IE840549L - Carbapenem process and intermediates - Google Patents

Carbapenem process and intermediates

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Publication number
IE840549L
IE840549L IE840549A IE54984A IE840549L IE 840549 L IE840549 L IE 840549L IE 840549 A IE840549 A IE 840549A IE 54984 A IE54984 A IE 54984A IE 840549 L IE840549 L IE 840549L
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IE
Ireland
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alkyl
formula
pyridinium
process according
mmol
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IE840549A
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IE57098B1 (en
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Bristol Myers Co
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    • C07D477/00—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
    • C07D213/16—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom containing only one pyridine ring
    • C07D213/20—Quaternary compounds thereof
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/65—One oxygen atom attached in position 3 or 5
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/73—Unsubstituted amino or imino radicals
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    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/84—Sulfur atoms
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    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07D477/00—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
    • C07D477/02—Preparation
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pyridine Compounds (AREA)

Abstract

Disclosed is a new and more efficient process for producing carbapenem antibiotic derivatives having a 2- substituent of the general formula S-A-R<14> wherein A represents cyclopentylene, cyclohexylene or C2- C6 alkylene optionally substituted by one or more C1-C4 alkyl groups and R<14> represents a quaternized nitrogen-containing aromatic or non-aromatic heterocycle attached to A through a quaternary nitrogen atom. The carbapenems produced by this process are of the formula <IMAGE> R<8> being hydrogen and R<1> being hydrogen or one of various defined organic groups or R<1> and R<8> together completing a ring and R<2> being hydrogen, an anion or a protecting group. The starting materials are of the formula <IMAGE> and H-S-A-R<14> L being a leaving group and R<2> being a protecting group. [GB2136802A]

Description

The pror»ont invention i :s dircctcd to a now process for Mu- |»r»•)Kir.it. i tm <>l! earbnp'-nom tier iv.»Li vo:; havino <'i 2-.r;ub« tj liuonf. «|| !.!»«■ -S-A-R'4 wherein A represents cyclopentylone, eyelohexylene or alkylene optionally substituted by one or more C,-C. alkyl groups 14 . and R represents a quatcrnized nitrogen-containing aromatic or non-aromatic heterocycle attached to A through a quaternary nitrogen atom. 10 The carbapenem derivatives prepared by the process of the present invention are disclosed and claimed by my colleagues C'houng U. Kim and Peter F. f^isco, Jr., in U.S. intent Applications Serial Nos. 366,910, 471,379 and 389,652 Tiled, respectively, Apri] 9, 1982, March 8, 1983 and June 18, 1982.
I') 20 U.S. Application 366,910 and its continuation-in-part U.S. Application Serial No. 471,379, filed March 8, 1^83, which continuation-in-part corresponds to West German Published Patent Application 3,312,533, disclose preparation of carbapenem antibiotics of the formula H A COOK IA whi-r.-in R .i of hydrogen; liydrofion and R* is selected from the group com; i t i rut substituted and unsuhstituted: alkyl, alkenyl and alkynyl, having from 1-10 carbon atoms; cycloalkyl anil cycloalkyl- i alkyl, having 3-6 carbon atoms in the cycloalkyl ring!and 1-6 carbon atoms in the alkyl moieties; phenyl; aralkyl, aralkenyl; and aralkynyl wherein the aryl moiety is Phenyl and the aliphatic portion has 1-6 carbon atoms; heteroaryl, heteroaralkyl, hetero-cyclyl and heterocyclylalky1 wherein the hetero atom or atoms in the above-named heterocyclic moieties are solected from the group 3 consisting of 1-4 oxygen, nitrogen or sulfur atoms and the alkyl moieties associated with said heterocyclic moieties have 1-6 carbon atoms; wherein the substituent or substituents relative to the above-named radicals are selected from the group consisting of C,-C, alkyl optionally substituted by I t> amino, halo, hydroxy or carboxyl halo -OR3 0 II 34 -OCNR R 0 II 34 -CNR R -NR3R4 /NR \ 3 VR I 3 4 -SOjNR R 0, H 34 -nkcnr r 0 r3cnr4--c°2r3 =0 0 II 3 -ocr 3 -sr O II 9 -sr 0 II 9 -sr* II 0 -cn 4 'n3 -OS03R3 -OSO.R3 -nh sogr -nr3c*nr4 R3 -NR3C02fi4 -no 2 wherein, relative to the above-named substituents, the 3 4 groups R and R are independently selected from hydrogen; alkyl, alkenyl and alkynyl, having from 1-10 carbon atoms; cycloalkyl', cycloalkylalkyl and alkylcycloalkyl, having 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl moieties; phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl moiety is phenyl and the aliphatic portion has 1-6 carbon atoms; and heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group consisting of 1-4 oxygen, nitrogen or sulfur atoms and the alkyl moieties associated with said heterocyclic moieties have 1-6 3 4 carbon atoms, or R and R taken together with the nitrogen to which at least one is attached may form a 5- or 6-membered nitrogen-containing heterocyclic ring; 9 3 R is as defined for R except that it may not be hydrogen; 1 8 or wherein R and R taken together represent Cj-C^q alkylidene or alkylidene substituted by hydroxy; A is cyclopentylene, cyclohexylene or C2-C& alkyiene optionally substituted by one or more C.-C. alkyl groups; 2 14 R is hydrogen, an anionic charge or a conventional s readily removable carboxyl protecting group, providing that when R2 is hydrogen or a protecting group, there is also present a counter anion; and © in represents a substituted or unsubstituted mono-, bi- or polycyclic aromatic heterocyclic radical containing at least one nitrogen in the ring and attached to A through a ring nitrogen, thereby foraiing a quaternary ammonium group; and pharmaceutical^ acceptable salts thereof by the process shown in the following reaction scheme: R8 H c^~N' ■ COOR 2* diphenyl chlorophosphate III R8 H R1- 0 It 'OP(OC6H5)2 COOR" rv HS-A-OK A = aljcylene or C5-Cg cycloalkylene R8 H S-A-OH \ 2' COOR methanesulfonyl chloride V J r8 h . s-a-0s02ch3 "coor 3© ~7" VI r8 h ,s-a-i y N;oor 2 ' o Ag PP (>® «= counter anion) ii r8 h ® r~\ s"*"0 2 1 coor & i'a z I ® r~~\ S-A"0 ^coor2 ia Application 389,652 and its continuation-in-part application 499,690 filed June 7, 1983 disclose preparation of carbapenem antibiotics of the formula R' 1 // - 0 IB 8 1 wherein R is hydrogen and fc is selected from the group consistinr: of hydrogen; substituted and unsubstituted: alkyl, alkenyl and alkynyl, having from 1-10 carbon atoms; cycloalkyl and cvcloalkyl-alkyl, having 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl moieties; phenyl; aralkyl, aralkenyl anc aralkynyl wherein the aryl moiety is phenyl and the aliphatic portion has 1-6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group consisting of 1-4 oxygen, nitrogen or sulfur atoms and the alkyl moieties associated with said heterocyclic moieties have 1-6 carbon atoms; wherein the substituent or substituents relative to the above-named radicals are independently selected from the group consisting of 8 C^-Cg alkyl optionally substituted by amino, halo, hydroxy or carboxyl halo -or3 O "34 -ocnr r 0 -cnr3r4 -nr3r4- nr3 -4 \r3r4 -so2nr3r4 o "34 -nhcnr r 0 3" 4 r cnr -co,,' 0 -ocr3 -sr3 0 » g -sr " 9 -sr ll 0 -cn -»3 3 -0s03rj -oso,r3 3 4 -nr s02r 3 -nr3c^nr4 k3 -m3co2nA -M02 (5 wherein, relative to the above-named substituents, the 3 4 groups R and R are independently selected from hydrogen; alkyl, alkenyl and alkynyl, having from 1-10 carbon atoms; 5 cycloalkyl, cycloalkylalkyl and alkylcycloalkyl, having 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl moieties; phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl moiety is phenyl and the aliphatic portion has 1-6 carbon atoms; and heteroaryl, 1(1 heteroaralkyl, heterocyclyl and heterocyelylalkyl wherein the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group consisting of 1-4 oxygen, nitrogen or sulfur atoms and the. alkyl moieties associated with said heterocyclic moieties have 1-6 i-1"' carbon atoms, or R3 and R4 taken together with the nitrogen to which at least one is attached may form a 5- or 6- 9 membered nitrogen-containing heterocyclic ring; R is as 3 defined for R except that it may not be hydrogen; or 18 wherein R and R taken together represent C.,-C10 alkyl-20 idene or c2_cio ^^ylidene substituted by hydroxy; R^ is selected from the group consisting of substituted and un-siibstituted: alkyl, alkenyl and alkynyl, having from 1-10 carbon atoms; cycloalkyl and cycloalkylalkyl, having 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms 25 in the alkyl moieties; phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl moiety is phenyl and the aliphatic portion has 1-6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the hetero atom or atoms in the above-named heterocyclic * 30 moieties are selected from the group consisting of 1-4 1 0 oxygen, nitrogen or sulfur atoms and the alkyl moieties associated with said heterocyclic moieties have 1-6 carbon atoms; wherein the above-named R radicals are optionally substituted by 1-3 substituents independently selected from: i i C^-Cg alkyl optionally substituted by aaino, fluoro, chloro, carboxyl, hydroxy or carbamoyl; fluoro, chloro or broino; i _3 ■ - or ? -oc0,r3 i -ocor3 ; 3 4 -ocoNsra ? -OSO,R3 ; -OXO' ; 3 A -NKE ; R3CONR4~ ; -nr3c02r4 ; 3 "3 4 -»r ccnr r % ~nr3so,r4 ; -SR3 ; O f t} -s-r ; 0 ,° * * g -s-r ; -so3r3 j -c02r3, ; 3 4 -conr r ; -CN; or phenyl optionally substituted by 1-3 fluoro, chloro, bromo, c^-cg alkyl, -or3, -nr3r4, -so,h3, -co,r3 or -conr3r4, wherein r3 , r-' fend R in such R substituents are as defined above; t ring so as to form a bridged polycvclic group; A is cyclopentylene, cr cvclohexvlene or C--C, alkylene optionally substituted by one or more alkyl croups; R is hydrogen, an anionic charge or a conventional readily removable carboxy1 protecting group, providing that when R*" is hydrogen or a protecting group, there is also present a counter ion; and represents a substituted or unsubstituted mono-, bi- or polycyclic non-aromatic heterocyclic radical containing at least one nitrogen in the ring and attached to A through a ring nitrogen, thereby forming a quaternary ammonium group; and pharmaceutical^ accept able salts thereof, by the process shown in the following reaction scheme: III 13 ,8 H IV 0 II 'P (OCgHg) 2 COOR 2' HS—A—OH > A= alkylene or Cj-Cg cycloalkylene ,8 H S—A OH ' COOR2' methanesuifonyl chloride -> R8 H S-A-0S02CH3 ' COOR' 2' VI R8 H -N -S-A-I COOR Aq+ X® ^ II ,8 H /7 0 R S-A— K COOR 2' optional de-blocking I "B IB To elaborate on the prior art scheme, starting material III is reacted in an inert organic solvent with diphenyl chlorophosphate in the presence of a base to give intermediate IV. Intermediate IV is then reacted with a mercaptan reagent of the formula HS-A-OH in an inert organic solvent and in the presence of a base to give intermediate V. Intermediate V is then acylated with methanesuifonyl chloride in an inert organic solvent and in the presence of base to it give intermediate VI which is reacted with a source of iodide ions in an inert organic solvent to give intermediate II. Intermediate II is reacted with the desired amine in an inert organic solvent and in the presence of silver ion to produce the quaternized product I'A or I'B which may then be de-'> blocked to give the corresponding de-blocked carbapenem of Formula IA or IE.
The above-described process has several disadvantages.
Thus, for example, the process involves several steps which advantageously could be reduced in number. The overall reaction yield is also quite low and the quaternization step is performed on the entire carbapenem compound. It would be desirable to have a new process for producing compounds of Formula IA or IB which (1) involves fewer reaction steps, (2) gives higher yields, (3) allows the quaternized amine to be formed first and then attached to the carbapenem nucleus at a later'stage in the synthesis and (4) can be used to more easily form quaternary amine products with a wide variety of amines, i.e. amines with steric hindrance and those with low pK^ values.
