirred for 1 hour at the same temperature. Methylene chloride was distilled off from the reaction mixture under reduced pressure, and the residue was dissolved in 150 ml of ethyl acetate. This solution is washed three times with 5% hydrochloric acid and once with an aqueous sodium chloride solution, and then dried over magnesium sulfate. The solvent was distilled off from this solution under reduced pressure, and the residue 7.3y was treated with n-hexane to obtain crude 3.
3.27y of -benzyloxycarbonyl-(1-methoxycarbonyl-2-methyl-1-propenyl)-2-azetidinone is obtained. The crude target product 3.71V thus obtained is subjected to column chromatography using silica gel 60y and eluted with chloroform. Fractions containing the target product are collected and chloroform is distilled off from the solution under reduced pressure to obtain purified product 3.059 of the target product. Mp
135-137 Product C0 Example 572 1.20 Da of 3-aminolactasilanic acid is suspended in 30 ml of 50% acetone aqueous solution.

Add 51N aqueous sodium hydroxide solution to this suspension under ice cooling.
Add m1 and dissolve. To this solution, while stirring under ice-cooling, 10ml of acetone containing 2.50y of benzyl chloroformate was gradually added dropwise over a period of 3 minutes (during which time the pH of the solution was maintained at 8 with 1N aqueous sodium hydroxide solution). ) and then stirred at the same temperature for 1 hour. Water was added to the reaction mixture, washed with diethyl ether, and then adjusted to pH 2 with hydrochloric acid. This aqueous solution was extracted with ethyl acetate and dried over magnesium sulfate. The ethyl acetate solution is concentrated under reduced pressure, and the residue is crystallized from diethyl ether to obtain 1.55y of 3-benzyloxycarbonylamino-1-(4-benzyloxycarbonyloxy-α-carboxybenzyl)-2-azetidinone. MPl38~14rC (decomposition)
.

Infrared absorption spectrum να-1 (nujiol): 3300, 1760, 174
0,1720,17030 Example 573 3-[2-[2-[4-chloro2-(4-(2-chloroacetamido)benzoyl)phenoxy]acetamido]-2-phenylacetamido]lactasilanic acid 15
0m9 and 25 mg of 2-mercaptopyridine at 0.1
4.2 ml of N aqueous sodium hydroxide solution and 5 ml of acetone
ml and stirred at room temperature for 1 hour and 0 minutes.

Acetone was distilled off from the reaction solution under reduced pressure, and 2.2 ml of 0.1N hydrochloric acid was added to the remaining aqueous solution, followed by ethyl acetate (30 ml).
mt and 10 ml) twice. After adjusting the remaining aqueous solution to pH 3 with 0.1N hydrochloric acid, 40ml of ethyl acetate was added.
Extract with 1. This extract and the extract obtained above are combined, washed with an aqueous sodium chloride solution, and then dried over magnesium sulfate. The solvent was distilled off from this solution under reduced pressure, and the resulting residue was powdered with diethyl ale to give 3-[2-[
2-[4-chloro2-[4-(2-(2-pyridylthio)acetamido)benzoyl]phenoxy]acetamido]-2-phenylacetamido]lactasilanic acid 1
Obtain 20 mg. MplO 9-114°C (decomposition). Example 574 650 mg of 3-[2-(2-(2-bromoacetamidomethyl)phenoxy)acetamido]lactasilanic acid was dissolved in 50 Tl. of water. After suspending in L, 1.25 Tr of 1N aqueous sodium hydroxide solution is added and dissolved.

This solution contains 198 mg of cysteine in a 1N aqueous sodium hydroxide solution. 3.83 mL of the liquid was added dropwise over a period of (9) minutes with stirring, and the mixture was stirred at room temperature for 3 hours. 1N to the reaction solution
Add 3.83 mL of hydrochloric acid to adjust the pH to 3.2 to 3.5, and then wash with ethyl acetate. The aqueous solution is concentrated to dryness under reduced pressure, methanol is added to the resulting residue, and then filtered. The suspension is concentrated to dryness under reduced pressure and the residue is powdered with acetone. 547 mg of the obtained powder was subjected to column chromatography using a nonionic adsorption resin Amperlite XAD-2 (trademark, manufactured by Rohm and Haas). Elute with water and then 50% methanol aqueous solution to collect fractions containing the target product. These fractions were combined and the solvent was distilled off under reduced pressure to obtain 1937!1 g of 3-[2-[2-(2-(2-amino-2-carboxyethylthio)acetamidomethyl)phenoxy]acetamido]lactasilanic acid. M
pl6l~165°C. Example 575 Sodium 5-(2
, 174 mg of 3,4,5,6-pentahydroxyhexanoylaminomethyl)-1,no-3,4-thiadiazole-2-thiolate are dissolved in 2 ml of water.

3-(2-chloroacetamido)lactasilanic acid 156WL9 and 1N aqueous sodium hydroxide solution 2TfL1 were added to this solution while stirring, and the mixture was stirred at the same temperature for 24 hours. Add 1 ml of 1N hydrochloric acid to the reaction solution to pH 3.5 to 4.0.
Wash with ethyl acetate. The remaining aqueous solution is concentrated under reduced pressure, and the resulting residue is subjected to column chromatography using 40 ml of nonionic adsorption resin Amperlite XAD-2 (trademark, manufactured by Rohm and Haas). Elute with water and then 50% methanol aqueous solution to collect fractions containing the target product. These fractions were combined and concentrated to dryness under reduced pressure, and the resulting residue was powdered with acetone to give 3-[2-(5-(2,3,4,5,6-pentahydroxyhexanoylaminomethyl) )-1,3,4-thiadiazol-2-ylthio)acetamido]lactasilanic acid 127 mg are obtained. Mp89-92] C0 Example 5
763-[2-[4-(4-chloroN-(2,2,2
-trichloroethoxycarbonyl)anilinomethyl)
320 m9 of phenoxy]-2-methylpropionamide]lactasilanic acid and 3 m of N,N-dimethylformamide
Dissolve in 1.

After adding 3.5 mL of acetic acid to this solution, the solution was cooled to 10°C, and while stirring, 1.35 y of zinc powder was added little by little and stirred at the same temperature for 1.5 hours. Take one portion of zinc dust from the reaction solution and wash with a small amount of N,N-dimethylformamide. This washing solution and the solution obtained above were combined, 80 ml of diluted hydrochloric acid was added, and then extracted with ethyl acetate. The extract is washed with water and then dried. The solvent is distilled off from this solution under reduced pressure and the resulting oil is washed with diisopropyl ether. Dissolve the residue in a small amount of ether, add diisopropyl ether, collect the precipitated crystals, and wash with diisopropyl ether to obtain 3I3-[2-(4
110 mg of -(4-chloroanilinomethyl)phenoxy)-2-methylpropionamide]lactasilazoic acid are obtained.

Mpl3O~136°C. Example 5773-[2-[2-
300 ml of (2-carboxymethoxyN-(2,2,2-trichloroethoxycarbonyl)benzylaminomethyl)phenoxy]acetamido]lactasilanic acid are dissolved in 2 ml of acetic acid.

Add 500 m9 of zinc powder to this solution at 15-20°C and stir for 2 and a half hours. Unreacted zinc from the reaction mixture? The collected residue is washed with acetic acid. After adding 20 TILL of ice water to this residue, it is filtered, and the bottom liquid is washed with ethyl acetate. The remaining aqueous solution is concentrated under reduced pressure under water cooling, and the residue is pulverized with acetone to obtain 205 m9 of 3-[2-(2-(2-carboxymethoxybenzylaminomethyl)phenoxy)acetamido]lactasilanic acid. Mpl59.5-16
4.5℃. Example 5783-[2-(2-(2,2,2
-Trichloroethoxycarbonylaminomethyl)phenoxy)acetamide]lactasilanic acid 250mg to 90%
% acetic acid aqueous solution.

Add 450 mg of zinc powder to this solution while stirring at room temperature, and stir at the same temperature for 1.5 hours. The reaction solution is filtered, and hydrogen sulfide gas is passed through the bottom solution under ice cooling. Precipitate? Take it out and wash it with water. This washing solution and Oki solution are combined and washed with ethyl acetate.
After concentrating the remaining aqueous solution under reduced pressure and adding acetone to the resulting residue to powder it? Tori is 3-[2-(
0.09 q of 2-aminomethylphenoxy)acetamido]lactasilanic acid is obtained. Infrared absorption spectrum νCm-1 (nujiol): 1725, 1650, 16
000 Example 579 3-(2-phenylglycinamide) lactasilanic acid 200 m9, sodium hydrogen carbonate 17
0 m9, 114 mg of 2-nitroanilinoxalyl chloride in a solution consisting of 10 ml of water and 8 ml of acetone.
Add 1 mt of acetone containing 1 ml of acetone, and stir for 1 hour under ice-cooling.

