JPH05230061A - New beta-lactam compound and its production - Google Patents

Abstract

PURPOSE:To obtain a new beta-lactam compound having excellent antimicrobial activity against imipenem-resistant Pseudomonas aeruginosa. CONSTITUTION:The objective compound of formula I {(j) is 0 or 1; R<1> is H, OH-protecting group or formula II to IV (Y is single bond, alkylene CO, etc.; R<5> and R<6> are H or OH-protecting group; Z is H, halogen NO2, CN, etc.); R<2> is H or carboxyl-protecting group; M is S or CH2; A is formula V to VII [(k), (l), (m) and (n) are 0-3; R<3> is H, alkyl, etc.; R<4> is formula II to IV; R<7> is H or alkyl; R<8> is H, protecting group of amino group, lower alkyl group, etc.; R<5> is R<7> or NH2-protecting group), etc., when R<1> is H or OH-protecting group formula VII to X, etc., when R<1> is formula II to IV]} and its salt, e.g. (4R,5S,6 S,8R,2'R,4'S)-3-[(1-(3,4-dihydroxybenzoyl)methyl-2- dimethylaminocarbonylpyrrolidin)-4-ylthio]-4-methyl-6-(1hydroxyethyl)-1- azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylic acid.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel β-lactam compound and a method for producing the same. More specifically, it relates to a penem or carbapenem derivative into which a catechol derivative or the like is introduced and a method for producing the same.

[0002]

2. Description of the Related Art Heretofore, one having a penem skeleton or a carbapenem skeleton has been reported as one of β-lactam compounds having an excellent antibacterial spectrum against a wide range of Gram-positive and Gram-negative bacteria.

[0003]

However, it has been reported that a resistant bacterium has appeared in imipenem, which is currently marketed in this field, and that it has been isolated from the clinical field. Therefore, the development of β-lactam compounds effective against those resistant bacteria, particularly resistant Pseudomonas aeruginosa, is expected.

[0004]

[Means for Solving the Problems] In order to solve the above-mentioned problems, as a result of intensive investigations by the present inventors, a penem or carbapenem derivative into which a catechol derivative or the like is introduced is superior to imipenem-resistant Pseudomonas aeruginosa. Further, they have found that they have antibacterial activity and completed the present invention.

That is, the present invention has the general formula [I]

[Chemical 64] [In the formula, j is 0 or 1, R ¹ is a hydrogen atom, a protective group for a hydroxyl group, or a group represented by any of the following general formulas (1) to (3), R ² is a hydrogen atom, a carboxyl group. The protecting group of the group, or the negative charge when A contains a positive charge,
Represents a methylene group substituted with a sulfur atom, a methylene group or a lower alkyl group. A represents the group shown below corresponding to R ¹ . That is, when [1] R ¹ represents a hydrogen atom or a hydroxyl-protecting group, A represents a group represented by any of the following general formulas (a) to (g). General formula (a)

[Chemical 65] (In formula, k, l, and m show the integer of 0-3 (however,
l and m do not become 0 at the same time). R ³ represents a hydrogen atom, a lower alkoxycarbonyl group, a carbamoyl group, a mono- or di-lower alkylaminocarbonyl group, a cyclic aminocarbonyl group, a lower alkyl group, or a substituted lower alkyl group, and R ⁴ represents the following general formula (1) To any of the groups represented by (3). General formula (1)

[Chemical 66] (In the formula, Y is a) single bond, b) lower alkylene group,
(C) lower alkenylene group, (d) carbonyl group, (e) carbonyl group, oxygen atom, or -NR ⁰ -group (in the formula, R
⁰ represents a hydrogen atom or a lower alkyl group. Or a lower alkylene group containing at least one), or a) lower alkenylene group containing at least one carbonyl group, oxygen atom, or —NR ⁰ — group (in the formula, R ⁰ has the same meaning as described above). R ⁵ and R ⁶ are a hydrogen atom or a hydroxyl-protecting group, and Z is a hydrogen atom, a halogen atom, a nitro group, a cyano group, a lower alkoxycarbonyl group, a carbamoyl group, or a mono- or di-lower alkylaminocarbonyl group. Indicates. ) General formula (2)

[Chemical 67] (In the formula, Y, Z, R ⁵ and R ⁶ have the same meanings as described above.) General formula (3)

[Chemical 68] (In the formula, Y, Z, R ⁵ and R ⁶ have the same meanings as described above.) General formula (b)

[Chemical 69] (Wherein k, l, m and R ⁴ have the same meanings as described above, and n
Represents an integer of 0 to 3. R ⁷ represents a hydrogen atom, a lower alkyl group or a substituted lower alkyl group, and R ⁸ represents a hydrogen atom, an amino group protecting group, a lower alkyl group or a substituted lower alkyl group. General formula (c)

[Chemical 70] (In the formula, k, l, m, n, R ⁴ and R ⁸ have the same meanings as described above.) General formula (d)

[Chemical 71] (In the formula, k, 1, m, n, R ⁴ , R ⁷ and R ⁸ have the same meanings as described above, p represents an integer of 0 to 5, and q represents an integer of 1 to 5. ^a represents an acid residue or intramolecular COO when R ² has a negative charge.) General formula (e)

[Chemical 72] (In the formulae, k, l, m, n, q, R ⁴ , R ⁷ , R ⁸ and X ^a have the same meanings as described above.) General formula (f)-(CH ₂ ) _k- O-R ⁴ (F) (In the formula, k and R ⁴ have the same meanings as described above.) General formula (g)-(CH ₂ ) _k -NR ⁷ -R ⁴ (g) (In the formula, k, R ⁴ and R ^{4 7} has the same meaning as described above.] [2] When R ¹ represents a group represented by any of the general formulas (1) to (3), A represents, for example, the following general formula (h)
To (p) represent an organic group. General formula (h)

[Chemical formula 73] (In the formula, k, l, m, R ³ and R ⁸ have the same meanings as described above.) General formula (i)

[Chemical 74] (In the formula, k, l, m and R ³ have the same meanings as described above.) General formula (j)

[Chemical 75] (Wherein k, l, m and R ³ have the same meanings as described above, r
Represents an integer of 0 to 2. ) General formula (k)

[Chemical 76] (In the formula, k and R ³ have the same meanings as described above.) General formula (l)

[Chemical 77] (In the formula, k and R ³ have the same meanings as described above.) General formula (m)

[Chemical 78] (In the formula, k, l and m have the same meanings as described above, and R ⁹ represents a hydrogen atom or an amino group-protecting group.) General formula (n)-(CH ₂ ) _k -R ¹⁰ (n) (Formula In the formula, k and R ¹⁰ represent a lower alkyl group or a substituted lower alkyl group.) General formula (o)

[Chemical 79] (In the formula, k, R ³ and R ¹⁰ have the same meanings as described above.) General formula (p)

[Chemical 80] (In the formula, k, l and m have the same meanings as described above.)]
The present invention relates to a novel β-lactam compound and a salt thereof. Among the compounds represented by the general formula [I], preferred are compounds having a negative charge when R ² is a hydrogen atom or A has a positive charge, and salts thereof. More preferred among them are compounds in which R ¹ is a hydrogen atom and A is represented by the general formulas (a) to (e) and salts thereof, or R ¹ is the general formula (1) to
The compound which is (3) and its salt can be mentioned.
Of these, particularly preferred are compounds having a pyrrolidine ring in A and salts thereof.

Further, the present invention relates to a process for producing the novel β-lactam compound represented by the above general formula [I] and salts thereof. That is, (method A), when j = 1 and A is (a) to (c), the general formula [II]

[Chemical 81] [In the formula, M has the same meaning as described above, R ^1a represents a hydrogen atom or a hydroxyl-protecting group, R ^2a represents a carboxyl-protecting group,
And L represent a reactive ester group of a hydroxyl group or a substituted or unsubstituted lower alkylsulfinyl group. A compound represented by], in the general formula [III-a] A ^a -SH [III-a] [wherein, the group A ^a represented by any one of formulas (a) ~ (c) Show. ] By reacting with a mercaptan compound represented by the general formula [Ia]

[Chemical formula 82] [In the formula, R ^1a , R ^2a , A ^a and M have the same meanings as described above. ] The compound represented by the general formula [III-b-
1], Q ¹ -SH [III-b-1] [In the formula, Q ¹ represents a group represented by the above general formula (h). ] The compound of the general formula [IV-
a]

[Chemical 83] [In the formula, R ^1a , R ^2a , Q ¹ and M have the same meanings as described above. ] To produce a compound represented by, then if R ⁸ is a protecting group of the amino group, after the removal reaction of the general formula (V) R ⁴ -X ^c [V] [wherein, R ⁴ has the same meaning as described above, and X ^c represents an acid residue. ] The compound represented by the said general formula [Ia] is manufactured by making it react with the compound represented by this. (Method B) When j = 1 and A is from (d) to (e), the general formula [II]

[Chemical 84] [In the formula, R ^1a , R ^2a , M and L have the same meanings as described above. Table a compound represented by the general formula [III-b-2] Q ² -SH [III-b-2) (wherein, Q ² is the following general formula (d ') or (e') in] Is shown as a group. General formula (d ')

[Chemical 85] (In the formula, k, l, m, n, p, R ⁷ and R ⁸ have the same meanings as described above.) General formula (e ′)

[Chemical formula 86] (In the formula, k, l, m, n, R ⁷ and R ⁸ have the same meanings as described above.)], And reacted with a mercaptan compound represented by the general formula [IV-b].

[Chemical 87] [In the formula, R ^1a , R ^2a , Q ² and X have the same meanings as described above. A compound represented by] followed by the general formula (VI) _{^{X b - (CH 2) q}} -R 4 (VI) wherein the same meaning as q and R ⁴ above, the X ^b is acid residue Show. ] The compound represented by the general formula [I
-B]

[Chemical 88] [Wherein R ^1a , R ^2a and M have the same meanings as described above,
A ^b represents a group represented by the general formula (d) or (e). ] The compound represented by these is manufactured. Further, (C method) When j = 1 and A is (f) to (g), the general formula [VII]

[Chemical 89] [In the formula, k, R ^1a , R ^2a and M represent the same meaning as described above, and Y ^a represents an oxygen atom or a —NR ⁷ — group (in the formula, R ⁷ represents the same meaning as described above). ] And a compound represented by the general formula [V] R ⁴ -X ^c [V] [In the formula, R ⁴ and X ^c have the same meanings as described above. ] The compound represented by the general formula [Ic]

[Chemical 90] [In the formula, R ¹ , R ^2a and M have the same meanings as described above,
A ^c represents a group represented by the general formula (f) or (g). ] The compound represented by these is manufactured. Moreover, (D method) When j = 0 and A is (a) to (c), the general formula [VIII]

[Chemical Formula 91] [In the formula, R ^1a , M, A ^a and R ^2a have the same meanings as described above, and R ¹¹ represents a lower alkyl group, an aryl group or a lower alkoxy group. ] The compound represented by general formula [Id] is heated.

[Chemical Formula 92] [In the formula, R ^1a , M, A ^a , and R ^2a have the same meanings as described above. ] The compound represented by these is manufactured. When (E method) j = 0 and A is (d) to (e), the general formula [IX]

[Chemical formula 93] [In the formula, R ^1a , M, Q ² , R ^2a and R ¹¹ have the same meanings as described above. ] The compound represented by the general formula [X] is heated.

[Chemical 94] [In the formula, R ^1a , M, Q ² and R ^2a have the same meanings as described above. A compound represented by] followed by the general formula (VI) _{^{X b - (CH 2) q}} -R 4 (VI) wherein, q, R ⁴ and X ^b are as defined above. ] The compound represented by the general formula [Ie]

[Chemical 95] [In the formula, R ^1a , M, ^Ab and R ^2C have the same meanings as described above. ] The compound represented by these is manufactured. When (F method) j = 0 and A is (f) to (g), the general formula [XI]

[Chemical 96] [In the formula, k, R ^1a , R ^2a and M represent the same meaning as described above, and Y ^a represents an oxygen atom or a —NR ⁷ — group (in the formula, R ⁷ represents the same meaning as described above). ] And a compound represented by the general formula [V] R ⁴ -X ^c [V] [In the formula, R ⁴ and X ^c have the same meanings as described above. ] The compound represented by the general formula [If]

[Chemical 97] [Wherein R ^1a , R ^2a and M have the same meanings as described above,
A ^c represents a group represented by the general formula (f) or (g). ] The compound represented by these is manufactured. When (G method) j = 1 and A is (h) to (n), the general formula [II]

[Chemical 98] [In the formula, R ^1a , R ^2a , M and L have the same meanings as described above. A compound represented by], in the general formula [III-c] A ^d -SH [III-c] [wherein, the group A ^d represented by any one of formulas (h) ~ (n) Show. ] By reacting with a mercaptan compound represented by the general formula [XII]

[Chemical 99] [In the formula, R ^1a , M, A ^d and R ^2a have the same meanings as described above. ] The compound represented by the formula [XIII] is then produced by removing the compound represented by the formula [XIII] when R ^1a is a hydroxyl-protecting group.

[Chemical 100] [In the formula, M, A ^d and R ^2a have the same meanings as described above. ] In addition, let it be a compound represented by these, General formula [XIV] R ^<1b > ^-Xd [XIV] [In formula, R ^<1b> shows group represented by said General formula (1)-(3), ^Xd is Indicates an acid residue. ] The compound represented by the general formula [I-g]

[Chemical 101] [In the formula, M, A ^d , R ^2a and R ^1b have the same meanings as described above. ] The compound represented by these is manufactured. When (H method) j = 1 and A is from (o) to (p), the general formula [Ig ′]

[Chemical 102] [Wherein R ^1b , M and R ^2a have the same meanings as described above,
A ^e represents a group represented by the general formula (1) or (m). Formula [XV] in R ¹⁰ -X ^e [XV] [wherein the compound represented by], R ¹⁰ is as defined above, X ^e represents an acid residue. ] Or by reacting with a compound represented by R ⁹
In the general formula [I-h], the reaction for removing the protective group for the amino group in the formula ( ₁ ) is carried out and then the reaction is carried out with a lower (C ₁ -C ₅ ) alkyl ester of formimidic acid.

[Chemical 103] [Wherein R ^1b , M and R ^2a have the same meanings as described above,
A ^f represents a group represented by the general formula (o) or (p). ] The compound represented by these is manufactured. When (I method) j = 0 and A is (h) to (n), the general formula [XVI]

[Chemical 104] [In the formula, R ^1a , M, ^Ad and R ^2a have the same meanings as described above, and R ¹¹ represents a lower alkyl group, an aryl group or a lower alkoxy group. ] The compound represented by general formula [XVII] is heated.

[Chemical 105] [In the formula, R ^1a , M, A ^d and R ^2a have the same meanings as described above. ] Then, when R ^1a is a hydroxyl-protecting group, the removal reaction is carried out, and then the compound of the general formula [XVIII]

[Chemical formula 106] [In the formula, M, A ^d and R ^2a have the same meanings as described above. A compound represented by] in more general formula [XIV] R ^1b -X ^d [XIV] [wherein, the R ^1b and X ^d represents the same meaning as above. ] The compound represented by the general formula [Ii]

[Chemical formula 107] [In the formula, M, A ^d , R ^2a and R ^1b have the same meanings as described above. ] The compound represented by these is manufactured. Further, (J method) When j = 0 and A is from (o) to (p), the general formula [Ii ′]

[Chemical 108] [Wherein R ^1b , M and R ^2c have the same meanings as described above,
A ^e represents a group represented by the general formula (1) or (m). Formula [XV] in R ¹⁰ -X ^e [XV] [wherein the compound represented by], R ¹⁰ is as defined above, X ^e represents an acid residue. ] Or by reacting with a compound represented by R ⁹
In the general formula [I-j], the reaction for removing the protective group for the amino group in step ( ₁ ) is carried out, and then the reaction is carried out with a lower (C ₁ -C ₅ ) alkyl ester of formimidic acid.

[Chemical 109] [Wherein R ^1b , M and R ^2a have the same meanings as described above,
A ^f represents a group represented by the general formula (o) or (p). ] The compound represented by these is manufactured. In addition, R ¹ , R
^When a β-lactam compound in which ⁵ , R ⁶ , R ⁸ or R ⁹ is a hydrogen atom and R ² is a hydrogen atom or a negative charge is desired, the following formulas [Ia] to [Ij] are used. The reaction of removing the protective group for the hydroxyl group, the removing reaction for the protective group for the carboxyl group and the removing reaction for the protective group for the amino group may be appropriately combined with the represented compound, or these protective groups may be removed simultaneously. And a method for producing a β-lactam compound represented by the above general formula [I] or a pharmacologically acceptable salt thereof.

The above general formulas [I], [Ia] and [I-
b], [I-c], [I-d], [I-e], [I-
f], [I-g], [I-g '], [I-h], [I-
i], [I-i '], [I-j], [II], [III]
-A], [III-b-1], [III-b-2],
[III-c], [IV-a], [IV-b],
[V], [VI], [VII], [VIII], [I
X], [X], [XI], [XII], [XIII],
R ¹ , R ⁵ , R ⁶ and R ^{1a in} [XIV], [XV], [XVI], [XVII] and [XVIII].
The protective group for the hydroxyl group in or the protective group for the amino group in R ⁸ and R ⁹ is preferably a lower alkoxycarbonyl group having 1 to 5 carbon atoms such as tert-butyloxycarbonyl, for example, 2-ethyl iodide. C1-C5 halogenoalkoxycarbonyl groups such as oxycarbonyl and 2,2,2-trichloroethyloxycarbonyl, for example, substituted or unsubstituted C3-C7 lower alkenyloxycarbonyl groups such as allyloxycarbonyl. , Aralkyloxycarbonyl groups such as benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, and trialkylsilyl groups such as trimethylsilyl and tert-butyldimethylsilyl. List It is. Further, as the hydroxyl-protecting group for R ⁵ and R ⁶ , other than the above, preferable examples include a linear or branched lower alkyl group having 1 to 5 carbon atoms such as methyl or tert-butyl, for example, C2-C5 lower alkoxymethyl groups such as methoxymethyl, ethoxymethyl and isobutoxymethyl, for example aralkyl groups such as benzyl, p-methoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, such as allyl, 2 Other examples include lower alkenyl groups having 3 to 7 carbon atoms such as -methylallyl and 3-methylallyl.

Further, as the protecting group for the carboxyl group in R ² and R ^2a, various kinds of commonly used protecting groups can be used, but preferably, for example, a linear group such as methyl, ethyl, isopropyl and tert-butyl. Or a branched chain lower alkyl group having 1 to 5 carbon atoms, such as 2-ethyl iodide or 2,2,2-trichloroethyl having 1 to 5 carbon atoms.
A halogeno lower alkyl group of 5, for example, methoxymethyl,
1 carbon atom such as ethoxymethyl and isobutoxymethyl
~ 5 lower alkoxymethyl groups such as acetoxymethyl, propionyloxymethyl, butyryloxymethyl, pivaloyloxymethyl, etc. lower aliphatic acyloxymethyl groups having 1-5 carbon atoms such as 1-ethoxycarbonyloxyethyl such 1- (C ₁ ~C ₅₎ lower alkoxycarbonyloxy ethyl group such as a benzyl, p- methoxybenzyl, o- nitrobenzyl, p-
Aralkyl groups such as nitrobenzyl, eg allyl,
3 carbon atoms such as 2-methylallyl and 3-methylallyl
~ 7 lower alkenyl groups, benzhydryl groups, or phthalidyl groups.

Examples of the lower alkyl substituent of the methylene group in M include those having 1 to 5 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl or n-pentyl.

The lower alkyl group for R ⁰ , R ³ , R ⁷ , R ⁸ , R ¹⁰ and R ¹¹ is, for example, carbon such as methyl, ethyl, n-propyl, isopropyl, n-butyl or n-pentyl. The thing of several 1-5 is mentioned. Examples of the lower alkoxy group for R ¹¹ include those having 1 to 5 carbon atoms such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy or n-pentoxy. Examples of the aryl group include phenyl, o-tolyl and p-tolyl.

The substituted lower alkyl group for R ³ , R ⁷ and R ⁸ is, for example, hydroxymethyl,
C1-C5 hydroxy lower alkyl groups such as 1-hydroxyethyl and 2-hydroxyethyl, for example, C1-C5 lower alkoxyalkyl groups such as methoxymethyl, 1-methoxyethyl and 2-ethoxyethyl, For example, aminomethyl, N-methylaminomethyl, N, N-
C1-C5 unsubstituted or mono- or di-lower alkylaminoalkyl groups such as dimethylaminomethyl and N-methylaminoethyl, such as carbamoylmethyl,
Examples include unsubstituted or mono- or di-lower alkylaminocarbonylalkyl groups having 1 to 5 carbon atoms such as methylaminocarbonylmethyl, dimethylaminocarbonylmethyl and 2- (dimethylaminocarbonyl) ethyl. Examples of the substituted lower alkyl group for R ¹⁰ include aminomethyl, acetylaminomethyl, carboxylmethyl, acetylmethyl, propionylmethyl, carbamoylmethyl, N-methylaminocarbonylmethyl, N, N-dimethylaminocarbonylmethyl, 2
-(Iminomethylamino) methyl, 2-aminoethyl,
2-acetylaminoethyl, 2-cyanoethyl, 2-methoxyethyl, 2-ethoxyethyl, 2-carboxyethyl, 2-hydroxyethyl, 2-carbamoylethyl, 2-N-methylaminocarbonylethyl, 2-N,
Examples thereof include those having 2 to 7 carbon atoms such as N-dimethylaminocarbonylethyl, 3-carboxypropyl, 4-hydroxybutyl, 5-hydroxypentyl and the like.

Examples of the lower alkoxycarbonyl group for R ³ include those having 2 to 5 carbon atoms such as methoxycarbonyl, ethoxycarbonyl, n-propyloxycarbonyl and tert-butyloxycarbonyl. Furthermore, examples of the mono- and di-lower alkylaminocarbonyl groups include those having 2 to 5 carbon atoms such as methylaminocarbonyl, dimethylaminocarbonyl, ethylaminocarbonyl, methylethylaminocarbonyl and diethylaminocarbonyl. Further, as the cyclic aminocarbonyl group for R ³ , the following 3
To 6-membered ring.

[Chemical 110]

Examples of the halogen atom in Z include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. Further, examples of the lower alkoxycarbonyl group include those having 2 to 5 carbon atoms such as methoxycarbonyl, ethoxycarbonyl, n-propyloxycarbonyl and tert-butyloxycarbonyl. Further, as the mono- and di-lower alkylaminocarbonyl group,
2 carbon atoms such as methylaminocarbonyl, dimethylaminocarbonyl, ethylaminocarbonyl, methylethylaminocarbonyl, diethylaminocarbonyl
~ 5 are mentioned.

The reactive ester of the hydroxyl group represented by L is, for example, benzenesulfonic acid ester, p-
Substituted or unsubstituted aryl sulfonic acid ester such as toluene sulfonic acid ester, p-nitrobenzene sulfonic acid ester and p-bromobenzene sulfonic acid ester, for example, lower alkane having 1 to 5 carbon atoms such as methane sulfonic acid ester and ethane sulfonic acid ester. Sulfonic acid esters, for example, C1-5 halogeno lower alkane sulfonic acid esters such as trifluoromethane sulfonic acid esters, diaryl phosphoric acid esters such as diphenyl phosphoric acid esters, chlorinated compounds such as esters with hydrogen halides, Examples thereof include halides such as bromide and iodide. Among these, preferred examples include p-toluenesulfonic acid ester, methanesulfonic acid ester, and diphenylphosphoric acid ester. Examples of the substituted or unsubstituted lower alkylsulfinyl group include, for example, methylsulfinyl, ethylsulfinyl, n-propylsulfinyl,
Examples thereof include those having 1 to 5 carbon atoms such as n-butylsulfinyl and 2- (acetylamino) ethylsulfinyl.

The acid residue in X ^a , X ^b , X ^c , X ^d and X ^e is, for example, an inorganic acid residue such as chlorine, bromine, fluorine or halogen such as iodine, eg benzenesulfonyloxy. , P-toluenesulfonyloxy, methanesulfonyloxy, trifluoromethanesulfonyloxy, etc., and the like.

Further, when the terminal of Y is a carbonyl group,
X ^c and X ^d have 2 to 2 carbon atoms such as ethoxycarbonyloxy and isopropyloxycarbonyloxy.
The lower alkoxycarbonyloxy group of 6 can also be mentioned.

Further, the lower alkylene group in Y includes those having 1 to 4 carbon atoms such as methylene, ethylene, propylene and butylene, and the lower alkenylene group includes those having 2 to 2 carbon atoms such as vinylene, propenylene and butynylene. 4 are mentioned. Furthermore, examples of the lower alkylene group containing at least one kind of carbonyl group, oxygen atom or —NR ⁰ — group include those shown below. _{-CO-CH 2 -, - CO} -CH 2 CH 2 -, - CH 2
_{-CO -, - CH 2 -CO-} CH 2 -, - CH 2 -CO
_{NMe -, - CH 2 -CO-} NH -, - CH 2 -CON
_{H-CH 2 -, - CH} 2 CH 2 -CO-NH -, - CH
_{2 CH 2 -CO-NMe -,} - CH 2 CH 2 CO-NM
_{e-CH 2 -, - COO} -CH 2 -, - CH 2 -COO
—, —CH ₂ —COO—CH ₂ CH ₂ — In addition, a carbonyl group, an oxygen atom or a —NR ⁰ — group is 1
Examples of the lower alkenylene group containing one or more species include those shown below. -CO-CH = CH -, - CH 2 -CO-CH = CH
_{-, - CH 2 -CO-NH} -CH = CH-CH 2 -, -
_{CH 2 -CO-NMe-CH =} CH-CH 2 -, - CO
_{O-CH 2 -CH = CH -} , - CH 2 -COO-CH =
CH-

Examples of other organic groups other than the general formulas (a) to (p) in A include cyclic alkyl groups having 3 to 8 carbon atoms such as cyclopropyl, cyclobutyl and cyclopentyl, and lower alkyl groups having 1 to 3 carbon atoms. A cyclic alkyl group having 3 to 8 carbon atoms as described above via an alkylene group, for example, 2-
A mono- or bicyclic heterocyclic group consisting of a total of 5 to 11 atoms such as pyrrolyl, 4-imidazolyl and 2-thiazolyl, of which 1 to 5 are heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom. Examples thereof include mono- or bicyclic heterocyclic groups as described above through a lower alkylene group having 1 to 3 carbon atoms.

The salt of the above general formula [I] is a conventional non-toxic salt. Examples of such salts include inorganic base salts such as sodium, potassium, calcium, magnesium and ammonium, organic base salts such as triethylammonium, pyridinium and diisopropylammonium, inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid. Examples thereof include addition salts such as organic acid addition salts of formic acid, acetic acid, methanesulfonic acid, benzenesulfonic acid and the like.

The method for producing the compound of the present invention is described in detail below. (Method A) The compound represented by the general formula [Ia] is obtained by reacting the compound represented by the general formula [II] and the mercaptan compound represented by the general formula [III-a] in an inert solvent,
It can be produced by reacting in the presence of a base (step A).

[Chemical 111] Among the inert solvents used in these reactions, dioxane, tetrahydrofuran, dimethylsulfoxide, acetonitrile, and hexamethylphosphoramide are preferable.

Examples of the base include inorganic bases such as sodium carbonate, potassium carbonate, sodium hydride, potassium hydride and potassium t-butoxy, such as pyridine, dimethylaminopyridine, triethylamine, diisopropylethylamine and 1,8-diazabicyclo [5. .4.
0] -7-undecene (DBU) and the like. Particularly preferred are diisopropylethylamine or DBU.

The base is required in an amount sufficient for the reaction to proceed sufficiently, and it can be carried out usually in an amount of 1 to 3 equivalents relative to the mercaptan compound represented by the general formula [III-a]. The mercaptan compound represented by the general formula [III-a] is required in an amount sufficient for the reaction to proceed sufficiently, and a large excess amount can be used, but it is usually 1 relative to the compound represented by the general formula [II]. ~ 2 equivalents can be used. The reaction temperature is −78 to + 60 ° C.,
The range of -40 to + 40 ° C is preferable. After the completion of the reaction, the product can be taken out by a usual organic chemical method.

The compound represented by the general formula [Ia] can also be produced in the following manner.

[Chemical 112] First, the compound represented by the general formula [II] and the general formula [II]
I-b-1] and a mercaptan compound represented by the formula [IV-a] are produced by the above step A. Then, a reaction for removing the amino-protecting group in R ⁸ is carried out from the compound represented by the general formula [IV-a] according to a known method. Method for removing this protecting group (step B)
Is a method known per se of treating with an acid, a base, a reducing agent, etc., for example, TW Greene: Protective Groups in
Reference can be made to Organic Synthesis, J. Wiley & Sons Inc., 1981. Preferable examples of the acid include trifluoroacetic acid, formic acid, boron trifluoride, aluminum chloride and the like or a mixture thereof. Preferable examples of the base include alkali metal carbonates such as sodium carbonate and potassium carbonate, alkali metal sulfides such as sodium sulfide and potassium sulfide, and tetrabutylammonium fluoride. Preferable examples of the reduction method include zinc and acetic acid, hydrogen and hydrogenolysis with palladium-carbon or platinum. Also,
A technique using tetrakistriphenylphosphine palladium can also be used.

The solvent used is not particularly limited as long as it does not adversely affect the reaction for removing the protecting group.
Water, alcohols such as methanol and ethanol, ethers such as tetrahydrofuran and dioxane, fatty acids such as acetic acid, halogenohydrocarbons such as dichloromethane, dichloroethane, chloroform and chlorobenzene, and mixed solvents thereof can be used. With respect to the reaction temperature, the reaction can be suppressed or promoted by appropriately cooling or heating, and the preferable temperature is −30 to + 40 ° C.

After the reaction for removing the protecting group is carried out in this manner, the compound represented by the general formula [V] is reacted in the presence of a base, if necessary, in an inert solvent (step C). The compound represented by the above general formula [Ia] can be produced. As the inert solvent used in this reaction, water, ketones such as acetone and methyl ethyl ketone,
Examples thereof include ethers such as tetrahydrofuran and dioxane, acetonitrile, dimethylformamide, and halogenohydrocarbons such as dichloromethane, dichloroethane and chloroform, which do not adversely influence the reaction, or a mixture thereof.

At this time, if necessary, an inorganic base such as sodium carbonate, potassium carbonate, sodium hydroxide or sodium hydride, or pyridine, dimethylaminopyridine, triethylamine, diisopropylethylamine,
An organic base such as DBU can coexist. The reaction temperature is not particularly limited, but is usually -40 to + 60 ° C.
Is preferred. After completion of the reaction, the product can be taken out by a usual organic chemical method.

(Method B) The compound represented by the general formula [Ib] can be produced as follows.

[Chemical 113] First, the compound represented by the general formula [II] and the general formula [II]
The compound represented by the general formula [IV-b] is produced by the step A from the mercaptan compound represented by Ib-2]. Then, the compound represented by the general formula [IV-b] is reacted with the compound represented by the general formula [VI] in an inert solvent (step D) to give the compound represented by the general formula [Ib]. Can be manufactured. Examples of the inert solvent used in this reaction include water, ketones such as acetone and methyl ethyl ketone, ethers such as tetrahydrofuran and dioxane, acetonitrile, dimethylformamide, or halogeno hydrocarbons such as dichloromethane, dichloroethane or chloroform. Examples thereof include solvents or mixtures thereof that do not adversely affect the above. The reaction temperature is not particularly limited, but is usually -40 to
A range of + 60 ° C is preferred. After completion of the reaction, the product can be taken out by a usual organic chemical method.

(Method C) The compound represented by the general formula [Ic] is produced by the above step C from the compound represented by the general formula [VII] and the compound represented by the general formula [V]. be able to.

[Chemical 114]

(Method D) The compound represented by the general formula [Id] can be produced by heating the compound represented by the general formula [VIII] in an inert solvent (step E). ..

[Chemical 115] Aromatic hydrocarbons such as benzene, toluene and xylene are suitable as the inert solvent, but ethers such as dioxane and tetrahydrofuran, various solvents such as cyclohexane and chloroform can also be used. The reaction temperature can be suppressed or promoted by appropriately cooling or heating, and it can be said that the preferable reaction temperature is 20 to 200 ° C. This step itself is a known method, for example, The Journal of
Antibiotics, vol.36, p.938-941,1983, The Journal
of Antibiotics, vol.41, p.780-787, 1988 or Jo
urnal of Medicinal Chemistry, vol.30, p.871-880, 1
It can be carried out according to the method described in 987.

