JPS6261984A - Manufacture of beta-lactam compound - Google Patents

Abstract

(57) [Abstract] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention]

The present invention is based on the formula (wherein R1 is a hydrogen atom or a lower alkyl group,
(R2 is an organic group capable of carrying a functional group that may be extracted with a common protecting group R2, and R3 is a hydrogen atom or a common carboxyl protecting group R3) or a salt thereof In producing the formula (,) [wherein, R1 has the same meaning as above, W is the formula (2
) is a group in which the thiocal is a group that can be substituted with a phosphoric acid group] A compound represented by the formula % formula % () (wherein, R2 has the same meaning as above, and 2 is an oxygen atom or a sulfur atom) is treated with a compound that introduces a thiocarboxylic acid group represented by (b) (wherein R1, R2 and 2 have the same meanings as above), (c) is treated with an acylating agent that introduces an acyl group of an oxalic acid half ester of the formula (wherein R3 is a common carboxyl protecting group); 2 has the same meaning as above) is treated with an organic compound of trivalent phosphorus, and the resulting compound of formula (d) (wherein R1, R2 and R3 have the same meaning as above) is treated with an organic compound of trivalent phosphorus. ) from the obtained compound represented by oxalyl ester group (
-Co-Coo-R3) and, if desired, the protecting group R3 and/or the protecting group R2 that may be present in the group R2 are removed in any order to transform those groups into hydrogen atoms. and optionally converting the obtained compound of formula (I) containing a salt-forming group into a salt, or converting the obtained salt into the free compound. This invention relates to an improved method for producing the compound represented by or a salt thereof. The improved method of the present invention resides in a number of surprising features. That is, formula (II) in which the hydroxyl group is not protected
It is particularly surprising that the 3,4-trans-compound of formula (I) is formed almost exclusively when used in the thiolation reaction (step a). Until now, protection of this hydroxyl group has always been carried out as a conventional method, and moreover, 3,4-cis-compounds have always been produced as by-products in the subsequent thiolation step. It is therefore unnecessary to selectively mine the 1/-hydroxy groups in the intermediates of formula (n) and formula (II) with other acyl or silyl groups, as has been customary up to now; And, in a single step, the compound of formula (5) can be substituted at the azetidinone nitrogen with the oxalate acyl group necessary for ring closure and protectively substituted at the 1'-position hydroxyl group with the same acyl group. , is quite advantageous. In addition, phosphorane, which is inevitably obtained as an intermediate, is β-
Forms only in 2-term N-vicinal carbonyls (
It is serious that step C) and that the theoretically possible reaction of the 1'-oxalyl ester group with the cal-nyl group does not occur. Finally, the improved method of the present invention allows the acyl group of the oxalic acid half ester of formula (-) to be very easily converted from the intermediate of formula (■) (i.e., without isomerization or without damaging the benem ring structure). ) and, if necessary and depending on the reaction conditions, other protecting groups R2i or R3
It has the surprising feature that it can be replaced by a hydrogen atom or a hydrogen atom. The hosts of penem compounds of formula (1) are known and the substituents R, , R2 and R5 have especially known meanings. Compounds of formula (1) that can be produced by the method of the invention are disclosed, for example, in the following patent specifications: Ciba-Geigy British Patent No. 2.013,676, European Patent No. 109.362,
Same No. 110,826, Same No. 112,283, Same No. 1
25.208, Belgian Patent No. 125,207, Belgian Patent @900,477, European Patent No. 148,128;
Beecham European Patent No. 46.36
No. 3] Bristo1My@
rs) Dutch Patent Nos. 7,909,055 and 7,909,056; U.S. Patent No. 4.2 g 2,1
No. 50; Farmitalia
) Belgian Patent No. 881,862, British Patent No. 2
, 097,786, German Patent No. 3,312,39
No. 3, Belgian Patent No. 900,316; Hoechst (
Hoecbst) European Patent No. 69,377, British Patent No. 2,122,619, British Patent No. 2,140,8
No. 07; Merch European Patent No. 2,210
European Patent No. 72,014, European Patent No. 87,792,
No. 115,308; Pfizer European Patent No. 130,025, 1'Ugx a 2,1
No. 01; Sankyo Belgian Patent No. 889,151
German Patent No. 3,231,596; Schering Corp. U.S. Patent No. 4,443,463; Belgian Patent No. 88
No. 1,012, U.S. Patent No. 4,423,055, European Patent No. 35,188, European Patent No. 58,317, U.S. Patent No. 4,431,654, European Patent No. 4,435,412,
European Patent No. 4,435,413, European Patent No. 4,503,064, European Patent No. 109,044, European Patent No. 118.875, European Patent No. 123,650, European Patent No. 121.502; Patent No. 115,969; Sumitomo European Patent No. 70,204 and European Patent No. 126,587; Takeda European Patent No. 69,373. The definitions of substituents R1, R2 and R3 given in these patent publications are intended to be included in the definition of the present invention. Substituents R1, R2, R2 in formula (1) to formula (■),
R3, R6, W and 2 have, inter alia, the following meanings, and in this context the term "lower" specifying groups and compounds:
Unless otherwise specified, the above groups and compounds contain 1 to 1 carbon atom.
It means containing 7 pieces, preferably 1 to 4 pieces. R1 as lower alkyl is preferably methyl or also ethyl, propyl, isopropyl or butyl. Compounds in which R1 is a hydrogen atom or preferably a methyl group are preferred. R'2 is preferably an organic group containing up to 18 carbon atoms, preferably up to 10 up to 10 carbon atoms, most preferably up to 5 carbon atoms, as known, for example, in Benam chemistry;
contains up to 5 nitrogen atoms, preferably up to 4 and/or up to 5 oxygen atoms, preferably up to 2, and/or up to 3 sulfur atoms, preferably up to 2 or most preferably 1 and R2 shall be capable of bonding to the benem ring via one of its carbon atoms as well as via a nitrogen, oxygen, or sulfur atom, and may be, for example, an unsubstituted or substituted lower arifatyl group. , a lower arifatyloxy group, a lower arifatylthio group, a ciflorarifatyl group, a ciflorarifatyloxy group, a ciflorarifatylthio group, an aryl group, an aryloxy group, an arylthio group, an aryl-lower arifatyl group, Aryl-lower aryfatyloxy group, aryl-lower aryfatylthio group, heterocyclic group,
Heterocyclic oxy group, heterocyclic thio group, heterocyclic-lower arifatyl group, heterocyclic-lower arifatyloxy group,
A heterocyclic-lower aryfatylthio group, a heterocyclic-lower aryphatyl group or a heterocyclic-lower aryphatyl group or a heterocyclic-lower aryphatyl group, and the above-mentioned cyfuroarifathyl and heterocyclyl are saturated or unsaturated. 1゛ノ、薯：'++ A lower arifatyl group is, for example, a lower alkyl group or a lower alkenyl group, and a lower arifatyloxy group or a lower arifatylthio group is bonded via an oxygen atom or a sulfur atom. It is a suitable lower arylthio group. A cyfuroarifatyl group is, for example, a cycloalkyl group or an unsaturated cycloalkyl group, such as a cycloalkenyl group.
It is a bamboo cycloalkagenyl group. A ciflorarifatyloxy group or a ciflorarifatylthio group is a corresponding ciflorarifatyl group bonded via an oxygen or sulfur atom. Aryl radicals are, for example, suitable monocyclic or also polycyclic radicals, such as bicyclic radicals, preferably phenyl or naphthyl radicals. An aryloxy group or an arylthio group is a suitable aryl group bonded via an oxygen or sulfur atom. The aryl lower alkenyl group, the aryl lower arylphrythyloxy group or the aryl-lower aryfatylthio group is, for example, a phenyl-lower alkyl group, a phenyl-lower alkoxy group or a phenyl-lower alkylthio group. A heterocyclic group, a heterocyclic oxy group or a heterocyclic thio group is preferably a suitable monocyclic or polycyclic, preferably monocyclic or bicyclic or also tricyclic group, for example a nitrogen atom , an unsaturated or partially saturated monocyclic 5- or 6-membered heteroaryl group optionally containing at least one heteroatom from the group consisting of oxygen and sulfur atoms, especially containing a ring nitrogen atom; radicals of this type, and may contain additional ring heteroatoms selected from oxygen atoms and sulfur atoms, such as suitable aza-, noade, triade, tetraaza-, oxa- -, oxazo-, oxanoade, oxatriaza-, thia-, thiaza-, thiadiazole or thiatriazo cyclic groups or suitable nohydro or tetrahydro groups, and also unsaturated or partially saturated, e.g. 5- or 6-membered benzo, nobenzo, pyrido or pyrimido derivatives. Examples of suitable heteroaryl groups are: pyrrolyl groups, e.g. 2-or 3-monoloryl groups, 2-or 3-pyrrolidinyl groups, soazonyl groups, e.g. imidazolyl groups, e.g. −． 2-. a 4- or 5-imidazolyl group, or a pyrazolyl group, e.g. 3- or 4
-Biragryl group, triazolyl group 1 e.g. 1.2.3
-triazol-4-yl group, L2,4- triazol-
5-yl group or 1,2.4-) lyazol-3-yl group, such as IH- or 2H-tetrazol-5- or -1-yl group, biritzyl group, such as 2-13- or 4
- birisol group, noasonyl group, e.g. pyrimidyl group,
For example, a 2-14- or 5-pyrimidyl group, or a pyranonyl group, such as a 2-pyranonyl group, a triazonyl group, such as a 1.2.4-triazon-6-yl group or a 1,3.5-trianon-2 -yl group, furyl group,
For example, a 2- or 3-furyl group, a 2- or 3-tetrahydromifuryl group, a chenyl group, e.g.
-chenyl group, oxacylyl group, e.g. 2- or 4
-Oxasilyl group, oxazoazolyl group, e.g. 1°2
．． 4-oxazazolyl-3-yl group, 1.2゜5-oxadiazol-3-yl group, 1,2.4-oxazoazol-5-yl group or 1,3.4-oxanoazol-2
-yl group, isoxazolyl group, e.g. 3-isoxazolyl group, thiazolyl group, e.g. 2- or 4-thiazolyl group, cyanoazolyl group, e.g. 1,2.4-thiadiazol-3-yl group, 1,2.5 -Thyanoazole-3
-yl group, 1,2.4-thianoazol-5-yl group or 1,3.4-thianoazol-2-yl group, or inthiazolyl group, such as 3- or 4-isothiagril group. The 5- and 6-membered heteroaryl groups mentioned can also be in particular in saturated form. Examples of such groups are the following: nohydroimidazolyl groups, such as 2,3-nohydroimigzolyl-4-yl groups, nohydrobiriminol groups, such as 1,2-nohydropyrido- 3
-yl group, nohydrobiriminol group, such as 1°2-dihydrobirimid-4-yl group, nohydro and tetrahydropyrazinyl group, such as 2.3-zohydrobyranon-5-yl group or 3.4.5゜6-tetrahydrobyranon-2-yl group or nohydro or tetrahydropyrazinyl group, e.g. 2,3,4,5-tetrahydro-
It is a 1,2,4-trianon-6-yl group. Polycyclic derivatives of the heteroaryl groups described are, for example, indo-
-2-yl group, indol-3-yl group, benzimidazol-2-yl group, benzopyrazol-3-yl group,
Quinolin-2-yl group or quinolin-4-yl group, benzothiazol-2-yl group, benzoxazole-2
-yl group, pyrido[2,3-b:]]pyrido-3-yl or pyrido(2,3-b) biryp-4-yl group. The heterocyclic-lower arifatyl group, the heterocyclic-lower arifatyloxy group, the heterocyclic-lower alinoacylthio group, the bicyclic oxy-lower ali7acyl group, or the heterocyclic thio-lower arifatyl group, for example, a lower alkyl group, a lower alkoxy group or a lower alkylthio group, said group being substituted with one or two heterocyclic groups, preferably via one of its carbon atoms or via an oxygen or sulfur atom. substituted with one of the above-mentioned heterocyclic groups bonded via a
Substituted with an unsaturated or partially saturated monocyclic 5- or 6-membered heteroaryl group containing 4 nitrogen atoms. The last-mentioned groups bonded via the nitrogen atom are, for example, the imidazol-1-yl group, the tetrahydro- or 4,5-dihydro-imidazol-1-yl group, the pyrazol-1-yl group, the 1,2. 4-) Liaguru-1-yl group, 1,2.3-triazol-1-yl group, tetrazol-1-yl group, tetrazol-2-yl group, 1-pyrisonio group, 1,2-dihydro-1-pyridyl group, 1,4-dihydro-1-pyrityl group, 1,2-dihydro-pyrimid-1-yl group or 1,4-dihydro-pyrimid-1-yl group. Heterocyclic groups also include
The lower aliphatic group can be attached via an oxygen atom or a sulfur atom. The above organic radicals R2 are unsubstituted or substituted with one or more, preferably one or two or also three, identical or different substituents selected from the group consisting of the following substituents: can be: free,
etherified or esterified (protected)
Hydroxy groups such as hydrococo, lower alkoxy, phenyl-lower alkoxy, lower alkanoyloxy or halodane atoms; free or etherified mercapto groups such as mercapto, lower alkylthio or phenylthio group; lower alkyl group; substituent [hydroxy group, lower alkoxy group, free or esterified or amidated
an unsubstituted or N-lower alkylated amino group (e.g. an amino group, a lower alkylamino group or no lower alkylamino group), a lower alkylene amino group, Lower alkanoylamino group, lower alkoxycar? a lower alkyl group substituted with a nylamino group (where n is unsubstituted or substituted with an amino group and/or a carboxy group), a mercapto group, a lower alkylthio group or a sulfo group; a lower alkylene group; Unsubstituted or lower alkylated aza-
lower alkylene groups, oxa-, dioxa- or thia lower alkylene groups; unsubstituted or substituted (including protected) amine groups, e.g.