After adding 30 mt of water to the reaction solution, the pH was adjusted to 2 with dilute hydrochloric acid and extracted with ethyl acetate. Add aqueous sodium hydrogen carbonate solution to the extract and stir briefly. Separate the aqueous layer and adjust the pH to 4 with dilute hydrochloric acid.
After adjusting to ~5, extract with ethyl acetate. The extract is washed with water and then dried with magnesium sulfate. The solvent is distilled off from this solution under reduced pressure, and the resulting residue σq
When the σ residue is powdered and treated with diisopropyl ether, 3
55 m9 of -[2-[N-(N-(2-nitrophenyl)oxamoyl)amide-2phenylacetamide]lactasilanic acid is obtained.

Mpl 55-159°C (decomposition). Example 580 After suspending 250 m9 of 3-[2-(2-aminomethylphenoxy)acetamide]lactasilanic acid in 5 ml of water, 105 m9 of sodium bicarbonate was added and dissolved.

After adding 5 ml of acetone to this solution, 2-(
5 mt of dry acetone containing 0.13 y of 4-chloro-2-nitrophenoxy)acetyl chloride is added dropwise, and the mixture is stirred at the same temperature for 2 hours. Acetone is distilled off from the reaction solution under reduced pressure, and the remaining aqueous solution is washed with ethyl acetate. This aqueous solution was adjusted to pH1~2 with dilute hydrochloric acid, and then extracted with ethyl acetate. After washing the extract with water and drying, the solvent is distilled off under reduced pressure. 220 mg of the obtained oil was mixed with 31 Tt1 of acetone.
After adding 0.7 mt of acetone containing 35 m9 of sodium 2-ethylhexanoate, the mixture was allowed to cool for 1 hour. This solution is filtered, about 40 ml of diethyl ether is added to the filter solution, and the precipitated crystals are filtered out and washed with diethyl ether to produce 3-[2-[2-(2-(4-chloro-2-nitrophenoxy)acetamide). 108 m9 of the sodium salt of methyl)phenoxyacetamido]lactasilanic acid are obtained. Mpll7.5-122 Example 5813-[2-
(2-Aminomethylphenoxy)acetamide] 250 m9 of lactasilanic acid is suspended in 5111 l of water, and then 105 mg of sodium hydrogen carbonate is added and dissolved.

After adding 5 ml of acetone to this solution, 5 ml of dry acetone containing 80 TL g of 2-bromoacetyl chloride was added dropwise under cooling at 0 to 5° C., and the mixture was stirred at the same temperature for 2 hours. Acetone is distilled off from the reaction solution under reduced pressure, and diluted hydrochloric acid is added to the remaining aqueous solution to adjust the pH to 2. This aqueous solution is extracted with ethyl acetate, and the extract is washed with water and dried over magnesium sulfate. The solvent was distilled off from this solution under reduced pressure, and the resulting oily residue was powdered with diethyl ether to give 3-[2
130 m9 of (2-(2-bromoacetamidomethyl)phenoxy)acetamido]lactasilanic acid are obtained.
Mpl52-155.5°C. Example 582 3-[2-(4-(3-amino-3-carboxy)
349Cypropoxy)phenyl)-2-hydroxyiminoacetamide] 1.0y of sodium salt of lactasilanic acid is dissolved in 10ml of water.

A 10% aqueous sodium hydroxide solution was added to this solution under ice cooling, and while maintaining the pH of the solution at pH 8 to 10, 0.0% acetic anhydride was added.
Drop 5 mL four times at intervals of one drop. The reaction mixture was adjusted to pH 2 with 10% hydrochloric acid, and the powder precipitated in the reaction mixture was taken out and washed with water to give 3-[2-(4-(3-acetamido-3-carboxypropoxy)phenyl)-2-acetoxy. iminoacetamide]-1-(α-carboxy 4-acetoxybenzyl)-2-azetidinone 0.66
Get y. Infrared absorption vector niν-1 (nujiol): 3250 (BrOad),
1735 (BrOad), 16500 Nuclear magnetic resonance absorption Svetani (internal standard: tetramethylsilane) δPpm [(CD3)2C0] 1.96 (3H, s) 2.08 (31 (, s) 2.24 (3H, s) ) 3.20 (2H, m) 3.37 (1H, d, d, J=6Hz, 2Hz) 3.9
~4.3 (3H, m) 4.70 (1H, q, J = 7Hz
) 5.20 (1H, m) 5.65 (1H, s) 6.8-7.8 (8H, m) Example 583 Dissolve 0.47y of cupric chloride (dihydrate) in 20ml of water .

After adding 2.5y of 3-[2-(4-(3-amino-3-carboxypropoxy)phenyl)glycinamide]lactasilanic acid to this solution, 10% ammonia water was added and P
Adjust to ll7.6. After adding 8 ml of dioxane to this solution, 0.8 ml of 2-phenylacetyl chloride was added under ice cooling.
5 mL of dioxane containing 5y was added dropwise over 4 minutes, and the mixture was stirred at the same temperature for 1 hour. (While dropping the dioxane solution, adjust the pH of the solution to 7.2 to 7.6 with 10% aqueous ammonia). The reaction solution was adjusted to pH 3 with 10% hydrochloric acid, and the precipitated crystals were taken off and washed with water. Add this crystal to 10T of water.
II and adjusted to pH 7. with 10% aqueous ammonia. Adjust to O and dissolve. Add this solution to Diaion CR-10 (
Apply to column chromatograph 3X Roughy using a 150ml column (trademark, manufactured by Mitsubishi Kasei Corporation).

Elute with 5% aqueous ammonia, collect fractions containing the target product, and concentrate under reduced pressure until the liquid volume is reduced to half.

This concentrated solution was treated with activated carbon, and the remaining solution was pH adjusted with 10% hydrochloric acid.
3 and filter out the crystals precipitated in the solution, 3-
0.12 Da of [2-(4-(3-amino-3-carboxyproboxy)phenyl)-2-(2-phenylacetamido)acetamide]lactasilanic acid is obtained. Mpl7
8-187C0 Infrared absorption spectrum νCm-1 (nujiol): 3250, 1740, 17
20 (shoulder), 1650, 16100 Example 584 3-[2-(4-(3-acetamido-3-carboxypropoxy)phenyl)-2-acetoxyiminoacetamide]-1-(4-acetoxyα-carboxybenzyl)- 0.40y of 2-azetidinone to 10y of methanol
Dissolve in m1.

A diethyl ether solution of diazomethane is added to this solution under ice cooling until the color of diazomethane no longer disappears, and the mixture is stirred at the same temperature for 1 hour. Diethyl ether is distilled off from the reaction solution, and the residue is subjected to column chromatography using silica gel 50y. Chloroform and methanol (
Elute with a mixture at a volume ratio of 10:1) and collect fractions containing the target product. The solvent was distilled off from this solution under reduced pressure to obtain powdered 3-[2-(4-(3-acetamido-3-methoxycarbonylpropoxy)phenyl)-2-acetoxyiminoacetamide]-1-(4-acetoxyα, methoxycarbonylbenzine)-2-azetidinone 150
Get mg. Mpl2O~123°C (decomposition). Infrared absorption spectrum νCTL-1 (nujiol): 3300
, 1740 (BrOad), 1655.

Example 585 3-[2-(4-(3-amino-3-carboxypropoxy)phenyl)-2-hydroxyiminoacetamide]lactasilanic acid 5.0f was dissolved in dimethyl sulfoxide 9
0T! Dissolve in a solution consisting of LL and 10 ml of methanol.

A diethyl ether solution of diazomethane is added dropwise to this solution under ice cooling until the color of diazomethane no longer disappears, and the mixture is stirred for 1 min. The reaction mixture was poured into 950Tn1 of ice water and left in the refrigerator overnight, and the crystals precipitated in the reaction solution were collected by centrifugation and dried to give crude 3-[2-(4-(3-amino-3-methoxy) Carbonylpropoxy)phenyl)-2-hydroxyiminoacetamide]-1-(α-methoxycarbonyl-4-hydroxybenzyl)-2-azetidinone 3.3y is obtained.

Out of 3.3y of this crude target substance, 1.5y was subjected to dry ascending column chromatography using silica gel (ascending method).
Elute with a mixed solvent of chloroform and methanol (actual ratio, 30:1). Fractions containing the target product are collected and the solvent is distilled off under reduced pressure. Obtained residue: 0.70y
is dissolved in acetone, methanol containing hydrogen chloride in an equimolar amount to the starting compound is added, and the mixture is concentrated to dryness under reduced pressure. The resulting residue is recrystallized from a mixed solvent of ethanol and methanol to obtain 0.48y of the purified target compound, a hydrochloride at the amino group. Mp2OO~201°C. Example 5861-(1-carboxy2-methylpropyl)-
A solution of 3.04 V of 3-(2-phenylacetamido)-2-azetidinone in 40 ml of tetrahydrofuran is cooled to -20°C.

