JPS58105992A - Penem derivative - Google Patents

Abstract

NEW MATERIAL:A compound of formulaI[R<1> is H, lower alkyl bearing hydroxyls as substituents; R<2> is cyclic amino of 3-7 membered ring including or not including O, S in the ring wherein the N may have a group of formula II (R<4>, R<5> are H, lower alkylene); R<3> is H, ester residue; A is single bond or lower alkylene]and its salt. EXAMPLE:6-(1-Hydroxyethyl)-2-(aziridin-2-yl)-2-penem-3-carboxylic acid. USE:Antibacterial: it shows high activity against gram-positive and gram-negative bacteria. PREPARATION:A compound of formula III (R<6> is H, lower alkyl bearing protected hydroxyls as substituents; R<7> is cyclic amine corresponding to R<2> with the N protected; R<8> is a group protecting a carboxyl; R<9> is alkyl) is heated to give a compound of formula IV, which is subjected to deprotection of R<8> and of the protecting groups included in R<6> and R<7> to give the compound of formulaI.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to specific penem derivatives having the general formula and their pharmacologically acceptable salts, as well as processes for their production.

In the above formula, R1 represents a hydrogen atom or a lower alkyl group having a hydroxyl group as a substituent, and R2 represents an oxygen atom t in the ring.
a is a cyclic amino group forming a three- to seven-membered ring that may or may not contain a sulfur atom; R3 represents a hydrogen atom or a biologically active ester residue, and M represents a single bond or a lower alkylene group.

Conventionally, many of the antibiotics widely used as medicines have been penicillins, which are fused ring β-lactam compounds, and cephalosporin compounds.

In recent years, chenamycin and olipanic acid having a 2-carbapenem structure have been discovered as β-lactam antibiotics having extremely strong antibacterial effects, and it has become important to develop new compounds using them as models. As a result of intensive research into the synthesis of new compounds with strong antibacterial activity using t-enamycin as a model, the present inventors succeeded in synthesizing a new compound having the general formula (1) and developing it as a pharmaceutical, and the present invention In the general formula f+1, R is preferably a hydrogen atom or a lower alkyl group such as methyl, ethyl, n-globyl, isopropyl, n-butyl, or isobutyl having a hydroxyl group as a substituent; aziridinyl, azenacinyl, pyrrolidinyl, piperisilyl, hexahydroazepinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, morpholinyl, thiomorpholinyl, tetrahydro-1,3-oxazinyl or tetrahydro-1,3-thi , a cyclic amino group forming a three- to seven-membered ring containing or not containing an oxygen atom or a sulfur atom in the ring, such as and R
5 is 4 same or different hydrogen atom or methyl, ethyl, n
- indicates a lower alkyl group such as globyl, n-butyl, isobutyl. ), where R is a hydrogen atom or a lower aliphatic acyloxymethyl group such as acetoxydimethyl, propionyloxymethyl, n-butyryloxymethyl, imbutyryloxymethyl, pivaloyloxymethyl, etc. , me, toxycarbonyloxymethyl, ethoxycarbonyloxymethyl, 1-ethoxycarbonyloxyethyl, 1-n-globoxycarbonyloxyethyl, 1-n-globoxycarbonyloxyglobil, lower alkoxycarbonyloxy lower alkyl group, or Compounds which are biologically active ester residues such as a phthalidyl group and in which A is a single bond or a lower alkylene group such as methylene, ethylene, trimethylene, propylene, and tetramethylene can be mentioned.

iu = is represented by the general formula (11, more preferably R is a hydrogen atom, hydroxymethyl, 1-hydroxyethyl,
1-hydroxypropyl ti is 2-hydroxy-2-Y
R is an aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, oxazolidinyl, thiazolidinyl, isothiazolidinyl, morpholinyl, thiomorpholinyl or tetrahydro-1,3-thioxazinyl group, and its %i:A atom is of the formula -〇-NR ``&4 (in the formula, R4 and R5 are the same or different and represent a hydrogen atom, methyl, ethyl or n-propyl group), and s, a, and R are hydrogen atoms, acetoxymethyl, pyryl, Mention may be made of compounds in which A is a baloyloxymethyl, 1-ethoxycarbonyloxyethyl or phthalidyl group, and A is a single bond, methylene, ethylene or trimethylene.

In the general formula (1), R is particularly preferably a hydrogen atom, 1-hydroxyethyl or 2-hydroxy-2-propyl group, and R2 is aziridinyl, azetidinyl,
A pyrrolidinyl, piperidinyl, oxazolidinyl, thiazolidinyl, morpholinyl or thiomorpholinyl atom has the formula -C# N R5 group (wherein R4 and R
5 is the same as or different from 4 and represents a hydrogen atom, methyl or ethyl group. ), examples include compounds where R is a hydrogen atom, pivaloyloxymethyl or 1-ethoxycarbonyloxyethyl group, and A is a J41 bond, methylene or ethylene. Note that in the compound having the general formula (1), optical isomers and stereoisomers based on asymmetric carbon atoms exist, and all of these isomers are represented by a single formula. The scope of allocation is not limited. however,
Preferably, a compound in which the carbon atom at the 5th position has the same coordination as penicillin A1, that is, a 'TE)R coordination, and a compound in which the hydroxyl group present in the substituent at the 6th position has the R coordination can be selected.

Compound (1) can also be converted into a salt form acceptable to 4FU, if necessary. Examples of such salts include salts of inorganic metals such as linium, sodium, potassium, calcium, and magnesium, and ammonium salts such as ammonium, cyclohexylammonium, diisopropylammonium, and triethylammonium. is sodium salt,
and potassium salt.

The compound of the present invention having the general formula ω belongs to a penem sieve conductor in which two bonds exist between the 2nd and 3rd positions of the penicillin ring, and is a novel compound having each of the cyclic amino derivatives at the 2nd position. These compounds are a group of compounds that exhibit anti-fc properties and are useful compounds as pharmaceuticals, or are intermediates in the synthesis of compounds that exhibit these activities.

Examples of the compounds having the general formula (1) obtained by the present invention include the compounds described below.

(1) 6-(1-Hydroxyethyl)-2-(aziridin-2-yl)-2-penem-3-carboxylic acid and its sodium, potassium salt or pivaloyloxymethyl ester.

(2) 6-(1-hydroxyethyl)-2-(acyridin-2-ylmethyl)-2-penem-3-carboxylic acid and its sodium salt, potassium salt or pivaloyloxymethyl ester (3) 6-CI -hydroxyethyl)-2-(1'1-
Formimidoylaziridin-2-ylmethyl)-2-
Penem-3-carboxylic acid and its sodium salt, potassium salt or pivaloyloxymethyl ester (4) 2-(azetidin-2-yl)-2-penem-
3-carboxylic acid and its sodium salt, potassium salt or pivaloyloxymethyl ester (5) 2-(N-formimidoylazetidin-2-yl)-2-penem-3-carboxylic acid and its sodium salt, Calirhammonoester or pivaloyloxymethyl ester (ε) 6-(1-hydroxyethyl)-2-(azetidin-2-yl)-2-penem-3-carboxylic acid and its sodium salt, potassium salt or pivaloyl Oxymethyl ester (7) 6-(1-hydroxyethyl)-
2-(N-formimidoylazetidin-2-yl)-
°2-Penemu-3-carboxylic acid and its sodium salt, potassium salt or pivaloyloxymethyl ester (8) li-(1-hydroxyethyl)-2-(N-acetimidoylazetidin-2-yl)- 2-penem-
3-Carboxylic acid and its sodium salt, potassium salt or pivaloyloxymethyl ester (9) 6-C2-hydroxy-2-propyl)-2-(
azetidin-2-yl)-2-penem-3-carboxylic acid and its sodium salt, potassium salt or pivaloyloxymethyl ester (1G) 2-(nacetidin-2-ylmethyl)-2-penem-3-carboxylic acid and its sodium salt, potassium salt or pivaloyloxymethyl ester (11) 2-(N-formimidoylazetidin-2-ylmethyl)-2-penem-3-carboxylic acid and its sodium salt, potassium salt or pivaloyloxymethyl ester; yloxymethyl ester (12) 6-(1-hydroxyethyl)-2-(azetidin-2-ylmethyl)-2-penem-3-carboxylic acid and its sodium salt, potassium salt or pivaloyloxymethyl ester (13 )6-(1-hydroxyethyl')-2-(N-
Formimidoylazetidin-2-yl 1fnt)-2
-Penem-3-carboxylic acid and its sodium salt, potassium salt or pivaloyloxymethyl ester (14) 11-(1-hydroxyethyl)-2-(N-
a7timidoyl azetidin-2-ylmethyl)-2-
Penem-3-carboxylic acid and its sodium salt, potassium salt or pinoyloyloxymethyl ester (15) 11-(2-hydroxy-2-propyl)-2
-(N-formimidoylazetidin-2-ylmethyl)-2-penem-3-carboxylic acid and its sodium salt, potassium salt or pivaloyloxymethyl ester (16) 6-(1-hydroxyethyl)-2 -(azetidin-2-ylpropyl)-2-penem-3-carboxylic acid and its sodium salt, potassium salt or pivaloyloxymethyl ester (17) 2-(azetidin-3-yl)-2-penem-
3-Carboxylic acid and its sodium salt, potassium salt or pivaloyloxymethyl ester (1B) 2-(N-formimidoylazetidine-3-
yl)-2-penem-3-carboxylic acid and its sodium salt, potassium salt or pivaloyloxymethyl ester (19) 6-(1-hydroxyethyl)-2-(azetidin-3-yl)-2-penem -3-Carboxylic acid and its sodium salt, potassium salt or pivaloyloxymethyl ester (20) 6-C1-hydroxyethyl)-2-(N-formimidoylaceticin-3-yl)-2-penem-
3-Carphonic acid and its sodium salt, potassium salt or pivaloyloxymethyl ester (21) 6-(1-hydroxyethyl)-2-(N-acetimidoylazetidin-3-yl)-2-penem-
3-Carboxylic acid and its sodium salt, potassium salt or pivaloyloxymethyl ester (22) 6-(2-hydroxy-2-propyl)-2-
(azetidin-3-yl)-2-penem-3-carboxylic acid and its sodium salt, potassium salt or pivaloyloxymethyl ester (23) 2-(azetidin-3-ylmethyl)-2-penem-3 -Carboxylic acid and its sodium salt, potassium salt or pivaloyloxymethyl ester (24) 2-(N-polumidoilacetidine-3-
ylmethyl)-2-penem-3-carboxylic acid and its sodium, potassium salt or pivaloyloxymethyl ester (25) 6-(1-hydroxyethyl)-
2-(azetidin-3-ylmethyl)-2-penem-3
-Carboxylic acid and its sodium salt, potassium salt or pivaloyloxymethyl ester (2g) I-(1-hydroxyethyl)-2-(N-formimidoylazetidin-3-ylmethyl]-2-penemu3- Carvone 1 and its thorium salt, potassium salt or pivaloyloxymethyl ester (27) l-(1-hydroxyethyl)-2-(N-acetimidoylazetidin-3-ylmethyl)-3-penem- 3-Carphonic acid and its sodium salt, potassium salt or bi/f-royloxymethyl ester (28) 6-(2-hydroxy-2-propyl)-2-
(N-formimidoylazetidin-3-ylmethyl)
-2-penem-3-carboxylic acid and its sodium salt, potassium salt or pivaloyloxymethyl ester (211) 6-(1-hydroxyethyl) -,2-(
Azetidin-3-yl 7゛lopyl)-1-penem-3
-Carboxylic acid and its sodium salt, potassium salt or pivaloyloxymethyl ester (30) 2-(pyrrolidin-2-yl)-2-penem-
3-Carboxylic acid and its sodium salt, potassium salt or pivaloyloxymethyl ester (3-2-(N-formimidoylpyrrolidine-2-
yl)-2-penem-3-carboxylic acid and its sodium salt, potassium salt or pivaloyloxymethyl ester (32) II-(1-hydroxyethyl)-2-(pyrrolidin-2-yl)-2-penem -3-carboxylic acid and its sodium salt, potassium salt or pivaloyloxymethyl ester (33) II-(1-hydroxyethyl)-2-(N-
Formimidoylpyrrolidin-2-yl)-2-penem-3-carboxylic acid and its sodium salt, potassium salt or pivaloyloxymethyl ester ($4) l-(1-hydroxyethyl)-2-(N- Acetimidoylpyrrolidin-2-yl)-2-penem-
3-Carboxylic acid and its sodium salt, potassium salt or pivaloyloxymethyl ester (35) 6-(2-hydroxy-2-propyl)-2-
(pyrrolidin-2-yl)-2-penem-3-carboxylic acid and its sodium salt, potassium salt or pivaloyloxymethyl ester (38) 2-pyrrolidin-2-ylmethyl)-2-
Penem-3-carboxylic acid and its natrilam salt, potassium salt or pivaloyloxymethyl ester (37) 2-(N-formimidoylpyrrolidine-2-
ylmethyl)-2-penem-3-carboxylic acid and its sodium salt, potassium salt or pivaloyloxymethyl ester (38) 6-(1-hydroxyethyl)-
2-(pyrrolidin-2-ylmethyl)-2-penem-3
-Carboxylic acid and its sodium salt, potassium salt or pivaloyloxymethyl ester (39) 6-C1-hydroxyethyl)-2-(N-formimidoylpyrrolidin-2-ylmethyl)-2-penem-3-carvone Acid and its sodium salt, potassium salt or pinoyloyloxymethyl ester (40) 8-(1-hydroxyethyl)-2-(N-acetimidoylpyrrolidin-2-ylmethyl)-2-penem-3-carboxylic acid and Its sodium salt, potassium salt or pinomaloyloxymethyl ester (41) 6-(2-hydroxy-2-propyl)-2-
(N-formimidoylpyrrolidin-2-ylmethyl)
-2-penem-3-carboxylic acid and its sodium salt, potassium salt or pivaloyloxymethyl ester (42) 6-(1-hydroxyethyl)-2-(pyrrolidin-2-ylethyl)-2-penem- 3-Carboxylic acid and its sodium salt, potassium salt or pivaloyloxymethyl ester (43) 2-(pyrrolidin-3-yl)-2-penem-
3-Carboxylic acid and its sodium salt, potassium salt or pivaloyloxymethyl ester (44) 2-(N-formimidoylpyrrolidine-3-
yl)-2-penem-3-carboxylic acid and its sodium salt, potassium salt or pivaloyloxymethyl ester (45) 6-(1-hydroxyethyl)-2-(pyrrolidin-3-yl)-2-penem -3-carboxylic acid and its sodium salt, potassium salt or pivaloyloxymethyl ester (46) 6-(1-hydroxyethyl)-2-(N
-formimidoylpyrrolidin-3-yl)-2-penem-3-carboxylic acid and its sodium salt, potassium salt or pivaloyloxymethyl ester (47) 6-(1-hydroxyethyl)-2-(N- Acetimidoylpyrrolidin-3-yl)-2-penem-
3-Carboxylic acid and its sodium salt, potassium salt or pivaloyloxymethyl ester (4B) 6-(2-hydroxy-2-propyl)-2-
(pyrrolidin-3-yl)-2-penem-3-carvone family and its sodium salt, potassium salt or pivaloyloxymethyl ester, (49) 2-(pyrrolidin-3-ylmethyl)-2-penem-3- Carboxylic acid and its sodium salt, potassium (product or pivaloyloxymethyl ester (50) 2-(N-formimidoylpyrrolidine = 3-