The present invention provides a novel process for preparation of carbapenem derivatives of the formula w)H>rei.n l<" is hydrogen iind K is ;;elocLc:d I roni hydroqon; substituted £md unsubstituled: nlkyi, alkenyl and alkynyl, having from 1-10 carbon atoms; cycloalkyl and cycloalkylalkyl, having 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl moieties; phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl moiety is phenyl and the aliphatic portion has 1-6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalky1 wherein the hetero atom or atoms in the above-named heterocyclic moieties are solectcd from 1-4 oxygen, nitrogen or sulfur atoms and the alkyl moieties associated with said heterocyclic moieties have 1-6 carbon atoms; wherein the substituent or substituents relative to the above-named radicals are selected from I 6 C^-Cg alkyl optionally substituted by amino, halo, hydroxy or carboxy] halo -or3 0 -oInr3^ -Hnr3R/ -nr3r4 •NR- nh3r4 -so2nr3r4 -nhcnr3r4 A r^cnr4- -co2r3 0 -oir3 -sr3 0 -!r* -sr" ft -cn -n„ 1 7 -0S03R3 -OoQ-R3 1 4 -NRjS02R -nr3c=nr4 -nr3co2r4 -N02 wherein, relative to the above-named substituents, the 3 4 groups R and R are independently selected from hydrogen; alkyl, alkenyl and alkynyl, having from 1-10 carbon atoms; r> cycloalkyl, cycloalkylalkyl and alkylcycloalkyl, having 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl moieties; phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl moiety is.phenyl and the aliphatic portion has 1-6 carbon atoms; and heteroaryl, 10 heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the hetero atom or atoms in the above-named heterocyclic moieties are selected from 1-4 oxygen, nitrogen or sulfur atoms and the alkyl moieties associated with said heterocyclic moieties have 1-6 15 carbon atoms, or R3 and R4 taken together with the ni-Srogen to which at least one is attached may form a 5- g or 6-membered nitroqoii-containing heterocyclic ring; R 3 is as defined for R except that it may not be hydrogen; 1 8 or wherein R and R taken together represent 20 alkylidene or c2"ciq alkylidene substituted by hydroxy; A is cyclopentylene, cyclohexylene or C2~C6 alkylene optionally substituted by one or more C--C. alkyl groups; 2 it R is hydrogen, an anionic charge or a readily removable carboxyl protecting group, providing 2 1 25 that when R is hydrogen or a protecting group, there is also present a counter 1 8 14 . anion; and R is a quaternized nitrogen-containing aromatic or non-aromatic heterocycle attached to A through a ring nitrogen, thereby forming a quaternary ajnmoniura group, or a pharmaceutically acceptable salt thereof, which process comprises reacting an intermediate of the formula 18 2' wherein R and R are as defined above, R is a readily removable carboxyl protecting group and L is a leaving group,with a thiol compound of the formula HS-A-R14 X9 VII 14 8 wherein A and R are as defined above and X is a counter anion in an inert solvent and in the presence of base, to produce a carbapenem product of the formula I* 1 8 21 14 © wherein R , R , R , A, R and X are as defined above and, if 2 ' desired, removing the carboxyl protecting group R to give the corresponding de-blocked compound of formula I, or a pharmaceutically acceptable salt thereof. 10 Also provided by the present invention are intermediates of Formula VII and processes for preparing such intermediates.
The carbapenem compounds of Formula I are potent antibacterial agents or intermediates useful in the preparation of such agents.
The compounds of general Formula I above contain the carbapenem nucleus derivatives. Alternatively, the compounds may be considered to have the basic structure ^ and named as 7-oxo-l-azabicyclo(3.2.0)hept-2-ene-2-carboxylic acid derivatives. While the present invention includes compounds wherein the relative stereochemistry of the 5,6-protons is cis as well as trans, the preferred compounds have the 5R,6S (trans) stereochemistry as in the case of thienamycin. and may thus be named as l-carba-2-penem-3-carboxylic acid The compounds of Formula I may be unsubstituted in the 6-position or substituted by substituent groups previously disclosed for other carbapenem derivatives. More specifically, 20 8 1 R may be hydrogen and R may be hydrogen or a non-hvdrogen substituent disclosed, for example, in European Patent Application 8 1 38, 869 (see definition of R,.) . Alternatively, R and R taken b together may be C2~C10 alkylidene or Cj-C^q alkylidene substituted, for example, by hydroxy. 1 8 To elaborate on the definitions for R and R : (a) The aliphatic "alkyl", "alkenyl" and "alkynyl" groups may be straight or branched chain having 1-10 carbon atoms; preferred are 1-6, most preferably 1-4, carbon groups; when part of another substituent, e.g. as in cycloalkylalkyl, or heteroaralkyl or aralkenyl, the alkyl, alkenyl and alkynyl group preferably contains 1-6, most preferably 1-4, carbon atoms. (b) "heteroaryl" includes mono-, bi- and polycyclic aromatic heterocyclic groups containing 1-4 O, N or S atoms; preferred arc r>- or 6- mcrrl* 'rod heterocycl ic rings such as, for ex/uiplo, thienyl, furyl, thiadiazolvl, oxadiazolyl, triazolyl, isothiazolyl, thiazolyl, imidazolyl, isoxazolyl, tetrazclvl, oxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl and pyrazolyl. (c) "heterocyclyl" includes mono-, bi- and polycyclic saturated or unsaturated non-aromatic heterocyclic groups containing 1-4 0, N or S atoms; preferred are 5- or 6-mcnlxjrec! heterocyclic rinqs such as, for cxnnplu, norpho] iny], piperaz.iny.1, piperidyl, pyrazolinyl, pyrazolidiny1, imidazolinyl, imidazolidinyl, pyrroliny1 and pyrrolid.iny.1.. (d) "halo" includes chloro, brojno, fluoro and iodo and is preferably chloro or bromo.
The torn: "ruadjly removable carboxyl protecting group" refers to a known ester group which has been employed to block a carboxyl group during the chemical reaction steps described below and which can be removed, if desired, by methods which do not result in any appreciable destruction of the remaining portion of the molecule, e.g. by chemical or enzymatic hydrolysis, treatment with chemical reducing agents under mild conditions, irradiation with ultraviolet light or catalytic hydrogenation. Examples of such ester protecting groups include benzhydryl, p-nitrobenzyl, 2-naphthylmethy1, allyl, benzyl, trichloroethyl, silyl such as trimethylsily1, phenacyl, p-methoxybenzy1, acetonyl, o-nitrobenzyl, 4-pyridyl- methyl and C.-C, alkyl such as methyl, ethyl or t-butyl. 1 0 Included within such protecting groups are those which are hydrolyzed under physiological conditions such as pivaloyloxy-methyl, acetoxymethyl, phthalidyl, indanyl and methoxymethy1. Particularly advantageous carboxyl protecting groups are p-nitrobenzyl which may be readily removed by catalytic hydro-genolysis and allyl which can be removed by Pd(P02)^-catalyzed reaction.
The pharmaceutical^ acceptable salts referred to above include the nontoxic acid addition salts, e.g. salts with iniiifi.il .n: it In kui 11 a:;, for uxoiipl'', hydrochloric, hydrobromic, hyili icxli <:, phosphoric and sulfuric and salts with organic acids such as maleic, acetic, citric, succinic, benzoic, tartaric, fumaric, mandelic, ascorbic, lactic, gluconic and malic. Compounds of Formula I in the form of acid addition salts may be written as R 8 H R 1 N X .6 R = H or protecting group o. '•> 0 d where X represents the acid anion. The counter anion X may be selected so as to provide pharmaceutically acceptable salts for therapeutic administration but, in the case of 0 intermediate compounds of Formula I, X may also be a toxic !) anion. In such a case the ion can be subsequently removed or substituted by a pharmaceutically acceptable anion to form active end product for therapeutic use. When acidic or basic 1 14 groups are present in the r group or on the quaternized R radical, the present invention may also include suitable 11> base or acid salts of these functional croups, e.g. acid addition salts in the case of a basic group and metal salts (e.g. sodium, potassium, calcium and aluminum), the ammonium salt and salts with nontoxic amines (e.g. trialkylamines, procaine, dibenzylamine, 1-ephenamine, N-benzyl-S-phenethylamine ;ind N,N'- l !> dibenzylethylenediamine) in Lhe case of an acidic oroup. 2 Compounds of Formula I wherein R is hydrogen, an anionic charge or a physiologically hydrolyzable ester group together with pharmaceutically acceptable salts thereof are useful as antibacterial agents. The remaining compounds of 2.0 Formula I are valuable intermediates which can be converted into the above-mentioned biologically active compounds. 25 a preferred embodiment of the present invention Dmpounds is hydrogen, CH^CH^- 8 1 comprises compounds of Formula I wherein R is hydrogen and R ch3 ch3 oh oh X. .ch-, c- or ch3ch- ch-j ch3 Among this subclass, the preferred compounds are those in which R^ is oh I chjch-, most preferably compounds having the absolute conficuration 5R, 6S , 8R.
Anothe" preferred embodiment comprises compounds of I in which R £ radical of the formula 1 8 Formula I in which R and R taken together form an alkylidene HOCH, V C= cff^ The alkylene or cycloalkylene radical A in the compounds of Formula I may be cyclopentylene cyclohexylene or C2~Cg alkylene optionally substituted by one or more C^-C4 10 alkyl substituents. Preferred A substituents are cyclopentylene, cyclohexylene or alkylene of the formula R10 R12 I I -c c- R11 L» in which R^, R^, R^"2 and R^ are each independently hydrogen or C^-C4 alkyl. A preferred embodiment comprises those compounds of 15 Formula I in which'substituent A is -CHjCI^-, -CHCH, CH, or -CH.CH-2 i 3 CH- 3 In the case of certain compounds of Formula I having a cycloalkylene or branched alkylene A substituent, one or more additional assymmetric carbon atoms may be created which result 20 in formation of diastereoisomers. The present invention includes mixtures of such diastereoisomers as well as the individual ourified diastereoisomers. 2 1 14 The quaternized R substituent may bo an optionally substituted mono-, bi- or polycyclic aromatic or non-aromatic heterocyclic radical containing at least one nitrogen in the ring and attached to A through a ring nitrogen, thereby forming '> a quaternary ammonium group. 14 One preferred class of R substituents may be represented by the general formula which is meant to define a substituted or unsubstituted mono-, 10 bi- or polycyclic heteroaryl radical containing at least one nitrogen in the ring and attached to a carbon atom of substituent A through a ring nitrogen, thereby forming a quaternary ammonium group. The heteroaryl radical may be optionally substituted by such substituents as C^-C4 alkyl, alkyl substituted by I 'j hydroxy, amino, carboxy or halo, C^-Cg cycloalkyl, C^-C4 alkoxy, C^-C^ alkylthio, amino, C^-C4 alkylamino, di(C^-C4 alkyl)amino, halo, alkanoylamino, alkanoyloxy, carboxy, 8 -C-0C1"C4 alkyl, hydroxy, amidino, guanidino, trifluoromethy1, phenyl, phenyl 20 substituted by one, two or three amino, halo, hydroxyl, trifluoro methyl, C^-C4 alkyl or C^-C4 alkoxy groups, heteroaryl and hetero aralkyl'in which the hetero atom or atoms in the above-named heterocyclic moieties are selected from 1-4 0, N or S atoms and the alkyl moiety associated with hetero-25 aralkyl has 1-6 carbon atoms.
