JPH1160576A - Tricyclic heterocyclic derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject new derivative strong in antimicrobial activities, stable to dehydropeptidase I, high in proportion in urine and useful as an antimicrobial agent. SOLUTION: The subject derivative is a tricyclic heterocyclic derivative of formulas I or II [R<1> is H or the like; (m), (k), (n) and (s) are each 0 or 1; (p) and (t) are each 0-2; R<2> is H or the like; R<3> is H or the like], e.g. (5S,6R,7R, or 11S)-11-(azetidin-3-ylthio)-5-[(R)-1-hydroxyethyl]-4-oxo-3-azatricyclo [5.4.0.0<3> ,<6> ] undeca-1-ene-2-carboxylic acid. The compound of formula I is obtained, for example, by subjecting a compound of formula III (R<7> is a protective group of OH) to an epoxy ring-opening reaction with a mercaptan compound of formula IV [R<2> pr and R<3> pr are (protected) R<2> and R<3> respectively] in the presence of a base, oxidizing the product of the epoxy ring-opening reaction, further reacting the oxidized product with an oxalyl chloride derivative to provide a compound of formula V (R<8> is a protective group of carboxy group) and cyclizing and deprotecting the compound of formula V.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to tricyclic heterocyclic derivatives (I) and (II) which are excellent antibacterial agents.

[0002]

BACKGROUND ART Thienamycin derivatives have excellent antibacterial activity, but are degraded by dehydropeptidase-I, which is an enzyme that inactivates thienamycin derivatives present in the human body, and lose their activity. Low (H. Kroppet et al., Antim).
icrob. Agents Chemother. , 2
2 62, (1982); S . R. Norrby et
al. , Ibid. , 23 , 300 (1983)).

[0003] On the other hand, tricyclic β-lactam compounds are disclosed in JP-A-3-167187 and JP-A-4-17.
Some compounds are reported in 8389. Compounds belonging to this family are called tribactams or trinems, of which Sanfetrinem is well known (Di Modugno et al., An.
timicrob. Agents Chemothe
r. , 38 , 2362 (1994)).

[0004]

Although thienamycin derivatives generally exhibit excellent antibacterial activity, they have problems of chemical stability and dehydropeptidase-I, while Saenamycin derivatives have a problem with Sa.
Trinem derivatives typified by nfetrinem have good stability against dehydropeptidase-I, but have a drawback that their antibacterial activity is slightly inferior to thienamycin derivatives. Therefore, the appearance of a trinem compound having good stability against dehydropeptidase-I and exhibiting excellent antibacterial activity has been desired.

[0005] The present inventors have conducted various studies to solve these drawbacks, and found that a novel tricyclic heterocyclic derivative has strong antibacterial activity, is stable against dehydropeptidase-I, and has a high urinary content. It was found to be expensive and completed the present invention.

[0006]

The tricyclic heterocyclic derivative of the present invention has the general formula

[0007]

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[0008] or

[0009]

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[0010]

In the formula, R ¹ represents a hydrogen atom or an ester residue which is hydrolyzed in vivo, and m, n, k and s
Represents 0 or 1, p and t represent 0, 1 or 2, R ² represents a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, or a group represented by the formula —C (ＮＨNH) R ⁴ (formula Wherein R ⁴ represents a hydrogen atom, an alkyl group having 1 to 3 carbon atoms or an amino group), a 2-imidazolin-2-yl group or a 2-thiazolin-2-yl group, and R ³ represents a hydrogen atom A carbamoyl group, a carbamoyl group substituted with 1 to 2 alkyl groups having 1 to 3 carbon atoms,

[0012]

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(Wherein R ⁵ is a hydrogen atom, having 1 to 3 carbon atoms)
Represents an alkyl group, formimidoyl group, acetimidoyl group, amidino group, 2-imidazolin-2-yl group or 2-thiazolin-2-yl group. ) Group or formula

[0014]

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(Wherein, r represents 0, 1 or 2, q represents 0 or 1, R ⁶ represents a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, a formimidoyl group, an acetimidoyl group, Amidino group, 2-imidazolin-2-yl group or 2-thiazolin-2-yl group).

In the description of formulas (I) and (II),
The “ester residue that undergoes hydrolysis in vivo” of R ¹ is
An ester residue that can be used as a group (group forming a so-called prodrug) that is cleaved in the human body by a chemical or biological method such as hydrolysis to form a free carboxylic acid compound or a salt thereof. Such an ester residue can be determined by administering to an experimental animal such as a rat or a mouse by oral or intravenous injection, and then examining the body fluid of the animal to detect the original compound or its salt. Examples of such a residue include groups widely used in the field of β-lactam antibiotics, for example, an alkyl group having 1 to 3 carbon atoms, an allyl group, an acyloxyalkyl group, an alkoxycarbonyloxyalkyl group, a phthalidyl group, A 5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl group and the like can be mentioned.

The above acyloxyalkyl group includes
For example, a pivaloyloxymethyl group, an isobutyryloxymethyl group, a 1- (isobutyryloxy) ethyl group, an acetoxymethyl group, a 1- (acetoxy) ethyl group,
Methylcyclohexylcarbonyloxymethyl group, 1-
And a methylcyclopentylcarbonyloxymethyl group. Examples of the alkoxycarbonyloxyalkyl group include a t-butoxycarbonyloxymethyl group, a 1- (methoxycarbonyloxy) ethyl group, a 1- (ethoxycarbonyloxy) ethyl group,
(Isopropoxycarbonyloxy) ethyl group, 1-
(T-butoxycarbonyloxy) ethyl group, 1- (cyclohexyloxycarbonyloxy) ethyl group, 1-
And a (cyclopentyloxycarbonyloxy) ethyl group.

R ¹ is preferably a hydrogen atom, 5-methyl-
2-oxo-1,3-dioxolen-4-ylmethyl group, acetoxymethyl group, pivaloyloxymethyl group,
1-methylcyclohexylcarbonyloxymethyl group,
A 1- (isopropoxycarbonyloxy) ethyl group or a 1- (cyclohexyloxycarbonyloxy) ethyl group, more preferably a hydrogen atom.

In the above, the "alkyl group having 1 to 3 carbon atoms" includes, for example, a methyl group, an ethyl group, a propyl group and an isopropyl group, preferably a methyl group or an ethyl group, more preferably It is a methyl group.

The “group represented by the formula —C (ＮＨNH) R ⁴ ” for R ² includes, for example, a formimidoyl group, an acetimidoyl group, a propionimidoyl group and an amidino group. Is a formimidoyl group, an acetimidoyl group or an amidino group.

R ² is preferably a hydrogen atom, a formimidoyl group, an acetimidoyl group or an amidino group, and more preferably a hydrogen atom.

The "carbamoyl group substituted by one or two alkyl groups having 1 to 3 carbon atoms" for R ³ includes, for example, a methylcarbamoyl group, an ethylcarbamoyl group, a propylcarbamoyl group, a dimethylcarbamoyl group, a diethylcarbamoyl group And a dipropylcarbamoyl group.

The "group represented by the formula" for R ³ includes, for example, a piperazin-1-ylcarbonyl group, a 4-methylpiperazin-1-ylcarbonyl group, a 4-formimidoylpiperazin-1-ylcarbonyl group, 4-acetimidoylpiperazin-1-ylcarbonyl group, 4-amidinopiperazin-1-ylcarbonyl group, 4- (2-imidazolin-2-yl) piperazin-1-ylcarbonyl group, 4- (2-thiazoline- 2-yl) piperazine-1
-Ylcarbonyl group and the like.

The “group represented by the formula” for R ³ includes, for example, a 3-aminoazetidin-1-ylcarbonyl group,
-Aminomethylazetidin-1-ylcarbonyl group, 3
-Methylaminoazetidin-1-ylcarbonyl group, 3
-(Methylaminomethyl) azetidin-1-ylcarbonyl group, 3-formimidoylaminoazetidin-1-
Ylcarbonyl group, 3-acetimidoylaminoazetidin-1-ylcarbonyl group, 3-guanidinoazetidin-1-ylcarbonyl group, 3- (2-imidazoline-
2-ylamino) azetidin-1-ylcarbonyl group,
3- (2-thiazolin-2-ylamino) azetidine-
1-ylcarbonyl group, 3- (formimidoylaminomethyl) azetidin-1-ylcarbonyl group, 3- (acetimidoylaminomethyl) azetidin-1-ylcarbonyl group, 3- (guanidinomethyl) azetidine-1
-Ylcarbonyl group, 3- (2-imidazolin-2-ylaminomethyl) azetidin-1-ylcarbonyl group,
3- (2-thiazolin-2-ylaminomethyl) azetidin-1-ylcarbonyl group, 3-aminopyrrolidine-
1-ylcarbonyl group, 3-aminomethylpyrrolidine-
1-ylcarbonyl group, 3-methylaminopyrrolidine-
1-ylcarbonyl group, 3- (methylaminomethyl) pyrrolidin-1-ylcarbonyl group, 3-formimidoylaminopyrrolidin-1-ylcarbonyl group, 3-acetimidoylaminopyrrolidin-1-ylcarbonyl group, 3 -Guanidinopyrrolidin-1-ylcarbonyl group, 3- (2-imidazolin-2-ylamino) pyrrolidin-1-ylcarbonyl group, 3- (2-thiazoline-
2-ylamino) pyrrolidin-1-ylcarbonyl group,
3- (formimidoylaminomethyl) pyrrolidine-1
-Ylcarbonyl group, 3- (acetimidoylaminomethyl) pyrrolidin-1-ylcarbonyl group, 3- (guanidinomethyl) pyrrolidin-1-ylcarbonyl group, 3
-(2-imidazolin-2-ylaminomethyl) pyrrolidin-1-ylcarbonyl group, 3- (2-thiazoline-
2-ylaminomethyl) pyrrolidin-1-ylcarbonyl group, 3-aminopiperidin-1-ylcarbonyl group,
3-aminomethylpiperidin-1-ylcarbonyl group,
3-methylaminopiperidin-1-ylcarbonyl group,
3- (methylaminomethyl) piperidin-1-ylcarbonyl group, 3-formimidoylaminopiperidin-1
-Ylcarbonyl group, 3-acetimidoylaminopiperidin-1-ylcarbonyl group, 3-guanidinopiperidin-1-ylcarbonyl group, 3- (2-imidazolin-2-ylamino) piperidin-1-ylcarbonyl group, 3 -(2-thiazolin-2-ylamino) piperidin-1-ylcarbonyl group, 3- (formimidoylaminomethyl) piperidin-1-ylcarbonyl group, 3-
(Acetimidoylaminomethyl) piperidin-1-ylcarbonyl group, 3- (guanidinomethyl) piperidin-1-ylcarbonyl group, 3- (2-imidazoline-2
-Ylaminomethyl) piperidin-1-ylcarbonyl group, 3- (2-thiazolin-2-ylaminomethyl) piperidin-1-ylcarbonyl group, 4-aminopiperidin-1-ylcarbonyl group, 4-aminomethylpiperidine -1-ylcarbonyl group, 4-methylaminopiperidin-1-ylcarbonyl group, 4- (methylaminomethyl) piperidin-1-ylcarbonyl group, 4-formimidoylaminopiperidin-1-ylcarbonyl group, 4
-Acetimidoylaminopiperidin-1-ylcarbonyl group, 4-guanidinopiperidin-1-ylcarbonyl group, 4- (2-imidazolin-2-ylamino) piperidin-1-ylcarbonyl group, 4- (2-thiazoline- 2-ylamino) piperidin-1-ylcarbonyl group, 4- (formimidoylaminomethyl) piperidin-1-ylcarbonyl group, 4- (acetimidoylaminomethyl) piperidin-1-ylcarbonyl group, 4-
(Guanidinomethyl) piperidin-1-ylcarbonyl group, 4- (2-imidazolin-2-ylaminomethyl)
Examples thereof include a piperidin-1-ylcarbonyl group and a 4- (2-thiazolin-2-ylaminomethyl) piperidin-1-ylcarbonyl group.

R ³ is preferably a hydrogen atom, a carbamoyl group, a dimethylcarbamoyl group, a piperazin-1-ylcarbonyl group, a 3-aminopyrrolidin-1-ylcarbonyl group or a 3-aminomethylpyrrolidin-1-ylcarbonyl group. And more preferably a hydrogen atom or a piperazin-1-ylcarbonyl group, and particularly preferably a hydrogen atom.

M is preferably 1, n is preferably 0, and p is preferably 0 or 1.

K is preferably 0, s is preferably 0, and t is preferably 0 or 1.

The compounds (I) and (II) of the present invention
Can be converted to a “pharmacologically acceptable salt” as necessary.

"Pharmacologically acceptable salts" include, for example, hydrochloride, hydrobromide, hydroiodide, phosphate, sulfate,
Minerates such as nitrates; sulfonates such as methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate; oxalate, tartrate, citrate, maleate , Succinate, acetate,
Acid addition salts such as organic acid salts such as benzoate, mandelate, ascorbate, lactate, gluconate, malate, glycine, lysine, arginine, ornithine, ornithine, glutamate, asparagine Amino acid salts such as acid salts, or inorganic salts such as lithium salts, sodium salts, potassium salts, calcium salts, and magnesium salts or salts with organic bases such as ammonium salts, triethylamine salts, diisopropylamine salts, and cyclohexylamine salts. And hydrochloride, hydrobromide, phosphate, sulfate, methanesulfonate, p-
Toluenesulfonate, oxalate, tartrate, citrate, acetate, lactate, glutamate, aspartate, sodium, potassium, ammonium or triethylamine salts, more preferably the sodium salt, Hydrochloride or sulfate.

The compounds (I) and (II) of the present invention
Can be left in the air, lyophilized from aqueous solutions,
Alternatively, by recrystallization, water may be absorbed, adsorbed water may be formed, or a hydrate may be formed. Such salts are also included in the present invention.

In the compound represented by the general formula (I) of the present invention, R ¹ is preferably a hydrogen atom, and R ² is preferably a hydrogen atom, a formimidyl group, an acetimidoyl group or an amidino group. , R ³ is a hydrogen atom, a carbamoyl group, a dimethylcarbamoyl group, a piperazin-1-ylcarbonyl group, a 3-aminopyrrolidin-1-ylcarbonyl group or a 3-aminomethylpyrrolidin-1-ylcarbonyl group, and m is 0. Or 1, n is 0 or 1, and p is 0, 1 or 2. More preferably, R ¹ is a hydrogen atom, R ² is a hydrogen atom, a formimidoyl group, an acetimidoyl group or amidino group, R ³ is a hydrogen atom or a piperazin-1-ylcarbonyl group, m is 0 or 1, n is 0 or 1, p is 0 or 1 It is a certain compound.

In the compound represented by the general formula (II) of the present invention, R ¹ is preferably a hydrogen atom, and R ² is preferably a hydrogen atom, a formimidyl group, an acetimidoyl group or an amidino group. , K is 0 or 1, s is 0 or 1, and t is 0 or 1. More preferably, R ¹ is a hydrogen atom, R ² is a hydrogen atom, and k is Is 0 or 1, s is 0, and t is 0 or 1.

In the compounds represented by formulas (I) and (II), the 5- and 6-positions have the same configuration as that of thienamycin. That is, in (I), (5
(S, 6R) arrangement, and (II), (5S, 6S) arrangement. The configuration at the α-position having a hydroxyl group at the 5-position substituent is the R configuration.

The configuration at the 7-position and the configuration at the position where the substituent on the C-ring is bonded indicate one or a mixture of stereoisomers. Preferred among these isomers are
In the general formula (I), it is an isomer of the (7S) configuration, and in the general formula (II), it is an isomer of the (7R) configuration.

Tables 1 and 2 show specific examples of the compounds represented by formulas (I) and (II). The abbreviations S-1 to 7, A-1 to 7, B-1 to 7, and C-
1-7, D-1-7, E-1-3 and F-1-3 are
The following substituents are respectively shown. Also, the “replacement position”
The bond position in the nitrogen-containing ring (azetidine, pyrrolidine or piperidine) of the C ring side chain is shown.

[0036]

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[0037]

TABLE 1 Compounds of general formula (I)

[0038]

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化合物 Compound number R ¹ R ² R ³ mnp Replacement position Ｉ I-1 S-1 S-1 S-1 100 3 'I-2 S-1 S-2 S-1 1000 3' I-3 S-1 S-3 S-1 1000 3 'I-4 S-1 S-4 S- 1 1 0 3 'I-5 S-1 S-5 S-1 1 0 3' I-6 S-1 S-6 S-1 1 0 0 3 'I-7 S-1 S-7 S -1 1 0 3 'I-8 S-1 S-1 S-1 1 0 1 3' I-9 S-1 S-2 S-1 1 0 1 3 'I-10 S-1 S-3 S-1 101 3 'I-11 S-1 S-4 S-1 110 3' I-12 S-1 S-5 S-1 101 3 'I-1 S-1 S-6 S-1 101 3 'I-14 S-1 S-7 S-1 101 3' I-15 S-1 S-1 S-1 110 2 4 'I- 16 S-1 S-2 S-1 10 24 'I-17 S-1 S-3 S-1 10 24' I-18 S-1 S-4 S-1 10 24 'I -19 S-1 S-5 S-1 10 24 'I-20 S-1 S-6 S-1 10 24' I-21 S-1 S-7 S-1 10 24 ' I-22 S-1 S-1 S-1 10 2 3 'I-23 S-1 S-2 S-1 10 2 3' I-24 S-1 S-3 S-1 10 2 3 'I-25 S-1 S-4 S-1 10 2 3' I-26 S-1 S-5 S-1 10 2 3 'I-27 S-1 S-6 S-1 10 2 3 'I-28 S-1 S-7 S-1 10 2 3' I-29 S-1 S-1 S-1 11 2 3 'I-30 S-1 S-2 S-1 11 2 3' I-31 S-1 S-3 S-1 1 1 2 3 'I-32 S-1 S-4 S-11 1 2 3 'I-33 S-1 S-5 S-1 1 1 2 3' I-34 S-1 S-6 S-1 1 1 1 2 3 'I-35 S-1 S-7 S-1 1 1 2 3 'I-36 S-1 S-1 S-1 1 1 1 1 3' I-37 S-1 S-2 S-1 1 1 1 1 3 'I-38 S-1 S-3 S- 1 1 1 1 1 3 'I-39 S-1 S-4 S-1 1 1 1 1 3' I-40 S-1 S-5 S-1 1 1 1 1 3 'I-41 S-1 S-6 S -1 1 1 1 3 'I-42 S-1 S-7 S-1 1 1 1 1 3' I-43 S-1 S-1 S-1 1 1 1 2 'I-44 S-1 S-2 S-1 11 1 2 'I-45 S-1 S-3 S-1 1 1 1 2' I-46 S-1 S- S-1 11 1 2 'I-47 S-1 S-6 S-1 11 1 2' I-48 S-1 S-7 S-1 1 1 1 2 'I-49 S-1 S- 1 A-1 101 4 'I-50 S-1 S-1 A-2 101 4' I-51 S-1 S-1 A-3 101 4 'I-52 S-1 S -1 A-4 101 4 'I-53 S-1 S-1 A-5 101 4' I-54 S-1 S-1 A-6 101 4 'I-55 S-1 S-1 A-7 101-4 'I-56 S-1 S-1 B-1 104' I-57 S-1 S-1 B-2 101 4 'I-58 S- 1 S-1 B-3 101 4 'I-59 S-1 S-1 B-4 101 4' I-60 S-1 S-1 B-5 101 4 'I-61 S -1 S-1 B-6 101 4 'I-62 S-1 S-1 B-7 101 4' I-6 S-1 S-1 C-1 101 4 'I-64 S-1 S-1 C-210 4' I-65 S-1 S-1 C-3 101 4 'I- 66 S-1 S-1 C-4 101 4 'I-67 S-1 S-1 C-5 101 4' I-68 S-1 S-1 C-6 101 4 'I -69 S-1 S-1 C-7 101 4 'I-70 S-1 S-1 E-1 10 14' I-71 S-1 S-1 E-2 10 14 ' I-72 S-1 S-1 D-1 101 4 'I-73 S-1 S-1 D-2 10 14' I-74 S-1 S-1 D-3 10 14 'I-75 S-1 S-1 D-4 101 4' I-76 S-1 S-1 D-5 101 4 'I-77 S-1 S-1 D-6 101 4 'I-78 S-1 S-1 D-7 101 4' I-79 S-1 S-1 E-3 10 1 4 'I-80 S-1 S-1 S-1 110 2' I-81 S-1 S-1 S-100 01 3 'I-82 S-1 S-1 S-10 00 3 'I-83 S-1 S-1 S-1 00 24' I-84 S-1 S-3 S-1 00 1 3 'I-85 S-1 S-4 S-1 0 0 1 3 'I-86 S-1 S-5 S-1 00 1 3' I-87 S-1 S-6 S-1 0 0 1 3 'I-88 S-1 S-7 S- 100 0 1 3 'I-89 S-1 S-3 S-100 0 3' I-90 S-1 S-4 S-1 00 0 3 'I-91 S-1 S-5 S -100 003 'I-92 S-1 S-6 S-100 003' I-93 S-1 S-7 S-100 003 'I-94 S-1 S-3 S-1002 'I-95 S-1 S-4 S-10024'I-96 S-1 S- S-10 00 24 'I-97 S-1 S-6 S-10 00 24' I-98 S-1 S-7 S-100 00 24 'I-99 S-1 S- 1 A-1 0 0 1 4 'I-100 S-1 S-1 B-1 0 1 4' I-101 S-1 S-1 F-1 0 0 1 4 'I-102 S-1 S -1 F-2 001 4 'I-103 S-1 S-1 F-3 001 4' I-104 S-1 S-1 F-1 10 1 4 'I-105 S-1 S-1 F-2 101 4 'I-106 S-1 S-1 F-3 101 4' ──────────────