(Method E) The compound represented by the general formula [Ie] can be produced as follows.

[Chemical formula 116] That is, the compound represented by the general formula [IX] is subjected to the step E to produce the compound represented by the general formula [X], and then the compound represented by the general formula [VI] and the step It can be manufactured by attaching D. (Method F) The compound represented by the general formula [If] can be produced by the step C from the compound represented by the general formula [XI] and the compound represented by the general formula [V]. ..

[Chemical 117]

(Method G) The compound represented by the general formula [Ig] can be produced as follows.

[Chemical 118] First, the compound represented by the general formula [II] and the general formula [II]
The compound represented by the general formula [XII] is produced by the step A from the mercaptan compound represented by Ic]. Next, when R ^1a is a hydroxyl-protecting group, the compound represented by the general formula [XII] is subjected to the reaction of removing the protective group in the above step B, and then the resulting compound of the general formula [XI
II] by subjecting the compound represented by the general formula [XIV] to the compound represented by the general formula [I-
The compound represented by g] can be manufactured.

(Method H) The compound represented by the general formula [Ih] can be produced as follows.

[Chemical 119] That is, the compound represented by the general formula [Ig ′] and the compound represented by the general formula [XV] are subjected to the step D. Alternatively, after the reaction for removing the amino-group-protecting group at R ⁹ of the compound represented by the general formula [Ig ′] is carried out by the above step B, a lower (C ₁ -C ₅ ) alkyl ester of formimidic acid is added. The reaction (step F) is carried out by a method known per se (for example, the method described in European Patent Application Publication No. 0289801).

(Method I) The compound represented by the general formula [Ii] can be produced as follows.

[Chemical 120] That is, a compound represented by the general formula [XVII] is produced by subjecting the compound represented by the general formula [XVI] to the step E, and then when R ^1a is a hydroxyl-protecting group, The compound of the formula [XVII] is subjected to the reaction of removing the protecting group in the above step B to give a compound of the general formula [X
VIII], the compound represented by the general formula [XIV] and the above step C can be applied to produce the compound represented by the general formula [Ii].

(Method J) The compound represented by the general formula [I-j] can be produced as follows.

[Chemical 121] That is, the compound represented by the general formula [Ii ′] and the compound represented by the general formula [XV] are subjected to the step D. Alternatively, the reaction of removing the amino-protecting group in R ⁹ of the compound represented by the general formula [Ii ′] is carried out in the step B, and then the step F is carried out.

The obtained general formulas [Ia] to [I-
j], if necessary, the reaction of removing the protective group for the carboxyl group in R ^2a , R ⁸ or R ⁹
Removal of the amino-protecting group in R, and R ^1a ,
By subjecting R ⁵ or R ^{6 to a} reaction in which the removal reaction of the hydroxyl-protecting group is appropriately combined, R ⁸ ,
A β-lactam compound represented by the general formula [I] in which at least one of R ⁹ , R ¹ , R ⁵ , or R ⁶ is a hydrogen atom, and R ² is a hydrogen atom or a negative charge is produced. be able to. After completion of the reaction, the product can be taken out by a usual organic chemistry method, for example, CHP-20P.
The reaction product can be obtained by subjecting it to column chromatography using an adsorption resin or the like, collecting the portion from which the target compound is eluted, and freeze-drying.

The compound represented by the general formula [II], which is the starting material compound of the present invention, is publicly known, for example, Tetrah.
edron Letters, vol.23, p.897-900, 1982, Heterocycl
es, vol.21, p.29-40, 1984 or European Patent Application Publication No. 0046363. In addition, the general formula [V
II] or the compound represented by the general formula [XI] is also known, for example, Chemical & Pharmaceutical Bulletin,
vol.29, p.3158-3172,1981, The Journal of Antibioti
cs, vol.36, p.938-941, 1983 or The Journal of
Antibiotics, vol.41, p.780-787, 1988. Further, compounds represented by the general formula [VIII], [IX] or [XVI] are also known, for example, The
Journal of Antibiotics, vol.36, p.938-941, 1983,
TheJournal of Antibiotics, vol.41, p.780-787, 19
88 or Journal of Medicinal Chemistry, vol.30,
It can be produced according to the method described in p.871-880, 1987.

On the other hand, general formulas [III-a] and [III-
b-1], [III-b-2] or [III-c]
The mercaptan compound represented by the following formula is known in various methods, for example, JP-A-60-58987, Japanese Patent Application No. 2-349.
It can be produced by the method described in Japanese Patent Publication No. 52 or Japanese Patent Application No. 2-212102.

The compound represented by the general formula [I] includes
There are optical isomers and stereoisomers based on the asymmetric carbons at the 5-position, 6-position and 8-position of the penem skeleton or 4-position, 5-position, 6-position and 8-position of the carbapenem skeleton, and all of these isomers are convenient for convenience. Although shown as a single formula, this is not intended to limit the scope of the invention, which is intended to include all isomers and isomer mixtures based on each asymmetric carbon atom. However, regarding the 5- and 6-position configurations, preferably, when M is a sulfur atom or a methylene group, the 5-position carbon atom has the R configuration (5R, 6).
S) -coordinated or (5R, 6R) -coordinated compound, when M is a methylene group substituted with a lower alkyl group and j = 0, the carbon atom at 5-position has R-coordinated (5R, 6S) Coordination or (5R, 6R) coordination compounds, when M is a methylene group substituted with a lower alkyl group and j = 1, the carbon atom at the 5 position has S coordination (5S, 6S) coordination Alternatively, compounds having (5S, 6R) coordination can be mentioned.
For the 8-position, a compound having an R-coordinate can be selected as a suitable one.

More preferred is the formula [Ik]

[Chemical formula 122] And the formula [I-1]

[Chemical 123] The compound shown by can be mentioned. Examples of the compound having the most suitable coordination include the compounds represented by the above general formula [Ik].

When producing isomers having such a coordination, the starting compounds [II], [VII] and [VII]
I], [IX], [XI] or [XVI] is carried out using the corresponding isomer.

Among the compounds represented by the general formula [I], preferred ones are those represented by the general formulas [Ia] and [I-
b], [Id], [Ie], [Ig] or [Ii] can be mentioned.
Particularly preferred are the above-mentioned general formulas [Ia] and [I-
b], [Id] or [Ie] can be mentioned.

When the compound represented by the general formula [I] has a hydroxypyridone moiety (general formula (2)
Alternatively, when the group represented by (3) is included), 1
The following formula (i) or (i
It is possible for tautomers represented by i) to exist, and the present invention includes all of them (however, the naming of compounds and the description of structural formulas are to be made in the pyridone form). (I) When the 1-position substituent is a hydrogen atom (general formula (2)
When the group represented by is included)

[Chemical formula 124] (Ii) When the 1-position substituent is a hydroxyl group (when the group represented by the general formula (3) is included)

[Chemical 125]

The compound of the present invention represented by the above general formula [I] is a penem or carbapenem derivative into which a catechol derivative or the like is introduced, and these compounds exhibit excellent antibacterial activity and are useful as pharmaceuticals. Alternatively, it is a key intermediate for compounds exhibiting their activity. Specific examples of the compound having the general formula [I] obtained by the present invention include, for example, Table 1- (1) and Table 1 below.
The compound shown in-(2) can be mentioned.

[Table 1]

The compounds exemplified in Table 1- (1) and Table 1- (2) have stereoisomers as described above, and the exemplified compounds include all isomers.

The novel β-lactam compound represented by the above general formula [I] according to the present invention is suitable for Gram-positive bacteria and Gram-negative bacteria such as Staphylococcus aureus, Streptococcus pyloriens, Escherichia coli and Pseudomonas aeruginosa. It is useful as an antibacterial agent showing excellent antibacterial activity. It is known that carbapenem compounds such as imipenem are unstable to DHP-I localized in the living body, especially in the kidney. However, the compound of the present invention is different in DHP-I although the degree varies depending on each compound. On the other hand, it can be mentioned as a characteristic that it is more stable, and some of the compounds of the present invention are extremely stable against DHP-I. In addition, it can be mentioned as a characteristic that the in vivo half-life (T _1/2 ) tends to be longer than that of imipenem or the like, although the degree varies depending on each compound. Further, the compound of the present invention can be mentioned as a feature that it exhibits excellent antibacterial activity against imipenem-resistant Pseudomonas aeruginosa.

Dosage forms for using the compound of the present invention as an antibacterial agent for treating bacterial infection include, for example, tablets,
Examples thereof include oral administration by capsules, powders, syrups and the like, or parenteral administration by intravenous injection, intramuscular injection, rectal administration and the like.

The above suitable dosage forms can be prepared by incorporating the active compound into an acceptable conventional carrier, excipient, binder, stabilizer and the like. When used in an injection form, an acceptable buffer, solubilizing agent, isotonic agent, etc. may be added.

The dose varies depending on the symptoms, age, body weight, dosage form, number of administrations, etc.
Administer 0 to 3000 mg once or in several divided doses. The dose can be reduced or increased as needed.

[0049]

EXAMPLES Next, the present invention will be described more specifically with reference to examples, but the present invention is not limited to these examples. The abbreviations used in the following examples have the following meanings. AOC: allyloxycarbonyl group BOC: t-butyloxycarbonyl group Me: methyl group Ph: phenyl group PNB: p-nitrobenzyl group PNZ: p-nitrobenzyloxycarbonyl group TBDMS: tert-butyldimethylsilyl group TMS: trimethylsilyl group

Example 1

[Chemical formula 126] a) (4R, 5R, 6S, 8R) -p-nitrobenzyl-3-diphenylphosphoryloxy-4-methyl-6-
(1-hydroxyethyl) -1-azabicyclo [3.
2.0] Hept-2-en-7-one-2-carboxylate (1.52 g) in dry acetonitrile (10 ml)
Dissolve in, and under ice cooling in a nitrogen stream (2S, 4S) -1-
A solution of allyloxycarbonyl-2-dimethylaminocarbonyl-4-mercaptopyrrolidine (877 mg) in dry acetonitrile (2 ml) was added, and then diisopropylethylamine (0.49 ml) was added, and the mixture was stirred for 1 hour as it was. The reaction solution was diluted with ethyl acetate, washed with a 2.5% aqueous solution of monopotassium phosphate, brine, dried over magnesium sulfate, and the solvent was removed. The residue was purified by silica gel column chromatography (4R, 5S, 6S, 8R,
2'S, 4'S) -p-nitrobenzyl-3-[(1-
Allyloxycarbonyl-2-dimethylaminocarbonylpyrrolidin) -4-ylthio] -4-methyl-6-
(1-hydroxyethyl) -1-azabicyclo [3.
2.0] Hept-2-en-7-one-2-carboxylate (1.0 g) was obtained.

IR _max cm ^-1 (neat): 3307 (br), 1770, 1
702, 1655 (sh), 1650, 1522, 1412,1347, 1140;

NMR δ ppm (CDCl ₃ ): 1.28 (3H, m), 1.37
(3H, m), 2.68 (1H, m), 2.97, 2.98,3.06, 3.11 (3H in total, each s), 3.27 (1H, m), 3.47 (2H, m), 3.64 (1H,
m), 4.12 (1H, m), 4.26 (2H, m), 4.74 (1H, m), 5.1 ~ 5.6 (4
H, m), 5.90 (1H, m), 7.65 (2H, d, J = 8.8Hz), 8.23 (2H, d, J =
8.8Hz).

B) (4R, 5S, 6S, 8R, 2'S,
4'S) -p-nitrobenzyl-3-[(1-allyloxycarbonyl-2-dimethylaminocarbonylpyrrolidin) -4-ylthio] -4-methyl-6- (1-hydroxyethyl) -1-azabicyclo [ 3.2.0] Hept-2-en-7-one-2-carboxylate (1.
65 g) was dissolved in dry tetrahydrofuran (30 ml), dimedone (1.66 g) was added in a nitrogen stream, and tetrakistriphenylphosphine palladium (3
42 mg) was added and the mixture was stirred for 10 minutes. By removing the desolvated residue by silica gel column chromatography, (4R, 5S, 6S, 8R, 2'S, 4'S) -p-
Nitrobenzyl-3-[(2-dimethylaminocarbonylpyrrolidine) -4-ylthio] -4-methyl-6-
(1-hydroxyethyl) -1-azabicyclo [3.
2.0] Hept-2-en-7-one-2-carboxylate (0.94 g) was obtained.

IR _max cm ^-1 (neat): 3370 (br), 1763, 1
698, 1638, 1518, 1381, 1342, 1203, 1137;

NMR δ ppm (CDCl ₃ ): 1.28 (3H, d, J = 7.3H
z), 1.36 (3H, d, J = 6.3Hz), 1.59 (1H, m), 2.59 (1H, m),
3.00 (3H, s), 3.02 (3H, s), 3.10 (1H, dd, J = 11.6Hz, 4.6H
z), 3.27 (2H, m), 3.39 (1H, m), 3.75 (1H, m), 3.94 (1H, t, J
= 7.9Hz), 4.25 (2H, m), 5.23 (1H, d, J = 13.8Hz), 5.50 (1H,
d, J = 13.8Hz), 7.67 (2H, d, J = 8.6Hz), 8.24 (2H, d, J = 8.6H)
z).

C) (4R, 5S, 6S, 8R, 2'S,
4'S) -p-nitrobenzyl-3-[(2-dimethylaminocarbonylpyrrolidin) -4-ylthio] -4-
Methyl-6- (1-hydroxyethyl) -1-azabicyclo [3.2.0] hept-2-en-7-one-2-
Carboxylate (137 mg) was dissolved in acetone (3 ml) and methylene chloride (2 ml) and 1-bromoacetyl-
3,4-Di- (p-nitrobenzyloxy) benzene (200 mg) was added, and the mixture was stirred at room temperature for 1 day. 0.02M
By washing with a phosphate buffer (pH = 7.0), drying with magnesium sulfate, removing the solvent, and purifying the residue by silica gel column chromatography (4R, 5S, 6S, 8R,
2'S, 4'S) -p-nitrobenzyl-3-[(1-
(3,4-di-p-nitrobenzyloxybenzoyl)
Methyl-2-dimethylaminocarbonylpyrrolidine)-
4-ylthio] -4-methyl-6- (1-hydroxyethyl) -1-azabicyclo [3.2.0] hept-2-
En-7-one-2-carboxylate (129 mg) was obtained.

IR _max cm ^-1 (neat): 3400 (br), 1763, 1
694, 1672, 1640, 1602, 1505, 1417, 1344, 1271, 120
7, 1177, 1133;

NMR δ ppm (CDCl ₃ ): 1.20 (3H, d, J = 7.3H
z), 1.35 (3H, d, J = 5.9Hz), 1.87 (1H, m), 2.74 (1H, m),
2.95 (3H, s), 3.03 (3H, s), 3.20 (3H, m), 3.37 (1H, m), 3.
75 (1H, d, J = 16.2Hz), 3.81 (1H, m), 3.99 (1H, t, J = 7.9Hz),
4.23 (1H, t, J = 6.3Hz), 4.32 (1H, d, J = 16.2Hz), 5.17 (1H,
d, J = 13.9Hz), 5.32 (2H, s), 5.37 (2H, s), 5.44 (1H, d, J = 1
3.9Hz), 6.93 (1H, d, J = 8.6Hz), 7.56 ~ 7.77 (7H, m), 7.9
6 (1H, d, J = 2.0Hz), 8.13 ~ 8.33 (6H, m).

D) (4R, 5S, 6S, 8R, 2'S,
4'S) -p-nitrobenzyl-3-[(1- (3,4
-Di-p-nitrobenzyloxybenzoyl) methyl-
2-Dimethylaminocarbonylpyrrolidin) -4-ylthio] -4-methyl-6- (1-hydroxyethyl)-
1-azabicyclo [3.2.0] hept-2-ene-7
-On-2-carboxylate (120 mg) was added to tetrahydrofuran (6 ml), 0.1M phosphate buffer (pH =
It was dissolved in 7.0, 6 ml) and 10% palladium on carbon (12
0 mg) was added, and hydrogenation was carried out at room temperature under atmospheric pressure for 2 hours. The catalyst was filtered off, the filtrate was washed 3 times with methylene chloride, the organic solvent in the aqueous layer was distilled off under reduced pressure, then filtered through a membrane filter, and the filtrate was purified by column chromatography using CHP-20P polymer. Fractions eluted with a 2 to 4% tetrahydrofuran aqueous solution were collected and freeze-dried to obtain white amorphous (4R, 5S, 6S, 8
R, 2'S, 4'S) -3-[(1- (3,4-Dihydroxybenzoyl) methyl-2-dimethylaminocarbonylpyrrolidin) -4-ylthio] -4-methyl-6-
(1-hydroxyethyl) -1-azabicyclo [3.
2.0] Hept-2-en-7-one-2-carboxylic acid was obtained.

UV _max nm (H ₂ O): 220, 263, 297;

IR _max cm ^-1 (KBr): 3400 (br), 1754, 16
20, 1594, 1388, 1289;

NMR δ ppm (D ₂ O): 1.19 (3H, d, J = 6.9H
z), 1.30 (3H, d, J = 6.3Hz), 1.72 (3H, m), 2.80 (1H, m), 2.
90 (3H, s), 3.01 (3H, s), 3.24 (3H, m), 3.40 (2H, m), 3.87
(1H, m), 3.95 ~ 4.30 (5H, m), 6.91 (1H, d, J = 8.3Hz), 7.45
(1H, s), 7.52 (1H, d, J = 8.3Hz).

Example 2

[Chemical 127] a) (4R, 5S, 6S, 8R, 2'S, 4'S) -p
-Nitrobenzyl-3-[(1-allyloxycarbonyl-2-dimethylaminocarbonylpyrrolidine) -4-
Ilthio] -4-methyl-6- (1-hydroxyethyl) -1-azabicyclo [3.2.0] hept-2-en-7-one-2-carboxylate (574 mg) was dried over methylene chloride (18 ml). Dimethone (560 mg) was added in a nitrogen stream, tetrakistriphenylphosphine palladium (116 mg) was added at room temperature, and the mixture was stirred for 20 minutes. After cooling the reaction solution to 0 ° C., diisopropylethylamine (115 mg) dissolved in dry methylene chloride (0.5 ml) was added, and then 3,4-di (t-butyldimethylsilyloxy) cinnamoyl chloride (about 1 mmo).
A solution of l) in dry methylene chloride (3 ml) was added dropwise. The reaction solution was washed with brine, dried over magnesium sulfate and sodium carbonate, the solvent was removed, and the residue was purified by silica gel column chromatography (4R, 5S, 6S, 8
R, 2'S, 4'S) -p-nitrobenzyl-3-
[{1- (3,4-Di (t-butyldimethylsilyloxy) cinnamoyl) -2-dimethylaminocarbonylpyrrolidine} -4-ylthio] -4-methyl-6- (1-
Hydroxyethyl) -1-azabicyclo [3.2.0]
Hept-2-en-7-one-2-carboxylate (446 mg) was obtained.

IR _max cm ^-1 (neat): 3400 (br), 1770, 1
707, 1655 (sh), 1642, 1602, 1593,1513, 1347, 1302,
1253, 1132;

NMR δ ppm (CDCl ₃ ): 0.19 (6H, s), 0.21
(6H, s), 0.98 (18H, s), 1.27 (3H, d, J = 6.9Hz), 1.37 (3H,
d, J = 6.3Hz), 2.63 (1H, m), 3.00 (3H, s), 3.21 (3H, s), 3.
25 ~ 3.55 (3H, m), 3.60 ~ 3.85 (2H, m), 4.20 ~ 4.40 (3H,
m), 4.98 (1H, t, J = 8.4Hz), 5.20 ~ 5.60 (2H, m), 6.46 (1H,
d, J = 16Hz), 6.81 (1H, d, J = 8.3Hz), 6.94 (1H, d, J = 2.0Hz),
7.05 (1H, dd, J = 2.0Hz and 8.3Hz), 7.56 (1H, d, J = 16H
z), 7.66 (2H, d, J = 8.9Hz), 8.24 (2H, d, J = 8.9Hz).

B) (4R, 5S, 6S, 8R, 2'S,
4'S) -p-nitrobenzyl-3-[(1- (3,4
-Di (t-butyldimethylsilyloxy) cinnamoyl) -2-dimethylaminocarbonylpyrrolidine} -4
-Ilthio] -4-methyl-6- (1-hydroxyethyl) -1-azabicyclo [3.2.0] hept-2-en-7-one-2-carboxylate (446 mg) was added to tetrahydrofuran (6.8 ml). ), Acetic acid (187 mg) was added at room temperature, and then a 1M-tetrabutylammonium fluoride tetrahydrofuran solution (1 ml) was added dropwise. After stirring for 1 hour, the reaction solution was diluted with ethyl acetate,
An aqueous solution of sodium hydrogen carbonate (262 mg) was added for neutralization, the organic layer was washed with brine, dried over magnesium sulfate, and the solvent was removed. The residue was purified by silica gel column chromatography (4R, 5S, 6S, 8R, 2'S,
4'S) -p-nitrobenzyl-3-[{1- (3,4
-Dihydroxycinnamoyl) -2-dimethylaminocarbonylpyrrolidin} -4-ylthio] -4-methyl-
6- (1-Hydroxyethyl) -1-azabicyclo [3.2.0] hept-2-en-7-one-2-carboxylate (220 mg) was obtained.

IR _max cm ^-1 (KBr): 3430 (br), 1768, 17
10, 1642, 1600, 1521, 1440, 1350,1286;

NMR δ ppm (CDCl ₃ -CD ₃ OD (9: 1)): 1.2
5 (3H, d, J = 7.3Hz), 1.33 (3H, d, J = 6.3Hz), 2.66 (1H, m),
3.00 (3H, s), 3.38 (3H, m), 3.70 (2H, m), 4.0 ~ 4.4 (3H,
m), 4.95 (1H, t, J = 8.6Hz), 5.2 ~ 5.6 (2H, m), 6.49 (1H, d,
J = 15Hz), 6.80 (1H, d, J = 8.3Hz), 6.92 (1H, d, J = 7.3Hz),
7.04 (1H, s), 7.49 (1H, d, J = 15Hz), 7.67 (2H, d, J = 8.9Hz),
8.24 (2H, d, J = 8.9Hz).

C) (4R, 5S, 6S, 8R, 2'S,
4'S) -p-nitrobenzyl-3-[{1- (3,4
-Dihydroxycinnamoyl) -2-dimethylaminocarbonylpyrrolidin} -4-ylthio] -4-methyl-
6- (1-hydroxyethyl) -1-azabicyclo [3.2.0] hept-2-en-7-one-2-carboxylate (258 mg) was added to tetrahydrofuran (1
3.0 ml), 0.1 M phosphate buffer (pH 7.0, 1)
3.0 ml), dissolved in 10% palladium on carbon (250 m
g) was added and hydrogenated at room temperature and atmospheric pressure for 1 hour. The catalyst was filtered off, the filtrate was washed 3 times with methylene chloride, the organic solvent in the aqueous layer was distilled off under reduced pressure, filtered through a membrane filter, and the filtrate was subjected to column chromatography with CHP-20P polymer and 2% tetrahydrofuran. The fraction eluted with the aqueous solution was freeze-dried to obtain white amorphous (4R, 5S, 6S, 8R, 2'S, 4'S) -3-
[{1- (3,4-dihydroxycinnamoyl) -2-
Dimethylaminocarbonylpyrrolidine} -4-ylthio] -4-methyl-6- (1-hydroxyethyl) -1
-Azabicyclo [3.2.0] hept-2-ene-7-
On-2-carboxylic acid was obtained.

UV _max nm (H ₂ O): 218 (sh), 245 (sh),
297;

IR _max cm ^-1 (KBr): 3420, 1739, 1634,
1585, 1390, 1289;

NMR δ ppm (D ₂ O): 1.22 (3H, d, J = 6.9H
z), 1.29 (3H, d, J = 6.6Hz), 1.83 (1H, m), 2.85 (1H, m), 2.
97 (3H, s), 3.19 (3H, s), 6.70 (1H, d, J = 15.5Hz), 6.94 (1
H, d, J = 8.3Hz), 7.14 (1H, dd, J = 8.3Hz and 2.0Hz), 7.22
(1H, d, J = 2.0Hz), 7.44 (1H, d, J = 15.5Hz).

Example 3

[Chemical 128] a) (4R, 5R, 6S, 8R) -p-nitrobenzyl-3-diphenylphosphoryloxy-4-methyl-6-
(1-hydroxyethyl) -1-azabicyclo [3.
2.0] Hept-2-en-7-one-2-carboxylate (772 mg) and (2S, 4S) -1-{(2-hydroxy-3-t-butyldimethylsilyloxy) benzoyl} -2- Dimethylaminocarbonyl-4-mercaptopyrrolidine (547 mg) was dissolved in dry acetonitrile (6 ml), diisopropylethylamine (168 mg) was added under ice cooling in a nitrogen stream, and the mixture was stirred for 50 minutes as it was. The reaction solution was diluted with ethyl acetate, washed with a 2.5% aqueous solution of monopotassium phosphate, washed with brine, dried over magnesium sulfate and sodium carbonate, removed of the solvent, and the residue was purified by silica gel column chromatography (4R,
5S, 6S, 8R, 2 ′S, 4 ′S) -p-Nitrobenzyl-3-[{1- (2-hydroxy-3- (t-butyldimethylsilyloxy) benzoyl) -2-dimethylaminocarbonylpyrrolidine } -4-ylthio] -4-
Methyl-6- (1-hydroxyethyl) -1-azabicyclo [3.2.0] hept-2-en-7-one-2-
The carboxylate (794 mg) was obtained.

IR _max cm ^-1 (neat): 3375 (br), 1758, 1
697, 1627, 1512, 1338, 1250;

NMR δ ppm (CDCl ₃ ): 0.20 (6H, s), 1.00
(9H, s), 1.25 (3H, d, J = 6.3Hz), 1.34 (3H, d, J = 6.3Hz), 2.
71 (1H, m), 3.01 (3H, s), 3.19 (3H, s), 3.5 ~ 4.35 (5H,
m), 5.0 to 5.6 (3H, m), 6.75 (1H, t, J = 7.9Hz), 6.94 (1H, d,
J = 7.9Hz), 7.00 (1H, d, J = 5.9Hz), 7.65 (2H, d, J = 8.9Hz),
8.23 (2H, d, J = 8.9Hz).

B) (4R, 5S, 6S, 8R, 2'S,
4'S) -p-nitrobenzyl-3-[{1- (2-hydroxy-3- (t-butyldimethylsilyloxy) benzoyl) -2-dimethylaminocarbonylpyrrolidine} -4-ylthio] -4-methyl -6- (1-hydroxyethyl) -1-azabicyclo [3.2.0] hept-2-en-7-one-2-carboxylate (741
mg) was dissolved in tetrahydrofuran (10 ml), acetic acid (173 mg) was added under ice cooling, and then a 1 M tetrabutylammonium fluoride tetrahydrofuran solution (0.96) was added.
ml) was added dropwise. After stirring at room temperature for 1 hour, the reaction solution was diluted with ethyl acetate, neutralized by adding an aqueous solution of sodium hydrogen carbonate (242 mg), and the organic layer was washed with brine, dried over magnesium sulfate, and desolvated (4R , 5S, 6
S, 8R, 2'S, 4'S) -p-nitrobenzyl-3
-[{1- (2,3-dihydroxybenzoyl) -2-
Dimethylaminocarbonylpyrrolidine} -4-ylthio] -4-methyl-6- (1-hydroxyethyl) -1
-Azabicyclo [3.2.0] hept-2-ene-7-
On-2-carboxylate was obtained.

IR _max cm ^-1 (neat): 3370 (br), 1762, 1
700 (br), 1634, 1518, 1344;

NMR δ ppm (CDCl ₃ ): 1.23 (3H, d, J = 7.3H
z), 1.34 (3H, d, J = 7.3Hz), 2.76 (1H, m), 3.00 (3H, s), 3.
17 (3H, s), 3.5 ~ 4.3 (5H, m), 5.1 ~ 5.6 (3H, m), 6.80 (1
H, t, J = 7.9Hz), 6.92 (1H, d, J = 6.3Hz), 7.01 (1H, d, J = 7.9H
z), 7.65 (2H, d, J = 8.9Hz), 8.23 (2H, d, J = 8.9Hz).

C) (4R, 5S, 6S, 8R, 2'S,
4'S) -p-nitrobenzyl-3-[{1- (2,3
-Dihydroxybenzoyl) -2-dimethylaminocarbonylpyrrolidine} -4-ylthio] -4-methyl-6
-(1-hydroxyethyl) -1-azabicyclo [3.
2.0] Hept-2-en-7-one-2-carboxylate (300 mg) in tetrahydrofuran (15 ml),
It was dissolved in 0.1 M phosphate buffer (15 ml), 10% palladium carbon (300 mg) was added, and hydrogenation was carried out at room temperature under atmospheric pressure for 1 hour. The catalyst was filtered off, the filtrate was washed with methylene chloride three times, the organic solvent in the aqueous layer was distilled off under reduced pressure, and the mixture was filtered with a membrane filter. The filtrate was subjected to column chromatography with CHP-20P polymer, 2-4%
Fractions eluted with an aqueous tetrahydrofuran solution were collected and freeze-dried to obtain white amorphous (4R, 5S,
6S, 8R, 2'S, 4'S) -3-[{1- (2,3
-Dihydroxybenzoyl) -2-dimethylaminocarbonylpyrrolidin) -4-ylthio] -4-methyl-6
-(1-hydroxyethyl) -1-azabicyclo [3.
2.0] Hept-2-en-7-one-2-carboxylic acid was obtained.

UV _max nm (H ₂ O): 297;

IR _max cm ^-1 (KBr): 3400 (br), 1752, 16
34, 1398, 1265;

NMR δ ppm (D ₂ O): 1.18 (3H, d, J = 7.3H
z), 1.31 (3H, d, J = 6.3Hz), 1.88 (1H, m), 2.86 (1H, m), 3.
01 (3H, s), 3.22 (3H, s), 6.66 (1H, dd, J = 7.6Hz and 1.3H
z), 6.86 (1H, t, J = 7.6Hz), 7.00 (1H, dd, J = 7.6Hz and 1.3
Hz).

Example 4

[Chemical formula 129] a) (4R, 5S, 6S, 8R, 2'S, 4'S) -p
-Nitrobenzyl-3- (1-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonylpyrrolidin-4-ylthio) -4-methyl-6- (1-hydroxyethyl) -1-azabicyclo [3.2.0] ] Hept-
2-en-7-one-2-carboxylate (8.35
g) and dimethylaminopyridine (392 mg) were dissolved in dry methylene chloride (40 ml), and a solution of diisopropylethylamine (2.48 g) in dry methylene chloride (7 ml) was added. (T-Butyldimethylsilyloxy) benzoyl chloride (10.5mm
ol) in dry methylene chloride (32 ml) was added dropwise, and the mixture was reacted with ice for 1 hour and further at room temperature overnight. The extract is washed with brine, dried over magnesium sulfate, removed of the solvent, and the residue is purified by silica gel column chromatography (4R, 5S,
6S, 8R, 2'S, 4'S) -p-nitrobenzyl-
3- (1-p-nitrobenzyloxycarbonyl-2-
Dimethylaminocarbonylpyrrolidin-4-ylthio)
-4-Methyl-6- [1- {3,4-di (t-butyldimethylsilyloxy) benzoyl} oxyethyl] -1
-Azabicyclo [3.2.0] hept-2-ene-7-
On-2-carboxylate (3.34 g) was obtained.

IR _max cm ^-1 (neat): 1777, 1708, 1653,
1599, 1515, 1415, 1404, 1346, 1298, 1252, 1207, 11
74, 1135, 1111;

NMR δppm (CDCl ₃ ): 0.20 (3H, s), 0.21
(3H, s), 0.22 (6H, s), 0.98 (18H, s), 1.27 (3H, m), 1.52 (3
H, m), 1.94 (1H, m), 2.72 (1H, m), 2.93 to 3.10 (6H, m), 3.
3 ~ 3.8 (3H, m), 4.0 ~ 4.2 (1H, m), 4.32 (1H, m), 4.72 (1
H, m), 5.03 ~ 5.51 (5H, m), 6.84 (1H, d, J = 7.9Hz), 7.4 ~
7.7 (6H, m), 8.18 ~ 8.23 (4H, m).