The heteroaryl radical attached to substituent A is preferably a 5- or 6- membered aromatic heterocyclic radical containing a quaternized nitrogen atom (which is directly bonded to a carbon atom of the alkylene or cycloalkylene radical) and, 10 optionally, one or more additional hetero atoms selected from O, N or S. While, in general, any heteroaryl radical bonded to A via a quaternized nitrogen atom is found to produce biologically active carbapenem derivatives, a preferred embodiment comprises compounds in which o represents a radical selected from 7 (a) 10 wherein R5, R^ and R*7 are independently selected from hydrogen; C1-C4 alkyl; C1"C(J alkyl substituted by hydroxy, amino, carboxy or halo; C^-Cg cycloalkyl; C^-C4 alkoxy; alkylthio; amino; C^-C4 alkylamino; di(C1~C4 alkyl)amino; halo; C1~C4 alkanoylamino; C^-C4 alkanoyloxy; carboxy; , -C-OC1"C4 alkyl; hydroxy, amidino; guanidino; trifluoromethyl; phenyl; phenyl substituted by one, two or three amino, halo, hydroxyl, trifluoromethyl, Cj"C4 alkyl I '"> or C^-C4 alkoxy groups; and heteroaryl and heteroaralkyl in which the hetero atom or atoms in the above-named heterocyclic moieties arc selected from 1-4 oxygen, nitroqen or sulfur atoms and the alkyl moiety associated with said heteroaralkyl moiety has 1-6 carbon atoms; or wherein two of or 20 R7 taken together may be a fused saturated carbocyclic ring, a fused aromatic carbocyclic ring, a fused saturated heterocyclic ring or a fused heteroaromatic ring, (b) n or :: c i o optionally substituted on a carbon atom by one or more substituents independently selected from C^-C^ alkyl; C^-C4 alkyl substituted by hydroxy, amino, carboxy or halogen; C^-Cg cycloalkyl; alkoxy; C^-C4 alkylthio; amino; alkylamino; di(C^-C4 alkyl) amino; halo; alkanoylamino; C^-C4 alkanoyloxy; O ll carboxy; -C-OC^-C^ alkyl; hydroxy; amidino; guanidino; trifluoromethyl; phenyl; phenyl substituted by one, two or three amino, halo, hydroxyl, trifluoromethyl, C^-C^ alkyl or C],~C4 alkoxy groups; and heteroaryl or heteroaralkyl in which the heteroatom or atoms in the above-named heterocyclic moieties are selected from 1-4 oxygen, nitroqen or sulfur atoms and the alkyl moiety associated with said heteroaralkyl moiety has 1-6 carbon atoms, or optionally substituted so as to form a fused carbocyclic or heterocyclic ring; (c) N II © ' J f optionally substituted on a carbon atom by one or more substituents independently selected from C^-C^ alkyl; C^-C^ alkyl substituted by hydroxy, amino, carboxy or halogen; C^-Cg cycloalkyl; C1~C4 alkoxy; C^-C^ alkylthio; amino; C1~C4 alkylamino; di(C^-C4 alkvl)-amino; halo; C^-C4 alkanoy1amino; C^-C4 alkanoyloxy; carboxy; -C-OC^-C4 alkyl; hydroxy; amidino; guanidino; trifluoromethyl; phenyl; phenyl substituted by one, two or three amino, halo. hydroxyl, trifluoromethyl, Cj_-C4 alkyl or C^-C^ alkoxy groups; and heteroaryl or heteroaralkyl in which the hetero atom or atoms in the above-named heterocyclic moieties are selected I'rom I —& oxytjcn, ni troocn or sulfur atoms and the alkyl moiety associated with said heteroaralkyl moiety has 1-G carbon atoms, or optionally substituted so as to form a fused carbocyclic or heterocyclic ring; «» P J* N I H n J optionally substituted on a carbon atom by one or more substituen independently selected from C^-C^ alkyl; C^~C4 alkyl substituted by hydroxy, amino, carboxy or halogen; C^-Cg cycloalkyl; C^-C^ alkoxy; C^-C^ alkylthio; amino; C1~C4 alkylamino; di(C^-C^ alkyl) amino; halo; C^~C'4 alkanoylamino; alkanoyloxy; carboxy; 0 II -C-OC-^-C^ alkyl; hydroxy; ajnidino; guanidino; trifluoromethyl; phenyl; phenyl substituted by one, two or three amino, halo, hydroxyl, trifluoromethyl, C^-C^ alkyl or C^-C^ alkoxy groups; and heteroaryl or heteroaralkyl in which the hetero atom or ato.Ts in the above-named heterocyclic moieties are selected from 1-1 uxytKin, nitrogen or .sulfur ;.itioim; and the- alkyl moiety associated with said heteroaralkyl moiety has 1-6 carbon atoms, or optionally substituted so as to form a fused carbocyclic or heterocyclic ring; (e) or O X' wherein X is 0, S or NRin which R is Cj_~C4 alkyl or phenyl, said radical being optionally substituted on a carbon atom by one or more substituents independently selected from C^-C^ alkyl; C^-C4 alkyl substituted by hydroxy, amino, carboxy or halogen; C^-Cg cycloalkyl; alkoxy; C^-C^ alkylthio; amino; alkylamino; difC^-C^ alkyl) amino; halo; CJ_~C4 alkanoy1amino; C^-C4 alkanoyloxy; carboxy; 0 II -C-0C^-C4 alkyl; hydroxy; amidino; guanidino; trifluoromethyl; phenyl; phenyl substituted by one, two or three amino, halo, hydroxyl, trifluoromethyl, C]_~C4 alkyl or C1-C(} alkoxy groups; and heteroaryl or heteroaralkyl in which the hetero atom or atoms in the above-named heterocyclic moieties are selected from l-'i oxyncn, nitrogen or sulfur atoms and Uio alkyl moiety associated with said heteroaralkyl moiety has 1-6 carbon atoms, or optionally substituted so as to form a fused carbocyclic or heterocyclic ring; © (f) e © n—N- N or wherein X is 0, S or NR in which R is C^-C^ alkyl or phenyl, said radical being optionally substituted on a carbon atom by one or more substituents independently selected from alkyl; C^-C^ alkyl substituted by hydroxy, amino, carboxy or halogen; C^-Cg cycloalkyl; alkoxy; C1-C(J alkylthio; amino; C^-C^ alkylamino; di(C^-C4 alkyl)amino; halo; alkanoylamino C^-C4 alkanoyloxy; carboxy; 0 II -C-OC^-C^ alkyl; hydroxy;- amidino; guanidino; trifluoromethyl; phenyl; phenyl substituted by one, two or three amino, halo, hydroxyl, trifluoromethyl, alkyl or alkoxy groups; and heteroaryl or heteroaralkyl in which the hetero atom or atoms in the above-named heterocyclic moieties are selected from 1-4 oxygen, nitrogen or sulfur atoms and the alkyl moiety associated with said heteroaralkyl moiety has 1-6 carbon atoms; and N^s^/N-R N N-R N =■ N ./ \ e N N-R N ,N or 30 wherein R is C^C^ alkyl or phenyl, said radical being optionally substituted on the carbon atom by a substituent selected from C^-C4 alkyl; C^-C4 alkyl substituted by hydroxy; amino, carboxy or halccen; C^-Cg cycloalkyl; C^-C4 alkoxy; C^-C^ alkylthio; amino; C^-C^ alkylamino; di(C^-C4 alkyl) amino; C^-C^ alkanoy lamino; carboxy; 0 -C-OC^-C4 alkyl; hydroxy; amidino; guanidino; trifluoromethyl; phenyl, phenyl substituted by one, two or three amino, halo, hydroxyl, trifluoromethyl, C^-C4 alkyl or C^-C4 alkoxy groups ; and heteroaryl or heteroaralkyl in which the hetero atom or 10 atoms in the above-named heterocyclic moieties are selected from 1-4 oxycjcn, nitrogen or sulfur atoms and the alkyl moiety associated with said heteroaralkyl moiety has 1-6 carbon atoms.
Within the above subclass, the preferred compounds are those in which substituent A is -CHjCI^-, -CjHCHj- , / \ or 1 8 ^ -CH^CH- and wherein either (a) R- and R taken together represent / CH, HOCH, C= c1C 8 1 or (b) R is hydrogen and R represents hydrogen, CH^CH2-, CH, CH OH ^ v^OH , ^/CH- , ^.C- or CH3CH- .
CH3 CH3 Q 20 Particularly preferred are the compounds wherein R is hydrogen and R^ is OH ch3ch- , preferably compounds having the absolute configuration 5R, 65, 8R. i A particularly preferred embodiment of the present invention comprises preparation of compounds wherein o represents a radical of the formula .
—N ' in which R^, R® and r' are independently selected from hyi:ro CH. oh oh •C- or CH3CH- o Particularly preferred are the compounds wherein R is hydrogen and R^" is CH3CH-, preferably compounds having the absolute configuration SR, 6S, 8R.
A most preferred embodiment of the present invention comprises preparation of compounds wherein represents a radical of the formula R* in which R5, R6 and R7 are independently selected from hydrogen, alkyl, nlkoxy, C^-C^ alkyl substituted by a hydroxy group, C^-C^ alkylthio and amino. Within this subclass, the preferred compounds are those wherein substituent A is -CT^CHj-, -tpiCHj- , / \ or -CH2CH- ch, \ / ch, 1 8 / " • and wherein either (a) R and R taken together represent hoch, c= / ch, 8 1 or (b) R is hydrogen and R represents hydrogen, CH^CH^, ch, ch, oh oh ^ I ch- , ^c- or ch3ch- ch3 ch3 g Particularly preferred are the compounds wherein R is hydrogen and is T ch3ch-, preferably compounds having the absolute configuration 5R, 6S, 8R.
Another preferred embodiment of the present invention comprises preparation of compounds wherein 33 represents a radical of the formula y SCH 3 C ^-ch3 Within this subclass, the preferred compounds are those wherein substituent A is -CHCHj-, -CHjCHj- , / \ or -CHjCH- ™3 ~\-V ^H3 1 8 '• and wherein either (a) R and R taXen together represent HOCH, jc oT3 8 1 or (b) R is hydrogen and R represents hydrogen, CH^CH^-, CH, CH, OH OH < < ! I CH- \ C- or CH3CH- . < g Particularly preferred are the compounds wherein R is i " hydrogen and R^ is OH I CHjCH-, preferably compounds having the absolute configuration SR, 6S, 8R.
Another preferred embodiment of the present invention comprises preparation of compounds wherein represents a pyridinium radical. Within this subclass, the preferred compounds are those wherein substituent A is -CHCH2- _/~\ «3 / \ / or -CUjCH- and wherein either (a) ' CH, 18 R and R taken together represent hoch, ^0= CH3 8 1 or (b) R is hydrogen and R represents hydrogen, CH-jCHj-, CH, CH, OH OH ^ I CH- , S^-C~ °r CH3CH- .
CH3 Clf^ g Particularly preferred are the compounds wherein P. is hydrogen and R^ is OH CH3 A most preferred embodiment of the present invention comprises the preparation of compounds of the formula OH H wherein represents ■o (11) -CHCH, N CH. (2) (4) (6) ( 8 ) (10 ) (12) R or S diastereoisomers i-JH, (13) -ch2ch2V ^ or (14) ■CH2 3 -CH2 "CH2 CH SCH, ■ct2ch28)'=( V' —CE, R,R or S,S diastereoisomers at two assyrrenetric carbons of the cyclohexyl group 3 0 2 and R is hydroqen, an anionic charge or a conventional readily removable carboxyl protecting group, providing that when is hydrogen or a proteci.ing group, there is also present a counter anion, and pharmaceutically acceptable acid addition salts thereof. 14 Another preferred class of quaternized R substituents may be represented by the general formula ,16 R © where R1® represents either (a) an optionally substituted 10 aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aryl, araliphatic, heteroaryl, heteroaraliphatic, heterocyclyl or heterocyclyl-aliphatic radical or (b) a divalent phenylene or C^-C^ alkylene group joined to the 16 15 ring so as to form a bridged polycyclic group. Thus R may be selected from substituted and unsubstituted: alkyl, alkenyl and alkynyl, having from 1-10 carbon atoms; cycloalkyl and cycloalkylalkyl, having 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl moieties; 20 phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl moiety is phenyl and the aliphatic portion has 1-6 carbon atoms; heteroaryl, heteroalkyl, heterocyclyl and hetero- cyclylalkyl wherein the hetero atom or atoms in the above- named heterocyclic moieties are selected from 1-4 oxygen, 25 nitrogen or sulfur atoms and the alkyl moieties associated with said heterocyclic moieties have 1-6 carbon atoms; wherein the above-named R16 radicals are optionally substituted by 1-3 substituents independently selected from: C^-Cg alkyl optionally substituted by asiino, fluoro, chloro, carboxyl, hydroxy or carbamoyl; fluoro, chloro or hromo; "OR3 ; -0C02R3 j -OCOR3 ? -OCONR3R4 i -OS02K3 ; -oxo' ; 3 d -US H ; 3 ' 4 R CONR - ; -NR3C0254 7 3 5 4 -NR C0M3R Jl ; 3 4 -NR SO^H . ; ™SR3 ? 0 T 9 -S-R ? 0 >° V®' -S-R / -s03r3 j -C02R3 ; 4 -CONRH 7 -CN; or phenyl optionally substituted by 1-3 fluoro, chloro, broino, C.-C, alkyl, -OS3, -NR3K°i, -SOjR , -C02R or -CONE a , wherein R , K and R9 in suchsubstituents are as defined above; 3 8 or may represent a divalent phenylene or C^-C^ alkylene group joined to the ring so a; to form a bridged polycyclic group and represents a substituted or unsubstituted mono-, bi- or polycyclic non-aromatic (which may be fused to another aromatic or non-aromatic ring) heterocyclic radical containing at least one nitrogen in the ring and attached to A through a ring nitrogen, thereby forming a quaternary ammonium group. The heterocyclic radical may be saturated or unsaturated (with 1-2 double bonds) and may contain up to two additional hetero atoms in addition to the quaternary nitrogen, such additional hetero atoms being selected from 0, S(0) , N, NR15 or NR17R18 wherein m is 0, 1 or 2, R15 is m hydrogen, optionally substituted C.-C, alkyl or optionally substituted 17 18 *** phenyl and R and R are each independently optionally substituted C^-Cg alkyl or optionally substituted phenyl.