To this solution, 5 ml of tetrahydrofuran solution containing 1.02 y of triethylamine is added under stirring. Next, the reaction temperature of this solution was raised to -100C, and then a solution of 5TTL of tetrahydrofuran containing 1.14q of ethyl chlorocarbonate was added dropwise over 5 minutes, followed by stirring at -10 to O'C for 2 hours.
Next, add 1.23 g of sodium azide to this solution and add 8 g of water.
Add 7α dissolved in mL at once, and stir at the same temperature for 3 times. The reaction solution was poured into 200 ml of ice water and extracted three times with 100 ml of methylene chloride. The extract was washed three times with 100 ml of water, dried over calcium chloride, and the solvent was distilled off under reduced pressure to obtain an oily 1-(1-azidocarbonyl-2-
methylpropyl)-3-(2-phenylacetamide)
3.0y of -2-azetidinone is obtained. Infrared absorption spectrum νCm-1 (nujiol): 2250, 1700,
16500 Example 587 2.6y of 1-(1-azidocarbonyl-2-methylpropyl)-3-(2-phenylacetamido)-2-azetidinone was dissolved in 50T of anhydrous toluene.
! Dissolve the two powders in Lt and heat to reflux.

Insoluble matter was removed from the reaction solution, 0.1 ml of 1-methylimidazole and 1.45 y of 2,2,2-trichloroethanol were added to the solution, and the mixture was heated and stirred at 80° C. for 1 hour. The solvent is distilled off from the reaction solution to obtain a viscous oily residue.

This oil was adsorbed on silica gel 8y and then subjected to column chromatography using 30 g of silica gel to isolate and purify it. Lou 3-(
2-phenylacetamido)-2-azetidinone 2.6
Get 6y. Infrared absorption spectrum νC! Tt-1 (nujiol): 3300, 1765,
[1740 (shoulder), 16500 Example 588 1-(1-carboxy-2-methylpropyl)-3-(
2-phenylacetamido)-2-azetidinone 1.5
0f1 triethylamine 0.51y1 diphenyl phosphoric azide 1.4 g and tertiary butyl alcohol 30 ml
The mixture consisting of is gradually heated and refluxed for 5 hours.

Tertiary butyl alcohol was distilled off from the reaction solution under reduced pressure,
The resulting residue is subjected to column chromatography using silica gel. Among the fractions eluted with a mixed solvent of benzene and ethyl acetate, fractions containing relatively pure compounds are collected, and after the solvent is distilled off and dried, 1-(1-tert-butoxycarbonylamino)-2 -Methylpropyl-3-(
2-phenylacetamido)-2-azetidinone 1.1
Get y. Mp64-66゜C0 Example 5891-(1
-Carboxy 2-methylpropyl)-3-(2-phenylacetamido)-2-azetidinone (3.04 y) dissolved in 200 ml of ethyl acetate is stirred and 199 ml of copper acetate (monohydrate) is added thereto.

4.9 J of lead tetraacetate was added to this mixed solution over a period of 5 minutes, and the mixture was heated under reflux for 3 minutes with stirring. Next, the reaction solution is filtered, and the bottom solution is washed successively with water, an aqueous sodium chloride solution, and an aqueous sodium bicarbonate solution, then washed twice with an aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. When the ethyl acetate solution was concentrated to dryness under reduced pressure, an oily 1-(1-
2.7y of acetoxy(2-methylpropyl)-3-(2-phenylacetamido)-2-azetidinone is obtained.
Infrared absorption spectrum να-1 (liquid film): 1760, 1735 (shoulder), 166
5.

Example 590 12.0 y of 3-[2-(4-(3-carboxy3-3-0J0-butoxycarbonylaminopropoxy)phenyl)-2-hydroxyiminoacetamide]lactasilanic acid was added to 75 ml of water containing 3.36 y of sodium bicarbonate. Wash with diethyl ether.

To this aqueous solution, 30y of 10% palladium on carbon was added as a catalyst, and 96% hydrogen gas was added in 4 hours at room temperature and 3.5 atm.
Absorb 0 mL and perform contact reflux. The catalyst is removed from the reaction solution, and the liquid is concentrated to about 20 ml under reduced pressure. This concentrated solution was adjusted to pH 4 with 5% hydrochloric acid, and then acetone was added. When the crystals precipitated in the solution are collected and dried, 3-[2
10.5 y of -amino-2-(4-(3-carboxy-3-tert-butoxycarbonylaminopropoxy)phenyl)acetamide]lactasilanic acid is obtained. Mp255
~2581C (decomposed).

Infrared absorption spectrum νc ``1 (nujiol): 3300 (BrOad),
1735, 1690.

Nuclear magnetic resonance absorption spectrum (internal standard: 2,2,3,3-tetradeuterose 3-
(sodium trimethylsilyl)propionate) δPp
m(D2O+NaHCO3): 1.33 (9FI, s) 2.12 (2H, m) 3.71 (1H, m) 3.9-4.3 (311, m) 5.32 (1H, s) 6 .8-7.0 (4H, m) 7.1-7.4 (41], m) Example 591 3-[2-(4-(3-amino-3-carboxypropoxy)phenyl)-2-hydroxy Iminoacetamide] Dissolve 20.0V of the sodium salt of lactasilanic acid in 50mL of water containing 3.84y of triethylamine.

To this solution, 50 ml of a dioxane solution containing 8.50 y of 2-tert-butoxycarbonyloxyimino-2-phenylacetonitrile is added, and the mixture is stirred at room temperature for 6 hours. Add 100 ml of water and 200 ml of ethyl acetate to the reaction mixture and shake briefly. Separate the aqueous layer and wash with ethyl acetate. After adjusting the aqueous solution to pH 3 with 1N hydrochloric acid, sodium chloride was added to saturate the solution. Add this solution to 200ml of ethyl acetate.
The extract was washed with a saturated aqueous sodium chloride solution and dried over magnesium sulfate. This solution was concentrated to dryness under reduced pressure, and the residue was powdered with chloroform and taken off. As a result, 3-[2-(4-(3-carboxy
butoxycarbonylaminopropoxy)phenyl)-
2-Hydroxyiminoacetamide]lactasilanic acid 1
Obtain 8.30y. M. P. l93-19rC (decomposition)
Infrared absorption spectrum νCm-1 (nujiol): 3280 (BrOad)
1730 (BrOad) 1680 (shoulder) Nuclear magnetic resonance absorption spectrum (internal standard: tetramethylsilane) δPpm (D6-dimethylsulfoxide) 1.35
(9H, s) 2.11 (2H, m) 3.13 (1H, m) 3.7-4.3 (4H, m) 5.03 (1H, m) 5.37 (1H, s) 6 .7-7.6 (811, m) 9.17 (1H, dJ=8 [1z) Example 592 3-[4-(3-amino-3-carboxypropoxy)
Phenylglyoxyroylamino]lactasilanic acid 2.
Example 591
1.349 of 3-[4-(3-carboxy-3-tert-butoxycarbo[nylaminopropoxy)phenylglyoxyroylamino]lactasilanic acid is obtained.

Infrared absorption spectrum νCm-1 (nujiol): 33
50-32001750,1730,1710,168
0,1660,. Nuclear magnetic resonance absorption spectrum (internal standard: tetramethylsilane) δPpm (D6-acetone) 1.40 (3H, s) 2.34 (2H, m) 3.30 (3.3F!F.lH, d, dJ =2,5H
z) 3.96 (1H, tJ=5Hz) 4.26 (2
H, tJ=6HZ) 4.40 (1H, m) 5.12~5.28 (1H, m) 5.56 (1H, s) 6.32 (1H, d, J=8Hz) 6.84~ 7.32 (6H, m) 8.18 (2H, d, J = 8Hz) 8.72 (1H, d, J = 8Hz) 8.96 (2H, br0ads) Example 593 3-[2-(4 -(3-carboxy3-tert-butoxycarbonylaminopropoxy)phenyl)-2-(5
-Chlorosalicyloylaminoacetamide] 725 ml of lactasilanic acid is suspended in 12 ml of benzene.

Add 3 2,2,2-trifluoroacetic acid to this suspension under ice-cooling.
．． 42y was added dropwise and stirred at the same temperature for 1 hour. Diethyl ether is added to the reaction mixture, and the powder precipitated in the solution is collected and washed with diethyl ether to give crude 3-[2
-(4-(3-amino-3-carboxypropoxy)phenyl)-2-(5-chlorosalicyloylamino)acetamide]lactasilanic acid is obtained. M. p, 222-2
26 LaC (disassembly).

Infrared absorption spectrum νc'1 (nujiol): 3200 (shoulder), 1750,
1730 (shoulder), 1680, 1610.

Nuclear magnetic resonance absorption spectrum (internal standard: tetramethylsilane) δPpm (D6-dimethylsulfoxide) 2.20 (
2H, m) 3.24 (1H, m) 3.69 (2H, m) 4.10 (2FI, m) 4.48 (1H, s) 4.67 (1H, m) 5.27 (1H, s) 6.8-7.4 (11H, m) Example 594 3-[2-(4-(3-carboxy3-tert-butoxycarbonylaminopropoxy)phenyl)-2-(3
-phenylureido)acetamide]lactasilanic acid 7
05Tn9 and 2,2,2-trifluoroacetic acid 3.4
2y was treated in the same manner as in Example 593 to obtain 3-[2-(4
116 m9 of -(3-amino-3-carboxypropoxy)phenyl)-2-(3-phenylureido)acetamide]lactasilanic acid are obtained.