B) (4R, 5S, 6S, 8R, 2'S,
4'S) -p-nitrobenzyl-3- (1-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonylpyrrolidin-4-ylthio) -4-methyl-6-
[1- {3,4-di (t-butyldimethylsilyloxy) benzoyl} oxyethyl] -1-azabicyclo [3.2.0] hept-2-en-7-one-2-carboxylate (1.0 g ) To tetrahydrofuran (12
ml), acetic acid (339 mg) was added under ice-cooling, and then 1M-tetrabutylammonium fluoride tetrahydrofuran solution (1.9 ml) was added dropwise. After stirring at room temperature for 1 hour, the reaction solution was diluted with ethyl acetate, neutralized by adding an aqueous solution of sodium hydrogen carbonate (475 mg), the organic layer was washed with water, dried over magnesium sulfate, and the solvent was removed. By purifying by chromatography (4
R, 5S, 6S, 8R, 2'S, 4'S) -p-Nitrobenzyl-3- (1-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonylpyrrolidine-4-
Ilthio) -4-methyl-6- [1- (3,4-dihydroxybenzoyl) oxyethyl] -1-azabicyclo [3.2.0] hept-2-en-7-one-2-carboxylate (316 mg) Got

IR _max cm ^-1 (neat): 3300 (br), 1764, 1
700, 1640, 1633, 1601, 1514, 1434, 1400, 1342, 128
7, 1206, 1177, 1107;

NMR δppm (CDCl ₃ ): 1.28 (3H, m), 1.49
(3H, m), 2.72 (1H, m), 2.94 ~ 3.17 (6H, m), 3.4 ~ 3.6
(2H, m), 4.12 (1H, m), 4.33 (1H, m), 4.79 (1H, m), 4.89
~ 5.50 (5H, m), 6.80 ~ 6.88 (1H, m), 7.10 (1H, d, J = 8.2H
z), 7.37 ~ 7.65 (5H, m), 8.1 ~ 8.2 (4H, m).

C) (4R, 5S, 6S, 8R, 2'S,
4'S) -p-nitrobenzyl-3- (1-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonylpyrrolidin-4-ylthio) -4-methyl-6-
[1- (3,4-Dihydroxybenzoyl) oxyethyl] -1-azabicyclo [3.2.0] hept-2-en-7-one-2-carboxylate (33 mg) was added to tetrahydrofuran (1.5 ml), 0 It was dissolved in 1M phosphate buffer (pH 7.0, 1.5 ml), 10% palladium carbon (41 mg) was added, and hydrogenation was carried out at room temperature under atmospheric pressure for 1 hour. The catalyst was filtered off, the filtrate was washed 3 times with methylene chloride, the organic solvent in the aqueous layer was distilled off under reduced pressure, and then filtered with a membrane filter. The filtrate was subjected to column chromatographic purification with CHP-20P polymer, and the elution fractions with a 2 to 16% tetrahydrofuran aqueous solution were collected and lyophilized to give white amorphous (4R, 5S, 6S, 8
R, 2'S, 4'S) -3- (2-Dimethylaminocarbonylpyrrolidin-4-ylthio) -4-methyl-6-
[1- (3,4-Dihydroxybenzoyl) oxyethyl] -1-azabicyclo [3.2.0] hept-2-en-7-one-2-carboxylic acid was obtained.

UV _max nm (H ₂ O): 262, 294;

IR _max cm ^-1 (KBr): 3440 (br), 1758, 16
02, 1394, 1282, 1223;

NMR δ ppm (D ₂ O): 1.25 (3H, m), 1.47
(3H, d, J = 4.3Hz), 2.99 (3H, s), 3.08 (3H, s), 5.50 (1H,
m), 6.91 (1H, m), 7.55 (2H, m).

Example 5

[Chemical 130] a) (4R, 5R, 6S, 8R) -allyl-3-diphenylphosphoryloxy-4-methyl-6- (1-trimethylsilyloxyethyl) -1-azabicyclo [3.
2.0] Hept-2-en-7-one-2-carboxylate (154 mg) and diisopropylethylamine (4
7 mg) in a solution of dry acetonitrile (3 ml) in a nitrogen stream under ice-cooling (2S, 4S) -1- (4,5-diallyloxy-2-pyridyl) methyl-2-dimethylaminocarbonyl-4-mercapto. A solution of pyrrolidine (102 mg) in dry acetonitrile (3 ml) was added, and the mixture was reacted overnight as it was. The reaction mixture was diluted with ethyl acetate, washed with water, brine, dried over magnesium sulfate and sodium carbonate, and the solvent was removed. The residue was purified by silica gel column chromatography (4R, 5S, 6S, 8R, 2'S). ，
4'S) -allyl-3-[{1- (4,5-diallyloxy-2-pyridyl) methyl-2-dimethylaminocarbonylpyrrolidin} -4-ylthio] -4-methyl-6
-(1-Trimethylsilyloxyethyl) -1-azabicyclo [3.2.0] hept-2-en-7-one-2
-Carboxylate (88 mg) was obtained.

IR _max cm ^-1 (neat): 1768, 1700, 1644,
1507, 1320, 1250, 1207, 1140;

NMR δ ppm (CDCl ₃ ): 0.13 (9H, s), 1.21
(3H, d, J = 7.3Hz), 1.26 (3H, d, J = 6.3Hz), 1.93 (1H, m), 2.
64 (1H, m), 2.8 ~ 3.4 (4H, m), 2.92 (3H, s), 3.06 (3H, s),
3.50 ~ 4.05 (4H, m), 4.05 (1H, dd, J = 2.6Hz and 9.2Hz),
4.19 (1H, m), 4.50 ~ 4.85 (6H, m), 5.20 ~ 5.55 (6H, m), 5.
85 ~ 6.20 (3H, m), 7.10 (1H, s), 8.04 (1H, s).

B) (4R, 5S, 6S, 8R, 2'S,
4'S) -allyl-3-[{1- (4,5-diallyloxy-2-pyridyl) methyl-2-dimethylaminocarbonylpyrrolidin} -4-ylthio] -4-methyl-6
-(1-Trimethylsilyloxyethyl) -1-azabicyclo [3.2.0] hept-2-en-7-one-2
-Carboxylate (88 mg) was dissolved in tetrahydrofuran (1.6 ml), acetic acid (31 mg) was added under ice-cooling, and then 1M-tetrabutylammonium fluoride tetrahydrofuran solution (0.13 ml) was added dropwise. After stirring for 1 hour, the reaction solution was diluted with ethyl acetate, neutralized by adding an aqueous solution of sodium hydrogen carbonate (55 mg), and the organic layer was washed with water and brine, dried over magnesium sulfate, and desolvated (4R , 5S, 6S, 8R, 2'S, 4 '
S) -allyl-3-[{1- (4,5-diallyloxy-2-pyridyl) methyl-2-dimethylaminocarbonylpyrrolidine} -4-ylthio] -4-methyl-6-
(1-hydroxyethyl) -1-azabicyclo [3.
2.0] Hept-2-en-7-one-2-carboxylate (73 mg) was obtained.

IR _max cm ^-1 (neat): 3350 (br), 1760, 1
690, 1633, 1504, 1315;

NMR δppm (CDCl ₃ ): 1.20 (3H, d, J = 7.3H
z), 1.35 (3H, d, J = 6.3Hz), 1.89 (1H, m), 2.93 (3H, s), 3.
06 (3H, s), 3.21 (1H, dd, J = 2.6Hz and 7.3Hz), 3.55 ~ 3.
90 (2H, m), 3.90 ~ 4.30 (2H, m), 4.50 ~ 4.90 (6H, m), 5.15
~ 5.55 (6H, m), 5.85 ~ 6.20 (3H, m), 7.14 (1H, s), 8.04 (1
H, s).

C) (4R, 5S, 6S, 8R, 2'S,
4'S) -allyl-3-[{1- (4,5-diallyloxy-2-pyridyl) methyl-2-dimethylaminocarbonylpyrrolidin} -4-ylthio] -4-methyl-6
-(1-hydroxyethyl) -1-azabicyclo [3.
2.0] Hept-2-en-7-one-2-carboxylate (85 mg) was dissolved in monochlorobenzene (2 ml), and aniline (0.124 ml) and tetrakistriphenylphosphine palladium under nitrogen cooling in a nitrogen stream. (4
7 mg) was added and stirred for 45 minutes. 0.02M in the reaction solution
Phosphate buffer (pH = 7.0) was added for liquid separation, the aqueous layer was washed with methylene chloride, the organic solvent in the aqueous layer was distilled off under reduced pressure, and then the organic solvent in the aqueous layer was reduced in pressure. Distilled off, CHP-2
Subjected to column chromatography with 0P polymer,
The fraction eluted with a 2 to 8% tetrahydrofuran aqueous solution was lyophilized to give a white amorphous substance (4R,
5S, 6S, 8R, 2'S, 4'S) -3-[{1-
(5-hydroxy-4-pyridon-2-yl) methyl-
2-Dimethylaminocarbonylpyrrolidine} -4-ylthio] -4-methyl-6- (1-hydroxyethyl)-
1-azabicyclo [3.2.0] hept-2-ene-7
-On-2-carboxylic acid was obtained.

UV _max nm (H ₂ O): 277, 302 (sh);

IR _max cm ^-1 (KBr): 3400 (br), 1756, 16
35, 1558, 1506, 1394, 1260;

NMR δ ppm (D ₂ O): 1.20 (3H, d, J = 7.3H
z), 1.29 (3H, d, J = 6.3Hz), 1.77 (1H, m), 2.85 (3H, s), 3.0
7 (3H, s), 2.85 ~ 3.50 (6H, m), 3.92 (2H, s), 4.16 (2H,
m), 4.23 (1H, m), 6.62 (1H, s), 7.71 (1H, s).

Example 6

[Chemical 131] a) (4R, 5R, 6S, 8R) -allyl-3-diphenylphosphoryloxy-4-methyl-6- (1-trimethylsilyloxyethyl) -1-azabicyclo [3.
2.0] Hept-2-en-7-one-2-carboxylate (114 mg) and diisopropylethylamine (3
5 mg) in dry acetonitrile (1 ml) in a nitrogen stream under ice-cooling (2S, 4S) -1- (4,5-diallyloxy-3-chlorophenyl) methyl-2-dimethylaminocarbonyl-4-mercapto. Pyrrolidine (93mg)
A dry acetonitrile (1 ml) solution of was added and reacted for 1 hour. 1,8-Diazabicyclo [5.4.0] undec-7-ene (DBU) (0.039 ml) was added, and the reaction was further continued for 1 hour. Then, the reaction solution was diluted with ethyl acetate, washed with water and washed with magnesium sulfate. It was dried with sodium carbonate and the solvent was removed. The residue was redissolved in ethyl acetate (10 ml), 1N hydrochloric acid (0.5 ml) was added under ice cooling, and the mixture was vigorously stirred for 5 minutes.
The reaction solution was diluted with ethyl acetate, washed with sodium hydrogen carbonate water, brine, dried and desolvated, and the residue was purified by silica gel column chromatography (4R, 5
S, 6S, 8R, 2'S, 4'S) -allyl-3-
[{1- (4,5-Diallyloxy-3-chlorophenyl) methyl-2-dimethylaminocarbonylpyrrolidine} -4-ylthio] -4-methyl-6- (1-hydroxyethyl) -1-azabicyclo [3. 2.0] Hept-2-en-7-one-2-carboxylate was obtained.

IR _max cm ^-1 (neat): 3350, 1758, 1688,
1627, 1475, 1412, 1312, 1265, 1198, 1125;

NMR δ ppm (CDCl ₃ ): 1.22 (3H, d, J = 7.3
Hz), 1.34 (3H, d, J = 6.3Hz), 1.97 (1H, m), 2.66 (1H, m),
2.81 (1H, dd, J = 9.9Hz and 7.3Hz), 2.90 (3H, s), 3.02 (3
H, s), 3.13 (1H, dd, J = 9.6Hz and 4.6Hz), 3.20 (1H, dd, J =
7.3Hz and 2.4Hz), 3.36 (1H, m), 3.41 (1H, d, J = 13.2H
z), 3.59 (1H, m), 3.70 (1H, m), 3.83 (1H, d, J = 13.2Hz), 4.
17 (2H, m), 4.56 (4H, m), 4.67 (1H, m), 4.80 (1H, m), 5.20
~ 5.40 (6H, m), 5.90 ~ 6.24 (3H, m), 6.88 (2H, m).

B) (4R, 5S, 6S, 8R, 2'S,
4'S) -allyl-3-[{1- (4,5-diallyloxy-3-chlorophenyl) methyl-2-dimethylaminocarbonylpyrrolidin} -4-ylthio] -4-methyl-6- (1-hydroxy Ethyl) -1-azabicyclo [3.2.0] hept-2-en-7-one-2-carboxylate (90 mg) was added to monochlorobenzene (2 ml).
Aniline (0.181
ml) and tetrakistriphenylphosphine palladium (47 mg) were added and stirred for 50 minutes. 0.
1M phosphate buffer (pH = 7.0) was added for liquid separation, the aqueous layer was washed twice with methylene chloride, the organic solvent in the aqueous layer was distilled off under reduced pressure, and column chromatography was performed using CHP-20P polymer. Then, the fraction eluted with a 2-4% aqueous tetrahydrofuran solution was freeze-dried to give a white amorphous product (4R, 5S, 6S, 8R, 2'S,
4'S) -3-[{1- (4,5-dihydroxy-3-
(Chlorophenyl) methyl-2-dimethylaminocarbonylpyrrolidine} -4-ylthio] -4-methyl-6-
(1-hydroxyethyl) -1-azabicyclo [3.
2.0] Hept-2-en-7-one-2-carboxylic acid was obtained.

UV _max nm (H ₂ O): 297;

IR _max cm ^-1 (KBr): 3380 (br), 1754, 15
93, 1392, 1291;

NMR δ ppm (D ₂ O): 1.19 (3H, d, J = 7.3H
z), 1.31 (3H, d, J = 6.6Hz), 1.71 (1H, m), 2.76 (3H, s), 2.8
5 (1H, m), 2.95 (3H, s), 3.37 (4H, m), 3.75 (1H, d, J = 12.5H
z), 3.90 (1H, m), 4.00 (1H, d, J = 12.5Hz), 4.22 (3H, m), 6.
79 (1H, s), 6.91 (1H, s).

The compounds of Examples 7 to 60 shown in the following Table 2, Table 3, Table 4, Table 5-i and Table 5-ii were obtained by the same method as in Examples 1 to 6 above.

[Table 2]

[Table 3]

[Table 4]

[Table 5]

Example 61

[Chemical 132] a) (4R, 5R, 6S, 8R) -p-nitrobenzyl-3-diphenylphosphoryloxy-4-methyl-6-
(1-hydroxyethyl) -1-azabicyclo [3.
2.0] Hept-2-en-7-one-2-carboxylate (356 mg) in dry acetonitrile (2.3 ml)
Dissolve in, and under ice cooling in a nitrogen stream (2S, 4S) -1-
p-nitrobenzyloxycarbonyl-2- (4,5-
A solution of diallyloxypyridine-2-carbonyl) aminomethyl-4-mercaptopyrrolidine (270 mg) in dry acetonitrile (2.3 ml) was added, then diisopropylethylamine (77 mg) was added, and the mixture was stirred for 2 hours as it was. The reaction solution was diluted with ethyl acetate, washed with water, brine, dried over magnesium sulfate-sodium carbonate, and the solvent was removed.
The residue was purified by silica gel column chromatography (4R, 5S, 6S, 8R, 2'S, 4 '
S) -p-nitrobenzyl-3- [1-p-nitrobenzyloxycarbonyl-2- (4,5-diallyloxypyridine-2-carbonylaminomethyl) pyrrolidine-
4-ylthio] -4-methyl-6- (1-hydroxyethyl) -1-azabicyclo [3.2.0] hept-2-
En-7-one-2-carboxylate (302 mg) was obtained.

IR _max cm ^-1 (neat): 3370 (br), 1762, 1
698, 1680 (sh), 1670 (sh), 1516,1502 (sh), 1341, 131
6, 1272, 1202;

NMR δ ppm (CDCl ₃ ): 1.27 (3H, d, J = 6.9H
z), 1.37 (3H, d, J = 6.3Hz), 2.56 (1H, m), 3.2 ~ 4.4 (10H,
m), 4.72 (4H, m), 5.1 ~ 5.6 (8H, m), 5.95 ~ 6.20 (2H,
m), 7.45 ~ 7.80 (5H, m), 7.95 ~ 8.45 (5H, m).

B) (4R, 5S, 6S, 8R, 2'S,
4'S) -p-nitrobenzyl-3- [1-p-nitrobenzyloxycarbonyl-2- (4,5-diallyloxypyridin-2-carbonylaminomethyl) pyrrolidin-4-ylthio] -4-methyl- 6- (1-hydroxyethyl) -1-azabicyclo [3.2.0] hept-
2-en-7-one-2-carboxylate (249m
g) was dissolved in dry methylene chloride (5.6 ml), dimedone (157 mg) was added in a nitrogen stream, and tetrakistriphenylphosphine palladium (32 mg) was added under ice cooling. The temperature was raised to room temperature, the mixture was stirred for 40 minutes, the solvent was removed, and the residue was purified by thin layer chromatography (4
R, 5S, 6S, 8R, 2'S, 4'S) -p-nitrobenzyl-3- [1-p-nitrobenzyloxycarbonyl-2- (5-hydroxy-4-pyridone-2-carbonylaminomethyl) ) Pyrrolidin-4-ylthio] -4
-Methyl-6- (1-hydroxyethyl) -1-azabicyclo [3.2.0] hept-2-en-7-one-2
-Carboxylate (156 mg) was obtained.

IR _max cm ^-1 (neat): 3320 (br), 1762, 1
695, 1518, 1342;

NMR δ ppm (CDCl ₃ -CD ₃ OD (9: 1)): 1.2
3 (3H, d, J = 7.3Hz), 1.33 (3H, d, J = 5.9Hz), 1.85 (1H, m),
2.63 (1H, m), 5.1 ~ 5.6 (4H, m), 7.4 ~ 7.8 (5H, m), 8.05
~ 8.35 (5H, m).

C) (4R, 5S, 6S, 8R, 2'S,
4'S) -p-nitrobenzyl-3- [1-p-nitrobenzyloxycarbonyl-2- (5-hydroxy-4)
-Pyridone-2-carbonylaminomethyl) pyrrolidin-4-ylthio] -4-methyl-6- (1-hydroxyethyl) -1-azabicyclo [3.2.0] hept-2
-En-7-one-2-carboxylate (114 mg)
Was dissolved in tetrahydrofuran (6 ml) and 0.1 M phosphate buffer (pH = 7.0, 6 ml), 10% palladium carbon (120 mg) was added, and hydrogenation was carried out at room temperature under atmospheric pressure for 1.5 hours. .. The catalyst was filtered off, the filtrate was washed with methylene chloride, the organic solvent in the aqueous layer was distilled off under reduced pressure, then filtered through a membrane filter, and the filtrate was purified by column chromatography with CHP-20P polymer to yield 2%. Fractions eluted with an aqueous tetrahydrofuran solution were collected and freeze-dried to obtain white amorphous (4R, 5S, 6S,
8R, 2 ′S, 4 ′S) -3- [2- (5-hydroxy-4-pyridone-2-carbonylaminomethyl) pyrrolidin-4-ylthio] -4-methyl-1-azabicyclo [3.2. 0] hept-2-en-7-one-2-carboxylic acid was obtained.

UV _max nm (H ₂ O): 295;

IR _max cm ^-1 (KBr): 3358 (br), 1752, 16
54, 1560. 1389;

NMR δ ppm (D ₂ O): 1.22 (3H, d, J = 6.6H
z), 1.30 (3H, d, J = 6.3Hz), 1.78 (1H, m), 2.76 (1H, m), 3.
25 ~ 4.35 (10H, m), 7.12 (1H, s), 7.76 (1H, s).

By the same method as in Example 61, the compounds of Examples 62 to 66 shown in Table 6 below were obtained.

[Table 6]

Example 67

[Chemical 133] (4R, 5S, 6S, 8R, 2'S, 4'S) -p-nitrobenzyl-3- [1-p-nitrobenzyloxycarbonyl-2- (4-methylpiperazin-1-ylcarbonyl) pyrrolidine- 4-ylthio] -4-methyl-6
-(1-hydroxyethyl) -1-azabicyclo [3.
2.0] Hept-2-en-7-one-2-carboxylate (147 mg) and 1-bromoacetyl-3,4-di (p-nitrobenzyloxy) benzene (200 mg) in acetone (3.0 ml) And was reacted at room temperature for 10 days. The solvent was distilled off under reduced pressure, and the residue was tetrahydrofuran (10.0 ml) and 0.1M-phosphate buffer solution (pH = 7.
0.1% ml), 10% palladium-carbon was added, and hydrogenation was carried out at room temperature under atmospheric pressure for 1.5 hours. After performing the same post-treatment as in Example 1, the product was purified by column chromatography with a CHP-20P polymer, and the elution fractions with an 8% tetrahydrofuran aqueous solution were collected and freeze-dried to obtain white amorphous (4R, 5S, 6
S, 8R, 2'S, 4'S) -3- [2- (4- (3,
4-dihydroxyphenylcarbonylmethyl) -4-methyl-piperazinium-1-ylcarbonyl) pyrrolidin-4-ylthio] -4-methyl-6- (1-hydroxyethyl) -1-azabicyclo [3.2.0] hept −
2-En-7-one-2-carboxylate was obtained. UV _max nm (H ₂ O): 301;

IR _max cm ^-1 (KBr): 3402 (br), 1758, 16
64, 1594. 1489, 1453, 1388, 1255, 1208, 1090;

NMR δ ppm (D ₂ O): 1.22 (3H, d, J = 7.3H
z), 1.30 (3H, d, J = 6.9Hz), 3.46 (3H, S), 6.64 (1H, d, J = 8.
3Hz), 7.24 (2H, m).

Example 68

[Chemical 134] (4R, 5S, 6S, 8R, 2'S, 4'S) -p-nitrobenzyl-3- [1-p-nitrobenzyloxycarbonyl-2-((2- (4-pyridyl) ethyl) methylamino Carbonyl) pyrrolidin-4-ylthio] -4
-Methyl-6- (1-hydroxyethyl) -1-azabicyclo [3.2.0] hept-2-en-7-one-2
-Carboxylate (248 mg) and 1-bromoacetyl-3,4-di (p-nitrobenzyloxy) benzene (228 mg) were dissolved in a mixed solvent of dry methylene chloride (4 ml) and dry dimethylformamide (2 ml) at room temperature. ,
Reacted for 10 days. Hydrogenation, post-treatment and purification (4R, 5S, 6S, 8
R, 2'S, 4'S) -3- [2-((2- (1-
(3,4-Dihydroxyphenylcarbonylmethyl) pyridinium-4-yl) ethyl) methylaminocarbonyl) pyrrolidin-4-ylthio] -4-methyl-6-
(1-hydroxyethyl) -1-azabicyclo [3.
2.0] Hept-2-en-7-one-2-carboxylate was obtained.

UV _max nm (H ₂ O): 286;

IR _max cm ^-1 (KBr): 3400 (br), 2364, 17
52, 1654. 1560, 1508, 1280;

NMR δppm (D ₂ O): 0.95 (3H, d, J = 6.9H
z), 1.28 (3H, d, J = 6.6Hz), 3.04 (3H, S), 6.89 (1H, d, J = 7.
9Hz), 7.2 ~ 7.5 (2H, m), 8.09 (2H, br.s), 8.70 (2H, br.
s).

Reference Example 1

[Chemical 135] a) 60% sodium hydride (8.0 g) was suspended in dry tetrahydrofuran (50 ml). After cooling with ice in a nitrogen stream, catechol (5.5 g) dissolved in dry tetrahydrofuran (25 ml) and dry hexamethylphosphoramide (60 ml) were added. After heating and stirring at 40 ° C. for 10 minutes, the mixture was ice-cooled again, a solution of p-nitrobenzyl bromide (9.5 g) in dry tetrahydrofuran (30 ml) was added, and the mixture was stirred for 10 minutes. The reaction solution was diluted with benzene, washed with 2.5% aqueous solution of monopotassium phosphate, washed with saline solution, dried over magnesium sulfate and removed of solvent. The residue was crystallized with ethyl acetate and collected by filtration.
1,2-di (p-nitrobenzyloxy) benzene (3.8 g) was obtained.

IR _max cm ^-1 (KBr): 1608, 1511, 1453,
1343, 1259, 1218, 1128, 1047;

NMR δ ppm (CDCl ₃ ): 5.26 (4H, s), 6.94
(4H, s), 7.62 (4H, d, J = 8.9Hz), 8.24 (4H, d, J = 8.9Hz).

B) Anhydrous aluminum chloride (1.27 g) was placed in a flask purged with nitrogen, and dried methylene chloride (1
0 ml) was added and the mixture was cooled to -10 ° C. Acetyl chloride (6
40 μl) and stirred for 10 minutes, then 1,2-di (p-nitrobenzyloxy) benzene (2.78 g)
Of dry methylene chloride (35 ml) was added dropwise over 5 minutes. After stirring for 10 minutes at the same temperature, the reaction solution was diluted with methylene chloride, and 0.1M phosphate buffer solution (pH = 7.0)
Washing, washing with sodium hydrogen carbonate water, drying over magnesium sulfate, removal of the solvent, crystallization of the residue with benzene, and filtration to obtain 1-acetyl-3,4-di (p-nitrobenzyloxy) benzene (2.81 g). Obtained.

IR _max cm ^-1 (KBr): 1673, 1607, 1586,
1516, 1430, 1352, 1276, 1218, 1151, 1040;

NMR δ ppm (CDCl ₃ ): 2.54 (3H, s), 5.31
(2H, s), 5.34 (2H, s), 6.92 (1H, d, J = 8.2Hz), 7.62 (6H,
m), 8.27 (4H, m).

C) To 1-acetyl-3,4-di (p-nitrobenzyloxy) benzene (5.0 g) was added dry tetrahydrofuran (350 ml), and the mixture was heated with stirring at 60 ° C. to dissolve it, and anhydrous aluminum chloride ( 150 mg) was added. Bromine (605 μl) dissolved in dry tetrahydrofuran (10 ml) was added thereto over 5 minutes, and the mixture was further stirred at the same temperature for 10 minutes and then cooled. 0.0 in the reaction solution
1M phosphate buffer (pH 7.0, 200 ml) was added, and the mixture was stirred for 1 hour under ice cooling, and the crystals were collected by filtration, water, ethanol,
The crystals were washed successively with ethyl acetate and dried under reduced pressure to give 1-bromoacetyl-3,4-di (p-nitrobenzyloxy) benzene (3.8 g).

IR _max cm ^-1 (KBr): 1667, 1607, 1517,
1437, 1348, 1278, 1224, 1150, 1108, 1037;

NMR δppm (CDCl ₃ ): 4.36 (2H, s), 5.31
(2H, s), 5.35 (2H, s), 6.95 (1H, d, J = 8.9Hz), 7.64 (6H,
m), 8.27 (4H, m).

Reference Example 2

[Chemical 136] Caffeic acid (3.60 g), tert-butyldimethylsilyl chloride (10.85 g) and imidazole (6.12 g) were dried over dimethylformamide (20 ml).
, And reacted overnight at room temperature. The reaction solution was diluted with toluene, washed with water and brine, dried over magnesium sulfate, and desolvated. The residue was dissolved in methanol (60 ml) and tetrahydrofuran (60 ml), a solution of sodium hydrogen carbonate (1.35 g) in water (20 ml) was added under ice cooling, and the mixture was stirred at room temperature for 1 hr. The reaction solution was acidified with diluted hydrochloric acid, extracted with ethyl acetate, washed with brine, dried over magnesium sulfate,
Removed the medium. The residue was crystallized with methanol and collected by filtration 3,4
-Di (t-butyldimethylsilyloxy) cinnamic acid (7.37 g) was obtained.

IR _max cm ^-1 (KBr): 3320 (br), 1690 (s
h), 1680, 1630, 1504, 1282, 1250;

NMR δ ppm (CDCl ₃ ): 0.22 (6H, s), 0.23
(6H, s), 0.99 (9H, s), 1.00 (9H, s), 6.25 (1H, d, J = 16Hz),
6.83 (1H, d, J = 8.6Hz), 7.03 (2H, s), 7.66 (1H, d, J = 16Hz).

The tert-butyldimethylsilyl ethers shown in Table 7 below were obtained in the same manner as in Reference Example 2 using the corresponding catechol derivatives.

[Table 7]

Reference Example 6

[Chemical 137] 2,3-Dihydroxybenzoic acid (4.62 g) was used, and 2-hydroxy-3- was prepared in the same manner as in Reference Example 2.
t-Butyldimethylsilyloxybenzoic acid was obtained.

IR _max cm ^-1 (neat): 1645, 1459, 1442,
1390, 1300, 1267, 1255, 1228, 1176, 1158;

NMR δ ppm (CDCl ₃ ): 0.22 (6H, s), 1.03
(9H, s), 6.80 (1H, m), 7.11 (1H, dd, J = 1.6Hz and 7.9H
z), 7.55 (1H, dd, J = 1.6Hz and 8.1Hz).

Reference Example 7

[Chemical 138] a) (2S, 4S) -1-allyloxycarbonyl-2
-Dimethylaminocarbonyl-4-benzoylthiopyrrolidine (2.53 g) was dissolved in dry methylene chloride (70 ml), dimedone (3.92 g) was added, and the mixture was stirred in a nitrogen stream.
Tetrakistriphenylphosphine palladium (809 mg) was added under ice cooling. After stirring for 30 minutes, 2-hydroxy-3-t-butyldimethylsilyloxybenzoic acid (1.88 g) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (1.34).
g) was added and reacted at 5 ° C for one day. The reaction solution was diluted with ethyl acetate, washed with dilute hydrochloric acid, brine, dried over magnesium sulfate, and the solvent was removed. By purifying the residue by silica gel column chromatography, (2S, 4S) -1- (2
-Hydroxy-3-t-butyldimethylsilyloxybenzoyl) -2-dimethylaminocarbonyl-4-benzoylthiopyrrolidine was obtained.

IR _max cm ^-1 (neat): 3150 (br), 1660, 1
650 (sh), 1630 (sh), 1574, 1444,1412, 1255, 1205;

NMR δ ppm (CDCl ₃ ): 0.21 (6H, s), 1.01
(9H, s), 2.06 (1H, m), 2.83 (1H, m), 3.03 (3H, s), 3.21 (3
H, s), 3.79 (1H, m), 4.13 (2H, m), 5.20 (1H, t, J = 8.3Hz),
6.72 (1H, t, J = 7.9Hz), 6.91 (1H, m), 7.03 (1H, d, J = 7.6H
z), 7.4 ~ 7.55 (2H, m), 7.55 ~ 7.70 (1H, m), 7.90 (2H, d
d, J = 1.5Hz and 8.5Hz).

B) (2S, 4S) -1- (2-hydroxy-3-t-butyldimethylsilyloxybenzoyl)
2-Dimethylaminocarbonyl-4-benzoylthiopyrrolidine (682 mg) was dissolved in methanol (3 ml), and a 30% methylamine methanol solution (399 mg) was added under ice cooling in a nitrogen stream. After stirring for 30 minutes, 30
% Methylamine methanol solution (399 mg) was added,
It was stirred for another 30 minutes. Monopotassium phosphate (1.05
g) was added and the mixture was extracted with methylene chloride. The organic layer was washed with a 2.5% aqueous solution of monopotassium phosphate, dried over magnesium sulfate and desolvated to give (2S, 4S) -1- (2-hydroxy-3). -T-butyldimethylsilyloxybenzoyl)
2-Dimethylaminocarbonyl-4-mercaptopyrrolidine was obtained. This was used in the next reaction without purification.

Reference Example 8

[Chemical 139] a) 1,2-dihydroxy-4-nitrobenzene (2.
0 g) and imidazole (4.4 g) were dissolved in dry dimethylformamide (10 ml), t-butyldimethylsilyl chloride (4.9 g) was added at room temperature, and the mixture was stirred at the same temperature for 1 day, then at 60 ° C. for 3 hours. Heated and stirred. After cooling, the reaction solution was diluted with benzene, washed with 0.1 M phosphate buffer (pH 7.0) and saturated saline, dried and desolvated, and the obtained crystals were washed with methanol and dried under reduced pressure. 1
-Nitro-3,4-di (t-butyldimethylsilyloxy) benzene (4.5 g) was obtained.