In a preferred embodiment represents a non-aromatic 4-7 membered, preferably 5- or 6- membered, N-containing heterocyclic ring containing Q-2 double bonds and 0-2 additional hetero-atoms selected from 0, S(0) , N, 15 17 18 15 ^ NR or NR" R wherein m is 0, 1 or 2, R is hydrogen, C.-C,. alkyl optionally substituted by 1-2 substituents indeoendentlv selected 3 3 4 3 * from -OR , -NR R , -C0,R , oxo, phenyl, fluoro, chloro, bromo, 3 3 4 -SOjR and -CONR R or phenyl optionally substituted by 1-3 substituents independently selected from C^-Cg alkyl, -OR3, -NR3R4, fluoro, chloro, bromo, -SOjR3, -COjR2 and -CONR3R4 and R17 and R13 are each independently C.-C, alkyl optionally substituted by T 7 A 1 1-2 substituents independently selected from -OR , -NR R , -C02S , oxo, phenyl, fluoro, chloro, bromo, -SOjR3 ar.d -CONR3R4 or pher.vl 3 8 optionally substituted by 1-3 substituents independently selected frem C,-C, alkyl, -OR3, -NR3R4, fluoro, chloro, bromo, -SO R , .16 ? 4 "3 4 15 -CO,R and -CONR R , wherein R and R in such heterocyclic NR or NR R18 groups are as defined above in connection with the R substituent. In such preferred embodiment the ■^O ring may be optionally substituted by 1-3 substituents independently selected from (a) C,-C. alkyl optionally substituted by 1-2 substituents JL b <3 independently selected from fluoro, chloro, bromo, -OR , -OCOR3, -OCONR3R4, oxo; -NR3R4, -NX3COR4, -NR3CONR3R4, -NR3S02R4, -SR3, -SO-jR3, -CO,R3 and -CONR3R4; (b) <-t~C5 alkenyl optionally substituted by 1-2 substituents independently selected from fluoro, chloro, bromo, -or3, -ocor3, -oconr3r4, oxo, ~nr3r4, -nr3cor4, -nr3conr3r4, -nr3so,r4, -sr3, -sojr3, -c02r3 and -conr3r4; (c) C2~Cg alkynyl optionally substituted by 1-2 substituents independently selected from fluoro, chloro, bromo, -or"*, -ocor3, -0c0nr3r4, oxo, -nr3r4, -nr3cor4, -nr3conr3r4, -nr3s02r4, -sr3, -sojr3, -cojr3 and -conr'3r4 ; (d) c3~cg cycloalkyl optionally substituted by 1-2 substituents independently selected from fluoro, chloro, bromo, -or3, -ocor3, -oconr3r4, oxo, -nr3r4, -nr3cor4, -nr3conr3r4 , -nr3s02r4, -sr3, -s03r3, -co,r3 and -conr3r4; (e) cycloalkylalkyl having 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl moiety, optionally substituted by 1-2 substituents independently selected from fluoro, chloro, bromo, -or3, -ocor3, -oconr3r4, oxo, -nr3r4, ~nr3cor4, -nr3conr3r4, -nr3so,r4, ~sr3, -s03r3, ~co,r3 and -conr3r4; 4 0 heteroaryl wherein the hetero atom or atoms are selected from 1-4 oxygen, nitrogen or sulfur atoms, optionally substituted by 1-2 substituents 3 independently selected from fluoro, chloro, brcnao, -or , -ocor3, -0c0nr3r4, oxo, ^-nr3r4, -nr3cor4, -nr3conr3r4, -nr3s02r4, -sr3, -sojr3, -c02r3 and -c0nr3r4; preferred heteroaryl radicals are 5- or 6-membered aromatic heterocyclic. rings; heteroaralkyl wherein the hetero atom or atoms are selected from 1-4 oxyqen, nitrogen or sulfur atoms and the alkyl moiety has 1-6 carbon atoms, optionally substituted by 1-2 substituents independently selected from j 3 3 4 fluoro, chloro, bromo, -OR , -OCOR , -OCONR R , oxo, 34 34 334 34 3 3 -NR R , -NR COR , -NR CONR R , -NR S0,R , -SR , -SO-R , 3 3 £ • ^ -CO,R and -CONR RJ; preferred heteroaralkyl are those in which the heteroaryl radical is a 5- or 6-membered aromatic heterocyclic ring and the alkyl moiety has 1-2 carbon atoms; heterocyclyl wherein the hetero atom or atoms are selected from 1-4 oxygon, nitrogen or sulfur atoms, optionally substituted by 1-2 substituents independently selected from fluoro, chloro, bromo, -or3, -ocor3, -oconr3r4, oxo, -nr3r4, -nr3cor4, -nr3conr3r4, -nr3s02r4, -sr3, -sojr3, -c02r3 and -conr3r4; preferred heterocyclyl are 5- or 6-membered saturated or unsaturated rings; heterocyclylalkyl wherein the hetero atom or atoms are selected from 1-4 oxygen, nitrogen or sulfur atoms and the alkyl moiety has 1-6 carbon atoms, optionally substituted by 1-2 substituents independently selected from fluoro, chloro, bromo, -OR3, -OCOR3, -OCOtiR3?. oxo, -nr3r4, -nr3cor4, -nr3conr3r4, -nr3s0,r4, -sr3, -so,?.3 3 3 4 " -COjR and -CONR R ; preferred heterocyclylalkyl are those in which the heterocyclyl moiety is a 5- or 6-membered saturated or unsaturated ring; '11 (j) fluoro, chloro or bromo; Ck) -OR3 ; (1) -OC02R3 ; (m) -OCOR3 ; '■> (n) -OCONR3R4 ; (o) -0S02R3 ; (p) oxo ; (q) -NR3R4 ; (r) R3C0NR4-; 10 (s) -NR3C02R4 ; (t) -NRJCONR3r'S ; (u) -NR3S02R4 ; (v) -SR3 ; (w) 0 ^ 9 -S-R ; (x) 0 O I • •> ^ Q -S-R ? ring as defined above is a non-aromatic heterocycle group.
This ring, however, may be fused to another ring which may be a saturated or unsaturated- carbocyclic ring, preferably a C^-C^ carbocyclic ring, a phenyl ring, a 4-7 membered heterocyclic '> {saturated or unsaturated) ring containing 1-3 hetero atoms selected from 0, N, NR^' or NR^R^® or a 5-6 membered heteroaromatic ring containing 1-3 hetero atoms selected 0, S(0) , 15 17 1ft 15 17 18 ^ N, NR or NR R in which m, R , R and R are as defined above. 10 The R^"® substituent of the non-aromatic R*4 radical may be either (a) an optionally substituted C^-Cg alkyl, alkenyl, ^"""lo alkynyl, cycloalkyl, C3-Cg cycloalkyl- C^-Cg alkyl, phenyl, phenyl-C^-Cg alkyl, phenyl-Cj-C^ alkenyl, phenyl-C.-C, alkynyl, heteroaryl, heteroaralkyl in which the £ 0 lr> alkyl moiety has 1-6 carbon atoms, heterocyclyl or heterocyclylalkyl in which the alkyl moiety has 1-6 carbon atoms or (b) a divalent phenylene or C.-C. alkylene group joined to the ring so as to form a bridged ring polycyclic group, e.g. a cuinuclidine group. The heteroaryl (or heteroaryl portion of heteroaralkyl) substituent may be a mono-, bi- or polycyclic aromatic heterocyclic group containing 1-4 O, N or S atoms; preferred are 5- or 6-membered heterocyclic rings such as thienyl, furyl, thiadiazolyl, oxadiazolyl, triazolyl, isothiazolvl, thiazolyl, imidazolyl, isoxazolyl, tetrazolyl, oxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl and pvrazolyi. The heterocyclyl (or heterocyclyl portion of heterocyclylalkyl) substituent may be a mono-, bi- or polycyclic saturated or unsaturated non-aromatic heterocyclic group containing 1-4 0, N or S atoms; preferred are 5- or 6-membered heterocyclic rings such as morpholinyl, piperazinyl, piperidyl, pyrazolinyl, pvrazolidinyl, imidazolinyl, imidazolidinyl, pyrrolinyl and pvrrolidinyl.
In the case where the R^® substituent is an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, phenyl,, pher.yl-alkyl, phenylalkenyl, phenylalkynyl, heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl group, such groups may be optionally substituted by 1-3 substituents independently selected from: (a) Ci-C5 alkyl optionally substituted by, preferably 1-3, amino, fluoro, chloro, carboxyl, hydroxy or carbamoyl groups; (b) fluoro, chloro or bromo; (c) -OR3 ; (d) -OCOjR3 ; (e) -OCOR3 ; (f) -OCONR3^'5 ; (g) -0S02R3 ; (h) -oxo ; (i) -NR3R4 ; (j) R3CONR4- ; (k) -NR3C0,R°i 3 3 4 (1) -NR CONR R : •1 4 (n) -NK3S02a4 ; (n) -SR3 ; (o) -SOR9 ; (p) -S02R9 ; (q) -S03R3 ; (r) -C02R3 ; (s) -CONR3R4 ; (t) -CN ; or (u) phenyl optionally substituted by 1-3 substituents in-.. dependently selected from fluoro, chloro, bromo, c1"c6 alkyl, -OR3, -NR3R4, -S03R3, -COjR3 or -CONR3R4, wherein, relative to the above-named R1^ substituents, the groups R3 and R4 are independently selected from hydrogen; alkyl, alkenyl and alkynyl, having 1-10 carbon atoms; cycloalkyl, cycloalkylalkyl and alkylcycloalkyl, having 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl moieties; phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl moiety is phenyl and the aliphatic portion has 1-6 carbon atoms; and heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the heteroaryl and heterocyclyl group or portion of a group is as defined above for R^® and the alkyl moieties associated with said heterocyclic moieties have 1-6 3 4 carbon atoms; or R ajid R taken together with the nitrogen to which at least one is attached may form a S- or 6-membered nitrogen-containing heterocyclic (as defined 5 9 3 above for R ) ring;* and R is as defined above for R except that it may not be hydrogen. A most preferred R^f substituent is C^-Cg alkyl, especially methyl.
In the cas? where R^6 is a divalent phenylene or C^_Cg alkylene group,, such group is bonded to another atom of the ring so as to form a bridged polycyclic ring, e.g. a quaternized cuinuclidine ring of the formula <1 5 A particularly preferred embodiment of the present invention comprises preparation of compounds of Formula I wherein represents CH3 \ -n 1?) ch" ^N® 0 ck N 'ft C? VTV Mtl W" • ■ Y ck CH, N S-? 0 / CH, <*, fT\y ' ® \ / ^-CH. wherein Y is hydrogen, C^-Cg alkyl, hydroxy, -SC^-Cg alkyl, carboxyl, carbamoyl, chloro, bromo, iodo," fluoro or phenyl. Within this subclass, the preferred compounds are those •k; wherein A is -CHCH2- ' / \ , -CH,CH- or CH 3 > / CH3 -(CHj)n~ in which n is 2, 3 or 4, more preferably those in which A is -CH2CHj-, -CH2CH2CH2-, -CTCH2- , /\ or -CH CH- CH3 / CH3 and most preferably those in which A is -CH.CH.,-, and wherein eithe: 18 (a) R and R taken together represent HOCH- 8 1 or (b) H is hydrogen and R represents hydrogen, CH^CH,-, OS CH C3 j OH ^CH- , JZ- or CH3CB- .
C33 CB3 8 Particularly preferred are the compounds wherein R is i hydrogen and R~ is OH I c33ca- especially compounds having the absolute confignrarioa 5R, 6S, 8R.