An amino group, a lower alkylamino group, a no-lower alkylamino group, a lower alkyleneamino group, a guanidino group, a carbamoylamino group, an acylamino group such as a lower alkanoylamino group or a lower alkoxycarbonylamino group (the group may be unsubstituted or substituted with groups and/or carboxy groups); free or functionally modified (including retained)
Carboxy or sulfo groups, such as carboxy groups, esterified carboxy groups, such as lower alkoxycarbonyl groups, amidated carboxy groups, such as carbamoyl groups or substituted carbamoyl groups, such as carbamoyl groups or N-mono- or N,N -No lower alkylated carbamoyl group, cyano group, sulfo group or sulfamoyl group; phenyl group or substituent [e.g. lower alkyl group, nitro group, amino group, hydroxy group, lower alkoxy group, carboxy group and/or halodan atom] phenyl group substituted with; cycloalkyl group; nitro group, oxo group and/or oxide group. The groups mentioned in relation to R2 and their substituents are, for example,
Lower alkyl has the following meanings: Lower alkyl is, for example, n-propyl, isopropyl, n-butyl, isobutyl, 5ec-butyl or t-butyl, and also n-inchyl, n
-hexyl group or n-heptyl group, preferably methyl group or ethyl group. Lower alkenyl groups include, for example, vinyl group, allyl group, 2
- methylallyl group, n-zolo(nyl group or inzoloinyl group). Lower alkoxy groups are, for example, methoxy, ethoxy, n-propoxy, isobutoxy, n-butoxy, isobutoxy or t-butoxy groups; n-inchyloxy, n-hexyloxy or n-hebutyloxy. Lower alkylthio groups are, for example, methylthio or ethylthio, and also n-propylthio, isozolobylthio or n-butylthio. Cycloalkyl groups preferably contain 3 to 8 ring members, most preferably 5 or 6 ring members, and are, for example, cyclopentyl or cyclohexyl, also cyclopropyl and cyclohegetyl. Cycloalkenyl groups are , for example contains 5 or 6 ring members, and a cycloalkasoenyl group contains, for example, 6 ring members and, for example, a 1-12- or 3-cyclohexenyl group, a 1- or 2-cyclohexenyl group. -cyclopentenyl group or 1,4-
It is a cyclohexagenyl group. Phenyl-lower alkyl group is, for example, benzyl group, 1
-Phenylethyl! "! or 2-phenylethyl group. Phenyl-lower alkoxy group is, for example, penzoloxy group or 1-phenylethoxy group. Lower alkanoyloxy group is, for example, formyloxy group, acetoxy group or propionyloxy group. The halodane atom is, for example, a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.The lower alkylamino group is, for example, a methylamino group, an ethylamino group, an n-propylamino group, an isozolopylamino group. or n-butylamino group, and the no-lower alkylamino group is, for example, dimethylamino group, noethylamino group, di-n-zolopylamino group or diisozolobylamino group. The lower alkylene amino group is preferably a carbon atom The lower alkanoylamino group is, for example, a formylamino group, an acetylamino group or a propionylamino group. Lower alkoxycarbinylamino groups substituted with an amino group and/or a calzegoxy group are, for example, methoxycarginylamino, ethoxycargenylamino or impropoxycarbinylamino groups, and also 2-amino-2 -carboxyethoxycarbinylamino group. The lower alkylene group as a substituent of the group R2 can be linear or branched and, for example, The carbon atom and/or the heteroatom at the position are bonded with 3 to 5 carbon atoms.Such a group is, for example, ' + 3-teOLJ'
y group, 1,4-butylene group, ]- or 2-methyl-1゜3-propylene group or 2,2-methyl-1
゜3-Propylene group. The non-alkylated or algylated other lower alkylene group, oxa-lower alkylene group, oxy-lower alkylene group or thia-lower alkylene group is preferably linear, but may also be branched. I can do it, and
For example, adjacent carbon atoms and/or heteroatoms in the organic group R2 are bonded through 3 to 5 carbon atoms. Examples of such groups are 1- or 2-aza-1,3-propylene groups,
1-Azo-1,4-butylene group, 1-methyl-1-aza-11-ethyl-1-aza-12-methyl-2-azo-
or 2-ethyl-2-aza-1,3-propylene group or 1-methyl-1-azo- or 2-methyl-2-azo-1,4-butylene group, and also 1-oxa-11
, 3-dioxa-, 1-thia- or 1,3-dithia-
1,3-propylene group, or 1-oxa-11,4-
Nooxer, 1-thia- or 1,4-dithia-1
, 4-butylene group. The N-mono lower alkylated carbamoyl group is, for example,
N-methylcarbamoyl group, N-ethyl force/rubamoyl group'! is a uN-f lovylcarpamoyl group. N, N
-No-lower alkylated carpamoyl group is, for example, N,
N-trimethylcarbamoyl group or N,N-noethylcarpamoyl group. Lower alkanoyl is, for example, formyl, acetyl or propionyl, lower alkenoyl is, for example, acryloyl, cycloalkanoyl contains 5 to 7 carbon atoms and is, for example, cyclohexyl. A sanoyl group and a phenyl-lower alkanoyl group are, for example, a phenylacetyl group. A lower alkoxysulfonyl group is, for example, a methoxysulfonyl group or an ethoxysulfonyl group. The lower alkoxycarbonyl group which can be substituted with an amino group or a carboxy group is, for example, a methanesulfonyl group, an ethoxycarbonyl group, an n-teroboxyl group, or a lower alkoxycarbonyl group which can be substituted with an amino group or a carboxy group. Nyl group or 2-amino-2-cal? It is a xyethoxy7carbonyl group. Hereinafter, the term "Kinpaku lower alkylthiocarbamoyl group" is, for example, a methylthiocarbamoyl group or an ethylthiocarbamoyl group. Examples of the lower alkanesulfonyl group include methanesulfonyl group and ethanesulfonyl J! - or a propanesulfonyl group f. Suitable lower aliphatic groups R2 include, for example, lower alkyl groups,
For example, methyl group, ethyl group, inpropyl group, isobutyl group or 5ee-butyl group, or substituent [hydroxy group, lower alkoxy group such as methoxy group or ethoxy group, lower alkanoyloxy group such as acetyloxy group], rogone atom For example, a chlorine or bromine atom, a mercapto group, a lower alkylthio group such as a methylthio group, an amine group, a lower alkylamino group such as a methylamino group or an ethylamine group, a lower alkylamino group such as a dimethylamino group, a guanidino group, a formamidino group, Lower alkanoylamino groups, such as acetylamino groups, lower alkoxycarzanylamino groups, such as ethoxycarbonylamino groups (wherein 7"L is substituted with an amino group and a carboxy group), such as 2-amino-2-
carboxyethoxycarbonylamino group, carboxy group, lower alkoxycarbunyl group, such as methoxy- or ethoxycarbonyl group, carbamoyl group, sulfo group,
sulfamoyl group and/or oxo group]
A lower alkyl group, preferably a methyl 4-ethyl group, n-propyl group or n-butyl group. Typical representatives of such lower aliphatic groups R2 are as follows: for example, methyl group, impropyl group, isobutyl group, 5ee-butyl group, butyl group, hydroxymethyl group,
1- or 2-hydroxyethyl, mercaptomethyl group, 2-methylthioethyl group, aminomethyl group, 1- or 2-aminoethyl group% 1-12- or 3-aminopropyl group, 1-. 2-Also, t/i3-aminobutyl group, guaninormethyl group, 1-sliced 2-guanidylethyl group, 1-. 2-4 or 3-guanidylzolobyl-7
+(, formamidinomethyl group, formamidino-1-
Katsutake-2-ethyl group or formamidino-1-, -
2- or -3-propyl group, calgeximethyl group, carbamoylmethyl, l, 21J l? xyethyl group, 2-
Carbamoylethyl group, carbamoyloxymethyl group,
1-. A 2- or 3-carbamoyloxypropyl group, a carboxy group or a lower alkoxycargenyl group, such as a methoxycargenyl group. The aryl-lower alkenyl group R2 is, for example, an unsubstituted or substituted phenyl-lower alkyl group, preferably a phenylmethyl group or a phenylethyl group, where the tit substituent is, for example, a lower alkyl group such as a methyl group, a nitro groups, hydroxy groups, lower alkoxy groups such as methoxy or ethoxy groups, carboxy groups and/or halodane atoms such as chlorine atoms. Suitable cyfuroarifatyl groups R2 are, for example, cycloalkenyl groups such as 1- or 2-cyclohexenyl groups,
or preferably a cyclohexagenyl group, tba1,
It is a 4-cycloalkanoyl group. Aryl group R2 is, for example, phenyl or preferably substituted phenyl, in which the substituents are one or more selected from the group consisting of the following substituents: amino, lower alkyl Amino groups such as methyl- or ethylamino groups, di-lower alkylamino groups, dimethylamine groups, lower alkyl groups such as methyl groups, amines lower alkyl groups such as 2-aminoethyl groups, lower alkylamino-lower alkyl groups such as 2-methylamino Ethyl group, lower alkoxycarbonylamine - lower alkyl group (this substituent is substituted with an amino group and a carboxy group) e.g. 2-(2-amino-2-carxyethoxycarbonylamino)ethyl group, lower alkoxycarbonyl an amino group (this substituent is substituted with an amine group and a carboxy group), e.g. 2-amino-
2-carboxyethoxycarbonylamine groups, nido groups, hydroxy groups, lower alkoxy groups such as methoxy or ethoxy groups, denene atoms such as chlorine or bromine atoms, and carboxy groups. The heterocyclic group R2 is preferably: a pyrrolyl group or a dihydropyrrolyl group (these groups are unsubstituted or substituted, e.g. with a lower alkyl group), e.g. 1-methyl-2 -pyrrolyl group or 4,5
-dihydro-3-pyrrolyl group: pyrrolidyl group or oxo-Ill [substituted pyrrolidyl group 1, e.g. 2- or 3-
pyrrolidyl group or 2-oxo-3- or Vi2-oxo-5-pyrroli sol group, diazolyl group (these groups may be unsubstituted or 1 e.g. carboxy group,
imidazolyl or pyrazolyl (e.g. 1-. 2-. 4- or 5'-imidazolyl group, 4- or 5-methyl-1-imidazole group, or 4,5-dimethyl-1-imidazole group, or 2-amino-4-imidazolyl group, or 3-pyrazolyl group, nitriazolyl group (this is unsubstituted or substituted, for example with lower alkyl, amine, carboxy-lower alkyl and/or phenyl groups, such as II(-1,2,3-triazol-4-yl) group, IF(-1,2,4-triazol-3-yl group or 1r(-1,2,4-)riazol-5-yl group, such as the corresponding unsubstituted group, l-methyl-IH~ 1
, 2,3-triazol-4-yl group, 5-methyl-sweet or 5-amino-IH-1,2,4-triazol-3
-yl Tawara, 3-methyl-1-phenyl-IH-1,2゜4-triazol-5-yl group, or 5-calzexymethyl- or 5-phenyl-IH-1゜2.4- triazol-3-yl; tetrazolyl (unsubstituted or unsubstituted, e.g., lower alkyl, carboxy-lower alkyl, sulfo-lower alkyl, no lower alkylamino-lower alkyl); for example IH-tetrazol-1-yl, IH- or 2H-
Tetrazol-5-yl group, such as lH-tetrazol-1-yl group, IH-tetrazol-5-yl group, 1-
Carboxymethyl-, 1-(2-carboxyethyl)-, 1-(2-sulfoethyl)-1l-(2-dimethylaminoethyl)- or l-phenyl-IH-tetrazol-5-yl, thiazolyl groups (e.g. % 2- or 4-thiazolyl group) or isothiazolyl group (e.g. 3-inchazolyl group) [these are unsubstituted A
or substituted with, for example, a lower alkyl group or an amino group] such as a 2-14- or 5-thiazolyl group, a 4-methyl-5- or 5-methyl-4-thiazolyl group, a 2-amino-4 -thiazolyl group, 2-amino-
4-methyl-5-thiazolyl group, 4,5-dimethyl-2
-thiazolyl group or 3-isothiazolyl group; thiadiazolyl group (which is unsubstituted or substituted with 1, for example a lower alkyl group, a hydroxy group, an amino group or a lower alkylamino group), for example 1, 2.