IR _max cm ^-1 (KBr): 1583, 1515, 1338,
1301, 1268, 1236, 1088;

NMR δ ppm (CDCl ₃ ): 0.15 (6H, s), 0,18
(6H, s), 0.96 (9H, s), 0.98 (9H, s), 6.16 (1H, d, J = 2.0Hz),
6.21 (1H, dd, J = 8.3Hz and 2.0Hz), 6.62 (1H, d, J = 8.3H
z).

B) 1-Nitro-3,4-di (t-butyldimethylsilyloxy) benzene (2.36 g) was dissolved in ethyl acetate (5 ml) and 10% palladium on carbon (23
6 mg) was added, and hydrogenation was carried out at room temperature under atmospheric pressure for 1 hour. The catalyst was filtered off, the filter cake was washed with ethyl acetate, and the filtration / washing liquid was removed to remove 1-amino-3,4-di (t-
Butyldimethylsilyloxy) benzene was obtained.

IR _max cm ^-1 (neat): 3450, 3360, 1614,
1581, 1508, 1468, 1461, 1441.1322, 1267, 1250, 12
23, 1180, 1122;

NMR δ ppm (CDCl ₃ ): 0.15 (6H, s), 0.19
(6H, s), 0.97 (9H, s), 0.98 (9H, s), 6.17 (1H, dd, J = 8.5Hz
And 2.7Hz), 6.23 (1H, d, J = 2.7Hz), 6.63 (1H, d, J = 8.5H
z).

C) 1-Amino-3,4-di (t-butyldimethylsilyloxy) benzene (354 mg) was dissolved in dry tetrahydrofuran (1.5 ml), and the solution was stirred under a nitrogen stream.
1.55 M n-butyllithium hexane solution (0.71 ml) was added under ice cooling. After stirring for 15 minutes, bromoacetic acid bromide (0.087 ml) was added at the same temperature, and further 3
Stir for 0 minutes. Sodium hydrogen carbonate (42m
g)) aqueous solution and ethyl acetate were added for extraction, washing with brine, drying with magnesium sulfate, removal of the solvent, and purification of the residue by silica gel column chromatography.
Bromoacetylamino-3,4-di (t-butyldimethylsilyloxy) benzene was obtained.

IR _max cm ^-1 (neat): 3280, 1655, 1607,
1507, 1420, 1405, 1294, 1250, 1225, 1206, 1120;

NMR δ ppm (CDCl ₃ ): 0.18 (6H, s), 0.23
(6H, s), 0.98 (9H, s), 0.99 (9H, s), 4.00 (2H, s), 6.78 (1
H, d, J = 8.6Hz), 6.83 (1H, dd, J = 2.3Hz and 8.6Hz), 7.25
(1H, d, J = 2.3Hz), 7.95 (1H, br.s).

Reference Example 9

[Chemical 140] a) (2S, 4S) -1-t-butoxycarbonyl-2
-Dimethylaminocarbonyl-4-benzoylthiopyrrolidine (7.56 g) was added to anisole (4.32 g) under ice cooling.
A solution of g) in trifluoroacetic acid (36 ml) was added dropwise, the temperature was raised to room temperature, and the mixture was stirred for 5.5 hours. The solvent of the reaction solution was removed under reduced pressure, diethyl ether was added to the residue, and the mixture was crystallized and collected by filtration. It was dried under reduced pressure to obtain (2S, 4S) -2-dimethylaminocarbonyl-4-benzoylthiopyrrolidine trifluoroacetic acid salt (5.82 g).

IR _max cm ^-1 (KBr): 3060 (br), 1668, 1
450, 1424, 1199, 1179, 1132;

NMR δ ppm (CDCl ₃ ): 1.95 to 2.15 (1H,
m), 3.06 (3H, s), 3.07 (3H, s), 3.35 ~ 3.55 (1H, m), 3.95
~ 4.15 (1H, m), 4.38 (1H, m), 5.04 (1H, t, J = 8.4Hz), 7.47
(2H, m), 7.62 (1H, m), 7.90 (2H, m).

B) (2S, 4S) -2-Dimethylaminocarbonyl-4-benzoylthiopyrrolidine trifluoroacetate (78 mg) and 4,5-diallyloxy-2-chloromethylpyridine (180 mg) were dried over methylene chloride (180 mg). 2 ml) and triethylamine (61 mg) was added under ice cooling in a nitrogen stream. After heating to room temperature and reacting for 4 days, washing with water, drying with sodium sulfate, removal of the solvent, and purification of the residue by silica gel thin layer chromatography (2
S, 4S) -1- (4,5-Diallyloxy-2-pyridyl) methyl-2-dimethylaminocarbonyl-4-benzoylthiopyrrolidine (212 mg) was obtained.

IR _max cm ^-1 (neat): 1655, 1588, 1580,
1510, 1445, 1395, 1322, 1242, 1207, 1172;

NMR δ ppm (CDCl ₃ ): 2.04 (1H, m), 2.7
~ 3.3 (3H, m), 2.93 (3H, s), 3.01 (3H, s), 3.5 ~ 3.9 (3
H, m), 4.22 (1H, m), 4.5 ~ 4.8 (4H, m), 5.2 ~ 5.5 (4H, m),
5.95, ~ 6.15 (2H, m), 7.20 (1H, s), 7.35 ~ 7.65 (3H, m),
7.91 (2H, m), 8.04 (1H, s).

The compounds shown in Tables 8 and 9 were obtained in the same manner as in Reference Example 9 using the corresponding alkylating agent.

[Table 8]

[Table 9]

Reference Example 23

[Chemical 141] a) (2S, 4R) -1-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonyl-4-hydroxypyrrolidine (500 mg) is dissolved in ethyl acetate (30 ml), 10% palladium carbon (500 mg) is added, and the mixture is allowed to stand at room temperature. Hydrogenation was carried out under normal pressure for 30 minutes. The catalyst was filtered off, the filtrate was concentrated under reduced pressure, and the residue was crystallized from benzene and collected by filtration to obtain (2S, 4R) -2-dimethylaminocarbonyl-4-hydroxypyrrolidine (195 mg).

IR _max cm ^-1 (KBr): 3279, 1636, 1387,
1102;

NMR δ ppm (CDCl ₃ ): 1.84 (1H, m), 2.14
(1H, m), 2.89 (1H, d, J = 12.9Hz), 2.98 (3H, s), 3.04 (3H,
s), 3.31 (1H, dd, J = 4.6Hz and 11.6Hz), 4.15 (1H, t, J =
8.1Hz), 4.45 (1H, m).

B) (2S, 4R) -2-dimethylaminocarbonyl-4-hydroxypyrrolidine (100 mg) and 3,4-diallyloxybenzaldehyde (137 mg)
Was dissolved in methanol (0.5 ml) and stirred at room temperature for 30 minutes. Then, under ice-cooling, a solution of sodium cyanoborohydride (13 mg) in methanol (0.5 ml) was added, and the mixture was stirred for 1 hour under ice-cooling and further for 1 hour at room temperature. The reaction solution was diluted with benzene and extracted with 2.5% aqueous solution of potassium phosphate-potassium. The aqueous layer was adjusted to pH 10 with 1N sodium hydroxide, extracted with methylene chloride, dried, and then subjected to removal of (2S, 4R) -1- (3,4-diallyloxybenzyl) -2-dimethyl. Aminocarbonyl-4-hydroxypyrrolidine (86 mg) was obtained.

NMR δ ppm (CDCl ₃ ): 2.61 (1H, dd, J = 3.2Hz
And 10.1Hz), 2.83 (3H, s), 2.90 (3H, s), 3.46 (1H, dd,
J = 5.4Hz and 10.1Hz), 3.55 to 4.00 (3H, m), 4.45 to 4.7
5 (5H, m), 5.2 ~ 5.5 (4H, m), 6.0 ~ 6.2 (2H, m), 6.82 (2H,
s), 6.95 (1H, s).

B) (2S, 4R) -1- (3,4-Diallyloxybenzyl) -2-dimethylaminocarbonyl-4-hydroxypyrrolidine (226 mg) and triphenylphosphine (247 mg) in dry tetrahydrofuran (0.5 ml). ), A solution of diethyl azodicarboxylate (164 mg) in dry tetrahydrofuran (0.2 ml) was added dropwise under a nitrogen stream under ice cooling, and the mixture was stirred for 0.5 hours. Thioacetic acid (72 mg) in dry tetrahydrofuran (0.2 m
l) After dropping the solution, the temperature was raised to room temperature and the mixture was stirred for 1 hour. The reaction solution was diluted with ethyl acetate, and sodium hydrogen carbonate (79
(mg) aqueous solution was added and extracted. The organic layers were combined, washed with brine, dried over sodium sulfate, and the solvent was removed. The residue was purified by silica gel thin layer chromatography to obtain (2S, 4S) -1- (3,4-diallyloxybenzyl) -2-dimethylaminocarbonyl-4-acetylthiopyrrolidine (108 mg).

IR _max cm ^-1 (neat): 1684, 1641, 1508,
1422, 1259, 1221, 1134, 1120 (sh);

NMR δ ppm (CDCl ₃ ): 1.60 to 1.94 (2H,
m), 2.28 (3H, s), 2.66 (1H, m), 2.91 (3H, s), 2.92 (3H,
s), 2.98 (1H, m), 3.47 (1H, d, J = 13.1Hz), 3.59 (1H, m),
3.84 (1H, d, J = 13.1Hz), 3.99 (1H, m), 4.57 ~ 4.63 (4H,
m), 5.24 ~ 5.30 (2H, m), 5.36 ~ 5.47 (2H, m), 6.00 ~ 6.17
(2H, m), 6.75 ~ 6.99 (3H, m).

The compounds shown in Table 10 were obtained in the same manner as in Reference Example 23 using 3-hydroxypyrrolidine.

[Table 10]

The compounds shown in Table 11 were obtained in the same manner as in Reference Example 9 or Reference Example 23.

[Table 11]

Reference Example 29

[Chemical 142] a) 3,4-Di (t-butyldimethylsilyloxy) phenylpropionic acid (2.054 g) was dissolved in dry tetrahydrofuran (20 ml), and triethylamine (607 mg) and ethyl chloroformate (651 mg) were cooled with ice in a nitrogen stream. ) Was added and stirred for 1 hour. 3-hydroxypyrrolidine (436 mg) in dry tetrahydrofuran (5
ml) solution was added and the mixture was further stirred for 1 hour. The reaction solution was diluted with ethyl acetate, washed with brine, dried over magnesium sulfate, and the solvent was removed. The residue was purified by silica gel column chromatography to give 1- [3,4-di (t-butyldimethylsilyloxy) phenylpropionyl] -3.
-Hydroxypyrrolidine (1.93g) was obtained.

IR _max cm ^-1 (neat): 3390 (br), 1620, 1
508, 1459, 1421, 1294, 1252, 1226,1158, 1122;

NMR δ ppm (CDCl ₃ ): 0.18 (6H, s), 0.18
(6H, s), 0.98 (9H, s), 0.98 (9H, s), 1.95 (2H, m), 2.52 (2
H, m), 2.85 (2H, t, J = 7.4Hz), 3.2 to 3.7 (4H, m), 4.47 (1
H, m), 6.64 (1H, d, J = 7.9Hz), 6.68 (1H, s), 6.73 (1H, d, J =
7.9Hz).

B) Lithium aluminum hydride (394
mg) in dry tetrahydrofuran (25 ml), and at room temperature in a nitrogen stream, 1- [3,4-di (t-butyldimethylsilyloxy) phenylpropionyl] -3-hydroxypyrrolidine (1.66 g) in dry tetrahydrofuran. (25 ml) solution was added dropwise. After heating under reflux for 1 hour, the temperature was returned to room temperature, water (3.36 ml) was added to decompose excess reducing agent, sodium sulfate (1.0 g) was added, and the mixture was stirred for 15 minutes. The insoluble matter was filtered off, the filtrate was removed, and the residue was purified by silica gel column chromatography to give 1
-[3,4-Di (t-butyldimethylsilyloxy) phenylpropyl] -3-hydroxypyrrolidine (736
mg) was obtained.

IR _max cm ^-1 (neat): 3350 (br), 1509, 1
471, 1460, 1420, 1290, 1250, 1222, 1157, 1127;

NMR δ ppm (CDCl ₃ ): 0.18 (6H, s), 0.19
(6H, s), 0.98 (9H, s), 0.98 (9H, s), 1.7〜1.9 (4H, m), 2.
12 ~ 2.35 (2H, m), 2.45 ~ 2.56 (4H, m), 2.74 (1H, m), 2.9
3 (1H, m), 4.33 (1H, m), 6.60 (1H, dd, J = 2.0Hz and 7.9H
z), 6.64 (1H, d, J = 2.0Hz), 6.73 (1H, d, J = 7.9Hz).

C) 1- [3,4-Di (t-butyldimethylsilyloxy) phenylpropyl] -3-hydroxypyrrolidine (844 mg) was dried over methylene chloride (17 ml).
Dissolved in triethylamine (27
5 mg) and methanesulfonic acid chloride (249 mg) were added, and the mixture was stirred for 1 hour. The reaction solution was diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate, and desolvated. Potassium thioacetate (620 mg) was added to the residue, and the mixture was stirred in dry dimethylformamide (14 ml) at 60 ° C for 2 hours. The mixture was diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate, and removed. By purifying the residue by silica gel column chromatography, 1- [3,
4-Di (t-butyldimethylsilyloxy) phenylpropyl] -3-acetylthiopyrrolidine (455 mg) was obtained.

IR _max cm ^-1 (neat): 1688, 1508, 1460,
1420, 1291, 1252, 1221;

NMR δ ppm (CDCl ₃ ): 0.18 (6H, s), 0.18
(6H, s), 0.98 (9H, s), 0.98 (9H, s), 1.6〜1.81 (3H, m),
2.30 (3H, s), 2.3 ~ 2.6 (6H, m), 2.64 (1H, m), 2.921H,
m), 3.92 (1H, m), 6.57 ~ 6.64 (2H, m), 6.72 (1H, d, J = 7.9H
z).

─────────────────────────────────────────────────── ───

[Procedure amendment]

[Submission date] November 5, 1991

[Procedure Amendment 1]

[Document name to be amended] Statement

[Name of item to be corrected] Full text

[Correction method] Change

[Correction content]

[Document name] Statement

Title: Novel β-lactam compound and process for producing the same

[Claims]

[Chemical 1] [In the formula, j is 0 or 1, R ¹ is a hydrogen atom, a protective group for a hydroxyl group, or a group represented by any of the following general formulas (1) to (3), R ² is a hydrogen atom, a carboxyl group. The protecting group of the group, or the negative charge when A contains a positive charge,
Represents a methylene group substituted with a sulfur atom, a methylene group or a lower alkyl group. A represents the group shown below corresponding to R ¹ . That is, when [1] R ¹ represents a hydrogen atom or a hydroxyl-protecting group, A is represented by the following general formula (a) to
The group represented by any of (g) is shown. General formula (a)

[Chemical 2] (In formula, k, l, and m show the integer of 0-3 (however,
l and m do not become 0 at the same time). R ³ represents a hydrogen atom, a lower alkoxycarbonyl group, a carbamoyl group, a mono- or di-lower alkylaminocarbonyl group, a cyclic aminocarbonyl group, a lower alkyl group, or a substituted lower alkyl group, and R ⁴ represents the following general formula (1) To any of the groups represented by (3). General formula (1)

[Chemical 3] (In the formula, Y is a) single bond, b) lower alkylene group,
(C) lower alkenylene group, (d) carbonyl group, (e) carbonyl group, oxygen atom, or -NR ⁰ -group (in the formula, R
⁰ represents a hydrogen atom or a lower alkyl group. Or a lower alkylene group containing at least one), or a) lower alkenylene group containing at least one carbonyl group, oxygen atom, or —NR ⁰ — group (in the formula, R ⁰ has the same meaning as described above). R ⁵ and R ⁶ are a hydrogen atom or a hydroxyl-protecting group, and Z is a hydrogen atom, a halogen atom, a nitro group, a cyano group, a lower alkoxycarbonyl group, a carbamoyl group, or a mono- or di-lower alkylaminocarbonyl group. Indicates. ) General formula (2)

[Chemical 4] (In the formula, Y, Z, R ⁵ and R ⁶ have the same meanings as described above.) General formula (3)

[Chemical 5] (In the formula, Y, Z, R ⁵ and R ⁶ have the same meanings as described above.) General formula (b)

[Chemical 6] (Wherein k, l, m and R ⁴ have the same meanings as described above, and n
Represents an integer of 0 to 3. R ⁷ represents a hydrogen atom, a lower alkyl group or a substituted lower alkyl group, and R ⁸ represents a hydrogen atom, an amino group protecting group, a lower alkyl group or a substituted lower alkyl group. General formula (c)

[Chemical 7] (In the formula, k, l, m, n, R ⁴ and R ⁸ have the same meanings as described above.) General formula (d)

[Chemical 8] (In the formula, k, 1, m, n, R ⁴ , R ⁷ and R ⁸ have the same meanings as described above, p represents an integer of 0 to 5, and q represents an integer of 1 to 5. ^a represents an acid residue or intramolecular COO when R ² has a negative charge.) General formula (e)

[Chemical 9] (In the formulae, k, l, m, n, q, R ⁴ , R ⁷ , R ⁸ and X ^a have the same meanings as described above.) General formula (f)-(CH ₂ ) _k- O-R ⁴ (F) (In the formula, k and R ⁴ have the same meanings as described above.) General formula (g)-(CH ₂ ) _k -NR ⁷ -R ⁴ (g) (In the formula, k, R ⁴ and R ^{4 7} has the same meaning as described above.] [2] When R ¹ represents a group represented by any of the general formulas (1) to (3), A represents the following general formula (h) to
The group represented by any of (p) or other organic groups are shown. General formula (h)

[Chemical 10] (In the formula, k, l, m, R ³ and R ⁸ have the same meanings as described above.) General formula (i)

[Chemical 11] (In the formula, k, l, m and R ³ have the same meanings as described above.) General formula (j)

[Chemical 12] (Wherein k, l, m and R ³ have the same meanings as described above, r
Represents an integer of 0 to 2. ) General formula (k)

[Chemical 13] (In the formula, k and R ³ have the same meanings as described above.) General formula (l)

[Chemical 14] (In the formula, k and R ³ have the same meanings as described above.) General formula (m)

[Chemical 15] (In the formula, k, l and m have the same meanings as described above, and R ⁹ represents a hydrogen atom or an amino group-protecting group.) General formula (n)-(CH ₂ ) _k -R ¹⁰ (n) (Formula In the formula, k has the same meaning as described above, and R ¹⁰ represents a lower alkyl group or a substituted lower alkyl group.) General formula (o)

[Chemical 16] (In the formula, k, R ³ and R ¹⁰ have the same meanings as described above.) General formula (p)

[Chemical 17] (In the formula, k, l and m have the same meanings as described above.)]
A novel β-lactam compound represented by and a salt thereof.

[Chemical 18] [In the formula, j is 0 or 1, R ¹ is a hydrogen atom, a protective group for a hydroxyl group, or a group represented by any of the following general formulas (1) to (3), R ² is a hydrogen atom, a carboxyl group. The protecting group of the group, or the negative charge when A contains a positive charge,
Represents a methylene group substituted with a sulfur atom, a methylene group or a lower alkyl group. A represents the group shown below corresponding to R ¹ . That is, when [1] R ¹ represents a hydrogen atom or a hydroxyl-protecting group, A represents a group represented by any of the following general formulas (a) to (g). General formula (a)

[Chemical 19] (In formula, k, l, and m show the integer of 0-3 (however,
l and m do not become 0 at the same time). R ³ represents a hydrogen atom, a lower alkoxycarbonyl group, a carbamoyl group, a mono- or di-lower alkylaminocarbonyl group, a cyclic aminocarbonyl group, a lower alkyl group, or a substituted lower alkyl group, and R ⁴ represents the following general formula (1) To any of the groups represented by (3). General formula (1)

[Chemical 20] (In the formula, Y is a) single bond, b) lower alkylene group,
(C) lower alkenylene group, (d) carbonyl group, (e) carbonyl group, oxygen atom, or -NR ⁰ -group (in the formula, R
⁰ represents a hydrogen atom or a lower alkyl group. Or a lower alkylene group containing at least one), or a) lower alkenylene group containing at least one carbonyl group, oxygen atom, or —NR ⁰ — group (in the formula, R ⁰ has the same meaning as described above). R ⁵ and R ⁶ are a hydrogen atom or a hydroxyl-protecting group, and Z is a hydrogen atom, a halogen atom, a nitro group, a cyano group, a lower alkoxycarbonyl group, a carbamoyl group, or a mono- or di-lower alkylaminocarbonyl group. Indicates. ) General formula (2)

[Chemical 21] (In the formula, Y, Z, R ⁵ and R ⁶ have the same meanings as described above.) General formula (3)

[Chemical formula 22] (In the formula, Y, Z, R ⁵ and R ⁶ have the same meanings as described above.) General formula (b)

[Chemical formula 23] (Wherein k, l, m and R ⁴ have the same meanings as described above, and n
Represents an integer of 0 to 3. R ⁷ represents a hydrogen atom, a lower alkyl group or a substituted lower alkyl group, and R ⁸ represents a hydrogen atom, an amino group protecting group, a lower alkyl group or a substituted lower alkyl group. General formula (c)

[Chemical formula 24] (In the formula, k, l, m, n, R ⁴ and R ⁸ have the same meanings as described above.) General formula (d)

[Chemical 25] (In the formula, k, 1, m, n, R ⁴ , R ⁷ and R ⁸ have the same meanings as described above, p represents an integer of 0 to 5, and q represents an integer of 1 to 5. ^a represents an acid residue or intramolecular COO when R ² has a negative charge.) General formula (e)

[Chemical formula 26] (In the formulae, k, l, m, n, q, R ⁴ , R ⁷ , R ⁸ and X ^a have the same meanings as described above.) General formula (f)-(CH ₂ ) _k- O-R ⁴ (F) (In the formula, k and R ⁴ have the same meanings as described above.) General formula (g)-(CH ₂ ) _k -NR ⁷ -R ⁴ (g) (In the formula, k, R ⁴ and R ^{4 7} has the same meaning as described above.] [2] When R ¹ represents a group represented by any of the general formulas (1) to (3), A represents the following general formula (h) to
The group represented by any of (p) or other organic groups are shown. General formula (h)

[Chemical 27] (In the formula, k, l, m, R ³ and R ⁸ have the same meanings as described above.) General formula (i)

[Chemical 28] (In the formula, k, l, m and R ³ have the same meanings as described above.) General formula (j)

[Chemical 29] (Wherein k, l, m and R ³ have the same meanings as described above, r
Represents an integer of 0 to 2. ) General formula (k)

[Chemical 30] (In the formula, k and R ³ have the same meanings as described above.) General formula (l)

[Chemical 31] (In the formula, k and R ³ have the same meanings as described above.) General formula (m)

[Chemical 32] (In the formula, k, l and m have the same meanings as described above, and R ⁹ represents a hydrogen atom or an amino group-protecting group.) General formula (n)-(CH ₂ ) _k -R ¹⁰ (n) (Formula In the formula, k has the same meaning as described above, and R ¹⁰ represents a lower alkyl group or a substituted lower alkyl group.) General formula (o)

[Chemical 33] (In the formula, k, R ³ and R ¹⁰ have the same meanings as described above.) General formula (p)

[Chemical 34] (In the formula, k, l and m have the same meanings as described above.)]
In producing a novel β-lactam compound represented by and a salt thereof, (Method A), when j = 1 and A is (a) to (c), the compound represented by the general formula [II]

[Chemical 35] [In the formula, M has the same meaning as described above, R ^1a represents a hydrogen atom or a hydroxyl-protecting group, R ^2a represents a carboxyl-protecting group,
And L represent a reactive ester group of a hydroxyl group or a substituted or unsubstituted lower alkylsulfinyl group. A compound represented by], in the general formula [III-a] A ^a -SH [III-a] [wherein, the group A ^a represented by any one of formulas (a) ~ (c) Show. ] By reacting with a mercaptan compound represented by the general formula [Ia]

[Chemical 36] [In the formula, R ^1a , R ^2a , A ^a and M have the same meanings as described above. ] The compound represented by the general formula [III-b-
1], Q ¹ -SH [III-b-1] [In the formula, Q ¹ represents a group represented by the above general formula (h). ] The compound of the general formula [IV-
a]

[Chemical 37] [In the formula, R ^1a , R ^2a , Q ¹ and M have the same meanings as described above. ] To produce a compound represented by, then if R ⁸ is a protecting group of the amino group, after the removal reaction of the general formula (V) R ⁴ -X ^c [V] [wherein, R ⁴ has the same meaning as described above, and X ^c represents an acid residue. ] To produce a compound represented by the general formula [Ia], or (Method B) j = 1 and A is (d) to (e) Is represented by the general formula [II]

[Chemical 38] [In the formula, R ^1a , R ^2a , M and L have the same meanings as described above. Table a compound represented by the general formula [III-b-2] Q ² -SH [III-b-2) (wherein, Q ² is the following general formula (d ') or (e') in] Is shown as a group. General formula (d ')

[Chemical Formula 39] (In the formula, k, l, m, n, p, R ⁷ and R ⁸ have the same meanings as described above.) General formula (e ′)

[Chemical 40] (In the formula, k, l, m, n, R ⁷ and R ⁸ have the same meanings as described above.)], And reacted with a mercaptan compound represented by the general formula [IV-b].

[Chemical 41] [In the formula, R ^1a , R ^2a , Q ² and M have the same meanings as described above. A compound represented by] followed by the general formula (VI) _{^{X b - (CH 2) q}} -R 4 (VI) wherein the same meaning as q and R ⁴ above, the X ^b is acid residue Show. ] The compound represented by the general formula [I
-B]

[Chemical 42] [Wherein R ^1a , R ^2a and M have the same meanings as described above,
A ^b represents a group represented by the general formula (d) or (e). ] When the compound represented by the following formula is produced or (Method C) j = 1 and A is (f) to (g), a compound of the general formula [VII]

[Chemical 43] [In the formula, k, R ^1a , R ^2a and M represent the same meaning as described above, and Y ^a represents an oxygen atom or a —NR ⁷ — group (in the formula, R ⁷ represents the same meaning as described above). ] And a compound represented by the general formula [V] R ⁴ -X ^c [V] [In the formula, R ⁴ and X ^c have the same meanings as described above. ] The compound represented by the general formula [Ic]

[Chemical 44] [In the formula, R ¹ , R ^2a and M have the same meanings as described above,
A ^c represents a group represented by the general formula (f) or (g). Or (A) is (a) to (c) in the case where j = 0 and (A) is (d), the compound represented by the general formula [VIII]

[Chemical 45] [In the formula, R ^1a , M, A ^a and R ^2a have the same meanings as described above, and R ¹¹ represents a lower alkyl group, an aryl group or a lower alkoxy group. ] The compound represented by general formula [Id] is heated.

[Chemical 46] [In the formula, R ^1a , M, A ^a , and R ^2a have the same meanings as described above. Or (A method) j = 0 and A is (d) to (e), the compound represented by the general formula [IX]

[Chemical 47] [In the formula, R ^1a , M, Q ² , R ^2a and R ¹¹ have the same meanings as described above. ] The compound represented by the general formula [X] is heated.

[Chemical 48] [In the formula, R ^1a , M, Q ² and R ^2a have the same meanings as described above. A compound represented by] followed by the general formula (VI) _{^{X b - (CH 2) q}} -R 4 (VI) wherein, q, R ⁴ and X ^b are as defined above. ] The compound represented by the general formula [Ie]

[Chemical 49] [In the formula, R ^1a , M, ^Ab and R ^2a have the same meanings as described above. Or a (F method) in which j = 0 and A is (f) to (g), a compound represented by the general formula [XI]

[Chemical 50] [In the formula, k, R ^1a , R ^2a , M and Y ^a have the same meanings as described above. ] And a compound represented by the general formula [V] R ⁴ -X ^c [V] [In the formula, R ⁴ and X ^c have the same meanings as described above. ] The compound represented by the general formula [If]

[Chemical 51] [Wherein R ^1a , R ^2a and M have the same meanings as described above,
A ^c represents a group represented by the general formula (f) or (g). Or a (G method) j = 1 and A is (h) to (n), a compound represented by the general formula [II]

[Chemical 52] [In the formula, R ^1a , R ^2a , M and L have the same meanings as described above. A compound represented by], in the general formula [III-c] A ^d -SH [III-c] [wherein, the group A ^d represented by any one of formulas (h) ~ (n) Show. ] By reacting with a mercaptan compound represented by the general formula [XII]

[Chemical 53] [In the formula, R ^1a , M, A ^d and R ^2a have the same meanings as described above. ] The compound represented by the formula [XIII] is then produced by removing the compound represented by the formula [XIII] when R ^1a is a hydroxyl-protecting group.

[Chemical 54] [In the formula, M, A ^d and R ^2a have the same meanings as described above. ] In addition, let it be a compound represented by these, General formula [XIV] R ^<1b > ^-Xd [XIV] [In formula, R ^<1b> shows group represented by said General formula (1)-(3), ^Xd is Indicates an acid residue. ] The compound represented by the general formula [I-g]

[Chemical 55] [In the formula, M, A ^d , R ^2a and R ^1b have the same meanings as described above. Or a (H method) in which j = 1 and A is from (o) to (p), a compound represented by the general formula [Ig ′]

[Chemical 56] [Wherein R ^1b , M and R ^2a have the same meanings as described above,
A ^e represents a group represented by the general formula (1) or (m). Formula [XV] in R ¹⁰ -X ^e [XV] [wherein the compound represented by], R ¹⁰ is as defined above, X ^e represents an acid residue. ] Or by reacting with a compound represented by R ⁹
In the general formula [I-h], the reaction for removing the protective group for the amino group in the formula ( ₁ ) is carried out and then the reaction is carried out with a lower (C ₁ -C ₅ ) alkyl ester of formimidic acid.

[Chemical 57] [Wherein R ^1b , M and R ^2a have the same meanings as described above,
A ^f represents a group represented by the general formula (o) or (p). Or a compound represented by the formula [XVI] when (Method I) j = 0 and A is (h) to (n)

[Chemical 58] [In the formula, R ^1a , M, A ^d and R ^2a have the same meanings as described above, and R ¹¹ represents a lower alkyl group, an aryl group or a lower alkoxy group. ] The compound represented by general formula [XVII] is heated.

[Chemical 59] [In the formula, R ^1a , M, A ^d and R ^2a have the same meanings as described above. ] Then, when R ^1a is a hydroxyl-protecting group, the removal reaction is carried out, and then the compound of the general formula [XVIII]

[Chemical 60] [In the formula, M, A ^d and R ^2a have the same meanings as described above. A compound represented by] in more general formula [XIV] R ^1b -X ^d [XIV] [wherein, the R ^1b and X ^d represents the same meaning as above. ] The compound represented by the general formula [Ii]

[Chemical formula 61] [In the formula, M, A ^d , R ^2a and R ^1b have the same meanings as described above. Or when (Method J) j = 0 and A is (o) to (p), a compound represented by the general formula [Ii ′]

[Chemical formula 62] [Wherein R ^1b , M and R ^2c have the same meanings as described above,
A ^e represents a group represented by the general formula (1) or (m). Formula [XV] in R ¹⁰ -X ^e [XV] [wherein the compound represented by], R ¹⁰ is as defined above, X ^e represents an acid residue. ] Or by reacting with a compound represented by R ⁹
In the general formula [I-j], the reaction for removing the protective group for the amino group in step ( ₁ ) is carried out, and then the reaction is carried out with a lower (C ₁ -C ₅ ) alkyl ester of formimidic acid.

[Chemical 63] [Wherein R ^1b , M and R ^2a have the same meanings as described above,
A ^f represents a group represented by the general formula (o) or (p). ] To produce a compound represented by, R ^1, R ^5,
When a β-lactam compound in which R ⁶ , R ⁸ or R ⁹ is a hydrogen atom and R ² is a hydrogen atom or a negative charge is desired, it is then represented by the general formulas [Ia] to [Ij]. Or a combination of the reaction for removing the protective group for the hydroxyl group, the reaction for removing the protective group for the carboxyl group, and the reaction for removing the protective group for the amino group, or the simultaneous removal of these protective groups. A process for producing a β-lactam compound represented by the above general formula [I] or a pharmacologically acceptable salt thereof, characterized by:

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel β-lactam compound and a method for producing the same. More specifically, it relates to a penem or carbapenem derivative into which a catechol derivative or the like is introduced and a method for producing the same.

