CA1204746A - .beta. LACTAMS - Google Patents
.beta. LACTAMSInfo
- Publication number
- CA1204746A CA1204746A CA000433590A CA433590A CA1204746A CA 1204746 A CA1204746 A CA 1204746A CA 000433590 A CA000433590 A CA 000433590A CA 433590 A CA433590 A CA 433590A CA 1204746 A CA1204746 A CA 1204746A
- Authority
- CA
- Canada
- Prior art keywords
- group
- alkenyl
- corresponding optical
- lower alkyl
- formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
- C07D205/085—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams with a nitrogen atom directly attached in position 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Indole Compounds (AREA)
Abstract
Abstract There are described .beta.-lactams of the general formula I
in which R1 represents lower 2-alkenyl or 1-alkenyl or a group of the formula -CH2-CH(OR4)2 (a) -CH2-CHO (b) -CO-CH ( OH ) 2 (c) (d)
in which R1 represents lower 2-alkenyl or 1-alkenyl or a group of the formula -CH2-CH(OR4)2 (a) -CH2-CHO (b) -CO-CH ( OH ) 2 (c) (d)
Description
~20~q~
The present invention is concerned with optically uniform ~-lactams of the general formula R.~R6 ~N
~R1 in which Rl represents lower 2-alkenyl, lower l-alkenyl or a group of the formula ~CH2-CH(oP~4)2 (a), CH2 CHO (b)~
-CO-CH(OH~2 (c)t 2CH2 - S ~ (d)~
[]n -CH=CH-~9 (e) -CHO t~) ;"~, R4 represents lower alkyl, R9 represents a tertiary lower cycloaliphatic or aliphatic amino group, n represents the number 0 or 1, R2 represents amino, azido, phthalimid~, (lower alkyl)-0-C0-CH=C(CH3)-NH-or Z-NH-, Z represents a readily cleavable acyl group, R6 and R7 each represent a lower hydro-carbon group which optionally contains oxygen and is attached via a carbon atom, or R6 and R7 together with the centre of chirality represent a 5- or 6-membered 0-heterocycle.which optionally-contains a further ring oxygen atom not directly linked to the centre of chirality and whi~h is optionally substituted by lower alkyl, iower alkoxy, oxo or spirocyclo-lower alkyl, with the proviso that when R2 signifies amino Rl represents lower 2-alkenyl or l-alkenyl or one of the groups (a), (c) and (d), and the corre~ponding optical antipodes thereof.
The Bolactams of general ~ormula I are, owing to their particular protecting groups ~ituated o~ ~he Nl-atom, vaiuable intermediates for the especially ready manufacture of ~-lacta~s having antimicro~ial properties, especially of Ml-sulpho-aze~idinones of the general formula R-~NH ~ R3 II
N
~03H
wherein R represents an acyl group whic~
is known, for example, from penic~llin or cephalosporin chemistryi for example an acyl group of the general for~ula ,,~
,.
H2N~
8 -co_ N
bR5 wherein R5 represents hydrogen, lower alkyl or carboxy-l~w~r aIkyl a~d R3 represents a lower or~a~ic group (e.g. car~amoyl or carbamoyloxymethyl).
Intermedia~es of ~ormula I which contaln directly cleava~le protecting groups are ~hose of the general formula R70 3.~
R~R 6 I I Ia ~ \R1 0
The present invention is concerned with optically uniform ~-lactams of the general formula R.~R6 ~N
~R1 in which Rl represents lower 2-alkenyl, lower l-alkenyl or a group of the formula ~CH2-CH(oP~4)2 (a), CH2 CHO (b)~
-CO-CH(OH~2 (c)t 2CH2 - S ~ (d)~
[]n -CH=CH-~9 (e) -CHO t~) ;"~, R4 represents lower alkyl, R9 represents a tertiary lower cycloaliphatic or aliphatic amino group, n represents the number 0 or 1, R2 represents amino, azido, phthalimid~, (lower alkyl)-0-C0-CH=C(CH3)-NH-or Z-NH-, Z represents a readily cleavable acyl group, R6 and R7 each represent a lower hydro-carbon group which optionally contains oxygen and is attached via a carbon atom, or R6 and R7 together with the centre of chirality represent a 5- or 6-membered 0-heterocycle.which optionally-contains a further ring oxygen atom not directly linked to the centre of chirality and whi~h is optionally substituted by lower alkyl, iower alkoxy, oxo or spirocyclo-lower alkyl, with the proviso that when R2 signifies amino Rl represents lower 2-alkenyl or l-alkenyl or one of the groups (a), (c) and (d), and the corre~ponding optical antipodes thereof.
The Bolactams of general ~ormula I are, owing to their particular protecting groups ~ituated o~ ~he Nl-atom, vaiuable intermediates for the especially ready manufacture of ~-lacta~s having antimicro~ial properties, especially of Ml-sulpho-aze~idinones of the general formula R-~NH ~ R3 II
N
~03H
wherein R represents an acyl group whic~
is known, for example, from penic~llin or cephalosporin chemistryi for example an acyl group of the general for~ula ,,~
,.
H2N~
8 -co_ N
bR5 wherein R5 represents hydrogen, lower alkyl or carboxy-l~w~r aIkyl a~d R3 represents a lower or~a~ic group (e.g. car~amoyl or carbamoyloxymethyl).
Intermedia~es of ~ormula I which contaln directly cleava~le protecting groups are ~hose of the general formula R70 3.~
R~R 6 I I Ia ~ \R1 0
2~
in which R~, R~ and R7 have the above significance and R10 re~resents 1--alkenyl or group (c) above, and the corresponding optical antipodes thereof.
The remaining intermediates of formula I, i.e. those in which Rl has a significance other than R10, are pre-products which, as will be described in detail hereinafter, can be converted readily into the above compounds of formula la.
The term ~lower aLkenyl~ signifies an ol~finic hydrocar~on group which can be straig~t-chain or branc~ed--chain.and which prefera~ly contains up to 8, especially up to 4, car~on atoms such as, for example, vinyl, 2--propenyl (allyl), l-propenyl, isopropenyl, 2-methallyl, 1- or 2-butenyl, 1- or 2-hesenyl, 1- or 2-heptenyl, 1-or 2 octenyl etc. The term ~lower alkyl" signifies, alone or in combinations such as ~lower alXoxycarbonyl" or "lower alkylsulphonyl", a saturat~d hydrocarbon group which can be straisht-chain or ~ranched-chain and which preferably.
contains up to 8, especially up to 4, carbon atoms such as, for example, methyl, e~hyl, n-propyl, isopropyl, n--butyl, isobutyl, sec-bu~yl, t-butyl, n-pentyl, isopentyl, n-hexyl, n-heptyl, n-octyl etc. The term ~lower alkoxy"
has an analogous significance. The term ~lower cycloalkyl"
signifies an alicyclic saturated hydrocarbon containing
in which R~, R~ and R7 have the above significance and R10 re~resents 1--alkenyl or group (c) above, and the corresponding optical antipodes thereof.
The remaining intermediates of formula I, i.e. those in which Rl has a significance other than R10, are pre-products which, as will be described in detail hereinafter, can be converted readily into the above compounds of formula la.
The term ~lower aLkenyl~ signifies an ol~finic hydrocar~on group which can be straig~t-chain or branc~ed--chain.and which prefera~ly contains up to 8, especially up to 4, car~on atoms such as, for example, vinyl, 2--propenyl (allyl), l-propenyl, isopropenyl, 2-methallyl, 1- or 2-butenyl, 1- or 2-hesenyl, 1- or 2-heptenyl, 1-or 2 octenyl etc. The term ~lower alkyl" signifies, alone or in combinations such as ~lower alXoxycarbonyl" or "lower alkylsulphonyl", a saturat~d hydrocarbon group which can be straisht-chain or ~ranched-chain and which preferably.
contains up to 8, especially up to 4, carbon atoms such as, for example, methyl, e~hyl, n-propyl, isopropyl, n--butyl, isobutyl, sec-bu~yl, t-butyl, n-pentyl, isopentyl, n-hexyl, n-heptyl, n-octyl etc. The term ~lower alkoxy"
has an analogous significance. The term ~lower cycloalkyl"
signifies an alicyclic saturated hydrocarbon containing
3~8 carbon atoms (e.g. cyclopropyl, cyclobu~yl, cyclo-pentyl, cyclohexyl, cycloheptyl, cyclooctyl). The term "lower alkanoyl" signifies an aliphatic carboxylic acid group which preferably contains up to 8 carbon atoms (e.g.
acetoxy, propionyloxy, isobutyryloxy). The term "lower alkanethioyl" has an analogous significance (e.g. thio-acetyl~thiopropionyl, khioisobutyryl). m e term "halogen"
represents all four halogens, especially chlorine and 25 bromine.
The tertiary lower aliphatic or cycloaliphatic.amino group present in grouP (e) above is pre~erably a S- or 6--mem~ered ring which optionally contains an oxygPn or ~L2~L7'~;
sulphur atom and which can be optlonally substituted by lower alkyl or lower alkoxy (e.g. morpholino, pyrrolidlno, piperidino, 4-methylpiperidino); it can, however, also be, for example, a di~lower alkylamino group (e.gO diethyl-5 am:L AO ) The term "readily cleavable acyl group" signifiesgroups such as, for example, lower alkoxycarbonyl which is optionally halogen-substituted (e.g. t-butoxycarbonyl or trichloroethoxycarbonyl), as well as benzyloxycarbonyl.
Preferably R is lowex 2-alkenyl, lower l-alkenyl or one of the groups (a), (b), (c) and (d).
Preferably, R6 is lower alkyl, phenyl-lower alkyl, lower alkoxy-alkyl (e.g. lower alkoxymethyl) and R7 is lower alkyl or phenyl-lower alkyl, or R6 and R7 together 15 with the centre of chirality, represent a group of the formula or ~ H3 Most preferred groups denoted by R -R7 are:
Rl: vinyl, 2-propenyl (allyl), l-pxopenyl~ 2,2-di-methoxyethyl, 2,2-diethoxyethyl, formylmethyl, dihydroxy-acPtyl, 2 phenylthioethyl, 2-phenylsulphinylethyl, 2--morpholinovi~yl, formyl.
R2: amlno, phthalimido, benzyloxycarbonylamlno, t-3~2(~
-butox~carbonylamino, 2-methoxycarbonyl-1-methyl-vinyl-amino.
R6 and R7 together with the centre of chirality:
The group X [(R)~ di-methyl-1~3-~1 ' -dioxolan-4-Yll -The compounds of formula I are present in the optically uniform cis-form, i.e. as the compound of the formula R ~ 6 r 1 Ic N
wherein ~1, R2, R6 and ~7 have the above significance, or as the corresponding optical antipode thereof of the formula R2 ~ 6 ~ N Id ~.R1 wherein Rl, R2, R6 and R7 have the above ignificance.
. . ^, . .
acetoxy, propionyloxy, isobutyryloxy). The term "lower alkanethioyl" has an analogous significance (e.g. thio-acetyl~thiopropionyl, khioisobutyryl). m e term "halogen"
represents all four halogens, especially chlorine and 25 bromine.