ylmethyl)-2-penem-3-carboxylic acid and its sodium salt, potassium salt or pivaloyloxymethyl ester (51) 8-(1-hydroxy diethyl)
-2-(pyrrolidin-3-ylmethyl)-2-penem-
3-Calphon r (and its sodium salt, potassium salt or pivaloyloxymethyl ester (52) 62(1-hydroxyethyl)-2-(N
-formimidoylpyrrolidin-3-ylmethyl)-2
-penem-3-carboxylic acid and its sodium salt,
Potassium salt or pivaloyloxymethyl ester (53-6-(1-hydroxyethyl)-2,-(N
-acetimidoylpyrrolidin-3-yl)-2
-Penem-3-carboxylic acid and its sodium salt, potassium salt or pivaloyloxymethyl ester (54) 6-(2-hydroxy-2-propyl)-2-
(N'-formimidoylpyrrolidin-3-ylmethyl)-2-penem-3-carboxylic acid and its sodium and potassium salts L<U pivaloyloxymethyl ester (55) $-C1-hydroxyethyl)- 2-(pyrrolidin-3-ylpropyl)-2-he$mu-3-carboxylic acid and its sodium salt, potassium salt or pivaloyloxymethyl ester (56) 2-(piperidin-2-yl)-2-penem-
3-Carboxylic acid and its sodium salt, potassium salt or pivaloyloxymethyl ester (57) 6-(1-hydroxyethyl)-2-(piperidin-2-yl)-2-penem-3-carboxylic acid and its Sodium salt, potassium salt or hahibaloyloxymethylester (58) 6-(1-hydroxyethyl)
-2-(N-formimidoylpiperidin-2-yl)
-2-penem-3-carboxylic acid and its sodium salt, potassium salt or pivaloyloxymethyl ester (ss) s-(t-hydroxyethyl)-z-(hybaricin-2-ylmethyl)-2-penem-3 -Carboxylic acid and its sodium salt, potassium salt or pivaloyloxymethyl ester (60) 8-(1-hydroxyethyl)-2-(N-formimidoylpiperidin-2-ylmethyl)'-2-penemu-3-carboxylic acid and its sodium salt, potassium salt or pivaloyloxymethyl ester (1) 3-carboxylic acid and its sodium salt, potassium salt or pivaloyloxymethyl ester (62) 6
-(1-Hydroxyethyl)-2-(N-formimidoylpiperidine- -2-penem-3-carboxylic acid and its sodium salt, potassium salt or pivaloyloxymethyl ester (63) 6-(1-hydroxy ethyl)-2-(hyheridin-3-ylmethyl-3-carboxylic acid and its sodium salt, potassium salt or pivaloyloxymethyl ester (64) 6-(1-hydroxyethyl>-t., -2
-, (N-formimidoylpiperidin-3-ylmethyl)-2-penem-3-carboxylic acid and its sodium salt, potassium salt or pivaloyloxymethyl ester (65) 6-(1-hydroxyethyl)-2 -(N-formimidoylpiperidin-3-ylethyl)-2-penem-3-carboxylic acid and its sodium salt, potassium salt or pivaloyloxymethyl ester (66) 8-(1-hydroxyethyl)-2- (piperidin-4-yl)-2-penem-3-carboxylic acid and its sodium salt, potassium salt or pivaloyloxymethyl ester (67) 6-(1-hydroxyethyl)-2-(N-formimidoyl piperidin-4-yl)-2-penem-
3-Carboxylic acid and its sodium salt, potassium salt or pivaloyloxymethyl ester (68) 6-(1-hydroxyethyl)-2-(piperidin-4-ylmethyl)-2-he$mu-3-carboxylic acid and its Sodium salt, potassium salt or pivaloyloxymethyl ester C6B) 6-(1-hydroxyethyl)-2-(N-formimidoylbi-lysin-4-ylmethyl)-2-
Penem-3-carboxylic acid and its sodium salt, potassium salt or piparoyloxymethyl ester (70) 6-(1-hydroxyethyl)-2-(oxazolidin-2-yl)-2-penem-3-carboxylic acid and Its sodium salt, potassium salt or pivaloyloxymethyl ester (71) 6-(1-hydroxyethyl)-2-(N-formimidoyloxazolidin-2-yl)-2-penem-3-carboxylic acid and its Sodium salt, potassium salt or pivaloyloxymethyl ester (72) 6-C1-hydroxyethyl)-2-(oxazolidin-2-ylmethyl)-2-penem-3-carboxylic acid and its sodium salt, potassium JM6 Pivaloyloxymethyl ester (73)@-(1-hydroxyethyl)-2-(oxazolidin-4-yl)-2-penem-3-carboxylic acid and its sodium salt, potassium salt or pivaloyloxymethyl ester (74) 6-(1-hydroxyethyl)-2-(N-formimidoyloxa/lysin-4-yl)-2-penem-3-carboxylic acid and its sodium salt, potassium salt or pivaloyloxymethyl Ester (75)@-(1-hydroxyethyl)-2-(oxazolidin-4-ylmethyl)-2-penem-3-carboxylic acid and its sodium salt, potassium salt or pivaloyloxymethyl ester (7@)6 -(1-hydroxyethyl)-2-(N-formimidoyloxazolidin-4-ylmethyl)-2
-Penem-3-carboxylic acid and its sodium salt, potassium 1ji or pivaloyloxymethyl ester (7F) @ -(1-hydroxyethyl)-2-(oxazolidin-5-yl)-2-penem-3-carvone Acid and its sodium salt, potassium salt or pivaloyloxymethyl ester C78) II -(1-hydroxyethyl)-2-
(oxazolidin-5-ylmethyl)-2-penem-3
-carboxylic acid and its sodium salt, potassium salt or pivaloyloxymethyl ester (7!I)8-C1-hydroxyethyl)-2-(thiazolidin-2-yl)-2-penem-3-carboxylic acid and its Sodium salt, potassium JAR Shikke pivaloyloxymethyl ester (110) 6-(1-hydroxyethyl)-2-(N-
Formimidoylthiazolidin-2-yl)-2-penem-3-carboxylic acid and its sodium, potassium salt or pivaloyloxymethyl ester (It) 6-(1-hydroxyethyl)-2-(thiazolidine-2 -ylmethyl)-2-penem-3-carboxylic acid and its sodium salt, potassium salt or pivaloyloxymethyl ester (82) 6-(1-hydroxyethyl)-2-(N-formimidoylthiazolidine-2- ylmethyl)-2-
Penem-3-carboxylic acid and its sodium salt, potassium t, Hk or pivaloyloxymethyl ester (83) 2-(thiazolidin-4-yl)-2-penem-3-carboxylic acid and its sodium salt, potassium salt or pivaloyloxymethyl ester (84) 8-(1-hydroxyethyl)-2-(thiazolidin-4-yl)-2-penem-3-carboxylate and its sodium salt, potassium salt or Sodium and potassium salts of pivaloyloxymethyl ester (as) @-1-hydroxyethyl)-Kouichi (N-formimidoylthiazolidin-4-yl)-2-penem-3-carvone ri2 and hiso or bivaloyloxymethyl ester (16) 6-(1-hydroxyethyl)-2-(thiazolidin-4-ylmethyl)-2-penem-3-carvone or 2 and its sodium salt, potassium salt or pivaloyloxymethyl Ester (117) 6-(1-hydroxyethyl)-2-(thiazolidin-4-ylethyl)-2-penem-3-carboxylic acid and its sodium salt, potassium salt or pivaloyloxymethyl ester (8!I) 6-(1-hydroxyethyl)-2-(N-
Formimidoylthiazolidin-4-ylmethyl)-2
-Penem-3-carboxylic acid and its sodium salt, potassium salt or hivaloyloxymethyl ester (89) 8-(1-hydroxyethyl)-2-(N-acetimidoyltinysilidin-4-ylmethyl and its sodium salt, potassium salt or pivaloyloxymethyl ester (80) 2-(thiazolidin-5-ylmethyl)-2-
Penem-3-carboxylic acid and its sodium salt, potassium salt or pivaloyloxymethyl ester (sl) e-(1-hydroxyethyl)-2-(thiasoricin-5-yl)-2-penem-3-carboxylic acid and its sodium salt, potassium salt or pivaloyloxymethyl ester (12) 6-(1-hydroxyethyl)-2-(N-formimidoylthiazolidin-5-ylcu-2-penem-3-carboxylic acid and Sodium salt, potassium salt or pivaloyloxymethyl ester (113) 6-(1-hydroxyethyl)-2-(thiazolidin-5-ylmethyl)-2-penem-3-carbo'/acid and its sodium salt, Potassium salt or pivaloyloxymethyl ester (94) 6-C1-hydroxyethyl)-2-(morpholin-3-yl)-2-penem-3-carboxylic acid and its sodium salt, potassium salt or pivaloyloxy Methyl ester (15) 6-(1-hydroxyethyl)-2-(thiomorpholin-3-yl)-2-penem-3-carboxylic acid and its sodium salt, potassium salt or pivaloyloxymethyl ester (116) 6-(1-hydroxyethyl)-2-(N-
Formimidoylthiomorpholin-3-ylmethyl)-
2-penem-3-carboxylic acid and its sodium salt,
Potassium salt or pivaloyloxymethyl ester This exemplary compound has stereoisomers and optical isomers as described above, and among these isomers, preferred is (5R).

6R) coordination or (5R#68) coordination, and the hydroxyl group contained in a lower alkyl group (e.g. hydroxyethyl group) having a hydroxyl group at the 6th position is the R coordination. be able to.

The novel compound (1) according to the present invention can be produced by the method shown below.

12) +3) (41
(51 (61
Tl) In the above m1 formula, R, RlR and A are the same as those mentioned above, RIS is a water-based atom or a lower alkyl group having a hydroferment group protected as an optional component, and R
is a rod-shaped r-mino group forming a three-membered ring or a seven-membered ring with or without a barium atom or sulfur atom in the ring, and its family atoms have a carrier group. R8 represents a carboxyl group f=1d, M, R'Un-butyl, n
- an alkyl group such as octyl or fc is phenyl, 0-
Y represents an aryl group such as tolyl, m-tolyl, p-)lyl, and Y is a base, a halogen atom such as iodine, an acetoxy group, an arylsulfonyl group such as benzenesulfonyl, and p-)luenesulfonyl. Or it represents an alkylsulfonyl group such as methylsulfonyl, ethylsulfonyl, n-glopylsulfonyl.

As the protecting group for the hydroxyl group in R6, benzyl, 0
-Nitrobenzyl, p-nitrobenzyl, aralkyl group, benzyloxycarbonyl, 0-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, aralkyloxycarbonyl group, benzhydryl group, trimethylsilyl, t-butyldimethylsilyl, etc. Examples include tri-lower alkylsilyl groups, lower aliphatic acyl groups such as acetyl, glopionyl, n-butyryl, and tetrahydropyranyl groups.

The amino group contained in R is benzyl, 0-
Examples include aralkyl groups such as nitrobenzyl and p-nitrobenzyl, benzyloxycarbonyl, aralkyloxycarbonyl groups such as 0-nitrobenzyloxycarbonyl p-nitrobenzyloxycarbonyl, and benzhydryl groups.

Carboxy group retention M yM R includes λ2-dibromoethyl, haloke/alkyl group such as 2,2.2-)lichloroethyl, aralkyl group such as benzyl, p-nitrobenzyl, benzhydryl group, acetoxymethyl,
Lower aliphatic syloxymethyl groups such as propionyloxymethyl, n-butyryloxymethyl, imbutyryloxymethyl, pivaloyloxymethyl, methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl, 1-ethoxycarbonyl Oxyethyl, 1-n-
Examples include lower alkoxycarbonyloxy, lower alkyl groups such as globoxylcarbonyloxinglopyr, and phthalidyl groups.

The first step is to convert a compound having the general formula (2) into a compound having the general formula M 8
-0-A-R' (7)1 (wherein R and 4A have the same meanings as described above,
M represents an alkali metal such as potassium or potassium. ) is reacted with an alkali metal salt of thio-8-tribenron having the formula (3) to produce a compound having the general formula (3).

Note that the compound having the general formula (2), which is the starting material for this step, is described in the application specification (Japanese Patent Application No.
No. 70688), and has the general formula (
The thio-8-carboxylic acid having 7) can be produced from the corresponding amino acid according to a conventional method.

The reaction is a compound having general formula (2)! Thio-8 having the general formula (1) of 1 to 1,5 lyz in the presence of a bath agent
- achieved by contacting with an alkali metal salt of a carboxylic acid. The solvent used in the reaction is not particularly limited as long as it does not participate in the reaction, but examples include water, alcohols such as methanol, ethanol, and n-glopanol, ketones such as acetone and menal ether ketone, Suitable are water-soluble ethers such as tetrahydrofuran and dioxane, dialkylamides such as dimethylformamide and dimethylacetamide, and mixtures of these nanyakuyoku MIJ and water. Although the reaction temperature is not particularly limited, it is usually suitably carried out at 0°C to 25°C. The time required for the reaction varies mainly depending on the type of raw material compound and the reaction temperature, but is approximately 30 minutes to 2 hours.

After the reaction is completed, the target compound (3) of this step is collected by a conventional method. For example, a water-immiscible organic solvent such as methylene chloride is added to the reaction mixture, and the mixture is washed with water.
It can be obtained by drying and distilling off the solvent.

The second step 8 is a compound having the general formula (3) with the general formula OHC
-002R8 (81 (wherein, R8 has the same meaning as described above)) by reacting with a glyoxylic acid ester derivative having the general formula (
4) This is a process for producing a compound that makes a sound.

The reaction is achieved by bringing the compound having the general formula (3) into contact with the compound having the general formula (8) in the presence of a solvent. Common substances used in the reaction are not limited to 4f% even if they are not involved in this reaction, but include aromatic hydrocarbons such as benzene and toluene, ethers such as tetrahydrofuran and dioxane, dimethylformamide, and dimethyl. Fatty acid dialkylamides such as acetamide and mixed solvents of these organic solvents are preferred. This addition reaction may be promoted in the presence of a base, but the bases used for this purpose include:
Organic bases such as triethylamine, diisopropylethylamine, pyridine or sodium silicate 1)
A 7 /L/It is possible to raise the minium molecular sieve. Although the reaction temperature is not particularly limited, it is preferable to conduct the reaction by heating to room temperature or the M flow temperature of the solvent used. The reaction time varies depending on the type of raw material compound and the reaction temperature, but is from 30 minutes to 20 hours.

After the reaction is completed, the target compound (4) of this step is collected from the reaction mixture according to a conventional method. For example, it can be obtained by washing the reaction mixture with water, drying it, and then distilling off the solvent and excess reagent.

The third step is a step of producing a compound having general formula (5), and is a step of halogenating a compound having general formula (4) and converting the obtained halogen compound into a phosphorus-ylide compound (5).

The initial halogenation reaction is achieved by bringing the compound having the general formula (4) into contact with a halogenating agent in the presence of a solvent. The halogenating agent used in the reaction is not particularly limited, but includes thionyl halides such as thionyl chloride and thionyl bromide, phosphorus oxyhalides such as phosphorus oxychloride (phosphorus pentachloride, phosphorus pentabromide), etc. Suitable examples include phosphorus halides such as or oxalyl halides such as oxalyl chloride. This reaction is preferably carried out in the presence of a base, and the F group used for this purpose is preferably an organic base such as triethylamine, diisopropylethylamine, pyridine or lutidine. The solvent used in the reaction is not particularly limited as long as it does not participate in this reaction, but ethers such as tetrahydrofuran and dioxane are suitable. The reaction temperature is not particularly limited, but a relatively low temperature is desirable to suppress the reaction.
It is preferable to carry out the process at a temperature of 0.degree. The time required for the reaction varies mainly depending on the type of raw material compound, reaction temperature, etc., but is approximately 10 minutes to 2 hours.

After the reaction is completed, the general formula (wherein R, R, R and M have the same meanings as described above, and 2 represents chlorine or bromine) represents 10 gene atoms.

] The target compound of this/X rogogenation step is collected from the reaction mixture according to a conventional method. For example, it can be obtained by distilling off the bath agent and excess reagent from the reaction mixture. The obtained target compound 1 is usually used in the next step reaction without further purification.

In addition, in the target compound (5a) thus obtained, the /10 gene atom represented by substituent 2 can be converted to other /X logon atoms by a known method. Sorting is done by treating the phased chlorine compounds with inorganic bromide or iodide salts such as lithium bromide or potassium iodide in an organic solvent such as ether.
It can be a bromine or iodine compound.

Then, the reaction of converting into a phosphorus-ylide compound is achieved by bringing the compound having the general formula (5&) into contact with a phosphine compound and a base in the presence of a solvent. Suitable reagents for the phosphine compound used in the reaction include tri-lower alkyl phosphines such as tri-n-butylphosphine, and triarylphosphines such as triphenylphosphine. As the base used, when a phosphine compound is used, organic bases such as triethylamine, diisoglopylethylamine, pyridine, and 2,6-lutidine are suitable. The solvent used in the reaction is not particularly limited as long as it does not participate in this reaction, but examples include aliphatic hydrocarbons such as hexane and cyclohexane, tetrahydrofuran, iodine ethers of dioxane, benzene, and toluene9. Aromatic hydrocarbons, dialkyl fatty acid amides such as dimethylformamide and dimethylacetamide, and mixed solvents of these organic solvents are suitable. Although the reaction temperature is not particularly limited, it is usually preferred to carry out the reaction at a temperature of 30 to 80°C, and if necessary, the reaction can be carried out in the atmosphere of an inert gas such as 1ilf element. The time required for the reaction mainly depends on the raw material compounds,
Although it varies depending on the reaction temperature, etc., it is about 1 to 60 hours.

After the reaction is completed, the target compound (5) of this step is collected from the reaction mixture according to a conventional method. For example, adding a water-immiscible organic solvent such as ethyl acetate and water to the reaction mixture;
It can be obtained by separating the organic solvent, washing it with water, drying it with a drying agent, and then distilling off the solvent from the organic solvent layer.

The fourth step is a step of producing a compound having general formula (6), in which a compound having general formula (5) is heated and subjected to a ring-closing reaction to produce a benem derivative having general formula (6).

The reaction is accomplished by heating the compound having the general formula (5) in the presence or absence of a solvent. The solvent used in the reaction is not particularly limited, but ethers such as dioxane, and aromatic hydrocarbons such as benzene, toluene, and xylene are suitable. There are no particular limitations on the heating reaction temperature, but it is usually preferable to carry out the reaction at 80 to 179°C in the presence of catalytic hydroquinone. It can be carried out in an atmosphere of active gas or, in the absence of a solvent, in a reaction vessel under reduced pressure. The time required for the reaction varies mainly depending on the type of raw material compound, reaction reaction, etc., but is approximately 5 to 10 hours.

After the reaction is completed, the target compound (6) of this step is collected from the reaction mixture according to a conventional method. For example, it can be obtained by distilling the solvent off the reaction mixture under reduced pressure, adding a mixed solvent of ethyl acetate and hexane to the residue to separate the precipitate, and distilling off the solvent from the VI liquid.

The '5th step is a step of producing a penem conductor having the general formula (1), which is the object compound of the present invention, and optionally,
Using a compound having the general formula (6), the protecting group for the hydroxyl group contained in R6, the protecting group for the cyclic amine 7 group contained in R7, or the protecting group for the carboxyl group R6 is removed, and the water M group and the cyclic group are removed, respectively. The reaction for restoring an amino group or a carboxy group, and 4 and R5 have the same meanings as described above. ).

That is, R in the compound having the general formula (6)
The reaction of removing the hydroxyl-retaining group contained in 6 and restoring the hydroxyl group is carried out using a conventional method to remove the hydroxyl-retaining group of the compound having the general formula (6), and to remove the hydroxyl-retaining group, aralkyl group, aralkyloxycarbonyl group, This is achieved by removing these carrier groups from a compound such as a benzhydryl group, a tri-lower alkylsilyl group, a lower h1f rib acyl group or a tetrahydropyranyl group.

When the protecting group for the hydroxyl group is an aralkyl group, an aralkyloxycarbonyl group, or a benzhydryl group, the removal reaction can be carried out by catalytic reduction of the corresponding compound (6) in the presence of a catalyst such as palladium-carbon. You can laugh.

The reaction is carried out in the presence of a solvent, and the solvent used is not particularly limited as long as it does not participate in this reaction.
Methanol 1. Alcohol such as ethanol ((,
Ethers such as tetrahydrofuran and dioxane,
Fatty acids such as acetic acid and these! ! A mixed solvent of a solvent and water is suitable. The reaction temperature is usually around aO ℃ to room temperature, and the reaction time is 800℃ for the raw material compound and reducing agent.
Although it varies depending on the type, it is usually 5 minutes to 12 hours.

When the protecting group for the hydroxyl group is a tri-lower alkylsilyl group, its removal reaction can be carried out by treating with the corresponding compound +6+ tetrabutylammonium fluorite. There are no particular limitations on the cutting agent used, but ethers such as tetrahydrofuran and dioxane are suitable. The reaction fi is suitably carried out by treating at around room temperature for 10 to 24 hours. Also, # such as monoacetic acid and trifluoroacetic acid can be added to accelerate the reaction.

When the hydroxyl group is a lower aliphatic acyl group,
The removal reaction can be carried out by treating the corresponding compound (6) with a base in the presence of an aqueous solvent. The solvent to be used is particularly limited if it is a solvent used in ordinary hydrolysis reactions, but water or a solution of water and methanol, ethanol, or n-glopanol can be used.
/L'cols or mixed solvents with organic solvents such as ethers such as tetrahydrofuran and dioxane are suitable. The base to be used is not particularly limited as long as it does not affect other parts of the compound, especially β-lactam, but preferably alkali metal carbonates such as sodium carbonate and potassium carbonate are used. The reaction temperature is not particularly limited, but is preferably from 0°C to around room temperature in order to suppress side reactions. The time required for the reaction varies depending on the type of raw material compound, reaction temperature, etc., but is usually 1 to 6 hours.

Furthermore, when the protecting group for the hydroxyl group is a tetrahydropyranyl group, the removal reaction can be carried out by bringing the corresponding compound (6) into contact with a fatty acid such as acetic acid and a mixed solvent of an organic solvent and water. I can do it. Although there are no particular limitations on the solvent used, ethers that are miscible with water such as tetrahydrofuran and dioxane are suitable. The reaction is preferably carried out at around room temperature, usually for 5 minutes to 3 hours.

Then, in compound (0), the carrier group of the cyclic amine 7 group contained in the substituent R is an aralkyl group, an aralkyloxycarbonyl group or a benzhydryl group.
The amino group can be restored by removing the protecting group by catalytic reduction.

The reaction conditions are the same as those for the reaction for removing the protecting group for the hydroxyl group contained in R6 described above. Therefore, both protecting groups can be removed at the same time.

Usually, after carrying out the reaction for removing the hydroxyl group ν and the protecting group for the amino group in the above compound (61), a process for removing the protecting group R8 for the carboxyl group is carried out to convert it into the carboxylic acid group 14. Removal of the Hokyo group varies depending on the method used, but is generally removed by methods known in the art. Preferably, reaction 11 is carried out according to the general formula (
This is achieved by contacting a compound having 6) in which the fit group R8 is a protective group that can be removed by reduction treatment, such as a halogenoalkyl group, an aralkyl group, or a benzhydryl group, with a reducing agent. As the reducing agent used in this reaction, zinc and acetic acid are suitable when the protecting group for the carboxyl group is a halogenoalkyl group, and when the protecting group is an aralkyl group or a benzhydryl group, aqueous and palladium-based reducing agents are preferable. Catalytic reduction catalysts such as carbon or sulfurized alkali metal sulfides such as aluminum or potassium sulfide are preferred. The reaction is carried out in the presence of a solvent, and the solvent used is not particularly limited as long as it does not participate in this reaction, but methanol,
Alcohols such as ethanol, ethers such as tetrahydrofuran and dioxane, fatty acids such as acetic acid, and mixed solvents of these organic solvents with water or phosphate buffer (pH 7.0) are suitable. The reaction temperature is usually around 0° C. to room temperature, and the reaction time is usually 30 minutes to 24 minutes, although it varies depending on the raw material compound and the type of reducing agent.

Nao, in the reduction reaction of this step, when the protecting group for the hydroxyl group contained in R6 or the cyclic amino group contained in R7 in compound (6) is an aralkyl group, aralkyloxycarbonyl group or benzhydryl group, the carboxyl group At the same time as the protecting group, the hydroxyl group and the protective group of the cyclic amino group are removed.

After the reaction is completed, the target compound of the reaction for removing the protecting group R of the carboxyl group is collected from the reaction mixture according to a conventional method. For example, it can be obtained by removing precipitated insoluble matter from the reaction mixture, temporarily washing the organic solvent with water, drying, and distilling off the solvent.

In addition, if the target compound is water-bathable, remove the precipitated insoluble matter from the reaction mixture, and if necessary, concentrate the ν solution under reduced pressure. It can be obtained by subjecting it to column chromatography using porous adsorption φ, 1 fat, separating the portion from which the target compound is eluted, and freeze-drying it.

■ 4 Indicates the same meaning as above. ) has the general formula 〇) obtained by the above-mentioned protecting group removal reaction.
Among the compounds having R2 converted to a cyclic amino group, a compound having the general formula % formula % (wherein R4 and R5 have the same meanings as described above, and R is methyl, ethyl, n-propyl, isopropyl,
Indicates a lower alkyl group such as n-butyl and isobutyl. ) is achieved by reacting with an imidoester compound having The reaction can be carried out by contacting the compound (1) in which R is a cyclic amine/group with an imide ester compound having the general formula (9) under alkaline conditions, preferably around pH 8 to 9.

The alkaline reagent used in the reaction is not particularly limited, but includes alkali metal hydroxides such as hydroxide, potassium hydroxide, and alkaline earth metal hydroxides such as calcium hydroxide and barium hydroxide. Salts of alkali metals such as carbonate, sodium carbonate, and potassium carbonate are preferred. This reaction is carried out in the presence of an aqueous solvent, and the solvents used include water or water and alcohols such as methanol, ethanol, and n-glopanol, ethers such as tetrahydrofuran and dioxane, dimethylformamide, dimethyl A mixed solvent with an organic solvent such as a fatty acid dialkylamide such as acetamide or a nitrile such as acetonitrile is suitable.

The reaction temperature is preferably a relatively low temperature of about 0° C. to room temperature. The time required for the reaction varies depending on the type of raw material compound, reaction temperature, etc., but is usually 5 minutes to 1 hour.

After the reaction is completed, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, if the reaction mixture is near neutral, Diaion HP20AG (manufactured by Mitsubishi Chemical Corporation)
The target compound is subjected to column chromatography using a porous adsorption resin such as
It can be obtained by freeze drying.

Next, the obtained compound can be converted into a carboxylic acid conductor by subjecting the obtained compound to removal of the carboxy group in accordance with the conventional method described above.

The target compound obtained in each of the above steps can be purified, if necessary, by conventional methods such as recrystallization, reprecipitation, preparative thin layer chromatography, column chromatography, etc.

The venem derivative of the present invention having the general formula (1) is a compound exhibiting excellent antibacterial activity, and when its activity was measured by an agar plate dilution method, it was found to be effective against Gram-positive bacteria such as Staphylococcus aureus and Bacillus subtilis. It showed activity against a wide range of pathogens, including Durham-negative cases such as Shigella and Colon-1, Klebsiella pneumoniae, Pneumoniae, and Durham-negative fungi.

Such compounds are therefore useful as antibacterial agents to treat bacterial infections caused by these pathogens. Examples of dosage forms for this purpose include oral administration in the form of tablets, capsules, granules, powders, syrups, etc., and parenteral administration in the form of intravenous injection, intramuscular injection, etc.

The dose of To-4 Dong varies depending on age, body weight, symptoms, etc., as well as the form of administration and the number of administrations, but it is usually administered to adults at a dose of about 250 to 3,000 cm per day, either once or in several divided doses.

Next, the present invention will be explained in more detail with reference to Reference Examples and Examples.

Reference example 1゜L←)-N-p nitropenzyloxycarbonyl-proline 11 was added to 20 m of anhydrous methylene chloride at 8% and then 0.975
Add 1 ml of triethylamine, add 0.47 ml of isobutyl chloroformate at -10°C, and stir at the same temperature for 40 minutes. Hydrogen sulfide gas is introduced into the reaction solution at −10° C. for 1 hour.

The mixture was made acidic with 2.5N sulfuric acid, and the produced thio-8-carboxylic acid was extracted with methylene chloride.

After drying over magnesium sulfate, the bath medium was distilled off under reduced pressure.
The desired thio-8-carboxylic acid 1t was obtained.

Exactly the same, p (1) operation, the following thio-8-
Obtain carboxylic acid.

(R) -N -p-Nitropenzyloxycarbonylbi-lysine-2-thio〇-carboxylic acid (R,8) -
N-p-Nitropenzyloxycarbonylhyheridine-2-thio-8-carboxylic acid Reference Example 2 To a 60ml ether solution of L12-1-nitropenzyloxycarbonylglolin 1.62 was added triethylamine 1.13+++1 at -15°C. Add 1.11f of isobutyl chloroformate, stir at -20°C for 1 hour, quickly filter the formed salt, and add 1.11f of isobutyl chloroformate. 1J (4~S times vigilante)
An ethereal solution of diazomethane was added thereto, stirred for 3 hours under water cooling, and further left at 5°C overnight. The reaction solution was washed with 5 g of water and then with water, and then dried with magnesium sulfate.

When the solvent is distilled off under reduced pressure, diazoketone compound 165f is obtained.

3. of the above diazoketone body 165f. Add 237~ of silver oxide in g at methanol solution and reflux for 30 minutes. After confirming the completion of the reaction by thin silica gel chromatography and 1fIIJ chromatography, it is filtered, and the solvent is distilled off under reduced pressure to obtain a crude product. Rabbit chromatography on a benzene:ethyl acetate-5:1 thread Rf = Q
, 1.2fk of the desired homocarboxylic acid methyl ester is obtained from the portion of 3.

2 ml of a 4N aqueous sodium hydroxide solution was added to a 16 m/methanol bath containing 132 vol of the above homoester while cooling with water, and the reaction system was gradually raised to 25° C. (about 2 hours). Exclude the ethyl acetate soluble portion, acidify the alkaline layer with 10% hydrochloric acid, and extract with ethyl acetate. After drying the extraction solution with magnesium sulfate, the bath medium is distilled off under reduced pressure to obtain the desired homogloline conductor 1f.

The homogloline derivative 1f thus obtained was dissolved in 20 ml of anhydrous menalene chloride, 0.97 ml of triethylamine and 0.47 d of isobutyl chloroformate were added at -15°C, and after stirring at the same temperature for 1 hour, the mixture was stirred at -1t°C. Blow hydrogen sulfide gas into the reaction solution.

After 1 hour, acidify with 2N sulfuric acid and thoroughly extract with methylene chloride. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 12 of the desired thio-8-acetic acid.

In exactly the same manner, thio-S-acetic acid shown below is obtained.

(5) -N-p-nitropenzyloxycarbonylpyrrolidin-2-ylthio-8-62 (81-N-I)
-Nitrobenzyloxycarbonylazetidin-2-ylthio-s -acetate e(R,S) -N -p-Nitrobenzyloxycarbonylbiperidin-2-ylthio-8
- to acetic acid) -N -p-nitrobenzyloxycarbonylthiazolidin-4-yl'thio-8-acetic acid Example 1, 1t of L-proline obtained according to Reference 1) The derivative was dissolved in 3.2 mg of IN sodium hydroxide under water cooling, and after stirring for 20 minutes, 770 m9 of (3R,4R)-4-acetoxy-
Slowly add a solution of 3-[i]-]1-tert-butyldimethylsilyloxyethyl]2-oxoazetidine in IBtai dioxane. After stirring for 1 hour under water cooling, methylene chloride was added to extract the product. After washing with water, it was separated and purified by rabbit chromatography in a 1:1 cyclohexane:ethyl acetate system.1. The desired title compound 1,2f was obtained.

Example 2. □１□ -1-tert-butyldimethylsilyloxy Example 1
By heating β-1actam, 1.1f of the 14 conductor, 930 ml of p-nitrobenzylglyoxylate and 1 drop of triethylamine in a Sheen-Stark laboratory apparatus in Toll's Pensen for 2 hours with occasional removal of water. Reflux. After 15 hours, the solvent was distilled off, and the residue was subjected to rabbit chromatography using a cyclohexane:ethyl acetate-1=1 system to obtain the desired title compound 1f.

Example 3゜Diobin ζ aminal 1f according to Example 2 was dissolved in anhydrous natrahydrofuran BOmt, λ6-lutidine 05g was added thereto, and then 11 mouths of 032 J of thionic chloride were added at -20°C. I can do it. It took 30 minutes to reduce the reaction temperature from -20℃ to 0.
As the temperature rises to 7° C., the salt will form slowly and the salt will be filtered out. The solvent is distilled off to obtain a crude chloride. Silica gel thin J-chromatography Rf-0,7 (SiCl]hexane:ethyl acetate-1:1). The above chloride compound is dioxane 2 (lI
64c dissolved, triphenylphosphine 1.2f and UL
Add @-Lutidine Q and @rtrl and heat and stir at 40 to SoC for 48 hours. Cyclohexane product:
Ethinoacetate v'y-1: By subjecting it to IL' rabbit chromatography, the desired i' ylide compound 7 is obtained.
T49 was obtained.

NMR spectrum (cDaz,) δ: 1.25 (3H, d,, T-4i) 1g) 13 ~ & 4 (
23H) The ylide compound 114■ obtained according to Example 4° and Example 3 was heated in xylene with a width of about 1
The mixture was heated and stirred at 50°C for 48 hours in the presence of a catalytic amount of hydroquinone, and after distilling off the solvent, it was subjected to rabbit chromatography in a cyclohexane:ethyl acetate-2:1 system.
The desired penem visit conductor 989 was obtained.

NMR spectrum (CDO2,) δ: 0.08 (OH5X2), 0.80 (tBu), 1.2
5(C)(,.

d, J-6-5H2), 1.8-12 (4H)
, 1 to 411 (4H), 4-4.4 (IH),
5.・'18 (2H), 5.1-5.5 (2H)
a 5.78 (IHed #J-3Hz)
el, 4-11.3 (4H) IR spectrum (liquid) v Ctn':
17110.1710 Example 5 Penem casting pure body 911119 obtained in Example 4 was melted in tetrahydrofuran 41, followed by ice cooling, and DTIIR.
l of acetic acid and 2259 g of tetrabutylammonicum fluoride trihydrate. 1 at 25℃ except for the water bath
Stir for 5 hours. Add ethyl acetate and wash with water. After drying the organic layer over magnesium sulfate, the product was subjected to preparative silica gel thin layer chromatography in a cyclohexane:ethyl acetate-1=1 system to obtain the desired title compound corresponding to Rf-Q, 2. I got 40 da.

NMR spectrum (cDc!z,) δ: 1.30 (3
H, 6, J-11Htx) s L 7-2.2 (
4H) a3.3~! 1 (4H), 4.0-4.3 (I
H), 5.2 (2H) 5.1-5.5 (3H), 7.4
~11.3 (4H) Example 6 40 μ of the penem compound obtained in Example 5 was dissolved in 3 rtrl of anhydrous tetrahydrofuran, 0.11 jJ), 2.7 m7 of phosphoric acid buffer (pH 1,04), and then 10 ml of phosphoric acid buffer (pH 1,04). Add a carbon catalyst from 80 to 50 ml at room temperature in a hydrogen stream.
Stir for an hour. Filter the catalyst and wash thoroughly with the above-mentioned mild solution. The filtrate was washed twice with ethyl acetate, and the aqueous layer was reduced to about 1/3 at a low temperature under reduced pressure.
Diaion HP20muG (100-200 mesh, Mitsubishi Chemical Industries, Ltd.)

Company H) After adsorption on a chromato tube filled with 2arxt,
Distilled water, then 2-thiacetone water, then 5-thiacetone water are poured out, and the desired fraction of the penem compound is obtained from both the 5% acetone water fractions. The collected fractions were lyophilized to obtain the desired penem compound am9.
4 (4H).

132 (2H, t, J-7Hz), &7~4.4 (2H
).

s, 5s (IH, a, r-2az) (Dss external standard) Example T.

D-proline and its corresponding thioic acid were obtained from Reference Example 1r, and then the same reactions as in Examples 1, 2, 3, 4, and 5.6 were carried out to obtain the desired title compound.

NMR spectrum (D20) δ: L 2 S (3H, 6, J-fa, 5 Hz) s
L B ~2.3 (4H), 3.32 (2H, t,
J-7Hz), 3.8-4.4 (2H), 5.65 (I
H, d, J-2Hz) (DBS external standard) Example 8 The corresponding thioacid is synthesized from DL-piperidine-2-carboxylic acid according to the method of reference column 1. Next, Example 1
The desired title compound was obtained by carrying out the reactions in the same manner as in steps 6 to 6.

NMR spectrum IL/ (cDcts) δ: 1.25 (
3H, d, J-6, 5Hz), 1.7-2.2 (6H)
, 3.3-4.4 (4H), 5.7 (IH, d, J-1
, 5Hz) (D1313 external reference) Execution row 9゜Reference row 2 obtained (S) -N-balanitrobenzyloxycarponyl-virolidin-2-ylthioacetic acid so
o m9 under ice-cooling IN-aqueous sodium hydroxide fl! i
Add 2.77 ml and stir for 20 minutes. Add (s Rf 4 R) 4-acetoxy-3-[(6
)-1-tert-butyldimethylsilyloxyethyl]-2-oxoazetidine 6001n9 in a dioxane 20 ml bath solution was slowly added, and the mixture was stirred for 1.5 hours under water cooling. Add methylene chloride and extract. The organic layer is washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the crude product was subjected to rabbit chromatography in a 2:1 cyclohexane:ethyl acetate system to obtain the desired compound 1f from the Rf, Q, and 40 portions.

NMR spectrum (CDCl2) δ: 006 (CHX 2 ) -083 (tBu) s
1.18 (CHs-d, J-1”Hz)
, 1.7~2.1 (4H*m) #2. ”'
-31 (3H), tO~4.4 (2H), 5.18 (2
H.

1, 5.27 (IH, d, J-2, 511), 6.8
4 (NH), 7.38-8.30 (4H, A2B2)
Example 10° Chill The azetidinone rust conductor 1f obtained in Example 9, p-nitrobenzylglyoxyleide hydrate 823~, and 1 drop of triethylamine are mixed occasionally using a Sheen-Stark laboratory apparatus in 59 ml of anhydrous benzene. Because I pour water 2
Heat to reflux for an hour. fBk was distilled off, and the crude product was separated and purified by rabbit chromatography in a cyclohexane:ethyl acetate 1:2 system.
The desired title compound *1y was obtained from part i.

NMR spectrum (ODOI-5) δ: 0.07 (OH
x2), 0.87('tBu), 1.20((,H,.

d, J-@Hz), 1.7-2. I 5 (4H, m),
19-3.65 (3H), 4.0-4.4 (2H)
, 519 (2H, θ), 5.25 (2H, 8), 5.
3 (IH).

5.55 (IH, d, J-2, 5Hz), 7.4-8.
4, (4H) Example 11゜Lysin-2-ylmethylcarbonylthio〕-3゜Example 1
1 t of the aminal compound, which had been prepared at 0.0 m), was dissolved in 15 ml of anhydrous tetrahydrofuran, added with 0.23 m/l of lutidine, and chlorinated by adding 0.14 * of thionyl chloride at -20°C. Stir at room temperature for 1 hour, quickly filter the precipitated salt, and evaporate the solvent under reduced pressure to obtain the crude chloride. The thus obtained chloride was dissolved in 30 mA of anhydrous dioxane, 514 mA of triphenylphosphine and 0.28 mA of lutidine. and 50-60'C for 20 hours.
Heat and stir. Cold troweled ethyl acetate was added, and the organic layer was washed with 5% saline and dried over magnesium sulfate.

After distilling off the solvent, it was subjected to rabbit chromatography using a 1:1 cyclohexane ethyl diacetate system to obtain the desired title compound 1,2f.
I got it. Silica gel thin layer chromatography Rf-Q,
2 (Cyclohexane: Ethyl acetate - 1:1) Example 12 The ylide compound 1.2f obtained in Stell Example 11 was dissolved in anhydrous toluene 80'ff17FC and heated at 90 to 100°C in the presence of hydroquinone as a catalyst for 20 minutes. Heat and stir for an hour. After cooling, distill off the solvent and use cyclohexane:ethyl acetate-2:1.
A portion of Rf, 9.3 was separated using silica gel Rabbit chromatography to obtain B [desired conjugate compound 390].

NMR spectrum (Si, DCZ s ) δ: o, 04 (
CH,,a),0.07(O)13. s), 0.
83 (tBu), 1.23 (C!H,,d,
, T-6,5H2), 1.8-2.1 (4H),
3.1-3.8 (5H), 4.0-4.4 (2
H), 5.17 (2H, θ), 5.23 (2H, AB type.

, T-14Hz), 5.55 (IH, d, J-2az)
.

73 to 8.25 (4H) Example 1 Penem visit conductor 370 In9 obtained in Example 12 to 20
The mixture was dissolved in rrrl of tetrahydrofuran, and then 0.3 ml of acetic acid and cass of tetrabutylammonium fluoride trihydrate were added under water cooling, the ice-water bath was removed, and the mixture was stirred at 25°C for 16 hours.

After adding ethyl acetate and washing the organic layer with water, it is dried over magnesium sulfate. After distilling off the solvent, the desired hydroxy form near Rf, Q, and 3 was separated and purified using rabbit chromatography in a cyclohexane:ethyl acetate-1:2 system to obtain the title substance 2.
82In9 (92CH) was obtained O NMR spectrum (CDC23) δ: 1.33 (3H, (1,, T-6:5H2), 1.7~
2.05 (4H), 3.42 (2H; t, J-7wz)
, 3. ．． 2-3.11 (2H), 4.0-4.4C2H
), 5.1TC2H).

5.25 (2H, AB type, J-14H2), 5.50 (
1)(, (1,, T-2H2), 7.35 ~ 8.3(
4H) Example 14゜ethyl]-2-[(2B)-pyrrolidine-2-Example 1
Dissolve the Roxipenem derivative 282■ obtained in step 3 in 12 ttrl of tetrahydrofuran.MLO 11M phosphoric acid solution (pH 7.04) 12 rnl, 10% in lye.
Add palladium-carbon catalyst 570 In9 and stir at room temperature under hydrogen atmosphere for 5 hours. The catalyst is filtered and further washed thoroughly with the above buffer solution. The filtrate is washed twice with ethyl acetate, and the aqueous layer is brought to about 2111 ml under reduced pressure at low temperature. After adsorption by placing it on a chromatography tube filled with Diaion HP20AG (100-200 mesh, Mitsubishi Chemical Industries, Ltd. room A fraction of the penem compound mentioned above is obtained. Lyophilize the dyed fraction and
The desired penem compounds 80~ were obtained.

NMR spectrum (D20) δ: 1,31 (3H, d, J-6,5HZ),
1.1-2.3 (4I(), 2.!l-15(4H)
, 31-44 (2H), 5.6JI (IH, djJ
-LSH2).

(Dis external standard) Example 15゜D-N-p-2) Lobenzyloxycarbony/L
/ A corresponding homothioproline conductor was obtained from Reference Example 2 from chlorin, and the desired title compound was obtained by the same reaction procedure as in the case of the L form of Examples 9 to 14.

NMR spectrum (D20) δ: 1.33 (3H, d, T, 6.5Hz), 1.8-1
3 (4H), 2. 45 (4H), 3J to 4.4 (2H
).

5.84 (IH, tl, J-1, 5Hz) (DB, 8
Example 16 Nitrobenzyl oxycarbonyl-azetidine A reaction was carried out according to Reference Example 2 to synthesize a thioacetic acid derivative from L-2-azetidinecarboxylic acid. Then, it was reacted with a 3-acetoxyazetidinone derivative according to Example 9 to obtain the desired title compound.

Melting point 143℃ Elemental analysis Calculated value as C24H55N,O,SSi: C! ,53.61;H,6.56;N,7.8
1 next value: f:! ,54.08;H,6.58;N,
7.71! Example 1 7.

Using the azetidinone derivative obtained in Example 16, the same procedure as in Examples 10 to 14 was carried out to obtain the desired neck Hr2.
The compound was obtained.

NMR spectrum (cDoz,) δ: 140 (3H, d, J-1i. 5Hz), 18-2.2
(2H), 2.9~λ5 (4H), 3.6~44 (2
H) e5. @8 (IH, d, J-
1-5 Hz) Example 18 Using the thioacetic acid derivative synthesized from DL-piperidinecarboxylic acid in Reference Example 2, the desired title compound was obtained by carrying out the same experimental operations as in Examples 9 to 14.

NMR spectrum (D20) δ: 1, 25 (3H, d, J-6.5Hz), 1.5-2.
2 (6H), 2.1-44 (4H), 3.1i to 4.
4 (2H).

5,60(IH,(1,J-1.5HgJ Example 1 9
.

Using L-thioproline, a thioacetic acid derivative synthesized according to Reference Example 2 was reacted with a 3-acetoxyacetidinone derivative in the same manner as in Example 9 to obtain the desired title compound.

Melting point 122°C NMR spectrum (CDCt,) δ: 0, 0 9 ( ”X 2 ) a O, 8 9 (
tBu) − 1.2 0 (CHs *d, J
-8.5Hz), 2.8-44 (5H), 4.0 ~ 4
, 8 (3H), 5.21 (2H, a), 5.28 (H!
j(1,, T-2.5Hz), 6.5(NH), 7
．． 4 to 8.3 (4H) Example 2 0.

-butyldimethylsilyloxyethyl)-2-Example 1
Aminal compound 1f (73.5%) is synthesized from the azetidinone derivative 1f obtained in Example 9 and p-nitrobenzylglyoxylate of 109 in the same manner as in Example 1o. Next, this amyl compound was converted into a chloride using 0.14 Wll of thionyl chloride and 0.23 M of 2,6-/l/l cuticle, and further mixed with 1 t of triphenylphosphine and 0.23 M of 2,6-/l/l.
The ylide compound is synthesized using 46 ml of 2,6-lutidine at 40-50°C.

The primary ylide compound is loaded in a cyclohexane:ethyl acetate-2:1 system to obtain the ylide compound 1fCT6'l). The thus obtained ylide compound was mixed with 100 ml of toluene (ttcm), stirred at 100°C for 10 hours in the presence of catalytic hydroquinone, and purified according to Example 12 to obtain the desired penem compound 418#l1II.

Silica gel thin layer chromatography Rf, (14(
Cyclohexane:ethyl acetate-2:1) Engineering R Spect J
L/ (liquid) ycrx.

1780.170O NMR spectrum (6Dcz,) δ: 0.04 (OH,), 0.08 ((1!H,), 0.8
2(tBu), 1.23(CHs, d,, T-6,5H
l, 2.7-44 (5H) #170 (IH, dd, J-
4 and 2Hz), 4.1-47 (3H), 5.20 (2
H, li), &25 (2H, AB type.

J-14HZ) s 5.52 (I H* d-J
2 Hz) #T, 35~8.3 (8H) Example 21゜ 40td of Penem visiting conductor 410~ obtained in Example 20
of anhydrous tetrahydrofuran, then 330In
9. Acetic acid and tetrabutylammonium fluoride, 1 ton of trihydrate were added under water cooling. The water bath was removed and the reaction solution was stirred at 25°C for 20 hours. After adding ethyl acetate and washing with water, the mixture is inverted with magnesium sulfate. After the solvent was distilled off, the reaction product was collected in ml fractions using preparative silica gel thin layer chromatography.
, V[,-benzene:ethyl acetate-3=1 system Rf
-0,18 portion was extracted and the desired title compound 3109
I got it.

NMR spectrum (CDC7,) δ: 1.30 (3
H, a, J-6, 5H2), 2.6-3.4 (5H)
s 3-67 (I H, d 6 jJ-6 and 1.5
Hz).

4.0-4.8 (3H), 5.29 (2H, act,
T-14Hj), 5.16 (2H, 8), 5.42 (I
H,d.

J -1,5Hz), Otsu 3 to 8.2 (8H) Iiro 1
Hydroxypenem conductor 310 obtained according to Example 21
F4 was replaced with tetrahydrofuran 15d and 01Hj) Mi
&kD (pH 7,04) IS Dissolve in ml, 1
Add 0φ palladium-reconstituted N 620 μm, and stir at 25° C. for 20 hours in an air atmosphere. Filter the catalyst and wash with buffer solution (C). After washing the resulting solution with 2N ethyl acetate, add 1
So h6 is brought to 7 me under reduced pressure. Diamond Aeon 120m
The product was purified in fraction A' according to Example 14 to obtain the desired title compound 909.

NMR spectrum (D, O) δ: 1-35 (3Hj6s J-6Hz) z 2.
9~l 7 (3H) #34~4.5 (4H, 5.6
6(1)1. d,, r-2H;) (DSS external standards) Patent applicant: Sankyo Co., Ltd. Agent: Patent attorney Shoji Kashiyama

Claims (1)

[Claims] 1. General formula [In the formula, 1 represents a hydrogen atom or a lower alkyl group having a hydroxyl group as a substituent, and R2 is a three-membered group that may or may not contain an oxygen atom or a sulfur atom in the ring. A cyclic amino group forming a ring to a seven-membered ring, whose nitrogen atom has the formula −〇,
NFI group (in the formula, 4 R4 and R5 are the same or different and represent a hydrogen atom or a lower alkyl group), and R
5 represents a hydrogen atom or a biologically active ester residue;
``mu'' represents a single bond or a lower alkylene group. ] and a pharmacologically acceptable salt thereof. 2. General formula (in the formula, R6 represents a hydrogen atom or a lower alkyl group having a protected hydroxyl group as a substituent, and R7 has r in the ring)
It elemental atom or 1-1: cyclic ami7 group forming a three- to seven-membered ring containing or not containing a sulfur atom, the nitrogen atom of which has a protective group; R8 is a carboxy group represents a protecting group, R9d represents an alkyl group or an aryl group, and M represents a single bond or a lower alkylene group. ) is heated to form a phosphorus-ylide compound having the general formula (
In the formula, R, R, R and M have the same meanings as described above. ), and then, if desired, the resulting compound is subjected to a reaction for removing the protective group R of the carboxyl group, and the corresponding protective groups contained in R and R are removed to form a carboxyl group, a hydroxyl group, or The compound is subjected to a reaction for restoring the cyclic amino group, and the 2-position 4 of the resulting compound is further expressed as a hydrogen atom or a lower alkyl group. ) [In the formula, R represents a hydrogen atom or a lower alkyl group having a hydroxyl group as a substituent, and R2 represents an oxygen atom or a sulfur atom in the ring. A cyclic amino group forming a three- to seven-membered ring, which may or may not contain a cyclic amino group, whose 'iji group atom has the formula -
8-IJR5 group 4 (wherein R4 and R5 are the same or different and represent a hydrogen atom or a lower alkyl group), R3 represents a hydrogen atom or a biologically active ester residue, A represents a single bond or a lower alkylene group. ]
A method for producing a penem derivative and a pharmacologically acceptable salt thereof.