[0040]

Table 2 Compounds of general formula (II)

[0041]

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化合物 Compound number R ¹ R ² kst Substitution position ＩＩ II-1 S-1 S-1 101 3 ' II-2 S-1 S-3 101 3 'II-3 S-1 S-4 101 3' II-4 S-1 S-5 101 3 'II-5 S-1 S- 6 101 3 'II-6 S-1 S-7 101 3' II-7 S-1 S-1 100 3 'II-8 S-1 S-3 310 3' II- 9 S-1 S-4 100 3 'II-10 S-1 S-5 100 3' II-11 S-1 S-6 100 3 'II-12 S-1 S-7 1 00 3 'II-13 S-1 S-1 10 2 4' II-14 S-1 S-3 10 2 4 'II-15 S-1 S-4 104' II-16 S-1 S-5 104 'II-17 S-1 S-6 104' II-18 S-1 S-7 10 24 'II-19 S-1 S-11 11 2' II-20 S-1 S-11 11 2 'II-21 S-1 S-11 12 2' II-22 S-1 S-1 1 1 1 3 'II-23 S-1 S-1 00 1 3' II-24 S-1 S-3 00 1 3 'II-25 S-1 S- 400 1 3 'II-26 S-1 S-500 1 3' II-27 S-1 S-600 1 3 'II-28 S-1 S-7 0 0 1 3' II- 29 S-1 S-1 00 3 'II-30 S-1 S-3 00 3' II-31 S-1 S-4 00 3 'II-32 S-1 S-5 0 0 0 3 'II-33 S-1 S-60 0 3 'II-34 S-1 S-7 00 00 3' II-35 S-1 S-100 0 2 4 'II-36 S-1 S-3 0 0 2 4' II-37 S- 1 S-4000-II'-38 S-1 S-500-4 'II-39 S-1 S600-204' II-40 S-1 S-700-224 'II-41 S-1 S-10 11 2' II-42 S-1 S-10 10 2 'II-43 S-1 S-10 12 2' II-44 S-1 S -10 01 3 'II-45 S-1 S-100 1 2' II-46 S-1 S-300 1 2 'II-47 S-1 S-400 01 2' II −48 S−1 S−500 1 2 ′ II−49 S−1 S−600 1 2 ′ II-50 S−1 S−700 1 2 ′ II-51 S−1 S−1 10 1 2 'II-52 S-1 S- 101 2 'II-53 S-1 S-4 101 2' II-54 S-1 S-5 101 2 'II-55 S-1 S-6 101 2' II-56 S-1 S-7 10 1 2 ′ ──────────────────────────────────── Also, the above In the table, the compound number I-
1, I-3, I-4, I-5, I-8, I-10, I-
12, I-29, I-36, I-38, I-39, I-
40, I-43, I-49, I-80, I-81, I-
82, I-83, I-84, I-85, I-86, I-
89, I-90, I-91, II-1, II-2, II
-3, II-4, II-7, II-23, II-24,
II-25, II-26, II-29, II-30, I
I-31, II-32, II-41, II-45, II
-46, II-47, II-48, II-51, II-
52, II-53 and II-54, more preferably Compound Nos. 1-1 and I-54.
3, I-4, I-5, I-8, I-10, I-11, I
-12, I-29, I-49, I-81, I-82, I
-84, I-85, I-86, I-89, I-90, I
-91, II-1, II-7, II-23, II-2
9, II-45 and II-51.

[0043]

BEST MODE FOR CARRYING OUT THE INVENTION A tricyclic heterocyclic derivative having the general formula (I) can be produced by the following method (Method A).

[0044]

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In the above formula, R ¹ , R ² , R ³ , m, n and p have the same meanings as described above, R ⁷ represents a hydroxyl-protecting group, and R ⁸ represents a carboxyl-protecting group. And R
² pr and R ³ pr represents a good R ² and R ³ also these are protected if it contains an amino group and / or imino groups in R ² and R ^3.

The “hydroxyl protecting group” for R ⁷ is a protecting group usually used in the field of synthetic organic chemistry, for example, a trialkylsilyl group such as trimethylsilyl, triethylsilyl and t-butyldimethylsilyl; Aralkyloxycarbonyl groups such as nitrobenzyloxycarbonyl and benzyloxycarbonyl; allyl optionally substituted with chlorine or methyl at the 2-position such as allyloxycarbonyl, 2-chloroallyloxycarbonyl and 2-methylallyloxycarbonyl Oxycarbonyl group; trimethylsilylethyloxycarbonyl, 2,
2 such as 2,2-trichloroethyloxycarbonyl
Examples thereof include an ethyloxycarbonyl group substituted by a trialkylsilyl or chlorine atom, preferably a t-butyldimethylsilyl group or an allyloxycarbonyl group, and particularly preferably a t-butyldimethylsilyl group.

The "protecting group for carboxyl group" of R ⁸ is a protecting group usually used in the field of synthetic organic chemistry, and is, for example, chlorine or methyl at the 2-position such as allyl, 2-chloroallyl or 2-methylallyl. An optionally substituted allyl group, an aralkyl group such as 4-nitrobenzyl;
A benzhydryl group, preferably an allyl group,
It is a nitrobenzyl group, particularly preferably an allyl group.

The "protecting group for amino group and imino group" contained in R ² pr and R ³ pr is a protecting group usually used in the field of synthetic organic chemistry, for example, allyloxycarbonyl, 2-chloroallyloxy. Carbonyl, 2
-An allyloxycarbonyl group which may be substituted at the 2-position with chlorine or methyl, such as -methylallyloxycarbonyl; aralkyloxycarbonyl groups, such as benzyloxycarbonyl and 4-nitrobenzyloxycarbonyl; It is an allyloxycarbonyl group or a 4-nitrobenzyloxycarbonyl group, particularly preferably an allyloxycarbonyl group.

In this method (method A), a compound having the formula (V) is produced by subjecting a compound having the formula (III) to an epoxy ring-opening reaction with a mercaptan having the formula (IV) in the presence of a base. Step A1), oxidizing the obtained compound (V),
A compound having the formula (VI) is prepared (Step A2), and then an oxalyl chloride derivative (ClCO
COOR ⁸ ) to produce a compound having the formula (VII) (Step A3), followed by a ring closure reaction to give a compound of the formula (VI)
The compound having II) is produced (Step A4), and finally, the protecting group is removed and, if necessary, converted to a pharmacologically acceptable salt or an ester which undergoes hydrolysis in vivo (Step A5).
Step) to produce a compound having the general formula (I). Hereinafter, each step will be described in detail.

(Step A1) Epoxy Ring Opening Reaction In step A1, a compound having the formula (III) is reacted with a mercaptan having the formula (IV) in an inert solvent in the presence of a base to give a compound of the formula (V This is a step of producing a compound having The compound having the formula (III) as a starting material has been reported in JP-A-3-167187. Further, the mercaptan having the formula (IV) is described in Miyade
ra et al. , J. et al. Antibiot. , 36,
1034 (1983); Kawamoto et
al. , Synlett, 1995, 575;
-28180; JP-A-2-3687; JP-A-4-24-2
It can be produced according to the method described in JP-A-11083 and JP-A-5-339269.

The solvent used is not particularly limited as long as it does not participate in the present reaction. Examples thereof include alcohols such as methanol, ethanol and propanol, ethers such as tetrahydrofuran, dioxane and 1,2-dimethoxyethane, and the like. Nitriles such as acetonitrile, amides such as N, N-dimethylformamide or N, N-dimethylacetamide or dimethylsulfoxide, water, and a mixed solvent thereof;
Preferably it is methanol or ethanol.

The base to be used is not particularly limited as long as it does not affect the other parts of the compound, particularly the β-lactam ring, but is preferably a base such as triethylamine, diisopropylethylamine or 4-dimethylaminopyridine. And particularly preferred is triethylamine or diisopropylethylamine.

The reaction temperature is not particularly limited, but is usually 0.
C. to 100.degree. C. (preferably 0.degree. C. to room temperature), and the reaction time is 30 minutes to 4 days (preferably 1 to 2 days).
It is.

After completion of the reaction, the target compound (V) of this reaction is collected from the reaction mixture according to a conventional method. For example, it can be obtained by adding an organic solvent immiscible with water to a reaction mixture or a residue obtained by distilling a solvent from the reaction mixture, washing with water, and distilling off the solvent. The obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography.

(Step A2) Oxidation reaction Step A2 is a step of oxidizing compound (V) to obtain compound (VI).

The oxidizing agent used is not particularly limited as long as it does not affect the other parts of the compound, but is preferably dimethyl sulfoxide and an acid such as acetic anhydride, trifluoroacetic anhydride, and succinic anhydride. An oxidizing agent with an anhydride and a base or an oxidizing agent with an acid chloride and a base such as dimethyl sulfoxide and oxalyl chloride,
Particularly preferred are dimethyl sulfoxide, oxalyl chloride and an oxidizing agent with a base.

The base to be used is not particularly limited as long as it does not affect the other parts of the compound, particularly the β-lactam ring, but preferably includes triethylamine and diisopropylethylamine, and particularly preferably. Triethylamine.

The solvent to be used is not particularly limited as long as it does not participate in the reaction. For example, halogenated hydrocarbons such as methylene chloride, chloroform and 1,2-dichloroethane, tetrahydrofuran, dioxane or 1,2
Ethers such as dimethoxyethane, preferably methylene chloride or chloroform.

The reaction temperature is not particularly limited, but is usually -7.
The reaction is carried out at 8 ° C to 50 ° C (preferably -60 ° C to room temperature), and the reaction time is 30 minutes to 48 hours (preferably 30 minutes to 10 hours).

After completion of the reaction, the target compound (VI) of the reaction is collected from the reaction mixture according to a conventional method. For example, it can be obtained by adding an organic solvent which is not mixed with water to a reaction mixture or a residue obtained by distilling off the solvent of the reaction mixture, washing with water and distilling off the solvent. The obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography.

(Step A3) Oxalylation reaction Step A3 is a step of reacting compound (VI) with an oxalyl chloride derivative (ClCOCOOR ⁸ ) in the presence of a base to produce compound (VII).

The solvent used is, for example, halogenated hydrocarbons such as methylene chloride, chloroform, 1,2-dichloroethane, nitriles such as acetonitrile, tetrahydrofuran, dioxane or 1,2-dichloromethane.
Ethers such as dimethoxyethane are preferred, and methylene chloride or chloroform is preferred.

The base used is, for example, an organic base such as triethylamine, diisopropylethylamine or 4-dimethylaminopyridine, and is preferably triethylamine or diisopropylethylamine.

The reaction temperature is not particularly limited, but is usually -20.
C. to 60.degree. C. (preferably 0.degree. C. to room temperature), and the reaction time is 30 minutes to 24 hours (preferably 30 minutes to 12 hours).

After completion of the reaction, the target compound (VII) of the present reaction is collected from the reaction mixture according to a conventional method. For example, it can be obtained by adding an organic solvent immiscible with water to a reaction mixture or a residue obtained by distilling off the solvent of the reaction mixture, washing with water and distilling off the solvent. The obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography.

(Step A4) Ring Closure Reaction Step A4 is a step of subjecting compound (VII) to a ring closure reaction in a molecule using a trivalent phosphorus compound to produce compound (VIII).

The trivalent phosphorus compounds used include, for example, trialkyl phosphites such as triethyl phosphite, trimethyl phosphite, tripropyl phosphite, tributyl phosphite, diethylmethylphosphonite, diethyl Examples include dialkylalkylphosphonites such as ethylphosphonite, preferably triethyl phosphite, trimethyl phosphite, diethylmethylphosphonite or diethylethylphosphonite.

Solvents used include, for example, aromatic hydrocarbons such as benzene, toluene, xylene and mesitylene, aliphatic hydrocarbons such as cyclohexane and decalin, dioxane, tetrahydrofuran and 1,2-diethoxyethane. Examples of such ethers include toluene, xylene and mesitylene.

The reaction temperature is not particularly limited, but is usually from 40 ° C. to 200 ° C. (preferably from 40 ° C. to 160 ° C.)
The reaction time is 30 minutes to 24 hours (preferably 30 minutes to 2 hours).
4 hours).

After completion of the reaction, the target compound (VIII) of this reaction is
The residue obtained by distilling off the solvent from the reaction solution can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography.

(Step A5) Deprotection Reaction Step A5 comprises a step of protecting the hydroxyl group R ^{7 of} compound (VIII),
Carboxyl protecting groups R ⁸ and R ² pr and R ³
When pr contains protecting groups, this step is a step of producing the target compound (I) by removing the protecting groups.

The protecting groups R ⁷ , R ⁸ , R ² pr and R ³ p
Although the removal of the protecting group contained in r differs depending on the type, generally, a method known in the art (“Pr
active Groups in Organi
c Synthesis, 2nd Edition "E
d. by T. by. W. Greene and P.S. G. FIG.
M. Wuts, 1991, John Wiley &
Sons, Inc. Etc.).

(1) When the protecting group R ⁷ is a trialkylsilyl group such as trimethylsilyl, triethylsilyl or t-butyldimethylsilyl, examples of the deprotecting agent include ammonium hydrogen fluoride and tetrabutylammonium fluoride. Such organic fluorine compounds and inorganic fluorine compounds such as potassium fluoride are preferred, and ammonium hydrogen fluoride or tetrabutylammonium fluoride is preferred.

The solvent used depends on the type of the deprotecting agent, but includes ethers such as tetrahydrofuran, dioxane or 1,2-dimethoxyethane, amides such as dimethylformamide, sulfoxides such as dimethylsulfoxide, and acetonitrile. Nitriles such as methylene chloride, chloroform or 1,2
-Hydrohalides such as dichloroethane, preferably tetrahydrofuran or dimethylformamide.

The reaction temperature is not particularly limited, but is usually -20 ° C.
To 100 ° C. (preferably 0 ° C. to 60 ° C.), and the reaction time is usually 30 minutes to 48 hours (preferably 30 minutes to 12 hours).

After completion of the reaction, the deprotected compound is collected from the reaction mixture according to a conventional method, and then, if R ² pr and R ³ pr contain a protecting group, the protecting group is removed and the protecting group R ⁸ is removed. It can be subjected to a reaction.

(2) When protecting group R ⁷ is an ethyloxycarbonyl group in which the 2-position is substituted by trialkylsilyl or chlorine, for example, trimethylsilylethyloxycarbonyl, 2,2,2-trichloroethyloxycarbonyl group Examples of the deprotecting agent include a Lewis acid such as boron trifluoride etherate and a metal-organic acid such as zinc-acetic acid, preferably boron trifluoride etherate or zinc-acetic acid.

The solvent used depends on the type of the deprotecting agent, but includes hydrogen halides such as chloroform or 1,2-dichloroethane, esters such as ethyl acetate, tetrahydrofuran, dioxane or 1,1,2-dichloroethane.
Examples include ethers such as 2-dimethoxyethane, nitriles such as acetonitrile, and alcohols such as methanol, ethanol or propanol, and preferably methylene chloride, ethyl acetate or tetrahydrofuran.

The reaction temperature is not particularly limited, but is usually -20 ° C.
To 100 ° C. (preferably 0 ° C. to 60 ° C.), and the reaction time is usually 30 minutes to 48 hours (preferably 30 minutes to 12 hours).

After completion of the reaction, the deprotected compound is collected from the reaction mixture according to a conventional method, and then, when R ² pr and R ³ pr contain a protecting group, the protecting group is removed and the protecting group R ⁸ is removed. It can be subjected to a reaction.

(3) The protecting group R ⁷ is an allyloxycarbonyl group which may be substituted at the 2-position with chlorine or methyl, such as allyloxycarbonyl, 2-chloroallyloxycarbonyl and 2-methylallyloxycarbonyl. When the protecting group R ⁸ is allyl, 2-chloroallyl, 2
When the 2-position such as -methylallyl is an allyl group which may be substituted with chlorine or methyl, the protecting groups contained in R ² pr and R ³ pr are allyloxycarbonyl, 2-chloroallyloxycarbonyl, When the 2-position is an allyloxycarbonyl group which may be substituted with chlorine or methyl such as methylallyloxycarbonyl, examples of the deprotecting agent include bis (triphenylphosphine) palladium chloride-tributyltin hydride and tetrakis (trikis). Palladiums such as phenylphosphine) palladium-tributyltin hydride-trialkyltin hydrides or palladiums such as tetrakis (triphenylphosphine) palladium-2-ethylhexanoate or sodium 2-ethylhexanoate Organic carboxylic acid alkali metal salts, and the like, preferably bis (triphenylphosphine) palladium chloride - is tributyltin hydride or tetrakis (triphenylphosphine) palladium 2-ethylhexanoic acid potassium.

The solvent used is not particularly limited as long as it does not participate in this reaction, but halogenated hydrocarbons such as methylene chloride, chloroform or 1,2-dichloroethane, and esters such as ethyl acetate. Ethers such as tetrahydrofuran, dioxane or 1,2-dimethoxyethane, nitriles such as acetonitrile, alcohols such as methanol, ethanol or propanol, water or a mixed solvent thereof. , Ethyl acetate or a mixed solvent thereof.

The reaction temperature is not particularly limited, but is usually -20 ° C.
To 100 ° C. (preferably 0 ° C. to 60 ° C.), and the reaction time is usually 30 minutes to 48 hours (preferably 30 minutes to 12 hours).

After completion of the reaction, the deprotected compound (I) is collected from the reaction mixture according to a conventional method. For example, it can be obtained by filtering off insolubles precipitated from the reaction mixture and then distilling off the solvent.

(4) When the protecting group R ⁷ is an aralkyloxycarbonyl group such as benzyloxycarbonyl or 4-nitrobenzyloxycarbonyl, the protecting group R ⁸ is an aralkyl group such as benzyl or 4-nitrobenzyl or benzhydryl. R ² pr and R ³
pr is benzyloxycarbonyl, 4
In the case of an aralkyloxycarbonyl group such as -nitrobenzyloxycarbonyl, examples of the deprotecting agent include hydrogen and a catalytic reduction catalyst such as palladium-carbon or an alkali metal sulfide such as sodium sulfide or potassium sulfide. Preferably they are hydrogen and palladium-carbon.

The solvent to be used is not particularly limited as long as it does not participate in the reaction, but halogenated hydrocarbons such as methylene chloride, chloroform or 1,2-dichloroethane, and esters such as ethyl acetate. Ethers such as tetrahydrofuran, dioxane or 1,2-dimethoxyethane, nitriles such as acetonitrile, alcohols such as methanol, ethanol or propanol or water or a mixed solvent thereof, preferably tetrahydrofuran or It is a tetrahydrofuran-water mixed solvent.

The reaction temperature is not particularly limited, but is usually from room temperature to 100 ° C. (preferably from room temperature to 60 ° C.), and the reaction time is usually from 30 minutes to 48 hours (preferably from 30 minutes to 20 hours).
Time).

After completion of the reaction, compound (I) is collected from the reaction mixture according to a conventional method. For example, it can be obtained by filtering off the catalyst used for the reaction and the precipitated insoluble matter from the reaction mixture, and then distilling off the solvent.

Note that R ⁷ , R ⁸ or R ² pr and R ³
If the protecting groups used by pr are removed by the same deprotecting agent, those protecting groups can be removed simultaneously.

The compound (I) thus obtained is
If necessary, it can be purified by a conventional method such as recrystallization, column chromatography, preparative liquid chromatography and the like. If necessary, it can be converted into an ester which undergoes hydrolysis in vivo by a conventional method (JP-A-5-50204), and can be purified as a pharmacologically acceptable salt by a conventional method.

In the method A, the compound represented by the general formula (VI) can also be produced by the following method (Step A6).

[0092]

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That is, it is achieved by reacting the compound having the formula (IX) with the enolate anion of the compound (X) produced from the compound (X).

The enolate anion of the compound (X) can be generated by reacting the compound (X) with a base such as lithium hexamethyldisilazane or lithium diisopropylamide, and then adding trimethylsilyltrifluoromethanesulfonate. And can be subjected to reaction with compound (IX) without isolation.

The solvent to be used is not particularly limited as long as it does not participate in the reaction. Methylene chloride, chloroform, 1,2
Halogenated hydrocarbons such as -dichloroethane; ethers such as tetrahydrofuran, dioxane or 1,2-dimethoxyethane, preferably tetrahydrofuran or methylene chloride.

The reaction temperature is not particularly limited, but is usually -7.
The reaction is carried out at a temperature of 8 ° C to 50 ° C (preferably -78 ° C to room temperature), and the reaction time is 15 minutes to 48 hours (preferably 30 minutes to 24 hours).

After completion of the reaction, compound (VI) is collected from the reaction mixture according to a conventional method. For example, it can be obtained by adding an organic solvent immiscible with water to a residue obtained by distilling off the solvent of the reaction mixture or the reaction mixture, washing with water, and distilling off the solvent. The obtained target compound can be obtained by a conventional method, if necessary.
For example, it can be further purified by recrystallization, reprecipitation or chromatography.

The starting material for Step A6, Compound (IX), which is commercially available, can be used, and Compound (X) is produced according to the following route.