The tertiary lower aliphatic or cycloaliphatic.amino group present in grouP (e) above is pre~erably a S- or 6--mem~ered ring which optionally contains an oxygPn or ~L2~L7'~;
sulphur atom and which can be optlonally substituted by lower alkyl or lower alkoxy (e.g. morpholino, pyrrolidlno, piperidino, 4-methylpiperidino); it can, however, also be, for example, a di~lower alkylamino group (e.gO diethyl-5 am:L AO ) The term "readily cleavable acyl group" signifiesgroups such as, for example, lower alkoxycarbonyl which is optionally halogen-substituted (e.g. t-butoxycarbonyl or trichloroethoxycarbonyl), as well as benzyloxycarbonyl.
Preferably R is lowex 2-alkenyl, lower l-alkenyl or one of the groups (a), (b), (c) and (d).
Preferably, R6 is lower alkyl, phenyl-lower alkyl, lower alkoxy-alkyl (e.g. lower alkoxymethyl) and R7 is lower alkyl or phenyl-lower alkyl, or R6 and R7 together 15 with the centre of chirality, represent a group of the formula or ~ H3 Most preferred groups denoted by R -R7 are:
Rl: vinyl, 2-propenyl (allyl), l-pxopenyl~ 2,2-di-methoxyethyl, 2,2-diethoxyethyl, formylmethyl, dihydroxy-acPtyl, 2 phenylthioethyl, 2-phenylsulphinylethyl, 2--morpholinovi~yl, formyl.
R2: amlno, phthalimido, benzyloxycarbonylamlno, t-3~2(~
-butox~carbonylamino, 2-methoxycarbonyl-1-methyl-vinyl-amino.
R6 and R7 together with the centre of chirality:
The group X [(R)~ di-methyl-1~3-~1 ' -dioxolan-4-Yll -The compounds of formula I are present in the optically uniform cis-form, i.e. as the compound of the formula R ~ 6 r 1 Ic N
wherein ~1, R2, R6 and ~7 have the above significance, or as the corresponding optical antipode thereof of the formula R2 ~ 6 ~ N Id ~.R1 wherein Rl, R2, R6 and R7 have the above ignificance.
. . ^, . .
4~
Tha ~lactams of formula I can be manufactured in accordance with the invention by reacting a reactive derivative of a carboxylic acid of ihe general formula in which R20 represents azido, phthalimido or the group ROC0-CH=C(CH3)-NH- and R represents lower alkyl, in the presence of a base with a compound of the general formula H~R6 N IV
Rl 1~
in which Rll represents lower 2-alkenyl or one of the groups (a) and (d) defined above and R6 and R7 are as defined above, or the corresponding optical antipode thereof, if desired in a thus-obtained compound of the general formula 7 20 R ~
~ Ie (~ ~Rl1 -i hi h Rll R20 R6 and R7 are as defined above, or the corresponding optical antipode thereof, converting a lower 2-alkenyl group present as R11 into the corresponding lower l-alkenyl group or into the group (e) or ~ ! 3 (f) or converting a group (a) present as Rll into the group ~b) or (c) or transforming a group (d) present as Rll into the vinyl or formyl group, if desired transforming the group R20 in a resulting compound of the general formula R 20 ,~ _HR 6 ~ If in which Rl, R2Q~ R6 and R7 are as defined above, or the corresponding optical antipode thereof, into the amino group, if desired reacting a thus-obtained compound of the general formula H2N ~ ~R6 Ig N~l in which Rl, R6 and R7 are as defined above, or the corresponding optical antipode thereof, ; with an agent yielding the group Z to give a compound of the general formula R 1 ~ H
N . Ih . \R1 _ in which Rl, R6 and R7 are as defined above , 7~;
and Z represents a readily cleavable acyl group, or the corresponding optical antipode thereof, and, if desired, in a resulting compou~d of the general formula Z ~H~R6 ~1 N Ih in which Rll, R6, R7 and Z are as defined above, or the-eorrespond~ng optical .antipode thereof,.
converting a lower 2-alkenyl group present as Rll into the corresponding l-alkenyl group or into the group (e) or (f) or converting a group (a) present as Rll into the group (b) or (c) or transforming a group (d) pre.sent as Rll into the vinyl or formyl group.
The ~eaction of a re~ct$~e deriYative of a carboxylic ac~d of formuL2 III with a compound of formula IV or the optical a~tlpode ~hereof is a cycloadaition which is familiar to a person killed in the art. Suitable reactive carboxylic acid derlvatives are, for example, the cor-responding carbox~lic ~cid halides, especially the car-boxylic acid ~hlorides, the corre~ponding car~o~ylic acid anhydrides and mixed anhydrides (e.g. with trifluoroacetic acid, mesltylenesulphonic acid and the like), the cor~
~ responding carboxylic acid imidazolides and the like.
; The reaction is conveniently carried out in the presence of a base, for example a tertiary amine such as triethylamine, and in an inert organic solvent, especially an ether such as tetrahydrofuran, diethyl ether, t-butyl methyl e~her, dioxan, ethylene glycol dimethyl ether or the liXe, a ~L2~
halogenated hydrocar~on suoh as methylene chloride, chloroform, 1,2-dlchloroethane or the like, acetonitrile, dimethylformamlde or the like. This cycloaddition is carried out in a temperature range of about -30C to about In the aforementioned reaction there is obtained a compound in the optically uniform cis-form, i.e. a compound of the general formula ~ or R70 \R11 (~R1 1 Iel Ie2 ; wherein Rll, R20, R6 and R7 have the above slgnificance.
Th compounds of formula IV or ~heir optical anti-podes used as starting materials can be prepared by reacting an aldehyde of the general formula P~7~ b 3~
o~
wherein R6 and R7 have the above significance or the optical antipode thereof with an amine of the general formula wherein R11 has the above significance.
. " .
- ~Z~4~4~
This reaction ls pre~2rably carried out in an inert organic -~olvent, for example in a halogenated hydrocarbon such as methylene chloride, chloroorm, 1,2-dichloroethane and the like or ln a hydrocarbon such as benzene, toluene and the like. The water formed during the ~eaction is preferably removed conti~uously, for example by azeotrspic distil- -lation or by wor~ing in the presence of a water-removin~
agent (e.g. in the presence of a suitable molecular sieve~
ox in the presence of a conven~ional drying agent such as po-tassium car~onate, magnesium sulphate and the like. When-the water formed is removed azeotxopically ~he reaction is carriPd out at the boiling point of the chosen solvent and when a water-~emoving agent is used the reaction is preferably carried out at room temperature.
The N-protecting groups Rll present in the resulting compound of formula Ie are not cleavable per se, but can be converted as follows into cleavable protecti~g groups R10 (see ~ormula Ia above):
I. Rll: lower 2-alkenyl R10: lower l-alken~l, e-s- C~2 C~=CH2---C~=C~-CX
~'Z~4~i Thi.~ i30merizatlon ls advantageously carried out using an lsomeri~ation catalyst, for example a palladium dihalide such as palladium di~hlorlde, a tris-(triphenylphosphine)--rhodium (I) halide such as the corresponding chloride or palladium-carbon and a proto~ic acid su~h as hydroGhloric acld or pho phoric acid. The lsomerization is ad~ant ge-ously carried out in an inert organic solvent such asethanol, me~hylene chloride or mixtures thereo~ with water and a~ a temperature between ahout 50C and the boiling point of ~he reaction mixture.
II. R~ CH2-CH~CH2 _ Rl: group (b) --C~2-C~O
Rl: group (e) -~R10: group (~) ~ C~=CH-~9 ~ C~0 The above transformation of the allyl group Rll into the group (b) and ~he reaction (e) ~ ) is preferably carried out by ozonolysis, i.e. by treatment with ozone gas in an inert organic solvent, for example in a lower alkanol such as methanol or in a chlorinated hydrocarbon such , .
47~
as methylene chloride or chloroform, and at a temperature between about -80C and 0C. The ozonide foxmed ls de-composed in ~he usual manner, for example by treatment with dimethylsulphlde or triphenylphosphine (without cooling).
The conversion (b~- ~(e) is carri~d out by reaction with a secondary lower aliphatic or cycloaliphatic amine, for example with morpholins, pyrrolidine, piperidine, 4--methylpiperidlne, diethylamine, especially wi~h morpholine.
This reaction is preferably effected in an lnert organic solvent such as methylene chloride or-chloroform and at a temperature between about 0C and the boiling point of the reactian mixture, pre~erably at room temperature.
III. R : group (a) _ Rl: group (b)~ R10: group (c) -cH2-c$(oR4)2~--p-c~2-cHo ~ -CO-C~(OH)2.
The transormation (a) _ (b) is preferably carried out using a tri-lower alkyliodosila~e, especially trimethyl-iodosilane, or p-toluenesulphonic acid. The reaction is preferably carried out in an lnert organic solvent such as acetonitrile and at a temperature between about 0C and SOC .
The oxidation (b)~--~(c) is preferably carried out using selenium dioxide under acidic conditions (e.g. in the presence of acetic acid). The reaction is preerably 7~
carried out in an inert organic solvent such as dioxan and at a temperature between room temperature and the boiling polnt of the reaction mlx~ure.
I~. R : group (d) - R10: vinyl _ R10: group (f) -C~12~12-S~ ~ -C~2C~I2-~ CH=C~I2_ -C~O.
10, The first step, the oxidation of the phenylthio-e~hyl yroup to phenylsulphinylethyl, is carried out by treatment ulth an organic or inorganic oxidizing agent.
As oxidl2ing agents there can be used various compou~ds which readily yield oxygen such as, for example, orga~ic peroxides, for example monosubstituted organic peroxides such as Cl-C4 alkyl or alkanoyl hydroperoxides such as t--butyl hydroperoxide, per~ormic acid, peracetic acid; as well as phenyl-su~stituted derivatives of these hydro-20 peroxides such as cumene hydroperoxide, perbe~2ei c acid .If deslr~d, the phenyl substituent can carry a further lower group (e.g. Cl-C4 aIkyl or alkoxy) or a halogen atom or a carboxy group (e.g. 4-methylperbenzoic acid, 4--methoxyper~en~oic acid, 3-chloroperbenzoic acid, mono-perphthalic acid)O As the oxidation agent there can alsobe used various in~rgan~coxidizing agents, for example, hydrogen peroxide; ozone; permanganates such as potassium or sodium permanganate; hypochlorites such as sodium, potassium or ammonium hypochlorite; peroxymonosulphuric acid and peroxydisulphuric acid. The use of 3-chloro-perbenzoic acid is preerred. The oxidation ls advanta-geously carried out ln an inert solvent, for example, in an aprotic inert solve~t such as tetrahydrofuran, d~oxan, methylene chloride, chloroform, e~hyl acetate or acetone;
or in a protic solv~nt such as water, a lower alkanol (e.g.
methanol, ethanol) or a lower alkanecarboxylic acid which i~ optionally halogenated (e.g. for~ic acid, acetic acid, trifluoroacatic acid). The reac~ion temperature ranges particul~rly at about -2~C to +7~c.
The degradatlon of the phenylsulphinylethyl group to the ~inyl group is carried ~ut by heating to about 100-200C, 15 pre~erably i~ an aprotic organic solvent such as hexa-methylenephosphoric acid triamide, dimethyl sulphoxide, dimethylformamlde, benzene or toluene. The reaction can be accelerated by the addition of an acceptor for the phenylsulphonic acid formed in the reaction, especlally suitable acceptors being trimethyl phosphite or propiolic acid esters such as,e.g. methyl ~ropiolate.