[0002]

2. Description of the Related Art Heretofore, one having a penem skeleton or a carbapenem skeleton has been reported as one of β-lactam compounds having an excellent antibacterial spectrum against a wide range of Gram-positive and Gram-negative bacteria.

[0003]

However, it has been reported that a resistant bacterium has appeared in imipenem, which is currently marketed in this field, and that it has been isolated from the clinical field. Therefore, the development of β-lactam compounds effective against those resistant bacteria, particularly resistant Pseudomonas aeruginosa, is expected.

[0004]

[Means for Solving the Problems] In order to solve the above-mentioned problems, as a result of intensive investigations by the present inventors, a penem or carbapenem derivative into which a catechol derivative or the like is introduced is superior to imipenem-resistant Pseudomonas aeruginosa. Further, they have found that they have antibacterial activity and completed the present invention.

That is, the present invention has the general formula [I]

[Chemical 64] [In the formula, j is 0 or 1, R ¹ is a hydrogen atom, a protective group for a hydroxyl group, or a group represented by any of the following general formulas (1) to (3), R ² is a hydrogen atom, a carboxyl group. The protecting group of the group, or the negative charge when A contains a positive charge,
Represents a methylene group substituted with a sulfur atom, a methylene group or a lower alkyl group. A represents the group shown below corresponding to R ¹ . That is, when [1] R ¹ represents a hydrogen atom or a hydroxyl-protecting group, A represents a group represented by any of the following general formulas (a) to (g). General formula (a)

[Chemical 65] (In formula, k, l, and m show the integer of 0-3 (however,
l and m do not become 0 at the same time). R ³ represents a hydrogen atom, a lower alkoxycarbonyl group, a carbamoyl group, a mono- or di-lower alkylaminocarbonyl group, a cyclic aminocarbonyl group, a lower alkyl group, or a substituted lower alkyl group, and R ⁴ represents the following general formula (1) To any of the groups represented by (3). General formula (1)

[Chemical 66] (In the formula, Y is a) single bond, b) lower alkylene group,
(C) lower alkenylene group, (d) carbonyl group, (e) carbonyl group, oxygen atom, or -NR ⁰ -group (in the formula, R
⁰ represents a hydrogen atom or a lower alkyl group. Or a lower alkylene group containing at least one), or a) lower alkenylene group containing at least one carbonyl group, oxygen atom, or —NR ⁰ — group (in the formula, R ⁰ has the same meaning as described above). R ⁵ and R ⁶ are a hydrogen atom or a hydroxyl-protecting group, and Z is a hydrogen atom, a halogen atom, a nitro group, a cyano group, a lower alkoxycarbonyl group, a carbamoyl group, or a mono- or di-lower alkylaminocarbonyl group. Indicates. ) General formula (2)

[Chemical 67] (In the formula, Y, Z, R ⁵ and R ⁶ have the same meanings as described above.) General formula (3)

[Chemical 68] (In the formula, Y, Z, R ⁵ and R ⁶ have the same meanings as described above.) General formula (b)

[Chemical 69] (Wherein k, l, m and R ⁴ have the same meanings as described above, and n
Represents an integer of 0 to 3. R ⁷ represents a hydrogen atom, a lower alkyl group or a substituted lower alkyl group, and R ⁸ represents a hydrogen atom, an amino group protecting group, a lower alkyl group or a substituted lower alkyl group. General formula (c)

[Chemical 70] (In the formula, k, l, m, n, R ⁴ and R ⁸ have the same meanings as described above.) General formula (d)

[Chemical 71] (In the formula, k, 1, m, n, R ⁴ , R ⁷ and R ⁸ have the same meanings as described above, p represents an integer of 0 to 5, and q represents an integer of 1 to 5. ^a represents an acid residue or intramolecular COO when R ² has a negative charge.) General formula (e)

[Chemical 72] (In the formulae, k, l, m, n, q, R ⁴ , R ⁷ , R ⁸ and X ^a have the same meanings as described above.) General formula (f)-(CH ₂ ) _k- O-R ⁴ (F) (In the formula, k and R ⁴ have the same meanings as described above.) General formula (g)-(CH ₂ ) _k -NR ⁷ -R ⁴ (g) (In the formula, k, R ⁴ and R ^{4 7} has the same meaning as described above.] [2] When R ¹ represents a group represented by any of the general formulas (1) to (3), A represents, for example, the following general formula (h)
To (p) represent an organic group. General formula (h)

[Chemical formula 73] (In the formula, k, l, m, R ³ and R ⁸ have the same meanings as described above.) General formula (i)

[Chemical 74] (In the formula, k, l, m and R ³ have the same meanings as described above.) General formula (j)

[Chemical 75] (Wherein k, l, m and R ³ have the same meanings as described above, r
Represents an integer of 0 to 2. ) General formula (k)

[Chemical 76] (In the formula, k and R ³ have the same meanings as described above.) General formula (l)

[Chemical 77] (In the formula, k and R ³ have the same meanings as described above.) General formula (m)

[Chemical 78] (In the formula, k, l and m have the same meanings as described above, and R ⁹ represents a hydrogen atom or an amino group-protecting group.) General formula (n)-(CH ₂ ) _k -R ¹⁰ (n) (Formula In the formula, k and R ¹⁰ represent a lower alkyl group or a substituted lower alkyl group.) General formula (o)

[Chemical 79] (In the formula, k, R ³ and R ¹⁰ have the same meanings as described above.) General formula (p)

[Chemical 80] (In the formula, k, l and m have the same meanings as described above.)]
The present invention relates to a novel β-lactam compound and a salt thereof. Among the compounds represented by the general formula [I], preferred are compounds having a negative charge when R ² is a hydrogen atom or A has a positive charge, and salts thereof. More preferred among them are compounds in which R ¹ is a hydrogen atom and A is represented by the general formulas (a) to (e) and salts thereof, or R ¹ is the general formula (1) to
The compound which is (3) and its salt can be mentioned.
Of these, particularly preferred are compounds having a pyrrolidine ring in A and salts thereof.

Further, the present invention relates to a process for producing the novel β-lactam compound represented by the above general formula [I] and salts thereof. That is, (method A), when j = 1 and A is (a) to (c), the general formula [II]

[Chemical 81] [In the formula, M has the same meaning as described above, R ^1a represents a hydrogen atom or a hydroxyl-protecting group, R ^2a represents a carboxyl-protecting group,
And L represent a reactive ester group of a hydroxyl group or a substituted or unsubstituted lower alkylsulfinyl group. A compound represented by], in the general formula [III-a] A ^a -SH [III-a] [wherein, the group A ^a represented by any one of formulas (a) ~ (c) Show. ] By reacting with a mercaptan compound represented by the general formula [Ia]

[Chemical formula 82] [In the formula, R ^1a , R ^2a , A ^a and M have the same meanings as described above. ] The compound represented by the general formula [III-b-
1], Q ¹ -SH [III-b-1] [In the formula, Q ¹ represents a group represented by the above general formula (h). ] The compound of the general formula [IV-
a]

[Chemical 83] [In the formula, R ^1a , R ^2a , Q ¹ and M have the same meanings as described above. ] To produce a compound represented by, then if R ⁸ is a protecting group of the amino group, after the removal reaction of the general formula (V) R ⁴ -X ^c [V] [wherein, R ⁴ has the same meaning as described above, and X ^c represents an acid residue. ] The compound represented by the said general formula [Ia] is manufactured by making it react with the compound represented by this. (Method B) When j = 1 and A is from (d) to (e), the general formula [II]

[Chemical 84] [In the formula, R ^1a , R ^2a , M and L have the same meanings as described above. Table a compound represented by the general formula [III-b-2] Q ² -SH [III-b-2) (wherein, Q ² is the following general formula (d ') or (e') in] Is shown as a group. General formula (d ')

[Chemical 85] (In the formula, k, l, m, n, p, R ⁷ and R ⁸ have the same meanings as described above.) General formula (e ′)

[Chemical formula 86] (In the formula, k, l, m, n, R ⁷ and R ⁸ have the same meanings as described above.)], And reacted with a mercaptan compound represented by the general formula [IV-b].

[Chemical 87] [In the formula, R ^1a , R ^2a , Q ² and X have the same meanings as described above. A compound represented by] followed by the general formula (VI) _{^{X b - (CH 2) q}} -R 4 (VI) wherein the same meaning as q and R ⁴ above, the X ^b is acid residue Show. ] The compound represented by the general formula [I
-B]

[Chemical 88] [Wherein R ^1a , R ^2a and M have the same meanings as described above,
A ^b represents a group represented by the general formula (d) or (e). ] The compound represented by these is manufactured. Further, (C method) When j = 1 and A is (f) to (g), the general formula [VII]

[Chemical 89] [In the formula, k, R ^1a , R ^2a and M represent the same meaning as described above, and Y ^a represents an oxygen atom or a —NR ⁷ — group (in the formula, R ⁷ represents the same meaning as described above). ] And a compound represented by the general formula [V] R ⁴ -X ^c [V] [In the formula, R ⁴ and X ^c have the same meanings as described above. ] The compound represented by the general formula [Ic]

[Chemical 90] [In the formula, R ¹ , R ^2a and M have the same meanings as described above,
A ^c represents a group represented by the general formula (f) or (g). ] The compound represented by these is manufactured. Moreover, (D method) When j = 0 and A is (a) to (c), the general formula [VIII]

[Chemical Formula 91] [In the formula, R ^1a , M, A ^a and R ^2a have the same meanings as described above, and R ¹¹ represents a lower alkyl group, an aryl group or a lower alkoxy group. ] The compound represented by general formula [Id] is heated.

[Chemical Formula 92] [In the formula, R ^1a , M, A ^a , and R ^2a have the same meanings as described above. ] The compound represented by these is manufactured. When (E method) j = 0 and A is (d) to (e), the general formula [IX]

[Chemical formula 93] [In the formula, R ^1a , M, Q ² , R ^2a and R ¹¹ have the same meanings as described above. ] The compound represented by the general formula [X] is heated.

[Chemical 94] [In the formula, R ^1a , M, Q ² and R ^2a have the same meanings as described above. A compound represented by] followed by the general formula (VI) _{^{X b - (CH 2) q}} -R 4 (VI) wherein, q, R ⁴ and X ^b are as defined above. ] The compound represented by the general formula [Ie]

[Chemical 95] [In the formula, R ^1a , M, ^Ab and R ^2C have the same meanings as described above. ] The compound represented by these is manufactured. When (F method) j = 0 and A is (f) to (g), the general formula [XI]

[Chemical 96] [In the formula, k, R ^1a , R ^2a and M represent the same meaning as described above, and Y ^a represents an oxygen atom or a —NR ⁷ — group (in the formula, R ⁷ represents the same meaning as described above). ] And a compound represented by the general formula [V] R ⁴ -X ^c [V] [In the formula, R ⁴ and X ^c have the same meanings as described above. ] The compound represented by the general formula [If]

[Chemical 97] [Wherein R ^1a , R ^2a and M have the same meanings as described above,
A ^c represents a group represented by the general formula (f) or (g). ] The compound represented by these is manufactured. When (G method) j = 1 and A is (h) to (n), the general formula [II]

[Chemical 98] [In the formula, R ^1a , R ^2a , M and L have the same meanings as described above. A compound represented by], in the general formula [III-c] A ^d -SH [III-c] [wherein, the group A ^d represented by any one of formulas (h) ~ (n) Show. ] By reacting with a mercaptan compound represented by the general formula [XII]

[Chemical 99] [In the formula, R ^1a , M, A ^d and R ^2a have the same meanings as described above. ] The compound represented by the formula [XIII] is then produced by removing the compound represented by the formula [XIII] when R ^1a is a hydroxyl-protecting group.

[Chemical 100] [In the formula, M, A ^d and R ^2a have the same meanings as described above. ] In addition, let it be a compound represented by these, General formula [XIV] R ^<1b > ^-Xd [XIV] [In formula, R ^<1b> shows group represented by said General formula (1)-(3), ^Xd is Indicates an acid residue. ] The compound represented by the general formula [I-g]

[Chemical 101] [In the formula, M, A ^d , R ^2a and R ^1b have the same meanings as described above. ] The compound represented by these is manufactured. When (H method) j = 1 and A is from (o) to (p), the general formula [Ig ′]

[Chemical 102] [Wherein R ^1b , M and R ^2a have the same meanings as described above,
A ^e represents a group represented by the general formula (1) or (m). Formula [XV] in R ¹⁰ -X ^e [XV] [wherein the compound represented by], R ¹⁰ is as defined above, X ^e represents an acid residue. ] Or by reacting with a compound represented by R ⁹
In the general formula [I-h], the reaction for removing the protective group for the amino group in the formula ( ₁ ) is carried out and then the reaction is carried out with a lower (C ₁ -C ₅ ) alkyl ester of formimidic acid.

[Chemical 103] [Wherein R ^1b , M and R ^2a have the same meanings as described above,
A ^f represents a group represented by the general formula (o) or (p). ] The compound represented by these is manufactured. When (I method) j = 0 and A is (h) to (n), the general formula [XVI]

[Chemical 104] [In the formula, R ^1a , M, ^Ad and R ^2a have the same meanings as described above, and R ¹¹ represents a lower alkyl group, an aryl group or a lower alkoxy group. ] The compound represented by general formula [XVII] is heated.

[Chemical 105] [In the formula, R ^1a , M, A ^d and R ^2a have the same meanings as described above. ] Then, when R ^1a is a hydroxyl-protecting group, the removal reaction is carried out, and then the compound of the general formula [XVIII]

[Chemical formula 106] [In the formula, M, A ^d and R ^2a have the same meanings as described above. A compound represented by] in more general formula [XIV] R ^1b -X ^d [XIV] [wherein, the R ^1b and X ^d represents the same meaning as above. ] The compound represented by the general formula [Ii]

[Chemical formula 107] [In the formula, M, A ^d , R ^2a and R ^1b have the same meanings as described above. ] The compound represented by these is manufactured. Further, (J method) When j = 0 and A is from (o) to (p), the general formula [Ii ′]

[Chemical 108] [Wherein R ^1b , M and R ^2c have the same meanings as described above,
A ^e represents a group represented by the general formula (1) or (m). Formula [XV] in R ¹⁰ -X ^e [XV] [wherein the compound represented by], R ¹⁰ is as defined above, X ^e represents an acid residue. ] Or by reacting with a compound represented by R ⁹
In the general formula [I-j], the reaction for removing the protective group for the amino group in step ( ₁ ) is carried out, and then the reaction is carried out with a lower (C ₁ -C ₅ ) alkyl ester of formimidic acid.

[Chemical 109] [Wherein R ^1b , M and R ^2a have the same meanings as described above,
A ^f represents a group represented by the general formula (o) or (p). ] The compound represented by these is manufactured. In addition, R ¹ , R
^When a β-lactam compound in which ⁵ , R ⁶ , R ⁸ or R ⁹ is a hydrogen atom and R ² is a hydrogen atom or a negative charge is desired, the following formulas [Ia] to [Ij] are used. The reaction of removing the protective group for the hydroxyl group, the removing reaction for the protective group for the carboxyl group and the removing reaction for the protective group for the amino group may be appropriately combined with the represented compound, or these protective groups may be removed simultaneously. And a method for producing a β-lactam compound represented by the above general formula [I] or a pharmacologically acceptable salt thereof.

The above general formulas [I], [Ia] and [I-
b], [I-c], [I-d], [I-e], [I-
f], [I-g], [I-g '], [I-h], [I-
i], [I-i '], [I-j], [II], [III]
-A], [III-b-1], [III-b-2],
[III-c], [IV-a], [IV-b],
[V], [VI], [VII], [VIII], [I
X], [X], [XI], [XII], [XIII],
R ¹ , R ⁵ , R ⁶ and R ^{1a in} [XIV], [XV], [XVI], [XVII] and [XVIII].
The protective group for the hydroxyl group in or the protective group for the amino group in R ⁸ and R ⁹ is preferably a lower alkoxycarbonyl group having 1 to 5 carbon atoms such as tert-butyloxycarbonyl, for example, 2-ethyl iodide. C1-C5 halogenoalkoxycarbonyl groups such as oxycarbonyl and 2,2,2-trichloroethyloxycarbonyl, for example, substituted or unsubstituted C3-C7 lower alkenyloxycarbonyl groups such as allyloxycarbonyl. , Aralkyloxycarbonyl groups such as benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, and trialkylsilyl groups such as trimethylsilyl and tert-butyldimethylsilyl. List It is. Further, as the hydroxyl-protecting group for R ⁵ and R ⁶ , other than the above, preferable examples include a linear or branched lower alkyl group having 1 to 5 carbon atoms such as methyl or tert-butyl, for example, C2-C5 lower alkoxymethyl groups such as methoxymethyl, ethoxymethyl and isobutoxymethyl, for example aralkyl groups such as benzyl, p-methoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, such as allyl, 2 Other examples include lower alkenyl groups having 3 to 7 carbon atoms such as -methylallyl and 3-methylallyl.

Further, as the protecting group for the carboxyl group in R ² and R ^2a, various kinds of commonly used protecting groups can be used, but preferably, for example, a linear group such as methyl, ethyl, isopropyl and tert-butyl. Or a branched chain lower alkyl group having 1 to 5 carbon atoms, such as 2-ethyl iodide or 2,2,2-trichloroethyl having 1 to 5 carbon atoms.
A halogeno lower alkyl group of 5, for example, methoxymethyl,
1 carbon atom such as ethoxymethyl and isobutoxymethyl
~ 5 lower alkoxymethyl groups such as acetoxymethyl, propionyloxymethyl, butyryloxymethyl, pivaloyloxymethyl, etc. lower aliphatic acyloxymethyl groups having 1-5 carbon atoms such as 1-ethoxycarbonyloxyethyl such 1- (C ₁ ~C ₅₎ lower alkoxycarbonyloxy ethyl group such as a benzyl, p- methoxybenzyl, o- nitrobenzyl, p-
Aralkyl groups such as nitrobenzyl, eg allyl,
3 carbon atoms such as 2-methylallyl and 3-methylallyl
~ 7 lower alkenyl groups, benzhydryl groups, or phthalidyl groups.

Examples of the lower alkyl substituent of the methylene group in M include those having 1 to 5 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl or n-pentyl.

The lower alkyl group for R ⁰ , R ³ , R ⁷ , R ⁸ , R ¹⁰ and R ¹¹ is, for example, carbon such as methyl, ethyl, n-propyl, isopropyl, n-butyl or n-pentyl. The thing of several 1-5 is mentioned. Examples of the lower alkoxy group for R ¹¹ include those having 1 to 5 carbon atoms such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy or n-pentoxy. Examples of the aryl group include phenyl, o-tolyl and p-tolyl.

The substituted lower alkyl group for R ³ , R ⁷ and R ⁸ is, for example, hydroxymethyl,
C1-C5 hydroxy lower alkyl groups such as 1-hydroxyethyl and 2-hydroxyethyl, for example, C1-C5 lower alkoxyalkyl groups such as methoxymethyl, 1-methoxyethyl and 2-ethoxyethyl, For example, aminomethyl, N-methylaminomethyl, N, N-
C1-C5 unsubstituted or mono- or di-lower alkylaminoalkyl groups such as dimethylaminomethyl and N-methylaminoethyl, such as carbamoylmethyl,
Examples include unsubstituted or mono- or di-lower alkylaminocarbonylalkyl groups having 1 to 5 carbon atoms such as methylaminocarbonylmethyl, dimethylaminocarbonylmethyl and 2- (dimethylaminocarbonyl) ethyl. Examples of the substituted lower alkyl group for R ¹⁰ include aminomethyl, acetylaminomethyl, carboxylmethyl, acetylmethyl, propionylmethyl, carbamoylmethyl, N-methylaminocarbonylmethyl, N, N-dimethylaminocarbonylmethyl, 2
-(Iminomethylamino) methyl, 2-aminoethyl,
2-acetylaminoethyl, 2-cyanoethyl, 2-methoxyethyl, 2-ethoxyethyl, 2-carboxyethyl, 2-hydroxyethyl, 2-carbamoylethyl, 2-N-methylaminocarbonylethyl, 2-N,
Examples thereof include those having 2 to 7 carbon atoms such as N-dimethylaminocarbonylethyl, 3-carboxypropyl, 4-hydroxybutyl, 5-hydroxypentyl and the like.

Examples of the lower alkoxycarbonyl group for R ³ include those having 2 to 5 carbon atoms such as methoxycarbonyl, ethoxycarbonyl, n-propyloxycarbonyl and tert-butyloxycarbonyl. Furthermore, examples of the mono- and di-lower alkylaminocarbonyl groups include those having 2 to 5 carbon atoms such as methylaminocarbonyl, dimethylaminocarbonyl, ethylaminocarbonyl, methylethylaminocarbonyl and diethylaminocarbonyl. Further, as the cyclic aminocarbonyl group for R ³ , the following 3
To 6-membered ring.

[Chemical 110]

Examples of the halogen atom in Z include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. Further, examples of the lower alkoxycarbonyl group include those having 2 to 5 carbon atoms such as methoxycarbonyl, ethoxycarbonyl, n-propyloxycarbonyl and tert-butyloxycarbonyl. Further, as the mono- and di-lower alkylaminocarbonyl group,
2 carbon atoms such as methylaminocarbonyl, dimethylaminocarbonyl, ethylaminocarbonyl, methylethylaminocarbonyl, diethylaminocarbonyl
~ 5 are mentioned.

The reactive ester of the hydroxyl group represented by L is, for example, benzenesulfonic acid ester, p-
Substituted or unsubstituted aryl sulfonic acid ester such as toluene sulfonic acid ester, p-nitrobenzene sulfonic acid ester and p-bromobenzene sulfonic acid ester, for example, lower alkane having 1 to 5 carbon atoms such as methane sulfonic acid ester and ethane sulfonic acid ester. Sulfonic acid esters, for example, C1-5 halogeno lower alkane sulfonic acid esters such as trifluoromethane sulfonic acid esters, diaryl phosphoric acid esters such as diphenyl phosphoric acid esters, chlorinated compounds such as esters with hydrogen halides, Examples thereof include halides such as bromide and iodide. Among these, preferred examples include p-toluenesulfonic acid ester, methanesulfonic acid ester, and diphenylphosphoric acid ester. Examples of the substituted or unsubstituted lower alkylsulfinyl group include, for example, methylsulfinyl, ethylsulfinyl, n-propylsulfinyl,
Examples thereof include those having 1 to 5 carbon atoms such as n-butylsulfinyl and 2- (acetylamino) ethylsulfinyl.

The acid residue in X ^a , X ^b , X ^c , X ^d and X ^e is, for example, an inorganic acid residue such as chlorine, bromine, fluorine or halogen such as iodine, eg benzenesulfonyloxy. , P-toluenesulfonyloxy, methanesulfonyloxy, trifluoromethanesulfonyloxy, etc., and the like.

Further, when the terminal of Y is a carbonyl group,
X ^c and X ^d have 2 to 2 carbon atoms such as ethoxycarbonyloxy and isopropyloxycarbonyloxy.
The lower alkoxycarbonyloxy group of 6 can also be mentioned.

Further, the lower alkylene group in Y includes those having 1 to 4 carbon atoms such as methylene, ethylene, propylene and butylene, and the lower alkenylene group includes those having 2 to 2 carbon atoms such as vinylene, propenylene and butynylene. 4 are mentioned. Furthermore, examples of the lower alkylene group containing at least one kind of carbonyl group, oxygen atom or —NR ⁰ — group include those shown below. _{-CO-CH 2 -, - CO} -CH 2 CH 2 -, - CH 2
_{-CO -, - CH 2 -CO-} CH 2 -, - CH 2 -CO
_{NMe -, - CH 2 -CO-} NH -, - CH 2 -CON
_{H-CH 2 -, - CH} 2 CH 2 -CO-NH -, - CH
_{2 CH 2 -CO-NMe -,} - CH 2 CH 2 CO-NM
_{e-CH 2 -, - COO} -CH 2 -, - CH 2 -COO
—, —CH ₂ —COO—CH ₂ CH ₂ — In addition, a carbonyl group, an oxygen atom or a —NR ⁰ — group is 1
Examples of the lower alkenylene group containing one or more species include those shown below. -CO-CH = CH -, - CH 2 -CO-CH = CH
_{-, - CH 2 -CO-NH} -CH = CH-CH 2 -, -
_{CH 2 -CO-NMe-CH =} CH-CH 2 -, - CO
_{O-CH 2 -CH = CH -} , - CH 2 -COO-CH =
CH-

Examples of other organic groups other than the general formulas (a) to (p) in A include cyclic alkyl groups having 3 to 8 carbon atoms such as cyclopropyl, cyclobutyl and cyclopentyl, and lower alkyl groups having 1 to 3 carbon atoms. A cyclic alkyl group having 3 to 8 carbon atoms as described above via an alkylene group, for example, 2-
A mono- or bicyclic heterocyclic group consisting of a total of 5 to 11 atoms such as pyrrolyl, 4-imidazolyl and 2-thiazolyl, of which 1 to 5 are heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom. Examples thereof include mono- or bicyclic heterocyclic groups as described above through a lower alkylene group having 1 to 3 carbon atoms.

The salt of the above general formula [I] is a conventional non-toxic salt. Examples of such salts include inorganic base salts such as sodium, potassium, calcium, magnesium and ammonium, organic base salts such as triethylammonium, pyridinium and diisopropylammonium, inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid. Examples thereof include addition salts such as organic acid addition salts of formic acid, acetic acid, methanesulfonic acid, benzenesulfonic acid and the like.

The method for producing the compound of the present invention is described in detail below. (Method A) The compound represented by the general formula [Ia] is obtained by reacting the compound represented by the general formula [II] and the mercaptan compound represented by the general formula [III-a] in an inert solvent,
It can be produced by reacting in the presence of a base (step A).

[Chemical 111] Among the inert solvents used in these reactions, dioxane, tetrahydrofuran, dimethylsulfoxide, acetonitrile, and hexamethylphosphoramide are preferable.

Examples of the base include inorganic bases such as sodium carbonate, potassium carbonate, sodium hydride, potassium hydride and potassium t-butoxy, such as pyridine, dimethylaminopyridine, triethylamine, diisopropylethylamine and 1,8-diazabicyclo [5. .4.
0] -7-undecene (DBU) and the like. Particularly preferred are diisopropylethylamine or DBU.

The base is required in an amount sufficient for the reaction to proceed sufficiently, and it can be carried out usually in an amount of 1 to 3 equivalents relative to the mercaptan compound represented by the general formula [III-a]. The mercaptan compound represented by the general formula [III-a] is required in an amount sufficient for the reaction to proceed sufficiently, and a large excess amount can be used, but it is usually 1 relative to the compound represented by the general formula [II]. ~ 2 equivalents can be used. The reaction temperature is −78 to + 60 ° C.,
The range of -40 to + 40 ° C is preferable. After the completion of the reaction, the product can be taken out by a usual organic chemical method.

The compound represented by the general formula [Ia] can also be produced in the following manner.

[Chemical 112] First, the compound represented by the general formula [II] and the general formula [II]
I-b-1] and a mercaptan compound represented by the formula [IV-a] are produced by the above step A. Then, a reaction for removing the amino-protecting group in R ⁸ is carried out from the compound represented by the general formula [IV-a] according to a known method. Method for removing this protecting group (step B)
Is a method known per se of treating with an acid, a base, a reducing agent, etc., for example, TW Greene: Protective Groups in
Reference can be made to Organic Synthesis, J. Wiley & Sons Inc., 1981. Preferable examples of the acid include trifluoroacetic acid, formic acid, boron trifluoride, aluminum chloride and the like or a mixture thereof. Preferable examples of the base include alkali metal carbonates such as sodium carbonate and potassium carbonate, alkali metal sulfides such as sodium sulfide and potassium sulfide, and tetrabutylammonium fluoride. Preferable examples of the reduction method include zinc and acetic acid, hydrogen and hydrogenolysis with palladium-carbon or platinum. Also,
A technique using tetrakistriphenylphosphine palladium can also be used.

The solvent used is not particularly limited as long as it does not adversely affect the reaction for removing the protecting group.
Water, alcohols such as methanol and ethanol, ethers such as tetrahydrofuran and dioxane, fatty acids such as acetic acid, halogenohydrocarbons such as dichloromethane, dichloroethane, chloroform and chlorobenzene, and mixed solvents thereof can be used. With respect to the reaction temperature, the reaction can be suppressed or promoted by appropriately cooling or heating, and the preferable temperature is −30 to + 40 ° C.

After the reaction for removing the protecting group is carried out in this manner, the compound represented by the general formula [V] is reacted in the presence of a base, if necessary, in an inert solvent (step C). The compound represented by the above general formula [Ia] can be produced. As the inert solvent used in this reaction, water, ketones such as acetone and methyl ethyl ketone,
Examples thereof include ethers such as tetrahydrofuran and dioxane, acetonitrile, dimethylformamide, and halogenohydrocarbons such as dichloromethane, dichloroethane and chloroform, which do not adversely influence the reaction, or a mixture thereof.

At this time, if necessary, an inorganic base such as sodium carbonate, potassium carbonate, sodium hydroxide or sodium hydride, or pyridine, dimethylaminopyridine, triethylamine, diisopropylethylamine,
An organic base such as DBU can coexist. The reaction temperature is not particularly limited, but is usually -40 to + 60 ° C.
Is preferred. After completion of the reaction, the product can be taken out by a usual organic chemical method.

(Method B) The compound represented by the general formula [Ib] can be produced as follows.

[Chemical 113] First, the compound represented by the general formula [II] and the general formula [II]
The compound represented by the general formula [IV-b] is produced by the step A from the mercaptan compound represented by Ib-2]. Then, the compound represented by the general formula [IV-b] is reacted with the compound represented by the general formula [VI] in an inert solvent (step D) to give the compound represented by the general formula [Ib]. Can be manufactured. Examples of the inert solvent used in this reaction include water, ketones such as acetone and methyl ethyl ketone, ethers such as tetrahydrofuran and dioxane, acetonitrile, dimethylformamide, or halogeno hydrocarbons such as dichloromethane, dichloroethane or chloroform. Examples thereof include solvents or mixtures thereof that do not adversely affect the above. The reaction temperature is not particularly limited, but is usually -40 to
A range of + 60 ° C is preferred. After completion of the reaction, the product can be taken out by a usual organic chemical method.

(Method C) The compound represented by the general formula [Ic] is produced by the above step C from the compound represented by the general formula [VII] and the compound represented by the general formula [V]. be able to.

[Chemical 114]

(Method D) The compound represented by the general formula [Id] can be produced by heating the compound represented by the general formula [VIII] in an inert solvent (step E). ..

[Chemical 115] Aromatic hydrocarbons such as benzene, toluene and xylene are suitable as the inert solvent, but ethers such as dioxane and tetrahydrofuran, various solvents such as cyclohexane and chloroform can also be used. The reaction temperature can be suppressed or promoted by appropriately cooling or heating, and it can be said that the preferable reaction temperature is 20 to 200 ° C. This step itself is a known method, for example, The Journal of
Antibiotics, vol.36, p.938-941,1983, The Journal
of Antibiotics, vol.41, p.780-787, 1988 or Jo
urnal of Medicinal Chemistry, vol.30, p.871-880, 1
It can be carried out according to the method described in 987.

(Method E) The compound represented by the general formula [Ie] can be produced as follows.

[Chemical formula 116] That is, the compound represented by the general formula [IX] is subjected to the step E to produce the compound represented by the general formula [X], and then the compound represented by the general formula [VI] and the step It can be manufactured by attaching D. (Method F) The compound represented by the general formula [If] can be produced by the step C from the compound represented by the general formula [XI] and the compound represented by the general formula [V]. ..

[Chemical 117]

(Method G) The compound represented by the general formula [Ig] can be produced as follows.

[Chemical 118] First, the compound represented by the general formula [II] and the general formula [II]
The compound represented by the general formula [XII] is produced by the step A from the mercaptan compound represented by Ic]. Next, when R ^1a is a hydroxyl-protecting group, the compound represented by the general formula [XII] is subjected to the reaction of removing the protective group in the above step B, and then the resulting compound of the general formula [XI
II] by subjecting the compound represented by the general formula [XIV] to the compound represented by the general formula [I-
The compound represented by g] can be manufactured.

(Method H) The compound represented by the general formula [Ih] can be produced as follows.

[Chemical 119] That is, the compound represented by the general formula [Ig ′] and the compound represented by the general formula [XV] are subjected to the step D. Alternatively, after the reaction for removing the amino-group-protecting group at R ⁹ of the compound represented by the general formula [Ig ′] is carried out by the above step B, a lower (C ₁ -C ₅ ) alkyl ester of formimidic acid is added. The reaction (step F) is carried out by a method known per se (for example, the method described in European Patent Application Publication No. 0289801).