[0099]

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That is, it is possible to produce the starting compound (X) by reacting 2-chlorocyclopentanone or 2-chlorocyclohexanone (XI) as a raw material with a mercaptan represented by the formula (IV) in the presence of a base. it can.

On the other hand, the tricyclic heterocyclic compound having the general formula (II) of the present invention can be produced by the following method (Method B).

[0102]

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In the above formula, R ¹ , R ² , R ⁷ , R ⁸ , k,
s, t and R ² pr are as defined above.

The present method (Method B) is a method for enolizing a compound having the formula (XII) in the presence of a base.
A compound having the formula (XIII) is produced by reacting a toanion (Step B1), and the obtained compound (XIII)
In the presence of a base with an oxalyl chloride derivative (ClCO
COOR ⁸ ) to produce a compound having the formula (XIV) (Step B2), followed by a ring closure reaction to obtain a compound of the formula (XIV)
A compound having V) is produced (Step B3), and finally the protecting group is removed and, if necessary, converted to a pharmacologically acceptable salt or an ester which undergoes hydrolysis in vivo (Step B4).
Step) to produce a compound having the general formula (II). Hereinafter, each step will be described in detail.

(Step B1) Substitution reaction In step B1, a compound having the formula (IX) is added to a compound (XI
In this step, the compound (XIII) is produced by reacting the enolate anion of the compound (XII) produced from I).

Here, the enolate anion of the compound (XII) is obtained by reacting the compound (XII) with t-butyldimethylsilyl trifluoromethanesulfonate in the presence of an organic base such as triethylamine or diisopropylethylamine, and then trimethylsilyl trifluoromethanesulfonate. Can be generated by adding
The compound can be subjected to a reaction with compound (IX) without isolation.

The solvent to be used is not particularly limited as long as it does not participate in the reaction. Methylene chloride, chloroform, 1,2
Halogenated hydrocarbons such as -dichloroethane; ethers such as tetrahydrofuran, dioxane or 1,2-dimethoxyethane, preferably tetrahydrofuran or methylene chloride.

Although the reaction temperature is not particularly limited, it is usually -7.
The reaction is carried out at a temperature of 8 ° C to 50 ° C (preferably -78 ° C to room temperature), and the reaction time is 15 minutes to 48 hours (preferably 30 minutes to 24 hours).

After completion of the reaction, the desired product (XIII) of the reaction is collected from the reaction mixture according to a conventional method. For example, it can be obtained by adding an organic solvent immiscible with water to a residue obtained by distilling off the solvent of the reaction mixture or the reaction mixture, washing with water, and distilling off the solvent. The obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography.

(Step B2) Oxalylation reaction Step B2 is a step of reacting compound (XIII) with an oxalyl chloride derivative (ClCOCOOR ⁸ ) in the presence of a base to produce compound (XIV). A3 of
This is achieved according to the method of the process.

(Step B3) Ring Closure Reaction Step B3 is a step of subjecting compound (XIV) to a ring closure reaction in a molecule using a trivalent phosphorus compound to produce compound (XV). This is achieved according to the method of the process.

(Step B4) Deprotection Reaction Step B4 comprises the step of protecting the hydroxyl-protecting group R ⁷ , the carboxyl-protecting group R ⁸ and the protecting group R ² pr of the compound (XV) when they are contained. The step of producing the target compound (II) by removing the protecting group of the above-mentioned step includes, if necessary, a step of converting into an ester or an acceptable salt which is hydrolyzed in vivo. Achieved according to the method.

Compound (II) thus obtained
If necessary, can be purified by a conventional method such as recrystallization, column chromatography, preparative liquid chromatography and the like. If necessary, it can be converted into an ester which undergoes hydrolysis in vivo by a conventional method (JP-A-5-50204), and can be purified as a pharmacologically acceptable salt by a conventional method.

Compound (XII) which is a starting material of Method B
Can be manufactured according to the following route.

[0115]

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That is, a diol compound represented by the formula (XVI) is subjected to a monotosylation reaction to produce a compound represented by the formula (XVII), which is then cyanated to give a compound (XV
III) to produce compound (XIX) by mesylation, thioacetylation to produce compound (XX), cyclization to produce compound (XXI) and introduction of R ² pr (XII) can be produced.

The tricyclic heterocyclic derivative having the general formula (I) or (II) of the present invention or a pharmaceutically acceptable salt thereof has excellent antibacterial activity against a wide range of pathogenic bacteria, so that it can treat infectious diseases. Alternatively, it is useful as an antibacterial agent for prevention (preferably treatment).

When the compound (I) or (II) and a pharmaceutically acceptable salt thereof are used as an antibacterial agent, the compound may be used as such or an appropriate pharmaceutically acceptable excipient,
It can be mixed with a diluent or the like and administered orally with tablets, capsules, granules, powders or syrups, or parenterally by intravenous injection, intramuscular injection or the like.

These preparations contain excipients (eg, lactose,
Sugar derivatives such as sucrose, glucose, mannitol, sorbite; starch derivatives such as corn starch, potato starch, α-starch, dextrin, carboxymethyl starch; crystalline cellulose, low-substituted hydroxypropyl cellulose, hydroxy Cellulose derivatives such as propylmethylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium, internally crosslinked sodium carboxymethylcellulose; gum arabic; dextran; pullulan; light anhydrous silicic acid, synthetic aluminum silicate; Silicate derivatives such as magnesium metasilicate aluminate; phosphate derivatives such as calcium phosphate; carbonate derivatives such as calcium carbonate; sulfate derivatives such as calcium sulfate; Agent Gelatin; polyvinylpyrrolidone;
Maglogol, etc.), disintegrants (for example, the above-mentioned excipients; croscarmellose sodium, carboxymethyl starch)
Disodium, chemically modified starch such as crosslinked polyvinylpyrrolidone, starch, cellulose derivatives, etc.), lubricants (eg, talc; stearic acid; metal stearate such as calcium stearate, magnesium stearate; colloidal silica) Luxes such as bee gum and gay wax; boric acid; glycol; carboxylic acids such as fumaric acid and adipic acid; sodium carboxylate salts such as sodium benzoate; sulfate salts such as sodium sulfate; Lauryl sulfates such as sodium lauryl sulfate and magnesium lauryl sulfate; silicic acids such as silicic anhydride and silicic acid hydrate; starch derivatives in the above-mentioned excipients); stabilizers (such as methylparaben and propylparaben) Paraoxybenzoic acid esters; chlorobutanol, Alcohols such as benzyl alcohol and phenylethyl alcohol; benzalkonium chloride; phenols such as phenol and cresol; thimerosal; acetic anhydride; Flavoring agents (for example, commonly used sweeteners, sour agents, flavors, etc.), suspending agents (for example, polysorbate 80, sodium carboxymethyl cellulose), diluents, solvents for preparations (for example, Water, ethanol, glycerin and the like) are used and manufactured by a known method.

The dosage depends on symptoms, age, etc., but in the case of oral administration, the lower limit is 10 mg (preferably 50 mg) and the upper limit is 2000 mg (preferably 10 mg).
00 mg), in the case of intravenous administration, a lower limit of 10 mg (preferably 50 mg) and an upper limit of 3000 mg (preferably 2000 mg) are administered to an adult 1 to 6 times per day depending on the symptoms. It is desirable to do.

Hereinafter, the present invention will be described in more detail with reference to Examples, Test Examples and Formulation Examples, but the scope of the present invention is not limited thereto. Incidentally, trimethylsilyl unless otherwise specified for the measurement of heavy water for nuclear magnetic resonance spectrum in the examples propionic acid sodium -d ₄
Was used as an internal standard, and tetramethylsilane was used as an internal standard for other solvents.

In the chemical formulas of the examples, TBS represents a t-butyldimethylsilyl group, TES represents a triethylsilyl group, and Allyl represents an allyl group.

[0123]

【Example】

Example 1 (5S, 6R, 7R, 11S) -11- (azetidine-
3-ylthio) -5-[(R) -1-hydroxyethyl] -4-oxo-3-azatricyclo [5.4.0.
0 ^3,6 ] undec-1-en-2-carboxylic acid (stereoisomer of exemplified compound I-1)

[0124]

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(1) (3S, 4R) -4-[(1R,
2S, 3S) -3- (1-allyloxycarbonylazetidin-3-ylthio) -2-hydroxycyclohexyl] -3-[(R) -1- (tert-butyldimethylsilyloxy) ethyl] azetidine-2- on

[0126]

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Under a nitrogen stream, 7.3 ml of a 1N aqueous sodium hydroxide solution was added to a solution of 1.50 g of 3-acetylthioazetidine-1-carboxylic acid allyl ester in 15 ml of methanol, and the mixture was stirred at room temperature for 1 hour. 7.3 ml of 1N hydrochloric acid was added to the reaction mixture, and the mixture was concentrated under reduced pressure. Ethyl acetate was added to the residue, washed with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 1-allyloxycarbonyl-3-mercaptoazetidine. Under a nitrogen stream, (3S, 4R) -4-[(1R, 2S, 3R)-
2,3-Epoxycyclohexyl] -3-[(R) -1
-(Tert-butyldimethylsilyloxyethyl) ethyl] azetidin-2-one (1.50 g) in methano-
To a 30 ml solution of toluene were added a solution of 1-allyloxycarbonyl-3-mercaptoazetidine in 5 ml of methanol and 1.3 ml of triethylamine, followed by stirring at room temperature for 20 hours. After completion of the reaction, ethyl acetate was added to the reaction mixture,
The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography (eluted with 30% ethyl acetate / hexane followed by 50% ethyl acetate / hexane) to obtain 2.19 g of the title compound as a pale brown amorphous.

Infrared absorption spectrum (KBr) ν max cm
^-1 : 3425, 3293, 1741, 1694, 1649,1472, 1448, 141
1. Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δppm: 0.10 (6
H, s), 0.89 (9H, s), 1.28 (3H, d, J = 6.2 Hz), 1.44-
1.70 (6H, m), 1.86-2.21 (2H, m), 2.88-2.98 (1H, m),
3.58-3.77 (2H, m), 3.81-3.93 (2H, m), 4.08-4.22
(1H, m), 4.30-4.41 (2H, m), 4.52-4.60 (2H, m), 5.1
8-5.37 (3H, m), 5.83-6.00 (1H, m). (2) (3S, 4R) -4-[(1R, 3S) -3-
(1-allyloxycarbonylazetidin-3-ylthio) -2-oxocyclohexyl] -3-[(R) -1
-(Tert-butyldimethylsilyloxy) ethyl]
Azetidin-2-one

[0129]

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1 ml of dimethyl sulfoxide was added dropwise to a solution of 0.63 ml of oxalyl chloride in 20 ml of dry dichloromethane at −78 ° C. in a stream of nitrogen.
A solution of 1.40 g of the compound obtained in (1) in 20 ml of dry dichloromethane was added dropwise and stirred for 30 minutes. Thereafter, 4 ml of triethylamine was added dropwise, the mixture was stirred for 30 minutes, and the temperature was gradually raised to room temperature. Ethyl acetate was added to the reaction mixture, washed with water and saturated saline, and dried over anhydrous magnesium sulfate.
It was concentrated under reduced pressure. The residue was separated by silica gel column chromatography (eluted with 50% ethyl acetate / hexane) to give 1.13 g of the title compound as a pale yellow powder.

Infrared absorption spectrum (KBr) ν max cm
^-1 : 3281, 1760, 1709, 1649, 1472,1462, 1447, 140
7. Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δppm: 0.07
(3H, s), 0.08 (3H, s), 0.87 (9H, s), 1.26 (3H, d,
J = 6.2 Hz), 1.54-2.20 (5H, m), 2.87-2.97 (1H, m),
3.28-3.93 (5H, m), 4.07 4.40 (4H, m), 4.52-4.58 (2
H, m), 5.17-5.35 (2H, m), 5.70-6.00 (2H, m). (3) (3S, 4R) -1-allyloxalyl-4-
[(1R, 3S) -3- (1-allyloxycarbonylazetidin-3-ylthio) -2-oxocyclohexyl] -3-[(R) -1- (tert-butyldimethylsilyloxy) ethyl] azetidine- 2-on

[0132]

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In a nitrogen stream, 0.84 g of allyl oxalyl chloride was added dropwise to a solution of 1.40 g of the compound obtained in Example 1- (2) and 0.79 ml of triethylamine in 30 ml of dry dichloromethane under ice-cooling, and the mixture was stirred at room temperature for 1 hour. Stirred. Ethyl acetate was added to the reaction mixture, washed with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography.
(Eluted with 20% ethyl acetate / hexane followed by 30% ethyl acetate / hexane) to give 1.41 g of the title compound as a colorless powder.

Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ )
δppm: 0.04 (3H, s), 0.07 (3H, s), 0.85 (9H, s),
1.21 (3H, d, J = 6.3 Hz), 1.40-1.60 (2H, m), 1.73-2.
20 (4H, m), 3.20-3.27 (1H, m), 3.30-3.37 (1H, m),
3.43-3.55 (1H, m), 3.66-3.76 (1H, m), 3.80-3.90 (1
H, m), 3.98-4.13 (1H, m), 4.22 4.40 (4H, m), 4.50-
4.58 (2H, m), 4.77-4.83 (2H, m), 5.17-5.47 (4H,
m), 5.80-6.06 (2H, m). (4) (5S, 6R, 7R, 11S) -11- (1-
Allyloxycarbonylazetidin-3-ylthio)-
5 - [(R) -1- ( tert- butyldimethylsilyloxy) ethyl] -4-oxo-3-azatricyclo [5.4.0.0 ^{3, 6]} undec-1-ene-2-carboxylic acid allyl

[0135]

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In a nitrogen stream, 1.35 g of the compound obtained in Example 1- (3) and 1.35 g of ethyl diethylphosphonite were added.
A solution of 00 g of 30 ml of dry toluene was refluxed with stirring for 8 hours. After the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (30% ethyl acetate /
(Eluted with hexane) to give 1.03 g of the title compound as a colorless powder.

Infrared absorption spectrum (KBr) ν max cm
^-1 : 1782, 1713, 1648, 1624, 1472, 1446, 1428, 140
5. Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δppm: 0.08
(6H, s), 0.89 (9H, s), 1.23 (3H, d, J = 6.2 Hz), 1.2
8-1.45 (1H, m), 1.55-2.08 (5H, m), 3.17-3.23 (1H,
m), 3.31-3.46 (1H, m), 3.52-3.66 (1H, m), 3.73-3.9
3 (2H, m), 4.10-4.35 (4H, m), 4.52-4.60 (2H, m),
4.65-4.82 (2H, m), 4.85-4.91 (1H, b), 5.18-5.52 (4
H, m), 5.83-6.06 (2H, m). (5) (5S, 6R, 7R, 11S) -11- (1-
Allyloxycarbonylazetidin-3-ylthio)-
5-[(R) -1-hydroxyethyl] -4-oxo-
3-azatricyclo [5.4.0.0 ^3,6 ] undeca
Allyl 1-ene-2-carboxylate

[0138]

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To a solution of 1.00 g of the compound obtained in Example 1- (4) in 20 ml of tetrahydrofuran was added 1.5 ml of acetic acid and 8.7 ml of 1M-tetrabutylammonium fluoride / tetrahydrofuran under a nitrogen stream, and the mixture was added at room temperature.
After stirring for an hour, the mixture was allowed to stand overnight. Ethyl acetate was added to the reaction mixture, and the mixture was washed with a saturated aqueous solution of sodium hydrogen carbonate, water, and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography (eluted with 50% ethyl acetate / hexane) to give 519 mg of the title compound as a colorless powder.

Infrared absorption spectrum (KBr) ν max cm
^-1 : 3447, 1779, 1711, 1648, 1623, 1446, 1409. Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δppm: 1.32
(3H, d, J = 6.3 Hz), 1.20-2.07 (7H, m), 3.22-3.29 (1
H, m), 3.38-3.65 (2H, m), 3.72-3.93 (2H, m), 4.17-
4.33 (4H, m), 4.50-4.59 (2H, m), 4.63-4.92 (3H,
m), 5.17-5.52 (4H, m), 5.82-6.07 (2H, m). (6) (5S, 6R, 7R, 11S) -11- (azetidin-3-ylthio) -5-[(R) -1-Hydroxyethyl] -4-oxo-3-azatricyclo [5.
4.0.0 ^3,6 ] Undec-1-en-2-carboxylic acid Compound 500 obtained in Example 1- (5) under a nitrogen stream
bis (triphenylphosphine) palladium (II) 38 under ice-cooling.
mg, 2 ml of tributyltin hydride and 0.11 ml of water were added, and the mixture was stirred for 30 minutes and further stirred at room temperature for 1 hour.
Dichloromethane was added to the reaction mixture, which was extracted three times with water. The aqueous layer was washed with dichloromethane and concentrated under reduced pressure to about 10 ml. The residue was subjected to reverse phase column chromatography.
After separation by [Cosmosil 75C18 PREP (Nacalai Tesque), elution with 3 to 9% acetonitrile / water], the mixture was concentrated under reduced pressure and lyophilized to obtain 88 mg of the target compound as a colorless powder.

Infrared absorption spectrum (KBr) ν max cm
^-1 : 3412, 1762, 1592, 1445, 1391,1347, 1336, 130
5. Nuclear magnetic resonance spectrum (400 MHz, D ₂ O) δppm: 1.26 (3H,
d, J = 6.4 Hz), 1.33-1.46 (1H, m), 1.65-2.00 (5H,
m), 3.37-3.50 (2H, m), 3.83-4.05 (3H, m), 4.17-4.2
8 (2H, m), 4.33-4.44 (2H, m), 4.73-4.92 (1H, m). Example 2 (5S, 6R, 7R, 11S) -5-[(R) -1-hydroxyethyl] -4-oxo-11-[(S) -pyrrolidin-3-ylthio-3-azatricyclo [5.4.
0.0 ^3,6 ] undec-1-en-2-carboxylic acid (stereoisomer of exemplified compound I-8)

[0142]

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(1) (3S, 4R) -3-[(R)-
1- (tert-butyldimethylsilyloxy) ethyl] -4-{(1R, 2S, 3S) -2-hydroxy-
3-[(3S) -1-allyloxycarbonylpyrrolidin-3-ylthio] cyclohexyl} azetidine-2-
on

[0144]

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(3S, 4R) -4-[(1R, 2S, 3
R) -2,3-Epoxycyclohexyl] -3-
[(R) -1- (tert-butyldimethylsilyloxy) ethyl] azetidin-2-one (1.00 g, 3.
07 mmol) of dry 1,2-diaminoethane (20 m
l) The solution was thoroughly degassed with argon and treated with 1-allyloxycarbonyl-3-acetylthiopyrrolidine (1.75 g, 7.8 mmol) in two equal batches and obtained. The mixture was stirred at room temperature for 0.5 hours. The mixture was treated again with 1-allyloxycarbonyl-3-acetylthiopyrrolidine (1.75 g, 7.8 mmol) and the resulting mixture was stirred at room temperature for another 0.5 hour. Thin layer chromatography (ethyl acetate / hexane =
1: 1) indicated the absence of the starting epoxide, indicating the presence of the product (Rf 0.3). The mixture was concentrated under reduced pressure and the product was isolated by silica gel chromatography (eluted with 10-50% ethyl acetate / hexane). Fractions 24-42 were collected and concentrated under reduced pressure to give the title compound (colorless foam, yield: 71%).

Nuclear magnetic resonance spectrum (300 MHz, CDCl ₃ )
δ: 0.0 (s, 6H), 0.8 (s, 9H), 1.2 (d, J = 6Hz, 3
H), 1.4-1.6 (br m, 5H), 2.0 (m, 1H), 2.15 (m, 1H),
2.83 (d, J = 5Hz, 1H), 2.90 (br s, 1H), 3.2-3.4 (b
rm, 5H), 3.50 (br m, 2H), 3.7 (m, 1H), 3.85 (m, 1
H), 4.1 (m, 1H), 4.5 (d, J = 6Hz, 2H), 5.2 (m, 4li
nes, 2H), 5.85 (m, 1H), 6.1 (broad s, 1H) MS (CI / NH3) m / z 513 (M + H ⁺ ). (2) (3S, 4R) -3-[(R ) -1- (ter
t-butyldimethylsilyloxy) ethyl] -4-
{(1R, 3S) -2-oxo-3-[(S) -1-allyloxycarbonylpyrrolidin-3-ylthio] cyclohexyl} azetidin-2-one

[0147]

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Dimethyl sulfoxide (0.40 ml,
5.47 mmol) of dry dichloromethane (10 ml)
The solution was cooled to −78 ° C. under an argon atmosphere, and oxalyl chloride (0.23 ml, 2.63 mmol) was injected using a syringe. The resulting solution is heated at -78 ° C for 1 hour.
After stirring for 5 minutes, the compound obtained in (1) (1.
15 g, 2.19 mmol) of dichloromethane (10 m
l) The solution was injected using a syringe and the resulting clear yellow solution was stirred at -78 ° C for 15 minutes. Next, triethylamine (1.5 ml, 11 mmol) was added to this solution.
l) was injected with a syringe at -78 ° C, the cooling bath was removed and the solution was allowed to warm to room temperature over 1 hour. The pale yellow suspension was diluted with saturated aqueous sodium bicarbonate. The organic layer was washed with water, and the combined aqueous layers were washed several times with dichloromethane. The combined organic layers were dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel chromatography. Fractions 15 to 20 were collected and concentrated under reduced pressure to give 806.5 mg (yield: 71) of the title compound.
%) As a colorless foam.