The degradation o~ the vinyl group to ~he ~ormyl group (which is optional, since the vinyl group is cleavable per se~ is carried out in the same manner as described abo~e in 5ection II or the con~ersio~ (e)~ (f).
The compounds of formula Ig can be obtained in 7~6 -accordance with the invention by transforming the group R20 in a compound of ~ormula If obtained into the amino group. This reaction is carrieA out according to methods which are known per se and which are famlliar to any person ~Xilled i~ the art, the method to be used depending on the nature of the group R . The phthalimido group can be removed, for example, by reaction with hydrazine, methyl-hydrazine ox the like, conve~ently in an lnert organic solvent. Suitable solvents are, for example, haiogenated hydrocarbons such as methylene chloride, chloroform and the like, ethers such as tetrahydrofuran, dioxan, t-butyl methyl ether and the like, etc~ The azido group ~an be reduced to the amino group, for example, using elemental hydrogen in the presence o~ a catalyst such as palladium--carbon, Raney-nickel, pla~inum oxide and th~ like, or by the action ~f hydrog~n sulphlde and a tertiary amine such as triethylamlna. The group ROCO-C~=C(C~3~-NX- can be conv~rted into the amino group, for examp1e, by mild acid hydrolysis.
By treating a compound of formula Ig with a~ agent yielding the group Z there is obtained in accordance with the invention a compound of formula Ih. Suitable agents yielding the group Z are, for example, di-t-butyl dicar-bonate or chloroformic acid esters such as benzyl chloro-formate, t-butyl chloroformate, 2,2,2-trichloroethyl chloro-formate and the like. The reaction is conveniently carried ~2'~
out in an inert organic solvent, for example in a halogen-ated hydrocar~on such as me~hylene chloride, chloroform and ~he like, and conveniently in the presence of an acid-S -binding agent such as butylene oxide, triethylamlne, quinuclidine etc. me reaction i~ conveni2ntly carried out at room temperature.
Some of the compounds of ~ormula Ih obtained con~ai~
non-cleavable groups Rl (groups Rl1; formula Ihl). These groups Rll can be conver~ed into cleavable groups Rl (groups R10) in the manner described above (see sections I-IV).
The group R1~H b in compounds of formulae Ib, Ie, If and Ih obtained can be converted into lower organic groups R3 as exemplified in Schemes I-III herein-after. For example, the hydrocarbon group R8 in an obtained compound of the general formula O ~ O
Ik I~
~\R1 in which R21 has the same meaning as R2 but is not amino, R8 represents a hydrocarbon group (e.g. methylene, ,~
` 3L2~7 ~
ethylene, oxomethylene, oyclo-hexylidene or, preferably iso-propylidene) and Rl has the above ; 5 ~ignificance, or the optical antipode thereof can be cleaved, for example ky treatment with a mlld acidic agent such as, for example, with a sulphonated ion exchanger, pyridinium p toluene-sulphonat~ or p-toluenesulphonic acid, in a l~wer alkanol such as methanol or ethanol or in aqueou~ tetrahydrofuran, preferably at room temperature to about 80C. There is obtained a~ optically active diol of the general ~ormula HQ H OH
~ Im ~\R1 in which Rl and R21 have the above sig~
nificance, or the optical antipode thereof.
The diol grouping i~ the thus-obtained compound of fo.rmula Im or in the optical an~ipode thereof ls cleaved, ~hera being obtained an aldehyde of the general ~ormula ~2~ 6 .
In ~ N
in which Rl and R21 have the above significance, or the optical antipode thereo~. This cle~vage is carried : out according to ~ethods kn~wn per se and can be accom plished, for example, with an alkali metal periodate such as sodium metaperiodate in water, optionally in admixture ~ith, for example, tetrahydrofuran or a lower alkanol such s methanol, me aldehyde groups of the aldehyde or formula In or o ~he optical antipode thereof can be reduced accoxding to known methods, for example by treatment with a complex metal hydride such as sodium borohydride in a lower aIka~ol such as ethanol, lsopropanol or the like. There is obtai~ed an alcohol o~ the g~neral formula R ~ CH2OH
. ~ Io : ~ - N
in which Rl and ~21 have the above signi~icance, or the optical antipode thereof.
Benzyloxy groups present such as, for example, in lZ~746 .
- 20 _ compounds of the gene~al formula ~H2 CH3 Ip N
~1 wherein Rl ~nd R21 have the above significance, or i~ the optical antipode thereof can be cleaved hydrogeno-lytlcally and the resulting corresponding car~inol of the general formula HO H
R21 ~C
~ \R1 Iq in which ~1 and R~l ha~e the above significance, o~ ~he optical antipode thereof can be reacted further, - for example in analogy to compound Iol in Scheme I herein-after.
The substituent in the 4-position can be functionally transformed further; for example, the aforementioned 4--formyl group or 4-hydroxymethyl group can be transformed in - 21 _ a manner known per se to a person skilled in the art (see the following Schemes I-III).
S In order ~o synthesize the desired antimicrobially--active ~ lactams (e.g. the ~-lact~ms of formula II above), ~he N-protecting group R10 present in an obtained compound of the general formula Ir N
~ )\R10 ~n which Rl R21 and R3 have the above significance, is cleaved o~f. Lower l-alkenyl groups (e.g. l-prop~nyl or vinyl) are cleaved off oxidativ~ly, e~pecially by trea~ment wi~h an alkali metal pexmanganate such as potassium permanganate, preferably an aqueous solution of potassium permanganate. If desired, the oxida~ion can be carried out using an alkali metal periodate (e.g. potassium periodate) in the presence of a catalytic amount o the aforementioned alkali metal permanganake. The reaction is pre~erably carried out in an aqueous buffered medium, especially buffered to pH 7-8, but it can also be carried out in a water-miscible orgaric solvent (e.g. acetone, dimethoxy-ethane, dioxan or tetrahydrofura~) with the additior. of a weak organic base such as pyridine or in a mixture of one ~;
~Z~4~46 of these solvents with the a~oxementioned aqueous buffer.
If desired, the reaction can also be carried out under phase-transfer catalysls, i.e. in the presence of an a~u~ous or non-a~ueous phase, fox example the above aqueous buf~r as well as a water-immiscible inert organic solvent such as, for example, methylene chloride or benzene. As phase~transfer ~atalysts there can be used the agents which are usually used ~or this purpose, especially organic quater~ary ammcnium halides such as benzyltriethylam~onium chloride, tetra-n-butylammonium bromide and cetyltrimethyl-~mmonium bromide. The oxidativa cleavage o~ 1-alk~nyl groups ~s preferably carried out at a temperature in the range of about 0C and 25C.
The hydroxyacetyl group [R as group (c)] and the for~yl group [R as group tf)] are pre-ferably cleaved off with an aqlleous strong base (e.g. with aque~us ammonia or a~ueous caustiG alXali) in an iner~
organic solvent (e.g. a halogenated hydrocar~on such as chloroform, carbon tetrachloride or me~hylene chloride) at a temperature between about 0C and +50C. The formyl group ca~, however, also be cleaved of by the action of a palladium- or rhodium-organic complex compound, for example tris-(triphenylphosphine)-chlororhodium.
After removal o~ the above protecting group R10, the group -S03H can be introduced in the l-position by reaction with a reactive derivative of sulphur trioxide, for example, , ....
,''-' ~2~7~6 ..
by reaction with complexes of sulphur trioxide and a base such as pyridine, tx~methylamine, picoline, dimethyl-formamide etc at abou~ 0-80C in an inert organic solvent (e.g. an ether such as dloxan, pyridine, dimethylormamide etc). Th~ amino group R2 in ~h~ 3-position can be liberated before or after the latter reaction by transform~tion of the group R~0 (in th above manner) or by clea~age o~ the pro~ec~ing group Z; ~or example, aralkoxycarbonyl groups (especially benzyloxycar~onyl) or the benzhydryl group can be cleaved off hydrogenolytieally (e.g. by the action of hydrogen and palladium-car~on), the t-butoxycarbonyl group can be cleaved off by treatm~snt wlth trifluoroace~iG acid or formlc acid, and the trichloroetho~ycarbonyl grollp can be cleaved o~f by treatment with zinc and a p~otonic acid such as acetic acid or hydrochloric acid. The liberated amino group R~ can su~sequently be acylated with a corres-pondingly substituted carboxylic acid or a reactive functional derivative thereo~, for example an acld a~hydrid~, acid amide, active ester (e.g. a thioester such as the benthia-zolyl thioester, by which means the widest vari~y of acyl groups such as those which are known, for example, from penicillin or cephalosphorin Ghemistry can be introduced.
For example, in this manner there can be manufactured according to methods known per se optically uniform anti-microbially active ~-lactams of the general formula ,1 ~Z(;~4~74~
.
H2N~' \
N ~ C - CONH R3 N ~ IIa ~R5 ~ N
03H.
wherein R5 represents hydrogen, lower 10alkyl or carboxy-l~wer alkyl and R3 represents a lowex o~ganic group (e.g.
carbamoyl or carbamoyloxy methyl), or the corre~pondlng optical antipodes thereo~.
Examples of corresponding conversio~s into end products are illustrated i~ Schemes I-III hereina~ter.
2~
c .
474~
C o . ' (~ )o~ _ _ --Z / ~z / '~ I
Z",~ ~Z/ ~Z/
~1 ol ~ O ~ I ~0:
=Z
p; o \ ~z \~z ~D
~Z 0~ / /
Z ~
z~ ! ¦~
~ ~ 3 ~Z~
u~
o I
,~ '` /~1 /~1 Z
~o :~ ~
~ O ~ ~ ~ ~ ~
~Z/ ~ ~
~;
~, ., 7a~
Z O o O
O ~. O
_ ~=2 j ~ ~ a ~ .
~4~4~i ;
Abbrevia~ions used in Schemes I, II and III
DMF - dimatLlylformamide Py = pyridine Py.S03 3 sulphur trioxide-pyridinium complex COX - reactive derivative of a carboxylic acid (e.g. acid anhydride, acid amide, active ester such as benzthiazolyl ester) R5~) = hydrogen, low~r alkyl (e.g. methyl), protected ca~bsxy-lower alkyl (e.g. pro-tected carboxy-me~hyl, protected l-methyl--l-ca~oxy-e~hyl). Prote~tng group: e.g.
t-butyl (cleavable with, for example, tri-~luoroacetic acid), benzyl and p-nitro-benzyl (cleavable with,. for example, hydrogen and palladium carbon), 2- (trimethylsilyl) --ethyl (cleavable wit~, for example, tetra-butyla~monium fluoride).
20 ~ - hydrogen, lower alkyl (e.g. methyl), car-boxy lower alkyl (e . g . carboxymethyl ,1--methyl- l-carboxy-ethyl ) .
R10 R21 = above significance.
Reactions which are not e~plained more precisely in Schemes I, II and III are carried out in the manner des-cribed in detail above.
~`
.,,, ~
, ",~,,~8 The foll~wlng Examples illustrate the present in-ventlon. All temperatures are glven in degrees Centigrade.
Ar - aromatic.