(Method I) The compound represented by the general formula [Ii] can be produced as follows.

[Chemical 120] That is, a compound represented by the general formula [XVII] is produced by subjecting the compound represented by the general formula [XVI] to the step E, and then when R ^1a is a hydroxyl-protecting group, The compound of the formula [XVII] is subjected to the reaction of removing the protecting group in the above step B to give a compound of the general formula [X
VIII], the compound represented by the general formula [XIV] and the above step C can be applied to produce the compound represented by the general formula [Ii].

(Method J) The compound represented by the general formula [I-j] can be produced as follows.

[Chemical 121] That is, the compound represented by the general formula [Ii ′] and the compound represented by the general formula [XV] are subjected to the step D. Alternatively, the reaction of removing the amino-protecting group in R ⁹ of the compound represented by the general formula [Ii ′] is carried out in the step B, and then the step F is carried out.

The obtained general formulas [Ia] to [I-
j], if necessary, the reaction of removing the protective group for the carboxyl group in R ^2a , R ⁸ or R ⁹
Removal of the amino-protecting group in R, and R ^1a ,
By subjecting R ⁵ or R ^{6 to a} reaction in which the removal reaction of the hydroxyl-protecting group is appropriately combined, R ⁸ ,
A β-lactam compound represented by the general formula [I] in which at least one of R ⁹ , R ¹ , R ⁵ , or R ⁶ is a hydrogen atom, and R ² is a hydrogen atom or a negative charge is produced. be able to. After completion of the reaction, the product can be taken out by a usual organic chemistry method, for example, CHP-20P.
The reaction product can be obtained by subjecting it to column chromatography using an adsorption resin or the like, collecting the portion from which the target compound is eluted, and freeze-drying.

The compound represented by the general formula [II], which is the starting material compound of the present invention, is publicly known, for example, Tetrah.
edron Letters, vol.23, p.897-900, 1982, Heterocycl
es, vol.21, p.29-40, 1984 or European Patent Application Publication No. 0046363. In addition, the general formula [V
II] or the compound represented by the general formula [XI] is also known, for example, Chemical & Pharmaceutical Bulletin,
vol.29, p.3158-3172,1981, The Journal of Antibioti
cs, vol.36, p.938-941, 1983 or The Journal of
Antibiotics, vol.41, p.780-787, 1988. Further, compounds represented by the general formula [VIII], [IX] or [XVI] are also known, for example, The
Journal of Antibiotics, vol.36, p.938-941, 1983,
TheJournal of Antibiotics, vol.41, p.780-787, 19
88 or Journal of Medicinal Chemistry, vol.30,
It can be produced according to the method described in p.871-880, 1987.

On the other hand, general formulas [III-a] and [III-
b-1], [III-b-2] or [III-c]
The mercaptan compound represented by the following formula is known in various methods, for example, JP-A-60-58987, Japanese Patent Application No. 2-349.
It can be produced by the method described in Japanese Patent Publication No. 52 or Japanese Patent Application No. 2-212102.

The compound represented by the general formula [I] includes
There are optical isomers and stereoisomers based on the asymmetric carbons at the 5-position, 6-position and 8-position of the penem skeleton or 4-position, 5-position, 6-position and 8-position of the carbapenem skeleton, and all of these isomers are convenient for convenience. Although shown as a single formula, this is not intended to limit the scope of the invention, which is intended to include all isomers and isomer mixtures based on each asymmetric carbon atom. However, regarding the 5- and 6-position configurations, preferably, when M is a sulfur atom or a methylene group, the 5-position carbon atom has the R configuration (5R, 6).
S) -coordinated or (5R, 6R) -coordinated compound, when M is a methylene group substituted with a lower alkyl group and j = 0, the carbon atom at 5-position has R-coordinated (5R, 6S) Coordination or (5R, 6R) coordination compounds, when M is a methylene group substituted with a lower alkyl group and j = 1, the carbon atom at the 5 position has S coordination (5S, 6S) coordination Alternatively, compounds having (5S, 6R) coordination can be mentioned.
For the 8-position, a compound having an R-coordinate can be selected as a suitable one.

More preferred is the formula [Ik]

[Chemical formula 122] And the formula [I-1]

[Chemical 123] The compound shown by can be mentioned. Examples of the compound having the most suitable coordination include the compounds represented by the above general formula [Ik].

When producing isomers having such a coordination, the starting compounds [II], [VII] and [VII]
I], [IX], [XI] or [XVI] is carried out using the corresponding isomer.

Among the compounds represented by the general formula [I], preferred ones are those represented by the general formulas [Ia] and [I-
b], [Id], [Ie], [Ig] or [Ii] can be mentioned.
Particularly preferred are the above-mentioned general formulas [Ia] and [I-
b], [Id] or [Ie] can be mentioned.

When the compound represented by the general formula [I] has a hydroxypyridone moiety (general formula (2)
Alternatively, when the group represented by (3) is included), 1
The following formula (i) or (i
It is possible for tautomers represented by i) to exist, and the present invention includes all of them (however, the naming of compounds and the description of structural formulas are to be made in the pyridone form). (I) When the 1-position substituent is a hydrogen atom (general formula (2)
When the group represented by is included)

[Chemical formula 124] (Ii) When the 1-position substituent is a hydroxyl group (when the group represented by the general formula (3) is included)

[Chemical 125]

The compound of the present invention represented by the above general formula [I] is a penem or carbapenem derivative into which a catechol derivative or the like is introduced, and these compounds exhibit excellent antibacterial activity and are useful as pharmaceuticals. Alternatively, it is a key intermediate for compounds exhibiting their activity. Specific examples of the compound having the general formula [I] obtained by the present invention include, for example, Table 1- (1) and Table 1 below.
The compound shown in-(2) can be mentioned.

[Table 1]

[Table 2]

[Table 3]

[Table 4]

[Table 5]

[Table 6]

[Table 7]

[Table 8]

[Table 9]

[Table 10]

[Table 11]

[Table 12]

[Table 13]

[Table 14]

[Table 15]

[Table 16]

[Table 17]

[Table 18]

The compounds exemplified in Table 1- (1) and Table 1- (2) have stereoisomers as described above, and the exemplified compounds include all isomers.

The novel β-lactam compound represented by the above general formula [I] according to the present invention is suitable for Gram-positive bacteria and Gram-negative bacteria such as Staphylococcus aureus, Streptococcus pyloriens, Escherichia coli and Pseudomonas aeruginosa. It is useful as an antibacterial agent showing excellent antibacterial activity. It is known that carbapenem compounds such as imipenem are unstable to DHP-I localized in the living body, especially in the kidney. However, the compound of the present invention is different in DHP-I although the degree varies depending on each compound. On the other hand, it can be mentioned as a characteristic that it is more stable, and some of the compounds of the present invention are extremely stable against DHP-I. In addition, it can be mentioned as a characteristic that the in vivo half-life (T _1/2 ) tends to be longer than that of imipenem or the like, although the degree varies depending on each compound. Further, the compound of the present invention can be mentioned as a feature that it exhibits excellent antibacterial activity against imipenem-resistant Pseudomonas aeruginosa.

Dosage forms for using the compound of the present invention as an antibacterial agent for treating bacterial infection include, for example, tablets,
Examples thereof include oral administration by capsules, powders, syrups and the like, or parenteral administration by intravenous injection, intramuscular injection, rectal administration and the like.

The above suitable dosage forms can be prepared by incorporating the active compound into an acceptable conventional carrier, excipient, binder, stabilizer and the like. When used in an injection form, an acceptable buffer, solubilizing agent, isotonic agent, etc. may be added.

The dose varies depending on the symptoms, age, body weight, dosage form, number of administrations, etc.
Administer 0 to 3000 mg once or in several divided doses. The dose can be reduced or increased as needed.

[0049]

EXAMPLES Next, the present invention will be described more specifically with reference to examples, but the present invention is not limited to these examples. The abbreviations used in the following examples have the following meanings. AOC: allyloxycarbonyl group BOC: t-butyloxycarbonyl group Me: methyl group Ph: phenyl group PNB: p-nitrobenzyl group PNZ: p-nitrobenzyloxycarbonyl group TBDMS: tert-butyldimethylsilyl group TMS: trimethylsilyl group

Example 1

[Chemical formula 126] a) (4R, 5R, 6S, 8R) -p-nitrobenzyl-3-diphenylphosphoryloxy-4-methyl-6-
(1-hydroxyethyl) -1-azabicyclo [3.
2.0] Hept-2-en-7-one-2-carboxylate (1.52 g) in dry acetonitrile (10 ml)
Dissolve in, and under ice cooling in a nitrogen stream (2S, 4S) -1-
A solution of allyloxycarbonyl-2-dimethylaminocarbonyl-4-mercaptopyrrolidine (877 mg) in dry acetonitrile (2 ml) was added, and then diisopropylethylamine (0.49 ml) was added, and the mixture was stirred for 1 hour as it was. The reaction solution was diluted with ethyl acetate, washed with a 2.5% aqueous solution of monopotassium phosphate, brine, dried over magnesium sulfate, and the solvent was removed. The residue was purified by silica gel column chromatography (4R, 5S, 6S, 8R,
2'S, 4'S) -p-nitrobenzyl-3-[(1-
Allyloxycarbonyl-2-dimethylaminocarbonylpyrrolidin) -4-ylthio] -4-methyl-6-
(1-hydroxyethyl) -1-azabicyclo [3.
2.0] Hept-2-en-7-one-2-carboxylate (1.0 g) was obtained.

IR _max cm ^-1 (neat): 3307 (br), 1770, 1
702, 1655 (sh), 1650, 1522, 1412,1347, 1140;

NMR δ ppm (CDCl ₃ ): 1.28 (3H, m), 1.37
(3H, m), 2.68 (1H, m), 2.97, 2.98,3.06, 3.11 (3H in total, each s), 3.27 (1H, m), 3.47 (2H, m), 3.64 (1H,
m), 4.12 (1H, m), 4.26 (2H, m), 4.74 (1H, m), 5.1 ~ 5.6 (4
H, m), 5.90 (1H, m), 7.65 (2H, d, J = 8.8Hz), 8.23 (2H, d, J =
8.8Hz).

B) (4R, 5S, 6S, 8R, 2'S,
4'S) -p-nitrobenzyl-3-[(1-allyloxycarbonyl-2-dimethylaminocarbonylpyrrolidin) -4-ylthio] -4-methyl-6- (1-hydroxyethyl) -1-azabicyclo [ 3.2.0] Hept-2-en-7-one-2-carboxylate (1.
65 g) was dissolved in dry tetrahydrofuran (30 ml), dimedone (1.66 g) was added in a nitrogen stream, and tetrakistriphenylphosphine palladium (3
42 mg) was added and the mixture was stirred for 10 minutes. By removing the desolvated residue by silica gel column chromatography, (4R, 5S, 6S, 8R, 2'S, 4'S) -p-
Nitrobenzyl-3-[(2-dimethylaminocarbonylpyrrolidine) -4-ylthio] -4-methyl-6-
(1-hydroxyethyl) -1-azabicyclo [3.
2.0] Hept-2-en-7-one-2-carboxylate (0.94 g) was obtained.

IR _max cm ^-1 (neat): 3370 (br), 1763, 1
698, 1638, 1518, 1381, 1342, 1203, 1137;

NMR δ ppm (CDCl ₃ ): 1.28 (3H, d, J = 7.3H
z), 1.36 (3H, d, J = 6.3Hz), 1.59 (1H, m), 2.59 (1H, m),
3.00 (3H, s), 3.02 (3H, s), 3.10 (1H, dd, J = 11.6Hz, 4.6H
z), 3.27 (2H, m), 3.39 (1H, m), 3.75 (1H, m), 3.94 (1H, t, J
= 7.9Hz), 4.25 (2H, m), 5.23 (1H, d, J = 13.8Hz), 5.50 (1H,
d, J = 13.8Hz), 7.67 (2H, d, J = 8.6Hz), 8.24 (2H, d, J = 8.6H)
z).

C) (4R, 5S, 6S, 8R, 2'S,
4'S) -p-nitrobenzyl-3-[(2-dimethylaminocarbonylpyrrolidin) -4-ylthio] -4-
Methyl-6- (1-hydroxyethyl) -1-azabicyclo [3.2.0] hept-2-en-7-one-2-
Carboxylate (137 mg) was dissolved in acetone (3 ml) and methylene chloride (2 ml) and 1-bromoacetyl-
3,4-Di- (p-nitrobenzyloxy) benzene (200 mg) was added, and the mixture was stirred at room temperature for 1 day. 0.02M
By washing with a phosphate buffer (pH = 7.0), drying with magnesium sulfate, removing the solvent, and purifying the residue by silica gel column chromatography (4R, 5S, 6S, 8R,
2'S, 4'S) -p-nitrobenzyl-3-[(1-
(3,4-di-p-nitrobenzyloxybenzoyl)
Methyl-2-dimethylaminocarbonylpyrrolidine)-
4-ylthio] -4-methyl-6- (1-hydroxyethyl) -1-azabicyclo [3.2.0] hept-2-
En-7-one-2-carboxylate (129 mg) was obtained.

IR _max cm ^-1 (neat): 3400 (br), 1763, 1
694, 1672, 1640, 1602, 1505, 1417, 1344, 1271, 120
7, 1177, 1133;

NMR δ ppm (CDCl ₃ ): 1.20 (3H, d, J = 7.3H
z), 1.35 (3H, d, J = 5.9Hz), 1.87 (1H, m), 2.74 (1H, m),
2.95 (3H, s), 3.03 (3H, s), 3.20 (3H, m), 3.37 (1H, m), 3.
75 (1H, d, J = 16.2Hz), 3.81 (1H, m), 3.99 (1H, t, J = 7.9Hz),
4.23 (1H, t, J = 6.3Hz), 4.32 (1H, d, J = 16.2Hz), 5.17 (1H,
d, J = 13.9Hz), 5.32 (2H, s), 5.37 (2H, s), 5.44 (1H, d, J = 1
3.9Hz), 6.93 (1H, d, J = 8.6Hz), 7.56 ~ 7.77 (7H, m), 7.9
6 (1H, d, J = 2.0Hz), 8.13 ~ 8.33 (6H, m).

D) (4R, 5S, 6S, 8R, 2'S,
4'S) -p-nitrobenzyl-3-[(1- (3,4
-Di-p-nitrobenzyloxybenzoyl) methyl-
2-Dimethylaminocarbonylpyrrolidin) -4-ylthio] -4-methyl-6- (1-hydroxyethyl)-
1-azabicyclo [3.2.0] hept-2-ene-7
-On-2-carboxylate (120 mg) was added to tetrahydrofuran (6 ml), 0.1M phosphate buffer (pH =
It was dissolved in 7.0, 6 ml) and 10% palladium on carbon (12
0 mg) was added, and hydrogenation was carried out at room temperature under atmospheric pressure for 2 hours. The catalyst was filtered off, the filtrate was washed 3 times with methylene chloride, the organic solvent in the aqueous layer was distilled off under reduced pressure, then filtered through a membrane filter, and the filtrate was purified by column chromatography using CHP-20P polymer. Fractions eluted with a 2 to 4% tetrahydrofuran aqueous solution were collected and freeze-dried to obtain white amorphous (4R, 5S, 6S, 8
R, 2'S, 4'S) -3-[(1- (3,4-Dihydroxybenzoyl) methyl-2-dimethylaminocarbonylpyrrolidin) -4-ylthio] -4-methyl-6-
(1-hydroxyethyl) -1-azabicyclo [3.
2.0] Hept-2-en-7-one-2-carboxylic acid was obtained.

UV _max nm (H ₂ O): 220, 263, 297;

IR _max cm ^-1 (KBr): 3400 (br), 1754, 16
20, 1594, 1388, 1289;

NMR δ ppm (D ₂ O): 1.19 (3H, d, J = 6.9H
z), 1.30 (3H, d, J = 6.3Hz), 1.72 (3H, m), 2.80 (1H, m), 2.
90 (3H, s), 3.01 (3H, s), 3.24 (3H, m), 3.40 (2H, m), 3.87
(1H, m), 3.95 ~ 4.30 (5H, m), 6.91 (1H, d, J = 8.3Hz), 7.45
(1H, s), 7.52 (1H, d, J = 8.3Hz).

Example 2

[Chemical 127] a) (4R, 5S, 6S, 8R, 2'S, 4'S) -p
-Nitrobenzyl-3-[(1-allyloxycarbonyl-2-dimethylaminocarbonylpyrrolidine) -4-
Ilthio] -4-methyl-6- (1-hydroxyethyl) -1-azabicyclo [3.2.0] hept-2-en-7-one-2-carboxylate (574 mg) was dried over methylene chloride (18 ml). Dimethone (560 mg) was added in a nitrogen stream, tetrakistriphenylphosphine palladium (116 mg) was added at room temperature, and the mixture was stirred for 20 minutes. After cooling the reaction solution to 0 ° C., diisopropylethylamine (115 mg) dissolved in dry methylene chloride (0.5 ml) was added, and then 3,4-di (t-butyldimethylsilyloxy) cinnamoyl chloride (about 1 mmo).
A solution of l) in dry methylene chloride (3 ml) was added dropwise. The reaction solution was washed with brine, dried over magnesium sulfate and sodium carbonate, the solvent was removed, and the residue was purified by silica gel column chromatography (4R, 5S, 6S, 8
R, 2'S, 4'S) -p-nitrobenzyl-3-
[{1- (3,4-Di (t-butyldimethylsilyloxy) cinnamoyl) -2-dimethylaminocarbonylpyrrolidine} -4-ylthio] -4-methyl-6- (1-
Hydroxyethyl) -1-azabicyclo [3.2.0]
Hept-2-en-7-one-2-carboxylate (446 mg) was obtained.

IR _max cm ^-1 (neat): 3400 (br), 1770, 1
707, 1655 (sh), 1642, 1602, 1593,1513, 1347, 1302,
1253, 1132;

NMR δ ppm (CDCl ₃ ): 0.19 (6H, s), 0.21
(6H, s), 0.98 (18H, s), 1.27 (3H, d, J = 6.9Hz), 1.37 (3H,
d, J = 6.3Hz), 2.63 (1H, m), 3.00 (3H, s), 3.21 (3H, s), 3.
25 ~ 3.55 (3H, m), 3.60 ~ 3.85 (2H, m), 4.20 ~ 4.40 (3H,
m), 4.98 (1H, t, J = 8.4Hz), 5.20 ~ 5.60 (2H, m), 6.46 (1H,
d, J = 16Hz), 6.81 (1H, d, J = 8.3Hz), 6.94 (1H, d, J = 2.0Hz),
7.05 (1H, dd, J = 2.0Hz and 8.3Hz), 7.56 (1H, d, J = 16H
z), 7.66 (2H, d, J = 8.9Hz), 8.24 (2H, d, J = 8.9Hz).

B) (4R, 5S, 6S, 8R, 2'S,
4'S) -p-nitrobenzyl-3-[(1- (3,4
-Di (t-butyldimethylsilyloxy) cinnamoyl) -2-dimethylaminocarbonylpyrrolidine} -4
-Ilthio] -4-methyl-6- (1-hydroxyethyl) -1-azabicyclo [3.2.0] hept-2-en-7-one-2-carboxylate (446 mg) was added to tetrahydrofuran (6.8 ml). ), Acetic acid (187 mg) was added at room temperature, and then a 1M-tetrabutylammonium fluoride tetrahydrofuran solution (1 ml) was added dropwise. After stirring for 1 hour, the reaction solution was diluted with ethyl acetate,
An aqueous solution of sodium hydrogen carbonate (262 mg) was added for neutralization, the organic layer was washed with brine, dried over magnesium sulfate, and the solvent was removed. The residue was purified by silica gel column chromatography (4R, 5S, 6S, 8R, 2'S,
4'S) -p-nitrobenzyl-3-[{1- (3,4
-Dihydroxycinnamoyl) -2-dimethylaminocarbonylpyrrolidin} -4-ylthio] -4-methyl-
6- (1-Hydroxyethyl) -1-azabicyclo [3.2.0] hept-2-en-7-one-2-carboxylate (220 mg) was obtained.

IR _max cm ^-1 (KBr): 3430 (br), 1768, 17
10, 1642, 1600, 1521, 1440, 1350,1286;

NMR δ ppm (CDCl ₃ -CD ₃ OD (9: 1)): 1.2
5 (3H, d, J = 7.3Hz), 1.33 (3H, d, J = 6.3Hz), 2.66 (1H, m),
3.00 (3H, s), 3.38 (3H, m), 3.70 (2H, m), 4.0 ~ 4.4 (3H,
m), 4.95 (1H, t, J = 8.6Hz), 5.2 ~ 5.6 (2H, m), 6.49 (1H, d,
J = 15Hz), 6.80 (1H, d, J = 8.3Hz), 6.92 (1H, d, J = 7.3Hz),
7.04 (1H, s), 7.49 (1H, d, J = 15Hz), 7.67 (2H, d, J = 8.9Hz),
8.24 (2H, d, J = 8.9Hz).

C) (4R, 5S, 6S, 8R, 2'S,
4'S) -p-nitrobenzyl-3-[{1- (3,4
-Dihydroxycinnamoyl) -2-dimethylaminocarbonylpyrrolidin} -4-ylthio] -4-methyl-
6- (1-hydroxyethyl) -1-azabicyclo [3.2.0] hept-2-en-7-one-2-carboxylate (258 mg) was added to tetrahydrofuran (1
3.0 ml), 0.1 M phosphate buffer (pH 7.0, 1)
3.0 ml), dissolved in 10% palladium on carbon (250 m
g) was added and hydrogenated at room temperature and atmospheric pressure for 1 hour. The catalyst was filtered off, the filtrate was washed 3 times with methylene chloride, the organic solvent in the aqueous layer was distilled off under reduced pressure, filtered through a membrane filter, and the filtrate was subjected to column chromatography with CHP-20P polymer and 2% tetrahydrofuran. The fraction eluted with the aqueous solution was freeze-dried to obtain white amorphous (4R, 5S, 6S, 8R, 2'S, 4'S) -3-
[{1- (3,4-dihydroxycinnamoyl) -2-
Dimethylaminocarbonylpyrrolidine} -4-ylthio] -4-methyl-6- (1-hydroxyethyl) -1
-Azabicyclo [3.2.0] hept-2-ene-7-
On-2-carboxylic acid was obtained.

UV _max nm (H ₂ O): 218 (sh), 245 (sh),
297;

IR _max cm ^-1 (KBr): 3420, 1739, 1634,
1585, 1390, 1289;

NMR δ ppm (D ₂ O): 1.22 (3H, d, J = 6.9H
z), 1.29 (3H, d, J = 6.6Hz), 1.83 (1H, m), 2.85 (1H, m), 2.
97 (3H, s), 3.19 (3H, s), 6.70 (1H, d, J = 15.5Hz), 6.94 (1
H, d, J = 8.3Hz), 7.14 (1H, dd, J = 8.3Hz and 2.0Hz), 7.22
(1H, d, J = 2.0Hz), 7.44 (1H, d, J = 15.5Hz).

Example 3

[Chemical 128] a) (4R, 5R, 6S, 8R) -p-nitrobenzyl-3-diphenylphosphoryloxy-4-methyl-6-
(1-hydroxyethyl) -1-azabicyclo [3.
2.0] Hept-2-en-7-one-2-carboxylate (772 mg) and (2S, 4S) -1-{(2-hydroxy-3-t-butyldimethylsilyloxy) benzoyl} -2- Dimethylaminocarbonyl-4-mercaptopyrrolidine (547 mg) was dissolved in dry acetonitrile (6 ml), diisopropylethylamine (168 mg) was added under ice cooling in a nitrogen stream, and the mixture was stirred for 50 minutes as it was. The reaction solution was diluted with ethyl acetate, washed with a 2.5% aqueous solution of monopotassium phosphate, washed with brine, dried over magnesium sulfate and sodium carbonate, removed of the solvent, and the residue was purified by silica gel column chromatography (4R,
5S, 6S, 8R, 2 ′S, 4 ′S) -p-Nitrobenzyl-3-[{1- (2-hydroxy-3- (t-butyldimethylsilyloxy) benzoyl) -2-dimethylaminocarbonylpyrrolidine } -4-ylthio] -4-
Methyl-6- (1-hydroxyethyl) -1-azabicyclo [3.2.0] hept-2-en-7-one-2-
The carboxylate (794 mg) was obtained.

IR _max cm ^-1 (neat): 3375 (br), 1758, 1
697, 1627, 1512, 1338, 1250;

NMR δ ppm (CDCl ₃ ): 0.20 (6H, s), 1.00
(9H, s), 1.25 (3H, d, J = 6.3Hz), 1.34 (3H, d, J = 6.3Hz), 2.
71 (1H, m), 3.01 (3H, s), 3.19 (3H, s), 3.5 ~ 4.35 (5H,
m), 5.0 to 5.6 (3H, m), 6.75 (1H, t, J = 7.9Hz), 6.94 (1H, d,
J = 7.9Hz), 7.00 (1H, d, J = 5.9Hz), 7.65 (2H, d, J = 8.9Hz),
8.23 (2H, d, J = 8.9Hz).

B) (4R, 5S, 6S, 8R, 2'S,
4'S) -p-nitrobenzyl-3-[{1- (2-hydroxy-3- (t-butyldimethylsilyloxy) benzoyl) -2-dimethylaminocarbonylpyrrolidine} -4-ylthio] -4-methyl -6- (1-hydroxyethyl) -1-azabicyclo [3.2.0] hept-2-en-7-one-2-carboxylate (741
mg) was dissolved in tetrahydrofuran (10 ml), acetic acid (173 mg) was added under ice cooling, and then a 1 M tetrabutylammonium fluoride tetrahydrofuran solution (0.96) was added.
ml) was added dropwise. After stirring at room temperature for 1 hour, the reaction solution was diluted with ethyl acetate, neutralized by adding an aqueous solution of sodium hydrogen carbonate (242 mg), and the organic layer was washed with brine, dried over magnesium sulfate, and desolvated (4R , 5S, 6
S, 8R, 2'S, 4'S) -p-nitrobenzyl-3
-[{1- (2,3-dihydroxybenzoyl) -2-
Dimethylaminocarbonylpyrrolidine} -4-ylthio] -4-methyl-6- (1-hydroxyethyl) -1
-Azabicyclo [3.2.0] hept-2-ene-7-
On-2-carboxylate was obtained.

IR _max cm ^-1 (neat): 3370 (br), 1762, 1
700 (br), 1634, 1518, 1344;

NMR δ ppm (CDCl ₃ ): 1.23 (3H, d, J = 7.3H
z), 1.34 (3H, d, J = 7.3Hz), 2.76 (1H, m), 3.00 (3H, s), 3.
17 (3H, s), 3.5 ~ 4.3 (5H, m), 5.1 ~ 5.6 (3H, m), 6.80 (1
H, t, J = 7.9Hz), 6.92 (1H, d, J = 6.3Hz), 7.01 (1H, d, J = 7.9H
z), 7.65 (2H, d, J = 8.9Hz), 8.23 (2H, d, J = 8.9Hz).

C) (4R, 5S, 6S, 8R, 2'S,
4'S) -p-nitrobenzyl-3-[{1- (2,3
-Dihydroxybenzoyl) -2-dimethylaminocarbonylpyrrolidine} -4-ylthio] -4-methyl-6
-(1-hydroxyethyl) -1-azabicyclo [3.
2.0] Hept-2-en-7-one-2-carboxylate (300 mg) in tetrahydrofuran (15 ml),
It was dissolved in 0.1 M phosphate buffer (15 ml), 10% palladium carbon (300 mg) was added, and hydrogenation was carried out at room temperature under atmospheric pressure for 1 hour. The catalyst was filtered off, the filtrate was washed with methylene chloride three times, the organic solvent in the aqueous layer was distilled off under reduced pressure, and the mixture was filtered with a membrane filter. The filtrate was subjected to column chromatography with CHP-20P polymer, 2-4%
Fractions eluted with an aqueous tetrahydrofuran solution were collected and freeze-dried to obtain white amorphous (4R, 5S,
6S, 8R, 2'S, 4'S) -3-[{1- (2,3
-Dihydroxybenzoyl) -2-dimethylaminocarbonylpyrrolidin) -4-ylthio] -4-methyl-6
-(1-hydroxyethyl) -1-azabicyclo [3.
2.0] Hept-2-en-7-one-2-carboxylic acid was obtained.

UV _max nm (H ₂ O): 297;

IR _max cm ^-1 (KBr): 3400 (br), 1752, 16
34, 1398, 1265;

NMR δ ppm (D ₂ O): 1.18 (3H, d, J = 7.3H
z), 1.31 (3H, d, J = 6.3Hz), 1.88 (1H, m), 2.86 (1H, m), 3.
01 (3H, s), 3.22 (3H, s), 6.66 (1H, dd, J = 7.6Hz and 1.3H
z), 6.86 (1H, t, J = 7.6Hz), 7.00 (1H, dd, J = 7.6Hz and 1.3
Hz).

Example 4

[Chemical formula 129] a) (4R, 5S, 6S, 8R, 2'S, 4'S) -p
-Nitrobenzyl-3- (1-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonylpyrrolidin-4-ylthio) -4-methyl-6- (1-hydroxyethyl) -1-azabicyclo [3.2.0] ] Hept-
2-en-7-one-2-carboxylate (8.35
g) and dimethylaminopyridine (392 mg) were dissolved in dry methylene chloride (40 ml), and a solution of diisopropylethylamine (2.48 g) in dry methylene chloride (7 ml) was added. (T-Butyldimethylsilyloxy) benzoyl chloride (10.5mm
ol) in dry methylene chloride (32 ml) was added dropwise, and the mixture was reacted with ice for 1 hour and further at room temperature overnight. The extract is washed with brine, dried over magnesium sulfate, removed of the solvent, and the residue is purified by silica gel column chromatography (4R, 5S,
6S, 8R, 2'S, 4'S) -p-nitrobenzyl-
3- (1-p-nitrobenzyloxycarbonyl-2-
Dimethylaminocarbonylpyrrolidin-4-ylthio)
-4-Methyl-6- [1- {3,4-di (t-butyldimethylsilyloxy) benzoyl} oxyethyl] -1
-Azabicyclo [3.2.0] hept-2-ene-7-
On-2-carboxylate (3.34 g) was obtained.

IR _max cm ^-1 (neat): 1777, 1708, 1653,
1599, 1515, 1415, 1404, 1346, 1298, 1252, 1207, 11
74, 1135, 1111;

NMR δppm (CDCl ₃ ): 0.20 (3H, s), 0.21
(3H, s), 0.22 (6H, s), 0.98 (18H, s), 1.27 (3H, m), 1.52 (3
H, m), 1.94 (1H, m), 2.72 (1H, m), 2.93 to 3.10 (6H, m), 3.
3 ~ 3.8 (3H, m), 4.0 ~ 4.2 (1H, m), 4.32 (1H, m), 4.72 (1
H, m), 5.03 ~ 5.51 (5H, m), 6.84 (1H, d, J = 7.9Hz), 7.4 ~
7.7 (6H, m), 8.18 ~ 8.23 (4H, m).

B) (4R, 5S, 6S, 8R, 2'S,
4'S) -p-nitrobenzyl-3- (1-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonylpyrrolidin-4-ylthio) -4-methyl-6-
[1- {3,4-di (t-butyldimethylsilyloxy) benzoyl} oxyethyl] -1-azabicyclo [3.2.0] hept-2-en-7-one-2-carboxylate (1.0 g ) To tetrahydrofuran (12
ml), acetic acid (339 mg) was added under ice-cooling, and then 1M-tetrabutylammonium fluoride tetrahydrofuran solution (1.9 ml) was added dropwise. After stirring at room temperature for 1 hour, the reaction solution was diluted with ethyl acetate, neutralized by adding an aqueous solution of sodium hydrogen carbonate (475 mg), the organic layer was washed with water, dried over magnesium sulfate, and the solvent was removed. By purifying by chromatography (4
R, 5S, 6S, 8R, 2'S, 4'S) -p-Nitrobenzyl-3- (1-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonylpyrrolidine-4-
Ilthio) -4-methyl-6- [1- (3,4-dihydroxybenzoyl) oxyethyl] -1-azabicyclo [3.2.0] hept-2-en-7-one-2-carboxylate (316 mg) Got

IR _max cm ^-1 (neat): 3300 (br), 1764, 1
700, 1640, 1633, 1601, 1514, 1434, 1400, 1342, 128
7, 1206, 1177, 1107;

NMR δppm (CDCl ₃ ): 1.28 (3H, m), 1.49
(3H, m), 2.72 (1H, m), 2.94 ~ 3.17 (6H, m), 3.4 ~ 3.6
(2H, m), 4.12 (1H, m), 4.33 (1H, m), 4.79 (1H, m), 4.89
~ 5.50 (5H, m), 6.80 ~ 6.88 (1H, m), 7.10 (1H, d, J = 8.2H
z), 7.37 ~ 7.65 (5H, m), 8.1 ~ 8.2 (4H, m).