Infrared absorption spectrum νd-1 (nujiol) 330017301650 (B
rOad), 1610 (shoulder), 16000 Magnetic resonance absorption spectrum (internal standard: tetramethylsilane) δPpm (D6-dimethylsulfoxide 2.20
(2H, m) 2.96 (1H, m) 4.83 (1H, m) 5.23 (1H, s) 5.39 (1H, s) 6.8-7.6 (13H, m) Implementation Example 595 3-[2-(4-(3-carboxy3-tert-butoxycarbonylaminopropoxy)phenyl)-2-(2
-Oxoimidazolidine-1-carbonylamino)acetamide] 350m9 of lactasilanic acid and 1.72y of trifluoroacetic acid were treated in the same manner as in Example 593 to produce crude 3-[2-(4-(3-coamino-3-carboxypropoxy) 101 m9 of phenyl)-2-(2-oxoimidazolidine-1-carbonylamino)acetamide]lactasilanic acid is obtained.

M. p. 2OO~203AC (decomposition).

Infrared absorption spectrum νCm-1 (nujiol): 3300 (BrOad),
1720, 1660 (shoulder), 1610.

The magnetic resonance absorption spectrum (internal standard: tetramethylsilane) δPPm (Cl6-dimethylsulfoxide) 2.1
4 (2H, m) 2.89 (1H, m) 3.1 to 3.9 (311, m) 4.09 (2H, m) 6.6 to 7.3 (■, m) 7.70 ( 1H,s) 8.94 (1H,m) Example 596 3-[2-(4-(3-carboxy-3-tertiary-butoxycarbonylaminopropoxyphenyl)-2-aminoacetamide]lactasilanic acid 1.76y was suspended in 15 ml of an 80% aqueous tetrahydrofuran solution, and triethylamine was added to adjust the pH to 7.5.

490 mg of 2-oxoimidazolidine-1-carboxylic acid chloride was added dropwise to this solution over about 10 minutes, and the mixture was stirred at room temperature for 1 hour. (During the dropwise addition of the acid chloride, triethylamine is added to keep the pH of the solution at 7 to 8.) After adding 30 ml of water to the reaction mixture, tetrahydrofuran is distilled off under reduced pressure, and the remaining aqueous solution is washed with ethyl acetate. After adding 50 ml of ethyl acetate to this aqueous solution, the solution was purified with 1N hydrochloric acid under ice cooling.
Adjust to H2. The aqueous layer and ethyl acetate layer are separated, and the ethyl acetate layer is washed with a saturated aqueous sodium chloride solution and then dried over magnesium sulfate. This solution was concentrated to dryness under reduced pressure and 3-[2-(4-(3-carboxy3-tert-butoxycarbonylaminopropoxy)phenyl)-2-
(2-oxoimidazolidine-1-carbonylaminoacetamide) 0.15 da of lactasilanic acid is obtained.
The aqueous layer separated earlier was allowed to stand, the precipitated powder was collected and crystallized with diethyl ether, yielding the same desired compound (1.06).
Get y.

Total yield 1.21 Da. Infrared absorption spectrum νCm-1 (
Nujiyor): 3300, 1730, 1660 (shoulder),
1610.

The magnetic resonance absorption spectrum (internal standard: tetramethylsilane) δPPm (D6-dimethylsulfoxide) 1.38 (
side, s) 2.07 (2H, m) 2.97 (1H, m) 3.2-4.2 (7H, m) 4.85 (1H, m) 5.25 (1H, m) 5. 32 (1H, s) 6.7-7.5 (8H, m) 7.62 (1H, s) 9.00 (1H, m) Example 597 3-[2-Amino-2-(4-(3 1.76y of carboxy-3-tert-butoxycarbonylaminopropoxy)phenyl)acetamide]lactasilanic acid and 490 mg of phenyl isocyanate were treated in the same manner as in Example 596, and 3-[2-(3-phenylureido)-2-
1.60 Da of (4-(3-carboxy-3-tert-butoxycarbonylaminopropoxy)phenyl)acetamide]lactasilanic acid is obtained.

M. p. 194-196°C (decomposition).

Infrared absorption spectrum νC77! -1 (nujiyor): 3350, 1740,
1720 (shoulder), 1660 (shoulder), the magnetic resonance absorption spectrum (internal standard: tetramethylsilane) δPPm (D6-dimethylsulfokide) 1.38 (
911, s) 2.09 (2H, m) 3.00 (1H, m) 3.75 (1H, m) 3.90-4.20 (Aim, m) 4.88 (1H, m) 5. 25 (1H, d, J=7Hz) 5.32 (1H, s) 6.8-7.6 (1311, m) 8.70 (1H, s) 9.00 (1H, m) Example 598 3 -[2-(4-(3-Carboxy 3-tert-butoxycarbonylaminopropoxy)phenyl)-2-aminoacetamide] 1.76 da of lactasilanic acid and 520 mg of benzoyl chloride were treated in the same manner as in Example 596, 3-[2-(4-(3-carboxy-3-tert-butoxycarbonylaminopropoxy)phenyl)-2
-benzamide acetamide]lactasilanic acid 1.40
Get y.

M. P. l88-19rC (decomposition). Infrared absorption spectrum να-1 (nujiol): 3300, 1740, 172
0 (1 shoulder), 1640, 1610.

The magnetic resonance absorption spectrum (internal standard: tetramethylsilane) δPPm (D6-dimethylsulfokide) 1.38 (
9H, s) 3.03 (1H, m) 3.77 (1H, m) 3.9 to 4.3 (3H, m) 4.90 (1H, m) 5.33 (1H, s), 5 .60 (1H, m) 6.7-7.6 (13H, m) 7.92 (1H, m) 8.80 (1H, m) Example 599 3-[2-(4-(3-carboxy) 3-tertiary-butoxycarbonylaminopropoxy)phenyl)-2-aminoacetamide]lactasilanic acid 3.52y and 5
-chlorosalicylic acid 1.25y1 aluminum chloride 10
5-chlorosalicylic acid chloride prepared from 6 ml of thionyl chloride was treated in the same manner as in Example 596,
3-[2-(4-(3-carboxy3-tertiary-butoxycarbonylaminopropoxy)phenyl)-2-(5
-Chlorosalicyloylamino)acetamide]lactasilanic acid 0.94y is obtained.

M. p. 2l8-223 ToC (decomposition).

Infrared absorption spectrum νCm-1 (nujiol): 3300 (BrOad)
1740, 1680 (shoulder), 1610.

The magnetic resonance absorption spectrum (internal standard: tetramethylsilane) δPPm (DG-dimethylsulfoxide) 1.34 (
91(,s) 3.26(1H,m) 3.66(1H,m) 4.00(2H,m) 4.48(1H,s) 4.70(1H,s) 5.29(1H ,s) 6.7-7.4 (11H,m) Example 600 3-[4-(3-carboxy-3-tertiary-butoxycarbonylaminopropoxy)phenylglyoxyroylamino]-1-(α- After suspending 330 mg of carboxy-4-benzyloxybenzyl-2-azetidinone in 3 ml of water, 95 mg of sodium bicarbonate was added and dissolved.

25 mg of sodium borohydride is added to this solution and stirred at room temperature for 2 hours. The reaction mixture was adjusted to pH2.5 with diluted hydrochloric acid.
3 and take the crystals precipitated in the mixed solution to 3-[
260 m9 of 2-(4-(3-carboxy 3-tert-butoxycarbonylaminopropoxy)phenyl)-2-hydroxyacetamide]-1-(α-carboxy 4-benzyloxybenzyl)-2-azetidinone are obtained. Infrared absorption spectrum ν Tsumugi: 3400, 3300-3200,
1740-1720, 1710, 1680.

Example 601 200 mg of 3-[2-(4-(3-carboxy 3-tertiary-butoxycarbonylaminopropoxy)phenyl)-2-hydroxyacetamide]-1-(α-carboxy 4-benzyloxybenzyl)-2-azetidinone Suspend in 2 ml of benzene.

Add 0.5 ml of 2,2,2-trifluoroacetic acid to this suspension at 5 to 7°C, and stir at the same temperature for 1.5 hours. Approximately 25 ml of diethyl ether is added to the reaction mixture and the precipitated solid is taken off. This solid was suspended in 15 ml of ethyl acetate,
Stir for 3 minutes at room temperature. The powder was extracted from the suspension and washed with diethyl ether to give 3-[2-(4-(3-amino-3-carboxypropoxy)phenyl)-2-hydroxyacetamide]-1-(α-carboxy-4-benzyl). (oxybenzyl)-2-azetidinone 120m9
get. M. p, l49-154°C (decomposed).

Infrared absorption spectrum ν crystal (nujiol): 3400-3200, 1730-
1720, 1660, 1610.

Example 6023-[4-(3-carboxy-3-tertiary-butoxycarbonylaminopropoxy)phenylglyoxyroylamino]-1-(α-carboxy-4-benzyloxycarbonyloxybenzyl)-2-azetidinone 650 mg and 2 ,2,2-trifluoroacetic acid 4
m1 is processed in the same manner as in Example 601 to obtain 3-[4-(
3-Amino-3-carboxypropoxy)phenylglyoxyroylamino]-1-(α-carboxy4-benzyloxycarbonyloxybenzyl)-2-azetidinone 100TfL9 is obtained.