A still more preferred embodiment of the present invention comprises preparation Of compounds of Formula I wherein represents <; CH3 \ \ CH 3 N \_/ 4 7 ch \V x A. ?-*> CH l^Y \/ 8 J=H3 -CH, SO CH N "\ NH or within this preferred subclass, the preferred compounds are those ciH" CH. wherein A is -CHCH,- , 1 ^ ch3 , -CH.CH- or ^ I -(CH^)^- in which n is 2, 3 or 4, more preferably those in which CH I CH A is -CH,CH,~, -CH..CH-CH,-, -CHCH- L C. C L i. | 2 ch3 or -CH,CH- , and 2| most preferably those in which A is -CH-CH-*-, and wherein either 18 (a) R and R taken together represent HOCH. ch3 8 1 or (b) R is hydrogen and R represents hydrogen, CHjCH^t, CH CH, 3\ CH- ch3i oh oh I or CH3CH' ch. 8 , Particularly preferred are the compounds wherein R is 1 . hydrogen and R is OH C33CH- , especially compounds having the absolute configuration SR, SS, 8R.
A still more preferred embodiment of the present invention comprises preparation of compounds of Formula I wherein =,16 T) 4 .-i reDresents CH, ^/0 in which Y is hydrogen, 0.,-Cg alkyl, hydroxy, -S-C^-Cg alkyl, carboxyl, carbamoyl, chloro, bromo, iodo, fluoro or phenyl.
Within this preferred s-ubclass, the preferred compounds are those wherein A is - (CH.,) - in which n is 2, 3 or 4, most <4 n preferably those in which A is -C3,C-i,- and wherein either IS -4 4 (a) R and R taken together represent HOCH, ^C~ cs3 8 1 or (b) R is hydrogen and represents hydrogen, CH3 jH , ?H CK- , JC- or CH-CH- .
CH3 CH3 8 Particularly preferred axe the compounds wherein R is hydrogen and is oh I ch3ch-, especially compounds having the absolute configuration 5R, 6S, 8R.
K roost preferred embodiment of the present invention comprises preparation of compounds of Formula I wherein "o represents ch Within this preferred subclass, the preferred compounds art those wherein A is -(CH,)- in which n is 2, 3 or 4, oost preferably those in which A is -CH.CH-- and wherein either 18 (a) R and R taken together represent H0C32, ch3 B 1 or (b) R is hydrogen and R" represents hydrogen, CH^CHj-, ch chajh ?h CH- , C- or ch-ch- ch3 CH3 0 Particularly preferred are the compounds wherein R is hydrogen and R^" is oh I ch3ch~, especially compounds having the absolute configuration SR, 6S, 8R. r, o A most preferred embodiment of the present invention comprises preparation of the compounds of the formula wherein (6a -CH nCH ) *2 2 ^OOR^ represents CH. gn I v_v /~A N-CH.
CH v_y e; s-^o (both a- arid S-diastereoisomers) \V —N N *\ /^ch3 5 and R is hydrogen, an anionic charge or a conventional readily 2 removable carboxyl protecting group, providing that when R is hydrogen or a protecting group, there is also present a counter ion, and pharmaceutically acceptable acid addition salts thereof.
It will be appreciated that certain products within 10 the scope of formula I may be formed as optical isomers as well as epimeric mixtures thereof. It is intended that the present invention include within its scope all such .optical isomers and epimeric mixtures. For example, when the 6-substituent is hydroxyethy1, such substituent may be in either the R or-S I'' configuration and the resulting isomers as well as epimeric mixtures thereof are encompassed by the present invention.
The process of the present invention utilizes the intermediate of the formula coor2' iv which has been disclosed, for example, in European Patent Application 38,869 and which may be prepared by the general methods described therein. L represents a conventional leaving group (defined as "X" in European Patent Application 38,869) such as chloro, bromo, iodo, benzenesulfonyloxy, p-toluene-sulfonyloxy, p-ni trobenzenosulfonyloxy, me thanesulfonyloxy, trifluoromethanesulfonyloxy, diphenoxyphosphinyloxy or dittri-chloroethoxy)phosphinyloxy. The preferred leaving group is diphenoxyphosphinyloxy. Intermediates of Formula IV are generally formed _in situ by reacting an intermediate of the formula r8 h r1 1 i* i N "^-COOR2 iii 18 2' wherein R , R and R are as defined above with a suitable acylating agent R -L. The preferred intermediate IV where L is diphenoxyphosphinyloxy may be prepared by reacting keto ester III in an inert organic solvent such as methylene chloride, acetonitrile or dimethylformamide with about an eguimolar amount of diphenyl chlorophosphate in ths presence of a base such as, for exairple, diisopropylethylamine, triethylamine, 4-dimethylaminopyridine nt ;i temperature of I roni about -20°C to +40°C, most preferably at about 0"C. Intermediate IV may be isolated, if desired, but is conveniently used as the starting material for the process of the present invention without isolation or purification.
In the present process, carbapenem intermediate IV is reacted with a quaternary amine thiol compound of the formula 14 HS—A—R xe VII wherein A is cyclopentylene, cyclohexylene or alkylene optionally substituted by one or more C^-C^ alkyl groups, most preferably cyclopentylene, cyclohexylene or R10 R12 i i -C C- i11 i13 in which R^, , R^2 and R13 are each independently hydrogen cr 6 C^-C^ alkyl, X is a counter anion associated with a strong acic such as Cl~, Br , CK^SO^ , CF^SO^ or ce3"^h°3* 31,6 P14 is a quaternized nitrogen-containing aromatic or non-aromatic hcterocycle as defined above. The reaction is carried out in an inert solvent such as acetonitrile, acetoni trile-dimethylforrnamidc-, tetrahyarofuran, tetrahvdrofuran-I^O, acetonitrile-K20 or acetone in the presence of base.. The nature of the base is not critical.
Best results, however, have been obtained when a non-nucleophilic tertiary amine base such as diisopropylethylamine, 1,8-diazabicyclo-[5.4.0]undec-7-ene, 1,5-diazabicyclo[4.3.0]non-5-ene or a tri(C^-C ,) alkvlamine such as triethylamine, tributylamine or triprapylamine H is employed. Reaction of intermediate IV with thiol VII may be carricd out over a wide temperature range, e.g. -15°C up to room temperature, but is preferably done at a temperature in the range of from -15°C to +15°C, most preferably at around 0°C.
The carbapenem product produced by reaction of the quaternary amine thiol VII with intermediate IV will have a € q counter anion associated with it [e.g. (CgH^O)2P02 , CI or the -anion associated with the quaternary thiol) which may at this stage be substituted by a different counter anion, e.g. one which is more pharmaceutically acceptable, by conventional procedures. Alternatively, the counter anion may be removed during the subsequent de-blocking step. Where the quaternized carbapenem ■ compound and counter anion form an insoluble product, the product may crystallize out as it is formed and be collected pure by filtration.
Following formation of the desired carbapenem product, the 2' carboxyl protecting group R of Compound I" may be optionally removed by conventional procedures such as solvolysis, chemical reduction or hydrogenation. Where a protecting group such as p-nitrobenzyl, benzyl, benzhydryl or 2-naphthylmethyl is used which can be removed by catalytic hydrogenation, intermediate I' iii a suitable solvent such as, for exartple, dioxane-water-ethanol, tetrahydrofuron- diethylether-buffer or tetrahydrofuran-aqueous dipotussium hydroqen phosphate-isopropanol may be treated under a hydroqen pressure of from 1 to 4 atmospheres in the presence of a hydrogenation catalyst such us, for example, palladium on charcoal,palladium hydroxide or platinum oxide at a temperature of from 0 to 50°C for from about 2' 0.24 to 4 hours. When R is a group such as o-nit robenzyl, pliotol.ys.is may also be used, for deblocking. Protecting groups such as 2,2,2-trichloroethyl may be removed by mild zinc reduction. The allyl protecting group may be removed by using a catalyst comprising a mixture of a palladium compound and triphenyl phosphine in a suitable aprotic solvent such as tetrahydrofuran, methylene chloride or diethyl ether. Similarly, other conventional carboxyl protecting groups may be removed by methods known to those skilled in the art. Finally, as mentioned above, compounds of formula I' 21 where R is a physiologically hydrolyzable ester such as acetoxy-methyl, phthalidyl, indanyl, pivaloyloxymethyl, aethoxymethyl, etc. may be administered directly to the host without de-blocking since such esters are hydrolyzed in vivo under physiological conditions. 1 8 It will be understood that where the R and/or R 14 substituent or the quaternized nucleophile R attached to substituent A contain a functional group which might interfere with the intended course of reaction, such group may be protected by a conventional blocking group and then subsequently de-blocked to regenerate the desired functional group. Suitable blocking groups and procedures for introducing and removing such croups are well known to those 5 1 skilled in the art.
As in the case of other g-lactam antibiotics, compounds of general Formula I may be converted by known procedures to pharmaceutically acceptable salts which, for purposes of the present invention, are substantially equivalent to the non-salted compounds. Thus, for example, one may dissolve a compound of 2 Formula I wherein R is an einionic charge in a suitable inert solvent and then add an equivalent of a pharmaceutically acceptabl acid. The desired acid addition salt may be recovered by conventional procedures, e.g. solvent precipitation, lyophiliza-tion, etc. Where other basic or acidic functional groups are present in the compound of Formula I, pharmaceutically acceptable base addition salts and acid addition salts may be similarly prepared by known methods. 2 A compound of Formula I where R is hydrogen or an anionic charge, or a pharmaceutically acceptable salt thereof may also be converted by conventional procedures to a corresponding 2 compound where R is a physiologically hydrolyzable ester croup, o 2 a compound of Formula X wherein R is a conventional carboxyl protecting group may be converted to the corresponding compound where R is hydrogen, an anionic charge or a physiologically hydrolyzable ester group, or a pharmaceutically acceptable salt thereof.
Certain of the thiol intermediates of Formula VII may be prepared, for example, by reacting a sulfide of the formula VIIIc wherein R^", R^, R^ and R^3 are each independently hydrogen or Ct-C^. alkyl with a heteroaromatic amine (as defined above) of the (V C' <# \J> or a non-aromatic heterocyclic amine (as defined above) of the formula and a strong acid. The reaction may be carried out in the presence or absence of an inert organic solvent which is preferably .1 non-polar organic solvent such as, for example, methylene chloride, benzene, xylene or toluene. Where the amine and sulfide reagents are liquids or where a solid amine is soluble it) in a liquid sulfide reagent, it is preferred to carry out the reaction without use of an additional solvent.
The particular strong acid used in the reaction is not critical and may be, for example, such strong inorganic or organic acids as, for example, hydrochloric, hydrobromic, methane-I r> sill Tonic, p-toluonesul fonic and trifluoromethanesulfonic.
Formation of the quaternary amine thiol intermediate VII may be carried out at a temperature in the range of from -20°C to 100°C. Preferred temperatures are generally in the range of about 50~70°C. 20 The sulfide reagent, preferably employed so that the approximately equimolar amounts excess, e.g. two to three moles acid. aromatic amine and acid are sulfide and acid are used in with the amine being used in of amine per mole of sulfide or 2T> The quaternary amine thiol intermediate will have a counter anion associated with it which will be determined by the particular acid employed. It is, of course, possible to substitute at this point a different counter anion by conventional procedures for use in the subsequent reaction with carbapenem UO intermediate IV. &G The carbapenem derivatives of general Formula I 2 wherein R is hydrogen, an anionic charge or a physiologically hydrolyzaile carboxyl protecting group, or the pharraaceuticaily acceptable salts thereof, are potent antibiotics active against 5 various grain-positive and gram-negative bacteria and they may be used, for example, as animal feed additives for promotion of qrowth as preservatives in food, as bactericides in industrial applications, for example in waterbased paint and in the white water of paper mills to inhibit the growth of harmful bacteria and as 10 disinfectants for destroying or inhibiting the growth of harmful bacteria on medical and dental equipment. They are especially useful, however, in the treatment of infectious disease in humar.s and other animals caused by gram-positive or gram-negative bacteria.
I 0 The pharmaceutically active compounds provided by the novel process of this invention may be used alone or formulated as pharmaceutical'compositions comprising, in addition to the active carbapenem ingredient, a pharmaceutically acceptable carrier or diluent. The compounds may be administered by a 20 variety of mear.s; those of principal interest include: orally, topically or parenterally (intravenous or intramuscular injection). The pharmaceutical compositions may be in solid form such as capsules, tablets, powders, etc., or in liquid form such as solutions, suspensions or emulsions. Compositions for injection, 30 the preferred route of delivery, may be prepared in unit cose for^ in ampules or in multidose containers and may contain formulatory agents such as suspending, stabilizing and dispersing agents. The compositions may be in ready to use form or in powder form for reconstitution at the time of delivery with a suitable vehicle 30 such as sterile water.