C) (4R, 5S, 6S, 8R, 2'S,
4'S) -p-nitrobenzyl-3- (1-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonylpyrrolidin-4-ylthio) -4-methyl-6-
[1- (3,4-Dihydroxybenzoyl) oxyethyl] -1-azabicyclo [3.2.0] hept-2-en-7-one-2-carboxylate (33 mg) was added to tetrahydrofuran (1.5 ml), 0 It was dissolved in 1M phosphate buffer (pH 7.0, 1.5 ml), 10% palladium carbon (41 mg) was added, and hydrogenation was carried out at room temperature under atmospheric pressure for 1 hour. The catalyst was filtered off, the filtrate was washed 3 times with methylene chloride, the organic solvent in the aqueous layer was distilled off under reduced pressure, and then filtered with a membrane filter. The filtrate was subjected to column chromatographic purification with CHP-20P polymer, and the elution fractions with a 2 to 16% tetrahydrofuran aqueous solution were collected and lyophilized to give white amorphous (4R, 5S, 6S, 8
R, 2'S, 4'S) -3- (2-Dimethylaminocarbonylpyrrolidin-4-ylthio) -4-methyl-6-
[1- (3,4-Dihydroxybenzoyl) oxyethyl] -1-azabicyclo [3.2.0] hept-2-en-7-one-2-carboxylic acid was obtained.

UV _max nm (H ₂ O): 262, 294;

IR _max cm ^-1 (KBr): 3440 (br), 1758, 16
02, 1394, 1282, 1223;

NMR δ ppm (D ₂ O): 1.25 (3H, m), 1.47
(3H, d, J = 4.3Hz), 2.99 (3H, s), 3.08 (3H, s), 5.50 (1H,
m), 6.91 (1H, m), 7.55 (2H, m).

Example 5

[Chemical 130] a) (4R, 5R, 6S, 8R) -allyl-3-diphenylphosphoryloxy-4-methyl-6- (1-trimethylsilyloxyethyl) -1-azabicyclo [3.
2.0] Hept-2-en-7-one-2-carboxylate (154 mg) and diisopropylethylamine (4
7 mg) in a solution of dry acetonitrile (3 ml) in a nitrogen stream under ice-cooling (2S, 4S) -1- (4,5-diallyloxy-2-pyridyl) methyl-2-dimethylaminocarbonyl-4-mercapto. A solution of pyrrolidine (102 mg) in dry acetonitrile (3 ml) was added, and the mixture was reacted overnight as it was. The reaction mixture was diluted with ethyl acetate, washed with water, brine, dried over magnesium sulfate and sodium carbonate, and the solvent was removed. The residue was purified by silica gel column chromatography (4R, 5S, 6S, 8R, 2'S). ，
4'S) -allyl-3-[{1- (4,5-diallyloxy-2-pyridyl) methyl-2-dimethylaminocarbonylpyrrolidin} -4-ylthio] -4-methyl-6
-(1-Trimethylsilyloxyethyl) -1-azabicyclo [3.2.0] hept-2-en-7-one-2
-Carboxylate (88 mg) was obtained.

IR _max cm ^-1 (neat): 1768, 1700, 1644,
1507, 1320, 1250, 1207, 1140;

NMR δ ppm (CDCl ₃ ): 0.13 (9H, s), 1.21
(3H, d, J = 7.3Hz), 1.26 (3H, d, J = 6.3Hz), 1.93 (1H, m), 2.
64 (1H, m), 2.8 ~ 3.4 (4H, m), 2.92 (3H, s), 3.06 (3H, s),
3.50 ~ 4.05 (4H, m), 4.05 (1H, dd, J = 2.6Hz and 9.2Hz),
4.19 (1H, m), 4.50 ~ 4.85 (6H, m), 5.20 ~ 5.55 (6H, m), 5.
85 ~ 6.20 (3H, m), 7.10 (1H, s), 8.04 (1H, s).

B) (4R, 5S, 6S, 8R, 2'S,
4'S) -allyl-3-[{1- (4,5-diallyloxy-2-pyridyl) methyl-2-dimethylaminocarbonylpyrrolidin} -4-ylthio] -4-methyl-6
-(1-Trimethylsilyloxyethyl) -1-azabicyclo [3.2.0] hept-2-en-7-one-2
-Carboxylate (88 mg) was dissolved in tetrahydrofuran (1.6 ml), acetic acid (31 mg) was added under ice-cooling, and then 1M-tetrabutylammonium fluoride tetrahydrofuran solution (0.13 ml) was added dropwise. After stirring for 1 hour, the reaction solution was diluted with ethyl acetate, neutralized by adding an aqueous solution of sodium hydrogen carbonate (55 mg), and the organic layer was washed with water and brine, dried over magnesium sulfate, and desolvated (4R , 5S, 6S, 8R, 2'S, 4 '
S) -allyl-3-[{1- (4,5-diallyloxy-2-pyridyl) methyl-2-dimethylaminocarbonylpyrrolidine} -4-ylthio] -4-methyl-6-
(1-hydroxyethyl) -1-azabicyclo [3.
2.0] Hept-2-en-7-one-2-carboxylate (73 mg) was obtained.

IR _max cm ^-1 (neat): 3350 (br), 1760, 1
690, 1633, 1504, 1315;

NMR δppm (CDCl ₃ ): 1.20 (3H, d, J = 7.3H
z), 1.35 (3H, d, J = 6.3Hz), 1.89 (1H, m), 2.93 (3H, s), 3.
06 (3H, s), 3.21 (1H, dd, J = 2.6Hz and 7.3Hz), 3.55 ~ 3.
90 (2H, m), 3.90 ~ 4.30 (2H, m), 4.50 ~ 4.90 (6H, m), 5.15
~ 5.55 (6H, m), 5.85 ~ 6.20 (3H, m), 7.14 (1H, s), 8.04 (1
H, s).

C) (4R, 5S, 6S, 8R, 2'S,
4'S) -allyl-3-[{1- (4,5-diallyloxy-2-pyridyl) methyl-2-dimethylaminocarbonylpyrrolidin} -4-ylthio] -4-methyl-6
-(1-hydroxyethyl) -1-azabicyclo [3.
2.0] Hept-2-en-7-one-2-carboxylate (85 mg) was dissolved in monochlorobenzene (2 ml), and aniline (0.124 ml) and tetrakistriphenylphosphine palladium under nitrogen cooling in a nitrogen stream. (4
7 mg) was added and stirred for 45 minutes. 0.02M in the reaction solution
Phosphate buffer (pH = 7.0) was added for liquid separation, the aqueous layer was washed with methylene chloride, the organic solvent in the aqueous layer was distilled off under reduced pressure, and then the organic solvent in the aqueous layer was reduced in pressure. Distilled off, CHP-2
Subjected to column chromatography with 0P polymer,
The fraction eluted with a 2 to 8% tetrahydrofuran aqueous solution was lyophilized to give a white amorphous substance (4R,
5S, 6S, 8R, 2'S, 4'S) -3-[{1-
(5-hydroxy-4-pyridon-2-yl) methyl-
2-Dimethylaminocarbonylpyrrolidine} -4-ylthio] -4-methyl-6- (1-hydroxyethyl)-
1-azabicyclo [3.2.0] hept-2-ene-7
-On-2-carboxylic acid was obtained.

UV _max nm (H ₂ O): 277, 302 (sh);

IR _max cm ^-1 (KBr): 3400 (br), 1756, 16
35, 1558, 1506, 1394, 1260;

NMR δ ppm (D ₂ O): 1.20 (3H, d, J = 7.3H
z), 1.29 (3H, d, J = 6.3Hz), 1.77 (1H, m), 2.85 (3H, s), 3.0
7 (3H, s), 2.85 ~ 3.50 (6H, m), 3.92 (2H, s), 4.16 (2H,
m), 4.23 (1H, m), 6.62 (1H, s), 7.71 (1H, s).

Example 6

[Chemical 131] a) (4R, 5R, 6S, 8R) -allyl-3-diphenylphosphoryloxy-4-methyl-6- (1-trimethylsilyloxyethyl) -1-azabicyclo [3.
2.0] Hept-2-en-7-one-2-carboxylate (114 mg) and diisopropylethylamine (3
5 mg) in dry acetonitrile (1 ml) in a nitrogen stream under ice-cooling (2S, 4S) -1- (4,5-diallyloxy-3-chlorophenyl) methyl-2-dimethylaminocarbonyl-4-mercapto. Pyrrolidine (93mg)
A dry acetonitrile (1 ml) solution of was added and reacted for 1 hour. 1,8-Diazabicyclo [5.4.0] undec-7-ene (DBU) (0.039 ml) was added, and the reaction was further continued for 1 hour. Then, the reaction solution was diluted with ethyl acetate, washed with water and washed with magnesium sulfate. It was dried with sodium carbonate and the solvent was removed. The residue was redissolved in ethyl acetate (10 ml), 1N hydrochloric acid (0.5 ml) was added under ice cooling, and the mixture was vigorously stirred for 5 minutes.
The reaction solution was diluted with ethyl acetate, washed with sodium hydrogen carbonate water, brine, dried and desolvated, and the residue was purified by silica gel column chromatography (4R, 5
S, 6S, 8R, 2'S, 4'S) -allyl-3-
[{1- (4,5-Diallyloxy-3-chlorophenyl) methyl-2-dimethylaminocarbonylpyrrolidine} -4-ylthio] -4-methyl-6- (1-hydroxyethyl) -1-azabicyclo [3. 2.0] Hept-2-en-7-one-2-carboxylate was obtained.

IR _max cm ^-1 (neat): 3350, 1758, 1688,
1627, 1475, 1412, 1312, 1265, 1198, 1125;

NMR δ ppm (CDCl ₃ ): 1.22 (3H, d, J = 7.3
Hz), 1.34 (3H, d, J = 6.3Hz), 1.97 (1H, m), 2.66 (1H, m),
2.81 (1H, dd, J = 9.9Hz and 7.3Hz), 2.90 (3H, s), 3.02 (3
H, s), 3.13 (1H, dd, J = 9.6Hz and 4.6Hz), 3.20 (1H, dd, J =
7.3Hz and 2.4Hz), 3.36 (1H, m), 3.41 (1H, d, J = 13.2H
z), 3.59 (1H, m), 3.70 (1H, m), 3.83 (1H, d, J = 13.2Hz), 4.
17 (2H, m), 4.56 (4H, m), 4.67 (1H, m), 4.80 (1H, m), 5.20
~ 5.40 (6H, m), 5.90 ~ 6.24 (3H, m), 6.88 (2H, m).

B) (4R, 5S, 6S, 8R, 2'S,
4'S) -allyl-3-[{1- (4,5-diallyloxy-3-chlorophenyl) methyl-2-dimethylaminocarbonylpyrrolidin} -4-ylthio] -4-methyl-6- (1-hydroxy Ethyl) -1-azabicyclo [3.2.0] hept-2-en-7-one-2-carboxylate (90 mg) was added to monochlorobenzene (2 ml).
Aniline (0.181
ml) and tetrakistriphenylphosphine palladium (47 mg) were added and stirred for 50 minutes. 0.
1M phosphate buffer (pH = 7.0) was added for liquid separation, the aqueous layer was washed twice with methylene chloride, the organic solvent in the aqueous layer was distilled off under reduced pressure, and column chromatography was performed using CHP-20P polymer. Then, the fraction eluted with a 2-4% aqueous tetrahydrofuran solution was freeze-dried to give a white amorphous product (4R, 5S, 6S, 8R, 2'S,
4'S) -3-[{1- (4,5-dihydroxy-3-
(Chlorophenyl) methyl-2-dimethylaminocarbonylpyrrolidine} -4-ylthio] -4-methyl-6-
(1-hydroxyethyl) -1-azabicyclo [3.
2.0] Hept-2-en-7-one-2-carboxylic acid was obtained.

UV _max nm (H ₂ O): 297;

IR _max cm ^-1 (KBr): 3380 (br), 1754, 15
93, 1392, 1291;

NMR δ ppm (D ₂ O): 1.19 (3H, d, J = 7.3H
z), 1.31 (3H, d, J = 6.6Hz), 1.71 (1H, m), 2.76 (3H, s), 2.8
5 (1H, m), 2.95 (3H, s), 3.37 (4H, m), 3.75 (1H, d, J = 12.5H
z), 3.90 (1H, m), 4.00 (1H, d, J = 12.5Hz), 4.22 (3H, m), 6.
79 (1H, s), 6.91 (1H, s).

The compounds of Examples 7 to 60 shown in the following Table 2, Table 3, Table 4, Table 5-i and Table 5-ii were obtained by the same method as in Examples 1 to 6 above.

[Table 19]

[Table 20]

[Table 21]

[Table 22]

[Table 23]

[Table 24]

[Table 25]

[Table 26]

[Table 27]

[Table 28]

[Table 29]

[Table 30]

[Table 31]

[Table 32]

[Table 33]

[Table 34]

[Table 35]

[Table 36]

[Table 37]

[Table 38]

[Table 39]

[Table 40]

[Table 41]

[Table 42]

[Table 43]

[Table 44]

[Table 45]

[Table 46]

[Table 47]

[Table 48]

[Table 49]

[Table 50]

[Table 51]

[Table 52]

[Table 53]

[Table 54]

[Table 55]

[Table 56]

[Table 57]

[Table 58]

[Table 59]

[Table 60]

[Table 61]

[Table 62]

[Table 63]

[Table 64]

[Table 65]

[Table 66]

[Table 67]

[Table 68]

[Table 69]

[Table 70]

[Table 71]

[Table 72]

[Table 73]

[Table 74]

[Table 75]

[Table 76]

[Table 77]

[Table 78]

[Table 79]

[Table 80]

[Table 81]

[Table 82]

[Table 83]

[Table 84]

[Table 85]

[Table 86]

[Table 87]

[Table 88]

[Table 89]

[Table 90]

[Table 91]

[Table 92]

[Table 93]

[Table 94]

[Table 95]

[Table 96]

[Table 97]

[Table 98]

[Table 99]

[Table 100]

[Table 101]

[Table 102]

[Table 103]

[Table 104]

[Table 105]

[Table 106]

[Table 107]

[Table 108]

[Table 109]

[Table 110]

[Table 111]

[Table 112]

[Table 113]

[Table 114]

[Table 115]

[Table 116]

[Table 117]

[Table 118]

[Table 119]

[Table 120]

[Table 121]

[Table 122]

[Table 123]

[Table 124]

[Table 125]

[Table 126]

[Table 127]

[Table 128]

[Table 129]

[Table 130]

[Table 131]

[Table 132]

[Table 133]

[Table 134]

[Table 135]

[Table 136]

[Table 137]

[Table 138]

[Table 139]

[Table 140]

[Table 141]

[Table 142]

[Table 143]

[Table 144]

[Table 145]

[Table 146]

[Table 147]

[Table 148]

[Table 149]

Example 61

[Chemical 132] a) (4R, 5R, 6S, 8R) -p-nitrobenzyl-3-diphenylphosphoryloxy-4-methyl-6-
(1-hydroxyethyl) -1-azabicyclo [3.
2.0] Hept-2-en-7-one-2-carboxylate (356 mg) in dry acetonitrile (2.3 ml)
Dissolve in, and under ice cooling in a nitrogen stream (2S, 4S) -1-
p-nitrobenzyloxycarbonyl-2- (4,5-
A solution of diallyloxypyridine-2-carbonyl) aminomethyl-4-mercaptopyrrolidine (270 mg) in dry acetonitrile (2.3 ml) was added, then diisopropylethylamine (77 mg) was added, and the mixture was stirred for 2 hours as it was. The reaction solution was diluted with ethyl acetate, washed with water, brine, dried over magnesium sulfate-sodium carbonate, and the solvent was removed.
The residue was purified by silica gel column chromatography (4R, 5S, 6S, 8R, 2'S, 4 '
S) -p-nitrobenzyl-3- [1-p-nitrobenzyloxycarbonyl-2- (4,5-diallyloxypyridine-2-carbonylaminomethyl) pyrrolidine-
4-ylthio] -4-methyl-6- (1-hydroxyethyl) -1-azabicyclo [3.2.0] hept-2-
En-7-one-2-carboxylate (302 mg) was obtained.

IR _max cm ^-1 (neat): 3370 (br), 1762, 1
698, 1680 (sh), 1670 (sh), 1516,1502 (sh), 1341, 131
6, 1272, 1202;

NMR δ ppm (CDCl ₃ ): 1.27 (3H, d, J = 6.9H
z), 1.37 (3H, d, J = 6.3Hz), 2.56 (1H, m), 3.2 ~ 4.4 (10H,
m), 4.72 (4H, m), 5.1 ~ 5.6 (8H, m), 5.95 ~ 6.20 (2H,
m), 7.45 ~ 7.80 (5H, m), 7.95 ~ 8.45 (5H, m).

B) (4R, 5S, 6S, 8R, 2'S,
4'S) -p-nitrobenzyl-3- [1-p-nitrobenzyloxycarbonyl-2- (4,5-diallyloxypyridin-2-carbonylaminomethyl) pyrrolidin-4-ylthio] -4-methyl- 6- (1-hydroxyethyl) -1-azabicyclo [3.2.0] hept-
2-en-7-one-2-carboxylate (249m
g) was dissolved in dry methylene chloride (5.6 ml), dimedone (157 mg) was added in a nitrogen stream, and tetrakistriphenylphosphine palladium (32 mg) was added under ice cooling. The temperature was raised to room temperature, the mixture was stirred for 40 minutes, the solvent was removed, and the residue was purified by thin layer chromatography (4
R, 5S, 6S, 8R, 2'S, 4'S) -p-nitrobenzyl-3- [1-p-nitrobenzyloxycarbonyl-2- (5-hydroxy-4-pyridone-2-carbonylaminomethyl) ) Pyrrolidin-4-ylthio] -4
-Methyl-6- (1-hydroxyethyl) -1-azabicyclo [3.2.0] hept-2-en-7-one-2
-Carboxylate (156 mg) was obtained.

IR _max cm ^-1 (neat): 3320 (br), 1762, 1
695, 1518, 1342;

NMR δ ppm (CDCl ₃ -CD ₃ OD (9: 1)): 1.2
3 (3H, d, J = 7.3Hz), 1.33 (3H, d, J = 5.9Hz), 1.85 (1H, m),
2.63 (1H, m), 5.1 ~ 5.6 (4H, m), 7.4 ~ 7.8 (5H, m), 8.05
~ 8.35 (5H, m).

C) (4R, 5S, 6S, 8R, 2'S,
4'S) -p-nitrobenzyl-3- [1-p-nitrobenzyloxycarbonyl-2- (5-hydroxy-4)
-Pyridone-2-carbonylaminomethyl) pyrrolidin-4-ylthio] -4-methyl-6- (1-hydroxyethyl) -1-azabicyclo [3.2.0] hept-2
-En-7-one-2-carboxylate (114 mg)
Was dissolved in tetrahydrofuran (6 ml) and 0.1 M phosphate buffer (pH = 7.0, 6 ml), 10% palladium carbon (120 mg) was added, and hydrogenation was carried out at room temperature under atmospheric pressure for 1.5 hours. .. The catalyst was filtered off, the filtrate was washed with methylene chloride, the organic solvent in the aqueous layer was distilled off under reduced pressure, then filtered through a membrane filter, and the filtrate was purified by column chromatography with CHP-20P polymer to yield 2%. Fractions eluted with an aqueous tetrahydrofuran solution were collected and freeze-dried to obtain white amorphous (4R, 5S, 6S,
8R, 2 ′S, 4 ′S) -3- [2- (5-hydroxy-4-pyridone-2-carbonylaminomethyl) pyrrolidin-4-ylthio] -4-methyl-1-azabicyclo [3.2. 0] hept-2-en-7-one-2-carboxylic acid was obtained.

UV _max nm (H ₂ O): 295;

IR _max cm ^-1 (KBr): 3358 (br), 1752, 16
54, 1560. 1389;

NMR δ ppm (D ₂ O): 1.22 (3H, d, J = 6.6H
z), 1.30 (3H, d, J = 6.3Hz), 1.78 (1H, m), 2.76 (1H, m), 3.
25 ~ 4.35 (10H, m), 7.12 (1H, s), 7.76 (1H, s).

By the same method as in Example 61, the compounds of Examples 62 to 66 shown in Table 6 below were obtained.

[Table 150]

[Table 151]

[Table 152]

[Table 153]

[Table 154]

[Table 155]

[Table 156]

[Table 157]

[Table 158]

[Table 159]

[Table 160]

[Table 161]

Example 67

[Chemical 133] (4R, 5S, 6S, 8R, 2'S, 4'S) -p-nitrobenzyl-3- [1-p-nitrobenzyloxycarbonyl-2- (4-methylpiperazin-1-ylcarbonyl) pyrrolidine- 4-ylthio] -4-methyl-6
-(1-hydroxyethyl) -1-azabicyclo [3.
2.0] Hept-2-en-7-one-2-carboxylate (147 mg) and 1-bromoacetyl-3,4-di (p-nitrobenzyloxy) benzene (200 mg) in acetone (3.0 ml) And was reacted at room temperature for 10 days. The solvent was distilled off under reduced pressure, and the residue was tetrahydrofuran (10.0 ml) and 0.1M-phosphate buffer solution (pH = 7.
0.1% ml), 10% palladium-carbon was added, and hydrogenation was carried out at room temperature under atmospheric pressure for 1.5 hours. After performing the same post-treatment as in Example 1, the product was purified by column chromatography with a CHP-20P polymer, and the elution fractions with an 8% tetrahydrofuran aqueous solution were collected and freeze-dried to obtain white amorphous (4R, 5S, 6
S, 8R, 2'S, 4'S) -3- [2- (4- (3,
4-dihydroxyphenylcarbonylmethyl) -4-methyl-piperazinium-1-ylcarbonyl) pyrrolidin-4-ylthio] -4-methyl-6- (1-hydroxyethyl) -1-azabicyclo [3.2.0] hept −
2-En-7-one-2-carboxylate was obtained. UV _max nm (H ₂ O): 301;

IR _max cm ^-1 (KBr): 3402 (br), 1758, 16
64, 1594. 1489, 1453, 1388, 1255, 1208, 1090;

NMR δ ppm (D ₂ O): 1.22 (3H, d, J = 7.3H
z), 1.30 (3H, d, J = 6.9Hz), 3.46 (3H, S), 6.64 (1H, d, J = 8.
3Hz), 7.24 (2H, m).

Example 68

[Chemical 134] (4R, 5S, 6S, 8R, 2'S, 4'S) -p-nitrobenzyl-3- [1-p-nitrobenzyloxycarbonyl-2-((2- (4-pyridyl) ethyl) methylamino Carbonyl) pyrrolidin-4-ylthio] -4
-Methyl-6- (1-hydroxyethyl) -1-azabicyclo [3.2.0] hept-2-en-7-one-2
-Carboxylate (248 mg) and 1-bromoacetyl-3,4-di (p-nitrobenzyloxy) benzene (228 mg) were dissolved in a mixed solvent of dry methylene chloride (4 ml) and dry dimethylformamide (2 ml) at room temperature. ,
Reacted for 10 days. Hydrogenation, post-treatment and purification (4R, 5S, 6S, 8
R, 2'S, 4'S) -3- [2-((2- (1-
(3,4-Dihydroxyphenylcarbonylmethyl) pyridinium-4-yl) ethyl) methylaminocarbonyl) pyrrolidin-4-ylthio] -4-methyl-6-
(1-hydroxyethyl) -1-azabicyclo [3.
2.0] Hept-2-en-7-one-2-carboxylate was obtained.

UV _max nm (H ₂ O): 286;

IR _max cm ^-1 (KBr): 3400 (br), 2364, 17
52, 1654. 1560, 1508, 1280;

NMR δppm (D ₂ O): 0.95 (3H, d, J = 6.9H
z), 1.28 (3H, d, J = 6.6Hz), 3.04 (3H, S), 6.89 (1H, d, J = 7.
9Hz), 7.2 ~ 7.5 (2H, m), 8.09 (2H, br.s), 8.70 (2H, br.
s).

Reference Example 1

[Chemical 135] a) 60% sodium hydride (8.0 g) was suspended in dry tetrahydrofuran (50 ml). After cooling with ice in a nitrogen stream, catechol (5.5 g) dissolved in dry tetrahydrofuran (25 ml) and dry hexamethylphosphoramide (60 ml) were added. After heating and stirring at 40 ° C. for 10 minutes, the mixture was ice-cooled again, a solution of p-nitrobenzyl bromide (9.5 g) in dry tetrahydrofuran (30 ml) was added, and the mixture was stirred for 10 minutes. The reaction solution was diluted with benzene, washed with 2.5% aqueous solution of monopotassium phosphate, washed with saline solution, dried over magnesium sulfate and removed of solvent. The residue was crystallized with ethyl acetate and collected by filtration.
1,2-di (p-nitrobenzyloxy) benzene (3.8 g) was obtained.

IR _max cm ^-1 (KBr): 1608, 1511, 1453,
1343, 1259, 1218, 1128, 1047;

NMR δ ppm (CDCl ₃ ): 5.26 (4H, s), 6.94
(4H, s), 7.62 (4H, d, J = 8.9Hz), 8.24 (4H, d, J = 8.9Hz).

B) Anhydrous aluminum chloride (1.27 g) was placed in a flask purged with nitrogen, and dried methylene chloride (1
0 ml) was added and the mixture was cooled to -10 ° C. Acetyl chloride (6
40 μl) and stirred for 10 minutes, then 1,2-di (p-nitrobenzyloxy) benzene (2.78 g)
Of dry methylene chloride (35 ml) was added dropwise over 5 minutes. After stirring for 10 minutes at the same temperature, the reaction solution was diluted with methylene chloride, and 0.1M phosphate buffer solution (pH = 7.0)
Washing, washing with sodium hydrogen carbonate water, drying over magnesium sulfate, removal of the solvent, crystallization of the residue with benzene, and filtration to obtain 1-acetyl-3,4-di (p-nitrobenzyloxy) benzene (2.81 g). Obtained.

IR _max cm ^-1 (KBr): 1673, 1607, 1586,
1516, 1430, 1352, 1276, 1218, 1151, 1040;

NMR δ ppm (CDCl ₃ ): 2.54 (3H, s), 5.31
(2H, s), 5.34 (2H, s), 6.92 (1H, d, J = 8.2Hz), 7.62 (6H,
m), 8.27 (4H, m).

C) To 1-acetyl-3,4-di (p-nitrobenzyloxy) benzene (5.0 g) was added dry tetrahydrofuran (350 ml), and the mixture was heated with stirring at 60 ° C. to dissolve it, and anhydrous aluminum chloride ( 150 mg) was added. Bromine (605 μl) dissolved in dry tetrahydrofuran (10 ml) was added thereto over 5 minutes, and the mixture was further stirred at the same temperature for 10 minutes and then cooled. 0.0 in the reaction solution
1M phosphate buffer (pH 7.0, 200 ml) was added, and the mixture was stirred for 1 hour under ice cooling, and the crystals were collected by filtration, water, ethanol,
The crystals were washed successively with ethyl acetate and dried under reduced pressure to give 1-bromoacetyl-3,4-di (p-nitrobenzyloxy) benzene (3.8 g).

IR _max cm ^-1 (KBr): 1667, 1607, 1517,
1437, 1348, 1278, 1224, 1150, 1108, 1037;

NMR δppm (CDCl ₃ ): 4.36 (2H, s), 5.31
(2H, s), 5.35 (2H, s), 6.95 (1H, d, J = 8.9Hz), 7.64 (6H,
m), 8.27 (4H, m).

Reference Example 2

[Chemical 136] Caffeic acid (3.60 g), tert-butyldimethylsilyl chloride (10.85 g) and imidazole (6.12 g) were dried over dimethylformamide (20 ml).
, And reacted overnight at room temperature. The reaction solution was diluted with toluene, washed with water and brine, dried over magnesium sulfate, and desolvated. The residue was dissolved in methanol (60 ml) and tetrahydrofuran (60 ml), a solution of sodium hydrogen carbonate (1.35 g) in water (20 ml) was added under ice cooling, and the mixture was stirred at room temperature for 1 hr. The reaction solution was acidified with diluted hydrochloric acid, extracted with ethyl acetate, washed with brine, dried over magnesium sulfate,
Removed the medium. The residue was crystallized with methanol and collected by filtration 3,4
-Di (t-butyldimethylsilyloxy) cinnamic acid (7.37 g) was obtained.

IR _max cm ^-1 (KBr): 3320 (br), 1690 (s
h), 1680, 1630, 1504, 1282, 1250;

NMR δ ppm (CDCl ₃ ): 0.22 (6H, s), 0.23
(6H, s), 0.99 (9H, s), 1.00 (9H, s), 6.25 (1H, d, J = 16Hz),
6.83 (1H, d, J = 8.6Hz), 7.03 (2H, s), 7.66 (1H, d, J = 16Hz).

The tert-butyldimethylsilyl ethers shown in Table 7 below were obtained in the same manner as in Reference Example 2 using the corresponding catechol derivatives.

[Table 162]

Reference Example 6

[Chemical 137] 2,3-Dihydroxybenzoic acid (4.62 g) was used, and 2-hydroxy-3- was prepared in the same manner as in Reference Example 2.
t-Butyldimethylsilyloxybenzoic acid was obtained.

IR _max cm ^-1 (neat): 1645, 1459, 1442,
1390, 1300, 1267, 1255, 1228, 1176, 1158;

NMR δ ppm (CDCl ₃ ): 0.22 (6H, s), 1.03
(9H, s), 6.80 (1H, m), 7.11 (1H, dd, J = 1.6Hz and 7.9H
z), 7.55 (1H, dd, J = 1.6Hz and 8.1Hz).

Reference Example 7

[Chemical 138] a) (2S, 4S) -1-allyloxycarbonyl-2
-Dimethylaminocarbonyl-4-benzoylthiopyrrolidine (2.53 g) was dissolved in dry methylene chloride (70 ml), dimedone (3.92 g) was added, and the mixture was stirred in a nitrogen stream.
Tetrakistriphenylphosphine palladium (809 mg) was added under ice cooling. After stirring for 30 minutes, 2-hydroxy-3-t-butyldimethylsilyloxybenzoic acid (1.88 g) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (1.34).
g) was added and reacted at 5 ° C for one day. The reaction solution was diluted with ethyl acetate, washed with dilute hydrochloric acid, brine, dried over magnesium sulfate, and the solvent was removed. By purifying the residue by silica gel column chromatography, (2S, 4S) -1- (2
-Hydroxy-3-t-butyldimethylsilyloxybenzoyl) -2-dimethylaminocarbonyl-4-benzoylthiopyrrolidine was obtained.

IR _max cm ^-1 (neat): 3150 (br), 1660, 1
650 (sh), 1630 (sh), 1574, 1444,1412, 1255, 1205;

NMR δ ppm (CDCl ₃ ): 0.21 (6H, s), 1.01
(9H, s), 2.06 (1H, m), 2.83 (1H, m), 3.03 (3H, s), 3.21 (3
H, s), 3.79 (1H, m), 4.13 (2H, m), 5.20 (1H, t, J = 8.3Hz),
6.72 (1H, t, J = 7.9Hz), 6.91 (1H, m), 7.03 (1H, d, J = 7.6H
z), 7.4 ~ 7.55 (2H, m), 7.55 ~ 7.70 (1H, m), 7.90 (2H, d
d, J = 1.5Hz and 8.5Hz).

B) (2S, 4S) -1- (2-hydroxy-3-t-butyldimethylsilyloxybenzoyl)
2-Dimethylaminocarbonyl-4-benzoylthiopyrrolidine (682 mg) was dissolved in methanol (3 ml), and a 30% methylamine methanol solution (399 mg) was added under ice cooling in a nitrogen stream. After stirring for 30 minutes, 30
% Methylamine methanol solution (399 mg) was added,
It was stirred for another 30 minutes. Monopotassium phosphate (1.05
g) was added and the mixture was extracted with methylene chloride. The organic layer was washed with a 2.5% aqueous solution of monopotassium phosphate, dried over magnesium sulfate and desolvated to give (2S, 4S) -1- (2-hydroxy-3). -T-butyldimethylsilyloxybenzoyl)
2-Dimethylaminocarbonyl-4-mercaptopyrrolidine was obtained. This was used in the next reaction without purification.