Nuclear magnetic resonance spectrum (300 MHz, CDCl ₃ )
δ: 0.0 (s, 6H), 0.8 (s, 9H), 1.2 (d, J = 6Hz, 3
H), 1.75 (m, 3H), 2.15 (m, 4H), 2.80 (br d, J = 6H
z, 1H), 3.1 (br m, 2H), 3.2-3.5 (4H), 3.85 (q, J =
6Hz, 1H), 4.0 (m, 1H), 4.1 (m, 1H), 4.5 (d, J = 6H
z, 2H), 5.2 (m, 4 lines, 2H), 5.6 (broad s, 1H), 5.
85 (m, 1H) MS ( CI / NH 3) m / z 511 (M + H +). (3) (3S, 4R) -1- allyl oxalyl 4-
{(1R, 3S) -3-[(S) -1-allyloxycarbonylpyrrolidin-3-ylthio] -2-oxocyclohexyl} -3-[(R) -1- (tert-butyldimethylsilyloxy) ethyl Azetidin-2-one

[0150]

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The compound obtained in (2) (2.0 g, 4.
0 mmol) in dichloromethane (50 ml) and triethylamine (1.3 ml, 8.0 mmol) at 0 ° C.
(Ice bath), treated with allyloxyoxalyl chloride (1.2 ml, 8.0 mmol) and the resulting mixture was stirred at 0 ° C. for 0.5 h. Thin layer chromatography showed the absence of starting material (Rf 0.4 in ethyl acetate / hexane = 1: 1) and the presence of the product, acylated azetidinone (Rf 0.7).
The solution was washed with water and brine, dried over magnesium sulfate, and concentrated under reduced pressure to give 3.0 g (100%) of the title compound.
%) As a dark oil which was used without purification.

(4) (5S, 6R, 7R, 11S)-
5-[(R) -1- (tert-butyldimethylsilyloxy) ethyl] -4-oxo-11-[(S) -1-
Allyloxycarbonylpyrrolidin-3-ylthio]-
3-azatricyclo [5.4.0.0 ^3,6 ] undeca
Allyl 1-ene-2-carboxylate

[0153]

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The compound obtained in (3) (300 mg,
0.5 mmol) of dry xylene (30 ml)
Treated with triethyl phosphite (1.0 ml) and the resulting mixture was heated at reflux for 1 hour. Thin layer chromatography showed the absence of the starting acylated azetidinone (Rf 0.2 in ethyl acetate / hexane = 1: 3) and the product tricyclic azetidinone (ethyl acetate / hexane = 1). : Rf 0.35) in E.3: 3. The solution was cooled and the solvent was removed under reduced pressure to give an oil. This oil was purified by silica gel chromatography. Fractions 9 to 18 were collected and concentrated under reduced pressure to obtain 144 mg (48%) of the title compound as a colorless oil.

Nuclear magnetic resonance spectrum (300 MHz, CDCl ₃ )
δ: 0.0 (s, 6H), 0.8 (s, 9H), 1.2 (d, J = 6Hz, 3H),
1.5-1.95 (m, 7H), 2.10 (br m, 1H), 3.1 (q, J = 4H
z, 2H), 3.2-3.5 (4H), 3.75 (q, J = 6Hz, 1H), 4.2
(m, 2H), 4.5 (d, J = 6Hz, 2H), 4.65 (m, 2H), 5.85
(m, 2H), 5.1-5.4 ( m, 7 lines, 4H), 4.8 (brs, 1H) MS (CI / NH 3) m / z 591.8 (M + H +). (5) (5S, 6R, 7R, 11S) -5-[(R)
-1-hydroxyethyl] -4-oxo-11-
[(S) -1-allyloxycarbonylpyrrolidine-3
-Ylthio] -3-azatricyclo [5.4.0.0
^3,6 ] Allyl undec-1-en-2-carboxylate

[0156]

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450 mg of the compound obtained in (4) (0.
761 mmol) of N-methylpyrrolidone 7 ml and dimethylformamide 7 ml solution were added with 1N tetrabutylammonium fluoride 3.5 ml and acetic acid 183 μl,
Then, 45 mg of ammonium hydrogen fluoride was added. The reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with 50 ml of ethyl acetate, 50 ml of water and 50 ml of a saline solution.
And washed. Ethyl acetate is dried over magnesium sulfate,
Filtered and evaporated. Purification by preparative thin-layer chromatography using ethyl acetate gave 120 mg of the title compound (33
%).

Nuclear magnetic resonance spectrum (300 MHz, CDCl ₃ )
δ: 1.21 (3H, d, J = 6.3 Hz), 1.6-2.25 (10H, m),
3.2 (2H, m), 3.3-3.6 (4H, m), 3.65 (1H, q), 4.20
(2H, m), 4.55 (2H, d), 4.70 (2H, dq), 4.85 (1H,
s), 5.25 (4H, ddd), 5.92 (2H, m). (6) (5S, 6R, 7R, 11S) -5-[(R)
-1-hydroxyethyl] -4-oxo-11-
[(S) -Pyrrolidin- ³ -ylthio] -3-azatricyclo [5.4.0.0 ^3,6 ] undec-1-en-2
-Carboxylic acid 120 mg (0.251 mmol) obtained in (5)
l) in a 4 ml dichloromethane solution at 0 ° C under an argon atmosphere, 29 μL (1.61 mmol) of water, bis (triphenylphosphine) palladium (II) 1 chloride
1.5 mg (0.016 mmol) and 0.15 ml (1.7 mmol) of tributyltin hydride were successively added. The reaction mixture is allowed to stand at 0 ° C. for 5 minutes, then at room temperature for 30 minutes.
After stirring for 20 minutes, 20 ml of dichloromethane was added, and the dichloromethane was extracted five times with 8 ml of water. This water was washed with 20 ml of dichloromethane and 20 ml of ethyl acetate. The aqueous layer was purified on a C-18 column, eluted with a 0-1% aqueous acetonitrile solution while adding 11 mg of sodium chloride, and the solution was freeze-dried and stabilized. Sodium chloride 1
32 mg (27%) of the desired compound containing 1 mg were obtained.

Nuclear magnetic resonance spectrum (300 MHz, D ₂ O)
δ: 1.30 (3H, d, J = 6.4 Hz), 1.45 (1H, m), 1.78 (2
H, m), 1.97 (4H, m), 2.42 (1H, dq), 3.3-3.67 (6H,
m), 4.27 (2H, m), 4.92 (1H, t) Infrared absorption spectrum (KBr) ν max cm ^-1 : 3408, 293
0, 1758, 1619, 1589. MS (ES) 352 MW = 352. Example 3 (5S, 6R, 7R, 11S) -5-[(R) -1-hydroxyethyl] -4-oxo-11-[(S) -piperidin-3-ylmethylthio] -3-azatricyclo [5 .4.0.0 ^3,6 ] undec-1-en-2-carboxylic acid (stereoisomer of Exemplified Compound I-29)

[0160]

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(1) (3S, 4R) -4-{(1R,
2S, 3S) -3-[(S) -1-allyloxycarbonylpiperidin-3-ylmethylthio] -2-hydroxycyclohexyl} -3-[(R) -1- (tert-
Butyldimethylsilyloxy) ethyl] azetidine-2
-ON

[0162]

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(S) -1-allyloxycarbonyl-3
-The title compound (1.03 g) was obtained in the same manner as in Example 1- (1) using -mercaptomethylpiperidine (1.1 g).

Infrared absorption spectrum (neat) ν max cm
^-1 : 3425, 3291, 2931, 2856, 1743, 1683, 1442, 126
0. Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δppm: 0.09
(6H, s), 0.89 (9H, s), 1.28 (3H, d, J = 6.9 Hz), 1.4
2-1.69 (10H, m), 1.90-2.10 (3H, m), 2.46 (2H, d, J
= 6.2 Hz), 2.85 (1H, br s), 2.95 (2H, d, J = 5.7Hz),
2.67-3.07 (1H, m), 3.65 (1H, d, J = 4.8Hz), 3.92 (1H,
br s), 3.78-4.22 (3H, m), 4.59 (2H, d, J = 5.5Hz), 5.
21 (1H, d, J = 10.5Hz), 5.30 (1H, d, J = 17.2Hz), 5.93
(1H, brs), 5.89-6.01 (1H, m). (2) (3S, 4R) -4-{(1R, 3S) -3-
[(S) -1-allyloxycarbonylpiperidine-3
-Ylmethylthio] -2-oxocyclohexyl} -3
-[(R) -1- (tert-butyldimethylsilyloxy) ethyl] azetidin-2-one

[0165]

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The compound obtained in Example 3- (1) (1.
The oily title compound (1.03 g) was obtained in the same manner as in Example 1- (2) using Compound (02g).

Infrared absorption spectrum (neat) ν max cm
^-1 : 3280, 2934, 2857, 1760, 1702, 1471, 1441. Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δppm: 0.07
(3H, s), 0.08 (3H, s), 0.88 (9H, s), 1.26 (3H, d, J =
6.1 Hz), 1.11-1.29 (1H, m), 1.40-2.21 (11H, m), 2.
27-2.42 (2H, m), 2.50-2.65 (1H, m), 2.79-2.92 (2H, m
m), 3.28-3.31 (1H, m), 3.43-3.51 (1H, m), 3.95-4.0
1 (1H, m), 4.03-4.23 (2H, m), 4.59 (2H, d, J = 5.4H
z), 5.21 (1H, d, J = 10.5Hz), 5.30 (1H, d, J = 17.4H
z), 5.70 (1H, brs), 5.87-6.01 (1H, m). (3) (3S, 4R) -1-allyloxalyl-4-
{(1R, 3S) -3-[(S) -1-allyloxycarbonylpiperidin-3-ylmethylthio] -2-oxocyclohexyl} -3-[(R) -1- (tert-
Butyldimethylsilyloxy) ethyl] azetidine-2
-ON

[0168]

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The compound obtained in Example 3- (2) (1.
In the same manner as in Example 1- (3), the title compound (1.01 g) was obtained in the form of a powder.

Infrared absorption spectrum (KBr) ν max
cm ^-1 : 2934, 1808, 1755,
1694, 1680, 1395, 1253. Nuclear magnetic resonance spectrum (270 MHz, CDCl
₃ ) δppm: 0.04 (3H, s), 0.07 (3H, s), 0.85 (9H,
s), 1.20 (3H, d, J = 6.3 Hz), 1.09-1.29 (1H, m), 1.3
6-1.83 (8H, m), 2.02-2.17 (3H, m), 2.19-2.36 (2H, m
m), 2.48-2.61 (1H, m), 2.75-2.85 (1H, m), 3.24-3.3
4 (2H, m), 3.94-4.07 (1H, m), 4.04-4.35 (3H, m),
4.58 (2H, d, J = 5.3Hz), 4.79 (2H, d, J = 6.0Hz), 5.17-
5.43 (4H, m), 5.89-6.03 (2H, m). (4) (5S, 6R, 7R, 11S) -11-
[(S) -1-allyloxycarbonylpiperidine-3
-Ylmethylthio] -5-[(R) -1- (tert-
Butyldimethylsilyloxy) ethyl] -4-oxo-
3-azatricyclo [5.4.0.0 ^3,6 ] undeca
Allyl 1-ene-2-carboxylate

[0171]

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The compound obtained in Example 3- (3) (1.
0 g) to give the title compound (579 mg) as an oil in the same manner as in Example 1- (4).

Infrared absorption spectrum (neat) ν max cm
^-1 : 2932, 2857, 1781, 1704, 1439, 1283, 1139. Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δppm: 0.079
(3H, s), 0.084 (3H, s), 0.89 (9H, s), 1.24 (3H, d,
J = 6.1 Hz), 1.08-1.89 (12H, m), 1.97-2.05 (1H, m),
2.25-2.41 (2H, m), 2.52-2.65 (1H, m), 2.79-2.89 (1
H, m), 3.20 (1H, dd, J = 6.3,3.3Hz) 3.36-3.47 (1H, m),
3.94-4.10 (1H, m), 4.11-4.25 (2H, m), 4.59 (2H, d,
J = 5.4Hz), 4.69-4.80 (3H, m), 5.18-5.47 (3H, m),
5.88-6.02 (2H, m). -Humanperoxyethyl] -4-oxo-3-asaditricyclo [5.4.0.0
^3,6 ] Allyl undec-1-en-2-carboxylate

[0174]

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The compound (56) obtained in Example 3- (3)
0 mg) was dissolved in dimethylformamide (5 ml) and N-methylpyrrolidone (2 ml), and ammonium hydrogen fluoride (206 mg) was added, followed by stirring at room temperature for 3 days. Example 1
-Treated and purified in the same manner as (4) to give the title compound (2
45 mg).

Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ )
δppm: 1.32 (3H, d, J = 6.3 Hz), 1.11-2.05 (11H, m),
2.23-2.42 (2H, m), 2.54-2.62 (2H, m), 2.80-2.90
(1H, m), 3.25 (1H, dd, J = 6.2,3.2Hz), 3.44-3.55 (1H,
m), 3.92-4.01 (1H, m), 4.06-4.29 (3H, m), 4.59 (2H,
d, J = 5.4Hz), 4.65-4.81 (2H, m), 4.81 (1H, br s), 5.
19-5.47 (4H, m), 5.88-6.04 (2H, m). (6) (5S, 6R, 7R, 11S) -5-[(R)
-1-hydroxyethyl] -4-oxo-11-
[(S) -Piperidin- ³ -ylmethylthio] -3-azatricyclo [5.4.0.0 ^3,6 ] undec-1-en-2-carboxylic acid Compound obtained in Example 3- (5) (100 mg) and a powdery target compound (88 mg) was obtained in the same manner as in Example 1- (6).

Infrared absorption spectrum (KBr) ν max cm
^-1 : 2935, 1782, 1762, 1590, 1215. Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δppm: 1.17
(3H, d, J = 6.2 Hz), 1.12-2.00 (11H, m), 2.34 (1H, t,
J = 6.5Hz), 2.51-2.55 (1H, m), 2.57-2.58 (2H, m), 2.73
-2.78 (1H, m), 3.16 (1H, dd, J = 6.4,3.4Hz), 3.12-3.
40 (2H, m), 4.00-4.49 (2H, m), 4.86 (1H, brs). Example 4 (5S, 6R, 7R, 11S) -5-[(R) -1-hydroxyethyl]- 4-oxo-11-[(2S, 4
S) -2- (Piperazin-1-ylcarbonyl) pyrrolidin-4-ylthio] -3-azatricyclo [5.4.
0.0 ^3,6 ] undec-1-en-2-carboxylic acid (stereoisomer of Exemplified Compound I-49)

[0178]

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(1) (3S, 4R) -4-{(1R,
2S, 3S) -3-[(2S, 4S) -2- (4-allyloxycarbonylpiperazin-1-ylcarbonyl)
Pyrrolidin-4-ylthio] -2-hydroxycyclohexyl} -3-[(R) -1- (tert-butyldimethylsilyloxy) ethyl] azetidin-2-one

[0180]

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(2S, 4S) -1-allyloxycarbonyl-2- (4-allyloxycarbonylpiperazine-
The title compound (1.58 g) was obtained in the same manner as in Example 1- (1) using (1-ylcarbonyl) -4-mercaptopyrrolidine (1.72 g).

Infrared absorption spectrum (neat) ν max cm
^-1 : 3428, 3308, 1752, 1706, 1650,1353. Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δppm: 0.10 (6
H, s), 0.89 (9H, s), 1.28 (3H, d, J = 6.0 Hz), 1.42-
2.09 (8H, m), 2.13-2.18 (1H, m), 2.54-2.61 (1H, m),
2.91-2.98 (2H, m), 3.38 (1H, t, J = 10.5Hz), 3.61 (1H,
(dd, J = 6.3,2.1Hz), 3.22-3.80 (9H, br s), 3.89-3.91
(1H, m), 4.02-4.20 (2H, m), 4.61 (2H, d, J = 5.5Hz),
4.54-4.73 (3H, m), 5.16-5.34 (4H, m), 5.90 (1H, br
s), 5.86-6.01 (1H, m). (2) (3S, 4R) -4-{(1R, 3S) -3-
[(2S, 4S) -2- (4-allyloxycarbonylpiperazin-1-ylcarbonyl) pyrrolidin-4-ylthio] -2-oxocyclohexyl} -3-[(R)-
1- (tert-butyldimethylsilyloxy) ethyl] azetidin-2-one

[0183]

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The compound obtained in Example 4- (1) (1.
58g) to give the title compound (1.15 g) as a powder in the same manner as in Example 1- (2).

Infrared absorption spectrum (neat) ν max cm
^-1 : 3289, 2933, 2859, 1761, 1705,1661, 1441. Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δppm: 0.07 (3
H, s), 0.09 (3H, s), 0.88 (9H, s), 1.25 (3H, d, J =
5.5 Hz), 1.52-1.68 (1H, m), 1.73-1.91 (3H, m), 2.0
5-2.20 (3H, m), 2.41-2.53 (1H, m), 2.90 (1H, dd, J =
5.6, 2.3Hz), 3.06-3.19 (1H, m), 3.33-3.80 (11H, m),
4.08-4.24 (3H, m), 4.61 (2H, d, J = 5.8Hz), 4.52-4.7
1 (3H, m), 5.16-5.34 (4H, m), 5.68 (1H, br s), 5.85
-6.01 (2H, m). (3) (3S, 4R) -1-allyloxalyl-4-
｛(1R, 3S) -3-[(2S, 4S) -2- (4-
Allyloxycarbonylpiperazin-1-ylcarbonyl) pyrrolidin-4-ylthio] -2-oxocyclohexyl} -3-[(R) -1- (tert-butyldimethylsilyloxy) ethyl] azetidin-2-one

[0186]

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The compound obtained in Example 4- (2) (1.
14g) to give the title compound (856 mg) in the form of a powder in the same manner as in Example 1- (3).

Infrared absorption spectrum (KBr) ν max cm ^-1 :
2935, 2860, 1809, 1755, 1704, 1662, 1409. Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δppm: 0.03,0.
04 (3H, sx2), 0.06,0.07 (3H, sx2), 0.85 (9H, s), 1.1
8 (3H, d, J = 6.3 Hz), 1.43-1.81 (3H, m), 1.97-2.20
(4H, m), 2.49-2.55 (1H, m), 2.88-2.96 (1H, m), 3.28
-3.73 (12H, m), 4.05-4.14 (1H, m), 4.24-4.56 (3H,
m), 4.57-4.70 (4H, m), 4.78 (2H, d, J = 6.0Hz), 5.1
9-5.44 (6H, m), 5.89-6.03 (3H, m). (4) (5S, 6R, 7R, 11S) -11-[(2
(S, 4S) -2- (4-allyloxycarbonylpiperazin-1-ylcarbonyl) pyrrolidin-4-ylthio] -5-[(R) -1- (tert-butyldimethylsilyloxy) ethyl] -4-oxo -3-azatricyclo [5.4.0.0 ^3,6 ] undec-1-en-2-
Allyl carboxylate

[0189]

Embedded image

The compound (84) obtained in Example 4- (3)
5 mg) to give the title compound (502 mg) as an oil in the same manner as in Example 1- (4).

Infrared absorption spectrum (KBr) ν max cm ^-1 :
2931, 2858, 1781, 1709, 1663, 1411. Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δppm: 0.08 (6
H, s), 0.89 (9H, s), 1.22 (3H, d, J = 6.0 Hz), 1.21-
1.44 (1H, m), 1.67-1.88 (5H, m), 1.96-2.05 (1H, m),
2.44-2.57 (1H, m), 3.09-3.17 (1H, m), 3.21 (1H, dd, J
= 6.0,3.4Hz), 3.37 (1H, t, J = 10.2Hz), 3.31-3.77 (10H,
m), 4.11-4.26 (3H, m), 4.59 (2H, d, J = 5.8Hz), 4.5
1-4.79 (4H, m), 4.91 (1H, s), 5.15-5.50 (6H, m), 5.
85-6.01 (3H, m). (5) (5S, 6R, 7R, 11S) -11-[(2
[S, 4S) -2- (4-allyloxycarbonylpiperazin-1-ylcarbonyl) pyrrolidin-4-ylthio] -5-[(R) -1-hydroxyethyl] -4-oxo-3-azatricyclo [5. 4.0.0 ^3,6 ] allyl undec-1-en-2-carboxylate

[0192]

Embedded image

The compound (49) obtained in Example 4- (4)
0 mg) to give the title compound (250 mg) as a powder in the same manner as in Example 3- (5).

Infrared absorption spectrum (KBr) ν max cm ^-1 :
3440, 2934, 2863, 1778, 1706, 1661, 1412, 1285. Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δppm: 1.32 (3
H, d, J = 6.3 Hz), 1.26-1.43 (1H, m), 1.69-2.09 (5H,
m), 2.42-2.55 (1H, m), 3.07-3.16 (1H, m), 3.25 (1H,
dd, J = 6.2,3.2Hz), 3.36 (1H, t, J = 10.3Hz), 3.31-3.79
(10H, m), 4.09-4.30 (3H, m), 4.61 (2H, d, J = 5.4H
z), 4.50-4.83 (4H, m), 4.93 (1H, br s), 5.17-5.49 (6
H, m), 5.85-6.02 (3H, m). (6) (5S, 6R, 7R, 11S) -5-[(R)
-1-hydroxyethyl] -4-oxo-11-[(2
(S, 4S) -2- (piperazin-1-ylcarbonyl)
Pyrrolidin-4-ylthio] -3-azatricyclo [5.4.0.0 ^3,6 ] undec-1-en-2-carboxylic acid Using the compound (243 mg) obtained in Example 4- (5). A powdery target compound (119 mg) was obtained in the same manner as in Example 1- (6).