The dosage to be administered depends to a large extent on the particular compound being used, the particular composition formulated, the route of administration, the nature and condition of the host and the particular situs and organism being treated. Selection of the particular preferred dosage and route of application, then, is left to the discretion of the therapist. In general, however, the compounds may be administered parenterally or orally to mammalian hosts in an amount of from about 5 to 200 mg/kg/day. Administration is generally carried out in divided doses, e.g. three to four times a day.
The following examples illustrate but do not limit the scope of the present invention.
Example 1 Preparation of 3-(2-(l-pyridiniura)ethylthio)-6<» -(1-(R) -hydroxyethyl ) -7-oxo-l-azablcyclo(3. 2.0) -hcpt:-:;-ene-2-carboxylate A. 1-(2-mercaptoe'chyl)pyr ldtnlum methane sulfonate To a suspension of pyridinium methanesulfonate in pyridine prepared by the dropwise addition of methanesulfonic acid (1.95 mL, 0.03 mol) to pyridine (8.0 mL, 0.099 mol) with cooling, was added ethylene sulfide (1.96 mL, 0.033 mol). The resulting mixture was stirred at 55°C for 16 h and concentrated under reduced pressure to a thtck syrup which was mixed with few mL of water. The solution was poured on top of a column (40 x 16 cm) of /J-bondapak C-18 which was eluted with water. Lyophylization of the appropriate fractions gave a colorless syrup 6.5 g (91%), ir (£ilm))Jmax: 2300-2600 (br, SH), 1635 (pyridinium), 1490, 1200 (sulfonate), 1068, 1060, 1045, 791, 780 cm-1, Iftar (DMS0-d6) 6: 2.32 (3H, s, CH3SO3-), 2.61,2.70, 2.73, 2.82 (1H, B part of A2B system, SH), 3.07 (211, m [with D20, 3.08 (2H, t, J-6.5 Hz) ], CH2S), 4.76 (2H, t, J-6.5 Hz, Cll2N+), 8.19 (211, m, Rra of pyridinium), 8.6 (1H, n, lio of pyridinium), 9.08 (2H, dd, J=»6.8 Hz, J-1.4 Hz, Ho of pyridinium), uv max: 206 (£5230), 258 (£ 3760) rap.
HETHOD A B. I- ^-lasrcaacoaShvDpvrldiniuiEi chlorida Permutit S-l CI An aqueous aoiucioa of cruda I ~ ( 2-mercaptoechyl)pyrldlnluta BethenaeulSonac® (9.4 g, 0.04 mol) was poured oa top of column (2.5 x 41 cc) o£ p«ermu£i£° S-I CI". Th® coiuwtn was METHOD B To a precoolsd (ice bath) pyridine (5.6 eL„ 70 uuaol) was edded pyridine hydrochloride (4.05 3, 35 tsfiol) end ethylene sulfide (2.1 mL„ 35 beoI) . The mixture was heated at 65 °C and stirred for 75 oln to give a two phases system. Ths lighear phase was removed. The remaining oil was washed vlth ether (5 k 10 mL) and pumped und®r high vacuum to give the title compound (90-100%) which was usad as such for tha nest step.
* Trade Mark C. Paranlerobensyl 3- [2~(I~pyrldinluia)ethylthlo )-6e - [1-(R)-hvdroxvethyl 3-7°oxo-l-a.aablcyclo(3.2.0)hepc--2-ene-2-carboxylate chloride A solution of p-nitrobengyl [1-(a)-hydroxyethyl ]-3,7-dlo:to~i-azablcyclo(3.2.0) hepeane-S-carboxylece (6.09 g, 17.5 ranol) in ececonicrila (20 aL) was cooled to -¥'j °C undar a nlcrogen acsaoophare and ersaeed a«ecas®iv«ly vtch dl-isopropylsehylaiaine (3.65 mL, 21.0 gaol) and dlphenyl chlorophospheea (4.34 b&, 21.0 mmol). The resulting mixture was stirred for 30 min &z 5°Ct cooled to -S°C and created successively with a solution of crude l-(2-iaar,capEoathyl)pyrldinlua chloride (4.3 g„ 24 mmol) In N c M-d IraaChyl 2o«aasidss (1.0 mL) and drop wise with dlisopropylechylassiaa: (3.65 sL, 21.0 aaol). The re: ace ion mixtures was stirred ac 0°C for 1 hrs cooled to "30°C and stirred for 15 min. more. The solid was filtered off and washed wich cold (-30°C) ecatonlcrile 3.77 g (65X) , ir (nujol) VmaK : 3300 (OH)s 1775 (C-0 of 8-lacCMi), 1690 (C-0 of ?OT ester), 1630 (pyridinium), 1605 (phenyl o£ PHB ester), 1515 (H02), 1333 cm'1- (MOj), ^-Har (DMSO-dg) 6: 1.17 (3E, d, J-6.1 HsP CH3CEOH), 3.2-3.75 (5H, H-4, 4- NJK(l?r) 2 OK • Trade Mark 01 H-6, CH2S), 3.75-4.5 (EH, H-5, CU3CflOH), 4.92 (2H, brt, J=6.5 Hz, CH2N+), 5.18 (1H, d, J=4.9 Hz, OH), 5.37 (center of ABq, Hz, CH2 of PNB), 7.69 (2H, d, J-8.7 Hz, Ho of PNB), 8.24 (d, J-8.7 Hz, Hm of PNB), 8.0-8.4 (411, Hm of PNB, Hm 52 of pyridinium), 8.66 (1H, m, Hp of pyridinium), 9.17 (2H, brd, J=5.5 Hz, Ho of pyridinium). The filtrate and washing were combined and diluted with ether (150 mL). The supernatant was decanted and the gum was dissolved 5 in water (40 mL) containing enough acetonitrile to have a solution which was poured on top of a column (3 x 10 cm) of ^i-bondapak C-18. The column was eluted with 10% acetonitrile - 90% water (150 inL) and 50% acetonitrile -50% water (100 mL) mixtures. The appropriate fractions 10 were combined and lyophylized after the acetonitrile has been removed under vacuum giving a yellowish powder. An NMR of it showed the presence of the title compound mixed with some p-nitrobenzyl 3-£2-(1-pyridinium)ethyl-thio]-6c-[l-(R)-hydroxyethyll-7-oxo-l-azabicyclo(3.2.0) 15 hept-2-ene-2-carboxylate diphenylphosphate (2:1). The powder was dissolved in water (minimum amount) and passed through a column (1.5 x 21 cm) of permutit S-lCl" with water. Lyophy11zation of the appropriate fractions gave 1.8 g (20%) of the title compound. 03 10 15 20 D. Paranltrobenzyl 3- [2-(l-pyrldlnium)cthylthlo ]-6<*- [1-(R) -hydroxy-ethyl ]-7-oxo-l-azablcylo(3.2. 0)hcpt-2-ene-2-carboxy late di phenyl phosphate.
A solution of p-nierobenzyl 6a - [1-(R)-hydroxyethyl 3-3,7-dioxo-l~azabicyclo(3.2.0) heptane-2-carboxylate (0.174 g, 0.50 mmol) In acetonitrile (2 mL) was cooled to 0°C under a nitrogen atmosphere and treated successively with di-isopropylethylamine (0.105 mL, 0.60 rnntol) and diphenyl chlorophosphate (0.124 mL, 0.60 mmol). The resulting solution was stirred for 30 min at 0°C and treated successively with a solution of l-(2-mercaptoethyl)pyridlnium methanesulfonate (0-170 g, 0.72 mmol) in acetonitrile (0.6 mL) and di-isopropylethylamine (0.105 aL, 0.60 mmol). The reaction mixture was stirred at 0°C for 15 min, diluted with cold (0°C) water (7 mL) and poured on top of a column (1.5 x 6.4 cm) of p-bondapak C-18. The column was eluted with a mixture of acetonitrile (25/i-50%) in water (75%-507,). The appropriate fractions were combined and lyophylized after the acetonitrile has been removed under vacuum giving a yellowish powder 0.33 g (92%), Ir (ICBr) "max ■ 3600-3000 (OH), 1765 (C-0 of B-lact,ira) , 1690 (00 of PNB ester), 1625 (pyridinium), 1585 (phenyl), 1510 (N02), 1330 (N02), 885 cm"! (N02), oa X) NEt (i,Pr)«, 4) HETt(i-?r)2 OS S 4 1llmn (DM-SO-rt^) 6: 1.16 (3H, d, J = 6.2 llz, CH CHOM), 4.87 (2)1, brt, J=--6.6 Hz, CH,,3), 5.37 (center of ABq , Ja b = 14.3 Hz, Cllg of PNB), 6.7-7.5 (phenyl), 7.6a (d, J-8.8 Hi, Ho of PNB), 8.23 (d, J=8.8 Hz, Hm of PNB), 8.0-8.3 (m, Hm of pyridinium), 8.4-8.8 (1H, Hp of pyridinium), 9,09 (2H, dd, J=6.7 Hz, J=1.3 Hz, Ho of pyridinium).
E.3- [2-(1-pyridinium)ethyl thiol-6d.~ Cl-(iL)-hydroxyethyl1-7-oxo-l-azabicyclo(3.2.0)hept-2-ene-2-carboxylate Method A C005N3 C?hO) Jo- 10% ?d/C, H, THT, EChec To a solution of p-nitrobenzyl 3-[2-(1-pyridinium) ethyl thio]-6eA-[l-(R)-hydroxyethyl] - 7-oxo-l-azabicyclo (3.2.0)hept-2-ene-2-carboxylate diphenylphosphate (0.16 g, 0.22 mmol) in wet tetrahydrofuran (10 mL) was added ether (10 mL), potassium phosphate monobasic-sodium hydroxide buffer pH 7.4 (16 mL, 0.05 M) and 10% palladium on charcoal (0.16 g). The resulting mixture was hydrogenated under 40 psi for 1 h at 25°C. The two phases were separated and the organic phase was extracted with water (2x3 mL). The aqueous solutions were combined, washed with ether (2 x 10 r.L) and poured on top of a column (1.5 x 6.2 cm) of /j-bondpak C-18 after the traces of organic solvents have been removed 3 under vacuum. EJution of the column with water gave after lyophylization of the appropriate fractions a yellowish powder 0.062 g (84%), ir (K^r) Vniax : 3700-3000 (OH), 1755 (C=0 of ^-lactam), 1630 (pyridinium), 5 1590 cm"1 (carboxylate), XHmr (DgO): 1.22 (3H, d, J = 6.4 Hz, CH3CH0H), 2.92 (d, J=9.1 Hz, H-4), 2.97 (d, J=9.1 Hz, H-4), 3.20 (dd, J = 2.5 Hz, J=6.1 Hz, H-6), 3.44 (t, J=6.0 Hz, CHgS), 3.93 (dd, J=9.1 Hz, J=2.5 Hz, H-5), 4.82 (t, J=6.0 Hz, CH2N+), 8.04 (m, Hm of pyridinium), 8.5 (m, 10 Hp of pyridinium), 8.82 (dd, J=3.2 Hz, £=1.1 Hz, Ho of pyrtdinium), uv (H,0) X.„QV: 259 (£5800), 296 (£7030) mp, c (nftX tjj = 13.5 H (measured at a concentration of 10~ M in phosphate buffer pH 7.4 at 36.8°C).
S 6 Method B oa A S3 ■s 0307NS CI 10H ?d/C,H, ->■ THF, other buffer 7.2 To a solution of p-nitrobenzyl 3- [2-(1-pyridinium) ethylthio]-6cs-[l-(R)-hydroxyethyl]-7-oxo-l-azabicyclo (3.2.0)hept-2-ene-2-carboxylate chloride (5.77 g, 11.4 mmol) in potassium phosphate monobasic-sodium hydroxide buffer (170 mL, 0.2 M, pH 7.22) was added tetrahydrofuran (30 mL), ether (30 mL) and 10% palladium on charcoal (5.7 g). The resulting mixture was hydrogenated at 22°C under 40 psi for 1 h and filtered on a Celite*pad. The pad was washed with water (2 x 15 mL). The filtrate and washings were combined and diluted with ether (100 mL). The aqueous phass was separated, washed with ether (3 x 100 mL) and poured on top of a column (4.5 x 20 cm) of jj-bondapak C-18 after the organic solvants have been removed under vacuum. Elution of the column with water followed by a mixture of 1% acetonitrile in water gave after lyophyllzation of the appropriate fractions 2.48 g (65%) of the title compound as a yellowish powder. The analytical data were identical to those reported for the compound prepared in the method A.