~xamol- 1 - To a Rolution, stirred at room temperature, o~ 18.6 ml (0.25 mol) of allylamlne ln 500 ml of methylene c~loride are added 50 g o~ molecular siev~ 4~ and, after 20 minutes, 32.5 g (0.25 mol) of isopropylidene-L-glyceraldehyde and lOO`g o~ magnesium sulphate. ~he mixture is su~sequently stirred at room tempexature or a further 1 hour. The organic ~olution of isopropylidene-L-glyceraldehyde allyl-lmln~ i5 cooled to -30 under argon and treated while stirring with 31.3 ml (0.25 mol) of triet~ylamine. A
solution of 45.25 g (0.25 mol) of phthaloylglycyl chloride in 200 ml of dry methylene chlortde is then added dropwise within 2 houxs and the mixture is subsequently stirred at room temperature for a further 12 hours. The mixture is washed three times with in each c~se 700 ml of water and 700 ml of sodium chloride solution, dried over magnesium sul-phate, filtered and evaporated. The residu~ is chromato-graphed on silica gel with cyclohexane/ethyl acetate (6:4).
There are obtained 50 g of N-[cis-(3S,4$)olallyl-4-[ (R)-. .
, . . ,~, ., ` I ~2~9~74~
- 3~ --2,2-dimethyl~1,3-dioxolan-4-yl)-2-o~o-3-aæetidinyl]--phthalimide as an oil; ~]20 ~ +115 (0.13 in chlorofo~m).
NMR tCDC13) ~ (ppm): 1.28 (3H, s), 1,41 ~3H, s), 3.36-4.5 (6~), 5.87 (1~, d, 5~z),
Tha ~lactams of formula I can be manufactured in accordance with the invention by reacting a reactive derivative of a carboxylic acid of ihe general formula in which R20 represents azido, phthalimido or the group ROC0-CH=C(CH3)-NH- and R represents lower alkyl, in the presence of a base with a compound of the general formula H~R6 N IV
Rl 1~
in which Rll represents lower 2-alkenyl or one of the groups (a) and (d) defined above and R6 and R7 are as defined above, or the corresponding optical antipode thereof, if desired in a thus-obtained compound of the general formula 7 20 R ~
~ Ie (~ ~Rl1 -i hi h Rll R20 R6 and R7 are as defined above, or the corresponding optical antipode thereof, converting a lower 2-alkenyl group present as R11 into the corresponding lower l-alkenyl group or into the group (e) or ~ ! 3 (f) or converting a group (a) present as Rll into the group ~b) or (c) or transforming a group (d) present as Rll into the vinyl or formyl group, if desired transforming the group R20 in a resulting compound of the general formula R 20 ,~ _HR 6 ~ If in which Rl, R2Q~ R6 and R7 are as defined above, or the corresponding optical antipode thereof, into the amino group, if desired reacting a thus-obtained compound of the general formula H2N ~ ~R6 Ig N~l in which Rl, R6 and R7 are as defined above, or the corresponding optical antipode thereof, ; with an agent yielding the group Z to give a compound of the general formula R 1 ~ H
N . Ih . \R1 _ in which Rl, R6 and R7 are as defined above , 7~;
and Z represents a readily cleavable acyl group, or the corresponding optical antipode thereof, and, if desired, in a resulting compou~d of the general formula Z ~H~R6 ~1 N Ih in which Rll, R6, R7 and Z are as defined above, or the-eorrespond~ng optical .antipode thereof,.
converting a lower 2-alkenyl group present as Rll into the corresponding l-alkenyl group or into the group (e) or (f) or converting a group (a) present as Rll into the group (b) or (c) or transforming a group (d) pre.sent as Rll into the vinyl or formyl group.
The ~eaction of a re~ct$~e deriYative of a carboxylic ac~d of formuL2 III with a compound of formula IV or the optical a~tlpode ~hereof is a cycloadaition which is familiar to a person killed in the art. Suitable reactive carboxylic acid derlvatives are, for example, the cor-responding carbox~lic ~cid halides, especially the car-boxylic acid ~hlorides, the corre~ponding car~o~ylic acid anhydrides and mixed anhydrides (e.g. with trifluoroacetic acid, mesltylenesulphonic acid and the like), the cor~
~ responding carboxylic acid imidazolides and the like.
; The reaction is conveniently carried out in the presence of a base, for example a tertiary amine such as triethylamine, and in an inert organic solvent, especially an ether such as tetrahydrofuran, diethyl ether, t-butyl methyl e~her, dioxan, ethylene glycol dimethyl ether or the liXe, a ~L2~
halogenated hydrocar~on suoh as methylene chloride, chloroform, 1,2-dlchloroethane or the like, acetonitrile, dimethylformamlde or the like. This cycloaddition is carried out in a temperature range of about -30C to about In the aforementioned reaction there is obtained a compound in the optically uniform cis-form, i.e. a compound of the general formula ~ or R70 \R11 (~R1 1 Iel Ie2 ; wherein Rll, R20, R6 and R7 have the above slgnificance.
Th compounds of formula IV or ~heir optical anti-podes used as starting materials can be prepared by reacting an aldehyde of the general formula P~7~ b 3~
o~
wherein R6 and R7 have the above significance or the optical antipode thereof with an amine of the general formula wherein R11 has the above significance.
. " .
- ~Z~4~4~
This reaction ls pre~2rably carried out in an inert organic -~olvent, for example in a halogenated hydrocarbon such as methylene chloride, chloroorm, 1,2-dichloroethane and the like or ln a hydrocarbon such as benzene, toluene and the like. The water formed during the ~eaction is preferably removed conti~uously, for example by azeotrspic distil- -lation or by wor~ing in the presence of a water-removin~
agent (e.g. in the presence of a suitable molecular sieve~
ox in the presence of a conven~ional drying agent such as po-tassium car~onate, magnesium sulphate and the like. When-the water formed is removed azeotxopically ~he reaction is carriPd out at the boiling point of the chosen solvent and when a water-~emoving agent is used the reaction is preferably carried out at room temperature.
The N-protecting groups Rll present in the resulting compound of formula Ie are not cleavable per se, but can be converted as follows into cleavable protecti~g groups R10 (see ~ormula Ia above):
I. Rll: lower 2-alkenyl R10: lower l-alken~l, e-s- C~2 C~=CH2---C~=C~-CX
~'Z~4~i Thi.~ i30merizatlon ls advantageously carried out using an lsomeri~ation catalyst, for example a palladium dihalide such as palladium di~hlorlde, a tris-(triphenylphosphine)--rhodium (I) halide such as the corresponding chloride or palladium-carbon and a proto~ic acid su~h as hydroGhloric acld or pho phoric acid. The lsomerization is ad~ant ge-ously carried out in an inert organic solvent such asethanol, me~hylene chloride or mixtures thereo~ with water and a~ a temperature between ahout 50C and the boiling point of ~he reaction mixture.
II. R~ CH2-CH~CH2 _ Rl: group (b) --C~2-C~O
Rl: group (e) -~R10: group (~) ~ C~=CH-~9 ~ C~0 The above transformation of the allyl group Rll into the group (b) and ~he reaction (e) ~ ) is preferably carried out by ozonolysis, i.e. by treatment with ozone gas in an inert organic solvent, for example in a lower alkanol such as methanol or in a chlorinated hydrocarbon such , .
47~
as methylene chloride or chloroform, and at a temperature between about -80C and 0C. The ozonide foxmed ls de-composed in ~he usual manner, for example by treatment with dimethylsulphlde or triphenylphosphine (without cooling).
The conversion (b~- ~(e) is carri~d out by reaction with a secondary lower aliphatic or cycloaliphatic amine, for example with morpholins, pyrrolidine, piperidine, 4--methylpiperidlne, diethylamine, especially wi~h morpholine.
This reaction is preferably effected in an lnert organic solvent such as methylene chloride or-chloroform and at a temperature between about 0C and the boiling point of the reactian mixture, pre~erably at room temperature.
III. R : group (a) _ Rl: group (b)~ R10: group (c) -cH2-c$(oR4)2~--p-c~2-cHo ~ -CO-C~(OH)2.
The transormation (a) _ (b) is preferably carried out using a tri-lower alkyliodosila~e, especially trimethyl-iodosilane, or p-toluenesulphonic acid. The reaction is preferably carried out in an lnert organic solvent such as acetonitrile and at a temperature between about 0C and SOC .
The oxidation (b)~--~(c) is preferably carried out using selenium dioxide under acidic conditions (e.g. in the presence of acetic acid). The reaction is preerably 7~
carried out in an inert organic solvent such as dioxan and at a temperature between room temperature and the boiling polnt of the reaction mlx~ure.
I~. R : group (d) - R10: vinyl _ R10: group (f) -C~12~12-S~ ~ -C~2C~I2-~ CH=C~I2_ -C~O.
10, The first step, the oxidation of the phenylthio-e~hyl yroup to phenylsulphinylethyl, is carried out by treatment ulth an organic or inorganic oxidizing agent.
As oxidl2ing agents there can be used various compou~ds which readily yield oxygen such as, for example, orga~ic peroxides, for example monosubstituted organic peroxides such as Cl-C4 alkyl or alkanoyl hydroperoxides such as t--butyl hydroperoxide, per~ormic acid, peracetic acid; as well as phenyl-su~stituted derivatives of these hydro-20 peroxides such as cumene hydroperoxide, perbe~2ei c acid .If deslr~d, the phenyl substituent can carry a further lower group (e.g. Cl-C4 aIkyl or alkoxy) or a halogen atom or a carboxy group (e.g. 4-methylperbenzoic acid, 4--methoxyper~en~oic acid, 3-chloroperbenzoic acid, mono-perphthalic acid)O As the oxidation agent there can alsobe used various in~rgan~coxidizing agents, for example, hydrogen peroxide; ozone; permanganates such as potassium or sodium permanganate; hypochlorites such as sodium, potassium or ammonium hypochlorite; peroxymonosulphuric acid and peroxydisulphuric acid. The use of 3-chloro-perbenzoic acid is preerred. The oxidation ls advanta-geously carried out ln an inert solvent, for example, in an aprotic inert solve~t such as tetrahydrofuran, d~oxan, methylene chloride, chloroform, e~hyl acetate or acetone;
or in a protic solv~nt such as water, a lower alkanol (e.g.
methanol, ethanol) or a lower alkanecarboxylic acid which i~ optionally halogenated (e.g. for~ic acid, acetic acid, trifluoroacatic acid). The reac~ion temperature ranges particul~rly at about -2~C to +7~c.
The degradatlon of the phenylsulphinylethyl group to the ~inyl group is carried ~ut by heating to about 100-200C, 15 pre~erably i~ an aprotic organic solvent such as hexa-methylenephosphoric acid triamide, dimethyl sulphoxide, dimethylformamlde, benzene or toluene. The reaction can be accelerated by the addition of an acceptor for the phenylsulphonic acid formed in the reaction, especlally suitable acceptors being trimethyl phosphite or propiolic acid esters such as,e.g. methyl ~ropiolate.
The degradation o~ the vinyl group to ~he ~ormyl group (which is optional, since the vinyl group is cleavable per se~ is carried out in the same manner as described abo~e in 5ection II or the con~ersio~ (e)~ (f).