Infrared absorption spectrum (KBr) ν max cm ^-1 :
3405, 2929, 1760, 1645, 1591, 1385, 1247. Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δppm: 1.27 (3
H, d, J = 6.3 Hz), 1.33-1.44 (1H, m), 1.64-1.98 (6H,
m), 2.69-2.76 (1H, m), 3.12-3.19 (5H, m), 3.33-3.44
(3H, m), 3.46 (1H, dd, J = 5.7,3.2Hz), 3.67-3.84 (4H,
m), 4.19 (1H, dd, J = 10.6,3.3Hz), 4.25 (1H, quint, J
= 6.2Hz), 4.38 (1H, dd, J = 9.0,6.9Hz), 4.82-4.84 (1H,
m) Example 5 (5S, 6R, 7R, 11S) -5-[(R) -1-hydroxyethyl] -4-oxo-11-[(S) -pyrrolidin-2-ylmethylthio] -3-azatricyclo [5.4.0.0 ^3,6 ] undec-1-en-2-carboxylic acid (stereoisomer of exemplified compound I-43)

[0196]

Embedded image

(1) (3S, 4R) -4-{(1R,
2S, 3S) -3-[(S) -1-allyloxycarbonylpyrrolidin-2-ylmethylthio] -2-hydroxycyclohexyl} -3-[(R) -1- (tert-
Butyldimethylsilyloxy) ethyl] azetidine-2
-ON

[0198]

Embedded image

(S) -1-allyloxycarbonyl-2
-Mercaptomethylpyrrolidine (1.38 g) in the same manner as in Example 1- (1), using the title compound (1.
65 g) were obtained.

Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δ
ppm: 0.09 (6H, s), 0.89 (9H, s), 1.27 (3H, d, J = 5.6
Hz), 1.39-2.17 (10H, m), 2.30-2.50 (2H, m), 2.94 (1
H, dd, J = 6.0,1.2Hz), 2.79-3.14 (2H, m), 3.41-3.45 (2
H, m), 3.65-3.69 (1H, m), 3.94-4.08 (2H, m), 4.08-4.2
4 (1H, m), 4.58 (2H, d, J = 5.1Hz), 5.22 (1H, d, J = 10.1
Hz), 5.31 (1H, d, J = 18.6Hz), 5.93 (1H, br s), 5.24-
5.87 (1H, m). (2) (3S, 4R) -4-{(1R, 3S) -3-
[(S) -1-allyloxycarbonylpyrrolidine-2
-Ylmethylthio] -2-oxocyclohexyl} -3
-[(R) -1- (tert-butyldimethylsilyloxy) ethyl] azetidin-2-one

[0201]

Embedded image

The compound obtained in Example 5- (1) (1.
The powdery title compound (1.46 g) was obtained in the same manner as in Example 1- (2) using the above compound (64 g).

Infrared absorption spectrum (KBr) ν max cm ^-1 :
3276, 2952, 2858, 1758, 1704, 1406, 1105. Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δppm: 0.07
(3H, s), 0.08 (3H, s), 0.88 (9H, s), 1.26 (3H, d, J =
6.2 Hz), 1.44-2.21 (10H, m), 2.32-2.48 (1H, m), 2.
76-2.85 (1H, m), 2.91 (1H, dd, J = 5.3,3.6Hz), 3.40-
3.47 (4H, m), 3.94-3.99 (1H, m), 4.09 (1H, br s),
4.10-4.23 (1H, m), 4.58-4.64 (2H, m), 5.20-5.34 (2H,
m), 5.69 (1H, brs), 5.89-6.02 (1H, m). (3) (3S, 4R) -1-allyloxalyl-4-
{(1R, 3S) -3-[(S) -1-allyloxycarbonylpyrrolidin-2-ylmethylthio] -2-oxocyclohexyl} -3-[(R) -1- (tert-
Butyldimethylsilyloxy) ethyl] azetidine-2
-ON

[0204]

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The compound obtained in Example 5- (2) (1.
45 g) to give the title compound (1.39 g) as an oil in the same manner as in Example 1- (3).

Infrared absorption spectrum (neat) ν max cm
^-1 : 2952, 2859, 1808, 1756, 1703,1401, 1214. Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δppm: 0.03
(3H, s), 0.07 (3H, s), 0.85 (9H, s), 1.22 (3H, d, J
= 7.3 Hz), 1.41-2.20 (10H, m), 2.24-2.41 (1H, m),
2.71-2.91 (1H, m), 3.29 (1H, br s), 3.35-3.44 (3H,
m), 3.88-4.11 (1H, m), 4.12-4.21 (1H, m), 4.26-4.35
(2H, m), 4.57-4.61 (2H, m), 4.78 (2H, d, J = 6.0Hz),
5.18-5.88 (4H, m), 5.90-6.01 (2H, m). (4) (5S, 6R, 7R, 11S) -11-
[(S) -1-allyloxycarbonylpyrrolidine-2
-Ylmethylthio] -5-[(R) -1- (tert-
Butyldimethylsilyloxy) ethyl] -4-oxo-
3-azatricyclo [5.4.0.0 ^3,6 ] undeca
Allyl 1-ene-2-carboxylate

[0207]

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The compound obtained in Example 5- (3) (1.
387 g) to give the title compound (808 mg) as an oil in the same manner as in Example 1- (4).

Infrared absorption spectrum (neat) ν max cm
^-1 : 2931, 2857, 1781, 1706, 1403,1284. Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δppm: 0.08 (6
H, s), 0.89 (9H, s), 1.23 (3H, d, J = 6.1 Hz), 1.29-
1.42 (1H, m), 1.68-2.05 (9H, m), 2.39-2.60 (1H, m),
2.89-2.95 (1H, m), 3.17 (1H, dd, J = 6.1,3.1Hz), 3.34-
3.51 (3H, m), 3.94-4.04 (1H, m), 4.08-4.25 (2H, m),
4.57-4.83 (4H, m), 4.90 (1H, brs) 5.17-5.47 (4H, m),
5.88-6.01 (2H, m). (5) (5S, 6R, 7R, 11S) -11-
[(S) -1-allyloxycarbonylpyrrolidine-2
-Ylmethylthio] -5-[(R) -1-hydroxyethyl] -4-oxo-3-azatricyclo [5.4.
0.0 ^3,6 ] allyl undec-1-en-2-carboxylate

[0210]

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The compound (80) obtained in Example 5- (4)
8 mg) to give the title compound (447 mg) as an oil in the same manner as in Example 3- (5).

Infrared absorption spectrum (neat) ν max cm
^-1 : 3439, 2936, 1777, 1705, 1285,1195. Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δppm: 1.33 (3
H, d, J = 6.1 Hz), 1.38-1.44 (1H, m), 1.68-2.04 (9H,
m), 2.35-2.59 (1H, m), 2.90-3.01 (1H, m), 3.22 (1H,
dd, J = 6.4,3.1Hz), 3.35-3.52 (3H, m), 3.96-4.19 (1H,
m), 4.20 (1H, dd, J = 10.4,3.1Hz), 4.24 (1H, quint, J =
6.2Hz), 4.51-4.86 (4H, m), 4.89-4.91 (1H, m), 5.18-5.
47 (4H, m), 5.87-6.03 (2H, m). (6) (5S, 6R, 7R, 11S) -5-[(R)
-1-hydroxyethyl] -4-oxo-11-
[(S) -Pyrrolidin-2-ylmethylthio] -3-azatricyclo [5.4.0.0 ^3,6 ] undec-1-en-2-carboxylic acid Compound obtained in Example 5- (5) (430 mg) and a powdery target compound (170 mg) was obtained in the same manner as in Example 1- (6).

Infrared absorption spectrum (KBr) ν max cm ^-1 :
3402, 2930, 1762, 1587, 1348, 1215. Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δppm: 1.29
(3H, d, J = 6.6 Hz), 1.30-1.42 (1H, m), 1.76-2.14 (10
H, m) 2.20-2.34 (1H, m), 2.70-2.90 (1H, m), 3.39 (1H, m
dd, J = 11.8, 6.6Hz), 3.34-3.48 (4H, m), 3.73-3.78 (1
H, m), 4.21-4.29 (2H, m), 4.90 (1H, brs). Example 6 (5S, 6R, 7R, 11S) -5-[(R) -1-hydroxyethyl] -4- Oxo-11-[(R) -pyrrolidin-3-ylmethylthio] -3-azatricyclo [5.4.0.0 ^3,6 ] undec-1-en-2-carboxylic acid (steric of exemplified compound I-36) Isomer)

[0214]

Embedded image

(1) (3S, 4R) -4-{(1R,
2S, 3S) -3-[(R) -1-allyloxycarbonylpyrrolidin-3-ylmethylthio] -2-hydroxycyclohexyl} -3-[(R) -1- (tert-
Butyldimethylsilyloxy) ethyl] azetidine-2
-ON

[0216]

Embedded image

(R) -3-acetylthiomethyl-1-allyloxycarbonylpyrrolidine (700 mg) was added to (3
S, 4R) -4-[(1R, 2S, 3R) -2,3-epoxycyclohexyl] -3-[(R) -1- (ter
[t-butyldimethylsilyloxy) ethyl] azetidin-2-one (624 mg) and ethylenediamine (1.9)
2 ml) and stirred at 60 ° C. for 3 hours. Example 1
The title compound (6) was treated and purified in the same manner as (1) to give a powder of the title compound (6).
90 mg).

Infrared absorption spectrum (KBr) ν max cm ^-1 :
3451, 2929, 1755, 1686, 1445, 1413. Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δppm: 0.10
(6H, s), 0.89 (9H, s), 1.28 (3H, d, J = 6.2 Hz), 1.4
4-1.76 (6H, m), 1.90-2.14 (3H, m), 2.34-2.44 (1H,
m), 2.54-2.64 (2H, m), 2.90-2.95 (2H, m), 3.11-3.16
(1H, m), 3.34-3.44 (1H, m), 3.44-3.55 (1H, m), 3.56-
3.69 (2H, m), 3.90-3.91 (1H, m), 4.08-4.22 (1H, m),
4.59 (2H, d, J = 5.4Hz), 5.21 (1H, d, J = 9.4Hz), 5.31 (1
H, d, J = 15.7Hz), 5.87 (1H, brs), 5.87-6.02 (1H, m). (2) (3S, 4R) -4-{(1R, 3S) -3-
[(R) -1-allyloxycarbonylpyrrolidine-3
-Ylmethylthio] -2-oxocyclohexyl} -3
-[(R) -1- (tert-butyldimethylsilyloxy) ethyl] azetidin-2-one

[0219]

Embedded image

The compound (69) obtained in Example 6- (1)
0 mg) to give the title compound (470 mg) as an oil in the same manner as in Example 1- (2).

Infrared absorption spectrum (neat) ν max cm
^-1 : 3275, 2934, 2858, 1760, 1704,1410, 1106. Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δppm: 0.07
(3H, s), 0.08 (3H, s), 0.88 (9H, s), 1.26 (3H, d, J =
6.2 Hz), 1.54-2.19 (8H, m), 2.34-2.52 (3H, m), 2.90
(1H, dd, J = 5.8,2.4Hz), 3.05-3.10 (1H, m), 3.32-3.6
2 (5H, m), 4.08-4.21 (2H, m), 4.59 (2H, d, J = 5.4H
z), 5.23 (1H, dd, J = 11.1,1.8Hz), 5.31 (1H, dd, J = 3.
2,1.3Hz), 5.69 (1H, brs), 5.89-6.00 (1H, m). (3) (3S, 4R) -1-allyloxalyl-4-
{(1R, 3S) -3-[(R) -1-allyloxycarbonylpyrrolidin-3-ylmethylthio] -2-oxocyclohexyl} -3-[(R) -1- (tert-
Butyldimethylsilyloxy) ethyl] azetidine-2
-ON

[0222]

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The compound (46) obtained in Example 6- (2)
0 mg) to give the title compound (287 mg) as an oil in the same manner as in Example 1- (3).

Infrared absorption spectrum (neat) ν max cm
^-1 : 2934, 2859, 1809, 1756, 1703,1409, 1215. Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δppm: 0.04
(3H, s), 0.07 (3H, s), 0.85 (9H, s), 1.20 (3H, d, J
= 6.4 Hz), 1.44-1.82 (4H, m), 1.97-2.17 (5H, m), 2.
30-2.48 (2H, m), 3.00-3.08 (1H, m), 3.30-3.39 (3H,
m), 3.42-3.61 (2H, m), 4.23-4.33 (2H, m), 4.58 (2H,
dd, J = 5.3, 1.3Hz), 4.76-4.80 (2H, m), 5.13-5.46 (4
H, m), 5.87-6.03 (2H, m). (4) (5S, 6R, 7R, 11S) -11-
[(R) -1-allyloxycarbonylpyrrolidine-3
-Ylmethylthio] -5-[(R) -1- (tert-
Butyldimethylsilyloxy) ethyl] -4-oxo-
3-azatricyclo [5.4.0.0 ^3,6 ] undeca
Allyl 1-ene-2-carboxylate

[0225]

Embedded image

The compound (28) obtained in Example 6- (3)
0 mg) to give the title compound (42 mg) in the same manner as in Example 1- (4).

(5) (5S, 6R, 7R, 11S)-
11-[(R) -1-allyloxycarbonylpyrrolidin-3-ylmethylthio] -5-[(R) -1-hydroxyethyl] -4-oxo-3-azatricyclo [5.
4.0.0 ^3,6 ] allyl undec-1-en-2-carboxylate

[0228]

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The compound (40) obtained in Example 6- (4)
mg) to give the title compound (27 mg) in the same manner as in Example 3- (5).

Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ )
δppm: 1.33 (3H, d, J = 6.2 Hz), 1.41-2.17 (6H, m),
2.36-2.57 (3H, m), 3.01-3.08 (1H, m), 3.25 (1H, dd,
J = 5.7,3.3Hz), 3.31-3.61 (5H, m), 3.85 (1H, dd, J = 10.
4, 3.2Hz), 4.25 (1H, quint, J = 6.8Hz), 4.59 (2H, d, J
= 5.4Hz), 4.65-4.86 (3H, m), 5.18-5.48 (4H, m), 5.88-
6.04 (2H, m). (6) (5S, 6R, 7R, 11S) -5-[(R)
-1-hydroxyethyl] -4-oxo-11-
[(R) -Pyrrolidin- ³ -ylmethylthio] -3-azatricyclo [5.4.0.0 ^3,6 ] undec-1-en-2-carboxylic acid Compound obtained in Example 6- (5) (25 mg) and a powdery target compound (10 mg) was obtained in the same manner as in Example 1- (6).

Infrared absorption spectrum (KBr) ν max cm ^-1 :
3382, 2929, 1759, 1600, 1389. Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δppm: 1.27
(3H, d, J = 6.4 Hz), 1.31-1.40 (1H, m), 1.67-1.97 (6
H, m) 2.23-2.27 (1H, m), 2.54-2.60 (3H, m), 2.93-3.01
(1H, m), 3.25-3.49 (5H, m), 4.21 (1H, dd, J = 9.5, 3.2
Hz), 4.25 (1H, quint, J = 6.3 Hz). Example 7 (5S, 6R, 7R, 11S) -5-[(R) -1-hydroxyethyl] -4-oxo-11-[(S ) -Pyrrolidin- ³ -ylmethylthio] -3-azatricyclo [5.4.0.0 ^3,6 ] undec-1-en-2-carboxylic acid (Exemplified Compound I-36)

[0232]

Embedded image

(1) (3S, 4R) -4-{(1R,
2S, 3S) -3-[(S) -1-allyloxycarbonylpyrrolidin-3-ylmethylthio] -2-hydroxycyclohexyl} -3-[(R) -1- (tert-
Butyldimethylsilyloxy) ethyl] azetidine-2
-ON

[0234]

Embedded image

Using (S) -3-acetylthiomethyl-1-allyloxycarbonylpyrrolidine (1.0 g), the title compound (1.07 g) was obtained in the form of a powder in the same manner as in Example 6- (1). Obtained.

Infrared absorption spectrum (KBr) ν max cm ^-1 :
3424, 3285, 2931, 2857, 1740, 1706, 1685, 1412. Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δppm: 0.10
(6H, s), 0.89 (9H, s), 1.28 (3H, d, J = 6.1 Hz), 1.4
2-1.73 (6H, m), 1.95-2.13 (2H, m), 2.34-2.43 (1H,
m), 2.52-2.65 (2H, m), 2.87-2.95 (2H, m), 3.07-3.20
(1H, m), 3.34-3.48 (1H, m), 3.48-3.58 (1H, m), 3.60-
3.69 (2H, m), 3.92 (1H, brs), 4.10-4.20 (1H, m), 4.59
(2H, d, J = 5.7Hz), 5.21 (1H, d, J = 10.1Hz), 5.31 (1H,
(dd, J = 17.2, 1.7Hz), 5.88-6.02 (2H, m). (2) (3S, 4R) -4 -− (1R, 3S) -3-
[(S) -1-allyloxycarbonylpyrrolidine-3
-Ylmethylthio] -2-oxocyclohexyl} -3
-[(R) -1- (tert-butyldimethylsilyloxy) ethyl] azetidin-2-one

[0237]

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The compound obtained in Example 7- (1) (1.
06g) to give the title compound as an oil (1.07 g) in the same manner as in Example 1- (2).

Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ )
δppm: 0.07 (3H, s), 0.08 (3H, s), 0.88 (9H, s), 1.2
6 (3H, d, J = 6.3 Hz), 1.70-2.21 (8H, m), 2.35-2.56
(3H, m), 2.90 (1H, dd, J = 5.9,2.2Hz), 3.05-3.09 (1H,
m), 3.33-3.68 (5H, m), 4.08-4.23 (2H, m), 5.21 (1
H, d, J = 10.4Hz), 5.30 (1H, dd, J = 17.2,1.34Hz), 5.70
(1H, brd, J = 7.8 Hz), 5.89-6.00 (1H, m). (3) (3S, 4R) -1-allyloxalyl-4-
{(1R, 3S) -3-[(S) -1-allyloxycarbonylpyrrolidin-3-ylmethylthio] -2-oxocyclohexyl} -3-[(R) -1- (tert-
Butyldimethylsilyloxy) ethyl] azetidine-2
-ON

[0240]

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The compound (60) obtained in Example 7- (2)
0 mg) to give the title compound (438 mg) as an oil in the same manner as in Example 1- (3).

Infrared absorption spectrum (neat) ν max cm
^-1 : 2933, 2859, 1808, 1756, 1704,1409, 1215. Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δppm: 0.04
(3H, s), 0.07 (3H, s), 0.85 (9H, s), 1.20 (3H, d, J
= 6.4 Hz), 1.44-1.80 (8H, m), 2.33-2.37 (3H, m), 3.02
-3.09 (1H, m), 3.28-3.64 (5H, m), 4.23-4.33 (3H, m),
4.58 (2H, d, J = 5.4Hz), 4.79 (2H, d, J = 6.0Hz), 5.18
-5.43 (4H, m), 5.89-6.01 (2H, m). (4) (5S, 6R, 7R, 11S) -11-
[(S) -1-allyloxycarbonylpyrrolidine-3
-Ylmethylthio] -5-[(R) -1- (tert-
Butyldimethylsilyloxy) ethyl] -4-oxo-
3-azatricyclo [5.4.0.0 ^3,6 ] undeca
Allyl 1-ene-2-carboxylate

[0243]

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The compound (42) obtained in Example 7- (3)
3 mg) to give the title compound (144 mg) in the same manner as in Example 1- (4).

Infrared absorption spectrum (neat) ν max cm
^-1 : 2932, 2858, 1781, 1709, 1283, 1196. Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δppm: 0.06
(6H, s), 0.89 (9H, s), 1.23 (3H, d, J = 6.1 Hz), 1.3
1-2.07 (8H, m), 2.37-2.56 (3H, m), 3.03-3.12 (1H,
m), 3.20 (1H, d, J = 6.2, 3.4Hz), 3.32-3.70 (4H, m),
4.11-4.25 (2H, m), 4.59 (2H, d, J = 5.5Hz), 4.62-4.80 (2
H, m), 4.85 (1H, br s), 5.18-5.47 (4H, m), 5.88-6.04
(5H, m). ] -4-oxo-3-asaditricyclo [5.4.0.0
^3,6 ] Allyl undec-1-en-2-carboxylate

[0246]

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The compound (14) obtained in Example 7- (4)
0 mg) to give the title compound as an oil (84 mg) in the same manner as in Example 3- (5).

Infrared absorption spectrum (neat) ν max cm
^-1 : 3436, 2936, 1779, 1707, 1445, 1195, 1135. Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δppm: 1.32
(3H, d, J = 6.2 Hz), 1.27-2.05 (8H, m), 2.34-2.56 (3
H, m), 3.02-3.09 (1H, m), 3.25 (1H, dd, J = 6.5,3.5H
z), 3.28-3.67 (4H, m), 4.21-4.32 (2H, m), 4.59 (2H,
d, J = 5.3Hz), 4.62-4.86 (3H, m), 5.18-5.47 (4H, m),
5.88-6.04 (2H, m). (6) (5S, 6R, 7R, 11S) -5-[(R)
-1-hydroxyethyl] -4-oxo-11-
[(S) -Pyrrolidin- ³ -ylmethylthio] -3-azatricyclo [5.4.0.0 ^3,6 ] undec-1-en-2-carboxylic acid Compound obtained in Example 7- (5) (81 mg) and a powdery target compound (47 mg) was obtained in the same manner as in Example 1- (6).