Reference Example 8

[Chemical 139] a) 1,2-dihydroxy-4-nitrobenzene (2.
0 g) and imidazole (4.4 g) were dissolved in dry dimethylformamide (10 ml), t-butyldimethylsilyl chloride (4.9 g) was added at room temperature, and the mixture was stirred at the same temperature for 1 day, then at 60 ° C. for 3 hours. Heated and stirred. After cooling, the reaction solution was diluted with benzene, washed with 0.1 M phosphate buffer (pH 7.0) and saturated saline, dried and desolvated, and the obtained crystals were washed with methanol and dried under reduced pressure. 1
-Nitro-3,4-di (t-butyldimethylsilyloxy) benzene (4.5 g) was obtained.

IR _max cm ^-1 (KBr): 1583, 1515, 1338,
1301, 1268, 1236, 1088;

NMR δ ppm (CDCl ₃ ): 0.15 (6H, s), 0,18
(6H, s), 0.96 (9H, s), 0.98 (9H, s), 6.16 (1H, d, J = 2.0Hz),
6.21 (1H, dd, J = 8.3Hz and 2.0Hz), 6.62 (1H, d, J = 8.3H
z).

B) 1-Nitro-3,4-di (t-butyldimethylsilyloxy) benzene (2.36 g) was dissolved in ethyl acetate (5 ml) and 10% palladium on carbon (23
6 mg) was added, and hydrogenation was carried out at room temperature under atmospheric pressure for 1 hour. The catalyst was filtered off, the filter cake was washed with ethyl acetate, and the filtration / washing liquid was removed to remove 1-amino-3,4-di (t-
Butyldimethylsilyloxy) benzene was obtained.

IR _max cm ^-1 (neat): 3450, 3360, 1614,
1581, 1508, 1468, 1461, 1441.1322, 1267, 1250, 12
23, 1180, 1122;

NMR δ ppm (CDCl ₃ ): 0.15 (6H, s), 0.19
(6H, s), 0.97 (9H, s), 0.98 (9H, s), 6.17 (1H, dd, J = 8.5Hz
And 2.7Hz), 6.23 (1H, d, J = 2.7Hz), 6.63 (1H, d, J = 8.5H
z).

C) 1-Amino-3,4-di (t-butyldimethylsilyloxy) benzene (354 mg) was dissolved in dry tetrahydrofuran (1.5 ml), and the solution was stirred under a nitrogen stream.
1.55 M n-butyllithium hexane solution (0.71 ml) was added under ice cooling. After stirring for 15 minutes, bromoacetic acid bromide (0.087 ml) was added at the same temperature, and further 3
Stir for 0 minutes. Sodium hydrogen carbonate (42m
g)) aqueous solution and ethyl acetate were added for extraction, washing with brine, drying with magnesium sulfate, removal of the solvent, and purification of the residue by silica gel column chromatography.
Bromoacetylamino-3,4-di (t-butyldimethylsilyloxy) benzene was obtained.

IR _max cm ^-1 (neat): 3280, 1655, 1607,
1507, 1420, 1405, 1294, 1250, 1225, 1206, 1120;

NMR δ ppm (CDCl ₃ ): 0.18 (6H, s), 0.23
(6H, s), 0.98 (9H, s), 0.99 (9H, s), 4.00 (2H, s), 6.78 (1
H, d, J = 8.6Hz), 6.83 (1H, dd, J = 2.3Hz and 8.6Hz), 7.25
(1H, d, J = 2.3Hz), 7.95 (1H, br.s).

Reference Example 9

[Chemical 140] a) (2S, 4S) -1-t-butoxycarbonyl-2
-Dimethylaminocarbonyl-4-benzoylthiopyrrolidine (7.56 g) was added to anisole (4.32 g) under ice cooling.
A solution of g) in trifluoroacetic acid (36 ml) was added dropwise, the temperature was raised to room temperature, and the mixture was stirred for 5.5 hours. The solvent of the reaction solution was removed under reduced pressure, diethyl ether was added to the residue, and the mixture was crystallized and collected by filtration. It was dried under reduced pressure to obtain (2S, 4S) -2-dimethylaminocarbonyl-4-benzoylthiopyrrolidine trifluoroacetic acid salt (5.82 g).

IR _max cm ^-1 (KBr): 3060 (br), 1668, 1
450, 1424, 1199, 1179, 1132;

NMR δ ppm (CDCl ₃ ): 1.95 to 2.15 (1H,
m), 3.06 (3H, s), 3.07 (3H, s), 3.35 ~ 3.55 (1H, m), 3.95
~ 4.15 (1H, m), 4.38 (1H, m), 5.04 (1H, t, J = 8.4Hz), 7.47
(2H, m), 7.62 (1H, m), 7.90 (2H, m).

B) (2S, 4S) -2-Dimethylaminocarbonyl-4-benzoylthiopyrrolidine trifluoroacetate (78 mg) and 4,5-diallyloxy-2-chloromethylpyridine (180 mg) were dried over methylene chloride (180 mg). 2 ml) and triethylamine (61 mg) was added under ice cooling in a nitrogen stream. After heating to room temperature and reacting for 4 days, washing with water, drying with sodium sulfate, removal of the solvent, and purification of the residue by silica gel thin layer chromatography (2
S, 4S) -1- (4,5-Diallyloxy-2-pyridyl) methyl-2-dimethylaminocarbonyl-4-benzoylthiopyrrolidine (212 mg) was obtained.

IR _max cm ^-1 (neat): 1655, 1588, 1580,
1510, 1445, 1395, 1322, 1242, 1207, 1172;

NMR δ ppm (CDCl ₃ ): 2.04 (1H, m), 2.7
~ 3.3 (3H, m), 2.93 (3H, s), 3.01 (3H, s), 3.5 ~ 3.9 (3
H, m), 4.22 (1H, m), 4.5 ~ 4.8 (4H, m), 5.2 ~ 5.5 (4H, m),
5.95, ~ 6.15 (2H, m), 7.20 (1H, s), 7.35 ~ 7.65 (3H, m),
7.91 (2H, m), 8.04 (1H, s).

The compounds shown in Tables 8 and 9 were obtained in the same manner as in Reference Example 9 using the corresponding alkylating agent.

[Table 163]

[Table 164]

[Table 165]

[Table 166]

[Table 167]

[Table 168]

[Table 169]

[Table 170]

[Table 171]

[Table 172]

[Table 173]

[Table 174]

[Table 175]

Reference Example 23

[Chemical 141] a) (2S, 4R) -1-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonyl-4-hydroxypyrrolidine (500 mg) is dissolved in ethyl acetate (30 ml), 10% palladium carbon (500 mg) is added, and the mixture is allowed to stand at room temperature. Hydrogenation was carried out under normal pressure for 30 minutes. The catalyst was filtered off, the filtrate was concentrated under reduced pressure, and the residue was crystallized from benzene and collected by filtration to obtain (2S, 4R) -2-dimethylaminocarbonyl-4-hydroxypyrrolidine (195 mg).

IR _max cm ^-1 (KBr): 3279, 1636, 1387,
1102;

NMR δ ppm (CDCl ₃ ): 1.84 (1H, m), 2.14
(1H, m), 2.89 (1H, d, J = 12.9Hz), 2.98 (3H, s), 3.04 (3H,
s), 3.31 (1H, dd, J = 4.6Hz and 11.6Hz), 4.15 (1H, t, J =
8.1Hz), 4.45 (1H, m).

B) (2S, 4R) -2-dimethylaminocarbonyl-4-hydroxypyrrolidine (100 mg) and 3,4-diallyloxybenzaldehyde (137 mg)
Was dissolved in methanol (0.5 ml) and stirred at room temperature for 30 minutes. Then, under ice-cooling, a solution of sodium cyanoborohydride (13 mg) in methanol (0.5 ml) was added, and the mixture was stirred for 1 hour under ice-cooling and further for 1 hour at room temperature. The reaction solution was diluted with benzene and extracted with 2.5% aqueous solution of potassium phosphate-potassium. The aqueous layer was adjusted to pH 10 with 1N sodium hydroxide, extracted with methylene chloride, dried, and then subjected to removal of (2S, 4R) -1- (3,4-diallyloxybenzyl) -2-dimethyl. Aminocarbonyl-4-hydroxypyrrolidine (86 mg) was obtained.

NMR δ ppm (CDCl ₃ ): 2.61 (1H, dd, J = 3.2Hz
And 10.1Hz), 2.83 (3H, s), 2.90 (3H, s), 3.46 (1H, dd,
J = 5.4Hz and 10.1Hz), 3.55 to 4.00 (3H, m), 4.45 to 4.7
5 (5H, m), 5.2 ~ 5.5 (4H, m), 6.0 ~ 6.2 (2H, m), 6.82 (2H,
s), 6.95 (1H, s).

B) (2S, 4R) -1- (3,4-Diallyloxybenzyl) -2-dimethylaminocarbonyl-4-hydroxypyrrolidine (226 mg) and triphenylphosphine (247 mg) in dry tetrahydrofuran (0.5 ml). ), A solution of diethyl azodicarboxylate (164 mg) in dry tetrahydrofuran (0.2 ml) was added dropwise under a nitrogen stream under ice cooling, and the mixture was stirred for 0.5 hours. Thioacetic acid (72 mg) in dry tetrahydrofuran (0.2 m
l) After dropping the solution, the temperature was raised to room temperature and the mixture was stirred for 1 hour. The reaction solution was diluted with ethyl acetate, and sodium hydrogen carbonate (79
(mg) aqueous solution was added and extracted. The organic layers were combined, washed with brine, dried over sodium sulfate, and the solvent was removed. The residue was purified by silica gel thin layer chromatography to obtain (2S, 4S) -1- (3,4-diallyloxybenzyl) -2-dimethylaminocarbonyl-4-acetylthiopyrrolidine (108 mg).

IR _max cm ^-1 (neat): 1684, 1641, 1508,
1422, 1259, 1221, 1134, 1120 (sh);

NMR δ ppm (CDCl ₃ ): 1.60 to 1.94 (2H,
m), 2.28 (3H, s), 2.66 (1H, m), 2.91 (3H, s), 2.92 (3H,
s), 2.98 (1H, m), 3.47 (1H, d, J = 13.1Hz), 3.59 (1H, m),
3.84 (1H, d, J = 13.1Hz), 3.99 (1H, m), 4.57 ~ 4.63 (4H,
m), 5.24 ~ 5.30 (2H, m), 5.36 ~ 5.47 (2H, m), 6.00 ~ 6.17
(2H, m), 6.75 ~ 6.99 (3H, m).

The compounds shown in Table 10 were obtained in the same manner as in Reference Example 23 using 3-hydroxypyrrolidine.

[Table 176]

[Table 177]

The compounds shown in Table 11 were obtained in the same manner as in Reference Example 9 or Reference Example 23.

[Table 178]

[Table 179]

[Table 180]

Reference Example 29

[Chemical 142] a) 3,4-Di (t-butyldimethylsilyloxy) phenylpropionic acid (2.054 g) was dissolved in dry tetrahydrofuran (20 ml), and triethylamine (607 mg) and ethyl chloroformate (651 mg) were cooled with ice in a nitrogen stream. ) Was added and stirred for 1 hour. 3-hydroxypyrrolidine (436 mg) in dry tetrahydrofuran (5
ml) solution was added and the mixture was further stirred for 1 hour. The reaction solution was diluted with ethyl acetate, washed with brine, dried over magnesium sulfate, and the solvent was removed. The residue was purified by silica gel column chromatography to give 1- [3,4-di (t-butyldimethylsilyloxy) phenylpropionyl] -3.
-Hydroxypyrrolidine (1.93g) was obtained.

IR _max cm ^-1 (neat): 3390 (br), 1620, 1
508, 1459, 1421, 1294, 1252, 1226,1158, 1122;

NMR δ ppm (CDCl ₃ ): 0.18 (6H, s), 0.18
(6H, s), 0.98 (9H, s), 0.98 (9H, s), 1.95 (2H, m), 2.52 (2
H, m), 2.85 (2H, t, J = 7.4Hz), 3.2 to 3.7 (4H, m), 4.47 (1
H, m), 6.64 (1H, d, J = 7.9Hz), 6.68 (1H, s), 6.73 (1H, d, J =
7.9Hz).

B) Lithium aluminum hydride (394
mg) in dry tetrahydrofuran (25 ml), and at room temperature in a nitrogen stream, 1- [3,4-di (t-butyldimethylsilyloxy) phenylpropionyl] -3-hydroxypyrrolidine (1.66 g) in dry tetrahydrofuran. (25 ml) solution was added dropwise. After heating under reflux for 1 hour, the temperature was returned to room temperature, water (3.36 ml) was added to decompose excess reducing agent, sodium sulfate (1.0 g) was added, and the mixture was stirred for 15 minutes. The insoluble matter was filtered off, the filtrate was removed, and the residue was purified by silica gel column chromatography to give 1
-[3,4-Di (t-butyldimethylsilyloxy) phenylpropyl] -3-hydroxypyrrolidine (736
mg) was obtained.

IR _max cm ^-1 (neat): 3350 (br), 1509, 1
471, 1460, 1420, 1290, 1250, 1222, 1157, 1127;

NMR δ ppm (CDCl ₃ ): 0.18 (6H, s), 0.19
(6H, s), 0.98 (9H, s), 0.98 (9H, s), 1.7〜1.9 (4H, m), 2.
12 ~ 2.35 (2H, m), 2.45 ~ 2.56 (4H, m), 2.74 (1H, m), 2.9
3 (1H, m), 4.33 (1H, m), 6.60 (1H, dd, J = 2.0Hz and 7.9H
z), 6.64 (1H, d, J = 2.0Hz), 6.73 (1H, d, J = 7.9Hz).

C) 1- [3,4-Di (t-butyldimethylsilyloxy) phenylpropyl] -3-hydroxypyrrolidine (844 mg) was dried over methylene chloride (17 ml).
Dissolved in triethylamine (27
5 mg) and methanesulfonic acid chloride (249 mg) were added, and the mixture was stirred for 1 hour. The reaction solution was diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate, and desolvated. Potassium thioacetate (620 mg) was added to the residue, and the mixture was stirred in dry dimethylformamide (14 ml) at 60 ° C for 2 hours. The mixture was diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate, and removed. By purifying the residue by silica gel column chromatography, 1- [3,
4-Di (t-butyldimethylsilyloxy) phenylpropyl] -3-acetylthiopyrrolidine (455 mg) was obtained.

IR _max cm ^-1 (neat): 1688, 1508, 1460,
1420, 1291, 1252, 1221;

NMR δ ppm (CDCl ₃ ): 0.18 (6H, s), 0.18
(6H, s), 0.98 (9H, s), 0.98 (9H, s), 1.6〜1.81 (3H, m),
2.30 (3H, s), 2.3 ~ 2.6 (6H, m), 2.64 (1H, m), 2.921H,
m), 3.92 (1H, m), 6.57 to 6.64 (2H, m), 6.
72 (1H, d, J = 7.9 Hz).

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification number Internal reference number FI Technical indication location A61K 31/44 7252-4C 31/445 7252-4C (72) Inventor Shintoshi Nagatoshi Kasuga, Konohana-ku, Osaka City 3-1,98 Idemaka Sumitomo Pharmaceutical Co., Ltd. (72) Inventor Manza Fukazawa 3-1,98 Kasuga, Kosuka Ward, Osaka City Sumitomo Pharmaceutical Co., Ltd. (72) Inventor Yoshihiro Sumita Sumitomo Pharmaceutical Co., Ltd. 3-98 Kasugadechu, Konohana-ku, Osaka

Claims (2)

[Claims] 1. A compound represented by the general formula [I]: [In the formula, j is 0 or 1, R ¹ is a hydrogen atom, a protective group for a hydroxyl group, or a group represented by any of the following general formulas (1) to (3), R ² is a hydrogen atom, a carboxyl group. The protecting group of the group, or the negative charge when A contains a positive charge,
Represents a methylene group substituted with a sulfur atom, a methylene group or a lower alkyl group. A represents the group shown below corresponding to R ¹ . That is, when [1] R ¹ represents a hydrogen atom or a hydroxyl-protecting group, A represents a group represented by any of the following general formulas (a) to (g). General formula (a) (In formula, k, l, and m show the integer of 0-3 (however,
l and m do not become 0 at the same time). R ³ represents a hydrogen atom, a lower alkoxycarbonyl group, a carbamoyl group, a mono- or di-lower alkylaminocarbonyl group, a cyclic aminocarbonyl group, a lower alkyl group, or a substituted lower alkyl group, and R ⁴ represents the following general formula (1) To any of the groups represented by (3). General formula (1) (In the formula, Y is a) single bond, b) lower alkylene group,
(C) lower alkenylene group, (d) carbonyl group, (e) carbonyl group, oxygen atom, or -NR ⁰ -group (in the formula, R
⁰ represents a hydrogen atom or a lower alkyl group. Or a lower alkylene group containing at least one), or a) lower alkenylene group containing at least one carbonyl group, oxygen atom, or —NR ⁰ — group (in the formula, R ⁰ has the same meaning as described above). R ⁵ and R ⁶ are a hydrogen atom or a hydroxyl-protecting group, and Z is a hydrogen atom, a halogen atom, a nitro group, a cyano group, a lower alkoxycarbonyl group, a carbamoyl group, or a mono- or di-lower alkylaminocarbonyl group. Indicates. ) General formula (2) (In the formula, Y, Z, R ⁵ and R ⁶ have the same meanings as described above.) General formula (3) (In the formula, Y, Z, R ⁵ and R ⁶ have the same meanings as described above.) General formula (b) (Wherein k, l, m and R ⁴ have the same meanings as described above, and n
Represents an integer of 0 to 3. R ⁷ represents a hydrogen atom, a lower alkyl group or a substituted lower alkyl group, and R ⁸ represents a hydrogen atom, an amino group protecting group, a lower alkyl group or a substituted lower alkyl group. General formula (c): (In the formula, k, l, m, n, R ⁴ and R ⁸ have the same meanings as described above.) General formula (d) (In the formula, k, 1, m, n, R ⁴ , R ⁷ and R ⁸ have the same meanings as described above, p represents an integer of 0 to 5, and q represents an integer of 1 to 5. ^a represents an intramolecular COO when the acid residue or R ² has a negative charge.) General formula (e) (In the formulae, k, l, m, n, q, R ⁴ , R ⁷ , R ⁸ and X ^a have the same meanings as described above.) General formula (f)-(CH ₂ ) _k- O-R ⁴ (F) (In the formula, k and R ⁴ have the same meanings as described above.) General formula (g)-(CH ₂ ) _k -NR ⁷ -R ⁴ (g) (In the formula, k, R ⁴ and R ^{4 7} has the same meaning as described above.] [2] When R ¹ represents a group represented by any of the general formulas (1) to (3), A represents the following general formula (h) to
The group represented by any of (p) or other organic groups are shown. General formula (h): (In the formulae, k, l, m, R ³ and R ⁸ have the same meanings as described above.) General formula (i) (In the formula, k, l, m and R ³ have the same meanings as described above.) General formula (j) (Wherein k, l, m and R ³ have the same meanings as described above, r
Represents an integer of 0 to 2. ) General formula (k) (In the formula, k and R ³ have the same meanings as described above.) General formula (l) (In the formula, k and R ³ have the same meanings as described above.) General formula (m) (In the formula, k, l and m have the same meanings as described above, and R ⁹ represents a hydrogen atom or an amino group-protecting group.) General formula (n)-(CH ₂ ) _k -R ¹⁰ (n) (Formula In the formula, k has the same meaning as described above, and R ¹⁰ represents a lower alkyl group or a substituted lower alkyl group.) General formula (o) (In the formula, k, R ³ and R ¹⁰ have the same meanings as described above.) General formula (p) (In the formula, k, l and m have the same meanings as described above.)]
A novel β-lactam compound represented by and a salt thereof. 2. A compound represented by the general formula [I]: [In the formula, j is 0 or 1, R ¹ is a hydrogen atom, a protective group for a hydroxyl group, or a group represented by any of the following general formulas (1) to (3), R ² is a hydrogen atom, a carboxyl group. The protecting group of the group, or the negative charge when A contains a positive charge,
Represents a methylene group substituted with a sulfur atom, a methylene group or a lower alkyl group. A represents the group shown below corresponding to R ¹ . That is, when [1] R ¹ represents a hydrogen atom or a hydroxyl-protecting group, A represents a group represented by any of the following general formulas (a) to (g). General formula (a): (In formula, k, l, and m show the integer of 0-3 (however,
l and m do not become 0 at the same time). R ³ represents a hydrogen atom, a lower alkoxycarbonyl group, a carbamoyl group, a mono- or di-lower alkylaminocarbonyl group, a cyclic aminocarbonyl group, a lower alkyl group, or a substituted lower alkyl group, and R ⁴ represents the following general formula (1) To any of the groups represented by (3). General formula (1) (In the formula, Y is a) single bond, b) lower alkylene group,
(C) lower alkenylene group, (d) carbonyl group, (e) carbonyl group, oxygen atom, or -NR ⁰ -group (in the formula, R
⁰ represents a hydrogen atom or a lower alkyl group. Or a lower alkylene group containing at least one), or a) lower alkenylene group containing at least one carbonyl group, oxygen atom, or —NR ⁰ — group (in the formula, R ⁰ has the same meaning as described above). R ⁵ and R ⁶ are a hydrogen atom or a hydroxyl-protecting group, and Z is a hydrogen atom, a halogen atom, a nitro group, a cyano group, a lower alkoxycarbonyl group, a carbamoyl group, or a mono- or di-lower alkylaminocarbonyl group. Indicates. ) General formula (2): (In the formula, Y, Z, R ⁵ and R ⁶ have the same meanings as described above.) General formula (3) (In the formula, Y, Z, R ⁵ and R ⁶ have the same meanings as described above.) General formula (b) (Wherein k, l, m and R ⁴ have the same meanings as described above, and n
Represents an integer of 0 to 3. R ⁷ represents a hydrogen atom, a lower alkyl group or a substituted lower alkyl group, and R ⁸ represents a hydrogen atom, an amino group protecting group, a lower alkyl group or a substituted lower alkyl group. General formula (c) (In the formulae, k, 1, m, n, R ⁴ and R ⁸ have the same meanings as described above.) General formula (d) (In the formula, k, 1, m, n, R ⁴ , R ⁷ and R ⁸ have the same meanings as described above, p represents an integer of 0 to 5, and q represents an integer of 1 to 5. ^a represents an intramolecular COO when the acid residue or R ² has a negative charge.) General formula (e) (In the formulae, k, l, m, n, q, R ⁴ , R ⁷ , R ⁸ and X ^a have the same meanings as described above.) General formula (f)-(CH ₂ ) _k- O-R ⁴ (F) (In the formula, k and R ⁴ have the same meanings as described above.) General formula (g)-(CH ₂ ) _k -NR ⁷ -R ⁴ (g) (In the formula, k, R ⁴ and R ^{4 7} has the same meaning as described above.] [2] When R ¹ represents a group represented by any of the general formulas (1) to (3), A represents the following general formula (h) to
The group represented by any of (p) or other organic groups are shown. General formula (h): (In the formulae, k, 1, m, R ³ and R ⁸ have the same meanings as described above.) General formula (i) (In the formulae, k, l, m and R ³ have the same meanings as described above.) General formula (j) (Wherein k, l, m and R ³ have the same meanings as described above, r
Represents an integer of 0 to 2. ) General formula (k) (In the formula, k and R ³ have the same meanings as described above.) General formula (l) (In the formula, k and R ³ have the same meanings as described above.) General formula (m) (In the formula, k, l and m have the same meanings as described above, and R ⁹ represents a hydrogen atom or an amino group-protecting group.) General formula (n)-(CH ₂ ) _k -R ¹⁰ (n) (Formula In the formula, k has the same meaning as described above, and R ¹⁰ represents a lower alkyl group or a substituted lower alkyl group.) General formula (o) (In the formula, k, R ³ and R ¹⁰ have the same meanings as described above.) General formula (p) (In the formula, k, l and m have the same meanings as described above.)]
In the production of the novel β-lactam compound represented by and a salt thereof, (Method A), when j = 1 and A is (a) to (c), the compound represented by the general formula [II] [In the formula, M has the same meaning as described above, R ^1a represents a hydrogen atom or a hydroxyl-protecting group, R ^2a represents a carboxyl-protecting group,
And L represent a reactive ester group of a hydroxyl group or a substituted or unsubstituted lower alkylsulfinyl group. A compound represented by], in the general formula [III-a] A ^a -SH [III-a] [wherein, the group A ^a represented by any one of formulas (a) ~ (c) Show. ] By reacting with a mercaptan compound represented by the general formula [Ia] [In the formula, R ^1a , R ^2a , A ^a and M have the same meanings as described above. ] The compound represented by the general formula [III-b-
1], Q ¹ -SH [III-b-1] [In the formula, Q ¹ represents a group represented by the above general formula (h). ] The compound of the general formula [IV-
a] [In the formula, R ^1a , R ^2a , Q ¹ and M have the same meanings as described above. ] To produce a compound represented by, then if R ⁸ is a protecting group of the amino group, after the removal reaction of the general formula (V) R ⁴ -X ^c [V] [wherein, R ⁴ has the same meaning as described above, and X ^c represents an acid residue. ] To produce a compound represented by the general formula [Ia], or (Method B) j = 1 and A is (d) to (e) Is represented by the general formula [II] [In the formula, R ^1a , R ^2a , M and L have the same meanings as described above. Table a compound represented by the general formula [III-b-2] Q ² -SH [III-b-2) (wherein, Q ² is the following general formula (d ') or (e') in] Is shown as a group. General formula (d ') (In the formulae, k, l, m, n, p, R ⁷ and R ⁸ have the same meanings as described above.) General formula (e ′) (In the formula, k, l, m, n, R ⁷ and R ⁸ have the same meanings as described above.)], And reacted with a mercaptan compound represented by the general formula [IV-b] [In the formula, R ^1a , R ^2a , Q ² and M have the same meanings as described above. A compound represented by] followed by the general formula (VI) _{^{X b - (CH 2) q}} -R 4 (VI) wherein the same meaning as q and R ⁴ above, the X ^b is acid residue Show. ] The compound represented by the general formula [I
-B] [Wherein R ^1a , R ^2a and M have the same meanings as described above,
A ^b represents a group represented by the general formula (d) or (e). Or when (Method C) j = 1 and A is (f) to (g), a compound of the general formula [VII] [In the formula, k, R ^1a , R ^2a and M represent the same meaning as described above, and Y ^a represents an oxygen atom or a —NR ⁷ — group (in the formula, R ⁷ represents the same meaning as described above). ] And a compound represented by the general formula [V] R ⁴ -X ^c [V] [In the formula, R ⁴ and X ^c have the same meanings as described above. ] The compound represented by the general formula [Ic] [In the formula, R ¹ , R ^2a and M have the same meanings as described above,
A ^c represents a group represented by the general formula (f) or (g). Or a (D method) j = 0 and A is (a) to (c), a compound of the general formula [VIII] [In the formula, R ^1a , M, A ^a and R ^2a have the same meanings as described above, and R ¹¹ represents a lower alkyl group, an aryl group or a lower alkoxy group. ] The compound represented by the general formula [Id] [In the formula, R ^1a , M, A ^a , and R ^2a have the same meanings as described above. Or when (E method) j = 0 and A is (d) to (e), a compound represented by the general formula [IX] [In the formula, R ^1a , M, Q ² , R ^2a and R ¹¹ have the same meanings as described above. ] By heating the compound represented by the general formula [X] [In the formula, R ^1a , M, Q ² and R ^2a have the same meanings as described above. A compound represented by] followed by the general formula (VI) _{^{X b - (CH 2) q}} -R 4 (VI) wherein, q, R ⁴ and X ^b are as defined above. ] The compound represented by the general formula [Ie] [In the formula, R ^1a , M, ^Ab and R ^2a have the same meanings as described above. Or when (Method F) j = 0 and A is (f) to (g), a compound of the general formula [XI] [In the formula, k, R ^1a , R ^2a , M and Y ^a have the same meanings as described above. ] And a compound represented by the general formula [V] R ⁴ -X ^c [V] [In the formula, R ⁴ and X ^c have the same meanings as described above. ] By reacting with a compound represented by the general formula [If] [Wherein R ^1a , R ^2a and M have the same meanings as described above,
A ^c represents a group represented by the general formula (f) or (g). Or a (G method) in which j = 1 and A is (h) to (n), a compound represented by the general formula [II] [In the formula, R ^1a , R ^2a , M and L have the same meanings as described above. A compound represented by], in the general formula [III-c] A ^d -SH [III-c] [wherein, the group A ^d represented by any one of formulas (h) ~ (n) Show. ] By reacting with a mercaptan compound represented by the general formula [XII] [In the formula, R ^1a , M, A ^d and R ^2a have the same meanings as described above. To produce a compound represented by], then when R ^1a is a protecting group of a hydroxyl group is subjected to the removal reaction of the general formula [XIII] embedded image [In the formula, M, A ^d and R ^2a have the same meanings as described above. ] In addition, let it be a compound represented by these, General formula [XIV] R ^<1b > ^-Xd [XIV] [In formula, R ^<1b> shows group represented by said General formula (1)-(3), ^Xd is Indicates an acid residue. ] The compound represented by the general formula [Ig] [In the formula, M, A ^d , R ^2a and R ^1b have the same meanings as described above. Or when (Method H) j = 1 and A is (o) to (p), a compound of the general formula [Ig ′] [Wherein R ^1b , M and R ^2a have the same meanings as described above,
A ^e represents a group represented by the general formula (1) or (m). Formula [XV] in R ¹⁰ -X ^e [XV] [wherein the compound represented by], R ¹⁰ is as defined above, X ^e represents an acid residue. ] Or by reacting with a compound represented by R ⁹
After removing the protecting group of the amino group in the formula ( ₁ ), it is reacted with a lower (C ₁ -C ₅ ) alkyl ester of formimidic acid to give a compound of the general formula [I-h] [Wherein R ^1b , M and R ^2a have the same meanings as described above,
A ^f represents a group represented by the general formula (o) or (p). Or when (Method I) j = 0 and A is (h) to (n), a compound of the general formula [XVI] [In the formula, R ^1a , M, A ^d and R ^2a have the same meanings as described above, and R ¹¹ represents a lower alkyl group, an aryl group or a lower alkoxy group. ] The compound of the general formula [XVII] [In the formula, R ^1a , M, A ^d and R ^2a have the same meanings as described above. ] Then, when R ^1a is a protective group for a hydroxyl group, the removal reaction is carried out, and then the compound of the general formula [XVIII] [In the formula, M, A ^d and R ^2a have the same meanings as described above. A compound represented by] in more general formula [XIV] R ^1b -X ^d [XIV] [wherein, the R ^1b and X ^d represents the same meaning as above. ] The compound of the general formula [Ii] [In the formula, M, A ^d , R ^2a and R ^1b have the same meanings as described above. Or when (Method J) j = 0 and A is (o) to (p), a compound represented by the general formula [Ii ′] [Wherein R ^1b , M and R ^2c have the same meanings as described above,
A ^e represents a group represented by the general formula (1) or (m). Formula [XV] in R ¹⁰ -X ^e [XV] [wherein the compound represented by], R ¹⁰ is as defined above, X ^e represents an acid residue. ] Or by reacting with a compound represented by R ⁹
After the reaction for removing the amino-protecting group is carried out, it is reacted with a lower (C ₁ -C ₅ ) alkyl ester of formimidic acid to give a compound of the general formula [I-j] [Wherein R ^1b , M and R ^2a have the same meanings as described above,
A ^f represents a group represented by the general formula (o) or (p). ] To produce a compound represented by, R ^1, R ^5,
When a β-lactam compound in which R ⁶ , R ⁸ or R ⁹ is a hydrogen atom and R ² is a hydrogen atom or a negative charge is desired, it is then represented by the general formulas [Ia] to [Ij]. Or a combination of the reaction for removing the protective group for the hydroxyl group, the reaction for removing the protective group for the carboxyl group, and the reaction for removing the protective group for the amino group, or the simultaneous removal of these protective groups. A process for producing a β-lactam compound represented by the above general formula [I] or a pharmacologically acceptable salt thereof, characterized by: