JPH05239058A - 3-pyrrolidinylthio-1-azabicyclo(3. 2. 0)hepto-2-ene-2-carboxylic acid compound - Google Patents

Abstract

PURPOSE:To provide a new compound inhibiting the growth of a wide range of pathogenic bacteria including gram-positive bacteria and gram-negative bacteria and useful as an antibacterial agent. CONSTITUTION:A compound of formula I (R<1> is carboxy, protected carboxy; R<2> is hydroxy (lower) alkyl, etc.; R<3> is H, lower alkyl; R<4> is hydroxy, lower alkoxy, etc.; R<5> is H, imino-protecting group; A is lower alkylene), e.g. (4R,5S,6 S)-3-[(2S,4S)-1-alluyoxycarbonyl-2-{(E)-3-t-butyldimethylsiloxy-1 propenyl}pyrolidin-4-ylthio]-6-[(R)-1-hydroxyethyl]-4-methyl-7-oxo-1- azabicyclo[3.2.0] hepto-2-ene-2-carboxylic acid allyl ester. The compound of formula I is obtained by reacting a compound of formula II with a compound of formula III in the presence of a base in a solvent under cooling to heating.

Description

Detailed Description of the Invention

[0001]

The present invention relates to a novel 3-pyrrolidinylthio-1-azabicyclo [3.2.0] hept-2-
It relates to ene-2-carboxylic acid compounds and their pharmaceutically acceptable salts. More specifically, the present invention relates to novel 3-pyrrolidinylthio-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid compounds having antibacterial activity and pharmaceutically acceptable salts thereof, The present invention relates to a method for producing them and an antibacterial agent containing them.

[0002]

Accordingly, one object of the present invention is to show a novel 3-pyrrolidinylthio-1-azabicyclo [3.2. 0] hept-2-ene-2-carboxylic acid compounds and pharmaceutically acceptable salts thereof. Another object of the present invention is the novel 3-pyrrolidinylthio-1-azabicyclo [3.2.0] hept-2-
It is intended to provide a method for producing an ene-2-carboxylic acid compound and a salt thereof. Still another object of the present invention is the 3-pyrrolidinylthio-1-azabicyclo [3.2.
0] A hept-2-ene-2-carboxylic acid compound and an antibacterial agent containing a pharmaceutically acceptable salt thereof as an active ingredient.

[0003]

The object compound, 3-pyrrolidinylthio-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid compound, is novel and has the following general formula:

[Chemical 36] [Wherein R ¹ is a carboxy group or a protected carboxy group, R ² is a hydroxy (lower) alkyl group or a protected hydroxy (lower) alkyl group, R ³ is hydrogen or a lower alkyl group, and R ⁴ is a hydroxy group. , A protected hydroxy group, a lower alkoxy group, a halogen, an optionally substituted amino group, or an optionally substituted heterocyclic group, R ⁵ is hydrogen or an imino protecting group, and A is a lower alkenylene group. Show. ] And a pharmaceutically acceptable salt thereof.

Suitable pharmaceutically acceptable salts of the object compound (I) are conventional non-toxic salts, for example salts with bases such as alkali metal salts (eg sodium salt,
Potassium salt, etc., alkaline earth metal salt (eg calcium salt, magnesium salt etc.), salt with inorganic base such as ammonium salt, organic amine salt (eg triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanol) Salts with organic bases such as amine salts, dicyclohexylamine salts, N, N'-dibenzylethylenediamine salts, etc .; inorganic acid addition salts (for example, hydrochlorides, hydrobromides, sulfates, phosphates, etc.) , Organic acid addition salts (eg formate, acetate, trifluoroacetate,
Salts with acids such as maleates, tartrates, methanesulfonates and benzenesulfonates; salts with basic or acidic amino acids (eg arginine, aspartic acid, glutamic acid); intermolecular or intramolecular tetra Graded salt;
And so on. In the above-mentioned intermolecular quaternary salt, the heterocyclic group represented by R ⁴ in the compound (I) contains at least one tertiary nitrogen atom (for example, pyridyl, imidazolyl, pyrazolyl, etc.), and the nitrogen atom is more suitable. Substituents such as lower alkyl (eg, methyl, ethyl, etc.), hydroxy (lower) alkyl (eg, 2
-Hydroxyethyl etc.), carbamoyl (lower) alkyl (eg carbamoylmethyl etc.), N- (or N, N-di) (lower) alkylcarbamoyl (lower)
Alkyl (eg N, N-dimethylcarbamoylmethyl etc.), N- (or N, N-bis) [hydroxy (lower) alkyl] carbamoyl (lower) alkyl [eg N- (or N, N-bis) (2- Hydroxyethyl) carbamoylmethyl, etc.] or said heterocyclic groups are adjacent by their tertiary nitrogen atoms "
A "(eg, pyridinio, 2-pyrazolio, 3-imidazolio, etc.) or the heterocyclic group of R ⁴ contains at least one nitrogen atom and is bound to the adjacent" A "at that nitrogen atom. (Eg pyrrolidine-
1-yl, piperazin-1-yl, etc.) and the nitrogen atom is substituted with a suitable substituent as described above, or R ^{4 is} di (lower) alkylamino (eg N-methyl-N-ethylamino). Etc.), N-lower alkyl-N
-Carbamoyl (lower) alkylamino (eg N-
Methyl-N-carbamoylmethylamino, etc.), N-lower alkyl-N- [N-hydroxy (lower) alkylcarbamoyl (lower) alkyl] amino [eg N-methyl-N- {N- (2-hydroxyethyl) carbamoyl] Methyl} amino, etc.] and the like, where the amino group is substituted with a suitable substituent as described above, it can be formed with an anion.

Suitable intermolecular quaternary salts include 1- (lower) alkyl-1-pyrrolidinio halides (eg 1
-Methyl-1-pyrrolidinioiodide, 1-methyl-1-pyrrolidiniochloride, etc.), 1- (lower) alkylpyridiniohalide (for example, 1-methyl-3-pyridinioiodide, 1- Methyl-3-pyridiniochloride, etc.), 1-carbamoyl (lower) alkylpyridiniohalide (eg 1-carbamoylmethyl-3)
-Pyridinioiodide, 1-carbamoylmethyl-
3-pyridinio chloride, etc.), 1- [N- (or N, N-di) (lower) alkylcarbamoyl (lower) alkyl] pyridiniohalide [eg 1- [N- (or N, N-di ) Methylcarbamoylmethyl] pyridinioiodide, 1- [N- (or N, N-di) methylcarbamoylmethyl] pyridiniochloride, etc.], 1
-[N- (or N, N-bis) {hydroxy (lower)
Alkylcarbamoyl} (lower) alkyl] pyridiniohalide [eg 1- [N- (or N, N-bis)]
(2-hydroxyethyl) carbamoylmethyl iodide, 1- [N- (or N, N-bis) (2-hydroxyethyl) carbamoylmethyl chloride, etc.], pyridinio halide (eg pyridinioiodide, pyridinium) Nio chloride, etc.), 3- (lower) alkylimidazoliohalide (for example, 3-methyl-1-imidazolioiodide, 3-methyl-1-imidazoliochloride, etc.), 3- (lower) alkylimidazoliohalide (for example, 3-methyl-2-imidazolioiodide, 3-methyl-2-imidazoliochloride, etc.),
N, N-di (lower) alkyl-N-carbamoylammoniohalide (eg N-methyl-N-ethyl-N-
Carbamoyl ammonio iodide, N-methyl-N
-Ethyl-N-carbamoylammonio chloride, N,
N-dimethyl-N-carbamoylammonioiodide, N, N-dimethyl-N-carbamoylmethylammoniochloride, etc.), 1- (lower) alkyl-1-piperazino halide (for example, 1-methyl-1-pipe) Radinoiodide, 1-methyl-1-piperazino chloride, etc.), 3-carbamoyl (lower) alkyl-1-imidazoliohalide (eg 3-carbamoylmethyl-1)
-Imidazolio iodide, 3-carbamoyl-1-
Imidazolio chloride, etc.), 2-pyrazoliohalide [for example, 2-pyrazolioiodide, 2-pyrazoliochloride, etc.), N, N-di (lower) alkyl-N-
[N- {hydroxy (lower) alkyl} carbamoyl (lower) alkyl] ammoniohalide [eg N,
N-dimethyl-N- {N- (2-hydroxyethyl) carbamoylmethyl} ammonio] iodide, N, N
-Dimethyl-N- {N- (2-hydroxyethyl) carbamoylmethyl} ammonio] chloride, etc.) and the like.

The objective compound (I) and the following intermediate compounds may have one or more pairs of stereoisomers such as optical isomers based on asymmetric carbon atoms, and these isomers are also present. It is also included in the scope of the present invention.
According to the present invention, the object compound (I) or a pharmaceutically acceptable salt thereof can be produced by the methods shown by the following reaction schemes.

Manufacturing method 1

[Chemical 37]

Manufacturing method 2

[Chemical 38]

Manufacturing method 3

[Chemical Formula 39]

Manufacturing method 4

[Chemical 40]

Manufacturing method 5

[Chemical 41]

Production Method 6

[Chemical 42]

Production Method 7

[Chemical 43]

Production Method 8

[Chemical 44]

Production Method 9

[Chemical 45]

Manufacturing method 10

[Chemical 46]

Manufacturing Method 11

[Chemical 47]

Production Method 12

[Chemical 48]

Manufacturing Method 13

[Chemical 49] Manufacturing method 14

[Chemical 50] [In the above formulas, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and A are as defined above, R ¹ _a is a protected carboxy group, and R ² _a is a protected hydroxy ( Lower) alkyl group, R ² _b is a hydroxy (lower) alkyl group, R ⁴ _a is a protected hydroxy group, R ⁵ _a is an imino protecting group, R ⁶ is a lower alkyl group, carbamoyl (lower) alkyl group, N-
(Or N, N-di) (lower) alkylcarbamoyl (lower) alkyl group or N- (or N, N-bis)
[Hydroxy (lower) alkyl] carbamoyl (lower)
An alkyl group, R ⁷ and R ⁸ are each a lower alkyl group, a carbamoyl (lower) alkyl group, or an N- [hydroxy (lower) alkyl] carbamoyl (lower) alkyl group, R ⁹ is an aryl group or a lower alkoxy group, X
Is an acid residue, Y is a halogen, a formula

[Chemical 51] The group represented by is an optionally substituted heterocyclic group containing a tertiary nitrogen atom, formula

[Chemical 52] The groups represented by each represent an optionally substituted heterocyclic group containing an imino moiety. ]

The compound (III) used in the production method 1 is novel and can be produced, for example, by the following method or a conventional method.

[Chemical 53] (In the formula, R ⁴ , R ⁵ and A are each as defined above, and R ¹⁰ represents a mercapto protecting group.) In the description of the present specification and the subsequent description thereof, the present invention includes within its scope. Suitable examples and illustrations of the various definitions are described in detail below. The term “lower” means 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, unless otherwise specified. Suitable "protected carboxy group" may include esterified carboxy, and examples of this "esterified carboxy" may include the following.

Preferred examples of the esterified carboxy ester moiety include the following. That is, it has a lower alkyl ester (eg, methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, tert-butyl ester, pentyl ester, hexyl ester, etc.), and one or more suitable substituents. Good lower alkyl esters such as lower alkanoyloxy (lower) alkyl esters [eg acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, hexanoyloxymethyl ester , 1- (or 2-)
Acetoxyethyl ester, 1- (or 2- or 3
-) Acetoxypropyl ester, 1- (or 2- or 3- or 4-) acetoxybutyl ester, 1-
(Or 2-) propionyloxyethyl ester, 1
-(Or 2- or 3-) propionyloxypropyl ester, 1- (or 2-) butyryloxyethyl ester, 1- (or 2-) isobutyryloxyethyl ester, 1- (or 2-) pivalo Yloxyethyl ester, 1- (or 2-) hexanoyloxyethyl ester, isobutyryloxymethyl ester, 2
-Ethyl butyryloxymethyl ester, 3,3-dimethylbutyryloxymethyl ester, 1- (or 2
-) Pentanoyloxyethyl ester and the like], lower alkanesulfonyl (lower) alkyl ester (such as 2-mesylethyl ester), mono (or di or tri) halo (lower) alkyl ester (such as 2-
Iodoethyl ester, 2,2,2-trichloroethyl ester, etc.), lower alkoxycarbonyloxy (lower) alkyl ester [eg methoxycarbonyloxymethyl ester, ethoxycarbonyloxymethyl ester, propoxycarbonyloxymethyl ester, tert-butoxycarbonyloxy] Methyl ester, 1- (or 2-) methoxycarbonyloxyethyl ester, 1- (or 2-) ethoxycarbonyloxyethyl ester, 1- (or 2-) isopropoxycarbonyloxyethyl ester, etc.], phthalidylidene (lower) alkyl Ester, or (5-lower alkyl-2-oxo-1,3-dioxol-4-yl)
(Lower) alkyl ester [eg (5-methyl-2
-Oxo-1,3-dioxol-4-yl) methyl ester, (5-ethyl-2-oxo-1,3-dioxol-4-yl) methyl ester, (5-propyl-2
-Oxo-1,3-dioxol-4-yl) ethyl ester, etc.]; lower alkenyl ester (eg vinyl ester, allyl ester etc.); lower alkynyl ester (eg ethynyl ester, propynyl ester etc.); One or more ar (lower) alkyl ester (eg, benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, trityl ester,
Benzhydryl ester, bis (methoxyphenyl) methyl ester, 3,4-dimethoxybenzyl ester,
4-hydroxy-3,5-di-tert-butylbenzyl ester and the like); aryl ester (eg phenyl ester, which may have one or more suitable substituents)
4-chlorophenyl ester, tolyl ester, ter
t-butylphenyl ester, xylyl ester, mesityl ester, cumenyl ester, etc.); phthalidyl ester and the like.

Preferred examples of the "protected carboxy group" thus defined include lower alkenyloxycarbonyl and phenyl (or nitrophenyl).
(Lower) alkoxycarbonyl can be mentioned, and more preferred are C ₂ -C ₄ alkenyloxycarbonyl and phenyl (or nitrophenyl) (C ₁
-C ₄₎ alkoxycarbonyl can be mentioned, as the most preferred and allyl oxycarbonyl. Suitable "hydroxy (lower) alkyl group" is linear or branched lower alkyl having a hydroxy group, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, 1- (hydroxymethyl) ethyl, 1-hydroxy- 1-Methylethyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl and the like can be mentioned. Among them, hydroxy (C ₁ -C ₄ ) alkyl can be mentioned as a more preferable example, and 1-hydroxy is most preferable. Mention may be made of ethyl. Suitable "protected hydroxy (lower) alkyl group" is a hydroxy protecting group such as the hydroxy group of hydroxy (lower) alkyl shown in the description of imino protecting group below, preferably lower alkenyloxycarbonyl or phenyl. (Or nitrophenyl) (lower) alkoxycarbonyl; (C ₆ such as mono- or di- or triphenyl (lower) alkyl (eg benzyl, benzhydryl, trityl, etc.)
--C ₁₀ ) ar (lower) alkyl; tri (lower) alkylsilyl (eg, trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, tert-butyldimethylsilyl, diisopropylmethylsilyl, etc.), tri (C ₆ -C ₁₀ ) arylsilyl ( For example, triphenylsilyl, etc.), tris [(C ₆ -C ₁₀ ) ar (lower)
Alkyl] silyl, eg tris [phenyl (lower)]
Alkyl] silyl (eg tribenzylsilyl etc.)
Tri-substituted silyl such as and those protected with other conventional hydroxy protecting groups.

Preferred examples of the "protected hydroxy (lower) alkyl group" defined as above include lower alkenyloxycarbonyloxy (lower) alkyl and [tri (lower) alkylsilyl] oxy (lower) alkyl. Among them, more preferable ones include C ₂ -C ₄ alkenyloxycarbonyloxy (C ₁
-C ₄ ) alkyl and [tri (C ₁ -C ₄ ) alkylsilyl] oxy (C ₁ -C ₄ ) alkyl may be mentioned, with 1- (allyloxycarbonyloxy) ethyl being most preferred. be able to. Suitable "lower alkyl group" may include straight chain or branched alkyl such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl and hexyl. Among them, more preferable examples include C. _1- C ₄
Alkyl can be mentioned, most preferably methyl. Suitable "lower alkoxy group" may include linear or branched alkoxy such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentyloxy, isopentyloxy, hexyloxy, etc., among which more preferable By way of example, mention may be made of C ₁ -C ₄ alkoxy, most preferably methoxy.

Suitable "halogen" may include chlorine, bromine, fluorine or iodine. Suitable "hydroxy protecting group" in "protected hydroxy group" may be the same as those described in the description of "protected hydroxy (lower) alkyl group", and more preferable examples are as follows. Can include tri (lower) alkylsilyl. Preferred examples of “protected hydroxy” as defined above include:
[Tri (lower) alkylsilyl] oxy can be mentioned, more preferable example is [tri (C ₁ -C ₄ ) alkylsilyl] oxy, and the most preferable example is tert-butyldimethyl. Mention may be made of silyloxy.

Preferred "optionally substituted amino group" is 1 or 2 suitable substituents, for example, lower alkyl as described above, carbamoyl (lower) alkyl as described below, N- [hydroxy (lower)]. Alkyl] carbamoyl (lower) alkyl, amino which may be substituted with a protecting group such as those described in the imino protecting group below can be mentioned, and preferred examples are amino, lower alkenyloxycarbonylamino,
N- (lower) alkyl-N-carbamoyl (lower) alkylamino, N- (lower) alkyl-N- [N- {hydroxy (lower) alkyl} carbamoyl (lower) alkyl] amino, di (lower) alkylamino And more preferable examples include amino, C ₂ -C ₄ alkenyloxycarbonylamino, N- (C ₁ -C ₄ ) alkyl-N-carbamoyl (C ₁ -C ₄ ) alkylamino, N
- (C ₁ -C ₄₎ alkyl-N-[N-{hydroxy (C
_1- C ₄ ) alkyl} carbamoyl (C ₁ -C ₄ ) alkyl] amino and di (C ₁ -C ₄ ) alkylamino can be mentioned, and the most preferable examples are amino and N-methyl-N-carbamoyl. Methylamino, allyloxycarbonylamino, N-methyl-N- [N- (2-hydroxyethyl) carbamoylmethyl] amino, N-ethyl-
Mention may be made of N-carbamoylmethylamino, N-methyl-N-ethylamino or N, N-dimethylamino.

The preferable "heterocyclic group" in the "optionally substituted heterocyclic group" is a saturated or unsaturated monocyclic group having at least one hetero atom such as oxygen atom, sulfur atom or nitrogen atom. Or, it means a polycyclic heterocyclic group. Examples of more preferable heterocyclic groups include the following. A 3- to 8-membered, more preferably 5- or 6-membered unsaturated heteromonocyclic group having 1 to 4 nitrogen atoms, for example pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl and its N-oxides, pyrimidyl, pyrazinyl, Pyridazinyl, triazolyl (eg 4H-1,
2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl and the like), tetrazolyl (for example 1H-tetrazolyl, 2H-tetrazolyl and the like), dihydrotriazinyl (for example 4,5 -Dihydro-1,2,4-triazinyl, 2,5-dihydro-1,2,4-triazinyl, etc.); 3- to 8-membered, more preferably 5- or 6-membered, having 1 to 4 nitrogen atoms. Saturated heteromonocyclic groups such as azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl, pyrazolidinyl, piperazinyl and the like; , Quinolyl,
Isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridyl, tetrazolopyridazinyl (eg, tetrazolo [1,5-b] pyridazinyl, etc.), dihydrotriazolopyridazinyl, etc .;

1 or 2 oxygen atoms and 1 nitrogen atom
A 3- to 8-membered, more preferably 5- or 6-membered unsaturated heteromonocyclic group having 3 to 3, for example, oxazolyl,
Isoxazolyl, oxadiazolyl (eg 1,
2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl and the like); and 3 to 8 members having 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms, preferably 5 or A 6-membered saturated heteromonocyclic group such as morpholinyl; a 7- to 12-membered unsaturated condensed heterocyclic group having 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms, such as benzoxazolyl, benzoxadiazolyl; -3- to 8-membered, preferably 5- or 6-membered unsaturated heteromonocyclic groups having 1 or 2 sulfur atoms and 1 to 3 nitrogen atoms, for example 1,3-thiazolyl, 1,2-thiazolyl, thiazolinyl, thiadiazolyl. (Eg 1,
2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,2,3-thiadiazolyl) and the like;

1 or 2 sulfur atoms and 1 nitrogen atom
A 3- to 8-membered saturated heteromonocyclic group having 1 to 3 members, such as thiazolidinyl; and a 3- to 8-membered, preferably 5- or 6-membered, unsaturated heteromonocyclic group having 1 sulfur atom, such as thienyl; A 3- to 8-membered, preferably 5- or 6-membered, saturated heteromonocyclic group having 1 sulfur atom, such as tetrahydrothienyl; 7- to 12-membered having 1 or 2 sulfur atoms and 1 to 3 nitrogen atoms Unsaturated condensed heterocyclic groups such as benzothiazolyl and benzothiadiazolyl. These heterocyclic groups may be substituted with one or more suitable substituents as shown below, preferably one or two. -Hydroxy, -protected hydroxy [a hydroxy group protected by a conventional hydroxy protecting group as shown in the description of protected hydroxy (lower) alkyl, more preferably tri (C ₁ -C ₄ ) alkylsilyloxy ( A hydroxy group protected by, for example, tert-butyldimethylsilyloxy, etc.]-A hydroxy (lower) alkyl as described above or a protected hydroxy (lower) alkyl, more preferably hydroxy (C ₁ -C ₄ ) alkyl (eg hydroxy). Methyl, hydroxyethyl, etc.) or tri (C ₁ -C ₄ ).
Alkylsilyloxy (C ₁ -C ₄ ) alkyl (eg tert-butyldimethylsilyloxymethyl etc.);-Halogen (eg chlorine, bromine, iodine or fluorine);-lower alkoxy [methoxy, ethoxy, propoxy,
A straight chain or branched alkoxy such as isopropoxy, butoxy, pentyloxy, hexyloxy, and more preferably C ₁ -C ₄ alkoxy (eg, methoxy)];

-Lower alkyl as described above, more preferably C ₁ -C ₄ alkyl (eg methyl, ethyl etc.);-Lower alkoxy (lower) alkyl [as the lower alkoxy part and the lower alkyl part, the lower alkoxy mentioned above] And lower alkyl, the same as those mentioned above can be mentioned, more preferably C ₁ -C ₄ alkoxy (C ₁ -C ₄ ) alkyl (for example, methoxymethyl etc.)]; Amino [this lower alkyl moiety can include the same ones listed above for lower alkyl, more preferably C ₁ -C ₄ alkylamino (eg, methylamino)]; -Protected lower alkylamino [wherein the amino group is protected by a conventional amino group as described above] Said such lower alkylamino group was, more preferably C ₁ -C ₄ alkylamino (e.g., methylamino)];

-Amino; -carbamoyl (lower) alkyl (such as carbamoylmethyl) as follows; -N- (or N, N-di) (lower) alkylcarbamoyl (lower) alkyl [this lower alkyl portion and carbamoyl ( Examples of the (lower) alkyl moiety include the same ones as described above, more preferably N-
(Or N, N-di) (C ₁ -C ₄ ) alkylcarbamoyl (C ₁ -C ₄ ) alkyl (such as methylcarbamoylmethyl, dimethylcarbamoylmethyl, etc.)]; -N- (or N, N-bis) [hydroxy (lower) alkyl] carbamoyl (lower) alkyl [The hydroxy (lower) alkyl moiety and carbamoyl (lower) alkyl moiety may be the same as those described above, and more preferably N- (or N, N-bis)
[Hydroxy (C ₁ -C ₄ ) alkyl] carbamoyl (C
₁ -C ₄₎ alkyl [e.g. N- (or N, N-bis) (2-hydroxyethyl) carbamoylmethyl, etc.) can be mentioned]; - oxo; like.

Further, when the heterocyclic group has an imino moiety in its ring, this imino moiety may be substituted with an appropriate substituent as described below. - said such lower alkyl (e.g. methyl, ethyl, etc.); - the such hydroxy (lower) alkyl (e.g. 2-hydroxyethyl, etc.); - such imino protecting groups below, more preferably C ₂ -C ₄
Alkenyloxycarbonyl (such as allyloxycarbonyl); and the like. As a preferred heterocyclic moiety,
3- to 8-membered, more preferably 5- or 6-membered saturated or unsaturated heteromonocyclic group having 1 to 4 nitrogen atoms, such as pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, and N-oxides, pyrimidyl thereof,
Pyrazinyl, pyridazinyl, triazolyl (eg 4
H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.),
Tetrazolyl (eg 1H-tetrazolyl, 2H-tetrazolyl etc.), dihydrotriazinyl (eg 4,5-dihydro-1,2,4-triazinyl, 2,5
-Dihydro-1,2,4-triazinyl, etc.), azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl, pyrazolidinyl, piperazinyl, etc., among which one or more aliphatic heterocyclic groups, preferably 1 To 2 suitable substituents, for example carbamoyl (lower) alkyl; lower alkyl; N-
(Or N, N-di) (lower) alkylcarbamoyl (lower) alkyl; N- (or N, N-bis) [hydroxy (lower) alkyl] carbamoyl (lower) alkyl; oxo; amino; hydroxy (lower) alkyl May be substituted with;

The "optionally substituted heterocyclic group containing a tertiary nitrogen atom" means the above-mentioned "substituted heterocyclic group containing at least one tertiary nitrogen atom such as pyridyl, imidazolyl, pyrazolyl and the like. Optionally heterocyclic group ”. The `` optionally substituted heterocyclic group containing an imino moiety '' refers to the above-mentioned `` optionally substituted heterocyclic group '' whose heterocycle contains at least one imino moiety such as pyrrolidinyl, imidazolyl and piperazinyl. means. When the heterocyclic group of R ⁴ is, for example, N- (lower) alkyl-1-imidazolio, a tautomer as shown by the following equilibrium formula exists.

[Chemical 54] All of these isomers are included in the scope of the present invention, but in the present specification, the target compound or the intermediate compound containing the tautomeric group is described by a notation corresponding to one of them for convenience, is there.

Preferred examples of the "optionally substituted heterocyclic group" include the following. -Pyridyl (eg pyridin-3-yl, 1-pyridinio etc.);-Pyrrolidinyl (eg pyrrolidin-1-yl etc.);-Lower alkylpyrrolidinyl (eg 1-methyl-1)
-Pyrrolidinio etc.);-Imidazolyl (e.g. imidazol-1-yl etc.);-Mono (or di) lower alkylimidazolyl (e.g. 1-methylimidazol-2-yl, 1,3-dimethyl-2-imidazolio, 2,3 -Dimethyl-1-imidazolio, 3-methyl-1-imidazolio, etc.)-Lower alkylpyridyl (e.g., 1-methyl-3-pyridinio, etc.);-[N, N-di (lower) alkylcarbamoyl (lower)
Alkyl] pyridyl [eg 1- (N, N-dimethylcarbamoylmethyl) -3-pyridinio etc.];-[carbamoyl (lower) alkyl] pyridyl [eg 1- (carbamoylmethyl) -3-pyridinio etc.]; -(Or N, N-bis) {hydroxy (lower)
Alkyl} carbamoyl (lower) alkyl] pyridyl [eg N- (or N, N-bis) (2-hydroxyethyl) carbamoylmethyl] -3-pyridinio etc.];-Carbamoyl (lower) alkylimidazolyl (eg 3-carbamoylmethyl -1-imidazolium, etc.);-(amino) [hydroxy (lower) alkyl] pyrazolyl [eg 5-amino-1- (2-hydroxyethyl) -2-pyrazolio, etc.];-[(Lower) alkyl (oxo) piperazinyl (Eg 1-methyl-3-oxo-1-piperazinio etc.);-[(lower) alkyl] (dioxo) piperazinyl (eg 4-ethyl-2,3-dioxopiperidine-1-
Ill etc.); etc.

Suitable "imino protecting groups" include acyls derived from carboxylic acids, carbonic acids, sulfonic acids and carbamic acids, such as carbamoyl, aliphatic acyls, aromatic acyls, heterocyclic acyls and aromatic groups or heterocycles. Examples thereof include aliphatic acyl substituted with a group. The aliphatic acyl, saturated or unsaturated acyclic or cyclic, for example, lower alkanoyl (e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, etc.), Lower alkylsulfonyl (eg mesyl, ethylsulfonyl,
Propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, pentylsulfonyl, hexylsulfonyl, etc., alkylsulfonyl, carbamoyl, N-alkylcarbamoyl (eg, methylcarbamoyl, ethylcarbamoyl, etc.), lower alkoxycarbonyl (eg, methoxycarbonyl, ethoxycarbonyl). , Propoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, etc.)
Alkoxycarbonyl, such as lower alkenyloxycarbonyl (eg vinyloxycarbonyl, allyloxycarbonyl, etc.), lower alkenoyl (eg, acryloyl, methacryloyl, crotonoyl, etc.), cyclo (lower) alkanecarbonyl (eg, cyclo) Propane carbonyl, cyclopentane carbonyl, cyclohexane carbonyl, etc.) and the like.

Examples of the aromatic acyl include C ₆ -C ₁₀ aroyl (eg benzoyl, toluoyl, xyloyl etc.), N- (C ₆ -C ₁₀ ) arylcarbamoyl (eg N-phenylcarbamoyl, N-tolylcarbamoyl, N - such naphthylcarbamoyl), C ₆ -C ₁₀ arenesulfonyl (e.g. benzenesulfonyl, tosyl, etc.), and the like. Examples of the aromatic group-substituted aliphatic acyl include aralkoxycarbonyl such as phenyl (lower) alkoxycarbonyl (eg, benzyloxycarbonyl, phenethyloxycarbonyl, etc.) and the like. These acyl groups may be further substituted with one or more appropriate substituents such as nitro, and preferable examples of the acyl having such a substituent include nitroaralkoxycarbonyl (eg nitrobenzyl). Oxycarbonyl etc.)
And so on.

Preferred examples of the "imino-protecting group" thus defined include lower alkenyloxycarbonyl and phenyl (or nitrophenyl) (lower) alkoxycarbonyl, more preferably C _2-. C ₄ alkenyloxycarbonyl and phenyl (or nitrophenyl) (C ₁ -C ₄ ) alkoxycarbonyl may be mentioned, most preferably allyloxycarbonyl. Suitable "carbamoyl (lower) alkyl group" is linear or branched lower alkyl having a carbamoyl group, for example, carbamoylmethyl, carbamoylethyl, carbamoylpropyl, 1- (carbamoylmethyl) ethyl, 1-carbamoyl-1-methyl. Examples thereof include ethyl, carbamoylbutyl, carbamoylpentyl, carbamoylhexyl, and the like. Among them, carbamoyl (C ₁ -C ₄ ) alkyl is more preferable, and carbamoylmethyl is most preferable. Suitable "lower alkenylene group", vinylene, propenylene (for example 1-propenylene, etc.) can be exemplified by straight-chain or branched, such as, a C ₂ -C ₄ alkenylene as preferred than among others The most preferable examples include vinylene and 1-propenylene.

Suitable "acid residue" is azide, halo.
Gen (eg chlorine, bromine, fluorine or iodine), etc.
Inorganic acid residue, acyloxy (eg benzenesulfon
Nyloxy, tosyloxy, methanesulfonyloxy
Such as organic acid residues, etc.
A more preferable example is halogen.
The most preferable one is iodine.
Wear. Suitable "mercapto protecting group" is as described above.
When acyl, mono or di or triphenyl (lower)
Alkyl (eg benzyl, phenethyl, benzhydride
(Ryl, trityl, etc.) (C₆-C_Ten) Al (low
Primary) alkyl, among which preferred examples
As lower alkanoyl, C₆-C_TenAroyl and
Triphenyl (lower) alkyl can be mentioned,
C is more preferable₁-C_FourAlkanoyl, C₆−
C_TenAroyl and triphenyl (C₁-C _Four) Alkyl
The most preferable one is benzo.
Mention may be made of yl, acetyl and trityl.
In the definition of compound (I), preferred examples are as follows.
You can list the following. R¹Is carboxy or
Esterified carboxy, R²Is hydroxy (low
Class) alkyl, lower alkenyloxycarbonyl (low
Class) alkyl or [tri (lower) alkylsilyl] o
Xy (lower) alkyl, R³Is hydrogen or lower alk
Le, R^FourIs hydroxy, [tri (lower) alkylsilyl
L] oxy, amino, di (lower) alkylamino, N-
(Lower) alkyl-N-carbamoyl (lower) alkyl
Amino, N- (lower) alkyl-N- [N- {hydroxy
Ci (lower) alkyl} carbamoyl (lower) alkyl]
Amino, (lower) alkenyloxycarbonylamino,
Lower alkoxy, halogen or 1 to 4 nitrogen atoms
Having 3 to 8 members, more preferably 5 or 6 members
Saturated or unsaturated heteromonocyclic group [The above heterocyclic group may be one
Or more, preferably 1 to 3 suitable substitutions
Groups such as carbamoyl (lower) alkyl, lower ar
Kill, N- (or N, N-di) (lower) alkyl calc
Vamoyl (lower) alkyl, N- (or N, N-bi
Subs) [hydroxy (lower) alkyl] carbamoyl (low
Primary) alkyl, hydroxy (lower) alkyl, amino,
Or may be substituted with oxo, etc.]

R ⁵ is hydrogen or lower alkenyloxycarbonyl, and A is lower alkenylene. In the definition of compound (I), more preferable examples include the following. R ¹ is carboxy, lower alkenyloxycarbonyl or phenyl (or nitrophenyl)
(Lower) alkoxycarbonyl, R ² is hydroxy (lower) alkyl, lower alkenyloxycarbonyl (lower) alkyl or [tri (lower) alkylsilyl] oxy (lower) alkyl, R ³ is hydrogen or lower alkyl, R ⁴ is hydroxy , [Tri (lower) alkylsilyl] oxy, amino, di (lower) alkylamino, N-
(Lower) alkyl-N-carbamoyl (lower) alkylamino, N- (lower) alkyl-N- [N- {hydroxy (lower) alkyl} carbamoyl (lower) alkyl]
Amino, (lower) alkenyloxycarbonylamino,
Lower alkoxy, halogen, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, and its N-oxide, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (for example, 4H-1,2,4-triazolyl,
1H-1,2,3-triazolyl, 2H-1,2,3-
Triazolyl etc.), tetrazolyl (eg 1H-tetrazolyl, 2H-tetrazolyl etc.), dihydrotriazinyl (eg 4,5-dihydro-1,2,4-triazinyl, 2,5-dihydro-1,2,4-triazinyl). Etc.), azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl, pyrazolidinyl or piperazinyl [wherein said heterocyclic group is one or more, preferably 1 or 2 suitable substituents such as carbamoyl (lower) alkyl, lower alkyl, N- (Or N, N
-Di) (lower) alkylcarbamoyl (lower) alkyl, N- (or N, N-bis) [hydroxy (lower)
Alkyl] carbamoyl (lower) alkyl, hydroxy (lower) alkyl, amino, oxo, etc. may be substituted],

R ⁵ is hydrogen or lower alkenyloxycarbonyl, and A is lower alkenylene. In the definition of compound (I), more preferable examples include the following. R ¹ is carboxy, lower alkenyloxycarbonyl or phenyl (or nitrophenyl) (lower) alkoxycarbonyl, R ² is hydroxy (lower) alkyl, lower alkenyloxycarbonyl (lower) alkyl or [tri (lower) alkylsilyl] oxy ( Lower) alkyl, R ³ is hydrogen or lower alkyl, R ⁴ is hydroxy, [tri (lower) alkylsilyl] oxy, amino, di (lower) alkylamino, N
-(Lower) alkyl-N-carbamoyl (lower) alkylamino, N- (lower) alkyl-N- [N- {hydroxy (lower) alkyl} carbamoyl (lower) alkyl] amino, (lower) alkenyloxycarbonylamino, Lower alkoxy, halogen, imidazolyl, pyrazolyl, pyridyl, pyrrolidinyl or piperazinyl [wherein said heterocyclic group is one or more, preferably 1 or 2 suitable substituents such as carbamoyl (lower) alkyl, lower alkyl, N- (Or N, N-di) (lower) alkylcarbamoyl (lower) alkyl or N-
(Or may be substituted with N, N-bis) [hydroxy (lower) alkyl] carbamoyl (lower) alkyl, hydroxy (lower) alkyl, amino, oxo, etc.], R ⁵ is hydrogen or lower alkenyloxycarbonyl,

A is lower alkenylene. In the definition of compound (I), the most preferable examples include the following. R ¹ is carboxy or allyloxycarbonyl, R ² is 1-hydroxyethyl or 1-allyloxycarbonyloxyethyl, R ³ is methyl, R
⁴ is hydroxy, tert-butyldimethylsilyloxy, methoxy, iodo, amino, N-methyl-N-ethylamino, N-methyl-N-carbamoylmethylamino, N, N-dimethyl-N-carbamoylmethylammonio, N -Methyl-N-ethyl-N-carbamoylmethylammonio, allyloxycarbonylamino, N, N
-Dimethyl-N- [N- (2-hydroxyethyl) carbamoylmethyl] ammonio, pyridin-3-yl, N
-Methyl-3-pyridinio, 1-pyridinio, N-carbamoylmethyl-3-pyridinio, N- (N, N-dimethylcarbamoylmethyl) -3-pyridinio, N- [N
-(2-Hydroxyethyl) carbamoylmethyl] -3
-Pyridinio, N- (N, N-bis (2-hydroxyethyl) carbamoylmethyl] -3-pyridinio, imidazol-1-yl, 3-methyl-1-imidazolio (or 1-methyl-1-imidazolio), 2 , 3-Dimethyl-1-imidazolio, 3-carbamoylmethyl-1-
Imidazolio, 1-methylimidazol-2-yl,
1,3-Dimethyl-2-imidazolio, 1- (2-hydroxyethyl) -5-amino-2-pyrazolio, pyrrolidin-1-yl, N-methyl-1-pyrrolidinio, 1-
Methyl-3-oxo-1-piperazinio or 4-ethyl-2,3-dioxopiperazin-1-yl, R ⁵ is hydrogen or allyloxycarbonyl, A is vinylene or propenylene. The method for producing the object compound (I) of the present invention is described in detail below.

(1) Production Method 1 Compound (I) or its salt can be produced by reacting compound (II) or its reactive derivative at the oxo group or its salt with compound (III) or its salt. it can. Suitable salt of the compound (II) may be a salt with a base as shown in the compound (I). The reactive derivative at the oxo group of the compound (II) is represented by the following formula (II ′), and it is preferable to use this reactive derivative in this reaction. This reactive derivative can be produced by reacting compound (II) or a salt thereof with an acylating agent.

[Chemical 55] (In the formula, R ¹ , R ² and R ³ are respectively as defined above, R ¹¹ is an acyl such as an imino protecting group, and further, for example, O derived from an organic phosphoric acid shown below is used. , O-substituted phosphono.)

Suitable acylating agents include conventional acylating agents which can introduce an acyl group into compound (II) as described above, and preferable acylating agents include
Organic sulfonic acid or organic phosphoric acid or acid halide,
Reactive derivatives thereof such as acid anhydrides, such as allenesulfonyl halides (eg, benzenesulfonyl chloride, p-toluenesulfonyl chloride, p-nitrobenzenesulfonyl chloride, p-bromobenzenesulfonyl chloride, etc.), allenesulfonic acid (eg, anhydrous benzene). Sulfonic acid, anhydrous p-toluenesulfonic acid, anhydrous p-nitrobenzenesulfonic acid, etc.), a lower alkanesulfonyl halide (eg, methanesulfonyl chloride, ethanesulfonyl chloride, trifluoromethanesulfonyl chloride, etc.) which may be further substituted with halogen, halogen Anhydrous lower alkanesulfonic acid which may have (for example, anhydrous methanesulfonic acid,
Examples include ethanesulfonic anhydride, trifluoromethanesulfonic anhydride, etc., di (lower) alkyl phosphorohalolides (eg, diethylphosphorochloridate), diarylphosphorohalolydates (eg, diphenylphosphorochloridate), etc. You can This acylation reaction is usually carried out in a conventional solvent that does not adversely influence the reaction, such as acetone, dioxane, acetonitrile, chloroform, dichloromethane, hexamethylphosphoramide, dichloroethane, tetrahydrofuran, ethyl acetate, dimethyl sulfoxide, N, N-dimethyl. It is carried out in a solvent such as formamide, pyridine, etc., or a mixture thereof.

When the above acylating agent is used in this reaction in the form of a free acid or a salt thereof, this reaction is carried out by a conventional condensing agent,
For example, a carbodiimide compound [for example, N, N'-diethylcarbodiimide, N, N'-diisopropylcarbodiimide, N, N'-dicyclohexylcarbodiimide, N-cyclohexyl-N'-morpholinoethylcarbodiimide, N-cyclohexyl-N '-(4- Diethylaminocyclohexyl) carbodiimide, N-ethyl-N ′-(3-dimethylaminopropyl) carbodiimide, etc.]; N, N′-carbonyldiimidazole, N,
N′-carbonylbis (2-methylimidazole); ketene imine compound (eg pentamethylene ketene-N
-Cyclohexylimine, diphenylketene-N-cyclohexylimine, etc.); ethoxyacetylene; 1-alkoxy-1-cycloethylene; ethyl polyphosphate; isopropyl polyphosphate; phosphorus oxychloride; phosphorus trichloride;
Thionyl chloride; Oxalyl chloride; Combination of triphenylphosphine and carbon tetrachloride or diazene dicarboxylate; 2-Ethyl-7-hydroxybenzisoxazolium salt; 2-Ethyl-5- (m-sulfophenyl) hydroxide Isoxazolium inner salt; 1- (p-chlorobenzenesulfonyloxy) -6-chloro-1H-benzotriazole; prepared by reacting N, N-dimethylformamide with thionyl chloride, phosgene, phosphorus oxychloride, etc. It is preferably carried out in the presence of so-called Vilsmeier reagent.

This acylation reaction is carried out by using an inorganic or organic base,
For example, alkali metal bicarbonates (eg sodium bicarbonate, potassium bicarbonate etc.), alkali metal carbonates (eg sodium carbonate, potassium carbonate etc.), alkaline earth metal carbonates (eg magnesium carbonate, calcium carbonate etc.), tri ( Lower) alkylamine (eg trimethylamine, triethylamine, N, N-diisopropyl-N-ethylamine etc.), pyridine compound [eg N, N-di (lower) alkyl such as pyridine, picoline, lutidine, N, N-dimethylaminopyridine etc. Aminopyridine etc.], quinoline, N-lower alkylmorpholine (eg N-methylmorpholine etc.),
It can be carried out in the presence of N, N-di (lower) alkylbenzylamine (eg N, N-dimethylbenzylamine etc.), alkali metal alkoxide (eg sodium methoxide, sodium ethoxide, potassium butoxide etc.) and the like. The reaction temperature of this acylation reaction is not particularly limited, and the reaction is usually performed under cooling or heating. Regarding the compound (II), the following formula (II
3,7-dioxo-1-azabicyclo [3.2.0] heptane ring structure represented by A) is represented by the following formula (IIB): 3-hydroxy-7-oxo-1-azabicyclo [3.2. It is well known that they have a tautomeric relationship with the [0] hept-2-ene ring structure, and these two ring structures are substantially the same.

[Chemical 56] The compound (II ′) or a salt thereof can be used for the reaction with the following compound (III) or a salt thereof with or without isolation. Suitable salts of the compound (III) may be the same as those shown for the compound (I) and silver salts. The reaction of the compound (II) or its reactive derivative or its salt with the compound (III) or its salt can be carried out in the presence of an organic or inorganic base as shown in the above description of the acylation reaction.
This reaction is carried out in a conventional solvent which does not adversely influence the reaction as shown in the above-mentioned acylation reaction. The reaction temperature is not particularly limited, and the reaction is usually performed under cooling or heating.

(2) Production Method 2 Compound (Ib) or a salt thereof can be produced by subjecting compound (Ia) or a salt thereof to _a carboxy-protecting group elimination reaction for R ¹ _a . Suitable salts of the compounds (Ia) and (Ib) may be the same as those shown for the compound (I). This reaction is
Usually, it is carried out by a conventional method such as hydrolysis or reduction. (I) Hydrolysis Hydrolysis is preferably carried out in the presence of a base or an acid. Suitable bases include alkali metal hydroxides (eg sodium hydroxide, potassium hydroxide etc.), alkaline earth metal hydroxides (eg magnesium hydroxide, calcium hydroxide etc.), alkali metal hydrides (eg hydrogenated). Sodium, potassium hydride, etc.), alkaline earth metal hydrides (eg calcium hydride),
Alkali metal alkoxides (eg sodium methoxide, sodium ethoxide, potassium tert-butoxide etc.), alkali metal carbonates (eg sodium carbonate, potassium carbonate etc.), alkaline earth metal carbonates (eg magnesium carbonate, calcium carbonate etc.),
Examples thereof include alkali metal bicarbonates (for example, sodium bicarbonate, potassium bicarbonate, etc.). Suitable acids include organic acids (eg formic acid, acetic acid, propionic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.) and inorganic acids (eg hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc.). Can be mentioned.
Hydrolysis under acidic conditions with trifluoroacetic acid
Usually, the reaction rate can be increased by adding a cation scavenger (for example, phenol, anisole, etc.). This reaction is generally carried out in a solvent which does not adversely influence the reaction, such as water, dichloromethane, alcohol (eg methanol, ethanol etc.), tetrahydrofuran, dioxane, acetone etc. or a mixture thereof. A liquid base or acid can also be used as a solvent. The reaction temperature is not particularly limited, and the reaction is usually performed under cooling or heating.

(Ii) Reduction As a reduction method applicable to this elimination reaction, for example, a metal (eg, zinc, zinc amalgam, etc.) or a chromium compound salt (eg, chromium chloride, chromium acetate, etc.) and an organic or Reduction using a combination with an inorganic acid (eg acetic acid, propionic acid, hydrochloric acid, sulfuric acid, etc.); conventional metal catalysts, eg palladium catalysts (eg palladium sponge, palladium black, palladium oxide, palladium charcoal, colloidal palladium, palladium barium sulfate). , Palladium-barium carbonate, palladium hydroxide charcoal, etc.), nickel catalyst (eg reduced nickel, nickel oxide, Raney nickel etc.), platinum catalyst (eg platinum plate, platinum sponge, platinum black, colloidal platinum, platinum oxide, platinum wire etc.) Conventional catalytic reduction in the presence of It can be mentioned. When this reaction is carried out by catalytic reduction, it is preferable to carry out the reaction under conditions of near neutrality. This reaction is usually a conventional solvent which does not adversely influence the reaction, such as water, alcohol (eg methanol, ethanol, propanol etc.), dioxane, tetrahydrofuran, acetic acid, buffer (eg phosphate buffer, acetic acid buffer etc.). Or a mixture thereof. The reaction temperature is not particularly limited, and the reaction is usually performed under cooling or heating. When the carboxy protecting group is an allyl group, the protecting group can be removed by hydrogenolysis using a palladium compound. Suitable palladium compounds used in this reaction include palladium charcoal, palladium hydroxide charcoal, palladium chloride, palladium-ligand complex such as tetrakis (triphenylphosphine) palladium (0), bis (dibenzylideneacetone) palladium (0), Di [1,2-bis (diphenylphosphino) ethane] palladium (0), tetrakis (triphenylphosphite) palladium (0), tetrakis (triethylphosphite) -palladium (0) and the like can be mentioned.

This reaction is carried out by a scavenger of an allyl group formed in the reaction system such as an amine (eg morpholine, N-methylaniline etc.), an activated methylene compound (eg dimedone, benzoyl acetate, 2-
Methyl-3-oxovaleric acid, etc., cyanohydrin compounds (eg, α-tetrahydropyranyloxybenzyl cyanide, etc.), lower alkanoic acids or salts thereof (eg, formic acid, acetic acid, ammonium formate, sodium acetate, 2
-Sodium ethylhexanoate), N-hydroxysuccinimide and the like are preferred. This reaction can be carried out in the presence of a base such as lower alkylamine (eg, butylamine, triethylamine, etc.) and pyridine. When a palladium-ligand complex is used in this reaction, this reaction is preferably performed in the presence of a corresponding ligand (eg, triphenylphosphine, triphenylphosphite, triethylphosphite, etc.). This reaction is usually a conventional solvent that does not adversely influence the reaction, such as water, methanol, ethanol,
It is carried out in the presence of propanol, dioxane, tetrahydrofuran, acetonitrile, chloroform, dichloromethane, dichloroethane, ethyl acetate and the like, or mixtures thereof. This elimination reaction may be selected depending on the type of the carboxy protecting group to be eliminated. It is also within the scope of this process if the hydroxy and / or imino and / or amino protecting groups of R ² and / or R ⁴ and / or R ⁵ are simultaneously eliminated during the reaction.

[0048] (3) Process 3 Compound (I-d) or a salt thereof can be prepared by subjecting the compound (I-c) or a salt thereof to an imino protective group elimination reaction of R ⁵ _a. Suitable salts of the compounds (Ic) and (Id) may be the same as those shown for the compound (I). This reaction is usually carried out by a conventional method such as hydrolysis or reduction. The method of hydrolysis and reduction and their reaction conditions (for example, reaction temperature, solvent, etc.) are the same as those of the compound (I-
Since the substance is substantially the same as that exemplified for the carboxy-protecting group elimination reaction in a), the above description is directly incorporated herein by reference. The case where the carboxy and / or hydroxy and / or amino protecting groups of R ¹ and / or R ² and / or R ⁴ are simultaneously removed during this reaction is also included in the scope of this production method.

[0049] (4) Process 4 Compound (I-f) or a salt thereof can be prepared by subjecting the compound (I-e) or a salt thereof to a hydroxy protecting group elimination reaction of the R ² _a. Suitable salts of the compounds (Ie) and (If) may be the same as those shown for the compound (I). This reaction is
Usually, it is carried out by a conventional method such as hydrolysis or reduction. The hydrolysis and reduction methods and their reaction conditions (for example, reaction temperature, solvent, etc.) are substantially the same as those exemplified for the carboxy-protecting group elimination reaction of compound (Ia) in Production Method 2. Therefore, the above description is directly incorporated herein by reference. When the hydroxy protecting group is tri (lower) alkylsilyl, the protecting group can be eliminated in the presence of tetra (lower) alkylammonium fluoride (eg, tetrabutylammonium fluoride). It is within the scope of this production method that the carboxy and / or hydroxy and / or imino protecting groups of R ¹ and / or R ⁴ and / or R ⁵ are simultaneously eliminated during the reaction.

[0050] (5) Process 5 Compound (I-h) or a salt thereof can be prepared by subjecting the compound (I-g) or a salt thereof to a hydroxy protecting group elimination reaction of R ⁴ _a. Suitable salts of the compound (I-h) may be the same as those shown for the compound (I). Suitable salt of the compound (I-g) may be a salt with a base as shown in the compound (I). This reaction is usually carried out by a conventional method such as hydrolysis or reduction. The hydrolysis and reduction methods and their reaction conditions (for example, reaction temperature, solvent, etc.) are substantially the same as those exemplified for the carboxy-protecting group elimination reaction of compound (Ia) in Production Method 2. Therefore, the above description is directly incorporated herein by reference. The case where the carboxy and / or hydroxy and / or imino protecting groups of R ¹ and / or R ² and / or R ⁵ are simultaneously removed during the reaction is also included in the scope of the present production method.

(6) Production Method 6 Compound (I-j) or a salt thereof can be produced by reacting compound (I-i) or a salt thereof with compound (IV). Compounds (I-i) and (I-
Suitable salts of j) may be the same as those shown for compound (I). This reaction is usually carried out in a conventional solvent that does not adversely influence the reaction, for example, a solvent such as water, dioxane, tetrahydrofuran, acetone, or a mixture thereof. The reaction temperature is not particularly limited, and the reaction is usually performed under cooling or heating.

(7) Production Method 7 Compound (I-1) or a salt thereof can be produced by reacting compound (Ik) or a salt thereof with compound (V). Compounds (Ik) and (I-
Suitable salts of l) may be the same as those shown for compound (I). This reaction is usually carried out in a conventional solvent that does not adversely influence the reaction, for example, a solvent such as water, dioxane, tetrahydrofuran, acetone, or a mixture thereof. The reaction temperature is not particularly limited, and the reaction is usually performed under cooling or heating.

(8) Production Method 8 Compound (In) or a salt thereof can be produced by reacting compound (Im) or a salt thereof with compound (VI). Compounds (Im) and (I-
Suitable salts of n) may be the same as those shown for compound (I). This reaction can be carried out in the presence of a conventional base as shown in the explanation of the production method 1. This reaction is usually carried out in a conventional solvent that does not adversely influence the reaction, for example, a solvent such as water, dioxane, tetrahydrofuran, acetone, or a mixture thereof. The reaction temperature is not particularly limited, and the reaction is usually performed under cooling or heating.

(9) Production Method 9 Compound (Io) or a salt thereof can be produced by reacting compound (Ik) or a salt thereof with compound (VII). Suitable salts of the compound (Io) may be the same as those shown for the compound (I). This reaction is usually carried out in a conventional solvent that does not adversely influence the reaction, for example, a solvent such as water, dioxane, tetrahydrofuran, acetone, or a mixture thereof. The reaction temperature is not particularly limited, and the reaction is usually performed under cooling or heating.

(10) Production Method 10 Compound (Ip) or a salt thereof can be produced by halogenating compound (Io) or its reactive derivative at the hydroxy group or a salt thereof. Suitable salts of the compounds (Io) and (Ip) may be the same as those shown for the compound (Ia). Suitable reactive derivative of the compound (Io) may be the same as those shown for the compound (II ′). Preferable examples of the halogenating agent used in the present production method include conventional ones capable of converting a hydroxy group into halogen, such as halogen (eg iodine,
Chlorine, bromine, etc.), or an alkali metal salt thereof (eg sodium iodide, sodium chloride etc.), phosphorus oxyhalide (eg phosphorus oxybromide, phosphorus oxychloride etc.), phosphorus pentahalide (eg phosphorus pentabromide, etc.) Phosphorus pentachloride, phosphorus pentafluoride, etc.), phosphorus trihalide (eg phosphorus tribromide, phosphorus trichloride, phosphorus trifluoride, etc.),
With thionyl halides (eg thionyl chloride, thionyl bromide), dihalogenated triphenylphosphines (eg triphenylphosphine dichloride, triphenylphosphine dibromide), triphenylphosphines and carbon tetrahalides (eg carbon tetrachloride) And the like. This reaction is usually carried out in a solvent which does not adversely influence the reaction, such as methylene chloride, acetone, chloroform, carbon tetrachloride, benzene, tetrahydrofuran, dimethylformamide, dimethylsulfoxide, etc., or a mixture thereof. . When the halogenating agent is liquid, it can also be used as a solvent. The reaction temperature is not particularly limited, and the reaction is carried out under cooling or heating.

(11) Production Method 11 Compound (Iq) or a salt thereof can be produced by reacting compound (Ik) or a salt thereof with compound (VIII). Suitable salts of the compound (Iq) may be the same as those shown for the compound (I). This reaction is usually carried out in a conventional solvent that does not adversely influence the reaction, for example, a solvent such as water, dioxane, tetrahydrofuran, acetone or the like, or a mixture thereof. The reaction temperature is not particularly limited,
Usually, the reaction is carried out under cooling or heating.

(12) Production Method 12 Compound (Ir) or a salt thereof can be produced by reacting compound (Ik) or a salt thereof with compound (IX). Suitable salt of the compound (Ir) may be the same as those shown for the compound (I). This reaction is usually carried out in a conventional solvent that does not adversely influence the reaction, for example, a solvent such as water, dioxane, tetrahydrofuran, acetone, or a mixture thereof. The reaction temperature is not particularly limited, and usually
The reaction is carried out under cooling or heating.

(13) Production Method 13 Compound (Is) or a salt thereof can be produced by reacting compound (Ik) or a salt thereof with compound (X). Suitable salts of the compound (Is) may be the same as those shown for the compound (I). This reaction is usually carried out in a conventional solvent that does not adversely influence the reaction, for example, a solvent such as water, dioxane, tetrahydrofuran, acetone, or a mixture thereof. The reaction temperature is not particularly limited, and the reaction is usually performed under cooling or heating. (14) Process 14 Compound (I-u) or a salt thereof can be prepared by subjecting the compound (I-t) or a salt thereof to an amino protecting group elimination reaction of the R ⁴ _b. Suitable salts of the compounds (It) and (Iu) may be the same as those shown for the compound (I). This reaction is usually carried out by a conventional method such as hydrolysis or reduction. The method of hydrolysis and reduction and their reaction conditions (for example, reaction temperature, solvent, etc.) are the same as those of the compound (I-
Since the substance is substantially the same as that exemplified for the carboxy-protecting group elimination reaction in a), the above description is directly incorporated herein by reference. The case where the carboxy and / or hydroxy protecting groups of R ¹ and / or R ² and / or R ⁴ are simultaneously removed during the reaction is also included in the scope of this production method. The target compound obtained by the above-mentioned production method can be isolated and purified by, for example, extraction, crystallization, fractional crystallization, recrystallization, chromatography and the like. The production method A of the novel raw material compound (III) or a salt thereof will be described in detail below.

Process A Compound (III) or a salt thereof can be prepared by reacting compound (III-
It can be produced by subjecting a) or a salt thereof to a mercapto protecting group elimination reaction. Compound (III-
Suitable salts of a) may be the same as those shown for compound (III). This elimination reaction is
It can be carried out according to a conventional method shown below, and the method may be selected depending on the kind of the mercapto protecting group to be eliminated. When the protecting group is an ar (lower) alkyl group, it is generally treated with, for example, a silver compound (eg, silver nitrate, silver carbonate, etc.) or in the presence of an acid (eg, trifluoroacetic acid) (mercapto compound ( For example, it can be eliminated by reacting it with 2-mercaptoethanol and the like. The reaction using the silver compound is preferably carried out in the presence of an organic base (eg pyridine). The obtained silver salt of compound (III) can be converted to its alkali metal salt by reacting with an alkali metal halide (eg, sodium iodide, potassium iodide, etc.) if necessary. When the protecting group is an acyl group, generally, it can be eliminated by solvolysis such as hydrolysis using an acid or base, alcoholysis using a base, and the like. Suitable acids or bases used in these reactions include the production method 2
The same as those shown in the description of hydrolysis of can be mentioned. This reaction is generally carried out in a solvent which does not adversely influence the reaction, such as water, alcohol (eg methanol, ethanol etc.), pyridine, N, N-dimethylformamide etc., or a mixture thereof. When the base or acid used is liquid, it can be used as a solvent. The alcoholysis is usually carried out in a conventional alcohol such as methanol or ethanol. The reaction temperature is not particularly limited,
Usually, the reaction is carried out under cooling or heating.

The object compound (I) of the present invention and its pharmaceutically acceptable salts are novel, exhibit high antibacterial activity and inhibit the growth of a wide range of pathogenic bacteria, including Gram-positive and Gram-negative bacteria, and are therefore antibacterial. It is useful as an agent. In the present invention, the target compound (I) having higher antibacterial activity is represented by the following formula

[Chemical 57] (In the formula, R ² _b , R ³ , R ⁴ and A are as defined above.) And a pharmaceutically acceptable salt thereof. In particular, compound (I) having the highest antibacterial activity is represented by the following formula

[Chemical 58] (In the formula, R ³ _a represents lower alkyl, R ⁴ and A are as defined above.) And a pharmaceutically acceptable salt thereof.

[0061]

EFFECTS OF THE INVENTION Next, in order to show the usefulness of the objective compound (I), the data of the antibacterial activity test of representative compounds of the objective compound (I) of the present invention are shown below. In vitro antibacterial activity Test method: In vitro antibacterial activity was measured by the following agar two-fold dilution method. Trypticase soy
One platinum loop of an overnight culture (10 ⁶ viable cells per ml) in broth was streaked and streak-inoculated on Heart Infusion Agar (HI agar) containing a concentration gradient of the test compound.
After incubating this at 37 ° C. for 20 hours, the minimum inhibitory concentration (MIC) was expressed in μg / ml. Test compound: Compound of Example 11-3) Test result:

[Table 1] For therapeutic administration, the object compound (I) of the present invention and a pharmaceutically acceptable salt thereof are used as an active ingredient in an organic or inorganic solid or liquid form suitable for oral and parenteral administration or external use. It is used in the form of a conventional pharmaceutical preparation containing it as a mixture with a pharmaceutically acceptable carrier such as an agent. The pharmaceutical preparation may be in a solid form such as tablets, granules, powders and capsules, and may be liquids, suspensions, syrups,
It may be a liquid such as an emulsion or a lemonade agent.

If necessary, auxiliary agents, stabilizers, wetting agents, and other conventional additives may be added to the above-mentioned preparations such as lactose, stearic acid, magnesium stearate, clay, sucrose, corn starch, talc, gelatin, agar, Pectin,
Peanut oil, olive oil, cocoa butter, ethylene glycol, tartaric acid, citric acid, fumaric acid and the like may be added. The dose of compound (I) will vary depending on the age and condition of the patient or the type of disease, the type of compound (I) to be applied, etc., but in general, the dose is in the range of 1 mg to about 4000 mg per day. Alternatively, a larger amount may be administered per patient. In the treatment of infectious diseases caused by pathogenic bacteria, the average single dose of the compound (I) of the present invention is about 1 mg, 10 mg, 50 mg, 100 mg, 250 m.
It may be used as g, 500 mg, 1000 mg, and 2000 mg.

[0063]

EXAMPLES The following Production Examples and Examples are provided to illustrate the present invention. Production Example 1-1) (2S, 4R) -1-allyloxycarbonyl-4-hydroxy-2-methoxycarbonylpyrrolidine (727
To a solution of g) in dimethylformamide (1450 ml) was added imidazole (302 g) and tert-butyldimethylchlorosilane (573 g) sequentially with cooling in an ice bath. The mixture is stirred at the same temperature for 1.5 hours and then at room temperature overnight. The reaction was stopped by adding water (1500 ml) to the mixture, and hexane-ethyl acetate (2: 1, 1500 ml).
Extract with x1, 750 ml x 1, 600 ml x 1).
The extracts were combined, water (1 lx2) and brine (1.5
After sequentially washing with 1 × 1), it is dried with magnesium sulfate.
The solvent was distilled off to give (2S, 4R) -1-allyloxycarbonyl-4-tert-butyldimethylsilyloxy-2-methoxycarbonylpyrrolidine (1.14 kg).
As a colorless oil. IR (neat): 1742, 1700 cm ^-1 NMR (CDCl ₃ , 200MHz, δ): 0.07 (6H, s), 0.87 (9H, s),
1.79-2.24 (2H, m), 3.44-3.52 (1H, m), 3.62-3.70 (1H,
m), 3.72 (1.5H, s, conformer), 3.75 (1.5H, s, conformer), 4.41-4.63 (4H, m), 5.15-5.35 (2H, m), 5.80-5.9
5 (1H, m)

Production Example 1-2) (2S, 4R) -1-allyloxycarbonyl-4-t
Sodium borohydride (44.0 g) was added to a solution of ert-butyldimethylsilyloxy-2-methoxycarbonylpyrrolidine (200 g) in tetrahydrofuran (600 ml) and ethanol (600 ml) little by little at room temperature, and the temperature of the mixture was adjusted to 30-35. Stir for 3 hours while maintaining at ℃. Brine (1 l) is added to this, and the mixture is extracted with ethyl acetate (600 ml × 2). The extracts are combined, washed with brine (1 l) and dried over magnesium sulfate. The solvent was distilled off to give (2S, 4R) -1-allyloxycarbonyl-4-tert-butyldimethylsilyloxy-
2-Hydroxymethylpyrrolidine (183 g) is obtained as a colorless paste. IR (neat): 3420, 1674 cm ^-1 NMR (CDCl ₃ , 200MHz, δ): 0.059 (3H, s), 0.064 (3H,
s), 0.87 (9H, s), 1.57-2.03 (2H, m), 3.40-3.74 (4H,
m), 4.11-4.32 (2H, m), 4.60-4.64 (3H, m), 5.19-5.36
(2H, m), 5.85-6.01 (1H, m)

Production Example 1-3) Oxalyl chloride (66.4 ml) in dichloromethane (1
800 ml) solution in a dry ice-acetone bath-6
Cool to 0 ° C. Dimethyl sulfoxide (99.
0 ml) is added dropwise at −60 to −50 ° C. over 20 minutes. After the completion of the dropping, the mixture was stirred at -60 ° C for 1 hour, and (2S, 4R) -1-allyloxycarbonyl-4 was added thereto.
A solution of -tert-butyldimethylsilyloxy-2-hydroxymethylpyrrolidine (200g) in dichloromethane (200ml) is added dropwise at -60 to -50 ° C over 30 minutes. The mixture is stirred at −50 to −40 ° C. for 1 hour, then triethylamine (442 ml) is added to quench the reaction. The mixture is warmed to 0 ° C. and stirred for 1 hour. Mix the mixture with water (1 lx1), 1N hydrochloric acid (1.5 lx
5), washed successively with saturated aqueous sodium bicarbonate solution (1 lx1) and brine (1 lx2) and dried over magnesium sulfate. The solvent was distilled off to obtain (2S, 4R) -1-allyloxycarbonyl-4-tert-butyldimethylsilyloxy-2-formylpyrrolidine (202.7 g).
As a brown oil. IR (neat): 1696 cm ^-1 NMR (CDCl ₃ , δ): 0.07 (6H, s), 0.87 (9H, s), 1.90-2.
09 (2H, m), 3.42-3.64 (2H, m), 4.30-4.41 (2H, m), 4.59
-4.64 (2H, m), 5.17-5.37 (2H, m), 5.81-5.97 (1H, m),
9.50 (0.5H, d, J = 3.3Hz, conformer), 9.58 (0.5H, d, J =
2.6Hz, conformer)

Production Example 1-4) 1.65M Butyllithium (67 ml) was added to a solution of N, N-diisopropylamine (15.4 ml) in tetrahydrofuran (150 ml) under nitrogen atmosphere at -40 to -10 ° C.
Add in. After stirring the mixture for 20 minutes, a solution of acetaldehyde-tert-butylimine (5.45 g) in tetrahydrofuran (10 ml) was added thereto at -60 ° C.
After the mixture was stirred at the same temperature for 30 minutes, diethyl chlorophosphate (7.9 ml) in tetrahydrofuran (1
0 ml) solution is added. The mixture is warmed to -10 ° C, stirred for 20 minutes and then cooled to -60 ° C. To this (2
A solution of S, 4R) -1-allyloxycarbonyl-2-formyl-4-tert-butyldimethylsiloxypyrrolidine (15.7 g) in tetrahydrofuran (50 ml) is added. The mixture is warmed to room temperature, stirred for half a day and then poured into a mixture of ethyl acetate (500 ml) and brine (250 ml). The mixture is adjusted to pH 4.0 with 10% hydrochloric acid. The organic layer is separated, washed with brine (250 ml) and dried over magnesium sulfate. The solvent is removed under reduced pressure. A solution of the residue in ethanol (100 ml) -tetrahydrofuran (100 ml) was added with sodium borohydride (4.0
g) is added at 0 ° C. The mixture was mixed with ethyl acetate (500m
Pour into a mixture of 1) and brine (250 ml) and adjust to pH 7.0 with 10% hydrochloric acid. Separate the organic layer and extract twice with ethyl acetate (200 ml). The organic layers are combined, washed twice with brine (200 ml) and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (2S, 4R).
-1-Allyloxycarbonyl-2-[(E) -3-hydroxy-1-propenyl] -4-tert-butyldimethylsiloxypyrrolidine (5.67 g) is obtained as a pale yellow oil. NMR (CDCl ₃ , δ): 0.06 (6H, s), 0.88 (9H, s), 1.66 (1
H, br s), 1.80 (1H, m), 1.9-2.2 (1H, m), 3.3-3.6 (2H,
m), 4.16 (2H, m), 4.3-4.7 (4H, m), 5.20 (1H, m), 5.29
(1H, m), 5.5-6.1 (3H, m)

Production Example 1-5) (2S, 4R) -1-allyloxycarbonyl-2-
[(E) -3-Hydroxy-1-propenyl] -4-t
ert-Butyldimethylsiloxypyrrolidine (9.59
g) in acetonitrile (100 ml) in concentrated hydrochloric acid (5
ml) at 0 ° C. After stirring the mixture for 30 minutes,
Pour into saturated aqueous sodium hydrogen carbonate solution (100 ml),
Extract 3 times with ethyl acetate (100 ml). The organic layers are combined, washed with brine (50 ml) and dried over magnesium sulfate. The solvent was removed under reduced pressure to (2S, 4R)
-1-Allyloxycarbonyl-2-[(E) -3-hydroxy-1-propenyl] -4-hydroxypyrrolidine (7.04 g) is obtained as a pale yellow oil. IR (neat): 3700, 2925, 1670, 1405 cm ^-1 NMR (CDCl ₃ , δ): 2.0-2.3 (4H, m), 3.63 (2H, m), 4.12
(2H, distorted d, J = 5.1Hz), 4.4-4.7 (4H, m), 5.1-5.5
(2H, m), 5.5-6.1 (3H, m)

Production Example 1-6) (2S, 4R) -1-allyloxycarbonyl-2-
A solution of [(E) -3-hydroxy-1-propenyl] -4-hydroxypyrrolidine (7.04 g) in N, N-dimethylformamide (30 ml) was added to tert-butyldimethylchlorosilane (5.0 g) and imidazole (2. 5
g) is added. After stirring the mixture for 2 hours, ethyl acetate (1
(00 ml), extracted twice, the organic layers were combined, and brine (5
After washing twice with 0 ml), it is dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography to give (2S, 4R) -1-
Allyloxycarbonyl-2-[(E) -3-tert
-Butyldimethylsilyloxy-1-propenyl] -4
-Hydroxypyrrolidine (4.53g) is obtained as a pale yellow oil. NMR (CDCl ₃ , δ): 0.59 (6H, s), 0.91 (9H, s), 1.79 (1
H, br s), 1.8-2.0 (1H, m), 2.0-2.2 (1H, m), 3.57 (2H,
m), 4.16 (2H, distorted d, J = 2.9Hz), 4.3-4.7 (4H, m), 5.
1-5.4 (2H, m), 5.5-5.7 (2H, m), 5.89 (1H, m)

Production Example 1-7) (2S, 4R) -1-allyloxycarbonyl-2-
[(E) -3-tert-butyldimethylsiloxy-1
-Propenyl] -4-hydroxypyrrolidine (4.53
To a solution of g) in tetrahydrofuran (40 ml) is added triphenylphosphine (5.25 g) and diethylazodicarboxylate (3.1 ml) at 0 ° C. Mix 3
After stirring for 0 minutes, thiobenzoic acid (2.8 ml) was added to it.
Add at ℃. The mixture is stirred at 0 ° C. for 30 minutes and then poured into saturated aqueous sodium hydrogen carbonate solution (40 ml). The mixture is extracted twice with ethyl acetate (100 ml), the organic layers are combined, washed twice with brine (50 ml) and then dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography to give (2
S, 4S) -1-allyloxycarbonyl-2-
[(E) -3-tert-butyldimethylsiloxy-1
-Propenyl] -4-benzoylthiopyrrolidine (5.
92 g) is obtained as a pale yellow oil. NMR (CDCl ₃ , δ): 0.07 (3H, s), 0.10 (3H, s), 0.91 (9
H, s), 1.90 (1H, m), 2.70 (1H, m), 3.41 (1H, m), 4.1-4.
4 (4H, m), 4.5 (1H, m), 4.5-4.7 (2H, m), 5.1-5.4 (2H,
m), 5.6-6.2 (3H, m), 7.3-7.8 (3H, m), 8.10 (2H, m)

Production Example 2 Oxalyl chloride (2.53 ml) and dichloromethane (9
0 ml) and dimethyl sulfoxide (4.31 m)
1) is added dropwise with stirring at -40 ° C to -50 ° C, and the mixture is stirred at the same temperature for 5 minutes. For this (2S, 4R)
A solution of -1-allyloxycarbonyl-4-tert-butyldimethylsiloxy-2- (hydroxymethyl) pyrrolidine (8.70 g) in dichloromethane (45 ml) is added dropwise at -40 ° C to -50 ° C. The mixture was stirred for 10 minutes, after which it was triethylamine (19.2 ml).
Is added dropwise, and the mixture is stirred at 0 to 10 ° C for 30 minutes. The insoluble material was filtered off, the filtrate was washed successively with 1N hydrochloric acid, water, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give (2S, 4R). -1-allyloxycarbonyl-4
-Tert-Butyldimethylsiloxy-2-formylpyrrolidine is obtained as a residue. On the other hand, 3-picolyltriphenylphosphonium chloride (11.8 g) in tetrahydrofuran (60 ml) -dimethylsulfoxide (6
0 ml) solution into potassium tert-butoxide (3.4
0 g) is added little by little at 0 to 5 ° C. with stirring, and the mixture is stirred at the same temperature for 30 minutes. The reaction mixture is added dropwise to a solution of the above residue in tetrahydrofuran (100 ml) at 0 ° C, and the mixture is stirred at the same temperature for 2 hours. Ethyl acetate was added to the reaction mixture,
The mixture is washed successively with 1N hydrochloric acid, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and the solvent is evaporated under reduced pressure. The residue is chromatographed on silica gel (250 g), eluting with a mixed solvent of n-hexane and ethyl acetate (2: 1, v / v). The first fraction was collected and the solvent was removed under reduced pressure to give (2S,
4R) -1-allyloxycarbonyl-4-tert-
Butyldimethylsiloxy-2-[(Z) -2- (pyridin-3-yl) vinyl] pyrrolidine (4.60 g) is obtained. NMR (CDCl ₃ , δ): 0.06 (6H, s), 0.80 (9H, s), 1.65-1.
90 (1H, m), 1.98-2.10 (1H, m), 3.34-3.56 (2H, m), 4.30
-4.39 (1H, m), 4.40-4.56 (2H, m), 4.70-4.90 (1H, m),
4.95-5.55 (2H, m), 5.64 (1H, dd, J = 9.4Hz, J = 11.6Hz),
5.70-6.00 (1H, m), 6.25-6.43 (1H, m), 7.17-7.25 (1H, m
m), 7.40-7.80 (1H, m), 8.40-8.50 (2H, m) The following fractions were collected and the solvent was distilled off under reduced pressure (2S, 4R).
-1-allyloxycarbonyl-4-tert-butyldimethylsiloxy-2-[(E) -2- (pyridine-3
-Yl) vinyl] pyrrolidine (3.73 g) is obtained. NMR (CDCl ₃ , δ): 0.06 (6H, s), 0.82 (9H, s), 1.76-1.
90 (1H, m), 1.96-2.10 (1H, m), 3.35-3.50 (2H, m), 4.25
-4.60 (4H, m), 4.90-5.25 (2H, m), 5.60-5.92 (1H, m),
6.08 (1H, br d), 6.25-6.50 (1H, m), 7.08-7.20 (1H,
m), 7.79 (1H, br d, J = 7.9Hz), 8.36 (1H, br d, J = 3.97H
z), 8.49 (1H, br s)

Production Example 3-1) (2S, 4R) -1-allyloxycarbonyl-4-t
ert-Butyldimethylsiloxy-2-[(Z) -2-
(Pyridin-3-yl) vinyl] pyrrolidine (4.59
g) in methanol (45 ml) in concentrated hydrochloric acid (3.18).
ml) is added with stirring at room temperature, and the mixture is allowed to stand at the same temperature overnight. 28% sodium methoxide was added to the reaction mixture.
A methanol solution (7.4 ml) is added under ice-cooling stirring, and the resulting insoluble matter is filtered off. The filtrate is evaporated under reduced pressure to give a residue. This is subjected to silica gel (150 g) chromatography, and eluted with a mixed solvent of chloroform and methanol (9: 1, v / v). Fractions containing the target compound were collected and the solvent was evaporated under reduced pressure to give (2S, 4R)-
1-allyloxycarbonyl-4-hydroxy-2-
[(Z) -2- (Pyridin-3-yl) vinyl] pyrrolidine (4.16 g) is obtained. NMR (CDCl ₃ , δ): 1.80-2.00 (1H, m), 2.10-2.50 (2H,
m), 3.48-3.73 (2H, m), 4.38-4.60 (3H, m), 4.89 (1H, d
d, J = 16.4Hz, J = 8.5Hz), 5.00-5.40 (2H, m), 5.69 (1H, d
d, J = 9.43Hz, J = 11.6Hz), 6.38-6.55 (1H, m), 7.20-7.26
(2H, m), 7.55-7.90 (1H, m), 8.38-8.60 (2H, m)

Production Example 3-2) (2S, 4R) -1-allyloxycarbonyl-4-hydroxy-2-[(Z) -2- (pyridin-3-yl)
Vinyl] pyrrolidine (4.15 g) in ethyl acetate (42
ml) -triethylamine (2.95 ml) solution, methanesulfonyl chloride (1.52 ml) is added dropwise under ice-cooling stirring, and the mixture is stirred at the same temperature for 1 hour. Ethyl acetate (100 ml) and water (50 ml) are added to the reaction mixture.
The organic layer is washed successively with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and the solvent is evaporated under reduced pressure. The residue obtained is chromatographed on silica gel (150 g), eluting with a mixed solvent of dichloromethane and acetone (9: 1, v / v). Fractions containing the target compound were collected and the solvent was evaporated under reduced pressure to give (2S, 4R) -1-allyloxycarbonyl-4.
-Methylsulfonyloxy-2-[(Z) -2- (pyridin-3-yl) vinyl] pyrrolidine (3.72g) is obtained. NMR (CDCl ₃ , δ): 1.98-2.10 (1H, m), 2.40-2.65 (1H,
m), 3.04 (3H, s), 3.69 (1H, dd, J = 3.53Hz, J = 13.3Hz),
3.90-4.10 (1H, m), 4.40-4.65 (2H, m), 4.89 (1H, dd, J =
8.78Hz, J = 16.5Hz), 5.05-5.40 (3H, m), 5.66 (1H, dd, J
= 9.40Hz, J = 11.5Hz), 5.71-6.10 (1H, m), 6.53 (1H, br
d, J = 11.4Hz), 7.28-7.34 (1H, m), 7.50-7.90 (1H, m), 8.
45-8.65 (2H, m)

Production Example 3-3) A solution of sodium hydride (0.55 g) in N, N-dimethylformamide (5 ml) was added to thioacetic acid (1.05 ml).
Is added dropwise with stirring under ice cooling. The mixture is stirred at the same temperature for 30 minutes. To this mixture was added (2S, 4R) -1-allyloxycarbonyl-4-methylsulfonyloxy-2-
A solution of [(Z) -2- (pyridin-3-yl) vinyl] pyrrolidine (3.71 g) in N, N-dimethylformamide (37 ml) is added at the same temperature while stirring. The mixture is stirred at 80-90 ° C for 2 hours. The reaction mixture is poured into ice water (100 ml) and extracted twice with ethyl acetate (100 ml). The extract is washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. The residue is chromatographed on silica gel (120 mg), eluting with a mixed solvent of dichloromethane and acetone (9: 1, v / v). Fractions containing the target compound were collected and the solvent was evaporated under reduced pressure to give (2S, 4S) -1-allyloxycarbonyl-4-acetylthio-2-
[(Z) -2- (Pyridin-3-yl) vinyl] pyrrolidine (3.14 g) is obtained. NMR (CDCl ₃ , δ): 1.70-1.95 (1H, m), 2.35 (3H, s), 2.
50-2.80 (1H, m), 3.35 (1H, dd, J = 6.77Hz, J = 10.8Hz), 3.
80-4.10 (2H, m), 4.35-4.65 (2H, m), 4.65-4.83 (1H,
m), 5.00-5.25 (2H, m), 5.78 (1H, dd, J = 9.25Hz, J = 11.6H
z), 5.60-6.00 (1H, m), 6.47 (1H, br d, J = 11.0Hz), 7.2
0-7.30 (1H, m), 7.40-7.80 (1H, m), 8.40-8.60 (2H, m)

Production Example 4-1) Substantially the same as Production Example 3-1), (2S, 4R)-
1-allyloxycarbonyl-4-hydroxy-2-
Obtain [(E) -2- (pyridin-3-yl) vinyl] pyrrolidine. NMR (CDCl ₃ , δ): 1.90-2.05 (1H, m), 2.15-2.35 (1H,
m), 3.58-3.80 (2H, m), 4.45-4.80 (4H, m), 5.05-5.40
(2H, m), 5.75-6.05 (1H, m), 6.10-6.30 (1H, br dd), 6.3
5-6.60 (1H, m), 7.20-7.30 (1H, m), 7.68 (1H, d, J = 7.87
Hz), 8.43 (1H, d, J = 3.99Hz), 8.56 (1H, d, J = 1.84Hz)

Production Example 4-2) (2S, 4R) -substantially the same as Production Example 3-2).
1-allyloxycarbonyl-4-methylsulfonyloxy-2-[(E) -2- (pyridin-3-yl) vinyl] pyrrolidine is obtained. NMR (CDCl ₃ , δ): 2.00-2.21 (1H, m), 2.52-2.68 (1H,
m), 3.07 (3H, s), 3.72 (1H, dd, J = 4.18Hz, J = 12.9Hz),
3.90-4.10 (1H, m), 4.50-4.80 (3H, m), 5.10-5.35 (3H,
m), 5.75-6.00 (1H, m), 6.19 (1H, dd, J = 8.2Hz, J = 17.1H
z), 6.50 (1H, br d, J = 17.1Hz), 7.23-7.30 (1H, m), 7.6
9 (1H, d, J = 7.90Hz), 8.49 (1H, d), 8.59 (1H, s)

Production Example 4-3) Substantially the same as Production Example 3-3), (2S, 4S)-
1-allyloxycarbonyl-4-acetylthio-2-
Obtain [(E) -2- (pyridin-3-yl) vinyl] pyrrolidine. NMR (CDCl ₃ , δ): 1.80-1.95 (1H, m), 2.34 (3H, s), 2.
60-2.81 (1H, m), 3.34-3.43 (1H, m), 3.94-4.17 (2H, m),
4.50-4.70 (3H, m), 5.10-5.38 (2H, m), 5.75-6.05 (1H,
m), 6.24 (1H, dd, J = 6.76Hz, J = 15.9Hz), 6.47 (1H, br d,
J = 15.9Hz), 7.21-7.28 (1H, m), 7.60-7.71 (1H, m), 8.4
0-8.60 (2H, m)

Production Example 5 (2S, 4R) -1-allyloxycarbonyl-2-
[(E) -3-Hydroxy-1-propenyl] -4-t
ert-Butyldimethylsiloxypyrrolidine (5.53
g) in dimethylformamide (55 ml) in oil in 6
Add 2% sodium hydride (0.75g). Then methyl iodide (2.4 ml) is added thereto at room temperature. After stirring the mixture for several hours, it is poured into a mixture of ethyl acetate and brine and adjusted to pH 7. The organic layer is separated, washed with brine and dried over magnesium sulfate. The solvent is removed under reduced pressure to give methyl ether (15.08 g). This methyl ether (15.08 g) in acetonitrile (10
0 ml) solution is added concentrated hydrochloric acid (7 ml) at 0 ° C. The mixture was stirred for 30 minutes, then poured into saturated aqueous sodium hydrogen carbonate solution (100 ml), and ethyl acetate (100 ml x 3) was added.
To extract. The organic layers are combined, washed with brine (50 ml) and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography to give (2S, 4R) -1-allyloxycarbonyl-2-[(E) -3-methoxy-1-propenyl]-.
4-Hydroxypyrrolidine (1.35 g) is obtained. This compound (1.35 g) in tetrahydrofuran (15 m
l) To the solution is added triphenylphosphine (2.2g) and diethylazodicarboxylate (1.3ml) at 0 ° C. After stirring the mixture for 1 hour, thiobenzoic acid (1.2 m
l) is added at 0 ° C. The mixture is stirred at 0 ° C. for 30 minutes,
Pour into saturated aqueous sodium hydrogen carbonate solution (15 ml). The mixture is extracted with ethyl acetate (50 ml × 2), the organic layers are combined, washed with brine and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography to give (2S, 4S) -1-
Allyloxycarbonyl-2-[(E) -3-methoxy-1-propenyl] -4-benzoylthiopyrrolidine (1.16 g) is obtained. NMR (CDCl ₃ , δ): 1.93 (1H, m), 2.68 (1H, m), 3.39 (3
H, s), 3.40 (1H, m), 3.90 (1H, m), 3.94 (2H, d, J = 3.7H
z), 4.0-4.3 (2H, m), 4.50 (1H, m), 4.59 (2H, m), 5.1-
5.4 (2H, m), 5.74 (2H, m), 5.7-6.1 (1H, m), 7.3-7.7 (3
H, m), 7.8-8.1 (2H, m)

Production Example 6-1) (2S, 4R) -1-allyloxycarbonyl-4-t
(Triphenylphosphoranylidene) acetaldehyde (107 g) is added to a solution of ert-butyldimethylsiloxy-2-formylpyrrolidine (75.5 g) in toluene (800 ml) and the mixture is refluxed for 1.5 hours. After cooling this to room temperature, the solvent was evaporated and the residue was subjected to silica gel chromatography to give (2S, 4R)-
1-allyloxycarbonyl-4-tert-butyldimethylsiloxy-2- (3-oxo-1-propenyl)
Pyrrolidine (59.7 g) is obtained as a brown oil. IR (neat): 2930, 2850, 1682, 1400, 1114, 834, 7
70 cm ^-1 NMR (CDCl ₃ , δ): 0.07 (6H, s), 0.87 (9H, s), 1.8-2.2
(2H, m), 3.4-3.6 (2H, m), 4.3-4.4 (1H, m), 4.5-4.8 (3
H, m), 5.2-5.3 (2H, m), 5.7-6.1 (1H, m), 6.1-6.2 (1H,
m), 6.6-6.9 (1H, m), 9.56 (1H, d, J = 7.7Hz)

Production Example 6-2) (2S, 4R) -1-allyloxycarbonyl-4-t
ert-Butyldimethylsiloxy-2- (3-oxo-
1-Propenyl) pyrrolidine (59.8 g) in ethanol (300 ml) -tetrahydrofuran (300 ml)
Sodium borohydride (6.66 g) is added to the solution with stirring in a water bath. After stirring the mixture for 1 hour, saturated aqueous sodium chloride solution (600 ml) was added thereto, and the mixture was extracted with ethyl acetate (300 ml × 3). Combine the extracts, water (500 ml x 5), saline (500 ml)
Wash with x2) and dry over anhydrous magnesium sulfate. The solvent was distilled off, and (2S, 4R) -1-allyloxycarbonyl-4-tert-butyldimethylsiloxy-2-
(3-Hydroxypropen-1-yl) pyrrolidine (5
9.4 g) is obtained as a pale brown oil. NMR (CDCl ₃ , δ): 1.93 (1H, m), 2.68 (1H, m), 3.39 (3
H, s), 3.40 (1H, m), 3.90 (1H, m), 3.94 (2H, d, J = 3.7H
z), 4.0-4.3 (2H, m), 4.50 (1H, m), 4.59 (2H, m), 5.1-
5.4 (2H, m), 5.74 (2H, m), 5.7-6.1 (1H, m), 7.3-7.7 (3
H, m), 7.8-8.1 (2H, m)

Production Example 7 To a suspension of 2-oxopiperazine (4.0 g) in N, N-dimethylformamide (30 ml) was added sodium hydrogencarbonate (3.4 g) at room temperature and the mixture was stirred. The reaction mixture was ice-cooled, iodomethane (2.8 ml) was added, the temperature was raised to room temperature, and the mixture was stirred for half a day. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: chloroform-methanol-28% aqueous ammonia = 4: 1: 0.
1), 1-methyl-3-oxopiperazine (2.0 g)
To get NMR (CDCl ₃ , δ): 2.36 (s, 3H), 2.62 (m, 2H), 3.07
(s, 2H), 3.40 (m, 2H), 6.1 (br s, 1H)

Production Example 8 A solution of methyl N, N-dimethylaminoacetate (12.3 ml) in methanol was added at room temperature to ethanolamine (6.0 m).
1) is added and the mixture is heated under reflux for 2.5 hours. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: chloroform-methanol = 4:
1), N- (2-hydroxyethyl) -2- (N, N-
Dimethylamino) acetamide (6.12 g) is obtained. NMR (CDCl ₃ , δ): 2.30 (s, 6H), 2.97 (s, 3H), 3.4-3.5
(m, 2H), 3.69-3.8 (m, 2H), 7.58 (br s, 1H)

Production Example 9-1) (2S, 4R) -1-allyloxycarbonyl-2-
((E) -3-Hydroxy-1-propenyl) -4-t
-Butyldimethylsiloxypyrrolidine (13.1 g) in dichloromethane at -50 ° C diphenyl chlorophosphate (22 ml) and 4- (N, N-dimethylamino).
Pyridine (14.0 g) is added and the mixture is stirred for 1 hour. The reaction mixture is poured into ethyl acetate-saturated saline, the organic layer is separated, and washed with 0.1N hydrochloric acid and saturated saline. After drying over magnesium sulfate, the solvent is removed under reduced pressure. The residue was dissolved in acetone (150 ml), this was added to an acetone suspension of sodium iodide (11.5 g), and the mixture was heated to 50 ° C.
Stir for 30 minutes. The reaction mixture is poured into ethyl acetate-saturated saline, the organic layer is separated, and washed with saturated aqueous sodium thiosulfate solution and saturated saline. After drying over magnesium sulfate, the solvent was removed under reduced pressure (2S, 4R) -1.
-Allyloxycarbonyl-2-((E) -3-iodo-1-propenyl) -4-t-butyldimethylsiloxypyrrolidine (27.0 g) is obtained. NMR (CDCl ₃ , δ): 0.06 (s, 6H), 0.87 (s, 9H), 1.8 (m,
1H), 2.0 (m, 1H), 3.3-3.7 (m, 2H), 3.86 (m, 2H), 4.2-
4.5 (m, 2H), 4.59 (m, 2H), 5.1-5.4 (m, 2H), 5.5-6.1
(m, 3H)

Production Example 9-2) A suspension of sodium hydride (60% w / w) (0.43 g) in N, N-dimethylformamide (100 ml) was added at 0 ° C. to 1-ethyl-2,3-di. Oxopiperazine (1.
42 g) is added and the mixture is stirred for 30 minutes. In the reaction mixture (2S,
4R) -1-allyloxycarbonyl-2-((E)-
A solution of 3-iodo-1-propenyl) -4-t-butyldimethylsiloxypyrrolidine (6.77 g) in N, N-dimethylformamide (4 ml) is added at 0 ° C and stirred.
The reaction mixture is poured into saturated saline and adjusted to pH 7 with 1N-hydrochloric acid, and then extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate, and then the solvent was removed under reduced pressure (2S, 4R) -1-allyloxycarbonyl-2-{(E) -3- (4-ethyl-2, 3-dioxopiperazin-1-yl) -1-propenyl} -4-t
-Butyldimethylsiloxypyrrolidine (4.5 g) is obtained. NMR (CDCl ₃ , δ): 0.06 (s, 6H), 0.87 (s, 9H), 1.7-2.0
(m, 1H), 2.0-2.2 (m, 1H), 3.3-3.8 (m, 6H), 3.9-4.2
(m, 2H), 4.34 (m, 1H), 4.45 (m, 1H), 4.6 (m, 2H), 5.1-
5.7 (m, 4H), 5.7-6.1 (m, 1H) IR (neat): 1650 cm ^-1