The compounds of formula Ig can be obtained in 7~6 -accordance with the invention by transforming the group R20 in a compound of ~ormula If obtained into the amino group. This reaction is carrieA out according to methods which are known per se and which are famlliar to any person ~Xilled i~ the art, the method to be used depending on the nature of the group R . The phthalimido group can be removed, for example, by reaction with hydrazine, methyl-hydrazine ox the like, conve~ently in an lnert organic solvent. Suitable solvents are, for example, haiogenated hydrocarbons such as methylene chloride, chloroform and the like, ethers such as tetrahydrofuran, dioxan, t-butyl methyl ether and the like, etc~ The azido group ~an be reduced to the amino group, for example, using elemental hydrogen in the presence o~ a catalyst such as palladium--carbon, Raney-nickel, pla~inum oxide and th~ like, or by the action ~f hydrog~n sulphlde and a tertiary amine such as triethylamlna. The group ROCO-C~=C(C~3~-NX- can be conv~rted into the amino group, for examp1e, by mild acid hydrolysis.
By treating a compound of formula Ig with a~ agent yielding the group Z there is obtained in accordance with the invention a compound of formula Ih. Suitable agents yielding the group Z are, for example, di-t-butyl dicar-bonate or chloroformic acid esters such as benzyl chloro-formate, t-butyl chloroformate, 2,2,2-trichloroethyl chloro-formate and the like. The reaction is conveniently carried ~2'~
out in an inert organic solvent, for example in a halogen-ated hydrocar~on such as me~hylene chloride, chloroform and ~he like, and conveniently in the presence of an acid-S -binding agent such as butylene oxide, triethylamlne, quinuclidine etc. me reaction i~ conveni2ntly carried out at room temperature.
Some of the compounds of ~ormula Ih obtained con~ai~
non-cleavable groups Rl (groups Rl1; formula Ihl). These groups Rll can be conver~ed into cleavable groups Rl (groups R10) in the manner described above (see sections I-IV).
The group R1~H b in compounds of formulae Ib, Ie, If and Ih obtained can be converted into lower organic groups R3 as exemplified in Schemes I-III herein-after. For example, the hydrocarbon group R8 in an obtained compound of the general formula O ~ O
Ik I~
~\R1 in which R21 has the same meaning as R2 but is not amino, R8 represents a hydrocarbon group (e.g. methylene, ,~
` 3L2~7 ~
ethylene, oxomethylene, oyclo-hexylidene or, preferably iso-propylidene) and Rl has the above ; 5 ~ignificance, or the optical antipode thereof can be cleaved, for example ky treatment with a mlld acidic agent such as, for example, with a sulphonated ion exchanger, pyridinium p toluene-sulphonat~ or p-toluenesulphonic acid, in a l~wer alkanol such as methanol or ethanol or in aqueou~ tetrahydrofuran, preferably at room temperature to about 80C. There is obtained a~ optically active diol of the general ~ormula HQ H OH
~ Im ~\R1 in which Rl and R21 have the above sig~
nificance, or the optical antipode thereof.
The diol grouping i~ the thus-obtained compound of fo.rmula Im or in the optical an~ipode thereof ls cleaved, ~hera being obtained an aldehyde of the general ~ormula ~2~ 6 .
In ~ N
in which Rl and R21 have the above significance, or the optical antipode thereo~. This cle~vage is carried : out according to ~ethods kn~wn per se and can be accom plished, for example, with an alkali metal periodate such as sodium metaperiodate in water, optionally in admixture ~ith, for example, tetrahydrofuran or a lower alkanol such s methanol, me aldehyde groups of the aldehyde or formula In or o ~he optical antipode thereof can be reduced accoxding to known methods, for example by treatment with a complex metal hydride such as sodium borohydride in a lower aIka~ol such as ethanol, lsopropanol or the like. There is obtai~ed an alcohol o~ the g~neral formula R ~ CH2OH
. ~ Io : ~ - N
in which Rl and ~21 have the above signi~icance, or the optical antipode thereof.
Benzyloxy groups present such as, for example, in lZ~746 .
- 20 _ compounds of the gene~al formula ~H2 CH3 Ip N
~1 wherein Rl ~nd R21 have the above significance, or i~ the optical antipode thereof can be cleaved hydrogeno-lytlcally and the resulting corresponding car~inol of the general formula HO H
R21 ~C
~ \R1 Iq in which ~1 and R~l ha~e the above significance, o~ ~he optical antipode thereof can be reacted further, - for example in analogy to compound Iol in Scheme I herein-after.
The substituent in the 4-position can be functionally transformed further; for example, the aforementioned 4--formyl group or 4-hydroxymethyl group can be transformed in - 21 _ a manner known per se to a person skilled in the art (see the following Schemes I-III).
S In order ~o synthesize the desired antimicrobially--active ~ lactams (e.g. the ~-lact~ms of formula II above), ~he N-protecting group R10 present in an obtained compound of the general formula Ir N
~ )\R10 ~n which Rl R21 and R3 have the above significance, is cleaved o~f. Lower l-alkenyl groups (e.g. l-prop~nyl or vinyl) are cleaved off oxidativ~ly, e~pecially by trea~ment wi~h an alkali metal pexmanganate such as potassium permanganate, preferably an aqueous solution of potassium permanganate. If desired, the oxida~ion can be carried out using an alkali metal periodate (e.g. potassium periodate) in the presence of a catalytic amount o the aforementioned alkali metal permanganake. The reaction is pre~erably carried out in an aqueous buffered medium, especially buffered to pH 7-8, but it can also be carried out in a water-miscible orgaric solvent (e.g. acetone, dimethoxy-ethane, dioxan or tetrahydrofura~) with the additior. of a weak organic base such as pyridine or in a mixture of one ~;
~Z~4~46 of these solvents with the a~oxementioned aqueous buffer.
If desired, the reaction can also be carried out under phase-transfer catalysls, i.e. in the presence of an a~u~ous or non-a~ueous phase, fox example the above aqueous buf~r as well as a water-immiscible inert organic solvent such as, for example, methylene chloride or benzene. As phase~transfer ~atalysts there can be used the agents which are usually used ~or this purpose, especially organic quater~ary ammcnium halides such as benzyltriethylam~onium chloride, tetra-n-butylammonium bromide and cetyltrimethyl-~mmonium bromide. The oxidativa cleavage o~ 1-alk~nyl groups ~s preferably carried out at a temperature in the range of about 0C and 25C.
The hydroxyacetyl group [R as group (c)] and the for~yl group [R as group tf)] are pre-ferably cleaved off with an aqlleous strong base (e.g. with aque~us ammonia or a~ueous caustiG alXali) in an iner~
organic solvent (e.g. a halogenated hydrocar~on such as chloroform, carbon tetrachloride or me~hylene chloride) at a temperature between about 0C and +50C. The formyl group ca~, however, also be cleaved of by the action of a palladium- or rhodium-organic complex compound, for example tris-(triphenylphosphine)-chlororhodium.
After removal o~ the above protecting group R10, the group -S03H can be introduced in the l-position by reaction with a reactive derivative of sulphur trioxide, for example, , ....
,''-' ~2~7~6 ..
by reaction with complexes of sulphur trioxide and a base such as pyridine, tx~methylamine, picoline, dimethyl-formamide etc at abou~ 0-80C in an inert organic solvent (e.g. an ether such as dloxan, pyridine, dimethylormamide etc). Th~ amino group R2 in ~h~ 3-position can be liberated before or after the latter reaction by transform~tion of the group R~0 (in th above manner) or by clea~age o~ the pro~ec~ing group Z; ~or example, aralkoxycarbonyl groups (especially benzyloxycar~onyl) or the benzhydryl group can be cleaved off hydrogenolytieally (e.g. by the action of hydrogen and palladium-car~on), the t-butoxycarbonyl group can be cleaved off by treatm~snt wlth trifluoroace~iG acid or formlc acid, and the trichloroetho~ycarbonyl grollp can be cleaved o~f by treatment with zinc and a p~otonic acid such as acetic acid or hydrochloric acid. The liberated amino group R~ can su~sequently be acylated with a corres-pondingly substituted carboxylic acid or a reactive functional derivative thereo~, for example an acld a~hydrid~, acid amide, active ester (e.g. a thioester such as the benthia-zolyl thioester, by which means the widest vari~y of acyl groups such as those which are known, for example, from penicillin or cephalosphorin Ghemistry can be introduced.
For example, in this manner there can be manufactured according to methods known per se optically uniform anti-microbially active ~-lactams of the general formula ,1 ~Z(;~4~74~
.
H2N~' \
N ~ C - CONH R3 N ~ IIa ~R5 ~ N
03H.
wherein R5 represents hydrogen, lower 10alkyl or carboxy-l~wer alkyl and R3 represents a lowex o~ganic group (e.g.
carbamoyl or carbamoyloxy methyl), or the corre~pondlng optical antipodes thereo~.
Examples of corresponding conversio~s into end products are illustrated i~ Schemes I-III hereina~ter.
2~
c .
474~
C o . ' (~ )o~ _ _ --Z / ~z / '~ I
Z",~ ~Z/ ~Z/
~1 ol ~ O ~ I ~0:
=Z
p; o \ ~z \~z ~D
~Z 0~ / /
Z ~
z~ ! ¦~
~ ~ 3 ~Z~
u~
o I
,~ '` /~1 /~1 Z
~o :~ ~
~ O ~ ~ ~ ~ ~
~Z/ ~ ~
~;
~, ., 7a~
Z O o O
O ~. O
_ ~=2 j ~ ~ a ~ .
~4~4~i ;
Abbrevia~ions used in Schemes I, II and III
DMF - dimatLlylformamide Py = pyridine Py.S03 3 sulphur trioxide-pyridinium complex COX - reactive derivative of a carboxylic acid (e.g. acid anhydride, acid amide, active ester such as benzthiazolyl ester) R5~) = hydrogen, low~r alkyl (e.g. methyl), protected ca~bsxy-lower alkyl (e.g. pro-tected carboxy-me~hyl, protected l-methyl--l-ca~oxy-e~hyl). Prote~tng group: e.g.
t-butyl (cleavable with, for example, tri-~luoroacetic acid), benzyl and p-nitro-benzyl (cleavable with,. for example, hydrogen and palladium carbon), 2- (trimethylsilyl) --ethyl (cleavable wit~, for example, tetra-butyla~monium fluoride).
20 ~ - hydrogen, lower alkyl (e.g. methyl), car-boxy lower alkyl (e . g . carboxymethyl ,1--methyl- l-carboxy-ethyl ) .
R10 R21 = above significance.
Reactions which are not e~plained more precisely in Schemes I, II and III are carried out in the manner des-cribed in detail above.
~`
.,,, ~
, ",~,,~8 The foll~wlng Examples illustrate the present in-ventlon. All temperatures are glven in degrees Centigrade.
Ar - aromatic.