" Trade; Mark ®7 Example 2 Preparation of 3-C2-(l-(3,5-di rnethylpyridinium) ethyl thiol] [l- (K) -hydroxyethy 1] -7-oxo-l-azabicyc lo (3.2.0. )hcp t-2-enc-2-carboxy 1 ate COO A. l-(2-mereaptoethy1)-3,5-dimethylpyridinlum methane-sulfonate / \ + N + HsOH To a suspension of 3,5-lutidinium methanesulfonate in 3,5-lutidine prepared by the addition of methune-sulfonic acid (0.65 mL, 0.010 mol) to cold 3,5-lutidine (2.51 mL, 0.022 mol) was added ethylene sulfide (0.655 mL, 0.011 mol). The resulting mixture was stirred under a nitrogen atmosphere at 55°C for 24 h, cooled to 23°C and diluted with water (5 mL) and ether (5 mL). The organic layer was separated and the aqueous solution was washed with ether (6x4 mL). The traces of ether were removed under vacuum and the solution was applied on top of a column (2.5 x 6.0 cm) of ^-bondapsk C-18. The column was elutcd with water and lyophi1ization of the S3 10 appropriate fractions gave a colourless syrup 2.4 p (91%); ir (film) nJ : 2520 (SH), 1620 (pyridinium), (TIclX 1600, 1495, 1325, 1305, 1283, 1200 (sulfonate), 1040, 938, 765, 680 cm-1; 1Hmr (DMSO c/&) 6: 2.31 (3H, s, CH3S03~), 2.47 (6H, s, CH3 on pyridinium), 2.57, 2.66, 2.69, 2.78 (1H, B part of AgB system, SH), 3.06 (2H, m[with D20 added (2H, t, J=6.5 Hz)], CH2S), 4.65 (2H, t, J=6.5 Hz, CHgN+), 8.34 (1H, s, Hp of pyridinium), 8.79 (2H, s, Ho of pyridinium); uv (Ho0) : 271 (£4860) C ITicLX my. Anal. calcd. for C10H17N03S2.0. 5H20: C44.09, H 6.66, N 5.14, S 23.54; found: C 44.26, H 6.49, N 5.17, s 24.18.
B. Paranltrobenzyl 3-C2-(1-(3,5-dlme thylpyrldinlum)) ethyl thiol -6«—CI-(B.) -hydroxyethyll-7-oxo-l-azabieyelo (3.2.0)hept-2-ene-2~carboxylate diphenylphosphate X) NEt(i?r). 15 To a cold (0°C) solution of p-ni trobenzyl 6t<-(l-(R)-hydroxyethyl)-3,7-dioxo-l-azabicyclo(3.2.0)heptane-2-carboxylate (0.523 g, 1.50 mmol) in acetonitrile (6.0 mL) kept under a nitrogen atmosphere was added diiso-20 propyls thy 1 amine (0.314 mL, 1.8 mmol) followed by diphenyl chlorophosphate (0.373 mL, 1.8 mnol). The reaction mixture was stirred for 30 min and treated with a solution of l-(2-mercaptoethyl)-3,5-dimethyl-pyridinium methanesulfonate (0.493 g, 1.87 mmol) in acetonitrile (1.9 mL) followed by diisopropyleehylaslne (0.314 niL, 1.8'lsboI) . The reeccion fixture was stirred re 0°C for 1 hr, diluted with cold (0°C) water (26 mL) And poured on cop of a column (7.0 t: 3.5 cm) of ;U-bondepek C-18. Elution o£ eha column wish 25-501 aceeonltrile - 7 5-501 wacer mixture gov® efesr lyophilisation of Che appropriate fractions 1.01 g (90%) o£ eha title compound aa yellowish powdar, ir (KBr) vB£U£: 3700-3100 (OH), 1778 (C-0 of 8-laccaa), 1700 (C=0 of PHB ester), 1635 (pyridinium), 1595 (phenyl), 1521 (K02), 1335 (K02), 859 era"1 (M02), lHar (BMSO d$) %: 1.16 (3Hr d, J-6.1 Ha, CH3CHOH), 2.43 (s, CH3 oa pyridinium) p 4.75 (2H, », CHjt'H") s 5.38 (csntar o£ ABq, Jg^-14.3 Hz, CHj of PWB) c S.6-7.5 (10H, bs phenyl), 7.70 (2K, d, J-8./ Hs„ Ho of PHB) s 8.0.-8.5 (3H, m„ Hp of pyrldiniusa, Hm of PNB), 8.82 (2H, 0, Ho of pyridinium), uv (H20) ^■ax:27° (£11570), 306 ( £ 7343) s4J. ikial■ cslcd. for €371133^301 oS?.H20: C 58.03, H 5.26, IS 5.48, S 4.18; found: C 57.98s H 5.05, N 5.22, S 4.34. 10 15 20 C. fg-( l-(3, 5-dimc thy 1 pyridinium) )o thyl t.hj ol -6a- [l-(Ji) -hydroxyethy l] -7-oxo-l-.-i7.abi eye lo( 3. 2 . 0)hept -2-cne-2-carboxylate To a solution of p-nitrobenzyl 3-[2-(l-(3,5-dimethylpyridinium)) ethylthio]-6d-[l-(R)-hydroxyethy1}-7-oxo-l-azabicyclo(3.2.0)hept-2-ene-2-carboxylate diphenylphosphate (0.600 g, 0.80 mmol) in wet tetrahydro-furan (36 mL) was added ether (36 mL), potassium phosphate monobasic-sodium hydroxide buffer (0.05M, pH 7.4, 44 mL) and 10% palladium on charcoal (0.60 g) . The resulting mixture was hydrogenated under 40 psi at 23°C for 1.25 h. The organic layer was separated and extracted with buffer (2x5 mL). Water layers were combined, filtered through a Celite pad, washed with ether (40 mL), pumped to eliminate traces of organic solvents and poured on top of a column (2.5 x 10.0 cm) of ^i-bondapak C-18.
Elution of the column with water and lyophilization of the appropriate fractions gave the title compound 0.186 g (64$) as a yellowish powder, ir (KBr) N' x ■" 3700-3100 (OH), 1760 (C=0 of p-lactam), 1595 crn 1(carboxylate), 1llmr (DjO) 6: 1.21 (3H, d, £-6.3 Hz, CH^CHOH), 2.45 (6H, s, Cll^ on pyridinium), 2.81 (d, £=9.2 Hz, H-4), 2.90 (d, £=9.2 Hz, H-4), 3.22 (dd, £=2.6 Hz, £=6.2 Hz, H-6), 3.40 (t, £-6.2 Hz, CH2S), 3.84 (dd, J=9.2 Hz, £=2.6 Hz, H-5), 4.15 (m, CHgCHOH), 4.71 COO 10 (t, J=6.2 Hz.CHgN ),e.21(in, a, Hp of pyridine) ,8.-16(21% s, Ho of pyridinium), uv (H»0) ^ : 279 (6.8345), 296 2^ c. max (£7714) m, Mn + 40-7 Example 3 Preparation of (5fl, 6£)-3- |"[2-hydroxymethylpyridlnio) ethyl]thio]-6-Tl-(R)-hydroxyethyl]-7-oxo-l-azablcyc]o 13.2.01 hept-2-ene-2-carboxylate 73 IT) A. 3-Hydroxymethyl-1-(2-mercaptoethyl)pyridinium trif luororacthane.'nil fonate Trtfluoroeaehanesulfonic acid (1.327 mL, 0.015 taol) was added dropwlse to 3-pyridinemechanol (2.91 mL, 0.030 mol), followed by ethylene sulfide (0.89 mL, 0.01S mol)• The resulting homogeneous mixture was heated (oil bath) at 50-70°C under N2 for 20 h. The reaction mixture was than taken up In HjO (15 mL) and extracted with CH2CI2 (5x5 mL). The aqueous phase was concentrated In vacuo and then applied to a C^g reverse-phase column. Elutton with H2O followed by evaporation of the relevant fractions gave a pale yellow oil. This material was rechromatographed to give a nearly colourless oil. After drying in vacuo (P2O5) this afforded the product (4.50 g, 94%) as a viscous oil. ir (film) Vmax:3^50 (s, OH), 2560 (w, SH) cm"l. iHmr (dg-scetone) 5: 9.10-8.05 (m, 4H, aromatic), 5.01 (t, J*"5.5 Hz, 2H, N-CH2), 4.93 (s, 2H, -CH20H), 4.43 (br S, 1H, -OH), 3.43-3.18 (m, 2H, S-CH2), 2.34-2.10 (in, 1H, SH). 7 4 B. p-Mierobansyl (5R.6S)-3- [2-Q-hydroxymeehyl-pygtdlnto)eehyiL Chip ]-6- [1-(R)-hydroKyeehyl)-7~ o;to--l-asabicyclo [3.2.0 3hept-2-ene -2-catrboxylaee 6. Iphs try loho ephat a XQ~° * co j«a 2 To £i solution of p-nierobsngyl (5R,6S)-6-[l-(R)-hydjrosysthyl3~387-dio:rco-i-fi2:ebieyclo [3.2.0)hepeaaa-2-earboxylacs (0.1/4 g, 0.50 mmol) in 2 eL of dry f.catonitrile wes added diiEopffopyleehylcosine (0.096 mL, 0.55 tciaol) ©c 0°C under t'lj• Diphenyl chlorophoeplieCe (0.114 @1.;, 0.55 mnol vea Chen added drop-rise and fcs rsactlcn mlxtxzcs wes atlrrsd ac Q°C for 30 win. A solution 3-hydroiryia<3thy!-l-(2-aarcapco raacelon mixeura w&s conconcrac«d in vacuo end eh® raaidual yellow gum web taken up is HoO (enough acseonierlle wee added to aid in dissolving che gum). This solution was applied co a Ciq reversa-phasa column which was aluted with 15% aceconierila-HsO* Lyophilisseion of the relevant fractions effordad chs produce (0.305 g, 81%) aa a beige-coloured solid, lr (KBr) Vmajt: 3420 (br, OH), 1775 (8-lactara CO), 1695 (-CO2PNB) cm°l; 1Hmr (<*6" acctone) 6: 9.44-7.72 (m, 8H, aromatic), 7.22-6.91 (m, 10H, diphenylphosphate),5.53, 5.27 (ABq,J« 14Hz,2H, benzyltc), 5.04 (t, J-7.4 Hs, 2H, H-CH2), 4.75 (s, 2H, CH2OH), 4.5-3.1 (m, 8H), 1.21 (d.J» 6.3 He, 3H, CHMa). 7 0 C. (5R,6S)-3- [2-(3-hydroxyniethylpvrldinlo)oChyl) ehlo ]-6- [l-(R)-hydroxyethyl)-7-ogo-l-azflblcyclo r, To a solution of p-nitrobenzyl (5R,6S)-3~ [2- (3-hydroxymethylpyridinio)ethyl thio ]-6- [l-(R)-hydroxyethyl ]-7-oxo-l-azabicyclo [3.2.0 ]-hept-2-ene-2-carboxylate diphenylphosphate (0.145 g, 0.194 mmol) in 10 mL of THF containing 5 drops of H2O, was 10 added 6.0 mL of phosphate buffer (0.05 M, pH 7.4), 0.145 g of 10% palladium-on-charcoal and 10 mL of ether. The mixture was hydrogenated (Parr) at 40 psi for 1 h and then filtered through a pad of Celite. The filter cake was washed with a little H2O and 15 ether and the aqueous phase was separated and extracted with ether (3x). The aqueous solution was then cooled at 0°C and the pH was adjusted to 7.0 with pH 7.4 buffer. After removing residual volatiles in vacuo the aqueous solution was applied 20 to a C^8 reverse-phase column which was eluted with H2O. Lyophilization of the relevant fractions gave the product (36 mg, 51%) an a light yellow solid. Further purification by reverse-phase hplc gave the pure product (31 mg, 41%) as a solid. ir (KBr) Vmax: 3300(bf, OH), 1755 ( B-lactam CO), 1590 (-CO2") cm"'-; ^Hnmr (D2O) 6: 8.78-7.94 (m,4H aromatic), 6.83 (t, J-6.0 He, 2H, N-CH2), 4.83 (s, 2H, CH20H), 78 4.16 (d of q, J"J'"6.2 Hz, IH, H-1'), 3.98 (d, of t, J-9.1 Hz, J'-2.6 Hz, IH, H-5), 3.75-3.20 (m, 3H), 3.20-2.65 (m, 211), 1.22 (d, J«6.4 Hz, 3H, CHMc); uv (H20) \„ax"- 294 (6 7614), 266 (£6936) nm; Cv (pH 7.4, 36.8°C) 14.0 h.