Production Example 9-3) (2S, 4R) -1-allyloxycarbonyl-2-
{(E) -3- (4-Ethyl-2,3-dioxopiperazin-1-yl) -1-propenyl} -4-t-butyldimethylsiloxypyrrolidine (4.5 g) in acetonitrile (45 ml). 12N hydrochloric acid (2.5m at 0 ° C)
l) is added dropwise and stirred for 30 minutes. Triethylamine (3.1 l) was added to the reaction mixture, the deposited precipitate was filtered off, the solvent was removed under reduced pressure, and (2S, 4R) -1-allyloxycarbonyl-2-{(E) -3- ( 4-ethyl-
2,3-Dioxopiperazin-1-yl) -1-propenyl} -4-hydroxypyrrolidine (1.47 g) is obtained. NMR (CDCl ₃ , δ): 1.9-2.1 (m, 2H), 2.1-2.3 (m, 1H),
3.3-3.7 (m, 6H), 3.98 (dd, J = 5.5, 14.1Hz, 1H), 4.17 (d
d, J = 5.0, 14.1Hz, 1H), 4.3-4.7 (m, 4H), 5.1-5.4 (m, 2
H), 5.4-5.8 (m, 2H), 5.8-6.1 (m, 1H)

Production Example 9-4) (2S, 4R) -1-allyloxycarbonyl-2-
To a tetrahydrofuran solution (15 ml) of {(E) -3- (4-ethyl-2,3-dioxopiperazin-1-yl) -1-propenyl} -4-hydroxypyrrolidine (1.47 g) at 0 ° C. was added. Phenylphosphine (1.6
g) and diethyl azodicarboxylate (1.0
ml) is added dropwise. After stirring at 0 ° C. for 1 hour, thiobenzoic acid (0.9 ml) was added dropwise and the mixture was stirred at 0 ° C. for 30 minutes. The reaction mixture is poured into saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer is washed with saturated brine and dried over magnesium sulfate. The solvent was removed under reduced pressure, the residue was purified by silica gel column chromatography,
(2S, 4S) -1-allyloxycarbonyl-2-
{(E) -3- (4-Ethyl-2,3-dioxopiperazin-1-yl) -1-propenyl} -4-benzoylthiopyrrolidine (1.3 g) is obtained. NMR (CDCl ₃ , δ): 1.17 (t, J = 7.2Hz, 3H), 1.89 (m, 1H),
2.5-2.9 (m, 1H), 3.2-3.7 (m, 7H), 3.7-4.3 (m, 4H),
4.47 (m, 1H), 4.57 (d, J = 5.4Hz, 2H), 5.1-5.4 (m, 2H),
5.4-6.1 (m, 3H), 7.3-7.7 (m, 3H), 8.14 (m, 2H)

Production Example 10-1) (2S, 4R) -1-allyloxycarbonyl-2-
((E) -3-iodo-1-propenyl) -4-t-butyldimethylsiloxypyrrolidine (4.51 g) N,
N-dimethylformamide solution (30 ml) was added at room temperature to sodium azide (1 g) and ammonium chloride (0.
8 g) is added and the mixture is stirred at 70 ° C. for 2 hours. The reaction mixture is poured into ethyl acetate-water (1: 1) (40 ml) and adjusted to pH 7.5-8.5 with saturated aqueous sodium hydrogen carbonate solution. The organic layer was separated, washed with water (10 ml) and saturated brine (10 ml) and washed with triphenylphosphine (2.9
g) is added and the mixture is stirred for 21 hours. The reaction mixture is water (50 m
l), adjust to pH 0.5 with 10% hydrochloric acid and stir for 40 minutes. The aqueous layer is separated and the organic layer is extracted with water (50 ml). The combined aqueous layer was washed with ethyl acetate (50 ml), tetrahydrofuran (150 ml) was added to the aqueous layer, and 30% aqueous sodium hydroxide solution was added to adjust the pH to 7.5 to 8.5 under ice cooling, and chlorocarbonic acid was added. Allyl (1.
3 ml) is added dropwise. After stirring for 30 minutes, the reaction mixture is extracted with ethyl acetate, and the organic layer is washed with saturated brine.
After drying over magnesium sulfate, the solvent was removed under reduced pressure and (2S, 4R) -1-allyloxycarbonyl-2-
{(E) -3- (allyloxycarbonylamino) -1
-Propenyl} -4-hydroxypyrrolidine (1.4
g) is obtained. NMR (CDCl ₃ , δ): 1.6-2.4 (m, 4H), 3.55 (m, 2H), 3.79
(m, 2H), 4.3-4.7 (m, 2H), 4.57 (m, 4H), 5.0-5.4 (m, 4
H), 5.58 (m, 2H), 5.7-6.1 (m, 2H)

Production Example 10-2) Substantially the same as Production Example 9-4), (2S, 4R)
-1-Allyloxycarbonyl-2-{(E) -3-
(Allyloxycarbonylamino) -1-propenyl}
From 4-hydroxypyrrolidine (1.4 g) (2S,
4S) -1-allyloxycarbonyl-2-{(E)-
3-allyloxycarbonylamino) -1-propenyl} -4-benzoylthiopyrrolidine (1.32 g) is obtained. NMR (CDCl ₃ , δ): 1.7-2.0 (m, 1H), 2.5-2.8 (m, 1H),
3.3-3.5 (m, 1H), 3.7-4.0 (m, 2H), 4.0-4.3 (m, 2H), 4.
3-4.8 (m, 5H), 5.0-5.4 (m, 4H), 5.67 (m, 1H), 5.7-6.1
(m, 2H), 7.3-7.7 (m, 3H), 7.8-8.0 (m, 2H)

Example 1 (4R) -2-diazo-4-[(2R, 3S) -3-
A solution of allyl [(1R) -1-hydroxyethyl] -4-oxoazetidin-2-yl] -3-oxopentanoate (4.4 g) in ethyl acetate (50 ml) was charged with rhodium octanoate (II) ( 78 mg) is added. The mixture is refluxed for 30 minutes and then the solvent is removed under reduced pressure. The residue is dissolved in acetonitrile (60 ml) and cooled to 0 ° C. Under a nitrogen atmosphere and at the same temperature, diphenylchlorophosphate (3.4 ml), N, N-diisopropyl-N-ethylamine (3.1 ml) and 4- (N, N-dimethylamino) pyridine (12.2 m) were added thereto.
g) is added to give the intermediate phosphate. (2S, 4S)
-1-Allyloxycarbonyl-2-[(E) -3-t
ert-Butyldimethylsiloxy-1-propenyl]-
To a solution of 4-benzoylthiopyrrolidine (5.9g) in methanol (60ml) was added 4.8N sodium methoxide-.
Methanol (2.6 ml) is added at 0 ° C. Mix 3
After stirring for 0 minutes, ethyl acetate (200 ml) and water (100 ml)
ml) and adjusted to pH 4.0 with 10% hydrochloric acid. Separate the organic layer and pour into brine (50 ml). The mixture was adjusted to pH 7.0 with saturated aqueous sodium hydrogen carbonate solution, the organic layer was separated and washed with brine (50 ml),
Dry over magnesium sulfate. After filtration, the solution was filled with N,
N-Dimethylformamide is added and the solvent is removed under reduced pressure to give the intermediate thiol. This was dissolved in acetonitrile (20 ml), this solution was added to the above acetonitrile solution of phosphate at 0 ° C., and N, N was added to this mixture at the same temperature.
N-diisopropyl-N-ethylamine (3.1 ml)
Add. The mixture is stirred at 0-5 ° C. for half a day, then poured into a mixture of ethyl acetate (300 ml) and brine (150 ml) and adjusted to pH 6.0 with saturated aqueous ammonium chloride solution. The organic layer is separated, washed with brine (100 ml) and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography to give (4R, 5S, 6S) -3-[(2S, 4S).
-1-Allyloxycarbonyl-2-{(E) -3-t
ert-Butyldimethylsiloxy-1-propenyl} pyrrolidin-4-ylthio] -6-[(R) -1-hydroxyethyl] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept- Allyl 2-ene-2-carboxylate (1.64 g) is obtained as a pale yellow oil. NMR (CDCl ₃ , δ): 0.06 (6H, s), 0.90 (9H, s), 1.26 (3
H, d, J = 7.2Hz), 1.35 (3H, d, J = 6.2Hz), 1.77 (1H, m), 2.0
-2.4 (2H, m), 2.4-2.7 (1H, m), 3.1-3.4 (3H, m), 3.57
(1H, m), 4.0-4.3 (5H, m), 4.49 (1H, m), 4.68 (2H, d, J =
12.0Hz), 4.68 (1H, m), 4.84 (1H, m), 5.1-5.3 (2H, m),
5.31 (1H, m), 5.44 (1H, m), 5.5-5.8 (2H, m), 5.8-6.1
(2H, m)

Example 2 (4R, 5S, 6S) -3-[(2S, 4S) -1-allyloxycarbonyl-2-{(E) -3-tert-
Butyldimethylsiloxy-1-propenyl} pyrrolidin-4-ylthio] -6-[(R) -1-hydroxyethyl] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2- Acetic acid (0.54 ml) is added to a solution of allyl ene-2-carboxylate (1.65 g) in tetrahydrofuran (10 ml) at room temperature. After stirring this mixture for a while, a solution of 70% tetrabutylammonium fluoride (3.0 g) in tetrahydrofuran (5.0 ml) is added thereto. After stirring this mixture for 4 hours, ethyl acetate (100 ml) and water (50 ml) were added.
Pour into the mixture. The organic layer was separated, and ethyl acetate (100
ml). Combine the organic layers, water (50 ml),
Wash with saturated aqueous sodium hydrogensulfate solution (50 ml) and brine (50 ml x 2) and dry over magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography to give (4R, 5S, 6
S) -3-[(2S, 4S) -1-Allyloxycarbonyl-2-{(E) -3-hydroxy-1-propenyl} pyrrolidin-4-ylthio] -6-[(R) -1-
Allyl hydroxyethyl] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate (0.77 g) is obtained as a pale yellow oil. IR (CH ₂ Cl ₂ ): 1765, 1695 cm ^-1 NMR (CDCl ₃ , δ): 1.27 (3H, d, J = 7.2Hz), 1.36 (3H, d, J
= 6.2Hz), 1.6-2.0 (3H, m), 2.59 (1H, dt, J = 6.4Hz, 13.3H
z), 3.2-3.5 (3H, m), 3.64 (1H, m), 4.0-4.4 (5H, m), 4.
4-4.9 (5H, m), 5.1-5.6 (4H, m), 5.6-6.1 (4H, m)

Example 3 (4R, 5S, 6S) -3-[(2S, 4S) -1-Allyloxycarbonyl-2-{(E) -3-hydroxy-1-propenyl} pyrrolidin-4-ylthio] -6-
[(R) -1-Hydroxyethyl] -4-methyl-7-
Oxo-1-azabicyclo [3.2.0] hept-2-
Triphenylphosphine (58.8 mg) is added to a solution of allyl ene-2-carboxylate (0.75 g) in tetrahydrofuran (9 ml) -ethanol (3 ml) at room temperature. Acetic acid (0.48 ml) and tetrakis (triphenylphosphine) palladium (0) (48.
5 mg) and tributyltin hydride (1.5 ml) are added with stirring. After 1 hour, ethyl acetate (50 ml) was poured into this mixture, and the precipitate was collected by filtration. This precipitate is dissolved in water (100 ml) and washed twice with ethyl acetate (50 ml). The solution is adjusted to pH 6 with saturated aqueous sodium hydrogen carbonate solution and concentrated under reduced pressure. Purification by chromatography using a non-ionic adsorption resin (Diaion HP-20; trademark, Mitsubishi Kasei Kogyo Co., Ltd.), followed by recrystallization from a mixture of water and acetonitrile, (4R, 5
S, 6S) -3-[(2S, 4S) -2-{(E) -3
-Hydroxy-1-propenyl} pyrrolidin-4-ylthio] -6-[(R) -1-hydroxyethyl] -4-
Methyl-7-oxo-1-azabicyclo [3.2.0]
Hept-2-ene-2-carboxylic acid (0.39 g) is obtained as white crystals. IR (Nujor): 3025, 1740, 1600, 1445, 1375 cm
^-1 NMR (D ₂ O, δ): 1.23 (3H, d, J = 7.2Hz), 1.30 (3H, d, J =
6.3Hz), 1.86 (1H, ddd, J = 7.5Hz, 9.7Hz, 14.0Hz), 2.79
(1H, dt, J = 7.7Hz, 14.0Hz), 3.2-3.6 (3H, m), 3.74 (1H,
dd, J = 7.3Hz, 12.4Hz), 3.9-4.4 (6H, m), 5.82 (1H, dd, J
= 7.9Hz, 15.5Hz), 6.13 (1H, dt, J = 15.5Hz, 4.8Hz)

Example 4 (4R) -2-diazo-4-[(2R, 3S) -3-
{(1R) -1-hydroxyethyl} -4-oxoazetidin-2-yl] -3-oxopentanoic acid allyl (2.0 g) in ethyl acetate (20 ml) solution containing rhodium octanoate (II) in a nitrogen stream, Add under reflux. The mixture is refluxed for 30 minutes and evaporated under reduced pressure to give a residue. Dissolve this in acetonitrile (20 ml),
Cool to 0-5 ° C. under nitrogen atmosphere. Diphenyl phosphorochloridate (1.48 ml) and N, N-diisopropyl-N-ethylamine (1.30 ml) are sequentially added to this solution, and the mixture is stirred under the same conditions for 3 hours. On the other hand,
(2S, 4S) -1-Allyloxycarbonyl-4-acetylthio-2-[(Z) -2- (pyridin-3-yl) vinyl] pyrrolidine (3.12 g) in methanol (15 ml) -tetrahydrofuran (15 ml) 28% sodium methoxide solution in methanol (1.8
2 ml) is added dropwise under ice cooling, and the mixture is stirred at the same temperature for 15 minutes. Acetic acid (0.65 ml) is added to the reaction mixture and the mixture is evaporated under reduced pressure. The residue obtained is dissolved in a mixture of ethyl acetate (60 ml) and water (50 ml). The organic layer was washed with saturated aqueous sodium chloride solution 2
It is washed twice, dried over anhydrous magnesium sulfate and then evaporated under reduced pressure to give a residue. This was N, N-dimethylacetamide (20 ml) and acetonitrile (10 m
Dissolve in the mixture of l). This solution and N, N-diisopropyl-N-ethylamine (1.89 ml) are added to the above solution under ice cooling with stirring. The mixture is stirred at the same temperature for 2 hours. Ethyl acetate (100 ml) and water (50 ml) are added to the reaction mixture with stirring. The organic layer is separated, washed twice with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and then the solvent is evaporated under reduced pressure. The residue obtained is chromatographed on silica gel (150 g),
Mixed solvent of chloroform and methanol (19: 1, v /
Elute in v). Fractions containing the target compound were collected and the solvent was evaporated under reduced pressure to give (4R, 5S, 6S) -3-[(2S,
4S) -1-allyloxycarbonyl-2-{(Z)-
2- (pyridin-3-yl) vinyl} pyrrolidin-4-
Il] thio-6-[(1R) -1-hydroxyethyl]
-4-Methyl-7-oxo-1-azabicyclo [3.
2.0] Allyl hept-2-ene-2-carboxylate (2.31 g) is obtained. IR (neat): 1765, 1700 (sh), 1690, 1625, 1540, 1
405, 1320 cm ^-1 NMR (CDCl ₃ , δ): 1.26 (3H, d, J = 7.23Hz), 1.35 (3H, d,
J = 6.25Hz), 1.70-1.95 (1H, m), 2.50-2.85 (1H, m), 3.20
-3.75 (3H, m), 3.90-4.15 (1H, m), 4.18-4.90 (7H, m),
5.00-6.10 (7H, m), 6.49 (1H, br d, J = 11.2Hz), 7.20-7.3
3 (1H, m), 7.45-7.90 (1H, m), 8.45-8.65 (2H, m)

Example 5 Substantially the same as Example 4, (4R, 5S, 6S)-
3-[(2S, 4S) -1-allyloxycarbonyl-
2-{(E) -2- (pyridin-3-yl) vinyl} pyrrolidin-4-yl] thio-6-[(1R) -1-hydroxyethyl] -4-methyl-7-oxo-1-azabicyclo Allyl [3.2.0] hept-2-ene-2-carboxylate is obtained. IR (neat): 1760, 1690, 1625, 1540, 1400, 1330 c
m ^-1 NMR (CDCl ₃ , δ): 1.38 (3H, d, J = 7.23Hz), 1.36 (3H, d,
J = 6.25Hz), 1.82-1.97 (1H, m), 2.50-2.80 (1H, m), 3.20
-3.80 (4H, m), 3.90-6.10 (14H, m), 6.27 (1H, dd, J = 7.17
Hz, J = 15.8Hz), 6.52 (1H, br d, J = 15.8Hz), 7.20-7.40
(1H, m), 7.65-7.78 (1H, m), 8.47 (1H, d, J = 3.48Hz), 8.
57 (1H, s)

Example 6-1) (4R, 5S, 6S) -3-[(2S, 4S) -1-allyloxycarbonyl-2-{(Z) -2- (pyridin-3-yl) vinyl} Pyrrolidin-4-yl] thio-6
-[(1R) -1-hydroxyethyl] -4-methyl-
7-oxo-1-azabicyclo [3.2.0] hept-
Tetrahydrofuran (45 ml) -ethanol (15 ml) of allyl 2-ene-2-carboxylate (1.36 g)
Triphenylphosphine (66 mg), acetic acid (0.58 ml), tetrakis (triphenylphosphine) palladium (0) (87 mg) and tributyltin hydride (2.71 ml) were sequentially added to the solution at room temperature with stirring. The mixture is stirred at the same temperature for 30 minutes. Water (60 ml) is added to the reaction mixture and the aqueous layer is separated. The organic layer is extracted twice with water (60 ml). The aqueous layer and extracts are combined, washed with ethyl acetate (60 ml) and adjusted to pH 6.2 with aqueous sodium bicarbonate solution. The organic solvent of this solution is distilled off. The obtained aqueous solution (10 ml) was chromatographed using a nonionic adsorption resin (Diaion HP20; trademark, Mitsubishi Kasei Co., Ltd.) (40 ml),
Water (80 ml), 5% acetone water (80 ml), 10%
Elute sequentially with acetone water (160 ml). Fractions containing the target compound were collected, the solvent was distilled off under reduced pressure, freeze-dried,
(4R, 5S, 6S) -6-[(1R) -1-Hydroxyethyl] -4-methyl-3-[(2S, 4S) -2-
{(Z) -2- (Pyridin-3-yl) vinyl} pyrrolidin-4-yl] thio-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid (0 0.70 g) is obtained. IR (Nujol): 1740, 1580 cm ^-1 NMR (D ₂ O, δ): 1.21 (3H, d, J = 7.16Hz), 1.30 (3H, d, J =
6.35Hz), 1.86-2.01 (1H, m), 2.78-2.94 (1H, m), 3.28-
3.50 (3H, m), 3.67 (1H, dd, J = 6.83Hz, J = 12.4Hz), 3.90-
4.30 (3H, m), 4.60 (1H, m), 6.06 (1H, dd, J = 10.1Hz, J = 1
1.3Hz), 6.93 (1H, d, J = 11.4Hz), 7.51 (1H, dd, J = 4.97H
z, J = 7.90Hz), 7.78 (1H, d, J = 7.95Hz), 8.40-8.52 (2H,
m) FAB Mass: 416.1 (M ⁺ +1)

Example 7-1) (4R, 5S, 6S) -3-[(2S, 4S) -1-allyloxycarbonyl-2-{(Z) -2- (pyridin-3-yl) vinyl}} Pyrrolidin-4-yl] thio-6
-[(1R) -1-hydroxyethyl] -4-methyl-
7-oxo-1-azabicyclo [3.2.0] hept-
Methyl iodide (2.65 ml) was added to a solution of allyl 2-ene-2-carboxylate (2.30 g) in acetone (20 ml).
Is added with stirring and the mixture is left at room temperature overnight. The reaction mixture was subjected to evaporation under reduced pressure, then dried under reduced pressure for 2 hours to give (4R, 5S, 6S) -3-[(2S, 4
S) -1-allyloxycarbonyl-2-{(Z) -2
-(1-Methyl-3-pyridinio) vinyl} pyrrolidin-4-yl] thio-6-[(1R) -1-hydroxyethyl] -4-methyl-7-oxo-1-azabicyclo [3.2.0] ] Hept-2-ene-2-carboxylic acid allyl iodide (2.64 g) is obtained. NMR (CDCl ₃ , δ): 1.26 (3H, d, J = 7.19Hz), 1.32 (3H, d,
J = 6.25Hz), 1.50-1.85 (1H, m), 2.65-2.90 (1H, m), 3.20
-3.45 (2H, m), 3.50-3.70 (1H, m), 3.80-4.30 (4H, m),
4.58 (3H, s), 4.50-4.90 (5H, m), 5.05-5.50 (5H, m), 5.
80-6.05 (3H, m), 6.53 (1H, d, J = 11.5Hz), 8.00-8.10 (1
H, m), 8.35 (1H, d, J = 8.17Hz), 8.93 (1H, d, J = 5.86Hz),
9.56 (1H, s)

Example 7-2) (4R, 5S, 6S) -3-[(2S, 4S) -1-allyloxycarbonyl-2-{(Z) -2- (1-methyl-3-pyridinio) Vinyl} pyrrolidin-4-yl]
Thio-6-[(1R) -1-hydroxyethyl] -4-
Methyl-7-oxo-1-azabicyclo [3.2.0]
Hept-2-ene-2-carboxylic acid allyl iodide (2.63 g), triphenylphosphine (101 m
g), acetic acid (0.88 ml) and tetrakis (triphenylphosphine) palladium (0) (134 mg) in tetrahydrofuran (26 ml) -ethanol (26 m
l) Tributyltin hydride (4.15 ml) is added dropwise to the solution with stirring at room temperature. The mixture is stirred at the same temperature for 30 minutes. The resulting precipitate was collected by filtration, washed with tetrahydrofuran (40 ml), dried under reduced pressure, and then washed with water (60 ml).
ml). This solution is a nonionic adsorption resin (Diaion HP-20; trademark, Mitsubishi Kasei Co., Ltd.)
Chromatography with (100 ml), eluting sequentially with water (300 ml), 5% aqueous acetone (500 ml). Fractions containing the target compound are collected and the solvent is evaporated under reduced pressure. The obtained residue (40 ml) was used as an ion exchange resin (Amberlyst A-26, Cl ⁻ type; trademark, Rohm &
Hearth Company (20ml), water (100ml)
ml) to elute. Lyophilize the eluate to (4R, 5
S, 6S) -6-[(1R) -1-hydroxyethyl]
-4-Methyl-3-[(2S, 4S) -2-{(Z)-
2- (1-Methyl-3-pyridinio) vinyl} pyrrolidin-4-yl] thio-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid chloride (653 mg) To get IR (Nujol): 1730, 1580-1560, 1250 cm ^-1 NMR (CDCl ₃ , δ): 1.22 (3H, d, J = 7.15Hz), 1.29 (3H, d,
J = 6.36Hz), 1.90-2.05 (1H, m), 2.80-3.00 (1H, m), 3.29
-3.60 (3H, m), 3.71 (1H, dd, J = 6.91Hz, J = 12.4Hz), 4.00
-4.35 (3H, m), 4.43 (3H, s), 4.43-4.65 (1H, m), 6.31
(1H, dd, J = 10.3Hz, J = 11.4Hz), 6.98 (1H, d, J = 11.5Hz),
8.05-8.15 (1H, m), 8.63 (1H, d, J = 12.3Hz), 8.75-8.90
(2H, m) FAB Mass: 430.1 (M ⁺ )

Example 8-1) (4R, 5S, 6S) -3-[(2S, 4S) -1-allyloxycarbonyl-2-{(Z) -2- (pyridin-3-yl) vinyl} Pyrrolidin-4-yl] thio-6
-[(1R) -1-hydroxyethyl] -4-methyl-
7-oxo-1-azabicyclo [3.2.0] hept-
A solution of allyl 2-ene-2-carboxylate (1.92 g) in acetone (10 ml) was added with iodoacetamide (1.98).
g) is added with stirring and the mixture is left standing at room temperature for 2 days.
The reaction mixture was evaporated under reduced pressure to give (4R, 5
S, 6S) -3-[(2S, 4S) -1-allyloxycarbonyl-2-{(Z) -2- (1-carbamoylmethyl-3-pyridinio) vinyl} pyrrolidin-4-yl] thio-6 -[(1R) -1-hydroxyethyl]-
4-Methyl-7-oxo-1-azabicyclo [3.2.
0] Hept-2-ene-2-carboxylic acid allyl iodide (3.88 g) is obtained as a crude residue. This compound is used as it is as a starting material compound in the next step.