M. p. 133-139°C (decomposition).

Infrared absorption spectrum ν Tsumugi: 3500, 3300-3200,
1760, 1720, 1680, 1660, 1600.

Example 6033-[4-(3-carboxy-3-tertiary-butoxycarbonylaminopropoxy)phenylglyoxyroylamino]-1-(α-carboxy-4-benzoyloxybenzyl)-2-azetidinone 650 m9
and 2,2,2-trifluoroacetic acid
&N 4 ml was treated in the same manner as in Example 601 to obtain 3-[
110 mg of [4-(3-amino-3-carboxypropoxy)phenylglyoxyroylamino]-1-(α-carboxy4-benzoyloxybenzyl)-2-azetidinone is obtained.

M. p, l8l. 5-184°C (decomposition).

Infrared absorption spectrum ν convexity: 3500, 3300, 1740,
1720, 1700, 1660, 1600.

Example 6043-[4-(3-tertiary-butoxycarbonylamino-3-carboxypropoxy)phenylglyooxyloyl]-1-(α-carboxy4-benzyloxybenzine)-2-azetidinone 220 mg and 2,2 , 0.5 ml of 2-trifluoroacetic acid in Example 60
1 to obtain 140 m9 of 3-[4-(3-amino-3-carboxypropoxy)phenylglyoxyroylamino]-1-(α-carboxy4-benzyloxybenzyl)-2-azetidinone.

M. p. l7O~175°C (decomposition).

Infrared absorption spectrum ν Crystal: 1680, 1660, 1600.

Example 605 1.17 da of [4-(3-carboxy-3-tertiary-butoxycarbonylaminopropoxy)phenylglyoxyroylamino]lactasilanic acid was suspended in a mixture of 10 ml of acetone and 10 ml of water, and then - At 10mC, 4ml of 1N sodium hydroxide aqueous solution
Add and allow time to dissolve.

To this solution, add 0.450% of benzyl chloroformate at -10°C.
5 mL of a dry acetone solution containing y and 2.6 ml of a 1N aqueous sodium hydroxide solution are added alternately over a period of 1 hour. Acetone is distilled off from the reaction mixture under reduced pressure, and the remaining aqueous solution is washed with ethyl acetate. This aqueous solution was adjusted to pH 2 with diluted hydrochloric acid and then extracted with ethyl acetate. The extract is washed with water and then dried with magnesium sulfate. This solution was concentrated to dryness under reduced pressure, resulting in 3-[4-(3-carboxy-3-tert-butoxycarbonylaminopropoxy)phenylglyoxyroylamino]-1-(α-carboxy-4
1.20 q of -benzyloxycarbonyloxybenzyl)-2-azetidinone are obtained. Infrared absorption spectrum The angle ν crystal (nujiol): 3400-3300, 1750,
1730-1710, 1690, 16700 nuclear magnetic resonance absorption spectrum (internal standard: tetramethylsilane) δPPm (D6-acetone) 1.39 (311, s) 2.20-2.44 (2H, m) 3.37, 3.43 (1H, d, d, J=2.5Hz
) 3.81 (1H, t, J=5Hz) 4.25 (2
H, t, J=6Hz) 5.12-5.26 (1H, m) 5.28 (2H, s) 5.64 (1H, s) 6.24 (1H, d, J=8Hz) 7. 00 to 7.60 (11H, m) 8.20 (1H, d, J = 8Hz) 8.68 (1H, d, J = 8Hz) Example 606 3-[4-(3-carboxy 3-3rd 960 m9 of butoxycarbonylaminopropoxy)phenylglyoxyroylamino]lactasilanic acid and 281 mg of benzoyl chloride were treated in the same manner as in Example 605 to obtain 3-
1.10 da of [4-(3-carboxy 3-tert-butoxycarbonylaminopropoxy)phenylglyoxyroylamino]-1-(α-carboxy 4-benzoyloxybenzyl)-2-azetidinone is obtained.

Infrared absorption spectrum ν crystal (nujiol): 3400-3200, 1740,
1720-1710, 1680, 1670.

Nuclear magnetic resonance absorption spectrum (internal standard: tetramethylsilane) δPPm (D6-acetone) 1.38 (3H, s) 2.26-2.44 (2H, m) 3.39, 3.45 (1H, d ,d,J=2,5Hz
) 4.00 (2H, t, J=5Hz) 4.24 (2
H, t, J=6Hz) 4.38 (1H, m) 5.06-5.30 (1H, m) 5.68 (1H, s) 6.24 (1H, d, J=8Hz) 7. 00-8.24 (13H, m) 8.72 (1H, d, J = 8Hz) Example 607 3-[4-(3-carboxy-3-tertiary-butoxycarbonylaminopropoxy)phenylglyoxylo,ylamino ] 585 mg of lactasilanic acid and 5 ml of dioxane
Dissolve in.

Add 3.3 m of 1N sodium hydroxide aqueous solution to this solution at 5°C.
After adding t, 680 m9 of benzyl bromide was added and reacted at the same temperature for 1 hour and at 10-15°C for 1 hour. The reaction solution is washed with ethyl acetate to which about 8 ml of water has been added. This aqueous solution was adjusted to pH 2 with dilute hydrochloric acid and extracted with ethyl acetate. This extract was washed with water, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to produce 3-[4-(3-carboxy-3-tertiary-butoxycarbonylaminopropoxy).
590 m9 of phenylglyoxyroylamino]-1-(α-carboxy-4-benzyloxybenzyl)-2-azetidinone is obtained. Infrared absorption spectrum ν crystal (nujiol): 3300-3200, 1740-1710,
1690, 16600 nuclear magnetic resonance absorption spectrum (internal (base: tetramethylsilane) δPPm (Yamaichi acetone) 1.42 (3FI, s) 2.28-2.54 (2H, m) 3.32-3. 38 (1H, d, d, J=2,5Hz)
3.93 (1H, t, J = 5Hz) 4.26 (2H, t
, J=6Hz) 4.32-4.52 (1H, m) 5.14 (2H, s) 5.55 (1H, s) 6.26 (1H, d, J=8Hz) 7.02-7 .46 (11H, m) 8.24 (2H, d, J = 8Hz) 8.70 (1H, d, J = 8Hz) Example 608 3-[4-(3-amino-3-carboxypropoxy)
Phenylglyoxyroylamino]lactasilanic acid 3.
00V1 30 ml of an aqueous solution consisting of 1.059 Da of methoxyamine hydrochloride and 1.47 Da of sodium bicarbonate was added to 9
React at 0°C for 3 hours.

The reaction mixture was concentrated to dryness under reduced pressure, and after adding ethanol to the residue, insoluble materials were removed. ? The liquid was concentrated under reduced pressure and the resulting residue was powdered with ethanol to give 3-[2-(4-
(3-amino-3-carboxypropoxy)phenyl)
-2-Methoxyiminoacetamide]lactasilanic acid 2
．． Obtain 61V. M. p. 210 to 215°C (decomposed).

Infrared absorption spectrum νi (nudyol): 1742 Nuclear magnetic resonance absorption spectrum [internal standard: 2,2,3,3-tetradium 3
−(Trimethylsilyl)propionate sodium δ
PPm(D2O) 2.02(2H,m) 3.13(1H,q,J=5,2Hz) 3.94(
3H, s) 3.7-4.1 (2H, m) 4.20 (2H, t, J = 6Hz) 4.98 (1H, p, J = 4,2Hz) 5.34 (
1H,s) 6.89,7.43(2H,.AB-Q,J=9Hz
) 6.96, 7.23 (?, AB-Q, J=9Hz)
Example 6093-[4-(3-Amino-3-carboxypropoxy)phenylglyoxyroylamino]lactasilanic acid 0.50 g and benzyloxyamine 0.2
7 da was treated in the same manner as in Example 608 to obtain 3-[2-(4
0.33y of -(3-amino-3-carboxypropoxy)phenyl-2-benzyloxyiminoacetamide]lactasilanic acid is obtained.

M. p. 18O-1840C (decomposition). Example 610 585 mg of 3-[4-(3-carboxy-3-tertiary-butoxycarbonylaminopropoxy)phenylglyoxyroylamino]lactasilanic acid was added to 10 ml of dioxane.
Dissolve in.

Add 1.0 V of 2,2,2-trichloroacetyl isocyanate to this solution and react at 50°C for 2 hours. The reaction mixture was concentrated under reduced pressure, diethyl ether was added to the residue to make it into powder, and the mixture was taken to give 3-[4-(3-carboxy-3-tert-butoxycarbonylaminopropoxy)phenylglyoxyroylamino]- 1-” [α-carboxy 4-(N-(2,2,2-trichloroacetyl)
Carbamoyloxy)benzyl]-2-azetidinone 6
Obtain 10 mg. Infrared absorption spectrum ν crystal (nujiol): 3350-3250, 1780, 1740
, 1720, 1660. Nuclear magnetic resonance absorption spectrum (internal standard: tetramethylsilane) δPPm((116-acetone) 1.55(311,s) 2.36-2.62(21(,m) 3.38,3.44(1H , d, d, J=2,5Hz)
3.99 (1H, t, J=5Hz) 4.20-4.42
(3H, m) 5.10 to 5.30 (1H, m) 5.64 (1H, s) 6.96 to 7.60 (61 (, m) 8.16 (2H, d, J = 8Hz) 8.68 (1H, d, J = 8Hz) Example 611 3-[4-(3-amino-3-carboxypropoxy)
Phenylglyoxyroylamino]lactasilanic acid 0.
After suspending 50y in 10ml of water, add 0 of sodium bicarbonate.
．． Add 40q and dissolve.

Add 0.23y of semicarbazide hydrochloride to this solution,
React at 70°C for 9 hours. After the reaction, the solution is filtered, the pH of the solution is adjusted to 2 with dilute hydrochloric acid, and then treated with charcoal powder. This aqueous solution was adjusted to pH 3 with a 1N aqueous sodium hydroxide solution, and the powder precipitated in the aqueous solution was scooped out to give 3-[2-(4-(3-
Amino-3-carboxypropoxy)phenyl)-2-
120 mg of (2-carbamoyl bimodal)acetamide]lactasilanic acid is obtained. Further, the mother liquor was concentrated to 5 ml, left to stand under ice cooling, and the precipitated powder was taken out to recover 40 mg of the same target product. Total yield 160mg.
Infrared absorption spectrum ν and 1fL (nujiol): 3400, 3300-32
00,1740,1720,1660,1640,16
00.

Nuclear magnetic resonance absorption spectrum (internal standard: 2, 2, 3, 3
-Sodium tetradeuterose-3-(trimethylsilyl)propionate]δPPm (D2O+NaHCO3)
: 2.24-2.36 (2H, m) 3.14, 3.20 (1H, d, d, J=2,5Hz
) 3.72~4.08(?, m) 4.19Q old, T
, J=6Hz) 4.93,4.99(1H,d,d,J=2,5Hz
) 5.30 (1H, s) 6.84-7.50 (13
H, m) Example 612 3-[4-(3-carboxy-3-tertiary-butoxycarbonylaminopropoxy)phenylglyoxyroylamino]-1-(α-carboxy-4-benzyloxybenzyl)-2-azetidinone After suspending 320 mg in 5 ml of water, 75 ml of hydroxylamine hydrochloride are added.

Add 170m9 of sodium hydrogen carbonate to this solution to pH 7.
-7.5 and react at 45-501°C for 4 hours. The reaction mixture was adjusted to pH2 with dilute hydrochloric acid, the precipitated solid was taken off, washed with water and dried to give 3-[2-(4-(3-
280 m9 of carboxy-3-tert-butoxycarbonylaminopropoxy)phenyl)-2-hydroxyiminoacetamide]-1-(α-carboxy4-benzyloxybenzyl)-2-azetidinone are obtained. M. p.
149.5-153°C (decomposition). Infrared absorption spectrum νCm-1 (nujiol): 3300 (BrOad),
1750-1720, 1670.

Example 613 3-[2-(4-(3-carboxy3-tert-butoxycarbonylaminopropoxy)phenyl)-2-hydroxyiminoacetamide]-1. -(α-carboxy4-benzyloxybenzyl)-2-azetidinone 2
40 ml of the suspension was suspended in 21 TL of benzene, 0.5 ml of 2,2,2-trifluoroacetic acid was added while stirring at 7°C, and the mixture was reacted at the same temperature for 2 hours.

After adding 25 nLt of diethyl ether to the reaction mixture, the precipitated solids are scraped off. This solid was suspended in a small amount of ethyl acetate and stirred three times. The powder in this suspension was taken out, washed with diethyl ether, and dried to give 3-[2-
(4-(3-amino-3-carboxypropoxy)phenyl)-2-hydroxyiminoacetamide]-1-(
α-carboxy4-benzyloxybenzyl)-2-
Azetidinone 180TrL9 is obtained. M. p, l64~
167.5℃.

Infrared absorption spectrum νd-1 (nujiol): 3400-3250,174
0,1660,1610.

Example 614 3-phthalimido 2-azetidinone and methyl 3-phenyl-2-bromopropionate were treated in the same manner as in Example 218 to obtain 3-phthalimido 1-(α-methoxycarbonyl-4-benzyloxyphenethyl)-2-azetidinone ( A mixture of two diastereomers at the asymmetric carbon atoms substituted at the 3- and 1-positions of the azetidinone ring is obtained.

Infrared absorption spectrum νo-1 (nujiol): 178
0,1760,1738,1705.

Example 615 3-amino-1-benzyloxycarbonylmethyl-2
- 0.41 da of p-toluenesulfonate of azetidinone and 0.12 y of triethylamine were added to 20 y of methylene chloride.
Dissolve in m1.

To this solution, 0 to 5 were added dropwise at C while stirring 0.17y of 2-(2-thienyl)acetyl chloride, and the mixture was allowed to react at the same temperature for 1 hour. The reaction solution was washed with dilute hydrochloric acid, water, and then concentrated to dryness to give 1-benzyloxycarbonylmethyl-3.
-[2-(2-thienyl)acetamide]-2 Example 6
0.71 da of 193-aminolactasilanic acid and 4-(3
0.53y of tertiary-butoxycarbonylamino-3-methoxycarbonylpropoxy)phenylglyoxy-azetidinone is obtained.

Infrared absorption spectrum νG-1 (liquid film): 3300, 1760, 1740, 1
660.

Nuclear magnetic resonance absorption spectrum δPPm (CDCl3): 3
．． 26, 3.31 (1H, d, dJ = 2,5Hz)
, 3.73 (1H, t, J = 6Hz), 3.78 (21
1, s), 4.04 (2H, s), 4.97-5.1
6 (1H, m), 5.17 (2H, s), 6.91~
7.26(611,m) 3-amino-2-azetidinone derivative (■) was reacted in the same manner as in Example 615 to obtain the compounds shown in the following table.

3
-[4-(3-tertiary-butoxycarbonylamino-3-
1.54y of methoxycarbonylpropoxy)phenylglyoxyroylamino]lactasilanic acid is obtained.

Nuclear magnetic resonance absorption spectrum δPPm (D2O+NaHCO3): 1.26 (9H,
s), 2.14 (2H, m), 3.06 (1H, q
, J = 5,2Hz), 3.60 (3H, s), 3.
4-4.4 (4H, m), 5.04 (1H, q, J=5
, 2Hz), 5.34 (1H, s), 6.84, 7.2
4 (4H, ABq, J=8Hz), 6.82, 7.86
(4H, ABq, J=8Hz) 3-amino-2-azetidinone derivative (■) was treated in the same manner as in Example 615 with a mixed acid anhydride obtained from the acid shown below and ethyl chloroformate, and the mixture shown in the table below was prepared. Obtain the compound.

Example 624 1-benzyloxycarbonylmethyl-3-phthalimide 0.364y of 2-azetidinone was added to 5ml of a mixed solvent of chloroform and ethanol (actual ratio 1:1)
Dissolve in

Add 1N of hydrazine (monohydrate) to this solution while stirring.
After adding 1 ml of ethanol solution, react for n hours. The solid precipitated in the reaction solution is removed, and the liquor solution is concentrated to dryness under reduced pressure. The residue was dissolved in a small amount of ethanol, and 1 ml of ethanol solution containing 190 ml of p-toluenesulfonyl chloride (monohydrate) was added under ice cooling, followed by stirring for a while. This solution is concentrated to dryness under reduced pressure, and 1 ml of ethanol and 2 mt of ethyl acetate are added to the resulting residue for crystallization.
When the crystals were collected and dried, 160% of 3-amino-1-benzyloxycarbonylmethyl-2-azetidinone was obtained.
Get mg. Furthermore, 40 mg of the same compound is recovered from the mother liquor. Total yield 200, Mpl 47.5-149°C. Example 625 3-[4-(3-amino-3-carboxypropoxy)
Phenylglyoxyroylamino]lactasilanic acid 0.
97y is suspended in 15 ml of water.

After adding and dissolving 0.4 q of sodium hydrogen carbonate to this suspension, 0.04 y of sodium borohydride was added twice and stirred under ice cooling for 4.5 hours. After adjusting the reaction solution to pH 3 with 10% hydrochloric acid, acetone 135TrLL was added and allowed to stand. When the crystals precipitated in the solution are removed and dried, 3-[
2-(4-(3-amino-3-carboxypropoxy)
0.31y of phenyl)-2-hydroxyacetamido]lactasilanic acid is obtained. Moreover, my mother. 0 identical compounds from the liquid
．． Collect 16y. Total yield 0.47y0 Infrared absorption spectrum να-1 (Nujiol): 3350, 3200, 172
5,1660,1615,15800 Example 626 3-[2-(4-(3-amino-3-carpoxypropoxy)phenyl)-2-hydroxyiminoacetamide]lactasilanic acid 10y was dissolved in sodium bicarbonate 5.83
Dissolve in 150 ml of water containing y.