5-thiadiazol-3-yl group, 1.3.4-thianoazol-2-yl group, 1゜2.4-thiadiazol-
3-yl group, or 1,2,4-thiadiazole-5-
yl group, such as the corresponding unsubstituted group, also 5-methyl-1 or 5-amino-1,3,4-thiadiazole-2
-yl group, 3-methyl-1,2,4-thiadiazole-
5-yl group, 5-amino- or 5-methylamino-1
, 2,4-thiadiazol-3-yl or 4-hydroxy-1,2,5-thiadiazol-3-yl, oxasilyl or isoxazolyl groups (which are unsubstituted or unsubstituted, e.g. amino groups) , lower alkyl and/or phenyl groups), e.g. 2- or 4-oxasilyl groups or 3-inxazolyl groups, e.g. the corresponding unsubstituted groups, and also 4-methyl-2-oxasilyl groups, 4 .5-diphenyl-2-oxasilyl group, 2-amino-4-oxasilyl group or 5-methyl-3-isoxazolyl group nioxadiazolyl group, which is unsubstituted or, for example, a lower alkyl group, an amine group or Phenyl group (phenyl group can be substituted with, for example, a nitro group)
For example, 1,2,4-oxazole-
5-yl, 1,2,4-oxazol-3-yl or 1,3,4-oxazol-2-yl, e.g.
Corresponding unsubstituted group: and also 5-methyl-1,3,
4-oxadiazol-2-yl group, 5-phenyl-1
,3,4-oxadiazol-2-yl group or 5-(
4-nitrophenyl)-1,3,4-oxacyaso
-2-yl, furyl or chenyl groups, which are unsubstituted or substituted, for example with halogen atoms or amino-lower alkyl groups, such as 2- or 3-furyl groups or 2- or 3-cheniA4, e.g. the corresponding unsubstituted group, 5
-methyl- or 5-aminomethyl-2-furyl group, or 5-aminomethyl-2-chenyl group, tetrahydrofuryl group substituted with oxo group, such as 2-oxotetrahydrofuryl group, pyridyl group (which may be unsubstituted or substituted, for example with hydroxy groups, halogen atoms, lower alkyl groups, amine groups and/or oxide groups), e.g. 2-23- or 4-
a pyridyl group, such as the corresponding unsubstituted group, 1-oxide-2-pyridyl group or 4-chloro-1-oxide-
2-pyridyl group, or 1,2-dihydropyrrolnor group, which is unsubstituted or substituted, for example with lower alkyl groups, amine groups, di-lower alkylamino groups, oxo groups and/or carboxy groups; 1,2-dihydro-4-pyrimidyl group, e.g. 2
-oxo-1,2-dihydro-4-pyrimidyl group or 6-methyl-15-methyl-16-amino-16-dimethylamino, 5-carboxy group or 6-carboxy-2-oxo-1,2-dihydro- 4-pyrimidyl group. Examples of the gold-paku heterocyclic lower aliphatic group R2 are as follows: an unsubstituted or substituted heterocyclic methyl group, a heterocyclic ethyl group or a heterocyclic zolopyl group, such as -col-1 -ylmethyl group or dihydropyrrol-1-ylmethyl group, said group being unsubstituted or substituted with a lower alkyl group or a halogen atom, and, for example, a pyrrol-1-ylmethyl group, 3-methylpyrrol-1-ylmethyl group, 3,4-dichloropyrrol-
1-methyl, 2,3- or 2,5-dihydropyrrol-1-ylmethyl, unsubstituted or oxo-substituted pyrrolidylmethyl, such as 2- or 3-pyrrolidylmethyl or 2-oxo-3-pyrrolidylmethyl group or 2-oxo-5-pyrrolidylmethyl group, diazolylmethyl group, e.g. imidazole-
1-ylmethyl, imidazol-4-ylmethyl or pyrazol-1-ylmethyl, said groups being unsubstituted or substituted, for example with lower alkyl; triazolyl Methyl group, for example IH-1,2,3-triazol-1-ylmethyl group, 1) I-1,2. 4-triazol-1-ylmethyl group or IH-1,
2,4-)lyazol-3-ylmethyl group, said group being unsubstituted or empty, such as lower alkyl group, carboxy-lower alkyl group, amino group and/or
or substituted with a phenyl group, for example,
the corresponding unsubstituted group, 4-dimethyl or 5-methyl-1,2,
3-triazol-1-ylmethyl group or 5-methyl-5-amino- or 5-phenyl-II (-1,2゜4-triazol-3-ylmethyl group; tetrazolylmethyl group, e.g. IH- Tetrazol-1-ylmethyl group, IH-tetrazol-1-eth-1-yl group, IH
-tetrazol-1-eth-2-yl group, IH-tetrazol-1-prodel-yl group, IH-tetrazol-1-prop-2-yl group, IH-tetrazol-1-
glob-3-yl, 2H-tetrazol-2-ylmethyl or IH-tetrazol-5-ylmethyl, said groups being unsubstituted or, for example,
lower alkyl group, calgexi lower alkyl group, sulfo-
The corresponding unsubstituted group, 5-amino-15-carboxymethyl-,5-(2-carxyethyl)-1
5-sulfomethyl-15-(2-dimethylaminoethyl)- or 5-phenyl-IH-tetrazol-1-ylmethyl group, 5-amino-15-carboxymethyl-5
5-sulfomethyl-15-(2-dimethylaminoethyl)- or 5-phenyl-2H-tetrazol-2-ylmethyl group, or 1-(2-carxyethyl)- or 1-(2-dimethylaminoethyl)- I/) -2H-tetrazol-5-ylmethyl, pyridylmethyl or dihydropyridylmethyl, for example pyridiniomethyl, 2-23- or 4-pyridylmethyl or 1
．． a 2- or 1,4-dihydropyrid-1-ylmethyl group, said group being unsubstituted or substituted, preferably with an oxo group, and can be further substituted, for example with a norogon atom; For example, 2-oxo-1,2-dihydropyrid-1-ylmethyl group or 4-oxo-1,4-dihydropyrid-1
-ylmethyl group, dihydropyrid-1-ylmethyl group,
For example, 2H-1,2-dihydro- or L/14H-1
,4-dihydro-pyrimid-1-ylmethyl group,
The groups are unsubstituted or substituted, preferably with oxo groups, and can be further substituted, for example with lower alkyl groups, amino groups, no-lower alkylamino groups or carboxy groups, for example: 2-oxo-1,2-dihydro-pyrimid-1-ylmethyl group, 6-methyl-15-methyl-16-amino-16-dimethylamino, 5-carboxy group or 6-carpoxy 2-oxo-1,2-dihydropyride -1-ylmethyl group or 4-oxo-1,4-dihydro-pyrimid-1-ylmethyl group, furylmethyl group, e.g. 2-
Furylmethyl group, tetrahydrofurylmethyl group,
Said radicals may be unsubstituted or substituted, for example with oxo, for example 2-oxotetrahydrofurylmethyl, thenylmethyl, e.g. a thiazolylmethyl group or a thiadiazolylmethyl group, which is unsubstituted or substituted, for example with an amine group, such as a 2-amino-oxazol-4-ylmethyl group, -aminothiazol-4-ylmethyl group or 5-amino-1,2
, 4-thiazodiazol-3-ylmethyl group, or indolylmethyl group, such as indol-3-ylmethyl group. Particularly preferred radicals R2 are those present in compounds of formula (1) which have particularly pronounced antimicrobial properties. Examples of such groups R2 are aminomethyl, 2-aminozolod-1-yl, carbamoyloxymethyl, 1
-methyltetrazol-5-ylthiomethyl group, 2-(
1-tetrazolyl)propyl group, 2-oxo-5-tetrahydrofurylmethyl group, 2-oxo-5-pyrrolidylmethyl group, 2-aminoethylthio group, 2-formamidinoethylthio group, 2-carbamoyloxyethylthio group group, 1-imidazolyl group, 4,5-dimethyl-1-imidazolyl group, 4-methyl-5-thiazolyl group, 5-methyl-4-thiazolyl group and 2-amino-4-methyl-5
-thiazolyl group, and protected derivatives of -tn et al. The functional groups present in the compound of formula (1), namely hydroxy group, cal? An xy group, an amino group or a sulfo group can be protected with a common protecting group R or R3. Common protecting groups are those readily available for use in penem, Knidyline, cephasporin and peptide chemistry. Such protecting groups protect the functional groups in question from undesirable removal and substitution reactions, etc. during the synthesis of the compound of formula (1) from its precursors, and allow removal without damaging the benem ring structure. I can do it. Such protecting groups can be easily removed, ie, without unwanted and hazardous secondary reactions, for example by solvolysis or reduction, or under physiological conditions. Protecting groups of this type and methods for their introduction and removal are described, for example, in the following documents: J, F, W. McOmie, 6 Protective Groups in Organic Chemistry
T. W. Green, Plenum Press, London, New York, 1973;
eeene), 1 Protecting groups in organic synthesis (Protec
tive Groupsin Organic Syn
thesig”, Wiley, New York, 1981: “1 The Peptides
es)', Vot, I, Schroeder I')7
5chroeder und Luo
bka), Academic Press (Academic
Pr@ms), London, New York, 196
5; and Houbsn-We
yl), 'Methodender of Organic Chemistry
Organiseben Chemie)', Vo
t, 15/1, rorg, Cime Verlag (
Georg ThiemeVerlmg), Schunotgard, 1974° In the compound of formula (1), the group R2
Hydroxy groups present therein can be protected, for example, with acyl groups. Examples of suitable acyl groups are: lower alkanoyl groups (which are unsubstituted or substituted with...o)f atoms, such as acetyl or trifluoroacetyl groups, benzoyl groups; (which may be unsubstituted or substituted with a nitro group), for example a benzoyl, 4-nitrobenzoyl or 2,4-dinitrobenzoyl group, a lower alkoxycarvinyl group (which may be unsubstituted or substituted with a nitro group). 2-bromoethoxycarbinyl group or 2,2,2-trichloroethoxycarbinyl group, lower 9 alkenyloxycargonyl group, such as allyloxycargonyl group, aIJ -lower alkenyloxy argonyl group (which may be substituted or substituted in the aryl ring)
For example, 3-7 enyl allyl oxycar? Nyl (cinnamyloxycarbonyl) group [wherein the aryl group, i.e. the phenyl group, can be substituted with one, two or more substituents of the following substituents: for example, a lower alkoxy group such as a methoxy group, ), a rhodan atom, e.g. a chlorine or fluorine atom, and/or a nitro group], or a phenyl-lower alkoxycarbonyl group (which is unsubstituted or substituted with a nitro group) e.g. 4-nitrobenzyloxycarbonyl Base. Further examples of suitable hydroxy protecting groups are as follows:
Trisubstituted silyl group, e.g. tri-lower alkylsilyl group, e.g. trimethylsilyl group, Matsuji t-butyl dimethylsilyl group, 2-halo lower alkyl group, e.g. 2-chloro-12
- bromo, 2-iodo and 2,2.2-)lichloroethyl groups, and phenyl-lower alkyl groups (which may or may not be substituted), rhodane atoms such as chlorine atoms, lower alkoxy groups such as methoxy groups and/or nitro (substituted with a group) such as the corresponding benzyl group. tri-lower alkylsilyl group, lower alkenyloxycal? Nyl groups and halogen-converted lower alkoxyl groups are preferred hydroxy protecting groups. The carboxyl group present in the radical R2, and also the carboxyl group present in the 3-position of the penem ring or in the 1-position of the oxalic acid half-ester, is usually protected in esterified form, and the ester group is mildly protected. Under mildly reductive conditions, such as hydrogenolytic conditions, or under mild solvolytic conditions, such as acidolytic or especially basic or neutral hydrolytic conditions. can be released. The protected carboxy group can also be an esterified carboxy group, which can be easily converted to a different functionally modified carboxy group, such as a different esterified carboxy group. Such esterified carboxy groups preferably contain lower alkyl groups branched at the 1-position or suitably substituted at the 1- or 2-position as the esterifying group. Preferred carboxy groups in esterified form, which also include the -COOR color, are inter alia lower alkoxycarbyl groups, such as methoxycarbyl groups,
Ethoxylic N-nyl group, inzolopoxycal? Nyl group or t datoxycargenyl group, and aryl or heteroarylmethoxycarbonyl group (1 to 3 7'
or one monocyclic heteroaryl group), each of the foregoing groups having one" or more, for example, a lower alkyl group, such as a t-lower alkyl group, such as a t-butyl group. groups, halogen atoms such as chlorine atoms and/or nitro groups. Examples of such groups are: penzyloxycarbinyl groups, which are unsubstituted or ,
For example, a 4-nitropentyloxycarbinyl group, a diphenylmethoxycarbonyl group or a triphenylmethoxycarbonyl group (substituted as described above)
for example a diphenylmethoxycarbonyl group, or a picolyloxycarbunyl group (unsubstituted or substituted, e.g. as described above),
A 4-picolyloxycarbunyl group, or a furfuryloxycarbo=kM, for example a 2-furfuryloxycarbonyl group, each of which is substituted or substituted, for example as described above. A further suitable group is
A lower alkanoylmethoxycarbunyl group, for example acetonyloxycarb? nyl group, amylmethoxycarbonyl group (wherein the aroyl group is preferably a benzoyl group, which benzoyl group is substituted, for example, with a halogen atom, e.g. a bromine atom), e.g. phenacyloxycarbonyl group, halo-lower alkoxycarbonyl group groups, e.g. 2-halo lower alkoxyl g
= group, example i is 2P212-) vchloroethoxycarzanyl group, 2-chloroethoxycarbonyl group,
2-promoethoxy group or 2-iodoethoxy group, mataha ω-halo lower alkoxycarbonyl group (wherein the lower alkoxy group contains 4 to 7 carbon atoms), e.g. 7I nyl group, phthalimidomethoxycarbunyl group, lower alkenyloxy:)'J A/ &nyl group, f9Lttd,
Allyloxycarbyl group, aryl lower alkenyloxycarbonyl group (which is unsubstituted or substituted in the aryl ring) e.g. 3-phenylalkoxycarbonyl (cinnamyloxycarbinyl) [where the aryl ring, i.e. The phenyl ring can be substituted with one or more of the following substituents: a lower alkoxy group such as a methoxy group, a halogen atom such as a chlorine or fluorine atom, and/or a nitro group],
or an ethoxycarbonyl group which is substituted in the 2-position by a lower alkylsulfonyl group, a cyano group, or by a trisubstituted silyl group, such as a tri-lower alkylsilyl group or a triphenylsilyl group, such as 2-methylsulfonylethoxycarbonyl group, 2-
cyanoethoxycarbyl group, 2-trimethylsilylethoxycarbonyl group or 2-(di-n-butylmethylsilyl)ethoxyruzenyl group. Carboxy protecting groups are also esterified carpoquine groups, which can be removed under physiological conditions. In the case of oral administration, it is expressed in the gastrointestinal tract (
It protects the compounds of I) from forming salts, thus preventing premature secretion, and in particular the acyloxymethoxycarbunyl group (where the acyl group is, for example, a group of an organic carboxylic acid, preferably a lower alkanecarboxylic acid). or a group of an arylcarboxylic acid, such as benzoic acid, which group can be substituted, for example, with an amine group, or where the acyloxymethyl group is intended to form a lactone group. Examples of such groups are: lower alkanoyloxymethoxycarbonyl group, amino-lower alkanoyloxymethoxycarbonyl group, preferably α-amino-lower alkanoyloxymethoxycarbonyl group, lower alkanoylaminomethoxycarbonyl group, benzyl group. aminomethoxycarvinyl group,
4-crotonolactonyl group and 4-butyrolactone-
4-yl group. can be desorbed under physiological conditions,
Examples of other esterified carboxyne groups R2 are as follows: 5-indanyloxycargenyl, 3-phthalidyloxycarbunyl, 1-lower alkoxycarbonyloxy-lower alkoxy/L /W nyl group, 1-
lower flukoxy lower alkoxycargonyl group or 2
-oxo-1,3-dioxolene-4-ylmethoxycarbinyl group, which is substituted with a lower alkyl group or a phenyl group in the 5-position of the dioxolene ring. Other protected carboxyne groups in esterified form are suitable organosilyloxycarbinyl groups and also organostannyloxycarbinyl groups. In these groups, the silicon atom or tin atom preferably contains a lower alkyl group, preferably a methyl group or an ethyl group, or a lower alkoxy group such as a methoxy group as a substituent. Suitable silyl and stannyl groups are in particular tri-lower alkylsilyl groups, preferably trimethylsilyl or dimethyl-tert-butylsilyl groups, or suitably substituted stannyl groups, for example)! j-n-
It is a butylstannyl group. Preferred protected groups include the 4-nitropenzoloxycarbonyl group, the lower W alkenyloxycarbonyl group or the allyloxycarbinyl group, and the ethoxycarbonyl group; Substituted in the 2-position by a lower alkylsulfonyl group, a cyanogen-based lower alkylsilyl group, such as a trimethylsilyl group or a di-n-butyl-methylsilyl group. Easily removable acylamino groups, acylimino groups, etherified submercaptoamino groups, and silylamino groups must be in the form of stannylamino groups, enabano groups, nitro groups, or azido groups7!I In a suitable acylamino group, the acyl group can be, for example,
Organic acids containing up to 18 carbon atoms, preferably alkanecarboxylic acids (which may be substituted with sidelights, heron atoms or phenyl groups) or benzoic acids (which may be substituted with e.g. (which can be substituted with a halodane atom, a lower alkoxy group or a nitro group) or an acyl group of a carboxylic acid half ester. Examples of such acyl groups are: lower alkanoyl groups such as phorbal, acetyl or propionyl, halo lower alkanoyl groups such as 2-haloacetyl, preferably 2-fluoro-12-promoyl. , 2-iodo-12,2,2-)refluoro- or 2,2.2
- trichloroacetyl group, benzoyl group or substituted benzoyl group such as benzoyl group, halobenzoyl group such as 4-chloropenzoyl X, low i alkoxybenzoyl group such as 4-methoxybenzoyl group, nitrobenzoyl group such as 4-nitrobenzoyl group . Particularly suitable acyl groups are also: lower alkenyloxycarvinyl groups, such as allyloxycarginyl groups, aryl-lower alkenyloxycarbyl groups, which are unsubstituted or aryl For example, 3-phenylallyloxycarbinyl (cinnamyloxycarzenyl) [where a ring group, i.e., a phenyl group, is substituted with two or more of the following groups] For example, a lower alkoxy group such as a methoxy group, a rhodane atom such as a chlorine or fluorine atom and/or a nitro group] or a lower alkoxycarbonyl group (which may be unsubstituted or substituted at the 1- or 2-position 6t) lower alkoxycarbinyl groups, such as methoxy- or ethoxy-carbonyl groups, unsubstituted or substituted pencyloxycarbinyl groups, e.g. pencyloxycarbinyl groups, 4-nitropene, soloxy carbinyl group, aroylmethoxycar is a nyl group (
The aroyl group here is preferably a benzoyl group or a benzoyl group substituted, for example by a halodane atom, for example by a bromine atom), or phenacyloxycarbinyl &
, 2-halo lower alkoxycarbonyl side light group 282
．． 2-) Lichloroethoxycarvinyl? ! , 2-chloroethoxycarbonyl group, 2-bromoethoxycarbonyl group or 2-iodoethoxycarbinyl group, or 2-(trisubstituted silyl)ethoxycarbonyl group, e.g.
tri-lower alkylsilylethoxycardenyl group, such as 2-trimethylsilylethoxycardenyl group or 2-trimethylsilylethoxycardenyl group;
(di-n-butylmethylsilyl)ethoxycarbonyl group, or 2-)lyarylsilylethoxycargenyl,
For example, IJ is a 2-triphenylsilylethoxycarbonyl group. Acylimino group

An acyl group is, for example, an acyl group of an organic dicarboxylic acid containing up to 12 carbon atoms, especially of suitable aromatic dicarboxylic acids, such as phthalic acid. Such groups are preferably acylimino groups. The etherified mercazotoamino group is preferably a phenylthioamino group (this group is unsubstituted or a lower alkyl group such as a methyl or butyl group, a lower alkoxy group such as a methoxy group, a halodane atom such as a chlorine or bromine atom, and/or substituted with a nitro group) or a bilysolthioamino group. Corresponding groups are, for example, 2- or 4-nitrophenylthioamino groups or 2-birisolthioamino groups. The silyl- or stannylamino group is preferably an organic silyl- or stannylamino group, in which the substituent on the silicon or tin atom is preferably a lower alkyl group, such as a methylura group, a methoxyl group, or a n-butyl group. or t-
A butyl group, or a lower alkoxy group such as a methoxy group. Particularly suitable silyl or stannyl groups are a tri-lower alkylsilyl group, preferably a trimethylsilyl group, and a trimethyl-t-butylsilyl group, or a suitably substituted stannyl group. For example, the tri-n-gtylstannyl group.Other conservative groups are, for example, the eno group, which has an electrophilic substituent at the double bond in the 2-position, such as the cal-nylstannyl group. Contains groups. Protecting groups of this type are, for example, 1-acyl-lower alk-1-en-2-yl groups, where the acyl group is, for example, a lower alkanecargenic acid such as acetic acid, benzoic acid (which acid is For example, a lower alkyl group such as a methyl or butyl group, a lower alkoxy group such as a methoxy group, a halodane atom such as a chlorine atom and/or a nitro group), or preferably a half ester of carbonic acid, such as a lower The alkyl half ester is the corresponding group of the methyl or ethyl half ester of carbonic acid, while the lower alk]-ene is preferably 1-proyne. Suitable protecting groups are preferably the 1-lower alkanoylderode-1-en-2-yl group, such as the ]-acetylzoloderode-1-en-2-yl group, or the 1-lower alkoxycarylderode-1-en-2-yl group, or 2-yl group example, t]-ethoxylic? Nylzolo 7'-1-en-1-yl group. Preferred protected f'' amino groups are, for example, at groups, phthalibados, nitro groups, lower alkenyloxycarboxylic groups such as nylamino groups, such as allyloxycargynylamino groups, and unsubstituted fC, nitro-substituted benzyloxy groups. Cal is a nylamino group. Surprisingly, when a cinnamyloxycarbonyl group is used as a protecting group in a compound where R2 is a protected aminomethyl group, formulas (11, A crystalline intermediate of (2) is obtained. The protected sulfo group in group R2 is preferably an esterified sulfo group, such as aliphatic, cycloaliphatic,
Cycloaliphatic - a sulfo group esterified with an aliphatic, aromatic or araliphatic alcohol, lower alkanol, or with a silyl or stannyl group, such as a tri-lower alkylsilyl group. In a sulfo group, the hydroxy group can be etherified, for example, in the same way as the hydroxy group in an esterified carboxy group. The meaning of R3 as a carboxyl protecting group can be deduced from the protected carboxyl group defined above. W in the compound of formula (n) is as defined in step (a). The salts of the compound of the present invention are preferably pharmaceutically acceptable non-toxic salts of the compound of formula (1). Such salts are formed, for example, from acid groups present in the compounds of formula (I), such as carboxyne groups and sulfo groups, and examples thereof are as follows: metal salts and ammonium salts, for example alkali metal and alkaline earth metal salts such as sodium, potassium, magnesium or carunium salts, and ammonium salts with ammonia or suitable organic amines such as lower alkyl amines such as triethylamine, human a
quinine-lower alkylamines, such as 2-hydroxyethylamine, bis(2-hydroquinoethyl)amine or tris(2-hydroxyethyl)amine, basic aliphatic esters of carboxylic acids, fat, 2-diethylaminoethyl 4-aminobenzoate , lower alkylene amines, ganiba, l-ethelpiperidine, cycloalkylamines, such as dicyclohexylamine, or benzylamines, such as N,N'-nobensol etherenediamine, dibenzylamine or N-pentrue β
-Salts with phenethylamine. Compounds of formula (1) having a basic group, for example an amino group, can form acid addition salts, for example, with the following acids: inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid, or suitable organic carboxylic acids or sulfonic acids. Acids, such as acetic acid, cono-phosphoric acid, fumaric acid, maleic acid, tartaric acid, 7-uric acid, citric acid, benzoic acid, mandelic acid, malic acid, ascorbic acid, methanesulfone
"!fc 4-Toluenesulfonic acid. The compounds of formula (1) containing acid and basic groups can also be in the form of internal salts, i.e. in the form of zwitterions. Isolation Or for purification it is also possible to use pharmaceutically acceptable salts. Only pharmaceutically acceptable non-toxic salts are used therapeutically and are preferred. Individuals of the method of the invention The steps are carried out as follows: Step (&) The starting compounds of formula (II) are known [for example, EP 82113, DE 3,224,055]
No. 3,013,997 or S. Hanessian et al., Journal of American Chemical Science (J-Am Chem.
, Soc, ) l 985 , 107 , 1438
-1439) or can be produced by a conventional method. The group W which can be substituted with the group -5-5-R2 is M-degrouped, for example, an acyloxy group [herein, the acyl group is, for example, an organic car-J? acid groups, such as lower alkanoyl groups, such as acetyl or zolobionyl groups, benzoyl groups or nitro-substituted benzoyl groups,
For example, a benzoyl group, a 4-nitrobenzoyl group or a 2,4-dinitrobenzoyl group, or a phenyl-lower alkanoyl group, such as a phenylacetyl group, a sulfonyl group Ro-8O2- (where R8 is an organic group, e.g.
a lower alkyl group or a hydroxy-substituted lower alkyl group, such as a methyl group, an ether group, a t-butyl group, a 2-hydroquinoether group, a 1-hydroquinzolof-2-yl group or a l-hydroxy/-2-methylglog-2-yl group, a benyl group, or optionally a di-lower alkyl group or a phenyl group, such as a phenyl group, a 4-bromophenyl group or a 4-methylphenyl group, which may be substituted with a di-lower alkyl group or a logone atom],... An orion atom is, for example, a bromine atom, an iodine atom or preferably a chlorine atom, or alternatively an at group. W is preferably an acetyloxy group, a pentyloxy group, a methanesulfonyl group, a benzenesulfonyl group, a toluenesulfonyl group-i*id chlorine atom. The starting compounds of formula (n) can be used as cis- or trans-compounds or mixtures of/su-trans-compounds. That is, the C4 atom of the azetenone ring can have an R-, S- or R,S-configuration. Compounds introducing a group of formula (I) are the corresponding thiocarboxylic acids H-8-C(-Z)-R2 themselves or their salts, such as alkali metal salts, such as sodium salts or caralim salts. Substitution can be carried out in an organic solvent, for example a lower vulcanol such as methanol or ethanol, a lower alkanone such as acetone, a lower alkane carboxy/amide such as dimethylformamide, or a similar inert solvent.The reaction is carried out at room temperature. It is usually carried out at high or low temperatures, e.g.
It can be carried out at temperatures in the range of 0°C. The groups introduced are oriented predominantly in the trans-position by the group R4-CH(OH). Step (b) In the intermediate of the formula (M, a functional group present in the group R2,
For example, Cal H? The groups, amine groups or hydroxy groups are protected by conventional protecting groups. The acylating agent for introducing the acyl group of the carboxylic acid of the formula (■) is the carboxylic acid of the formula (■) itself or a reactive functional derivative or a salt thereof. Therefore, it is necessary to use at least 2 equivalents of acylating agent. When the free acid of formula (■) is used for acylation, the reaction is generally carried out in the presence of a suitable condensing agent. Examples of condensing agents include Common: carbodiimide, example 1', N, N'
-soethylcargodiimide, N,N'-dizolopylcarpdiimide, N,N'-di7chlorohexylcarbonimide or N-ethyl-N/~3-tumethylaminozolobylcarbosoimide, a suitable carbonyl compound ,
For example, carbinyldiimidazole, or 1,2-oxacillium compounds, such as 2-ethyl-5-phenyl-1,2-oxacillium-3'-sulfonate or 2-L-butyl-5-methyl-1,2- Oxazolium no! -chlorate, or a suitable ananolamino compound, such as 2-ethoxy/-1-ethoxy/cargoni-1,2-dihydroquinoline. The condensation reaction is preferably carried out in an anhydrous reaction medium, preferably in an inert solvent such as methylene chloride, dimethylformamide, acetonitrile or tetrahydrofuran, with cooling or heating as desired or necessary, e.g. The process is carried out at a temperature in the range -40 DEG C. to +100 DEG C., preferably about -20 DEG C. to +50 DEG C., optionally in an inert gas atmosphere, such as a nitrogen atmosphere. The reactivity of the carboxylic acid of formula (V), i.e., carboxylic acid? The intermediate-forming, functional t/I: derivatives are preferably anhydrides, preferably mixed anhydrides, of inorganic acids, such as hydrohalic acids, and, for example, the corresponding carboxylic acids... eg carboxylic acid bromides or preferably carboxylic acid chlorides, and also carboxylic acid chlorides. Other inorganic acids suitable for forming mixed anhydrides are phosphorus-containing acids such as phosphoric acid, soethylphosphoric acid or phosphorous acid, sulfur-containing acids such as sulfuric acid, or heptahydrohydric acid. Reactive functional derivatives of carboxylic acids of the formula (■) may also include organic carboxylic acids, e.g.
・lower alkanecarbic acids substituted with rhodan atoms, e.g. 7 atoms or chlorine atoms or cyano groups, e.g. pivalic acid, invaleric acid, trifluoroacetic acid or 71) acetic acid, or lower alkyl half esters of carbonic acid, e.g. It is formed by combining with the bovine ester of ethyl or inbutyl or with an organic, e.g. aliphatic or aromatic, sulfonic acid such as methanesulfone ri or p'''' toluenesulfonic acid. Functional derivatives may also include activated esters with vinylogous alcohols or enols, such as vinylic lower alkenols, iminomethyl ester halides, such as d-methyliminomethyl ester chloride, which are derived from carboxylic acids of formula (V). ) and, for example, the formula ((CH
,)2N@=C(C4)CH3)Cto dimethyl-(
1-10 loeteridene)-Iminiumc. (which can be obtained, for example, from N,N-dimethylacetamide and phosdan or oxalyl chloride), aryl esters, e.g. phenyl esters substituted with rhodane atoms e.g. chlorine atoms and/or nitro groups e.g. Chlorophenyl, 4-nitrophenylmataha 2,4-dinitro ester, N-heteroaromatic ester such as N-benzotriazole ester, or N-nor/ruamino ester example, t ij
N-succinimino or N-phthalimino ester. Preferred acylating agents are acid halides such as chlorides, most preferably allyl oxalate chloride. Acylation with a reactive functional derivative of a carboxylic acid of formula (■), preferably an acid halide, is preferably carried out in the presence of a suitable acid acceptor, such as a suitable organic base. Examples of suitable organic bases is: an amine, such as a tertiary amine, such as a tri-lower alkylamine, such as trimethylamine, triethylamine or ethyldiinzolobylamine, or a N,N-no-lower alkylamine, such as N,N Suitable acid acceptors are also inorganic bases, such as alkali metal or alkaline earth metal hydroxides, carbonates or bicarbonates;
For example, sodium, potassium or calcium hydroxides, sodium, potassium or calcium carbonates or sodium, potassium or calcium bicarbonates. Acylation with reactive functional derivatives of carboxylic acids of formula (V) is preferably carried out in inert, preferably anhydrous solvents or solvent mixtures, such as carboxamides such as formamides such as trimethylformamide, halodanized carbonized Hydrogen such as methylene chloride, carbon tetrachloride or chlorobenzene, hydrogen such as acetone, cyclic ethers such as tetrahydroether, esters such as [,6[ether], or nitriles such as acetonitrile, or mixtures thereof. and, as necessary or desired, at low or high temperatures, e.g., from about -40°C to +10°C.
It is carried out at a temperature in the range of 0 DEG C., preferably -10 DEG C. to +50 DEG C. and, if necessary, in an atmosphere of an inert gas, for example nitrogen. The reactive functional derivative of the acid of formula (V) to be used in the acylation reaction can be formed in situ. Step (c) The organic compound of trivalent phosphorus is, for example, derived from phosphoric acid and preferably an ester with a lower alkanol such as methanol or ethanol, and/or an unsubstituted or substituted aromatic hydroxy compound, such as phenol. or an ester with pyrocatechol, or of the formula P(ORa)-N(Rb)2, where R& and Rb- are each independently another lower alkyl group, such as a methyl group or an aryl group, such as a phenyl group. It is an amide ester of Preferred trivalent phosphorous compounds are tri-lower alkyl phosphites such as trimethyl phosphite, triethyl phosphite or triinzolobyl phosphite. The reaction is preferably carried out in an inert organic solvent, such as an aromatic hydrocarbon, such as benzene or toluene, an ether, such as dioxane or tetrahydrochloride, or a halodanated hydrocarbon, such as methylene chloride or chloroform. 20-80℃, preferably about 40℃
Performed at a temperature in the range of ~60<0>C, one molar equivalent of a compound of formula (-) is reacted with two molar equivalents of a phosphorus compound. A preferred procedure is to charge a reactor with a compound of formula (5) in an inert solvent and to react the phosphorus compound, preferably dissolved in the same inert solvent, over a substantial period of time, e.g. dropwise over a period of time and heating the reaction mixture to about 100-110° C. to complete the reaction. In a preferred embodiment of this process, a starting material of formula (-' is prepared as indicated above and is reacted with the trivalent phosphorous organic compound without isolation from the reaction mixture. Step (d) In the obtained compound of formula (4), protecting groups R3, R5
0-Co-Co and any protecting group R2 present in the group R2, for example a protected car? Kyfur groups, hydroxyl groups, amine groups and/or sulfo groups can be removed in a manner known per se, for example by solvolysis, preferably by hydrolysis, alcoholysis or acidolysis, or by reduction, preferably by hydrogenolysis or chemical reduction. , can be removed stepwise and in any order or simultaneously, and replaced by hydrogen, as appropriate. Thus, the oxalyl ester group, -Co-Coo-R
. can be removed stepwise and/or selectively (ie, while retaining the protecting group R3 or other protecting group R2 on the 4-carboxyl group) and by substitution with hydrogen. This removal may be carried out under alcoholic conditions, e.g.
It is carried out in the presence of an alkali metal hydroxide, for example lithium, sodium or potassium hydroxide, or the corresponding carbonate or, preferably, bicarbonate (preferably catalyst t or up to equimolar amounts of i). Suitable solvents are, for example, water and water-soluble solvents such as lower alkanols such as methanolethanol or inzolopanol, lower ketones such as acetone, lower cyclic ethers such as dioxane or tetrahydrofuran, lower nitriles such as acetonitrile, lower amides such as dimethylformamide, or lower sulfoxides. For example, it is a mixture with dimethyl sulfoxide. Saponification is preferably carried out in aqueous methanol (approximately 80%
%) in the presence of sodium bicarbonate. The margin temperature below is the condensation temperature or boiling point of the solvent used, that is,
It ranges from about -20°C to +100°C. It is generally preferred that the reaction be carried out at a low temperature, ie, at a temperature in the range of 0<0>C to 20<0>C, most preferably about 0<0>C. It is also possible to first remove the R1 group by the method described below and then completely convert the obtained 1'-oxalic acid half ester under the above-mentioned alkaline conditions. Protected carboxy groups, such as the -CCO-R5 group, can be liberated by methods known per se. For example, a t-lower alkoxycarbonyl group substituted with a trisubstituted silyl group in the 2-position or a lower alkoxy group in the 1-position or a lower alkoxycarginyl group or a substituted or unsubstituted diphenylmethoxycarbonyl group For example, Carbon 1! I2 can be converted into a free carboxy group by treatment with for example formic acid or trifluoroacetic acid and optionally adding a nucleophilic compound such as phenol or anisole. Unsubstituted or substituted penzyloxycarmenyl groups can be removed, for example, by hydrogenolysis, ie by treatment with hydrogen in the presence of a metal hydrogenation catalyst, such as a parent radium catalyst. Also, a suitably substituted pencil oxycar? It is possible to convert the nyl group fil, t to a free rhodexy group by chemical reduction, and this conversion is one example. The nascent hydrogen is usually treated with an alkali metal dithionite, such as sodium dithionite, or with a reducing metal, such as tin, or with a reducing metal salt, such as chromium ω) salt, such as chromium chloride. Hydrogen donors capable of producing 1, for example, suitable caldic acids such as lower alkane caldic acids (which caldic acids are unsubstituted or substituted with 1, for example with hydrogenyloxy), such as acetic acid, formic acid or Removal of the 8-allylic protecting group is carried out by treatment in the presence of glycolic acid, or an alcohol or a thiol, preferably with the addition of water, for example with a palladium compound, e.g.
Tetrakis(triphenylphosphine)palladium,
Acceptors of allyl groups, such as acetylacetone, preferably in the presence of nometone, and optionally triphenylphosphine, or carbonyl, for example 2-
This can be carried out by adding ethylhexanoic acid or a salt thereof and reacting. By treatment with 1M elemental gold metal or metal salt as described above, a 2-halo lower alkoxycarzanyl group (if necessary, a 2-bromo-lower alkoxycarbonyl group can be converted to a corresponding sulfur 2--1 -1
'-AM after converting alkoxycarbonyl group into free carboxy group Kf) or aroylmethoxycarbonyl group
It is possible to exchange. On the other hand, the 70ylmethoxycarbonyl group also has nucleophilicity (
Preferably salt-forming reagents, such as sodium thiophenolate, can be removed by treatment with sodium iodide. The presence of macrocyclic polyethers ("crown ethers") with substituted 2-silylethoxycaryl, Th&i, salts of hydrofluoric acid that donate fluorine anions, e.g. alkaline platform fluorides 1 e.g. sodium fluoride K , or can be converted to a free carboxyl group by treatment with an organic quaternary base fluoride 1, such as a tetra-lower alkyl ammonium fluoride, such as tetrabutylammonium fluoride. Carboxyl groups costelated with organosilyl or stannyl groups, such as tri-lower alkylsilyl groups or tri-lower alkyl stannyl groups, can be liberated in the usual manner by solvolysis, e.g. by treatment with water or alcohol. can do. 2
A lower alkoxycarbunyl group substituted by a lower alkylsulfonyl group or a cyano group in the - position is 1
For example, bases such as alkali metal hydroxides or alkaline earth metal hydroxides or alkali metal carbonates or alkaline earth metal carbonates, such as sodium or potassium hydroxides or sodium or potassium carbonates. It can be converted to a free carboxy group by In compounds of formula (■) in which the group R2 contains a protected hydroxy group as a substituent, the protected human-roxy group can be converted into a free heroxy group in a manner known per se. For example, H-P protected by a suitable acyl group or by an organosilyl or stannyl group.
Roxy groups are liberated in the same manner as the corresponding protected amino groups (see below). Tri-lower alkylsilyl groups can also be removed, for example, with tetrabutylammonium fluoride and acetic acid (under these conditions, carboxy groups protected with trisubstituted silylethoxy groups are not removed). 2-no-low lower alkyl groups and unsubstituted or substituted benzyl groups are removed by reduction◇ In compounds of formula (■) containing protected amine groups, said groups can be removed in a manner known per se, e.g. Depending on the nature of the protecting group, it can be converted into the free amine group, preferably by solvolysis or reduction. For example, 2
-lower alkoxycarbonylamino group (after converting the 2-pro7-lower alkoxylupinylamino group to a 2·-iop-lower alkoxycarbonylamino group if necessary), aroylmethoxycarbonylamino group, or - The nitrobenzyloxycarbinylamino group can be treated with a suitable chemical reducing agent, such as zinc, in the presence of a suitable carboxylic acid, such as aqueous acetic acid, or catalytically decomposed with hydrogen in the presence of a parent radium catalyst. It can be removed by The aroylmethoxycarbonylamino group can also be removed by treatment with a nucleophilic (preferably salt-forming) reagent, such as sodium thiophenolate, and the 4-nitrobenzyloxycarbonylamino group It can also be desorbed by treatment with an alkali metal dithionite, for example sodium dithionite. An unsubstituted or substituted benzyloxycarbonylamino group can be removed, for example, by hydrogenolysis, i.e. by treatment with hydrogen in the presence of a suitable hydrogenation catalyst, such as a gradium catalyst, and allyl Oxycarbonylamino group. For example, in the presence of an acceptor for an allyl group, such as acetyl-heptaton or, preferably, dimedone, and optionally triphenylphosphine, react with a parent radium compound such as tetrakis(triphenylphos-2yne)tucladium. and by treatment with a carboxylic acid such as 2-ethylhexanoic acid or a salt thereof. Amine groups protected with organosilyl or stannyl groups can be liberated by hydrolysis or alcoholysis, for example, and protected with 2-halo lower alkanoyl groups, e.g. 2-chloroacetyl groups. The amino groups obtained are treated with thiourea in the presence of a base, or with a thiolate salt such as an alkali metal thiolate, or with thiourea, and the resulting condensation product is subsequently subjected to solvolysis, e.g. alcoholysis or hydrolysis. It can be liberated by An amine group protected by a 2-substituted silylethoxycarbonyl group is a macrocyclic polyether (“crown ether”).
) in the presence of a fluorine anion-donating salt of hydrofluoric acid, such as an alkali metal fluoride, such as sodium heptafluoride, or with an organic quaternary base, such as a tetra-lower alkyl ammonium fluoride, such as tetraethylammonium fluoride. It can be converted to a free amino group by treatment. Amino groups protected in the form of an azide or nitro group can be prepared, for example, by reduction, e.g. by catalytic hydrogenation with hydrogen in the presence of a hydrogenation catalyst, e.g. platinum oxide,... or radium or Raney nickel. , or converted to free amine groups by treatment with zinc in the presence of an acid such as acetic acid. Amine groups retained in the form of phthalimide groups can be converted into free amine groups by reaction with hydrazine. Additionally, arylthioamino groups can be converted to amines by treatment with nucleophilic reagents such as sulfite. Protected, especially esterified, sulfo groups are liberated in the same way as protected carboxy groups. Salts of the compound of formula (1) containing a salt-forming group can be produced by methods known per se. Thus, salts of compounds of formula (1) containing free carboxy or sulfo groups can be prepared, for example, from metal compounds such as alkali metal salts of suitable organic carboxylic acids, such as α-ethylcaproic acid. or with an inorganic alkali metal or alkaline earth metal salt, such as bicarbonate, or with ammonia or a suitable organic amine, preferably with a chemical
It can be formed by mixing or by using a slight excess of salt-forming agent. Acid addition salts of compounds of formula (1) are obtained in conventional manner, for example by treatment with a suitable acid or a suitable anion exchange reagent. Internal salts of formula (I) can be formed, for example, by neutralizing a salt, such as an acid addition salt, to the isotropic point, for example with a weak base, or by treating it with an ion exchange agent. Salts can be converted to the free compounds in the usual manner (metal and ammonium salts, for example, by treatment with a suitable acid, and acid addition salts, for example, by treatment with a suitable base). I can do it. In all subsequent conversions of the resulting compounds of formula (1), reactions taking place under weakly alkaline or preferably neutral conditions are preferred. The process of the invention also uses the compounds obtained as intermediates as starting materials and carries out the remaining steps with them, or the process can be carried out at any stage as well as in the individual steps (a) to Includes embodiments that discontinue at (d). Furthermore, the starting materials can be used in the form of derivatives, or alternatively. It can be prepared in situ, optionally under reaction conditions. The present invention also relates to novel compounds of formula (1), formula (7), formula (6) and formula (2). The novel compounds of formula (1) are particularly characterized in that R2 is a cinnamyloxycarbonylaminomethyl group, and R1 and R3 have the meanings given above, the preferred meaning of R1 is a methyl group and that of R5 is an allyl group. It is the basis. The novel compounds of formula (V) are in particular those in which R2 is a cinnamyloxycarbonylaminomethyl group and R2 and 2 have the abovementioned (particularly preferred) meanings. In the novel compounds of formula (VD and formula (4)), R2
・And R3 have a predetermined (Special V is preferred) meaning? have Formula (1), Formula (IV), Formula ('vll) and Formula (■)
Particularly preferred compounds are those in crystalline form, in which R2 is a cinnamyloxycarbonylaminomethyl group. The invention will be illustrated by the following examples. In the 11 examples, the following abbreviations are used: TLC: thin layer chromatogram IR: infrared spectrum Uv: ultraviolet spectrum Example 1 Zetidinone (,) 60 rnl water and 40 m IN aqueous NaOH
A solution of 14.2 II (40 mmol) of N-allyloxycarponylteoglycine dicyclohexylammonium salt in 0.1 d of methylene chloride is extracted with three portions of 20 d of methylene chloride, and the aqueous phase is diluted with 0.1 d of methylene chloride. Adjust the pH to 7-8 with about 1 rnt of IN aqueous HCl. The resulting aqueous thiol acid solution was dissolved in 100 ml of acetonitrile (7) (3R,4R
, l'R)-3-(1'hydroxyethyl)-4--<
Zoyloxy-2-azetidinone 4.70.9 (20
millimolar) solution over 5 minutes at 30°C. Then 0. IN aqueous NILOH2- is added at 25°C and the batch is aged at 25°C for 30-35 minutes. For finishing, 250% ethyl acetate and NaCA
Charge the '301 into a separatory funnel and then add the reaction mixture. After separating the aqueous phase by placing it in a tray, remove the organic phase by 5 minutes.
% aqueous Na I (CO3 solution) and twice with Prine 50 g and dried over sodium sulfate. The solvent is removed on a rotary evaporator. The title compound is an amorphous powder. The crude product can be prepared by chromatography on silica dal (2:3 mixture of toluene/ethyl acetate). Rf value = 0.
．． 23C Merck plate, developed with toluene/ethyl acetate (1:4):ninhydrin]. The same compound can also be obtained as follows. (b) 360 ml of water and 240 ml of IN aqueous NaOH
A solution of N-allyloxycarbonylthioglycine dicyclohexylammonium salt 85.2!1 (239 mmol) in mi was extracted with three portions of 40 mJ of methylene chloride, and the aqueous phase was extracted with IN aqueous HC1 with about 0.5 mJ of P1
'(adjust to 7-8. The resulting aqueous thiol acid solution r
(3S,4R,1'R)-3-(1'-hydroxyethyl)-4-t-butylsulfonyl-2-azetidinone 3 in 300 mA of acetonitrile and 202 oml of H2
0.11 (128 mmol) over 5 minutes at 28°C. Then 0. IN aqueous NaO
H12,71J was added at 25°C and the patch was incubated at 25°C.
Stir for 30 minutes. For finishing, 70% ethyl acetate
0d and NaC1901 in a separatory funnel, then add the reaction mixture. After good shaking and separation of the organic phase, the organic phase was diluted with 54 NaHCOs aqueous solution 100-1.
twice and twice with 100 ml of concentrated sodium hydrochloride solution and dried over kW sodium sodium chloride. The solvent is completely removed on a rotary evaporator. CH2C42100- is then added to the partially crystalline residue and the crystalline unreacted extract is isolated by filtration and dried. The lachrymal fluid is concentrated by evaporation and chromatographed on silica dal 30 (l), eluting with toluene/ethyl acetate (4:6). The title compound obtained has an Rf value of 0.23 [Merck board, toluene/acetic acid]. Ethyl (4:1); developed with ninhydrin. (c) A solution of N-allyloxycarbonylthioglycine dicyclohexylammonium salt 42411 (1.2 mmol) in 1.2 ml of IN aqueous NaOH was dissolved in 1.5 ml of methylene chloride. Extract in 3 parts and aqueous phase 0.01
Adjust p) (8-9 with IN aqueous HCl. The resulting aqueous thiol acid solution was diluted with (3S,4R,1'R)-3-(1'-hydroxyethyl)-4 in 1.71!Ll of acetonitrile. -acetoxy-2-azetidinone 173.21
Add to a solution of n9 (1 μIJ%) at 25°C. Then add 0,1 IN aqueous NaOHO, and stir the patch for 35 minutes at 21-23°C. Finishing is carried out as in Example 1(a). After chromatography of the crude product (2-3 mixtures of toluene/acetic acid and ether) the title compound is obtained. Example 2: 80 ml of (3S, 4R, 1'R)-3-(1
'-Hydroxyethyl)-4-(N-allyloxycar?nylglycylnao)-2-azetidinone 2.88.9
3.86 ml (31,5 mmol) of freshly distilled allyloxalyl chloride and N-ethelduisopropyl were added to a solution of (10,0 mmol) at -10°C to -15°C with stirring and vigorous removal of moisture. Amine 7.69d
(44.8 mmol) were added continuously and stirring continued for 30 minutes at -10°C. The IR sample contains a characteristic oxalimide at 1820 crn-'.
Shows carbonyl absorption. For work-up, the reaction mixture was diluted with CH2C6250-, three times with ice-cold water, and diluted with ice-water and saturated Na HC.
Wash once with Os aqueous solution 5rILl. The aqueous phase is CH2C
Extract once at 62. The combined organic phases were dissolved in Na2S
Dry over O4, concentrate by evaporation in vacuo and dry the crude product under high vacuum. Allyl (3S, 4R, 1'R
)-2-(4-(N-allyloxycal?nylglycylthio)-3-(1'-allyloxyoxalyloxyethyl)-2-oxo-1-azetinonyl]-2-oxoacetate-containing viscous liquid [ IR(CH2Cl2
) 1760(C)] is dissolved in Nooxane 30 solution and this solution is treated with triethyl phosphite 7rnlc (40.2 mmol) under silica at room temperature. After 15 hours at room temperature no more oxalimide can be detected in the IR spectrum (band at 1820α-1). The reaction mixture was concentrated by vacuum evaporation and
The material is washed with 3×2 portions of toluene and 3×2 ml of decane and stripped under high vacuum of each of the separating agents to remove excess phosphite/phosphate. For crude phosphorane conversion, dissolve in Nooxa 7250M and stir at 105-110°C for 5 hours. Allyl(5R,68,1'R) -2-allyloxycal+Rnylaminomethyl-6-(1'-(allyloxyoxalyloxy)ethyl)-2-'? Reaction mixture containing Nemu 3-carboxylate [For analysis, a sample of the crude product is purified on silica gel and eluent with a 4:1 mixture of toluene/ethyl acetate; 8 UV (EtOH)
315 nm: IR(CH2C62)3440(
NI():1790.1770,1745°1720(
C)") is concentrated by vacuum evaporation to about 15 WLlK, then 100 mj of methanol/H20 (8:2) and 251 nl of saturated N*HCOs water bath are added at 0 °C. After 20 min, the reaction mixture is dissolved in ethyl acetate 300 mj! and H2
Pour into O50rnl. The organic phase is separated and the aqueous phase is extracted again with 10011 Ll of ethyl acetate. The combined organic phases are dried over N1□S04 and concentrated in vacuo to a volume of 50 ml. Pour the residue into 200 TIL of methylene chloride.
, dry over Na 2 SO 4 and concentrate completely in vacuo. The residue is chromatographed on silica gel 80I, eluting with toluene/ethyl acetate (3:2). The title compound is ether/hexane (3-near)
obtained after crystallization from Melting point: ・141-141.5
°C; Rf value = 0.20C Merck plate, toluene/ethyl acetate (1:l)). Example 3 Allyl(5R,6R.1'R)-2-allyloxycal in tetrahydrofuran 7.5a is nylaminomethyl-6-(1'-hydroxyethyl)-2-penem-3-
Cal? A solution of xylate 313 (0.85 mmol) and tsumetone 174.6 (1.24 mmol) was flushed with argon for 5 minutes and then detrakis (
triphenylphosphine) and radium 27■ (0,0
23 mmol) was added at room temperature under alcohol, a precipitate began to form after about 5 minutes, and after stirring for a further 2 hours, it was isolated by filtration, washed with about 10 m7 of tetrahydro7ranine, then washed in H2O4 ml. dissolve. Add a small amount of activated charcoal to the Paenoille color solution with a micro spatula, then add two small amounts of TonsllX.
Add Fuller's soil). The mixture is then stirred well for 5 minutes, filtered through a Hyflo, and concentrated under high vacuum. Dense crystal slurry in cold ethanol 3
d and filter with suction. The colorless crystals are washed with 2 rnl of tetrahydrofuran and dried under high vacuum. The title compound has an Rf value of 0.50 (TLC: N
20. 0PTI UPC42); Cα3g0=+176(
c=0.5°N20). Example 4 (a) N-Si'7namyloxycargonylteoglycine 30 L8 in IN aqueous NaOH 1,2rnt
A solution of jn9 (1.2 mmol) was added to 0. IN aqueous HC
1 to -8 and (3R14R1′R)-(1/-hydroxyethyl) in acetonidonyl 2rILl.
-4-benzoyloxy-2-azededinone 235ml
II (1 mmol) at 25°C. 0.1
Add 0.1-N NaOH*f (= 0.1 - solution i) and stir the reaction mixture for 25 minutes at 25-26 °C. The organic phase was diluted with 5% Na
Wash with aqueous HCOs 5d, twice with prine 51, dry over sodium sulfate and remove the solvent on a rotary evaporator. The residue was mixed with toluene/vinegar ζ ether (2:
3) Dissolve in 20 mJ, stir with silica kettle 19 for 15 minutes, filter through a G2I lath frit, and settle. The title compound is obtained in the form of an amorphous powder. A crystalline, superficial compound with a melting point of 100-101 DEG C. is obtained from methylene chloride/noinzolobyl ether (approximately 1.1). The same compound can also be obtained as follows: (θ Following the procedure of method (a), (:3t<,4R,l
Starting from 173 μm (1 mmol) of -3-(1′-hydroxyethyl)-4-acetoxy-2-azetidinone, the crude product is chromatographed.
Silica gel, toluene/ethyl acetate (2:3>3゜(
C) Following the procedure of method (LL), (3S, 4R, 1'R
) -3-(1'-Hydroxyethyl)-4-t-butylsulfonyl-2-azetidinone 235d (1 mmol) and the crude product is chromatographed [silica gel, toluene/ethyl acetate (2: 3)
). The starting material N-cinnamyl oxica/L/bonylthioglycine can be prepared as follows: 13.4 g of cinnamyl alcohol (10 g) in 25 g of toluene.
0 mmol) solution of 20% of phosdan in toluene
Add dropwise to 78 ml of solution over 15 minutes at 0°C. Warm the reddish-brown emulsion to room temperature, while
Blow in and stir for 9 minutes. Toluene in vacuum (0
, 1 torr) and the residue is added at 0° C. to a solution of 3.75 g (50 mmol) of glycine, 121 ml of water and 6.77 ml of 30% aqueous NaOH solution. Then, 6.07 m of 30% NaOH aqueous solution was added.
1 was added dropwise over 10 minutes at 5-15°C. The reaction mixture is stirred for 2 hours (p) 112) and then poured into 70 ml of ethyl acetate and 70 ml of water. Separate the aqueous phase and wash with ethyl acetate 20M (2N aqueous)
(Adjust the pH to 1-2 with C1 and extract the precipitated N-cinnamyloxycarvinylglycine with a total amount of 120 ml of ethyl acetate. The combined organic phases are
Wash once with ml, dry over Na2SO4 and remove the solvent on a rotary evaporator. The title compound was dissolved in 50 mJ of ethyl acetate and 25 mJ of hexane.
Crystallize from 1. Melting point: 129-130°C. To a suspension of 7.81.9 (33.2 mm/l) of N-cinnamyloxycarvinylglycine in 66 mm of ethyl acetate was added 4.76 mm (36.4 mm/l) of isobutyl chloroformate. ) was added at -10°C to -15°C, then at the same temperature 4 ml of N-methylmorpholine (36,3
mmol) dropwise. This reaction mixture was heated to -10℃~-
Stir for 1 hour at 15°C. Further, N-methylmorpholine IJ (36.3 mmol) was added dropwise over a total of 30 minutes, during which time hydrogen sulfide gas was simultaneously introduced. After the addition of hydrogen sulfide is complete, add a weak nitrogen light under stirring to -10°C.
Introduce over 1 hour at ~-15°C. Then 2
23.2 m of N aqueous HCt was added dropwise, at a temperature of about 0°C.
and sparge with nitrogen for an additional 30 minutes. The reaction mixture is then poured into 300 ml of ethyl acetate, and the aqueous phase (pi-112) is separated off and then extracted with ethyl acetate. The combined organic phases are washed twice with a 20 m prine, dried over Na 2 S Oa and the solvent is removed on a rotary evaporator. Recrystallization of the crude product from ether/hexane at 0<0>C gives the analytically pure title compound, mp 67-69<0>C. Example 5 (3S,4R,1'R)- in 3.2 ml of methylene chloride
3-(r-Hydroxyethyl)-4-(N-cinnamyloxycarginylglycylthio)-2-7zetidine (crude product of Example 4) A solution of 3101n9 (0,852 mmol) was added at -10°C to At −15° C., with stirring and exclusion of moisture, 0.216 WLl (1,75 mmol) of freshly distilled allyloxaline chloride and 0.30 tM (1,
75 mmol) and stirring until -1
Continue at 0°C for 30 minutes. The IR sample (CH2Cl2) is
A characteristic oxalimide-carbonyl absorption is shown at 1820 cm-'. For work-up, the reaction mixture is diluted with 22 ml of CH2Ct and washed with two portions of 4 d each of aqueous buffer solution. The aqueous phase is extracted once with CH2C22. The combined organic phases were dried over Na2SO4, concentrated by vacuum evaporation,
The crude product is then dried under high vacuum. Allyl (38,4R
, 1'R)-2-(4-(N-cinnamyloxycarbonylglycylthio)-3-(1'-allyloxyoxalyloxyethyl)-2-oxo-1-azetidinyl]
-2-oxoa 1725 (L!l), dioxane 0
．． 0.51 ml of tridimethylphosphite (2
, 1 mmol). After 15 hours at room temperature,
No further oxarylimide can be detected in the IR spectrum (band at 1820 cm-'). Excess phosphite/phosphate was removed from the reaction mixture under vacuum [bulb tube θ: 0.
1 Torr]. The remaining phosphorane was dissolved in 3.3 ml of dioxane for cyclization and heated at 100° C.
Stir for 2 hours. Allyl(5R168,1'R)-2
-cinnamyloxycargenylaminomethyl-6-(1
'-(allyloxyoxalyloxy)ethylcou2-
Reaction mixture containing penem-3-caldexylate [
For analysis, a sample of the crude cyclization product is purified on silica gel and eluted with toluene/ethyl acetate (9:1): mp 8
7-88°C, UV protection # (Etol() = 31
5 °C m, IR spectrum (in CF2Cl2) = 3440
(NH), 1795.1770, 1745.1720 (
)] is concentrated by evaporation at room temperature and the residue is dissolved in 4d of methanol. Then 54 NaHCOs
2rnl of aqueous solution are added dropwise at 0° C. and the precipitated title compound is isolated by filtration and recrystallized from methanol. Melting point: 178-180°C. Example 6 Allyl (5R,6S. 1'R)-6-(1'-hydroxyethyl)-2-cinnamyl oxycarboxylic acid in 1 rnl of tetrahydrofuran monocargonic acid? Nylaminomethyl-2-penem-2
- Cal xylate 48 μm (0.108 mmol) and dimedoms 22.3 μm (
A solution of tetrakis(triphenylphosphine) was flushed with nitrogen for 5 minutes and then treated with tetrakis(triphenylphosphine).
Add 1.61n9 palladium at room temperature. The title compound begins to precipitate about 30 minutes in diameter. After stirring for a further 2.5 hours, the product is isolated by filtration, washed well with tetrahydrofuran and dried under high vacuum to give the title compound: R4=0.50 (TLC: H2O,0P
TI UPC12): U V Schector (H2O
Medium): 328nm0 or less margin

Claims (1)

[Claims] 1. Formula ▲ Numerical formula, chemical formula, table, etc. ▼ (I) (In the formula, R_1 is a hydrogen atom or a lower alkyl group, and R_2 is protected with a common protecting group R^0_2. is an organic group that can carry a functional group that may contain
R_3 is a hydrogen atom or a normal carboxyl protecting group R^
0_3) In producing the compound or its salt represented by (a) Formula ▲ Numerical formula, chemical formula, table, etc. ▼ (II) [In the formula, R_1 has the same meaning as above, and W has the same meaning as described below. formula(
It is a group that can be substituted with the thiocarboxylic acid group of is an oxygen atom or a sulfur atom). has the same meaning as above) The obtained compound represented by the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (V) (In the formula, R^0_3 is a common carboxyl protecting group) (c) Formula ▲ Numerical formula, chemical formula, table, etc. ▼ (VII) (In the formula, R_1, R_2, R^0_3 and Z are The obtained compound represented by (same meaning as above) is treated with an organic compound of trivalent phosphorus, and the resulting compound represented by (d) formula ▲ has a numerical formula, chemical formula, table, etc. ▼ (VIII) (wherein R_1 , R_2 and R^0_3 have the same meanings as above) from the obtained compound represented by the oxalyl ester group (
-CO-COO-R^0_3) and, if desired, protecting group R^0_3 and/or group R_2
the protective groups R^0_2 that may be present in the resulting compound of formula (I) are removed in any order and these groups are replaced by hydrogen atoms, and optionally containing salt-forming groups. A method for producing a compound represented by the formula (I) or a salt thereof, which comprises converting into a salt or converting the obtained salt into a free compound. 2, R_1 is a hydrogen atom or a methyl group, W is an acyloxy group, a sulfonyl group -SO_2-R_0,
where R_0 is an organic group, a halogen atom or an azide group, Z is an oxygen atom or a sulfur atom, and R_2 is an organic group containing up to 18 carbon atoms, preferably up to 10 and most preferably up to 5. and R_2 contains up to 5 nitrogen atoms, preferably up to 4 nitrogen atoms, and/or up to 5 oxygen atoms, preferably up to 2 oxygen atoms, and/or up to 3 sulfur atoms, preferably up to 2 sulfur atoms, and most preferably up to 2 sulfur atoms.
and R_2 shall be capable of bonding to the penem ring through one of its carbon atoms as well as through a nitrogen, oxygen or sulfur atom, and R^0_3 shall be a carboxyl-protected The method according to claim 1, wherein the method is a group of: 3. R_1 is a hydrogen atom or a methyl group, and W is a lower alkanoyloxy group, or a benzoyloxy group or a phenyl-lower alkyloxy group (each is unsubstituted or substituted with nitro) , -SO_2-R_0 group [where R_0 is a lower alkyl group, a hydroxy-substituted lower alkyl group, a benzyl group, or a phenyl group (the phenyl group is unsubstituted or substituted with, for example, a lower alkyl group or a halogen atom) ] or a halogen atom, Z is an oxygen atom or a sulfur atom, and R_2
is an unsubstituted or substituted lower arifatyl group, lower arifatyloxy group, lower arifatylthio group, cycloarifatyl group, cycloarifatyloxy group, cycloarifatylthio group, aryl group, aryloxy group, arylthio group, aryl-lower arifatyl group, aryl-lower arifatyloxy group, aryl-lower arifatylthio group, heterocyclic group, heterocyclic oxy group, heterocyclic thio group, heterocyclic-lower arifatyl group, a heterocyclic-lower arifatyloxy group, a heterocyclic-lower arifatylthio group, a heterocyclic-lower arifatyl group, or a heterocyclic thio-lower arifatyl group, and the above-mentioned cycloariphatyl group and heterocycle The formula group shall be saturated or unsaturated, and R^0_3 is a lower alkyl group, an arylmethyl group, a heteroarylmethyl group, a lower alkanoylmethyl group, an aroylmethyl group, a halo-lower alkyl group,
The method according to claim 1, wherein the group is a lower alkenyl group, a 2-lower alkylsulfonylethyl group, a 2-cyanoethyl group, a 2-tri-lower alkylsilylethyl group, or a 2-triphenylsilylethyl group. 4. The method according to claim 1, wherein R^0_3 is an allyl group. 5, R_1 is a hydrogen atom or a methyl group, W is a bersyloxy group, Z is an oxygen atom or a sulfur atom, R_2 is an aminomethyl group, 2-aminoprop-1
-yl group, carbamoyloxymethyl group, 1-methyltetrazol-5-ylthiomethyl group, 2-(1-tetrazolyl)propyl group, 2-oxo-5-tetrahydrofurylmethyl group, 2-oxo-5-pyrrolidylmethyl group ,
2-aminoethylthio group, 2-formamidinoethylthio group, 2-carbamoyloxyethylthio group, 1-imidazole group, 4,5-dimethyl-1-imidazolyl group,
4-methyl-5-thiazolyl, 5-methyl-4-thiazolyl and 2-amino-4-methyl-5-thiazolyl groups, and their protected derivatives, and R^0_3 is an allyl group. The method according to claim 1. 6. The method according to claim 1, wherein R^0_2 is an allyloxycarbonyl group. 7, (3R, 4R, 1'R)-3-(1'-hydroxyethyl)-4-benzoyloxy-2-azetidinone or (3S, 4R, 1'R)-3-(1'-hydroxyethyl) -4-t-butylsulfonyl-2-azetidinone and N-allyloxycarbonylthioglycine were reacted to obtain (3S,4R,1'R)-3-(1'-
The resulting allyl (5S, 6R, 1'R )-2
-allyloxycarbonylaminomethyl-6-[1'-
(allyloxyoxalyloxy)ethyl]-2-penem-3-carboxylate is removed from the protecting groups at the 1'-hydroxy and 3-carboxy groups and (
5R, 6S, 1'R)-2-aminomethyl-6-(1'
2. A process according to claim 1, which comprises isolating 2-penem-3-carboxylic acid (-hydroxyethyl)-2-penem-3-carboxylic acid. 8. The method according to claim 1, wherein R^0_2 is a cinnamyloxycarbonyl group. 9, (3R, 4R, 1'R)-3-(1'-hydroxyethyl)-4-benzoyloxy-2-azetidinone,
(3R, 4R, 1'R)-3-(1'-hydroxyethyl)-4-acetoxy-2-azetidinone or (3R
, 4R, 1'R)-3-(1'-hydroxyethyl)-
4-t-butylsulfonyl-2-azetidinone and N-cinnamyloxycarbonylthioglycine are reacted,
The obtained (3S, 4R, 1′R)-3-(1′-hydroxyethyl)-4-(N-cinnamyloxycarbonylglycylthio)-2-azetidinone was added in the presence of N-ethyldiisopropylamine. , treated with allyloxalyl chloride, the obtained allyl (5S, 6R, 1'R)-2-
Allyloxycarbonylaminomethyl-6-[1'-(
Allyloxyoxalyloxy)ethyl]-2-penem-3-carboxylate was deprotected from the 1'-hydroxy and 3-carboxy groups and (5
R, 6S, 1'R)-2-aminomethyl-6-(1'-
2. A process according to claim 1, which comprises isolating hydroxyethyl)-2-penem-3-carboxylic acid. 10. Use the compound obtained as an intermediate as starting material and carry out the remaining steps with it or interrupt the process at any stage or carry out individual steps (a) to (d) ) A method according to any one of claims 1 to 6. 11. Either the compound obtained as an intermediate is used as starting material and the remaining steps are carried out with it, or the process is interrupted at any stage or the individual steps (a) to ( d). 12. A compound of formula (I) according to claim 1, wherein R_2 is a cinnamyloxycarbonylaminomethyl group, and R_1 and R_3 have the defined meanings. 13. Allyl (5R, 6
S, 1'R)-3-(1'-hydroxyethyl)-2-
Cinnamyloxycarbonylaminomethyl-penem-3
- Carboxylate. 14. A compound of formula (IV) according to claim 1, wherein R_2 is a cinnamyloxycarbonylaminomethyl group, and R_1 and Z have the defined meanings. 15, (3S, 4R, 1
'R)-3-(1'-hydroxyethyl)-4-(N-
Cinnamyloxycarbonylglycylthio)-2-azetidinone. 16. The compound of formula (VI) according to claim 1, wherein R_1, R_2, R^0_3 and Z have the prescribed meanings. 17, allyl (3S, 4
R, 1'R)-2-[4-(N-allyloxycarbonylglycylthio)-3-(1'-allyloxyoxalyloxyethyl)-2-oxo-1-azetidinyl]-
2-Oxoacetate. 18, allyl (3S, 4
R, 1'R)-2-[4-(N-cinnamyloxycarbonylglycylthio)-3-(1'-allyloxyoxalyloxyethyl)-2-oxo-1-azetidinyl]-oxoacetate. 19. The compound of formula (VIII) according to claim 1, wherein R_1, R_2 and R^0_3 have the prescribed meanings. 20, allyl (5R, 6
S, 1'R)-2-allyloxycarbonylaminomethyl-6-[1'-(allyloxyoxalyloxy)ethyl]-2-penem-3-carboxylate. 21, allyl (5R, 6
S, 1'R)-2-cinnamyloxycarbonylaminomethyl-6-[1'-(allyloxyoxalyloxy)ethyl]-2-penem-3-carboxylate.