Example 8-2) Substantially the same as Example 7-2) (4R, 5S, 6)
S) -3-[(2S, 4S) -2-{(Z) -2- (1
-Carbamoylmethyl-3-pyridinio) vinyl} pyrrolidin-4-yl] thio-6-[(1R) -1-hydroxyethyl] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept 2-En-2-carboxylic acid chloride (605 mg) is obtained. IR (nujol): 1740, 1690, 1580, 1290 cm ^-1 NMR (D ₂ O, δ): 1.21 (3H, d, J = 7.14Hz), 1.29 (3H, d, J =
6.35Hz), 1.85-2.05 (1H, m), 2.78-2.95 (1H, m), 3.30-
3.55 (3H, m), 3.72 (1H, dd, J = 6.94Hz, J = 12.4Hz), 4.00-
4.35 (3H, m), 4.40-4.60 (1H, m), 5.58 (2H, s), 6.33 (1
H, dd, J = 10.0Hz, J = 11.3Hz), 7.02 (1H, d, J = 11.5Hz), 8.
08-8.21 (1H, m), 8.55 (1H, d, J = 8.18Hz), 8.65-8.95 (2
H, m) FAB Mass: 473.1 (M ⁺ )

Example 9-1) (4R, 5S, 6) was carried out in substantially the same manner as in Example 7-1).
S) -3-[(2S, 4S) -1-allyloxycarbonyl-2-{(E) -2- (1-methyl-3-pyridinio) vinyl} pyrrolidin-4-yl] thio-6-[( 1
R) -1-Hydroxyethyl] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate allyl is obtained. This compound is used as it is as a starting material compound in the next step.

Example 9-2) Substantially the same as (4R, 5S, 6) in the same manner as in Example 7-2).
S) -6-[(1R) -1-hydroxyethyl] -4-
Methyl-3-[(2S, 4S) -2-{(E) -2-
(1-Methyl-3-pyridinio) vinyl} pyrrolidine-
4-yl] thio-7-oxo-1-azabicyclo [3.
2.0] Hept-2-ene-2-carboxylic acid / chloride is obtained. IR (nujol): 1740-1720, 1570-1530, 1130 cm ^-1 NMR (D ₂ O, δ): 1.24 (3H, d, J = 7.16), 1.30 (3H, d, J = 6.
34Hz), 1.90-2.15 (1H, m), 2.80-3.05 (1H, m), 3.35-3.5
5 (3H, m), 3.81 (1H, dd, J = 7.00Hz, J = 12.4Hz), 4.00-4.3
0 (3H, m), 4.41 (3H, s), 6.75 (1H, dd, J = 7.83Hz, J = 16.0
Hz), 6.98 (1H, d, J = 16.0Hz), 8.03 (1H, dd, J = 6.1Hz, J =
8.1Hz), 8.62 (1H, d, J = 8.2Hz), 8.71 (1H, d, J = 6.1Hz),
8.93 (1H, s) FAB Mass: 430.2 (M ⁺ )

Example 10-1) Substantially the same as Example 11-1) (4R, 5S,
6S) -3-[(2S, 4S) -1-allyloxycarbonyl-2-{(E) -2- (1-methylimidazol-2-yl) vinyl} pyrrolidin-4-yl] thio-6
-[(1R) -1-allyloxycarbonyloxyethyl] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid allyl is obtained. IR (neat): 1760-1740, 1680, 1400, 1320 cm ^-1 NMR (CDCl ₃ , δ): 1.27 (3H, d, J = 7.18Hz), 1.48 (3H, d,
J = 6.29Hz), 1.80-2.00 (1H, m), 2.60-2.80 (1H, m), 3.30
-3.45 (2H, m), 3.55-3.65 (1H, m), 3.66 (3H, s), 4.45-
4.90 (7H, m), 5.10-5.55 (6H, m), 5.80-6.05 (3H, m), 6.
30-6.75 (2H, m), 6.84 (1H, s), 7.04 (1H, s)

Example 10-2) Substantially the same as in Example 7-1) (4R, 5S, 6)
S) -3-[(2S, 4S) -1-allyloxycarbonyl-2-{(E) -2- (1,3-dimethyl-2-imidazolio) vinyl} pyrrolidin-4-yl] thio-6
-[(1R) -1-allyloxycarbonyloxyethyl] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid allyl iodide is obtained. This compound is used as it is as a starting material compound in the next step.

Example 10-3) Substantially the same as (4R, 5S, 6) in the same manner as in Example 7-2).
S) -3-[(2S, 4S) -2-{(E) -2-
(1,3-Dimethyl-2-imidazolio) vinyl} pyrrolidin-4-yl] thio-6-[(1R) -1-hydroxyethyl] -4-methyl-7-oxo-1-azabicyclo [3.2. 0] hept-2-ene-2-carboxylic acid / chloride is obtained. IR (nujor): 1760-1740, 1590 cm ^-1 NMR (D ₂ O, δ): 1.24 (3H, d, J = 7.19Hz), 1.30 (3H, d, J =
6.35Hz), 1.90-2.10 (1H, m), 2.80-3.00 (1H, m), 3.30-
3.50 (2H, m), 4.05-4.35 (2H, m), 6.82 (1H, s), 7.46 (1
H, s) FAB Mass: 433.1 (M ⁺ )

Example 11-1) A solution of dimethylsulfoxide (0.48 ml) and dichloromethane (20 ml) was added with oxalyl chloride (0.28 m).
1) was added dropwise with stirring at -40 ° C, and this solution was added at the same temperature to 5
Stir for minutes. (4R, 5S, 6S) -3-
[(2S, 4S) -1-allyloxycarbonyl-2-
(Hydroxymethyl) pyrrolidin-4-yl] thio-6
Of-[(1R) -1-allyloxycarbonyloxyethyl] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate allyl (1.69 g) Dichloromethane (8 ml) solution-
Add dropwise at 50 ° C to -40 ° C. After stirring for 10 minutes, triethylamine (2.14 ml) is added dropwise thereto, and the mixture is stirred at 10 ° C for 30 minutes. The insoluble material is filtered off, and the filtrate is washed successively with 1N hydrochloric acid, water, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution. The organic layer is dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure to obtain a residue. On the other hand, 3-picolyltriphenylphosphonium chloride (1.32 g) in tetrahydrofuran (7 m
1) -Dimethylsulfoxide (7 ml) solution was added potassium tert-butoxide (0.38 g) at −10 ° C. with stirring, and the mixture was stirred at 0 ° C. for 15 minutes. The reaction mixture is added dropwise to a solution of the above residue in tetrahydrofuran (20 ml) at 0 ° C., and the mixture is stirred at the same temperature for 2 hours. Ethyl acetate (100 ml) is added to the reaction mixture. This is washed successively with 1N hydrochloric acid, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. The residue obtained is chromatographed on silica gel (100 g), n-
Elute with a mixed solvent of hexane and ethyl acetate (1: 2, v / v). Fractions containing the target compound were collected and the solvent was evaporated under reduced pressure to give (4R, 5S, 6S) -3-[(2S, 4S)
-1-Allyloxycarbonyl-2- {2- (pyridin-3-yl) vinyl} pyrrolidin-4-yl] thio-6
-[(1R) -1-allyloxycarbonyloxyethyl] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate allyl (1.17 g) obtain. IR (neat): 1770, 1740, 1700, 1540, 1435, 1400,
1260 cm ^-1 NMR (CDCl ₃ , δ): 1.26 (3H, d × 2), 1.48 (3H, d), 1.70
-2.00 (1H, m), 2.50-2.75 (1H, m), 5.75-6.10 (3H, m),
6.15-6.35 (1H, d × 2), 6.50 (1H, bd), 8.40-8.60 (2H, m)

Example 11-2) (4R, 5S, 6S) -3-[(2S, 4S) -1-allyloxycarbonyl-2- {2- (pyridin-3-yl) vinyl} pyrrolidine-4- Ill] thio-6-[(1
R) -1-Allyloxycarbonyloxyethyl] -4
-Methyl-7-oxo-1-azabicyclo [3.2.
0] allyl hept-2-ene-2-carboxylate (1.1
Methyl iodide (1.16 ml) is added to a solution of 6 g) in acetone (10 ml), the mixture is stirred at room temperature for 1 hour and then left at the same temperature overnight. The reaction mixture is subjected to evaporation operation under reduced pressure. The obtained residue was treated with silica gel (1
00g) Chromatography and elute with a mixed solvent of chloroform and methanol (4: 1, v / v). Fractions containing the target compound were collected, the solvent was distilled off under reduced pressure, and (4
R, 5S, 6S) -3-[(2S, 4S) -1-Allyloxycarbonyl-2- {2- (1-methyl-3-pyridinio) vinyl} pyrrolidin-4-yl] thio-6-
[(1R) -1-allyloxycarbonyloxyethyl] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid allyl iodide (0.76 g ) Get. NMR (CDCl ₃ , δ): 1.28 (3H, t, J = 7.3Hz), 1.47 (3H, t, J)
= 6.22Hz), 1.50-2.10 (2H, m), 2.65-2.85 (1H, m), 3.60-
4.30 (3H, m), 4.50-4.90 (9H, m), 5.05-5.55 (7H, m),
5.80-6.10 (3H, m), 6.40-7.00 (2H, m), 7.99-8.06 (1H,
d × 2, J = 6.40Hz), 8.33, 8.40 (1H, d × 2, J = 8.56Hz, J
= 7.96Hz), 8.92,9.08 (1H), 9.38, 9.63 (1H)

Example 11-3) (4R, 5S, 6S) -3-[(2S, 4S) -1-allyloxycarbonyl-2- {2- (1-methyl-3-)
Pyridinio) vinyl} pyrrolidin-4-yl] thio-6
-[(1R) -1-allyloxycarbonyloxyethyl] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid allyl iodide (0. 76 g), triphenylphosphine (26 mg), acetic acid (0.34 ml) and tetrakis (triphenylphosphine) palladium (0) (34.
4 mg) of tetrahydrofuran (8 ml) -ethanol (8 ml) in tributyltin hydride (1.60 m)
1) is added dropwise at room temperature with stirring. The mixture is stirred at the same temperature for 30 minutes. The resulting precipitate was collected by filtration, washed with tetrahydrofuran (10 ml), and then washed with dichloromethane (20
(ml) and water (50 ml). The aqueous layer is separated, washed with dichloromethane (20 ml) and then evaporated under reduced pressure to remove the organic solvent. The resulting aqueous solution (10 ml) was mixed with a nonionic adsorption resin (Diaion HP-20; trademark, Mitsubishi Kasei Co., Ltd.) (30 m
Chromatography with l), water (120 m
1) and 5% acetone in water (150 ml) are successively eluted. Fractions containing the target compound are collected and the solvent is evaporated under reduced pressure. The residue obtained (20 ml) is passed through an ion exchange resin (Amberlyst A-26, Cl ⁻ type; trademark, Rohm & Haas Company) (5 ml) and eluted with water (50 ml). The eluate was lyophilized to (4R, 5S, 6
S) -6-[(1R) -1-hydroxyethyl] -4-
Methyl-3-[(2S, 4S) -2- {2- (1-methyl-3-pyridinio) vinyl} pyrrolidin-4-yl]
Thio-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid chloride (0.17
g) is obtained. IR (nujor): 1740, 1580, 1300-1260, 1150 cm ^-1 NMR (D ₂ O, δ): 1.20-1.32 (6H, m), 1.80-2.10 (1H, m),
2.75-3.00 (1H, m), 3.20-4.65 (11H, m), 6.31, 6.75 (1
H), 6.94, 7.10 (1H), 7.90-8.13 (1H, m), 8.40-8.93 (3
H, m) FAB Mass: 430.2 (M ⁺ )

Example 12 (4R) -2-diazo-4-[(2R, 3S) -3-
Allyl [(1R) -1-hydroxyethyl] -4-oxoazetidin-2-yl] -3-oxopentanoate (8
To a solution of 56 mg) in ethyl acetate (10 ml) is added rhodium (II) octoate in a nitrogen stream. Mix 15
Reflux for minutes and then remove the solvent under reduced pressure. The residue is dissolved in acetonitrile (10 ml) and cooled to 0 ° C. Diphenyl chlorophosphate (0.64 ml), N, N-diisopropyl- was added to the mixture at the same temperature under nitrogen atmosphere.
N-ethylamine (0.6 ml) and 4- (N, N-
Dimethylamino) pyridine (16 mg) is added to give the intermediate phosphate salt. (2S, 4S) -1-allyloxycarbonyl-2-[(E) -3-methoxy-1-propenyl) -4-benzoylthiopyrrolidine (1.16)
To a solution of g) in methanol (10 ml) is added 4.8N sodium methoxide-methanol (0.5 ml) at 0 ° C. After stirring the mixture for 3 hours, ethyl acetate (100 ml)
Pour into a mixture of water and brine (100 ml) and adjust to pH 4.0. Separate the organic layer and pour into brine (50 ml). The mixture is adjusted to pH 7.0, the organic layer is separated, washed with brine and dried over magnesium sulfate. After filtration, N, N-dimethylformamide (1
0 ml) and the mixture is concentrated under reduced pressure to give the intermediate thiol. This was dissolved in acetonitrile (20 ml) and added to a solution of the phosphate salt in acetonitrile (10 ml) at 0 ° C., and N, N-diisopropyl-N was added to this mixture.
-Ethylamine (0.6 ml) is added at the same temperature. The mixture was stirred at 0-5 ° C for half a day and then ethyl acetate (150m
1) and brine (100 ml), pH = 6.
Adjust to 0. The organic layer is separated, washed with brine (50 ml) and then dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography to give (4R, 5S, 6S) -3-[(2
S, 4S) -1-allyloxycarbonyl-2-
{(E) -3-Methoxy-1-propenyl} pyrrolidin-4-ylthio] -6-[(R) -1-hydroxyethyl] -4-methyl-7-oxo-1-azabicyclo [3.2.0] ] Allyl hept-2-ene-2-carboxylate (1.0 g) is obtained as a pale yellow oil. IR (neat): 3450, 2850, 1770, 1680 cm ^-1 NMR (CDCl ₃ , δ): 1.26 (3H, d, J = 7.2Hz), 1.36 (3H, d, J)
= 6.3Hz), 1.6-2.1 (2H, m), 2.4-2.8 (1H, m), 3.2-3.8 (4
H, m), 3.32 (3H, s), 3.92 (3H, m), 4.23 (1H, m), 4.3-4.
9 (6H, m), 5.1-5.6 (4H, m), 5.7 (2H, m), 5.7-6.1 (2H,
m)

Example 13 (4R, 5S, 6S) -3-[(2S, 4S) -1-allyloxycarbonyl-2-{(E) -3-iodo-1
-Propenyl} pyrrolidin-4-ylthio] -6-
[(R) -1-Hydroxyethyl] -4-methyl-7-
Oxo-1-azabicyclo [3.2.0] hept-2-
Pyrrolidine (0.83 ml) is added to a solution of allyl ene-2-carboxylate (3.1 g) in dichloromethane (30 ml) under a nitrogen stream. The mixture is stirred for 1 hour and then poured into a mixture of ethyl acetate (200 ml) and brine (100 ml). The mixture is adjusted to pH 6.5 and the organic layer is separated. It is washed with water (100 ml x 3) and brine (100 ml) and dried over magnesium sulfate. The solvent was removed under reduced pressure to give (4R, 5S, 6S)-
3-[(2S, 4S) -1-allyloxycarbonyl-
2-{(E) -3- (pyrrolidin-1-yl) -1-propenyl} pyrrolidin-4-ylthio] -6-[(R)
-1-Hydroxyethyl] -4-methyl-7-oxo-
1-azabicyclo [3.2.0] hept-2-ene-2
-Allyl carboxylic acid iodide (2.9 g) is obtained. Tetrahydrofuran of this compound (2.9 g) (40 m
l) -Ethanol (12.5 ml) solution was added with triphenylphosphine (0.21 g) at room temperature. Acetic acid (1.4 ml), tetrakis (triphenylphosphine) palladium (0) (173 mg) and tributyltin hydride (5.4 ml) are added to this mixture with stirring. After stirring the mixture for 30 minutes, it was added with ethyl acetate (200 m
1) is poured and the precipitate is collected by filtration. This precipitate was washed with water (10
0 ml) and wash with ethyl acetate (200 ml x 2). This solution was concentrated under reduced pressure and purified with a nonionic adsorption resin (Diaion HP-20; trademark, Mitsubishi Kasei Co., Ltd.), Amberlyst A26, γ-alumina, ODS and HP-20 to obtain (4R, 5S , 6S) -3
-[(2S, 4S) -2-{(E) -3- (pyrrolidin-1-yl) -1-propenyl} pyrrolidin-4-ylthio] -6-[(R) -1-hydroxyethyl] -4 −
Methyl-7-oxo-1-azabicyclo [3.2.0]
Hept-2-ene-2-carboxylic acid hydrochloride (0.17
g) is obtained. IR (nujor): 3025, 1745, 1580 cm ^-1 NMR (D ₂ O, δ): 1.23 (3H, d, J = 7.4Hz), 1.30 (3H, d, J =
6.4Hz), 1.57 (1H, m), 1.93 (2H, m), 2.06 (4H, m), 2.60
(1H, m), 3.0-4.0 (14H, m), 4.0-4.2 (2H, m), 5.7-6.0
(1H, m), 6.0-6.3 (1H, m)

Example 14 Substantially the same as Example 16 (4R, 5S, 6S)
-3-[(2S, 4S) -2-{(E) -3- (N-carbamoylmethyl-N-ethyl-N-methylammonio) -1-propenyl} pyrrolidin-4-yl] thio-
6-[(1R) -1-hydroxyethyl] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid chloride is obtained. IR (nujor): 1740, 1680 cm ^-1 NMR (CDCl ₃ , δ): 1.23 (3H, d, J = 7.2Hz), 1.30 (3H, d, J
= 6.4Hz), 1.40 (3H, t, J = 7.3Hz), 1.9-2.1 (1H, m), 2.8-
3.0 (1H, m), 3.21 (3H, d, J = 2.0Hz), 3.3-3.8 (6H, m), 4.
07 (2H, s), 4.2-4.6 (6H, m), 6.1-6.5 (2H, m)

Example 15 Substantially the same as Example 16 (4R, 5S, 6S)
-6-[(1R) -1-hydroxyethyl] -4-methyl-7-oxo-3-[(2S, 4S) -2-[(E)
-3- (1-Methyl-1-pyrrolidinio) -1-propenyl} pyrrolidin-4-yl] thio-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid chloride is obtained. . IR (nujor): 1740 cm ^-1 NMR (CDCl ₃ , δ): 1.23 (3H, d, J = 7.2Hz), 1.30 (3H, d, J
= 6.4Hz), 1.9-2.0 (1H, m), 2.1-2.3 (4H, m), 2.8-2.9 (1
H, m), 3.06 (3H, s), 3.3-3.6 (7H, m), 3.73 (1H, dd, J =
6.6Hz, 12.5Hz), 4.0-4.5 (4H, m), 4.05 (2H, d, J = 6.8H
z), 6.1-6.4 (2H, m)

Example 16 (4R, 5S, 6S) -3-[(2S, 4S) -1-allyloxycarbonyl-2-{(E) -3-iodo-1
-Propenyl} pyrrolidin-4-yl] thio-6-
[(1R) -1-hydroxyethyl] -4-methyl-7
-Oxo-1-azabicyclo [3.2.0] hept-2
A solution of allyl-ene-2-carboxylate (441 mg) in dichloromethane (4.4 ml) with pyridine (0.594 m).
1) is added at room temperature and the solution is stirred for 1.5 hours. The solvent was removed under reduced pressure and the residue was triturated with ether,
A yellow powder (468 mg) is obtained. This powder (453m
g), triphenylphosphine (17 mg), acetic acid (0.10 ml) and tetrakis (triphenylphosphine) palladium (0) (23 mg) in ethanol (4.5 ml) -tetrahydrofuran (4.5 ml) solution with tributyltin hydride ( 0.43 ml) is added dropwise at room temperature. After stirring for 30 minutes, tetrahydrofuran (4.5 ml) is added and the precipitate is obtained by decantation. Tetrahydrofuran (4.5 m
Wash with 1 × 4) and dissolve in water (9.0 ml). The solution is washed with ethyl acetate (9.0 ml x 2) and then concentrated to about 5.0 ml. This solution was chromatographed using a nonionic adsorption resin (Diaion HP-20; trademark, Mitsubishi Kasei Co., Ltd.) (45 ml),
Elute with water (90 ml) and 4% aqueous acetone successively.
Fractions containing the desired compound are collected and concentrated to 10 ml. This solution is used as an ion exchange resin (Amberlyst A-26, C
l ^- type; trademark, Rohm & Haas Company) (1.4
ml) and elute with water (10 ml). The eluate was freeze-dried to obtain (4R, 5S, 6S) -6-[(1R)-
1-Hydroxyethyl] -4-methyl-7-oxo-3
-[(2S, 4S) -2-{(E) -3- (1-pyridinio) -1-propenyl} pyrrolidin-4-yl] thio-1-azabicyclo [3.2.0] hept-2-ene −
Allyl 2-carboxylate (51 mg) is obtained as a white solid. IR (Nujol): 1730 cm ^-1 NMR (CDCl ₃ , δ): 1.21 (3H, d, J = 7.2Hz), 1.28 (3H, d, J)
= 6.4Hz), 1.8-2.0 (1H, m), 2.7-3.0 (1H, m), 3.3-3.5 (3
H, m), 3.71 (1H, dd, J = 6.8Hz, 12.5Hz), 4.0-4.2 (1H, m),
4.2-4.5 (3H, m), 5.32 (2H, d, J = 5.8Hz), 6.1-6.4 (2H,
m), 8.07-8.14 (2H, m), 8.56-8.64 (1H, m), 8.84-8.86
(2H, m)

Example 17 (4R, 5S, 6S) -3-[(2S, 4S) -1-allyloxycarbonyl-2-{(E) -3-hydroxy-1-propenyl) pyrrolidin-4-yl] Thio-6-
[(1R) -1-hydroxyethyl] -4-methyl-7
-Oxo-1-azabicyclo [3.2.0] hept-2
4-Dimethylaminopyridine (106 mg) and diphenyl chlorophosphate (0.1 mg) in a solution of allyl-ene-2-carboxylate (370 mg) in dichloromethane (1.9 ml).
59 ml) were sequentially added at -50 ° C, and this solution was added at the same temperature to 4
Stir for 0 minutes. Ethyl acetate (12 ml) was added thereto, and the mixture was mixed with saturated aqueous sodium hydrogen carbonate solution (2 m
l), 0.1N hydrochloric acid (5 ml), water (10 ml) and saturated aqueous sodium chloride solution (10 ml) in that order,
Then, it is dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give (4R, 5S, 6S) -3-[(2S, 4S).
-1-Allyloxycarbonyl-2-{(E) -3-
(Diphenoxyphosphoryloxy) -1-propenyl}
Pyrrolidin-4-yl] thio-6-[(1R) -1-hydroxyethyl] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid allyl (536 mg) is obtained as a light brown paste. IR (neat): 2940, 1764, 1692, 1592, 1400, 960 cm
^-1 NMR (CDCl ₃ , δ): 1.25 (3H, d, J = 7.2Hz), 1.36 (3H, d, J)
= 6.3Hz), 1.6-1.9 (2H, m), 2.4-2.7 (1H, m), 3.1-3.5 (3
H, m), 3.5-3.8 (1H, m), 3.9-5.0 (10H, m), 5.1-5.6 (4H,
m), 5.6-6.1 (4H, m), 7.2-7.4 (10H, m)

Example 18 (4R, 5S, 6S) -3-[(2S, 4S) -1-allyloxycarbonyl-2-{(E) -3- (diphenoxyphosphoryloxy) -1-propenyl} pyrrolidine Allyl (-4-yl] thio-6-[(1R) -1-hydroxyethyl] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate Sodium iodide (178 mg) is added to a solution of 431 mg) in acetone (3.0 ml) and the mixture is stirred at 50 ° C. for 30 minutes. To this water (5.0 ml) and ethyl acetate (15 ml) are added and the mixture is stirred vigorously for a few minutes. The aqueous layer is separated, the organic layer is washed with water (10 ml × 1), saturated aqueous sodium thiosulfate solution (10 ml × 1), saturated aqueous sodium chloride solution (10 ml × 2), and then dried over anhydrous magnesium sulfate. Evaporate the solvent,
(4R, 5S, 6S) -3-[(2S, 4S) -1-allyloxycarbonyl-2-{(E) -3-iodo-1
-Propenyl} pyrrolidin-4-yl] thio-6-
[(1R) -1-hydroxyethyl] -4-methyl-7
-Oxo-1-azabicyclo [3.2.0] hept-2
-Allyl ene-2-carboxylate (451 mg) is obtained as a yellow solid. IR (CHCl ₃ ): 1762, 1682 cm ^-1 NMR (CDCl ₃ , δ): 1.26 (3H, d, J = 7.3Hz), 1.36 (3H, d, J
= 6.3Hz), 1.6-2.0 (2H, m), 2.5-2.7 (1H, m), 3.2-3.5 (3
H, m), 3.5-3.7 (1H, m), 3.7-4.9 (10H, m), 5.1-5.6 (4H,
m), 5.6-6.1 (4H, m)

Example 19 (4R, 5S, 6S) -3-[(2S, 4S) -1-allyloxycarbonyl-2-{(E) -3-methoxy-
1-propenyl) pyrrolidin-4-ylthio] -6-
[(1R) -1-hydroxyethyl] -4-methyl-7
-Oxo-1-azabicyclo [3.2.0] hept-2
Triphenylphosphine (78.7 mg) was added to a solution of allyl-ene-2-carboxylate (1.0 g) in tetrahydrofuran (15 ml) -ethanol (5 ml) at room temperature. Acetic acid (0.66 ml) and tetrakis (triphenylphosphine) palladium (0) (66.
2 mg) and tributyltin hydride (2.0 ml) are added. After stirring the mixture for 30 minutes, ethyl acetate (100 ml) was poured into this, and the precipitate was collected by filtration. The precipitate was dissolved in water (200 ml), and ethyl acetate (200 ml x
Wash with 2). The solution is adjusted to pH 6 and concentrated under reduced pressure. Purify by chromatography using HP-20 and silica gel to (4R, 5S, 6S) -3-[(2
S, 4S) -2-{(E) -3-Methoxy-1-propenyl) pyrrolidin-4-ylthio] -6-[(1R)-
1-Hydroxyethyl] -4-methyl-7-oxo-1
-Azabicyclo [3.2.0] hept-2-ene-2-
The carboxylic acid (0.24g) is obtained as white crystals. IR (Nujol): 3300, 1740, 1570 cm ^-1 NMR (D ₂ O, δ): 1.23 (3H, d, J = 7.2Hz), 1.30 (3H, d, J =
6.4Hz), 1.86 (1H, m), 2.80 (1H, dt, J = 14.3Hz, 7.7Hz),
3.3-3.5 (3H, m), 3.38 (3H, s), 3.71 (1H, dd, J = 12.4Hz,
7.3Hz), 4.06 (3H, m), 4.2-4.4 (3H, m), 5.91 (1H, dd, J
= 15.6Hz, 7.5Hz), 6.07 (1H, dt, J = 15.6Hz, 5.3Hz)

Example 20 Substantially the same as Example 16 (4R, 5S, 6S)
-6-[(1R) -1-hydroxyethyl] -4-methyl-3-[(2S, 4S) -2-{(E) -3- (1-
Methyl-3-imidazolidinio) -1-propenyl} pyrrolidin-4-yl] thio-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid chloride is obtained. IR (Nujol): 1740, 1570 cm ^-1 NMR (CDCl ₃ , δ): 1.23 (3H, d, J = 7.2Hz), 1.30 (3H, d, J
= 6.3Hz), 1.7-2.0 (1H, m), 2.6-2.9 (1H, m), 3.3-3.5 (3
H, m), 3.63 (1H, dd, J = 6.6Hz, 12.4Hz), 3.92 (3H, s), 4.
0-4.1 (1H, m), 4.1-4.4 (3H, m), 4.89 (2H, d, J = 5.7Hz),
5.9-6.3 (2H, m), 7.48 (2H, s), 8.75 (1H, s)

Example 21 Substantially the same as Example 7-1), (4R, 5S,
6S) -3-[(2S, 4S) -1-allyloxycarbonyl-2-{(Z) -2- (pyridin-3-yl) vinyl} pyrrolidin-4-yl] thio-6-[(1R) −
1-Hydroxyethyl] -4-methyl-7-oxo-1
-Azabicyclo [3.2.0] hept-2-ene-2-
Allyl carboxylate (1.80 g) and N, N-dimethyl-
2-reacting with iodoacetamide (2.13 g),
(4R, 5S, 6S) -3-[(2S, 4S) -1-allyloxycarbonyl-2-[(Z) -2- {1-
(N, N-Dimethylcarbamoylmethyl) -3-pyridinio} vinyl] pyrrolidin-4-yl] thio-6-
[(1R) -1-hydroxyethyl] -4-methyl-7
-Oxo-1-azabicyclo [3.2.0] hept-2
-Ene-2-carboxylic acid allyl iodide (2.51
g) is obtained. This compound is used as it is as a starting material compound in the next step.

Example 22 Substantially the same as Example 7-1), (4R, 5S,
6S) -3-[(2S, 4S) -1-allyloxycarbonyl-2-{(Z) -2- (pyridin-3-yl) vinyl} pyrrolidin-4-yl] thio-6-[(1R) −
1-Hydroxyethyl] -4-methyl-7-oxo-1
-Azabicyclo [3.2.0] hept-2-ene-2-
Allyl carboxylate (2.03 g) was reacted with N- (2-hydroxyethyl) -2-iodoacetamide (2.58 g) in acetone (10 ml) to give (4R, 5S, 6
S) -3-[(2S, 4S) -1-allyloxycarbonyl-2-[(Z) -2- [1- {N- (2-hydroxyethyl) carbamoylmethyl} -3-pyridinio] vinyl] pyrrolidine -4-yl] thio-6-[(1R)-
1-Hydroxyethyl] -4-methyl-7-oxo-1
-Azabicyclo [3.2.0] hept-2-ene-2-
Allyl carboxylic acid iodide (2.89 g) is obtained. This compound is used as it is as a starting material compound in the next step.

Example 23 Substantially the same as Example 7-1), (4R, 5S,
6S) -3-[(2S, 4S) -1-allyloxycarbonyl-2-{(E) -2- (pyridin-3-yl) vinyl} pyrrolidin-4-yl] thio-6-[(1R) −
1-Hydroxyethyl] -4-methyl-7-oxo-1
-Azabicyclo [3.2.0] hept-2-ene-2-
Allyl carboxylate (4.03 g) was reacted with N- (2-hydroxyethyl) -2-iodoacetamide (5.13 g) in acetone (20 ml) to give (4R, 5S, 6
S) -3-[(2S, 4S) -1-allyloxycarbonyl-2-[(E) -2- [1- {N- (2-hydroxyethyl) carbamoylmethyl} -3-pyridinio] vinyl] pyrrolidine -4-yl] thio-6-[(1R)-
1-Hydroxyethyl] -4-methyl-7-oxo-1
-Azabicyclo [3.2.0] hept-2-ene-2-
Allyl carboxylic acid iodide (5.74 g) is obtained. This compound is used as it is as a starting material compound in the next step.

Example 24 Substantially the same as Example 7-1), (4R, 5S,
6S) -3-[(2S, 4S) -1-allyloxycarbonyl-2-{(Z) -2- (pyridin-3-yl) vinyl} pyrrolidin-4-yl] thio-6-[(1R) −
1-Hydroxyethyl] -4-methyl-7-oxo-1
-Azabicyclo [3.2.0] hept-2-ene-2-
Allyl carboxylate (1.50 g) was added to N, N-bis (2-
Hydroxyethyl) -2-iodoacetamide (2.28
g) with acetone (8 ml) to give (4R, 5
S, 6S) -3-[(2S, 4S) -1-Allyloxycarbonyl-2-[(Z) -2- [1- {N, N-bis (2-hydroxyethyl) carbamoylmethyl} -3-
Pyridinio] vinyl] pyrrolidin-4-yl] thio-6
-[(1R) -1-hydroxyethyl] -4-methyl-
7-oxo-1-azabicyclo [3.2.0] hept-
2-ene-2-carboxylic acid allyl iodide (2.26
g) is obtained. This compound is used as it is as a starting material compound in the next step.

Example 25 Substantially the same as Example 7-1), (4R, 5S,
6S) -3-[(2S, 4S) -1-allyloxycarbonyl-2-{(E) -2- (pyridin-3-yl) vinyl} pyrrolidin-4-yl] thio-6-[(1R) −
1-Hydroxyethyl] -4-methyl-7-oxo-1
-Azabicyclo [3.2.0] hept-2-ene-2-
Allyl carboxylate (3.88 g) was added to acetone (18 m
l) and reacted with (4R, 5S, 6S) -3-
[(2S, 4S) -1-allyloxycarbonyl-2-
{(E) -2- (1-carbamoylmethyl-3-pyridinio) vinyl] pyrrolidin-4-yl] thio-6-
[(1R) -1-hydroxyethyl] -4-methyl-7
-Oxo-1-azabicyclo [3.2.0] hept-2
-Ene-2-carboxylic acid allyl iodide (5.21
g) is obtained. This compound is used as it is as a starting material compound in the next step.

Example 26 Substantially the same as Example 7-2), (4R, 5S,
6S) -3-[(2S, 4S) -1-allyloxycarbonyl-2-[(Z) -2- {1- (N, N-dimethylcarbamoylmethyl) -3-pyridinio} vinyl] pyrrolidine-4- Yl] thio-6-[(1R) -1-hydroxyethyl] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid allyl iodide ( 2.51 g) of triphenylphosphine (87 mg), acetic acid (0.76 ml), tetrakis (triphenylphosphine) palladium (0) (116)
mg) and tri-n-butyltin hydride (3.59 m)
1) and tetrahydrofuran (25 ml) -ethanol (25 ml) to give (4R, 5S, 6S)-
3-[(2S, 4S) -2-[(Z) -2- {1-
(N, N-Dimethylcarbamoylmethyl) -3-pyridinio} vinyl] pyrrolidin-4-yl] thio-6-
[(1R) -1-hydroxyethyl] -4-methyl-7
-Oxo-1-azabicyclo [3.2.0] hept-2
-Ene-2-carboxylic acid chloride (575 mg) is obtained. IR (Nujol): 1730, 1650-1630, 1570 cm ^-1 NMR (D ₂ O, δ): 1.22 (3H, d, J = 7.31Hz), 1.29 (3H, d, J =
6.34Hz), 1.89-2.05 (1H, m), 2.78-2.95 (1H, m), 3.03
(3H, s), 3.17 (3H, s), 3.28-3.55 (3H, m), 3.71 (1H, d
d, J = 6.76Hz, J = 12.3Hz), 4.00-4.35 (3H, m), 4.45-4.60
(1H, m), 5.77 (2H, s), 6.33 (1H, t, J = 10.8Hz), 6.99 (1
H, d, J = 11.5Hz), 8.05-8.20 (1H, m), 8.54 (1H, d, J = 8.07H
z), 8.60-8.85 (2H, m) FAB Mass: 501.1 (M ⁺ )

Example 27 Substantially the same as Example 7-2), (4R, 5S,
6S) -3-[(2S, 4S) -1-allyloxycarbonyl-2-[(Z) -2- [1- {N- (2-hydroxyethyl) carbamoylmethyl} -3-pyridinio]]
Vinyl] pyrrolidin-4-yl] thio-6-[(1R)
-1-Hydroxyethyl] -4-methyl-7-oxo-
1-azabicyclo [3.2.0] hept-2-ene-2
-Allyl carboxylic acid iodide (2.89 g) with triphenylphosphine (99 mg) and acetic acid (0.86 m)
l), tetrakis (triphenylphosphine) palladium (0) (130 mg) and tri-n-butyltin hydride (4.04 ml) and tetrahydrofuran (30 m).
l) -react in ethanol (30 ml) to give (4
R, 5S, 6S) -6-[(1R) -1-Hydroxyethyl] -3-[(2S, 4S) -2-[(Z) -2-
[1- {N- (2-hydroxyethyl) carbamoylmethyl} -3-pyridinio] vinyl] pyrrolidin-4-yl] thio-4-methyl-7-oxo-1-azabicyclo [3.2.0] hept- 2-Ene-2-carboxylic acid chloride (636 mg) is obtained. IR (Nujol): 1740-1720, 1670-1620, 1590-1560
cm ^-1 NMR (D ₂ O, δ): 1.22 (3H, d, J = 7.19Hz), 1.29 (3H, d, J =
6.37Hz), 1.89-2.05 (1H, m), 2.78-2.94 (1H, m), 3.31-
3.80 (8H, m), 3.95-4.65 (4H, m), 5.54 (2H, s), 6.34 (1
H, t, J = 11.4Hz), 6.99 (1H, d, J = 11.4Hz), 8.17 (1H, t, J =
8.18Hz), 8.54 (1H, d, J = 8.18Hz), 8.75-8.83 (2H, m) FAB Mass: 517.2 (M ⁺ )

Example 28 Substantially the same as Example 7-2), (4R, 5S,
6S) -3-[(2S, 4S) -1-allyloxycarbonyl-2-[(E) -2- [1- {N- (2-hydroxyethyl) carbamoylmethyl} -3-pyridinio]
Vinyl] pyrrolidin-4-yl] thio-6-[(1R)
-1-Hydroxyethyl] -4-methyl-7-oxo-
1-azabicyclo [3.2.0] hept-2-ene-2
-Allyl carboxylic acid iodide (5.74 g) as triphenylphosphine (200 mg) and acetic acid (1.71 m)
l), tetrakis (triphenylphosphine) palladium (0) (260 mg) and tri-n-butyltin hydride (8.04 ml) and tetrahydrofuran (60 m).
l) -react in ethanol (60 ml) to give (4
R, 5S, 6S) -6-[(1R) -1-Hydroxyethyl] -3-[(2S, 4S) -2-[(E) -2-
[1- {N- (2-hydroxyethyl) carbamoylmethyl} -3-pyridinio] vinyl] pyrrolidin-4-yl] thio-4-methyl-7-oxo-1-azabicyclo [3.2.0] hept- 2-Ene-2-carboxylic acid chloride (547 mg) is obtained. IR (Nujor): 1750-1730, 1660, 1580-1540, 1245
cm ^-1 NMR (D ₂ O, δ): 1.25 (3H, d, J = 7.19Hz), 1.31 (3H, d, J =
6.33Hz), 1.94-2.10 (1H, m), 2.80-3.00 (1H, m), 3.35-
4.35 (11H, m), 4.56 (1H, ABq, J = 8.0Hz), 5.53 (2H, s),
6.78 (1H, dd, J = 7.7Hz, J = 16.0Hz), 7.03 (1H, d, J = 16.0H
z), 8.13 (1H, dd, J = 6.2Hz, J = 8.1Hz), 8.75 (2H, m), 8.
97 (1H, s) FAB Mass: 517.2 (M ⁺ )

Example 29 Substantially the same as Example 7-2), (4R, 5S,
6S) -3-[(2S, 4S) -1-allyloxycarbonyl-2-[(Z) -2- [1- {N, N-bis (2
-Hydroxyethyl) carbamoylmethyl} -3-pyridinio] vinyl] pyrrolidin-4-yl] thio-6-
[(1R) -1-hydroxyethyl] -4-methyl-7
-Oxo-1-azabicyclo [3.2.0] hept-2
-Ene-2-carboxylic acid allyl iodide (2.26
g) triphenylphosphine (73 mg), acetic acid (0.64 ml), tetrakis (triphenylphosphine) palladium (0) (96 mg) and hydrogenated tri-.
Reaction with n-butyltin (2.99 ml) in tetrahydrofuran (23 ml) -ethanol (23 ml) gave (4R, 5S, 6S) -6-[(1R) -1-hydroxyethyl] -3-[(2S , 4S) -2-[(Z)
-2- [1- {N, N-bis (2-hydroxyethyl)
Carbamoylmethyl} -3-pyridinio] vinyl] pyrrolidin-4-yl] thio-4-methyl-7-oxo-1
-Azabicyclo [3.2.0] hept-2-ene-2-
Obtain the carboxylic acid chloride (463 mg). IR (Nujol): 1730, 1630-1620, 1570-1550 cm ^-1 NMR (D ₂ O, δ): 1.22 (3H, d, J = 7.13Hz), 1.29 (3H, d, J =
6.36Hz), 1.89-2.05 (1H, m), 2.78-2.93 (1H, m), 3.32-
4.70 (17H, m), 5.89 (2H, s), 6.33 (1H, t, J = 11.3Hz), 6.
99 (1H, d, J = 11.3Hz), 8.16 (1H, t, J = 6.98Hz), 8.55 (1H,
d, J = 8.06Hz), 8.67-8.77 (2H, m)

Example 30 Substantially the same as Example 7-2), (4R, 5S,
6S) -3-[(2S, 4S) -1-allyloxycarbonyl-2-{(E) -2- (1-carbamoylmethyl-3-pyridinio) vinyl} pyrrolidin-4-yl] thio-6- [ (1R) -1-hydroxyethyl] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid allyl iodide (5.21 g) was added to triphenyl. Phosphine (189m
g), acetic acid (1.65 ml), tetrakis (triphenylphosphine) palladium (0) (250 mg) and tri-n-butyltin hydride (7.74 ml) reacted in tetrahydrofuran (50 ml) -ethanol (50 ml). Then, (4R, 5S, 6S) -3-[(2S,
4S) -2-{(E) -2- (1-carbamoylmethyl-3-pyridinio) vinyl} pyrrolidin-4-yl] thio-4-methyl-7-oxo-1-azabicyclo [3.
2.0] Hept-2-ene-2-carboxylic acid / chloride (676 mg) is obtained. IR (nujor): 1740, 1690, 1580, 1290 cm ^-1 NMR (D ₂ O, δ): 1.22 (3H, d, J = 7.21Hz), 1.28 (3H, d, J =
6.35Hz), 1.93-2.08 (1H, m), 2.80-2.98 (1H, m), 3.30-
3.52 (3H, m), 3.78 (1H, dd, J = 6.95Hz, J = 12.5Hz), 3.90-
4.20 (3H, m), 4.59 (1H, ABq, J = 7.97Hz, J = 16.1Hz), 5.53
(2H, s), 6.75 (1H, dd, J = 7.83Hz, J = 16.0Hz), 7.08 (1
H, d, J = 16.0Hz), 8.10 (1H, dd, J = 6.4Hz, J = 8.06Hz), 8.0
7 (2H, d, J = 6.4Hz), 8.93 (1H, s) FAB Mass: 473.1 (M ⁺ )

Example 31 Substantially the same as Example 16 (4R, 5S, 6S)
-3-[(2S, 4S) -1-allyloxycarbonyl-2-{(E) -3-iodo-1-propenyl} pyrrolidin-4-ylthio] -4-methyl-6-{(R) -1
-Hydroxyethyl} -7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate allyl (6.03 g) and 1-methyl-3-oxopiperazine (2.0 g) were added. (4R, 5S, 6S) -3-[(2S, 4
S) -2-{(E) -3- (1-methyl-3-oxo-
1-piperazinio) -1-propenyl} pyrrolidine-4
-Ylthio] -4-methyl-6-{(R) -1-hydroxyethyl} -7-oxo-1-azabicyclo [3.
2.0] Hept-2-ene-2-carboxylic acid chloride (0.12 g) is obtained. NMR (D ₂ O, δ): 1.23 (d, J = 7.2Hz, 3H), 1.29 (d, J = 6.4H
z, 3H), 1.9-2.1 (m, 1H), 2.8-3.0 (m, 1H), 3.25 (s, 2
H), 3.3-3.6 (m, 3H), 3.6-3.9 (m, 3H), 3.78 (s, 3H), 4.
0-4.4 (m, 7H), 4.3-4.6 (m, 1H), 6.1-6.4 (m, 1H), 6.46
(dd, J = 7.2, 15.2Hz, 1H) IR (Nujol): 3200, 1740, 1665 cm ^-1

Example 32-1) A solution of a trifluoroacetic acid adduct of N-methylacetamide (2.0 g) in N, N-dimethylformamide (1
Triethylamine (1.4 ml) was added to 0 ml) at room temperature, and (4R, 5S, 6S) -3-[(2S, 4
S) -1-allyloxycarbonyl-2-{(E) -3
-Iodo-1-propenyl} pyrrolidin-4-ylthio] -4-methyl-6-{(R) -1-hydroxyethyl} -7-oxo-1-azabicyclo [3.2.0] hept-2-ene A solution of allyl-2-carboxylate (3.1 g) in N, N-dimethylformamide (10 ml) is added, and the mixture is stirred for 9 hours. The solvent was removed under reduced pressure (4R, 5
S, 6S) -3-[(2S, 4S) -1-Allyloxycarbonyl-2-{(E) -3- (N-methyl-N-carbamoylmethylamino) -1-propenyl} pyrrolidin-4-ylthio } -4-Methyl-6-{(R) -1-
Allyl hydroxyethyl} -7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate (2.04 g) is obtained. NMR (CDCl ₃ , δ): 1.27 (d, J = 7.1Hz, 3H), 1.36 (d, J = 6.
2Hz, 3H), 1.7-2.0 (m, 1H), 2.4-2.8 (m, 1H), 3.0-3.8
(m, 8H), 3.8-5.0 (m, 14H), 5.0-6.2 (m, 8H)

Example 32-2) (4R, 5S, 6S) -3-[(2S, 4S) -1-allyloxycarbonyl-2-{(E) -3- (N-methyl-N-carbamoylmethyl) Amino) -1-propenyl} pyrrolidin-4-ylthio} -4-methyl-6-
{(R) -1-hydroxyethyl} -7-oxo-1-
Azabicyclo [3.2.0] hept-2-ene-2-carboxylate allyl (2.04 g) in ethanol (8.5 m
l) -tetrahydrofuran (25 ml) mixed solution,
Triphenylphosphine (0.1g), acetic acid (0.9m
1) and tetrakis (triphenylphosphine) palladium (0) (90 mg) are added at room temperature. Tributyltin hydride (2.7 ml) is added to the reaction mixture, and the mixture is stirred at room temperature for 15 minutes. The deposited precipitate is separated by filtration, washed with ethyl acetate, dissolved in water (50 ml) and adjusted to pH 4.4 with 1N hydrochloric acid. After concentration under reduced pressure, nonionic adsorption resin Diaion HP-20 (manufactured by Mitsubishi Kasei) (200
ml) for purification (developing solvent: water-acetonitrile = 8)
5:15), followed by strong basic resin Amberlyst A-2
Ion exchange is performed with 6 (made by Rohm and Haas) (10 ml). (Developing solvent: water). Activated charcoal was added to the solution, the solvent was concentrated under reduced pressure after filtration, and freeze-dried (4R, 5
S, 6S) -3-[(2S, 4S) -2-{(E) -3
-(N-methyl-N-carbamoylmethylamino) -1
-Propenyl} pyrrolidin-4-ylthio} -4-methyl-6-{(R) -1-hydroxyethyl} -7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic The hydrochloride salt (80 mg) is obtained. NMR (D ₂ O, δ): 1.23 (d, J = 7.2Hz, 3H), 1.30 (d, J = 6.4H
z, 3H), 1.8-2.0 (m, 1H), 2.7-3.0 (m, 1H), 2.76 (br s,
2H), 3.2-3.6 (m, 4H), 3.6-3.9 (m, 4H), 4.0-4.5 (m, 5
H), 5.8-6.2 (m, 2H) IR (Nujor): 3300, 1740, 1685 cm ^-1

Example 33 Substantially the same as Example 16 (4R, 5S, 6S)
-3-[(2S, 4S) -1-allyloxycarbonyl-2-{(E) -3-iodo-1-propenyl} pyrrolidin-4-ylthio] -4-methyl-6-{(R) -1
-Hydroxyethyl} -7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate allyl (6.03 g) and N- (2-hydroxyethyl) -2
-(N, N-dimethylamino) acetamide (2.92
(4R, 5S, 6S) -3-[(2S, 4S) -2 by reacting g) and then a deallylation reaction.
-{(E) -3- {N- (N- (2-hydroxyethyl) carbamoylmethyl) -N, N-dimethylammonio} -1-propenyl} pyrrolidin-4-ylthio]-
4-Methyl-6-{(R) -1-hydroxyethyl}-
7-oxo-1-azabicyclo [3.2.0] hept-
2-Ene-2-carboxylic acid chloride (0.53 g) is obtained. NMR (D ₂ O, δ): 1.23 (d, J = 7.2Hz, 3H), 1.30 (d, J = 6.4H
z, 3H), 1.96 (m, 1H), 2.88 (m, 1H), 3.28 (s, 6H), 3.3-
3.6 (m, 5H), 3.6-3.9 (m, 3H), 4.09 (s, 2H), 4.2-4.4
(m, 4H), 6.20 (m, 1H), 6.38 (dd, J = 6.8, 15.4Hz, 1H) IR (nujor): 3200, 1740 cm ^-1

Example 34-1) Substantially the same as Example 1, (4R) -2-diazo-4-[(2R, 3S) -3-{(1R) -1-hydroxyethyl}- 4-oxoazetidin-2-yl] -3
-Allyl oxopentanoate (0.86 g) and (2S, 4
S) -1-allyloxycarbonyl-2- {3- (4-
Ethyl-2,3-dioxopiperazin-1-yl) -1
-Propenyl} -4-benzoylthiopyrrolidine (1.
3g) to (4R, 5S, 6S) -3-[(2S, 4
S) -1-allyloxycarbonyl-2- {3- (4-
Ethyl-2,3-dioxopiperazin-1-yl) -1
-Propenyl} pyrrolidin-4-ylthio] -4-methyl-6-{(R) -1-hydroxyethyl} -7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carvone Allyl acid (0.69 g) is obtained. NMR (CDCl ₃ , δ): 1.1-1.6 (m, 9H), 1.7-2.7 (m, 2H),
3.2-4.9 (m, 21H), 5.1-6.2 (m, 8H) IR (neat): 3450, 1765, 1725 cm ^-1

Example 34-2) Substantially the same as Example 19, (4R, 5S, 6)
S) -3-[(2S, 4S) -1-allyloxycarbonyl-2- {3- (4-ethyl-2,3-dioxopiperazin-1-yl) -1-propenyl} pyrrolidine-4
-Ylthio] -4-methyl-6-{(R) -1-hydroxyethyl} -7-oxo-1-azabicyclo [3.
2.0] Allyl hept-2-ene-2-carboxylate (0.69 g) was deallylated (4R, 5S, 6S).
-3-[(2S, 4S) -2- {3- (4-ethyl-
2,3-Dioxopiperazin-1-yl) -1-propenyl} pyrrolidin-4-ylthio] -4-methyl-6-
{(R) -1-hydroxyethyl} -7-oxo-1-
Azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid (0.27 g) is obtained. NMR (D ₂ O, δ): 1.19 (t, J = 7.3Hz, 3H), 1.22 (d, J = 7.2H
z, 3H), 1.30 (d, J = 6.4Hz, 3H), 1.83 (m, 1H), 2.77 (dt,
J = 14.0, 7.6Hz, 1H), 3.2-3.6 (m, 5H), 3.6-3.8 (m, 5H),
3.9-4.2 (m, 3H), 4.2-4.4 (m, 3H), 5.7-6.1 (m, 2H) IR (nujor): 3300, 1740, 1650 cm ^-1

Example 35-1) (4R) -2-diazo-substantially the same as in Example 1.
4-[(2R, 3S) -3-{(1R) -1-hydroxyethyl} -4-oxoazetidin-2-yl] -3-
Allyl oxopentanoate (0.95 g) and (2S, 4
S) -1-allyloxycarbonyl-2-{(E) -3
-(Allyloxycarbonylamino) -1-propenyl} -4-benzoylthiopyrrolidine (1.32 g) to (4R, 5S, 6S) -3-[(2S, 4S) -1-
Allyloxycarbonyl-2-{(E) -3-allyloxycarbonylamino) -1-propenyl} pyrrolidin-4-ylthio] -4-methyl-6-{(R) -1-hydroxyethyl} -7-oxo -1-Azabicyclo [3.2.0] allyl allyl (0.58 g) is obtained. NMR (CDCl ₃ , δ): 1.26 (d, J = 7.2Hz, 3H), 1.36 (d, J = 6.
2Hz, 3H), 1.6-2.0 (m, 1H), 2.5-2.7 (m, 1H), 3.1-5.1
(m, 16H), 5.1-5.4 (m, 6H), 5.61 (m, 2H), 5.7-6.1 (m, 3
H)

Example 35-2) Substantially the same as Example 19 (4R, 5S, 6S)
-3-[(2S, 4S) -1-allyloxycarbonyl-2-{(E) -3-allyloxycarbonylamino)
-1-Propenyl} pyrrolidin-4-ylthio] -4-
Methyl-6-{(R) -1-hydroxyethyl} -7-
Oxo-1-azabicyclo [3.2.0] hept-2-
Allyl ene-2-carboxylate (0.58 g) is deallylated to (4R, 5S, 6S) -3-[(2S, 4S)-
2-{(E) -3-Amino-1-propenyl} pyrrolidin-4-ylthio] -4-methyl-6-{(R) -1-
Hydroxyethyl} -7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid acetate (80 mg) is obtained. NMR (D ₂ O, δ): 1.23 (d, J = 7.2Hz, 3H), 1.30 (d, J = 6.3H
z, 3H), 1.7-2.0 (m, 1H), 1.92 (s, 3H), 2.8 (m, 1H), 3.
2-3.6 (m, 4H), 3.69 (m, 4H), 3.9-4.2 (m, 1H), 4.2-4.4
(m, 3H), 6.07 (m, 2H) IR (Nujor): 1730 cm ^-1

Example 36-1) To a solution of 1- (2-hydroxyethyl) -5-aminopyrazole (0.32 g) in dichloromethane (1 ml),
1,1,1,3,3, at an internal temperature of 20-30 ° C under nitrogen flow
3-Hexamethyldisilazane (0.39 ml) is added dropwise and the mixture is stirred for 15 minutes. Further, trimethylsilyl chloride (0.23 ml) was added dropwise to this reaction solution at the same temperature, and the mixture was stirred for 2 hours. After completion of the reaction, insoluble matter in the reaction solution is filtered off, and the filtrate is concentrated under reduced pressure. The obtained residue was dissolved in dichloromethane (1 ml), and (4R, 5S, 6S) -3-
[(2S, 4S) -1-allyloxycarbonyl-2-
((E) -3-iodo-1-propenyl) pyrrolidine-
4-yl] thio-6-[(R) -1-hydroxyethyl] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate allyl (0 0.5 g) in dichloromethane (2.5 ml) is added with stirring and the mixture is left overnight. Saturated aqueous ammonium chloride (1 ml) and ethanol (1
0 ml) is added to adjust the pH to 4 to 5, the mixture is stirred for 20 minutes, and then concentrated under reduced pressure. The obtained residue was extracted with a mixed solution of tetrahydrofuran (20 ml) and ethanol (20 ml), and the extract was concentrated under reduced pressure to give (4R, 5S, 6S) -3.
-[(2S, 4S) -1-allyloxycarbonyl-2
-{(E) -3- (1- (2-hydroxyethyl) -5
-Amino-2-pyrazolio) -1-propenyl} pyrrolidin-4-yl] thio-6-[(R) -1-hydroxyethyl] -4-methyl-7-oxo-1-azabicyclo [3.2.0] ] Hept-2-ene-2-carboxylic acid allyl iodide is obtained. The compound obtained is immediately subjected to the next reaction.

Example 36-2) (4R, 5S, 6S) -3-[(2S, 4S) -1-allyloxycarbonyl-2-{(E) -3- (1- (2
-Hydroxyethyl) -5-amino-2-pyrazolio)
-1-Propenyl} pyrrolidin-4-yl] thio-6-
[(R) -1-Hydroxyethyl] -4-methyl-7-
Oxo-1-azabicyclo [3.2.0] hept-2-
Allyl ene-2-carboxylate / iodide was dissolved in a mixed solution of ethanol (5 ml) and tetrahydrofuran (5 ml), and triphenylphosphine (44 mg) and acetic acid (0 .1
9 ml), tetrakis (triphenylphosphine) palladium (0) (38 mg) and tributyltin (0.89)
ml) are added sequentially and the mixture is stirred for 30 minutes. Ethyl acetate (30 ml) was added to the reaction solution, the obtained solid was collected by filtration with a glass filter, and the residue was filtered with ethyl acetate (30 ml).
ml) and tetrahydrofuran (30 ml), and dried under reduced pressure. The obtained solid is dissolved in water (50 ml), washed twice with ethyl acetate (20 ml), and the aqueous layer portion is concentrated under reduced pressure (about 20 ml). The obtained residue was subjected to nonionic adsorption resin, Diaion HP-20 (manufactured by Mitsubishi Kasei) (20 ml), washed with water (40 ml), and then 5
Purify by eluting with% acetone in water. Fractions containing the desired product are collected and concentrated under reduced pressure (concentrated to 10 ml). This concentrated solution was passed through a strongly basic resin, Amberlyst A-26 (Cl ^- type) (5 ml), and then freeze-dried (solvent: water) (4R, 5S, 6S) -3-[(2S, 4S ) -2-
{(E) -3- (1- (2-hydroxyethyl) -5-
Amino-2-pyrazolio) -1-propenyl} pyrrolidin-4-yl] thio-6-[(R) -1-hydroxyethyl] -4-methyl-7-oxo-1-azabicyclo [3.2.0] Hept-2-ene-2-carboxylic acid chloride (50.7 mg) is obtained. IR (nujor): 1740, 1580-1560 cm ^-1 NMR (D ₂ O, δ): 1.22 (3H, d, J = 7.19Hz), 1.39 (3H, d, J =
6.34Hz), 1.70-1.95 (1H, m), 2.45-2.90 (2H, m), 3.30-
4.45 (13H, m), 5.55-5.75 (1H, m), 6.02 (1H, d, J = 3.35H
z), 6.02-6.20 (1H, m), 7.88 (1H, d, J = 3.4Hz) FAB Mass; 478 (M ⁺ )

Example 37 Substantially the same as Example 16 (4R, 5S, 6S)
-3-[(2S, 4S) -1-allyloxycarbonyl-2-{(E) -3-iodo-1-propenyl} pyrrolidin-4-yl] thio-6-[(1R) -1-hydroxyethyl ] -4-Methyl-7-oxo-1-azabicyclo [3.2.0] allyl hept-2-ene-2-carboxylate (5.15 g) and 2- (dimethylamino) acetic acid amide (1.31 g) Is reacted and then deprotected to give (4R, 5S, 6S) -3-[(2S, 4S)
-2-{(E) -3- (N-carbamoyl-N, N-dimethylammonio) -1-propenyl} pyrrolidine-4
-Yl] thio-6-[(1R) -1-hydroxyethyl] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid chloride (464 mg ) Get. NMR (CDCl ₃ , 200MHz) δ: 1.23 (d, J = 7.2Hz, 3H), 1.30
(d, J = 6.4Hz, 3H), 1.9-2.1 (m, 1H), 2.8-3.0 (m, 1H), 3.
3-3.8 (m, 10H), 4.11 (s, 2H), 4.2-4.7 (m, 6H), 6.2-6.4
(m, 2H) IR (Nujor): 1746, 1680 cm ^-1

Example 38 (4R, 5S, 6
S) -3-[(2S, 4S) -1-Allyloxycarbonyl-2-{(E) -3-iodo-1-propenyl} pyrrolidin-4-yl] thio-6-[(1R) -1- Hydroxyethyl] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate allyl (5.00 g) and 1,2-dimethylimidazole (2.39 g) ), Followed by deprotection to give (4R, 5S, 6S) -6-[(1R) -1
-Hydroxyethyl] -4-methyl-3-[(2S, 4
S) -2-{(E) -3- (2,3-Dimethyl-1-imidazolio) -1-propenyl} pyrrolidin-4-yl] thio-7-oxo-1-azabicyclo [3.2.
0] hept-2-ene-2-carboxylic acid chloride (1.2
2 g) are obtained. NMR (CDCl ₃ , 200MHz) δ: 1.22 (d, J = 7.2Hz, 3H), 1.30
(d, J = 6.4Hz, 3H), 1.6-1.8 (m, 1H), 2.58 (s, 3H), 2.6-
2.8 (m, 1H), 3.2-3.6 (m, 4H), 3.80 (s, 3H), 4.0-4.3
(m, 4H), 4.93 (s, 2H), 5.8-6.1 (m, 2H), 7.36 (br s, 2
H) IR (Nujor): 1732, 1574 cm ^-1

Example 39 Substantially the same as Example 16, (4R, 5S, 6
S) -3-[(2S, 4S) -1-Allyloxycarbonyl-2-{(E) -3-iodo-1-propenyl} pyrrolidin-4-yl] thio-6-[(1R) -1- Hydroxyethyl] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate allyl (8.00 g) and 1- (carbamoylmethyl)
By reacting with imidazole (4.99 g) followed by deprotection, (4R, 5S, 6S) -3-[(2
S, 4S) -2-{(E) -3- {3- (carbamoylmethyl) -3-imidazolio} -1-propenyl} pyrrolidin-4-yl] thio-6-[(1R) -1-hydroxyethyl ] -4-Methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid chloride (849 mg) is obtained. NMR (CDCl ₃ , 200MHz) δ: 1.22 (d, J = 7.2Hz, 3H), 1.30
(d, J = 6.4Hz, 3H), 1.6-1.8 (m, 1H), 2.6-2.8 (m, 1H), 3.
2-3.6 (m, 4H), 4.0-4.3 (m, 4H), 4.93 (d, J = 5.0Hz, 2H),
5.13 (s, 2H), 6.0-6.2 (m, 2H), 7.55 (s, 1H), 7.56 (s, 1
H), 8.9 (br s, 1H) IR (nujor): 1734, 1678, 1570 cm ^-1

─────────────────────────────────────────────────── ───Continued from the front page (51) Int.Cl. ⁵ Identification code Internal reference number FI technical display location A61K 31/495 7252-4C

Claims (3)

[Claims] 1. The formula: [Wherein R ¹ is a carboxy group or a protected carboxy group, R ² is a hydroxy (lower) alkyl group or a protected hydroxy (lower) alkyl group, R ³ is hydrogen or a lower alkyl group, and R ⁴ is a hydroxy group. , A protected hydroxy group, a lower alkoxy group, a halogen, an optionally substituted amino group, or an optionally substituted heterocyclic group, R ⁵ represents hydrogen or an imino protecting group, and A represents a lower alkenylene group. . ] The compound represented by these, and its pharmaceutically acceptable salt. 2. The formula: [Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and A are as defined in claim (1). ] A method for producing a compound represented by the formula: or a salt thereof, comprising: (Wherein R ¹ , R ² and R ³ are as defined above) or a reactive derivative or salt thereof in the oxo group is represented by the formula: (Wherein R ⁴ , R ⁵ and A are as defined above) and reacted with a compound represented by the formula: (Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and A are as defined above) or a salt thereof is obtained, or (b) a compound represented by the formula: ^{(Wherein, R 2, R 3, R} 4, R 5 and A are each as defined above, R ¹ _a is. Showing a protected carboxy group) The compound represented by or a salt thereof R ¹ _a By subjecting it to a carboxy protecting group elimination reaction of the formula: (Wherein R ² , R ³ , R ⁴ , R ⁵ and A are as defined above) or a salt thereof is obtained, or (c) a compound represented by the formula: (Wherein R ¹ , R ² , R ³ , R ⁴ and A are as defined above, and R ⁵ _a represents an imino protecting group.), Or a salt thereof is converted into imino of R ⁵ _a . By subjecting it to a protecting group elimination reaction, the compound of formula (Wherein R ¹ , R ² , R ³ , R ⁴ and A are as defined above) or a salt thereof is obtained, or (d) a compound represented by the formula: (Wherein R ¹ , R ³ , R ⁴ , R ⁵ and A are as defined above, and R ² _a represents a protected hydroxy (lower) alkyl group) or a salt thereof. By subjecting R ² _{a to} the hydroxy protecting group elimination reaction: (Wherein R ¹ , R ³ , R ⁴ , R ⁵ and A are as defined above, and R ² _b represents a hydroxy (lower) alkyl group), or a salt thereof is obtained. , (E) Formula ^{(Wherein, R 1, R 2, R} 3, R 5 and A are each as defined above, R ⁴ _a is. Showing a protected hydroxy group) compound represented by or a salt thereof R ⁴ _a By subjecting it to a hydroxy protecting group elimination reaction of the formula: (In the formula, R ¹ , R ² , R ³ , R ⁵ and A are as defined above, and R ⁴ _b represents an amino-substituted aliphatic heterocyclic group.)
A compound represented by (Wherein R ¹ _a , R ² , R ³ , R ⁵ and A are as defined above, respectively; The group represented by is an optionally substituted heterocyclic group containing a tertiary nitrogen atom. ) Is a compound represented by the formula R ⁶ -X [wherein R ⁶ is a lower alkyl group, a carboxy (lower) alkyl group, N- (or N, N-di) (lower) alkylcarbamoyl (lower) An alkyl group or N- (or N, N-bis) [hydroxy (lower) alkyl] carbamoyl (lower) alkyl group, and X represents an acid residue, respectively. ] By reacting with a compound represented by the formula: (Wherein R ¹ _a , R ² , R ³ , R ⁵ , R ⁶ , A and The groups represented by are as defined above. ) Or a salt thereof, or a compound of the formula (g) (Wherein R ¹ _a , R ² , R ³ , R ⁵ _a , A and X are as defined above) or a salt thereof is represented by the formula: (In the formula, R ⁶ is as defined above, and R ⁷ and R ⁸
Is a lower alkyl group or carbamoyl (lower), respectively
Indicates an alkyl group. ) By reacting with a compound of the formula (Wherein R ¹ _a , R ² , R ³ , R ⁵ _a , R ⁶ , R ⁷ , R ⁸ , A and X are as defined above) or a salt thereof is obtained. , (H) Formula (Wherein R ¹ , R ² , R ³ and R ⁵ are as defined above) or a salt thereof is represented by the formula: (Wherein R ⁴ and X are as defined above, and R ⁹ represents an aryl group or a lower alkoxy group), and then reacted with a compound represented by the formula: (Wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as defined above) or a salt thereof is obtained, or (i) a compound represented by the formula: (Wherein R ¹ _a , R ² , R ³ , R ⁵ _a , A and X are as defined above) or a salt thereof is represented by the formula: (In the formula, The group represented by is an optionally substituted heterocyclic group containing a tertiary nitrogen atom. ) By reacting with a compound of the formula (Wherein R ¹ _a , R ² , R ³ , R ⁵ _a , A, X and The groups represented by are as defined above. ) Or a salt thereof, or a compound represented by the formula (j): (Wherein R ¹ _a , R ² , R ³ , R ⁵ _a and A are as defined above), or a reactive derivative thereof in the hydroxy group or a salt thereof is halogenated, [Chemical 30] (Wherein R ¹ _a , R ² , R ³ , R ⁵ _a and A are as defined above, and R ⁵ _a represents halogen.), Or a salt thereof is obtained, or (k ) Formula (Wherein R ¹ _a , R ² , R ³ , R ⁵ _a , A and X are as defined above) or a salt thereof is represented by the formula: (In the formula, The group represented by is an optionally substituted heterocyclic group containing an imino moiety. ) And reacting it with a compound of the formula (Wherein R ¹ _a , R ² , R ³ , R ⁵ _a , A, X and The groups represented by are as defined above. ) A compound represented by the formula (1) or a salt thereof is obtained. 3. An antibacterial agent comprising the compound of claim (1) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.