To this solution was added 50Tf11 of acetone under ice cooling, and the mixture was stirred for a while. 20 ml of an acetone solution containing 3.36 g of chloroacetyl chloride is added dropwise to this solution while stirring, and the mixture is allowed to react at the same temperature for 4 hours. Acetone is distilled off from the reaction solution, and the remaining aqueous solution is washed with ether. This aqueous solution was adjusted to pH 2 with 10% hydrochloric acid and then extracted with ethyl acetate. The extract is washed with water and saturated aqueous sodium chloride solution, and then dried over magnesium sulfate. This ethyl acetate solution was concentrated to dryness under reduced pressure, and the resulting residue was crystallized from benzene to give 3-[2-(4-(3-carboxy 3-(2
-chloroacetamido)propoxy)phenyl)-2-
Hydroxyiminoacetamide]lactasilanic acid 8.0
Obtain 1g. Infrared absorption spectrum ν-1 (nujiol): 3250, 1730, 172
0,1650.

Example 627 To 1.0y of sodium salt of 3-[2-(4-(3-amino-3-carboxypropoxy)phenyl)-2-hydroxyiminoacetamide]lactasilanic acid, 44% of formic acid was added.
A solution obtained by stirring 0 m9 and acetic anhydride 820 m9 in advance was added and treated in the same manner as in Example 626 to obtain 3.
0.461 of -[2-(4-(3-formamido-3-carboxypropoxy)phenyl)-2-hydroxyiminoacetamide]lactasilanic acid is obtained.

Mpll 9-123°C (decomposition).

Example 628 3-[2-tert-butoxycarbonylamino-2-(4
-Hydroxyfenino L/. ) Acetamide] 0.40 y of lactasilanic acid is suspended in 2 ml of benzene.

After adding 3 drops of anisole to this suspension at 5-7℃,
Add 1 ml of 2,2-trifluoroacetic acid and react at the same temperature for 1 hour. Add 30 ml of ether to the reaction solution and take off the precipitated solid. This solid was suspended in 10 TfL1 of ethyl acetate and stirred at room temperature for 1 hour. The powder in this suspension is taken, washed with ether, and then dried to obtain 0.3 da of 3-[2-amino-2-(4-hydroxyphenyl)acetamido]lactasilanic acid. Mp2O5-209°C.

Example 629 3-[4-(3-tertiary-butoxycarbonylamino-3
1.10 y of -carboxypropoxy)phenylglyoxyroylamino]lactasilanic acid was treated in the same manner as in Example 628 to give 0 y of 3-[4-(3-amino-3-carboxypropoxy)phenylglyoxyroylamino]lactasilanic acid. Get .60f.

Mp225-230'C (decomposition). Example 630 4.5y of 3-[2-(4-(3-tert-butoxycarbonylamino-3-carboxypropoxy)phenyl)-2-hydroxyiminoacetamide]lactasilanic acid is dissolved in 30 mL of ethyl acetate.

An ether solution containing diazomethane is gradually added dropwise to this solution under ice cooling until the color of diazomethane no longer disappears. The reaction solution is washed with a 5% aqueous sodium hydrogen carbonate solution and water, and then dried. This solution was concentrated to dryness under reduced pressure, and 4.9q of the resulting oil was subjected to column chromatography using 100f of silica gel. Elute with methanol and chloroform (volume ratio 1:50) and collect fractions containing the target compound. The solvent was distilled off from this eluate, and the residue was crystallized with chloroform to yield 3-[2-(4-(3-tertiary-butoxycarbonylamino-3-methoxycarbonylpropoxy)phenyl)-2-hydroxyiminoacetamide. ] 3.28y of lactasilanic acid methyl ester is obtained. Mpl43-146°C.

Example 631 0.50 y of 1-(4-benzyloxy-α-methoxycarbonylbenzyl)-4-methylthio 3-phthalimide 2-azetidinone is dissolved in 5 ml of dry dioxane.

Dioxane 15 containing 5 mt of Raney nickel in this solution
Add m1 and react at 40-50°C for 2 hours. After the reaction, the Raney nickel is removed and the p solution is concentrated to dryness under reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with water, and then dried over magnesium sulfate. When the solvent was distilled off from this solution, 0.07q of 1-(4-benzyloxy-α-methoxycarbonylbenzyl)-3-phthalimide 2-azetidinone [compound I] and 1-(4-hydroxyα-methoxycarbonylbenzyl)- 0.10q of 3-phthalimide 2-azetidinone (compound) is obtained.
Physical constant Compound A Infrared absorption spectrum ν [-1 (liquid film): 1780, 1760, 1740, 1
7200 compound infrared absorption spectrum νa-1 (liquid film): 3350, 1780, 1760, 1
740, Example 6323-[4-(3-(4-methoxybenzyloxycarbonyl)-3-tert-butoxycarbonylaminopropoxy)phenylglyoxyroylamino]-1-(α-methoxycarbonylbenzyl)-2
-Dissolve azetidinone in 8 mt of methanol.

Add 4ml of 1N aqueous sodium hydroxide solution to this solution under ice cooling.
Add and stir for 1 hour. After the reaction, methanol is distilled off under reduced pressure, and the remaining aqueous layer is adjusted to pH 2 with diluted hydrochloric acid, and then extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, and concentrated to dryness to give crude 3-[4-(3-(
4-Methoxybenzyloxycarbonyl)-3-tert-butoxycarbonylaminopropoxy)phenylglyoxyroylamino]-1-(α-carbonylbenzyl)
0.89y of -2-azetidinone is obtained. Infrared absorption spectrum να-1 (liquid film): 3400-3300,176
0,1740,1710,1680-1660.

Example 633 3-[4-(3-amino-3-carboxypropoxy)
Phenylglyoxyroylamino]lactasilanic acid 50
0 m9 and 300 m9 of thiosemicarbazide in 10 m of water.
1.

Add sodium hydrogen carbonate to this suspension and adjust the pH to 7. O~7
．． 5 and then stirred at 90°C for 4 hours. The precipitate in the reaction mixture was removed, and the solution was adjusted to pH 4.0 with dilute hydrochloric acid. Adjust to O. Crystals formed in the solution are removed, and the solution is purified with dilute hydrochloric acid.
After adjusting the H to 3.2 to 3.5, concentrate until the liquid volume becomes 7 mL. The precipitate formed in the concentrated solution is removed by P, and the bottom solution is left overnight. The crystals precipitated in the solution are collected, washed with acetone, and then dried to obtain 100 m9 of 3-[2-(4-(3-amino-3-carboxypropoxy)phenyl)-2-thiosemicarbazonoacetamide]lactasilanic acid. . Mp2O6~207.5miC (decomposition).

Example 634 3-[4-(3-amino-3-carboxypropoxy)
Phenylglyoxyroylamino]lactasilanic acid 0.
5q and p- of 2-aminooxyacetic acid ethyl ester
0.3 da of toluenesulfonate was treated in the same manner as in Example 633 to obtain 3-[2-(4-(3-amino-3-carboxypropoxy)phenyl)-2-ethoxycarbonylmethoxyiminoacetamide]lactasilanic acid 310j!
Get 9.

Nuclear magnetic resonance absorption spectrum δPPm (D2O+NaHC
O3): 1.13 (3H, t, J = 7Hz), 2.38 (2H
, m), 3.15, 3.19 (1H, d, d, J=2,
4Hz), 3.80-4.04 (3H, m), 4.18
(3H, m), 4.66 (2H, s), 4.98, 5.
02 (1H, d, d, J = 2,4Hz), 5.35 (1
H, s), 6.84-7.73 (8H, m) Example 63
5 3-[4-(3-tertiary butoxycarbonylamino-3
-carboxypropoxy)phenylglyoxyroylamino]lactasilanic acid and 0.13 V of methanesulfonohydrazide were treated in the same manner as in Example 633 to produce 3-[2-(4-(3-tertiary butoxycarbonyl) 0.33y of amino-3-carboxypropoxy)phenyl)-2-hydrazonoacetamide]lactasilanic acid is obtained.

Nuclear magnetic resonance absorption spectrum δPPm [(CD3)2S0] 1.36(91(,s), 2.00-2.12(2H
, m), 3.04-3.14 (1H, m), 3.58
~3.70 (1H, m), 3.94 ~ 4.12 (2H,
m), 4.84-4.94 (2H, m), 5.31 (I
H, s), 6.76-7.36 (811, m), 8.6
6 (IH, d, J = 8 Hz) Example 636 1-(α-Benzyloxycarbonyl-4-benzyloxybenzyl)-3-phthalimide 1.81 g of 2-azetidinone was added to a solution consisting of 15 ml of methanol and 30 mL of acetic acid. Melt it.

1.0y of 10% palladium on carbon is added to this solution for catalytic reduction in a hydrogen stream, and the calculated amount of hydrogen is absorbed over a period of 11 hours at room temperature and pressure. The reaction solution was concentrated to dryness under reduced pressure, and the residue was treated with ethyl acetate and filtrated to obtain 0.95 g of crude 3-phthalimidolactasilanic acid. This product is recrystallized from a mixed solvent of ethyl acetate and acetone to obtain a purified product. Mp2O2~203'
C (decomposition). Example 637 1-(α-methoxycarbonylbenzyl)-3-phthalimide 0.36y of 2-azetidinone and 0.22y of N,N-dimethyl-1,3-propanediamine were dissolved in a mixed solvent consisting of 5T1LL of methanol and 5ml of chloroform, Stir for 1 hour at room temperature.

The reaction solution was concentrated to dryness under reduced pressure, and 20ml of ethyl acetate was added to the residue.
A mixture of t and 20 ml of water is added. The aqueous layer is separated, and the remaining ethyl acetate layer is extracted with 31 rL1 of 1N hydrochloric acid and 10 ml water. The extracts were combined, adjusted to pH 6 with an aqueous sodium bicarbonate solution, and diluted with 10 ml of ethyl acetate.
Extract once. The ethyl acetate extract is washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. This solution was concentrated to dryness under reduced pressure to obtain 0.13 da of 3-amino-1-(α-methoxycarbonylbenzyl)-2-azetidinone. Infrared absorption spectrum 1 νDh (liquid film): 3400, 1750, 17100
Example 6 3-phthalimido 2-azetidinone derivative
37 to obtain the compounds shown in the following table.

0'J Example 640 3-(3-promopylboylamino)lactasilanic acid 1
11m9 of water and 1N potassium hydroxide aqueous solution 0
．． Dissolve in an aqueous solution consisting of 56 ml.

This solution was mixed with 44.2m9 of cysteine hydrochloride and 3Tn water.
The mixture was added dropwise to a mixed solution of 1 and 0.84 ml of 1N aqueous potassium hydroxide solution while stirring under ice cooling, and the mixture was stirred at the same temperature for 1.5 hours. The reaction solution was adjusted to pH 4 with diluted hydrochloric acid, and then concentrated to dryness under reduced pressure. The resulting residue was dissolved in 20 ml of methanol and filtered. After concentrating the honeycomb solution to dryness, it was dissolved in a small amount of water and subjected to column chromatography using adsorption resin Amperlite XAD-2 (trademark, manufactured by Rohm and Haas). Elute with water and collect fractions containing the target product. The eluate was concentrated to dryness under reduced pressure, and the residue was crystallized with ethanol to give 3-[3-(2-amino-2-carboxyethylthio).
67m9 of pyruvoylamino]lactasilanic acid is obtained. M
pl62-169c (decomposition). Example 641 280 ml of 3-[2-(4-(3-amino-3-carboxypropoxy)phenyl)-2-ethoxycarbonylmethoxyiminoacetamide]lactasilanic acid are dissolved in 3 ml of methanol.

Add 2 ml of 1N sodium hydroxide aqueous solution to this solution under ice cooling.
and stirred at the same temperature for 1 hour and then at room temperature for 4 hours.
Methanol is distilled off from the reaction solution under reduced pressure, and the remaining aqueous solution is washed with ethyl acetate. This aqueous solution was diluted with diluted hydrochloric acid to pH
3.5, and filter out the crystals precipitated in the solution. When this crystal is washed with acetone and dried, 3-[2-(
160 mg of 4-(3-amino-3-carboxypropoxy)phenyl)-2-carboxymethoxyiminoacetamide]lactasilanic acid is obtained. Mpl 78-180°C (decomposition).

Example 642 3-[4-(3-phthalimidopropoxy)phenylglyoxyroylamino]lactasilanic acid 1.13y1 triethylamine 0.41y and N,N-dimethyl-1
, 0.45y of 3-propanediamine in 17m of methanol
Dissolve in L and react at 0°C for 7 hours.

The reaction solution was concentrated to dryness under reduced pressure, the residue was dissolved in 10 TL of water, and the pH was adjusted to 4.8 with 10% hydrochloric acid. This aqueous solution is subjected to column chromatography using adsorption resin Amperlite X, AD-4 (trademark, manufactured by Rohm and Haas). Elute with water and then methanol to collect fractions containing the target substance. The solvent was distilled off from the eluate under reduced pressure, and the residue was crystallized from acetone and then recrystallized from water to give 3-[
200 WLg of 4-(3-aminopropoxy)phenylglyoxyroylamino]lactasilanic acid are obtained. Mp2
2l~223 acid C0 Example 643 3-[2-[4-(3-carboxy 3-(2-flutaimidoacetamido)propoxy)phenyl]-2-hydroxyiminoacetamido]lactasilanic acid 0.3y
and N,N-dimethyl-1,3-propanediamine 0
．． 2V was reacted in the same manner as in Example 642, and 3-[2-[4
80 mg of -(3-(2-aminoacetamide)-3-carboxypropoxy)phenyl]-2-hydroxyiminoacetamide]lactasilanic acid is obtained.

Infrared absorption spectrum ν crystal (nujiol): 3500-3300, 1730,
1690, 1670, 1610-1600.

Nuclear magnetic resonance absorption spectrum δPPm (D2O+NaHC
O3): 2.18-2.32 (2H, m) 3.09,3
．． 15 (1H, q, J = 2,5Hz) 3.76 (2FI
, s), 3.96 (1H, t, J=5Hz), 4.10
(2H, t, J=6Hz), 4.35~4.52 (1H
, m), 5.01, 5.07 (1H, q, J=2,5H
z), 5.36 (1H, s), 6.88-7.51 (8
H, m) Example 6443-[2-[4-(3-(2-tert-butoxycarbonylamino-2-phenylacetamide)-3-carboxypropoxy)phenyl]-2-
Hydroxyiminoacetamide]lactasilanic acid 0.5
Suspend Da in 4 mL of benzene.

After adding 0.5 mL of anisole to this suspension),
At C, 1.5 mt of 2,2,2-trifluoroacetic acid was added and stirred at the same temperature for 1 hour. Add 30ml of ether to the reaction solution.
and remove the solid that precipitates. This solid was suspended in a small amount of ethyl acetate, stirred at room temperature, and the insoluble matter was removed. 250,771 g of propoxy)phenyl]-2-hydroxyiminoacetamido]lactasilanic acid are obtained. Infrared absorption spectrum ν
Crystal (nujiyor): 3350-3200, 1730, 1
690, 1680-1660, 1620-16000 nuclear magnetic resonance absorption spectrum δPPm (D2O+NaHCO
3): 2.18-2.40 (2H, m), 3.12, 3
．． 18 (1H, qJ=2.5Hz), 3.78, 4.0
0(31(,m), 4.32~4.56(1H,m
), 5.02, 5.08 (1H, q, J = 2,5Hz)
,5.16(1H,s),5.36(1H,s),6・
75-7.40 (13H, m) Compounds shown in the following table are obtained in the same manner as in Example 644.

Example 647 3-[2-(4-(3-Amino-3-carboxypropoxy)phenyl)-2-hydroxyiminoacetamide] 0.5 V of lactasilanic acid was dissolved in 10 mL of water, and then 0.5 V of sodium bicarbonate was added under ice cooling. 210y
Add.

To this solution, 5 ml of acetone solution containing 0.34 f of 2-phthalimidoacetic acid chloride was added dropwise and reacted at the same temperature for 2 hours and then at room temperature for 17 hours. The reaction solution was adjusted to PH2 with dilute hydrochloric acid.
and extract with ethyl acetate. The extract is washed with water and dried over magnesium sulfate. This solution was concentrated to dryness under reduced pressure, and the residue was crystallized with chloroform and then collected to give 3-[2
0.42y of -(4-(3-carboxy3-(2-phthalimidoacetamide)propoxy)phenyl)-2-hydroxyiminoacetamide]lactasilanic acid is obtained. Infrared absorption spectrum νChang (nujiyor). 340
0,3350-3250,1780,1750,174
0,1730,1710,1660.

Nuclear magnetic resonance absorption spectrum δPPm (CD3OD): 2
．． 20-2.40 (2H, m), 3.92 (1H
, t, J=5Hz), 4.12(2H, t, J=6Hz
), 4.42 (2H, s), 4.64-4.80 (1H
, m), 5.09, 5.15 (1H, q, J=2,5H
z), 5.56 (1H, s), 6.84-7.91 (1
2H,m) The sodium salt of 3-[2-(4-(3-amino-3-carboxypropoxy)phenyl)-2-hydroxyiminoacetamide]lactasilanic acid and the acylating agent were treated in the same manner as in Example 647 to obtain the following: Obtain the compounds in the table.

Claims (1)

[Claims] 1 General formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ [In the formula, R_1 is an amino group or an acylamino group, A
means hydrogen or a group represented by the formula ▲ Numerical formula, chemical formula, table, etc. group, benzyloxycarbonylamino group, 2-(2-nitrophenoxy)acetamido group, or 2-(2-nitrophenoxy)-2-methylpropionamide group, A is a formula ▲ a mathematical formula, chemical formula, table, etc. Yes▼(In the formula, R
^z has the same meaning as above), and when R_1 is 2-[4-(3-amino-3-carboxypropoxy)phenyl]-2-hydroxyiminoacetamide group, A is and its salts.