Infrared absorption spectrum (KBr) ν max cm ^-1 :
3379, 2930, 1763, 1587, 1389. Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δppm: 1.27
(3H, d, J = 6.4 Hz), 1.36-1.45 (1H, m), 1.67-1.85 (3
H, m) 1.85-1.93 (3H, m), 2.16-2.24 (1H, m), 2.50-2.6
3 (3H, m), 2.99 (1H, dd, J = 11.8, 7.9Hz), 3.27-3.55 (6
H, m), 4.21 (1H, dd, J = 10.6, 3.3Hz), 4.24 (1H, quin
Example 8, (5S, 6R, 7R, 11S) -11- (1-acetimidoylazetidin-3-ylthio) -5-[(R)-
1-hydroxyethyl] -4-oxo-3-azatricyclo [5.4.0.0 ^3,6 ] undec-1-en-2-
Carboxylic acid (stereoisomer of Exemplified Compound I-4)

[0250]

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Using 1- (N-allyloxycarbonylacetimidoyl) -3-mercaptoazetidine, Examples 1- (1), (2), (3), (4), (5),
The title compound can be obtained in the same manner as in (6).

Example 9 (5S, 6R, 7R, 11S) -11- (1-amidinoazetidin-3-ylthio) -5-[(R) -1-hydroxyethyl] -4-oxo-3-azatricyclo [5.4.0.0 ^3,6 ] undec-1-en-2-carboxylic acid (stereoisomer of exemplified compound I-5)

[0253]

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Using 1- [N, N-bis (allyloxycarbonyl) amidino] -3-mercaptoazetidine, Examples 1- (1), (2), (3), (4),
The title compound can be obtained in the same manner as in (5) and (6).

Example 10 (5S, 6R, 7R, 11S) -11- (1-Formimidoylazetidin-3-ylthio) -5-[(R)-
1-hydroxyethyl] -4-oxo-3-azatricyclo [5.4.0.0 ^3,6 ] undec-1-en-2-
Carboxylic acid (stereoisomer of exemplified compound I-3)

[0256]

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Using 1- (N-allyloxycarbonylformimidyl) -3-mercaptoazetidine, Examples 1- (1), (2), (3), (4), (5),
The title compound can be obtained in the same manner as in (6).

Example 11 (5S, 6R, 7R, 11S) -11-[(S) -1-
Acetimidylpyrrolidin-3-ylthio) -5
[(R) -1-hydroxyethyl] -4-oxo-3-
Azatricyclo [5.4.0.0 ^3,6 ] undeca-1-
Ene-2-carboxylic acid (stereoisomer of Exemplified Compound I-11)

[0259]

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Using (S) -1- (N-allyloxycarbonylacetimidoyl) -3-mercaptopyrrolidine, Examples 1- (1), (2), (3), (4),
The title compound can be obtained in the same manner as in (5) and (6).

Example 12 (5S, 6R, 7R, 11S) -11-[(S) -1-
Amidinopyrrolidin-3-ylthio) -5-[(R)-
1-hydroxyethyl] -4-oxo-3-azatricyclo [5.4.0.0 ^3,6 ] undec-1-en-2-
Carboxylic acid (stereoisomer of Exemplified Compound I-12)

[0262]

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Using (S) -1-[(N, N′-bis (allyloxycarbonyl) amidino] -3-mercaptopyrrolidine, Examples 1- (1), (2), (3),
The title compound can be obtained in the same manner as in (4), (5) and (6).

Example 13 (5S, 6R, 7R, 11S) -11-[(S) -1-
Formimidoylpyrrolidin-3-ylthio) -5
[(R) -1-hydroxyethyl] -4-oxo-3-
Azatricyclo [5.4.0.0 ^3,6 ] undeca-1-
Ene-2-carboxylic acid (stereoisomer of Exemplified Compound I-10)

[0265]

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Using (S) -1- (N-allyloxycarbonylformidoyl) -3-mercaptopyrrolidine, Examples 1- (1), (2), (3), (4),
The title compound can be obtained in the same manner as in (5) and (6).

Example 14 (5S, 6R, 7R, 10RS) -5-[(R) -1-
Hydroxyethyl] -4-oxo-10-[(S) -pyrrolidin-3-ylthio] -3-azatricyclo [5.
3.0.0 ^3,6 ] dec-1-en-2-carboxylic acid (stereoisomer of exemplified compound I-81)

[0268]

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(1) (3S, 4R) -4-{(1R
S, 3RS) -1-[(S) -1-allyloxycarbonylpyrrolidin-3-ylthio] -2-oxocyclopentyl} -3-[(R) -1- (tert-butyldimethylsilyloxy) ethyl] azetidine -2-one

[0270]

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1M lithium hexamethyldisilazane 80
to a 180 ml solution of
(RS) -2-[(S) -1-allyloxycarbonylpyrrolidin-3-ylthio] cyclopentanone 9 at 8 ° C
g (39.9 mmol) of tetrahydrofuran 30 ml
The solution was added dropwise. The reaction mixture was stirred at -78 ° C for 30 minutes, then (3S, 4R) -4-acetoxy-3-
[(R) -1- (tert-butyldimethylsilyloxy) ethyl] -2-azetidinone 8.8 g (30.6 m
mol) of tetrahydrofuran in 100 ml.
It was added dropwise at ° C. The resulting mixture was stirred for 70 minutes and then quenched with saturated ammonium chloride solution (100ml). The resulting mixture was extracted three times with 150 ml of ethyl acetate. The ethyl acetate was washed with brine, dried over magnesium sulfate, filtered and evaporated to 15 g of an oil (98 g).
%). The residue was purified by flash chromatography on silica gel using a gradient of hexane to 100% ethyl acetate. This gave 7.2 g (47%) of the earlier-eluting isomer of the title compound with the later-eluting isomer of 4.
8 g (31%) were obtained.

(Isomer which eluted early)

[0273]

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Nuclear magnetic resonance spectrum (300 MHz, CDCl ₃ )
δ: -0.085 (3H, s), -0.080 (3H, s), 0.80 (9H, s),
1.08 (3H, d, J = 6.3 Hz), 1.60 (2H, m), 1.7-2.2 (5
H, m), 2.50 (1H, q), 2.85 (1H, s), 3.15 (2H, m),
3.35 (2H, q), 3.66 (1H, dd), 3.80 (1H, d), 4.05 (1
H, m), 4.40 (2H, dd), 5.08 (2H, ddd), 5.79 (1H,
m), 6.9 (1H, d) Infrared absorption spectrum (NEAT) ν max cm ^-1 : 2931, 174
9, 1709,1409. (Isomer that eluted late)

[0275]

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Nuclear magnetic resonance spectrum (300 MHz, CDCl ₃ )
δ: -0.08 (3H, s), 0.00 (3H, s), 0.80 (9H, s), 1.20
(3H, d, J = 6.3 Hz), 1.60 (1H, dd), 3.05 (1H, q),
3.15-3.55 (3H, m), 3.61 (1H, dd), 4.20 (2H, s), 4.5
0 (2H, d), 5.16 (2H, ddd), 5.85 (1H, m), 6.10 (1H,
d). Infrared absorption spectrum (NEAT) ν max cm ^-1 : 2930, 177
7, 1709, 1409. (2) (3S, 4R) -1-allyloxalyl-4-
{(1S, 3RS) -3-[(S) -1-allyloxycarbonylpyrrolidin-3-ylthio] -2-oxocyclopentyl} -3-[(R) -1- (tert-butyldimethylsilyloxy) ethyl Azetidin-2-one (isomer which eluted early)

[0277]

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To a solution of 3.3 g (6.6 mmol) of the rapidly eluted isomer obtained in Example 14- (1) in 25 ml of dry dichloromethane, 5 ml of pyridine and 5.3 ml (37 mmol) of triethylamine were added. This solution is
The mixture was cooled to -10 ° C under an argon atmosphere, and 3.4 g (22.8 mmol) of allyl oxalyl chloride was added. The solution was stirred under an argon atmosphere and left to room temperature over 4 hours. 25 ml of dichloromethane was added, and the reaction mixture was washed with 50 ml of cold 1N hydrochloric acid, 50 ml of a saturated sodium hydrogen carbonate solution and 50 ml of brine. The dichloromethane solution was dried over magnesium sulfate, filtered and evaporated to give the title compound (4.0 g, 99%) as an oil.

Nuclear magnetic resonance spectrum (300 MHz, CDCl ₃ )
δ: 0.00 (3H, s), 0.07 (3H, s), 0.84 (9H, s), 1.25
(3H, d, J = 6.4), 1.75 (1H, m), 1.9-2.4 (6H, m),
2.60 (1H, m), 3.3-3.6 (4H, m), 3.88 (1H, dd), 4.33
(1H, ddd), 4.58 (2H, d), 4.78 (4H, m), 5.15-5.45 (4
H, m), 5.95 (2H, m). (3) (5S, 6R, 7R, 10RS)
[(S) -1-allyloxycarbonylpyrrolidine-3
-Ylthio] -5-[(R) -1- (tert-butyldimethylsilyloxy) ethyl] -4-oxo-3-azatricyclo [5.3.0.0 ^3,6 ] dec-1-en-
Allyl 2-carboxylate

[0280]

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Compound 4 obtained in Example 14- (2)
To a solution of 0 g (6.6 mmol) in 105 ml of toluene,
Hydroquinone 12mg and triethyl phosphite 5m
1 was added. The mixture was refluxed for 18 hours under an atmosphere of argon. The toluene solution was evaporated to dryness. The residue was dissolved in 100 ml of dichloromethane, washed with 50 ml of brine, dried over magnesium sulfate, filtered and evaporated to dryness to give 4.0 g (105%) of the compound. Residue, 5
Purification by flash chromatography on silica gel using a gradient of 50% ethyl acetate / hexane to 50% ethyl acetate / hexane gave the title compound (1.0 g, 26%).

Nuclear magnetic resonance spectrum (300 MHz, CDCl ₃ )
δ: 0.06 (3H, s), 0.07 (3H, s), 0.85 (9H, s), 1.30
(3H, d, J = 6.1 Hz), 1.85 (2H, m), 2.10 (1H, m), 2.
25 (2H, m), 2.5-2.7 (3H, m), 3.10 (1H, m), 3.33 (2
H, m), 3.45-3.62 (2H, m), 3.84 (1H, ddd), 4.01 (1H,
d, J = 2.31 Hz), 4.20 (1H, s), 4.58 (2H, dd), 4.70
(2H, m), 5.16 (4H, m), 5.92 (2H, m). Infrared absorption spectrum (NEAT) ν max cm ^-1 : 2930, 177
7, 1709, 1409. MS (DCI -NH 3) 576 MW = 576. (4) (5S, 6R, 7R, 10RS) -10-
[(S) -1-allyloxycarbonylpyrrolidine-3
-Ylthio] -5-[(R) -1-hydroxyethyl]
-4-oxo-3-azatricyclo [5.3.0.0
^3,6 ] Allyl deca-1-en-2-carboxylate

[0283]

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Compound 14 obtained in Example 14- (3)
To a solution of 0 mg of 5 ml of N-methylpyrrolidione and 5 ml of dimethylformamide, 1.52 ml of 1N tetrabutylammonium fluoride and 92 μl of acetic acid were added.
25 mg of ammonium hydrogen fluoride were added. The mixture
Stir at room temperature for 18 hours. The mixture is treated with 50 ml of ethyl acetate.
and washed with 50 ml of water and 50 ml of saline.
The ethyl acetate was dried over magnesium sulfate, filtered, and evaporated to dryness. The title compound was developed with ethyl acetate and purified by preparative thin-layer chromatography to give the title compound (15
0 mg, 88%).

Nuclear magnetic resonance spectrum (300 MHz, CDCl ₃ )
δ: 1.29 (3H, d, J = 6.3 Hz), 1.88 (2H, q), 2.13
(1H, m), 2.30 (2H, m), 2.45-2.80 (2H, m), 3.00 (1
H, q), 3.25 (2H, m), 3.48 (1H, m), 3.56 (1H, m), 4.0
8 (1H, d), 4.18 (1H, m), 4.52 (2H, d), 4.65 (2H, d
dd), 5.1-5.4 (4H, m), 5.88 (2H, m). Infrared absorption spectrum (NEAT) ν max cm ^-1 : 2970, 1768,
1697, 1412. (5) (5S, 6R, 7R, 10RS) -5-
[(R) -1-hydroxyethyl] -4-oxo-10
-[(S) -Pyrrolidin- ³ -ylthio] -3-azatricyclo [5.3.0.0 ^3,6 ] dec-1-en-2-
Carboxylic acid Under an argon atmosphere, a solution of the compound obtained in Example 14- (4) (65 mg) in dichloromethane (10 ml) was added at 0 ° C.
15 μl (0.84 mmol) of water, 6.5 mg of bis (triphenylphosphine) palladium (II) dichloride
(0.009 mmol), tributyltin hydride 0.2
2 μl (0.8 mmol) were added. Mix the mixture at 0 ° C
Stirred at room temperature for 40 minutes. The reaction mixture was diluted with 200 ml of dichloromethane and extracted five times with 35 ml of water. The aqueous layer was washed twice with 100 ml of dichloromethane and once with 50 ml of ethyl acetate. The aqueous layer was lyophilized to give 50 mg (105%) of the compound. The title compound was
Purification was performed on a C-18 silica gel column while eluting with a 2% aqueous acetonitrile solution to obtain 33 mg of the desired compound (69 mg).
%).

Nuclear magnetic resonance spectrum (300 MHz, D ₂ O)
δ: 1.27 (3H, d, J = 6.3 Hz), 1.92 (2H, m), 2.05 (1
H, dd), 2.25 (2H, m), 2.40 (2H, m), 2.50 (2H, m),
3.15 (2H, m), 3.32 (1H, m), 3.55 (2H.m), 4.10 (1
(H, d, J = 2.1 Hz), 4.22 (1H, s) infrared absorption spectrum
(KBr) ν max cm ^-1 : 3422, 2965, 1742, 1598, 1400. MS (electspray) 338 MW = 338. Example 15 (5S, 6R, 7S, 10RS) -10-[(S) -1
-Allyloxycarbonylpyrrolidin-3-ylthio]
-5-[(R) -1-hydroxyethyl] -4-oxo-3-azatricyclo [5.3.0.0 ^3,6 ] deca-1
-Ene-2-carboxylate (stereoisomer of Exemplified Compound I-81)

[0287]

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(1) (3S, 4R) -4-{(1R,
3RS) -3-[(S) -1-allyloxycarbonylpyrrolidin-3-ylthio] -2-oxocyclopentyl} -3-[(R) -1-hydroxyethyl] azetidin-2-one

[0289]

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To a solution of 1.4 g (2.8 mmol) of the slowly eluted isomer obtained in Example 14- (1) in 30 ml of acetonitrile was added 4.2 ml of 1N tetrabutylammonium fluoride, and the reaction mixture was allowed to stand at room temperature. Stir for 18 hours. The solution was diluted with 50 ml of ethyl acetate and diluted with 50 ml of saline.
Washed with ml. The ethyl acetate was dried over magnesium sulfate, filtered, and evaporated to give 1.0 g (93%) of the compound. This compound was treated with ethyl acetate / hexane (1/1)
Purification by flash chromatography on silica gel using afforded the title compound (0.75 g, 70%).

Nuclear magnetic resonance spectrum (300 MHz, CDCl ₃ )
δ: 1.34 (3H, d, J = 6.3 Hz), 1.68 (1H, dd), 1.80
(1H, q), 1.98 (1H, m), 2.25 (4H, m), 2.61 (1H,
m), 2.90 (1H, dd), 3.08 (2H, m), 3.33 (1H, m), 3.4
5 (2H, m), 3.70 (1H, m), 2.1-4.17 (2H, s), 4.54 (2
H, d), 5.22 (2H, q), 5.90 (1H, m), 6.40 (1H, d). (2) (3S, 4R) -4-{(1R, 3RS) -3
-[(S) -1-allyloxycarbonylpyrrolidine-
3-ylthio] -2-oxocyclopentyl} -3-
[(R) -1- (triethylsilyloxy) ethyl] azetidin-2-one (slowly eluted isomer)

[0292]

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Example 1 with cooling in an ice bath under an argon atmosphere
0.75 g of the compound obtained in 5- (1) (1.96 mm
ol) in 50 ml of dichloromethane and triethylamine 2
1.80 g (11.9 mmol) of triethylchlorosilane was added to the ml (14 mmol) solution and 2 ml of pyridine. The solution was washed with 25 ml of cold 1N hydrochloric acid, 25 ml of saturated sodium hydrogen carbonate solution and 25 ml of brine. The dichloromethane was dried over magnesium sulfate, filtered and evaporated to dryness. The residue was stirred for 1 hour with a solution of 25 ml of methanol, 25 g of silica gel and 100 mg of potassium fluoride in 2 ml of water. The mixture was filtered and the silica gel was washed with 50 ml of ethyl acetate. The filtrate is evaporated to dryness and the product is purified by flash chromatography on silica gel using a gradient of 10% ethyl acetate / hexane to 50% ethyl acetate to give the title compound (0.6 g, 62%). Was.

Nuclear magnetic resonance spectrum (300 MHz, CDCl ₃ )
δ: 0.58 (2H, q, J = 7.9 Hz), 0.93 (3H.t), 1.28
(3H, d, J = 6.4 Hz), 1.50 (1H, m), 1.65 (1H, dd),
1.8-2.0 (2H, m), 2.17 (2H, m), 2.30 (2H, m), 2.60
(1H, m), 2.82 (1H, s), 3.09 (1H, m), 3.50 (1H, m),
3.70 (1H, m), 4.28 (1H, s), 4.29 (1H, q), 4.55 (2H,
d, J = 5.4 Hz), 5.22 (1H, ddd), 5.90 (1H, m), 5.9
8 (1H, d). (3) (3S, 4R) -1-allyloxalyl-4-
{(1R, 3RS) -3-[(S) -1-allyloxycarbonylpyrrolidin-3-ylthio] -2-oxocyclopentyl} -3-[(R) -1- (triethylsilyloxyethyl) azetidine-2 -ON

[0295]

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In an ice / acetone bath under an argon atmosphere, 90 mg (0.18 mg) of the compound obtained in Example 15- (2) was obtained.
mmol) in 10 ml of dry dichloromethane, 0.1 ml of pyridine and 0.15 ml (1 mmol) of triethylamine.
l) and then allyl oxalyl chloride 100
mg (0.67 mmol) was added. Bring the solution to room temperature for 1 hour.
Stir for 8 hours. The solution was diluted with 10 ml of dichloromethane and washed with 10 ml of cold 1N hydrochloric acid, 10 ml of saturated sodium hydrogen carbonate solution and 10 ml of brine. The dichloromethane is dried over magnesium sulfate, filtered, evaporated to dryness,
The title compound (110 mg, 100%) was obtained.

Nuclear magnetic resonance spectrum (300 MHz, CDCl ₃ )
δ: 0.59 (2H, q, J = 7.9 Hz), 0.92 (3H, t), 1.29
(3H, d, J = 6.5 Hz), 1.52 (1H, m), 1.79 (1H, m),
2.00 (1H, m), 2.1-2.45 (3H, m), 2.55 (1H, dd), 3.10
(1H, m), 3.42 (2H, s), 3.50 (2H, m), 3.78 (1H, d
d), 4.40 (1H, ddd), 4.56 (2H, d), 4.77 (2H, d), 4.
79 (1H, m), 5.15-5.4 (4H, m), 5.92 (2H, m). (4) (5S, 6R, 7R, 10RS)
[(S) -1-allyloxycarbonylpyrrolidine-3
-Ylthio] -4-oxo-5-[(R) -1- (triethylsilyloxy) ethyl] -3-azatricyclo [5.3.0.0 ^3,6 ] dec-1-ene-2-carboxylic acid Allyl

[0298]

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Under an argon atmosphere, a solution of 110 mg (0.18 mmol) of the compound obtained in Example 15- (3) in 5 ml of xylene, 1 mg of hydroquinone and 0.2 ml of triethyl phosphite were refluxed for 6 hours. The reaction mixture is distilled off under high vacuum and the residue is washed with dichloromethane 10
Dissolved in ml. The dichloromethane was washed with 10 ml of brine, dried over magnesium sulfate, filtered and evaporated to dryness. The residue was purified on a preparative thin-layer chromatography plate using ethyl acetate / hexane (1/1) to give the title compound (10 mg, 10%).

Nuclear magnetic resonance spectrum (300 MHz, CDCl ₃ )
δ: 0.67 (2H, q, J = 7.9 Hz), 1.02 (3H, t), 1.27
(3H, d, J = 6.2 Hz), 1.6-1.8 (3H, m), 2.08 (1H, d
d), 2.15 (1H, m), 2.45 (1H, m), 2.65 (1H, dt), 2.95
(1H, m), 3.20 (1H, m), 3.40 (2H, m), 3.60 (1H, m),
3.73 (1H, m), 401 (1H, s), 4025 (2H, 5), 4.46 (1
H, d), 4.60 (2H, d), 4.78 (2H, m), 5.2-5.5 (4H,
m), 6.00 (2H, m). Infrared absorption spectrum (NEAT) ν max cm ^-1 : 2954, 179
4, 1709, 1410. MS (DCI -NH 3) 576. (5) (5S, 6R, 7S, 10RS) -10-
[(S) -1-allyloxycarbonylpyrrolidine-3
-Ylthio] -5-[(R) -1-hydroxyethyl]
-4-oxo-3-azatricyclo [5.3.0.0
^3,6 ] Allyl deca-1-ene-2-carboxylate 5 mg (0.00 mg) of the compound obtained in Example 15- (4)
To a solution of 9 mmol) in 1 ml of dimethylformamide was added 5 mg of ammonium hydrogen fluoride and stirred for 18 hours. The mixture was diluted with 10 ml of ethyl acetate,
Washed with 0 ml. The ethyl acetate was dried over magnesium sulfate, filtered and evaporated to dryness to give 4 mg of compound (95%).
%). This compound was purified by thin-layer chromatography (silica gel) using ethyl acetate to obtain the desired compound (1 mg, 23%).

Nuclear magnetic resonance spectrum (300 MHz, CDCl ₃ )
δ: 1.29 (3H, d, J = 6.3 Hz), 1.6-2.2 (5H, m), 3.
20 (2H, m), 3.25-3.58 (4H, m), 3.72 (2H, q), 4.20
(2H, t), 4.56 (2H, dd), 4.72 (2H, ddd), 4.86 (1H,
s), 5.15-5.48 (4H, m), 5.92 (2H, m). Infrared absorption spectrum (NEAT) ν max cm ^-1 : 2942, 1767,
1694, 1442. MS (DCI-NH 3) 462 MW = 462 Example 16 (5S, 6S, 7R, 9RS) -5 -. [(R) -1- hydroxyethyl] -4-oxo-9 - [( S) -Pyrrolidin-2-yl] -10-thia-3-azatricyclo [5.3.0.0 ^3,6 ] dec-1-en-2-carboxylic acid (stereoisomer of exemplified compound II-41)

[0302]

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(1) (3S, 4S) -4-{(3R
S, 5RS) -5-[(S) -allyloxycarbonylpyrrolidin-2-yl] -2-oxo-1-thiacyclopent-3-yl} -3-[(R) -1- (tert-
Butyldimethylsilyloxy) ethyl] azetidine-2
-ON

[0304]

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Early eluting isomer of allyl (S) -2-[(RS) -oxotetrahydro-2-thiophen-5-yl] -1-pyrrolidinecarboxylate (a series)
1.75 g of triethylamine was added to a stirred solution of 3.7 g (14.4 mmol) of 50 ml of dichloromethane (dry).
(17.3 mmol), and then 5.73 g of tert-butyldimethylsilyltrifluoromethanesulfonate (TBDMS-triflate) under an argon atmosphere.
(21.6 mmol) was added dropwise at -20 ° C. The reaction mixture was stirred for 3 hours while standing at room temperature. The reaction mixture was then re-cooled to −10 ° C.
(3S, 4R) -4-acetoxy-3-[(R) -1-
(Tert-butyldimethylsilyloxy) ethyl]-
A solution of 5.71 g (15.8 mmol) of 2-azetidinone in 30 ml of dichloromethane was added dropwise. After 5 minutes, trimethylsilyl trifluoromethanesulfonate (TMS-
(Triflate) 327 mg (1.44 mmol) was added and the reaction mixture was stirred for 10 hours while the temperature was raised to room temperature. The reaction mixture is diluted with dichloromethane, washed with aqueous NaHCO ₃ and water, and extracted with Na ₂ SO ₄
And dried. The solvent was distilled off to give a gum, which was treated with a saturated solution of potassium fluoride in methanol. Then, the solvent was distilled off under reduced pressure, and the residue was suspended in water and extracted with ether. The combined organic layers were washed with water and saturated sodium chloride solution and dried over sodium sulfate. The solvent was distilled off to give a gum, which was chromatographed (25% ethyl acetate / hexane) to give a total of 5.7 g (82%) of the two diastereomers. Was.

The main isomer (3S, 4S) -4-{(3R, 5RS) -5-5
[(S) -allyloxycarbonylpyrrolidin-2-yl] -2-oxo-1-thiacyclopent-3-yl}
-3-[(R) -1- (tert-butyldimethylsilyloxy) ethyl] azetidin-2-one

[0307]

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Nuclear magnetic resonance spectrum (300 MHz, CDCl ₃ )
δ: 0.00 (s, 6H), 0.80 (s, 9H), 1.13 (d, 3H, J = 6.
3 Hz) 1.7-2.0 (m, 4H), 2.2-2.4 (m, 2H), 2.89 (dd,
1HJ = 4.0, J = 2.5 Hz), 3.1-3.5 (m, 3H), 3.85 (m,
1H), 4.0-4.2 (m, 3H), 4.5 (brd, 2H), 5.16 (dm, 1H,
J = 10.4 Hz), 5.23 (dm, 1H, J = 17.2 Hz), 5.87-5.
95 (m, 2H). Infrared absorption spectrum (film) ν max cm ^-1 : 3883,
2956, 2857, 1763, 1702, 1402, 1104, 835, 776. MS (DCI): 500 (M + NH ₄ , 20%), 483 (M + H, 100) .MS (EI): 521 (M + K, 30%), 505 (M + Na, 100), 483 (M +
H, 5). Secondary isomer eluted early (3S, 4S) -4-{(3S, 5RS) -5-
[(S) -allyloxycarbonylpyrrolidin-2-yl] -2-oxo-1-thiacyclopent-3-yl}
-3-[(R) -1- (tert-butyldimethylsilyloxy) ethyl] azetidin-2-one

[0309]

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Nuclear magnetic resonance spectrum (300 MHz, CDCl ₃ )
δ: 0.00 (s, 6H), 0.81 (s, 9H), 1.13 (d, 3H, J = 6.
3 Hz), 1.60-2.00 (m, 5H), 2.34 (m, 1H), 2.65-2.80
(m, 2H), 3.25 (m, 1H), 3.45 (brd, 1H), 3.55 (dd, 1
H, J = 1.6 Hz, J = 9.4 Hz), 4.12 (m, 2H), 4.5 (d,
2H, J = 5.3 Hz), 5.14 (dm, 1H, J = 10.2 Hz), 5.24
(dd, 1H, J = 17.2, J = 1.5 Hz), 5.88 (m, 1H), 6.6
(s, 1H) .MS (DCI): 500 (M + NH ₄ , 100%), 483 (M + H, 75), 273 (1
0). (2) (3S, 4S) -4-｛(3S, 5RS) -5
-[(S) -allyloxycarbonylpyrrolidine-2-
Yl] -2-oxo-1-thiacyclopenta-3-yl} -3-[(R) -1-hydroxyethyl] azetidin-2-one

[0311]

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Under an argon atmosphere, 1.0 ml (7.5 mmol) of a boron trifluoride-ether complex compound was added to a stirring solution of 3.0 g (6.22 mmol) of the compound obtained in Example 16- (1) in 40 ml of acetonitrile. Was added dropwise at -20 ° C. The reaction mixture was stirred at room temperature for 2 hours, then quenched with saturated aqueous NaHCO ₃ , extracted with ethyl acetate, washed with water and brine, and dried over Na ₂ SO ₄ .
Evaporation of the solvent gave a colorless gum, which was chromatographed (100% ethyl acetate) to give 2.25 g (88%) of the title compound as a white foam. Was.

Nuclear magnetic resonance spectrum (300 MHz, CDCl ₃ )
δ: 1.22 (d, 3H, J = 6.32 Hz), 1.7-2.4 (m, 6H), 2.
98 (dd, 1H, J = 5.98, J = 1.71 Hz), 3.19 (brd, 1
H), 3.3-3.5 (m, 2H), 3.85-4.15 (m, 4H), 4.51 (dm,
2H, J = 5.44 Hz), 5.17 (brd, 1H, J = 10.3 Hz), 5.26
(dm, 1H, J = 17.2 Hz), 5.85 (dm, 1H), 6.45 (s, 1
H) .MS (DCI): 386 (M + NH ₄ , 100%), 369 (M + H, 30), 342 (2
5), 325 (30). (3) (3S, 4S) -4-｛(3R, 5RS) -5
-[(S) -allyloxycarbonylpyrrolidine-2-
Yl] -2-oxo-1-thiacyclopenta-3-yl} -3-[(R) -1- (triethylsilyloxy)
Ethyl] azetidin-2-one

[0314]

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Compound 1 obtained in Example 16- (2)
To a stirred solution of 0 g (5.52 mmol) in 30 ml of anhydrous DMF, 1.89 g (27.62 mmol) of imidazole.
And then 2.78 m of triethylsilyl chloride
1 (16.5 mmol) was added dropwise at 0 ° C. The reaction mixture was stirred at room temperature for 10 hours, diluted with water and extracted with ether. The combined ether layers were washed with water and brine,
Dried over Na ₂ SO ₄ . The solvent was distilled off to give a gum, which was chromatographed (30% ethyl acetate / 30% CH ₂ Cl ₂ / hexane) to give 2.35 g (88%) of the title compound. Obtained.

Nuclear magnetic resonance spectrum (300 MHz, CDCl ₃ )
δ: 0.61 (q, 6H, J = 7.9 Hz), 0.95 (t, 9H, J = 7.9
Hz), 1.22 (d, 3H, J = 6.3 Hz), 1.75-2.1 (m, 4H),
2.3 (m, 2H), 2.95 (brd, 1H), 3.2-3.6 (m, 3H), 3.95
(brd, 1H), 4.1-4.25 (m, 3H), 4.58 (dm, 2H, J = 4.4
Hz), 5.23 (brd, 1H, J = 10.5 Hz), 5.30 (dm, 1H, J
= 17.2 Hz), 5.95 (m , 2H) MS (DCI):. 500 (M + NH 4, 30%), 483 (M + H, 100), 466 (3
5), 453 (20), 308 (20). Infrared absorption spectrum (film) ν max cm ^-1 : 3275,
2955, 1766, 1694, 1401, 1283, 1240, 1102, 1010, 7
28. (4) (3S, 4S) -1-allyloxalyl-4-
{(3R, 5RS) -5-[(S) -allyloxycarbonylpyrrolidin-2-yl] -2-oxo-1-thiacyclopent-3-yl} -3-[(R) -1- (triethyl Silyloxy) ethyl] azetidin-2-one

[0317]

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Under an argon atmosphere, a stirred solution of 600 mg (1.25 mmol) of the compound obtained in Example 16- (3) and 10 ml of freshly distilled CH ₂ Cl ₂ containing 0.26 ml (1.86 mmol) of triethylamine was added to a stirred solution. 0.2 ml (1.49 mmol) of allyl oxalyl chloride was added dropwise at -20 ° C. The mixture was stirred for 1 hour, then partitioned between dichloromethane and aqueous NaHCO _3, the layers were separated, the aqueous layer was extracted with dichloromethane. The combined organic extracts were washed with water and brine, and dried over Na ₂ SO _4. Evaporation of the solvent gave a gum, which was chromatographed (30% ethyl acetate / hexane) to give 700 mg (94%) of the title compound as a gum.

Nuclear magnetic resonance spectrum (300 MHz, acetone
-d ₆ ) δ: 0.04 (q, 6H, J = 8.1 Hz), 0.38 (t, 9H, J
= 8.1 Hz), 0.71 (d, 3H, J = 6.3 Hz), 1.20-1.60
(m, 4H), 1.96 (m, 1H), 2.23 (brd, 1H), 2.8-3.1 (br
d, 3H), 3.4 (brd, 1H), 4.55 (brd, 1H), 3.85 (m, 1
H), 3.98-4.10 (brd, 3H), 4.22 (dm, 2H, J = 5.8 H
z), 4.56-4.90 (m, 4H), 5.40 (m, 2H) .MS (DCI): 612 (M + NH ₄ , 100%), 595 (M + H, 5), 466 (1
5). (5) (5S, 6S, 7R, 9RS) -9-[(S)
-1-allyloxycarbonylpyrrolidin-2-yl]
Oxo-10-thia -5 - [(R) -1- (triethylsilyl oxy) ethyl] -3-azatricyclo [5.3.0.0 ^{3, 6]} dec-1-ene-2-carboxylic Allyl acid

[0320]

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Compound 70 obtained in Example 16- (4)
To a stirred solution of 0 mg (1.18 mmol) in 15 ml of distilled xylene, were added 2-3 hydroquinone crystals and 1.17 g (7.07 mmol) of triethyl phosphite. The reaction mixture was heated at 140 ° C. for 14
Heat for a period of time, then cool to room temperature, remove volatiles under high vacuum and chromatograph the residue (20% ethyl acetate / 20% CH ₂ Cl ₂ / hexane) to give the title compound. 398 mg (60%) were obtained as a gum.

Nuclear magnetic resonance spectrum (300 MHz, CDCl ₃ )
d: 0.68 (q, 6H, J = 8.0 Hz), 0.93 (t, 9H, J = 8.0
Hz), 1.25 (bnd, 3H), 1.33-2.0 (m, 5H), 2.25 (m, 1
H), 3.28-3.52 (m, 3H), 3.86 (m, 1H), 4.2 (brd, 3
H), 4.32 (dd, 1H), 4.56 (bd, 2H), 4.7 (m, 2H), 5.15
-5.45 (m, 4H), 5.92 (m, 2H). MS (DCI): 563 (M + H, 100%), 380 (30), 363 (45). (6) (5S, 6S, 7R, 9RS) -9-[(S)
-1-allyloxycarbonylpyrrolidin-2-yl]
-5-[(R) -1-hydroxyethyl] -4-oxo-10-thia-3-azatricyclo [5.3.0.0
^3,6 ] Allyl deca-1-en-2-carboxylate

[0323]

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Compound 78 obtained in Example 16- (5)
To a stirred solution of mg (0.139 mmol) in 1 ml of anhydrous DMF and 0.33 ml of N-methylpyrrolidinone, 79 mg (1.4 mmol) of ammonium hydrogen fluoride were added, and the mixture was stirred for 2 hours, diluted with ethyl acetate, diluted with water and brine. Washed several times with water and dried over Na ₂ SO ₄ . Evaporation of the solvent gave a gum, which was chromatographed (100% ethyl acetate) to give 500 mg of the title compound.
g (80%) was obtained as a gum.

Nuclear magnetic resonance spectrum (300 MHz, CDCl ₃ )
δ: 1.18 (brd, 3H), 1.65-2.1 (m, 5H), 2.25 (brd, 1
H), 3.2-3.6 (m, 3H), 3.85 (m, 1H), 4.05-4.2 (m, 3
H), 4.3 (dd, 1H), 4.50 (dm, 2H), 4.65 (m, 2H), 5.1
-5.4 (m, 4H), 5.35 (m, 2H) .MS (DCI): 466 (M + NH ₄ , 1
00%), 449 (M + H, 100), 405 (25). (7) (5S, 6S, 7R, 9RS) -5-[(R)-
1-hydroxyethyl] -4-oxo-9-[(S)-
Pyrrolidin-2-yl] -10-thia-3-azatricyclo [5.3.0.0 ^3,6 ] dec-1-en-2-carboxylic acid 55 mg of the compound obtained in Example 16- (6) ( 0.1
23 mmol) in a stirred solution of ₂ ml of dry CH ₂ Cl ₂ ,
0.008 ml (0.49 mmol) of water, 8.6 mg of bis (triphenylphosphine) palladium dichloride
(0.0123 mmol) and 15 mg of NaCl,
It was added continuously at 0 ° C. To this reaction mixture, 0.01 ml (0.49 mmol) of tributyltin hydride was added very slowly at the same temperature under an argon atmosphere, stirred for 30 minutes, and partitioned between dichloromethane and water. The organic layer was extracted with water and the combined aqueous layers were washed three times with CH ₂ Cl ₂ ,
Washed three times with ethyl acetate and lyophilized to give the title compound as a pale yellow solid.

Nuclear magnetic resonance spectrum (300 MHz, D ₂ O)
δ: 1.31 (d, 3H, J = 7.9 Hz), 1.82-2.3 (m, 5H), 2.
5 (brd, 1H), 3.38-3.52 (m, 2H), 3.74 (m, 1H), 4.0-
4.12 (m, 2H), 4.25 (m, 2H), 4.45 (dd, 1H). DCI (H ₂ O / ES in CH ₃ CN): 369 (M + Na + Na, 15%), 347 (M +
Na, 45), 325 (M + H, 40), 239 (100) .DCI (ES in MeOH): 401 (M + MeOH + Na + Na, 35%), 379 (M
+ MeOH + Na, 55), 369 (M + Na + Na, 15), 347 (M + Na, 35), 2
Example 17 (5S, 6S, 7S, 9RS) -5-[(R) -1-hydroxyethyl] -4-oxo-9-[(S) -pyrrolidin-2-yl] -10 -Thia- ³ -azatricyclo [5.3.0.0 ^3,6 ] dec-1-ene-2-carboxylic acid (stereoisomer of Exemplified Compound II-45)

[0327]

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(1) (3S, 4S) -4-{(3S,
5RS) -5-[(S) -allyloxycarbonylpyrrolidin-2-yl] -2-oxo-1-thiacyclopent-3-yl} -3-[(R) -1-hydroxyethyl] azetidine-2 -ON

[0329]

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By using 1.4 g of the secondary isomer of Example 16- (1) which eluted earlier, 750 mg (71%) of the title compound was obtained in the same manner as in Example 16- (2).

Nuclear magnetic resonance spectrum (300 MHz, CDCl ₃ )
δ: 1.27 (d, 3H, J = 6.3 Hz), 1.7-2.1 (m, 6H), 2.4
3 (m, 1H), 2.75-2.98 (m, 2H), 3.33 (m, 1H), 3.52
(brd, 1H), 3.66 (dd, 1H, J = 9.1, J = 2.0 Hz), 4.08
-4.22 (m, 2H), 4.50 (brd, 1H), 4.6 (d, 2H, 5.38 H
z), 5.22 (brd, 1H, 10.2 Hz), 5.34 (brd, 1H, J = 1
7.2 Hz, J = 2.5 Hz), 5.92 (m, 1H), 6.23 (s, 1H) .MS (DCI): 386 (M + NH ₄ , 30%), 369 (M + H, 45), 325 (10
0). MS (EI): 407 (M + K, 15%), 391 (M + Na, 100), 369 (5). (2) (3S, 4S) -4-｛(3S, 5RS)- 5
-[(S) -allyloxycarbonylpyrrolidine-2-
Yl] -2-oxo-1-thiacyclopenta-3-yl} -3-[(R) -1- (triethylsilyloxy)
Ethyl] azetidin-2-one

[0332]

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Compound 17 obtained in Example 17- (1)
760 mg (83%) of the title compound was obtained in the same manner as in Example 16- (3) using 0 mg.

Nuclear magnetic resonance spectrum (300 MHz, CDCl ₃ )
δ: 0.54 (q, 6H, J = 7.6 Hz), 0.89 (t, 9H, J = 7.
6 Hz), 1.7 (d, 3H, J = 6.3 Hz), 1.65 (m, 1H), 1.8-
2.0 (m, 5H), 2.35 (m, 1H), 2.65-2.78 (m, 2H), 3.27
(brd, 1H), 3.45 (brd, 1H), 3.55 (brd, 1H, J = 9.3
Hz), 4.08-4.2 (m, 2H), 4.54 (dm, 2H, J = 4.9 Hz),
5.16 (brd, 1H, J = 10.4 Hz), 5.24 (dm, 1H, J = 17.
2 Hz), 5.88 (m, 1H), 6.58 (s, 1H). Infrared absorption spectrum (film) ν max cm ^-1 : 329
7, 2954, 2876, 1762,1695, 1404, 1331, 1101, 1008,
745. MS (DCI) 500 (M + NH 4, 85%), 483 (M + H, 100). (3) (3S, 4S) -1- allyl oxalyl 4-
{(3S, 5RS) -5-[(S) -allyloxycarbonylpyrrolidin-2-yl] -2-oxo-1-thiacyclopent-3-yl} -3-[(R) -1- (triethyl Silyloxy) ethyl] azetidin-2-one

[0335]

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Compound 17 obtained in Example 17- (2)
560 mg (90%) of the title compound was obtained in the same manner as in Example 16- (4) using 0 mg.

Nuclear magnetic resonance spectrum (300 MHz, CDCl ₃ )
δ: 0.51 (q, 6H, J = 7.7 Hz), 0.86 (t, 9H, J = 7.7 Hz)
Hz), 1.15 (d, 3H, J = 6.4 Hz), 1.8-2.1 (m, 6H),
2.35 (m, 1H), 3.28 (m, 2H), 3.5 (brd, 2H), 4.15 (br
d, 1H), 4.25 (brd, 2H), 4.54 (brd, 2H), 4.65 (brd,
2H), 4.74 (dm, 2H, J = 6.0 Hz), 5.1-5.4 (m, 4H),
5.80-5.98 (m, 2H). Infrared absorption spectrum (film) ν max cm ^-1 : 295
7, 2879, 1809, 1746,1698, 1397, 1313, 1184, 1156,
. 1014, 978, 943, 743. MS (DCI): 612 (M + NH 4, 100%), 595 (M + H, 30) (4) (5S, 6S, 7S, 9RS) -9 - [( S)
-1-allyloxycarbonylpyrrolidin-2-yl]
Oxo-10-thia -5 - [(R) -1- (triethylsilyl oxy) ethyl] -3-azatricyclo [5.3.0.0 ^{3, 6]} dec-1-ene-2-carboxylic Allyl acid

[0338]

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Compound 35 obtained in Example 17- (3)
Using 0 mg and in the same manner as in Example 16- (5), 61 mg (19%) of the title compound was obtained.

Nuclear magnetic resonance spectrum (300 MHz, CDCl ₃ )
δ: 0.52 (q, 6H, J = 7.8 Hz), 0.88 (t, 9H, J = 7.8
Hz), 1.2 (brd, 3H), 1.6-2.0 (m, 5H), 2.26 (m, 1
H), 3.10 (dd, 1H), 3.30 (m, 1H), 3.40-3.70 (brd, 2
H), 3.88 (dd, 1H, m), 4.00-4.20 (m, 3H), 4.51 (br
d, 2H), 4.65 (m, 2H), 5.12-5.40 (m, 4H), 5.85 (m,
2H). MS (DCI): 563 (M + H, 45%), 536 (100), 519 (10). (5) (5S, 6S, 7S, 9RS) -9-[(S)
-1-allyloxycarbonylpyrrolidin-2-yl]
-5-[(R) -1-hydroxyethyl] -4-oxo-10-thia-3-azatricyclo [5.3.0.0
^3,6 ] Allyl deca-1-en-2-carboxylate

[0341]

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Compound 17 obtained in Example 17- (4)
The title compound (25 mg, 45%) was obtained in the same manner as in Example 16- (6) using the above compound (mg).

MS (DCI): 466 (M + NH ₄ , 30%), 449 (M + H,
100), 405 (25). (7) (5S, 6S, 7S, 9RS) -5-[(R)
-1-hydroxyethyl] -4-oxo-9-"(S)
-Pyrrolidin-2-yl] -10-thia-3-azatricyclo [5.3.0.0 ^3,6 ] dec-1-en-2-carboxylic acid 18 mg of the compound obtained in Example 17- (5) In the same manner as in Example 16- (7),
g (61%).

Nuclear magnetic resonance spectrum (300 MHz, D ₂ O)
δ: 1.35 (d, 3H, J = 7.9 Hz), 1.8-2.23 (m, 4H), 2.
38 (brd, 1H), 2.68 (m, 1H), 3.40-3.55 (m, 3H), 3.9
2 (m, 1H), 4.05 -4.20 (m, 2H), 4.30 (m, 1H), 4.52
(m, 1H). Infrared absorption spectrum (KBr) ν max cm ^-1 : 3449, 175
2, 1607, 1387. MS (ES): 369 (M + H + Na + Na, 30%), 347 (M + Na, 100), 32
5 (M + H, 10), 157 (45). Example 18 (5S, 6S, 7R, 9RS) -9-[(S) -1-allyloxycarbonylpyrrolidin-2-yl] -4-oxo- 10-thia-5-[(R) -1- (triethylsilyloxy) ethyl] -3-azatricyclo [5.3.
0.0 ^3,6 ] allyl-1-en-2-carboxylate (stereoisomer of Exemplified Compound II-45)

[0345]

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(1) (3S, 4S) -4-{(3R
S, 5RS) -5-[(S) -allyloxycarbonylpyrrolidin-2-yl] -2-oxo-1-thiacyclopent-3-yl} -3-[(R) -1- (tert-
Butyldimethylsilyloxy) ethyl] azetidine-2
-ON

[0347]

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(S) -2-[(RS) -oxotetrahydro-2-thiophen-5-yl] -1-pyrrolidine-
Slowly eluted isomer of allyl carboxylate (b series)
1.97 g and (3S, 4R) -4-acetoxy-3-
Using 3.04 g of [(R) -1- (tert-butyldimethylsilyloxy) ethyl] -2-azetidinone, two diastereomers (the title compound) 2 in the same manner as in Example 16- (1). 0.5 g (68%) of an inseparable mixture was obtained.

MS (DCI): 500 (M + NH ₄ , 3%), 483 (M + H, 10
0). (2) (3S, 4S) -4-｛(3RS, 5RS)-
5-[(S) -allyloxycarbonylpyrrolidine-2
-Yl] -2-oxo-1-thiacyclopenta-3-yl} -3-[(R) -1-hydroxyethyl] azetidin-2-one

[0350]

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Compound 18 obtained in Example 18- (1)
Using 4 g, 1.46 g of the two diastereomers (the title compound) in the same manner as in Example 16- (2) (8
(0%).

(3) (3S, 4S) -4-{(3R
S, 5RS) -5-[(S) -allyloxycarbonylpyrrolidin-2-yl] -2-oxo-1-thiacyclopent-3-yl} -3-[(R) -1- (triethylsilyloxy ) Ethyl] azetidin-2-one

[0353]

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Compound 18 obtained in Example 18- (2)
Two diastereomers (the title compound) were obtained in the same manner as in Example 16- (3) using 46 g of the mixture.
40 g (71%) of an inseparable mixture were obtained.

(4) (3S, 4S) -4-{(3R
(S, 5RS) -5-[(S) -allyloxycarbonylpyrrolidin-2-yl] -2-oxo-1-thiacyclopent-3-yl} -1-triethylsilyl-3-
[(R) -1- (triethylsilyloxy) ethyl] azetidin-2-one

[0356]

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Compound 70 obtained in Example 18- (3)
To a stirred solution of 0 mg (1.42 mmol) of 15 ml of freshly distilled dichloromethane was added 0.6 ml of triethylamine.
ml (4.26 mmol) was added followed by 0.36 ml (0.898 mmol) of triethylsilyl chloride at -20 <0> C. The reaction mixture is stirred for 8 hours, diluted with dichloromethane, washed with water and brine, dried Na ₂
And dried over SO _4. The gum was obtained by evaporation of the solvent, and the gum was chromatographed to give the ditriethylsilyl compound as a separable diastereomer.

Main isomer (3S, 4S) -4-{(3S, 5RS) -5
[(S) -allyloxycarbonylpyrrolidin-2-yl] -2-oxo-1-thiacyclopent-3-yl}
-1-triethylsilyl-3-[(R) -1- (triethylsilyloxy) ethyl] azetidin-2-one

[0359]

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Nuclear magnetic resonance spectrum (300 MHz, CDCl ₃ )
δ: 0.52 (q, 6H, J = 7.9 Hz), 0.71 (m, 6H), 0.88
(t, 9H, J = 7.2 Hz), 1.08 (d, 3H, J = 6.2 Hz), 1.5
2-2.8 (m, 6H), 2.84 (dd, 1H, J = 4.35 and 2.56 Hz),
3.00 (m, 1H), 3.30 (m, 1H), 3.60 (m, 1H), 3.92 (d
d, 1H, J = 4.4 and 2.0 Hz), 4.06-4.30 (m, 3H), 4.5
2 (dm, 2H, J = 5.68 Hz). Infrared absorption spectrum (film) ν max cm ^-1 : 2955,
2877, 1745, 1694, 1649, 1458, 1401, 1322, 1240, 1
102, 1004, 746. MS (DCI ): 614 (M + NH 4, 10%), 597 (M + H, 100), 308 (2
0). Secondary isomer (3S, 4S) -4-{(3R, 5RS) -5-
[(S) -allyloxycarbonylpyrrolidin-2-yl] -2-oxo-1-thiacyclopent-3-yl}
-1-triethylsilyl-3-[(R) -1- (triethylsilyloxy) ethyl] azetidin-2-one

[0361]

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Nuclear magnetic resonance spectrum (300 MHz, CDCl ₃ )
δ: 0.54 (q, 6H, J = 7.9 Hz), 0.70 (m, 6H), 0.90
(m, 18H), 1.19 (d, 3H, J = 6.1 Hz), 1.18-2.3 (m, 6
H), 2.8 (m, 2H), 3.33 (M, 1H), 3.55 (brd, 1H), 3.9
9-4.38 (m, 4H), 4.54 (d, 2H, J = 4.74 Hz), 5.21
(m, 2H), 5.88 (m, 2H). Infrared absorption spectrum (film) ν max cm ^-1 : 295
6, 2877, 1746, 1694,1649, 1455, 1398, 1329, 1235,
1178, 1106, 1003, 725, 672. MS (DCI): 597 (M + H, 100%), 308 (75). (5) (3S, 4S) -4-｛(3R, 5RS) -5
-[(S) -allyloxycarbonylpyrrolidine-2-
Yl] -2-oxo-1-thiacyclopenta-3-yl} -3-[(R) -1- (triethylsilyloxy)
Ethyl] azetidin-2-one

[0363]

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The secondary isomer (210 mg, 0.035 mmol) obtained in Example 18- (4) was treated with a saturated solution of potassium fluoride in methanol (5 ml), stirred for 10 minutes, and the solvent was removed under reduced pressure. Removed. Suspend the residue in water,
Extracted with ether. The combined ether layers were washed with water and brine and dried. Evaporation of the solvent gave a residue which was chromatographed (50% ethyl acetate / hexane) to give 158 mg (91%) of the title compound as a gum.

Nuclear magnetic resonance spectrum (300 MHz, CDCl ₃ )
δ: 0.7 (q, 6H, J = 7.8 Hz), 0.92 (t, 9H, J = 7.8
Hz), 1.23 (d, 3H, J = 6.2 Hz), 1.8-2.0 (m, 6H), 2.
8-2.95 (m, 2H), 3.36 (m, 1H), 3.7 (brd, 1H), 4.1-4.
4 (m, 4H), 4.58 (d, 2H, J = 5.5 Hz), 5.21 (dm, 1H,
J = 10.4 Hz), 5.29 (dm, 1H, J = 17.3 Hz), 5.9 (m,
2H). Infrared absorption spectrum (film) ν max cm ^-1 : 2958,
2880, 1765, 1706, 1676, 1400, 1329, 1176, 1057, 7
30.MS (DCI): 500 (M + NH ₄ , 45%), 483 (M + H, 100), 453 (1
0), 154 (20). (6) (3S, 4S) -1-allyloxalyl-4-
{(3R, 5RS) -5-[(S) -allyloxycarbonylpyrrolidin-2-yl] -2-oxo-1-thiacyclopent-3-yl} -3-[(R) -1- (triethyl Silyloxy) ethyl] azetidin-2-one

[0366]

Embedded image

Compound 18 obtained in Example 18- (5)
Using 0 mg and in the same manner as in Example 16- (4), 110 mg (66%) of the title compound was obtained.

Nuclear magnetic resonance spectrum (300 MHz, CDCl ₃ )
δ: 0.56 (q, 6H, J = 7.7 Hz), 0.91 (t, 9H, J = 7.7 Hz)
Hz), 1.25 (d, 3H, J = 6.3 Hz), 1.8-2.0 (m, 5H),
2.4 (m, 1H), 3.15-3.7 (m, 4H), 4.3 (m, 3H), 4.45
(-dd, 1H, J1 = 4.6 Hz, J2 = 4.8Hz), 4.6 (brd, 2H), 4.7
8 (dm, 2H, J = 6.0 Hz), 5.18-5.45 (m, 4H), 5.95
(m, 2H). (7) ｛(5S, 6S, 7R, 9RS) -9-
[(S) -1-allyloxycarbonylpyrrolidine-2
-Yl] -4-oxo-10-thia-5-[(R) -1
Allyl-(triethylsilyloxy) ethyl] -3-azatricyclo [5.3.0.0 ^3,6 ] dec-1-en-2-carboxylate Using 110 mg of the compound obtained in Example 18- (6). Thus, 28 mg (26%) of the title compound was obtained in the same manner as in Example 16- (5).

Nuclear magnetic resonance spectrum (300 MHz, CDCl ₃ )
δ: 0.61 (q, 6H, J = 7.8 Hz), 0.96 (t, 9H, J = 7.8
Hz), 1.23 (d, 3H, J = 6.1 Hz), 1.6-2.2 (m, 6H),
3.31 (dd, 1H, J = 6.2 and 5.2 Hz), 3.4-3.8 (m, 3H),
4.25 (m, 3H), 4.55-4.8 (m, 5H), 5.20-5.47 (m, 4
H), 5.95 (m, 2H). Infrared absorption spectrum (film) ν max cm ^-1 : 3440,
2956, 2877, 1788, 1694, 1596, 1444, 1404, 1317, 1
280, 1139, 1004, 928, 732. MS (DCI):. 580 (M + NH 4, 5%), 563 (M + H, 35%) Example 19 (5R, 6S, 7S, 9RS) -5 -[(R) -1-Hydroxyethyl] -4-oxo-9-[(S) -pyrrolidin-2-yl] -10-thia-3-azatricyclo [5.3.0.0 ^3,6 ] deca -1-ene-2-carboxylic acid (stereoisomer of exemplified compound II-45)

[0370]

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(1) (3S, 4S) -1-allyloxalyl-4-{(3RS, 5RS) -5-[(S) -allyloxycarbonylpyrrolidin-2-yl] -2-oxo-1-thia Cyclopenta-3-yl} -3-
[(R) -1- (triethylsilyloxy) ethyl] azetidin-2-one

[0372]

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The compound (7) obtained in Example 18- (3)
50 mg) to give 750 mg (75%) of the title compound as an inseparable mixture of isomers in a manner similar to Example 16- (4).

(2) (5S, 6S, 7S, 9RS)-
9-[(S) -1-allyloxycarbonylpyrrolidin-2-yl] -4-oxo-10-thia-5-[(R)
-1- (triethylsilyl oxy) ethyl] -3-azatricyclo [5.3.0.0 ^{3, 6]} dec-1-ene -2
-Allyl carboxylate

[0375]

Embedded image

Compound 19 obtained in Example 19- (1)
Using 0 mg and in the same manner as in Example 16- (5), 220 mg (33%) of the title compound was obtained.

Nuclear magnetic resonance spectrum (300 MHz, CDCl ₃ )
δ: 0.58 (q, 6H, J = 7.8 Hz), 0.94 (t, 9H, J = 7.
8 Hz), 1.27 (d, 3H, J = 6.1 Hz), 1.6-2.2 (m, 5H),
2.45 (brd, 1H), 3.04 (dm, 1H, J = 7.3 Hz), 3.4 (m,
1H), 3.62 (m, 1H), 3.82-3.97 (m, 2H), 4.07-4.42 (m,
3H), 4.55 (brd, 2H), 4.6-4.8 (m, 2H), 5.17-5.44
(m, 4H), 5.86-6.0 (m, 2H). Infrared absorption spectrum (film) ν max cm ^-1 : 3017,
2956, 2912, 2877, 1770, 1694, 1582, 1403, 1327, 1
216, 1137, 1107, 750. MS (DCI): 580 (M + NH ₄ , 15%), 563 (M + H, 100), 363
(3) (5S, 6S, 7S, 9RS) -9-[(S)
-1-allyloxycarbonylpyrrolidin-2-yl]
-5-[(R) -1-hydroxyethyl] -4-oxo-10-thia-3-azatricyclo [5.3.0.0
^3,6 ] Allyl deca-1-en-2-carboxylate

[0378]

Embedded image

Compound 72 obtained in Example 19- (2)
Using 30 mg (52%) of the title compound was obtained in the same manner as in Example 16- (6).

Nuclear magnetic resonance spectrum (300 MHz, CDCl ₃ )
δ: 1.33 (d, 3H, J = 6.1 Hz), 1.65-2.2 (m, 5H), 2.
54 (brd, 1H), 3.13 (dm, 1H, J = 7.1 Hz), 3.38-3.48
(m, 1H), 3.58-3.69 (m, 1H), 3.96 (m, 2H), 4.10-4.4
0 (m, 3H), 4.58 (brd, 2H), 4.62-4.82 (m, 2H), 5.20
.. -5.46 (m, 4H) , 5.80 (m, 2H) MS (DCI): 466 (M + NH 4, 100%), 449 (M + H, 60) Infrared absorption spectrum (film) ν max cm ^{- 1} : 3450,
3018, 2962, 1770, 1693, 1582, 1405, 1328, 1216, 1
123, 756. (4) (5S, 6S, 7S, 9RS) -5-[(R)
-1-Hydroxyethyl] -4-oxo-9-[(S)
-Pyrrolidin-2-yl] -10-thia-3-azatricyclo [5.3.0.0 ^3,6 ] dec-1-en-2-carboxylic acid 37 mg of the compound obtained in Example 19- (3) And 27 mg (52%) of the target compound were obtained in the same manner as in Example 16- (7).

Nuclear magnetic resonance spectrum (300 MHz, D ₂ O)
δ: 1.17 (d, 3H, J = 6.5 Hz), 1.59-1.72 (m, 1H),
1.90-2.13 (m, 3H), 2.19-2.30 (m, 2H), 3.20-3.30
(m, 3H), 3.66-3.78 (m, 1H), 3.95-4.18 (m, 4H). Infrared absorption spectrum (KBr) ν max cm ^-1 : 3406, 296
6, 2933, 1753, 1606,1562, 1545, 1386, 1258, 1137,
1082, 768.MS (EI): 649 (M + M + H, 20%), 347 (M + Na, 5), 325 (M +
H, 100), 264 (20). Test Example 1 The compound represented by the general formula (I) or (II) obtained in the examples showed good antibacterial activity against various pathogenic bacteria. In particular, methicillin-resistant Staphylococcus aureus (MRS)
Excellent antibacterial activity against A).

Test Example 2 The compound represented by the formula (I) or (II) obtained in the examples showed a high urinary recovery rate when administered subcutaneously to mice.

Formulation Example 1 Injection 500 mg of the compound of Example 1 is dissolved in 5 ml of distilled water for injection, passed through a filter for sterilization, and then lyophilized to give a lyophilized preparation for injection.

Formulation Example 2 Capsule Compound of Example 1 50 mg Lactose 128 mg Corn starch 70 mg Magnesium stearate 2 mg 250 mg After mixing the powder of the above formulation and passing through a 60-mesh sieve, the powder is mixed with 250 mg of No. 3 gelatin capsule Into a capsule.

Formulation Example 3 Tablets Compound of Example 1 50 mg Lactose 126 mg Maize starch 23 mg Magnesium stearate 1 mg 200 mg The powder of the above formulation was mixed, wet-granulated using corn starch paste, dried, and pressed with a tablet machine. Lock it, 1
Tablets 200 mg tablets. The tablets can be sugar-coated as needed.

[0386]

Industrial Applicability The tricyclic heterocyclic derivative having the general formula (I) or (II) or a pharmaceutically acceptable salt thereof according to the present invention exhibits excellent antibacterial activity and is effective against β-lactamase-producing bacteria. Also have excellent activity. That is, the compound (I) or (II) of the present invention is a gram-positive bacterium such as Staphylococcus aureus or enterococcus, a gram-negative bacillus such as Escherichia coli, Shigella, Klebsiella pneumoniae, deformed bacterium, Serratia, Enterobacter, or Pseudomonas aeruginosa. It exhibits antibacterial activity against a wide range of pathogenic bacteria including anaerobic bacteria such as bacteria and Bacteroides fragilis, and particularly shows strong antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA), which has recently become a problem. In addition, although thienamycin compounds are easily metabolized by mammals, the compounds of the present invention (I) or (I)
I) shows excellent stability against dehydropeptidase-I, which is known as an enzyme that catalyzes the inactivation of thienamycin, and has a high urine recovery rate. Furthermore, compound (I) or (II) has low toxicity. Therefore, the tricyclic heterocyclic derivative having the general formula (I) or (II) of the present invention or a pharmaceutically acceptable salt thereof is excellent in treating or preventing (preferably treating) bacterial infections caused by these pathogenic bacteria. It is an antibacterial agent.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ Identification symbol FI C07D 495/14 C07D 495/14 F (72) Inventor Michael Tracy Ravenswood Avenue, Menlo Park, 94025, California, United States Ravenswood Avenue 333 SRL International, Pharmaceutical Discovery Division (72) Inventor Andrew B. Kelson United States, 94025, Menlo Park, California, Ravenswood Avenue 333 SRI International, Pharmaceutical Discovery Division (72) Inventor Kenneth Jay. Ryan United States, 94025, Menlo Park, California, Menlo Park, Ravenswood Avenue 333 SRI International, Pharmaceutical Discovery Division (72) Inventor Verapasi Appender United States, 94025, California, Menlo Park, Ravenswood Avenue, 333 SRI International Robert Discovery, Pharmaceutical Discovery Division (72). WEP United States, 94025, Menlo Park, California, Ravenswood Avenue 333 SIR International, Pharmaceutical Discovery Division

Claims (1)

[Claims] 1. A compound of the general formula Or In the formula, R ¹ represents a hydrogen atom or an ester residue that undergoes hydrolysis in vivo, m, n, k and s represent 0 or 1, p and t represent 0, 1 or 2, R ² is a hydrogen atom, an alkyl group having 1 to 3 carbon atoms,
(= NH) group (wherein represented by R ^4, R ⁴ is a hydrogen atom,
It represents an alkyl group or an amino group having 1 to 3 carbon atoms. ), A 2-imidazolin-2-yl group or a 2-thiazolin-2-yl group, and R ³ is a carbamoyl substituted with a hydrogen atom, a carbamoyl group, or one or two alkyl groups having 1 to 3 carbon atoms. Group,
Formula 3 (In the formula, R ⁵ represents a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, a formimidyl group, an acetimidoyl group, an amidino group, a 2-imidazolin-2-yl group or a 2-thiazolin-2-yl group. Or a group represented by the formula: (In the formula, r represents 0, 1 or 2, q represents 0 or 1, R ⁶ represents a hydrogen atom, an alkyl group having 1 to 3 carbon atoms,
It represents a formimidoyl group, an acetimidoyl group, an amidino group, a 2-imidazolin-2-yl group or a 2-thiazolin-2-yl group. ). Or a pharmacologically acceptable salt thereof.