~xamol- 1 - To a Rolution, stirred at room temperature, o~ 18.6 ml (0.25 mol) of allylamlne ln 500 ml of methylene c~loride are added 50 g o~ molecular siev~ 4~ and, after 20 minutes, 32.5 g (0.25 mol) of isopropylidene-L-glyceraldehyde and lOO`g o~ magnesium sulphate. ~he mixture is su~sequently stirred at room tempexature or a further 1 hour. The organic ~olution of isopropylidene-L-glyceraldehyde allyl-lmln~ i5 cooled to -30 under argon and treated while stirring with 31.3 ml (0.25 mol) of triet~ylamine. A
solution of 45.25 g (0.25 mol) of phthaloylglycyl chloride in 200 ml of dry methylene chlortde is then added dropwise within 2 houxs and the mixture is subsequently stirred at room temperature for a further 12 hours. The mixture is washed three times with in each c~se 700 ml of water and 700 ml of sodium chloride solution, dried over magnesium sul-phate, filtered and evaporated. The residu~ is chromato-graphed on silica gel with cyclohexane/ethyl acetate (6:4).
There are obtained 50 g of N-[cis-(3S,4$)olallyl-4-[ (R)-. .
, . . ,~, ., ` I ~2~9~74~
- 3~ --2,2-dimethyl~1,3-dioxolan-4-yl)-2-o~o-3-aæetidinyl]--phthalimide as an oil; ~]20 ~ +115 (0.13 in chlorofo~m).
NMR tCDC13) ~ (ppm): 1.28 (3H, s), 1,41 ~3H, s), 3.36-4.5 (6~), 5.87 (1~, d, 5~z),
5.18-5.5 (2~, m, C~2=), 5.68-6.16 (lX, m, C~=), 7.87 (~, m, Ar).
Exam ~e 2 15: -A suspension o~ 25 g (70.2 mmol) of No[ci~-(3S,4S)--l-allyl-4-[(R) 2,2-dimethyl~1,3-dioxolan-4-yl)-2-oxo-3--azetidinyl~-phthalimide and 0.5 g o~ palladium di~hloride in 300 ml of methylane chlorlde and 30 ml of water is heated under reflux conditio~s for 3 hours while stirring. A~ter cooling and filtra~ion, the organic p~ase is separated, washed with water, dried over magnesium sulphate, filtered and evaporated. There are obtained 24 g of N r [ ciS- ~ 3S,4S)--4O[(R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-oxo~ prope~yl)--3-azetidinyl]-phthalimlde as a foam; []20 = +77.7o (c =
0.153 in chloroform).
NMR (CDC13) ~ (ppm): 1.26 (3H, s, CH3), 1.42 (3H, s, C~3), 1.71 (3H, dd, 1.5 and 6.5 ~z, C~3), 3.34-3.76 (2~, m, C~2), 3.97--4.52 (2H, m, H4 and CH), 5.3~
(lH, d, S.S Hz, H3), 5.67-6.05 - (lH, m, =C~-CX3), 6.4 (lH, dd, l.S
and 14 Hz, =C~-N-), 7.82 (4H, m, Ar) .
.~f ~2~
Exam~le 3 A 301ution of 0.356 g (l mmol) of N-[cis-(3S,4S)-4--[(R)-2,2-dimethyl~1,3 dioxolan-4-yl]o2-oxo-l~ propenyl)--3-azetidinyl]-phthalimlde and 0.26 ml of pyridine i~ 50 ml o~ aceton~ and 50 ml o water is treated dropwise while stirring at 5 with a solution of 0~22 g (1.4 mmol) of potassium permanganate in 50 ml of acetone and 50 ml of water. After 3 hours, t~e mixture is filtered and the filtrate i5 evaporated. The residue is chromatographed on silica gel with cyclohexane/ethyl acetate (6:4). There is obtained 0.29 g of N-[cis-(3S,4S)-4-[tR)-2,20dimethyl-1,3-~ -dioxolan-4-yl~-2-oxo-3-azetidi~yl~phthallmide as a foam.
; 15 NMR (CDCl3) ~ (ppm): 1.3 (3H, s, CH3), 1.45 (3H, s, CX3), 3.3-4.5 (4H, m), 5.4 (lH, d~ 5.5~z, H3), 7.0 (lH, s, -N~)~
7.9 (4H, Ar)~
, ,.
~0~746 ~Q~
A sslu~ion of 20 g 556 mmol) of N-~ci~-(3S,4S)-4--~R) 2,2-dimethyl-1,3-dioxolan-4 yl]-2-oxo-1-(1-propenyl)--3-azetidinyl]-phthalimide in 200 ml of methyLene chloride is treated with 5.9 ml ~119 mmol) of methyl hydrazine.
The mlxtur~ is heated to 60 while stirring for 2 hours.
Aft~r cooling and filtration, ~he filtrate is ~aporated.
The resldue is d~ssolved in 200 ml of methylen~ chloride and treated wl~h 14.6 ml of butylene oxide. While stirring at 20 the mixture is treated dropwise with 12 ml o~ carbo-benzoxy chloride a~d stirred overnight. The mixture is washed ~hree times with 200 ml o water each tlme, ~ried over magnesium.sulphate, ~iltered and evaporated. The residue is treated with 200 ml of ether and the crystalline precipitate is filtar2d off under suction. There are ob-tained 14.5 g of benzyl cls-(3S,4S)-4-~(R)-2,2-dime~hyl--1, 3-dioxolan-4Oyl] -2-oxo~ propenyl) o3-azetidine~
car~amate; [a]20 = I-8 ~c = 1 in chloro~orm).
NMR (CDC13) ~ (ppm): 1.35 (3H, s, C~3~, 1.43 (3H, s, CH3), 1.6 (3H, ~, 6 Hz, CH3), . 3.68-4.32, (4~I, m), 5.03-~.2 (3X, m),. 5.5-6.3 (3~, m), 7.3 (5H, Ar).
~'1 2~ 6 ExamPle 5 A solution of 32.7 g (90.8 mmol) of benzyl c~s-(3S,4S)-4-[(R)~2,2-dimethyl-1,3 dioxolan-4-yl]-2-oxo-1-(1-propenyl)--3-azetidineca~bamate and 2S ml of pyridine in 150 ml of acetone, 75 ml of water and 150 ml of dimethoxyethane ls treated while stirxing at 20 within 90 mlAutes with 2?.5 g (173.7 mmol~ o~ potassium permanganate. The internal temperature o~ the reaction vessel is held below 50. The mlxture is ~iltered over siliceous earth and the filtrate is evaporated. The residue is dissolved in methylene chlo-ride, dried over magnesium sulphate, filtered and the filtrate is evaporated~ The crystalline residue is taken up in ethex and filtered off u~der suction. 20 g of benzyl cis-(3S,4S)-4-[(R)-2,2-dime~hyl-1,3-dioxulan-4-yl]-2-oxo--3-azetidinecarbamate are obtained.
A solution of 1 g (2.77 mmol) of benzyl cis-(3S,4S)--4-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl~-2-oxo-1~ propenyl)--3-azetidinecarbamate in 110 ml of methanol is cooled to -30 and treated with 6 mmol of ozone during 15 minutes.
me cooling means is subsequently removed and the mixture is treated with 5 ml of dimethylsulphide. A~ter 4 hours, the . ., .. .
~'2~7~ i -mixture is evapora~ed. The recidue is dissolved in methyl-ene chloride and washed with water. The organic phase is dried over mag~esium sulphate, filtered and evaporated.
5 There is obtained 0.98 g of benzyl c1s-(3S,4S)-4-~(R)-2,2--dimethyl-l,3 dioxolan-4 yl]o2-oxo-1 formyl-3-azetidine-carbamate.
NMR (CDC13) 0 (ppm): 1.36 (3H, s), 1.38 (3H, s), 4-4.56 (4H, m), 5~17 (2~, 9), 5.41-5.67 (1~, q), 6 (NH, d), 7.4 (5H, Ar), 8.87 (lH, s).
~ e ~
0.1 g (2.8 mmol) of benzyl cis-(3S,4S)-4-~(R)-2,2--dimethyl-1,3-dioxolan~4-yl~-2-oxo-1-formyl-3-azetidine-carbamate is dissolved in 10 ml o~ methylene chloride.
After the addition of a mix~ure of 0.1 ml o~ a 25% a~ueous zmmonium hydroxide solution and S ml o~ water, the mixture is stirred vigorously for 5 hours. The organic phase is separated and the aqueous phase is extxacted twice with 10 ml of methylene chloride each time. The organic extracts are combi~ed, dried over magnesium sulphate, filtered and evaporated. There is obtai~ed 0.08 g of benzyl Ci5- ( 3S,4S)-25 -4-[(R3-2,2-dimethyl-1,3-dioxolan-4-yl] 2-oxo-3-azetidine-carbamate.
NMR (CDC13) ~ (ppm)o 1.32 (3H, s), 1,43 (3H, s), 3.6-4.4 (4H, m), 5.12-5.2 (3H, m), 5.93 (lH, d, NH), 6.22 (lH, s, NH azetidine).
Exam ~e 2 15: -A suspension o~ 25 g (70.2 mmol) of No[ci~-(3S,4S)--l-allyl-4-[(R) 2,2-dimethyl~1,3-dioxolan-4-yl)-2-oxo-3--azetidinyl~-phthalimide and 0.5 g o~ palladium di~hloride in 300 ml of methylane chlorlde and 30 ml of water is heated under reflux conditio~s for 3 hours while stirring. A~ter cooling and filtra~ion, the organic p~ase is separated, washed with water, dried over magnesium sulphate, filtered and evaporated. There are obtained 24 g of N r [ ciS- ~ 3S,4S)--4O[(R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-oxo~ prope~yl)--3-azetidinyl]-phthalimlde as a foam; []20 = +77.7o (c =
0.153 in chloroform).
NMR (CDC13) ~ (ppm): 1.26 (3H, s, CH3), 1.42 (3H, s, C~3), 1.71 (3H, dd, 1.5 and 6.5 ~z, C~3), 3.34-3.76 (2~, m, C~2), 3.97--4.52 (2H, m, H4 and CH), 5.3~
(lH, d, S.S Hz, H3), 5.67-6.05 - (lH, m, =C~-CX3), 6.4 (lH, dd, l.S
and 14 Hz, =C~-N-), 7.82 (4H, m, Ar) .
.~f ~2~
Exam~le 3 A 301ution of 0.356 g (l mmol) of N-[cis-(3S,4S)-4--[(R)-2,2-dimethyl~1,3 dioxolan-4-yl]o2-oxo-l~ propenyl)--3-azetidinyl]-phthalimlde and 0.26 ml of pyridine i~ 50 ml o~ aceton~ and 50 ml o water is treated dropwise while stirring at 5 with a solution of 0~22 g (1.4 mmol) of potassium permanganate in 50 ml of acetone and 50 ml of water. After 3 hours, t~e mixture is filtered and the filtrate i5 evaporated. The residue is chromatographed on silica gel with cyclohexane/ethyl acetate (6:4). There is obtained 0.29 g of N-[cis-(3S,4S)-4-[tR)-2,20dimethyl-1,3-~ -dioxolan-4-yl~-2-oxo-3-azetidi~yl~phthallmide as a foam.
; 15 NMR (CDCl3) ~ (ppm): 1.3 (3H, s, CH3), 1.45 (3H, s, CX3), 3.3-4.5 (4H, m), 5.4 (lH, d~ 5.5~z, H3), 7.0 (lH, s, -N~)~
7.9 (4H, Ar)~
, ,.
~0~746 ~Q~
A sslu~ion of 20 g 556 mmol) of N-~ci~-(3S,4S)-4--~R) 2,2-dimethyl-1,3-dioxolan-4 yl]-2-oxo-1-(1-propenyl)--3-azetidinyl]-phthalimide in 200 ml of methyLene chloride is treated with 5.9 ml ~119 mmol) of methyl hydrazine.
The mlxtur~ is heated to 60 while stirring for 2 hours.
Aft~r cooling and filtration, ~he filtrate is ~aporated.
The resldue is d~ssolved in 200 ml of methylen~ chloride and treated wl~h 14.6 ml of butylene oxide. While stirring at 20 the mixture is treated dropwise with 12 ml o~ carbo-benzoxy chloride a~d stirred overnight. The mixture is washed ~hree times with 200 ml o water each tlme, ~ried over magnesium.sulphate, ~iltered and evaporated. The residue is treated with 200 ml of ether and the crystalline precipitate is filtar2d off under suction. There are ob-tained 14.5 g of benzyl cls-(3S,4S)-4-~(R)-2,2-dime~hyl--1, 3-dioxolan-4Oyl] -2-oxo~ propenyl) o3-azetidine~
car~amate; [a]20 = I-8 ~c = 1 in chloro~orm).
NMR (CDC13) ~ (ppm): 1.35 (3H, s, C~3~, 1.43 (3H, s, CH3), 1.6 (3H, ~, 6 Hz, CH3), . 3.68-4.32, (4~I, m), 5.03-~.2 (3X, m),. 5.5-6.3 (3~, m), 7.3 (5H, Ar).
~'1 2~ 6 ExamPle 5 A solution of 32.7 g (90.8 mmol) of benzyl c~s-(3S,4S)-4-[(R)~2,2-dimethyl-1,3 dioxolan-4-yl]-2-oxo-1-(1-propenyl)--3-azetidineca~bamate and 2S ml of pyridine in 150 ml of acetone, 75 ml of water and 150 ml of dimethoxyethane ls treated while stirxing at 20 within 90 mlAutes with 2?.5 g (173.7 mmol~ o~ potassium permanganate. The internal temperature o~ the reaction vessel is held below 50. The mlxture is ~iltered over siliceous earth and the filtrate is evaporated. The residue is dissolved in methylene chlo-ride, dried over magnesium sulphate, filtered and the filtrate is evaporated~ The crystalline residue is taken up in ethex and filtered off u~der suction. 20 g of benzyl cis-(3S,4S)-4-[(R)-2,2-dime~hyl-1,3-dioxulan-4-yl]-2-oxo--3-azetidinecarbamate are obtained.
A solution of 1 g (2.77 mmol) of benzyl cis-(3S,4S)--4-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl~-2-oxo-1~ propenyl)--3-azetidinecarbamate in 110 ml of methanol is cooled to -30 and treated with 6 mmol of ozone during 15 minutes.
me cooling means is subsequently removed and the mixture is treated with 5 ml of dimethylsulphide. A~ter 4 hours, the . ., .. .
~'2~7~ i -mixture is evapora~ed. The recidue is dissolved in methyl-ene chloride and washed with water. The organic phase is dried over mag~esium sulphate, filtered and evaporated.
5 There is obtained 0.98 g of benzyl c1s-(3S,4S)-4-~(R)-2,2--dimethyl-l,3 dioxolan-4 yl]o2-oxo-1 formyl-3-azetidine-carbamate.
NMR (CDC13) 0 (ppm): 1.36 (3H, s), 1.38 (3H, s), 4-4.56 (4H, m), 5~17 (2~, 9), 5.41-5.67 (1~, q), 6 (NH, d), 7.4 (5H, Ar), 8.87 (lH, s).
~ e ~
0.1 g (2.8 mmol) of benzyl cis-(3S,4S)-4-~(R)-2,2--dimethyl-1,3-dioxolan~4-yl~-2-oxo-1-formyl-3-azetidine-carbamate is dissolved in 10 ml o~ methylene chloride.
After the addition of a mix~ure of 0.1 ml o~ a 25% a~ueous zmmonium hydroxide solution and S ml o~ water, the mixture is stirred vigorously for 5 hours. The organic phase is separated and the aqueous phase is extxacted twice with 10 ml of methylene chloride each time. The organic extracts are combi~ed, dried over magnesium sulphate, filtered and evaporated. There is obtai~ed 0.08 g of benzyl Ci5- ( 3S,4S)-25 -4-[(R3-2,2-dimethyl-1,3-dioxolan-4-yl] 2-oxo-3-azetidine-carbamate.
NMR (CDC13) ~ (ppm)o 1.32 (3H, s), 1,43 (3H, s), 3.6-4.4 (4H, m), 5.12-5.2 (3H, m), 5.93 (lH, d, NH), 6.22 (lH, s, NH azetidine).
Claims (24)
1. A process for the manufacture of an optically uniform .beta.-lactam of the general formula I
in which R1 represents lower 2-alkenyl, lower l-alkenyl or a group of the formula -CH2-CH(OR4)2 (a), -CH2-CHO (b), -CO-CH(OH)2 (c), (d), -CH=CH-R9 (e) or -CHO (f), R4 represents lower alkyl, R9 represents a tertiary lower cycloaliphatic or aliphatic amino group, n represents the number 0 or 1, R2 represents amino, azido, phthalimido, (lower alkyl)-O-CO-CH=C(CH3)-NH-or Z-NH-, Z represents a readily cleavable acyl group, R6 and R7 each represent a lower hydro-carbon group which optionally contains oxygen and is attached via a carbon atom, or R6 and R7 together with the centre of chirality represent a 5- or 6-membered O-heterocycle which optionally contains a further ring oxygen atom not directly linked to the centre of chirality and which is optionally substituted by lower alkyl, lower alkoxy, oxo or spirocyclo-lower alkyl, with the proviso that when R2 signifies amino R1 represents lower 2-alkenyl or 1-alkenyl or one of the groups (a), (c) and (d), or the corresponding optical antipode thereof, which process comprises reacting a reactive derivative of a carboxylic acid of the general formula in which R20 represents azido, phthalimido or the group ROCO CH=C(CH3)-NH- and R represents lower alkyl, in the presence of a base with a compound of the general formula IV
in which R11 represents lower 2-alkenyl or one of the groups (a) and (d) defined above and R6 and R7 are as defined above, or the corresponding optical antipode thereof, if desired in a thus-obtained compound of the general formula Ie in which R11, R20 , R6 and R7 are as defined above, or the corresponding optical antipode thereof, converting a lower 2-alkenyl group present as R11 into the corresponding lower 1-alkenyl group or into the group (e) or (f) or converting a group (a) present as R11 into the group (b) or (c) or transforming a group (d) present as R11 into the vinyl or formyl group, if desired transforming the group R20 in a resulting compound of the general formula If in which R1, R20, R6 and R7 are as defined above, or the corresponding optical antipode thereof, into the amino group, if desired reacting a thus-obtained compound of the general formula Ig in which R1, R6 and R7 are as defined above, or the corresponding optical antipode thereof, with an agent yielding the group Z to give a compound of the general formula Ih in which R1, R6 and R7 are as defined above and Z represents a readily cleavable acyl group, or the corresponding optical antipode thereof, and, if desired, in a resulting compound of the general formula Ih1 in which R11, R6, R7 and Z are as defined above, or the corresponding optical antipode thereof, converting a lower 2-alkenyl group present as R11 into the corresponding 1-alkenyl group or into the group (e) or (f) or converting a group (a) present as R11 into the group (b) or (c) or transforming a group (d) present as R11 into the vinyl or formyl group.
in which R1 represents lower 2-alkenyl, lower l-alkenyl or a group of the formula -CH2-CH(OR4)2 (a), -CH2-CHO (b), -CO-CH(OH)2 (c), (d), -CH=CH-R9 (e) or -CHO (f), R4 represents lower alkyl, R9 represents a tertiary lower cycloaliphatic or aliphatic amino group, n represents the number 0 or 1, R2 represents amino, azido, phthalimido, (lower alkyl)-O-CO-CH=C(CH3)-NH-or Z-NH-, Z represents a readily cleavable acyl group, R6 and R7 each represent a lower hydro-carbon group which optionally contains oxygen and is attached via a carbon atom, or R6 and R7 together with the centre of chirality represent a 5- or 6-membered O-heterocycle which optionally contains a further ring oxygen atom not directly linked to the centre of chirality and which is optionally substituted by lower alkyl, lower alkoxy, oxo or spirocyclo-lower alkyl, with the proviso that when R2 signifies amino R1 represents lower 2-alkenyl or 1-alkenyl or one of the groups (a), (c) and (d), or the corresponding optical antipode thereof, which process comprises reacting a reactive derivative of a carboxylic acid of the general formula in which R20 represents azido, phthalimido or the group ROCO CH=C(CH3)-NH- and R represents lower alkyl, in the presence of a base with a compound of the general formula IV
in which R11 represents lower 2-alkenyl or one of the groups (a) and (d) defined above and R6 and R7 are as defined above, or the corresponding optical antipode thereof, if desired in a thus-obtained compound of the general formula Ie in which R11, R20 , R6 and R7 are as defined above, or the corresponding optical antipode thereof, converting a lower 2-alkenyl group present as R11 into the corresponding lower 1-alkenyl group or into the group (e) or (f) or converting a group (a) present as R11 into the group (b) or (c) or transforming a group (d) present as R11 into the vinyl or formyl group, if desired transforming the group R20 in a resulting compound of the general formula If in which R1, R20, R6 and R7 are as defined above, or the corresponding optical antipode thereof, into the amino group, if desired reacting a thus-obtained compound of the general formula Ig in which R1, R6 and R7 are as defined above, or the corresponding optical antipode thereof, with an agent yielding the group Z to give a compound of the general formula Ih in which R1, R6 and R7 are as defined above and Z represents a readily cleavable acyl group, or the corresponding optical antipode thereof, and, if desired, in a resulting compound of the general formula Ih1 in which R11, R6, R7 and Z are as defined above, or the corresponding optical antipode thereof, converting a lower 2-alkenyl group present as R11 into the corresponding 1-alkenyl group or into the group (e) or (f) or converting a group (a) present as R11 into the group (b) or (c) or transforming a group (d) present as R11 into the vinyl or formyl group.
2. A process according to claim 1 for the manufacture of a compound for formula I, wherein R1 represents lower 2-alkenyl, lower 1-alkenyl or one of the groups (a), (b), (c) and (d), or the corresponding optical antipode thereof, characterised in that correspondingly substituted starting materials are used.
3. A process according to claim 1 for the manufacture of a compound of formula I, wherein R2 represents amino, phthalimido, benzyloxycarbonylamino, t-butoxycarbonylamino or 2-methoxycarbonyl-1-methyl-vinylamino, or the correspond-ing optical antipode thereof, characterised in that correspond-ingly substituted starting materials are used.
4. A process according to claim 1 for the manufacture of a compound of formula I, wherein R6 represents lower alkyl, phenyl-lower alkyl or lower alkoxy-alkyl and R7 represents lower alkyl or phenyl-lower alkyl, or R6 and R7 together with the centre of chirality represent a group of the formula or the corresponding optical antipode thereof, characterised in that correspondingly substituted starting materials are used.
5. A process according to claim 4 for the manufacture of a compound of formula I, wherein R6 and R7 together with the centre of chirality represent the group [(R)-2,2-dimethyl-1,3-dioxolan-4-yl], or the corresponding optical antipode thereof, characterised in that correspond-ingly substituted starting materials are used.
6. A process according to claim 1 for the manufacture of a compound of formula I, wherein R1 represents vinyl, 2-propenyl (allyl), 1-propenyl, 2,2-dimethoxyethyl 9 2,2-diethoxyethyl, formylmethyl, dihydroxyacetyl, 2-phenyl-thioethyl or 2-phenylsulphinylethyl, or the corresponding optical antipode thereof, characterised in that correspondingly substituted starting materials are used.
7. A process according to claim 6 for the manufacture of a compound of formula I, wherein R1 represents 2-propenyl or 1-propenyl, or the corresponding optical antipode thereof, characterised in that correspondingly substituted starting materials are used.
8. A process according to claim 1 for the manufacture of a compound of formula I, wherein R1 represents 2-morpholino-vinyl or formyl, or the corresponding optical antipode thereof, characterised in that correspondingly substituted starting materials are used.
9. A process for the manufacture of N-[cis-(3S,4S)-1-allyl-4-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-oxo-3-azetidinyl]-phthalimide which comprises reacting a reactive derivative of N-phthaloyl-glycine in the presence of a base with iso-propylidene-L-glyceraldehyde allyl imine.
10. A process according to claim 9, wherein the acid chloride is used as reactive derivative.
11. A process according to claim 9, wherein a tertiary amine is used as a base.
12. A process for the manufacture of N-[cis-(3S,4S)-4-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-oxo-1-(1-propenyl)-3-azetidinyl]phthalimide which comprises isomerizing the allyl group in N-[cis-(3S,4S)-l-allyl-4-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-oxo-3-azetidinyl]phthalimide obtained according to claim 9 in the presence of an isomerization catalyst.
13. A process according to claim 12, wherein a palladium dihalide or a tris(triphenylphosphine)rhodium(I) halide is used as isomerization catalyst.
14. A process-according to claim 13, wherein corresponding chlorides are used.
15. Optically uniform .beta.-lactams of the general formula I
in which R1 represents lower 2-alkenyl, lower 1-alkenyl or a group of the formula -CH2-CH(OR4)2 (a), -CH2-CHO (b), -CO-H(OH)2 (c), (d), -CH=CH-R9 (e) -CHO (f), R4 represents lower alkyl, R9 represents a tertiary lower cycloaliphatic or aliphatic amino group, n represents the number 0 or 1, R2 represents amino, azido, phthalimido, (lower alkyl) O-CO-CH=C(CH3)-NH-or Z-NH-, Z represents a readily cleavable acyl group, R6 and R7 each represent a lower hydro-carbon group which optionally contains oxygen and is attached via a carbon atom, or R6 and R7 together with the centre of chirality represent a 5- or 6-membered O-heterocycle which optionally contains a further ring oxygen atom not directly linked to the centre of chirality and which is optionally substituted by lower alkyl, lower alkoxy, oxo or spirocyclo-lower alkyl, with the proviso that when R2 signifies amino R1 represents lower 2-alkenyl or 1-alkenyl or one of the groups (a), (c) and (d), and the corresponding optical antipodes thereof, whenever manufactured according to the process as claimed in claim 1 or by an obvious chemical equivalent thereof.
in which R1 represents lower 2-alkenyl, lower 1-alkenyl or a group of the formula -CH2-CH(OR4)2 (a), -CH2-CHO (b), -CO-H(OH)2 (c), (d), -CH=CH-R9 (e) -CHO (f), R4 represents lower alkyl, R9 represents a tertiary lower cycloaliphatic or aliphatic amino group, n represents the number 0 or 1, R2 represents amino, azido, phthalimido, (lower alkyl) O-CO-CH=C(CH3)-NH-or Z-NH-, Z represents a readily cleavable acyl group, R6 and R7 each represent a lower hydro-carbon group which optionally contains oxygen and is attached via a carbon atom, or R6 and R7 together with the centre of chirality represent a 5- or 6-membered O-heterocycle which optionally contains a further ring oxygen atom not directly linked to the centre of chirality and which is optionally substituted by lower alkyl, lower alkoxy, oxo or spirocyclo-lower alkyl, with the proviso that when R2 signifies amino R1 represents lower 2-alkenyl or 1-alkenyl or one of the groups (a), (c) and (d), and the corresponding optical antipodes thereof, whenever manufactured according to the process as claimed in claim 1 or by an obvious chemical equivalent thereof.
16. Compounds according to claim 15, wherein R1 represents lower 2-alkenyl, lower 1-alkenyl or one of the groups (a), (b), (c) and (d), whenever manufactured according to the process as claimed in claim 2 or by an obvious chemical equivalent thereof.
17. Compounds according to claim 15, wherein R2 represents amino, phthalimido, benzyloxycarbonylamino, t-butoxycarbonyl-amino or 2-methoxycarbonyl-1-methyl-vinylamino, and the corresponding optical antipodes thereof, whenever manufactured according to the process as claimed in claim 3 or by an obvious chemical equivalent thereof.
18. Compounds according to claim 15, wherein R6 represents lower alkyl, phenyl-lower alkyl or lower alkoxy-alkyl and R7 represents lower alkyl or phenyl-lower alkyl, or R6 and R7 together with the centre of chirality represent a group of the formula and the corresponding optical antipodes thereof, whenever manufactured according to the process as claimed in claim 4 or by an obvious chemical equivalent thereof.
19. Compounds according to claim 15, wherein R6 and R7 together with the centre of chirality represent the group and the corresponding optical antipodes thereof, whenever manufactured according to the process as claimed in claim 5 or by an obvious chemical equivalent thereof.
20. Compounds according to claim 15, wherein R1 represents vinyl, 2-propenyl (allyl), 1-propenyl, 2,2-dimethoxyethyl, 2,2-diethoxyethyl, formylmethyl, dihydroxyacetyl, 2-phenyl-thioethyl or 2-phenylsulphinylethyl, and the corresponding optical antipodes thereof, whenever manufactured according to the process as claimed in claim 6 or by an obvious chemical equivalent thereof.
21. Compounds according to claim 15, wherein R1 represents 2-propenyl or 1 propenyl, and the corresponding optical antipodes thereof, whenever manufactured according to the process as claimed in claim 7 or by an obvious chemical equivalent thereof.
22. Compounds according to claim 15, wherein R1 represents 2-morpholinovinyl or formyl, and the corresponding optical antipodes thereof, whenever manufactured according to the process as claimed in claim 8 or by an obvious chemical equivalent thereof.
23. N-[cis-(3S,4S)-1-allyl-4-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-oxo-3-azetidinyl]-phthalimide, whenever manufactured according to the process as claimed in claim 9, 10 or 11 or by an obvious chemical equivalent thereof.
24. N-[cis-(3S,4S)-4-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-oxo-1-(1-propenyl)-3-azetidinyl]-phthalimide, whenever manufactured according to the process as claimed in claim 12, 13 or 14 or by an obvious chemical equivalent thereof.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH4961/82 | 1982-08-19 | ||
| CH496182 | 1982-08-19 | ||
| CH3643/83 | 1983-07-01 | ||
| CH364383 | 1983-07-01 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1204746A true CA1204746A (en) | 1986-05-20 |
Family
ID=25693512
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000433590A Expired CA1204746A (en) | 1982-08-19 | 1983-07-29 | .beta. LACTAMS |
Country Status (10)
| Country | Link |
|---|---|
| EP (1) | EP0101598B1 (en) |
| JP (1) | JPS5953465A (en) |
| AU (1) | AU564378B2 (en) |
| CA (1) | CA1204746A (en) |
| DE (1) | DE3376319D1 (en) |
| DK (1) | DK378683A (en) |
| IE (1) | IE55996B1 (en) |
| IL (1) | IL69486A (en) |
| NZ (1) | NZ205246A (en) |
| PH (1) | PH22479A (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA1251454A (en) * | 1983-01-20 | 1989-03-21 | Gerard Schmid | PROCESS FOR THE MANUFACTURE OF .beta.-LACTAMES |
| DK36784A (en) * | 1983-02-25 | 1984-08-26 | Hoffmann La Roche | PROCEDURE FOR PREPARING CHIRAL ALDEHYDES |
| US4576749A (en) * | 1983-10-03 | 1986-03-18 | E. R. Squibb & Sons, Inc. | 3-Acylamino-1-carboxymethylaminocarbonyl-2-azetidinones |
| DE3588039T2 (en) * | 1984-08-06 | 1995-11-16 | Fujisawa Pharmaceutical Co | Azetidinone derivatives and process for their preparation. |
| EP0232017A1 (en) * | 1986-01-23 | 1987-08-12 | The Upjohn Company | Antimicrobial N-acyl-2-azetidinones |
| IT1282956B1 (en) * | 1996-05-06 | 1998-04-02 | Opos Biochimica Srl | PROCEDURE FOR THE PREPARATION OF AN AZETIDINONE |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4012383A (en) * | 1975-01-02 | 1977-03-15 | Bristol-Myers Company | Δ2,3 -1,4-morpholine-2-carboxylic acids and derivatives thereof useful in preparation of antibacteria agents |
| AU516665B2 (en) * | 1975-10-06 | 1981-06-18 | Fujisawa Pharmaceutical Co., Ltd | 2-azetidone compounds |
| JPS56125361A (en) * | 1980-03-07 | 1981-10-01 | Sagami Chem Res Center | Azetidinone compound |
| CA1262128A (en) * | 1981-08-27 | 1989-10-03 | Christian N. Hubschwerlen | .beta.-lactams |
-
1983
- 1983-07-29 CA CA000433590A patent/CA1204746A/en not_active Expired
- 1983-08-10 EP EP83107910A patent/EP0101598B1/en not_active Expired
- 1983-08-10 DE DE8383107910T patent/DE3376319D1/en not_active Expired
- 1983-08-12 IL IL69486A patent/IL69486A/en unknown
- 1983-08-12 NZ NZ205246A patent/NZ205246A/en unknown
- 1983-08-15 AU AU17979/83A patent/AU564378B2/en not_active Ceased
- 1983-08-17 PH PH29407A patent/PH22479A/en unknown
- 1983-08-18 DK DK378683A patent/DK378683A/en not_active Application Discontinuation
- 1983-08-18 IE IE1931/83A patent/IE55996B1/en unknown
- 1983-08-18 JP JP58149722A patent/JPS5953465A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS5953465A (en) | 1984-03-28 |
| DE3376319D1 (en) | 1988-05-26 |
| JPH0587515B2 (en) | 1993-12-16 |
| IE55996B1 (en) | 1991-03-13 |
| IL69486A (en) | 1987-07-31 |
| DK378683D0 (en) | 1983-08-18 |
| AU564378B2 (en) | 1987-08-13 |
| EP0101598B1 (en) | 1988-04-20 |
| EP0101598A1 (en) | 1984-02-29 |
| AU1797983A (en) | 1984-02-23 |
| DK378683A (en) | 1984-02-20 |
| PH22479A (en) | 1988-09-12 |
| IE831931L (en) | 1984-02-19 |
| IL69486A0 (en) | 1983-11-30 |
| NZ205246A (en) | 1986-12-05 |
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