Preparation of (5R.6S)-3- [2-(4-hydroxymet:hvlpyrldinlo)et:hylt:hlo]-6-[l-(R)-hydroxyethyl ]-7-oxo-l-azabtcyclo [3.2.0jhept- Example 4 10 2-ene-2-carboxylate 75 A. 4-Hydroxymqthy1-l-(2-mcrcaptoothyl)pyridinlum tri fluoromethanesu 1fonate ~G8,CE A i hscb2CJ; To a solution of 4-pyridinemethanol (1.635 g, 0.015 mol) in 10 mL of CHgCl2, at 0°C under N2, was added drop- wise trifluoromethanesulfonic acid (1.327 mL, 0.015 mol).
A yellow-brown oil rapidly separated out. An additional equivalent of 4-pyridinemethanol (1.635 g, 0.015 mol) was added to this mixture and the solvent was removed under reduced pressure to give an oil. To this oil was added ethylene sulfide (0.891 mL, 0.015 mol) and the resulting homogeneous mixture was heated (oil bath) at about 60°C for 3 h. The reaction mixture was then taken up in 15 mL of H^O and the aqueous solution was washed with CH^Clg (5x5 mL). After removing residual organic solvent in vacuo the aqueous solution was applied to a C18 reverse~Phase column. Elution with H,,0 and subsequent evaporation of the relevant fractions afforded an oil which was further dried in vacuo over to Sive the product (4.64 g, 97%) as a colourless oil. ir (film) V : 3455 (s, OH), 2565, (w, SH) cm ^; ^Hnmr (dE-acetone) max o 6: 9.07, 8.18 (ABq, J = 6.8 Hz, 4H, aromatic), 5.03 (s, 2H, CH20H), 4.96 (t, J=6.5 liz, 2H, N-CH2), 4.09 (br s, IH, -OH). 3.5-3.1 (m, 2H, S-CHg) , 2.25 (brs; 1M, -SH). so B. p-Nltrobrny.yl ( 5fj, 6'->) -3- f2- ( 4-hydroxyni^ i.lyy 1 py r iriin io) ethyl thio~]-6-Cl-(B)-hydroxyr:thy]]-7-oxo-l-azabicyclo [3.2.0!1 hept-2-enc — 2-carboxy 1 ate dipln.'ny 1 phosphate To a solution of p-nitrobenzyl (5R,6S)-6-[l-(R)-hydroxyethyl]-3,7-dioxo-l-azabicyclo[3.2.Oj heptane-2-carboxylate (0.348 g, 1.0 mmol) in 6 mL of dry acetonitrile, at 0°C under N,,, was added dropwise diisopropyl-ethylamine (0.191 mL, 1.1 mmol) followed by diphenyl chlorophosphate (0.228 mL, 1.1 mmol). The resulting golden-yellow solution was stirred at 0°C for 40 min. To this solution was added a solution of 4-hydroxymethyl-1-(2-mereap toethy1)pyridinium trifluorome thanesulfonate (0.447 g, 1.4 mmol) in 1 mL of acetonitrile, followed by diisopropylethylamine (0.191 mL, 1.1 mmol). A reddish-black gum separated from the reaction mixture. After 20 min at 0°C the reaction mixture was filtered and concentrated in vacuo. The residue was taken up in a minimum volume of acetorvitrile-H^O (1:1) and applied to a reverse-phase column. Elution with ?5% acetonitrile HgO and subsequent lyophi1ization of the relevant fraction 8 1 gave the product (0.353 g, 4756) as a cream-colourcd solid. ir (KBr)V :3240 (br, OH), 1775 (fi-lactam CO), max - ' 1695 (-COgPNB) cm ; Hnmr (dg-acetone) 6: 9.24-7.84 (m, 8H, aromatic), 7.4-6.9 (m, 10H, diphenylphosphate), 5.52, S.24 (ABq, £=14 Hz, 2H, benzylic), 5.15-4.80 (m, 4H), 4.45-3.05 (m, 7H), 1.35 (d, J=6.6 Hz, 3H, CHMe). 82 C . ( 5jj., GS ) -3- C2- ( 4-hydroxyme thy lpy rid inio ) e thy 1 th io] -6- fl- ( H ) -hydroxye thyl] -7-oxo-l - azabioyc lo £3 . 2 . 0] hep t-?-c~nt:- 2-carboxy lata OH a \ 7° O' CO PKB • 3^ 2 ■ * OH A mixture of p-nitrobenzyl (5R,6S)-3-[2-(4-hydroxy-methylpyridinio)ethyl thio] - 6- [l -(R)-hydroxyethyl}-7-oxo 1-azabicyclo [3.2.0]hept-2-ene-2-carboxylate diphenylphosphate (0.348 g, 0.465 mmol) and 10% palladium-on-charcoal (0.35 g) in 11 mL of phosphate buffer (0.05 M, pH 7.4), 5 mL of THF and 10 rnL of ether was hydrogenated at 40 psi for 1.25 h. The mixture was then filtered through a Celite pad and the aqueous phase was washed with ether (3 x). The pH of the aqueous solution was then adjusted to 7.0 using additional pH 7.4 buffer. After removing residual volatiles in vacuo the aqueous solution was applied to a C^g reverse-phase column. Elution with 2% acetonitrile-HgO and subsequent lyophil-ization gave a yellow-brown solid. This material was re chromatographed (C^g reverse-phase/HgO) to give the desired product (0.060 g, 36%) as a light yellow solid. ir (KBr) V • 3400 (br, OH), 1755 (£-lactam CO), 1590 max (-C02 ) cm-1; innmr (DjO) 6: 8.73, 7.96 (ABq, J = G.8 Hz, 4H, aromatic), 4.93 (s, 2H, CHgOH), 4.77 (t. J^6.0 Hz, 83 211, N-CH2), 4.15 (d of q, J=J'= 6.3 Hz, IH, H-1'), 3.96 (d of t, J-9.2 Hz, J'=2.6 Hz, IH, H-5), 3.65-3.20 (m, 3H), 3.13-2.62 (m, 2U), 1.21 (d, J=6.3 Hz, 3H, CHMe); uv (»20) ^max: 295 (£6880)> 2S6 (£5595), 224 (£8111) run; (pH 7.4, 36.8#C) 14.5 h 34 Example 5 Preparation of 3- £?-(1-(2-me thylpyridini um)) -ethylthio]-6 Elution of the column with 25% acetonitrile - 75% water and with 50% acetonitrile - 50% water gave after lyophilization of the appropriate fractions 1.06 g, (96%) of the title compound as a yellowish powder, ir (KBr) v» : 3650-3100 (OH), 1770 (C=0 of fl-lactam), 1695 and max 1690 (C=0 of PNB ester), 1630 (pyridinium), 1595 (phenyl), 1518 (N02), 1335 (N02), 890 cm-1 (N02), XHmr (DMSO, d&) 8: 1.15 (3H, d, J=6.1 Hz, CH^CHOH), 2.87 (s, CH3 on pyridinium), 3.6-4.4 (2H, m, H-5, CH^CHOH), 4.75 (2H, m, CH2N+), 5.37 (center of ABq, J = 14 Hz, CH2 of PNB), 6.5-7.4 (10 H, m, phenyl), 7.70 (2H, d, J=8.8 Hz, Ho of PNB), 8.0 (2H, m, Hm of pyridinium), 8.24 (2H, d, J=8.8 Hz, Hm of PNB), 8.50 (IH, m, Hp of pyridinium), 8.95 (IH, brd, J=6.1 Hz, Ho of pyridinium), uv (HgO) 7vmax." 265 (£11990), 314 (t8020)mp C. 3-f2-(l-(2-methylpyridinium))ethylthio]-6a -[l-(R)-hydroxyethyl]-7-oxo-l-azablcyclo(3.2.0)hept-2-ene-carboxylate OH J I THF, ether, buffer 10* ?4/C, a COOPKB (?h0) 2J»0 OH COO S7 To a solution of p-nitrobenzyl 3-[2-(l-(2-methy1-pyridinium))ethyl thio)-6 ot>-Q-( R) -hydroxyethyf}-7-oxo-l-azabicyclo(3.2.0)hept-2-ene-2-carboxylate diphenylphosphate (0.66 g, 0.90 mmol) in wet 5 tatrahydroturan (34 mL) was added ether (34 mL), potassium phosphate monobasic-sodium hydroxide buffer (0.15 M, 16.5 mL, pH 7.22) and 10% palladium on charcoal (0.66 g). The resulting mixture was hydrogenated under 40 psi at 23"C for 1.25 h. The *0 organic layer was separated and extracted with buffer (2x6 mL). Water layers were combined, filtered through a Celite pad, washed with ether (40 mL), pumped to eliminate traces of organic solvents and poured on top of a column (2.5 x 10 cm) of p-bondapak C-18. Elution of the column with water and lyophylizatlon of the appropriate fractions gave the title compound 0.098 g (31%) as a yellowish powder, ir (KBr) V „ : 3650-3100 (OH); 1755 (CssO of /J-lactam), 1630 (pyridinium), 1595 cm" 20 (carboxylase), 1Hmr (DjO) 1.20 (3H, d, J=6.3 Hz, CH3CH0H), 2.83 (s, CH3 on pyridinium), 2.7-3.1 (5H, H-4, CHg on pyridinium), 3.1-3.7 (3H, m, CHgS, H-6), 3.90 (dd, J=9.1 Hz, J = 2.6 Hz, H-5), 3.1 (m, CHgCHOH), 4.78 (t, J=6.2 Hz, CH2N+), 7.8 26 (2H, ni, Hm of pyridinium), 8.3 (IH, m, Hp of pyridinium), 8.65 (IH, m, Ho of pyridinium), uv (H2°) A max:268 (G-9350), 296 (&8840) mp, WD23 +41" (c 0.5, HjO), Ty = 15.0 h (measured at a concentration of 10-4 M in phosphate buffer 30 pH 7.4 at 36.8°C). 88 Example 6 Preparation of 3-1"_2-( 1 -(4-methylpyridInium)-o thy 1 thiol -6a.- l](ii) - hydroxyethyll -7-oxo-l-azabicyclo(3.2.0)hept-2-ene-2-carboxylate 5 COO :h 3 A. l-(2-rnercaptoethyl)-4-m6thylpyridinium methanesulfonate To a suspension of 4-picolinium methanesulfonate in 4-picoline prepared by the addition of methanesulfor.ic 10 acid (0.65 mL, 0.010 mol) to 4-picoline (2.14 mL, 0.022 mol) in cooling was added ethylene sulfide (0.655 mL, 0.011 mol). The reaction mixture was stirred under a nitrogen atmosphere at 55°C for 24 h, cooled to 23°C and diluted with water (5 mL) and ether (10 mL). The 15 organic layer was separated and the aqueous layer was washed with ether (5x5 mL) and applied on top of a column (2.5 x 10 cm) of ji-bondapak C-18 after traces of ether have been removed under reduced pressure. Elution of the column with 1554 acetonitrile 85% water 20 mixture fjave after lyophylization of the appropriate fractions a colorless 8R 10 15 20 syrup 2.66 g (100%), ir (film) \>max: 2500 (SH), 1640 (pyridinium), 1572, 1520, 1478, 1200 (sulfonate), 1040, 833 and 768 cm-1, XHmr (DMS0-^6) 8: 2.31 (3H, s, CH3S03~), 2.62 (s, CH3 on pyridinium), 3.2-2.9 (4H, SH, CH3 on pyridinium), 3.04 (2H, m, CHgS), 4.68 (2H, t, J=6.4 Hz, CH2W*), 8.01 (2H, d, J=6.6 Hs, Hm of pyridinium), 8.89 (2H, d, J=6.6 Hs, Ho of pyridinium), uv (H,0) \ „ : 256 (.64100), 221 (367544) mu. d. A max ' B. l-(2-mercaptoethyl)-4-methylpyrldinium p-toluene-sulfonate To a suspension of p-toluenesulfonic acid (1.72 g, 0.01 mol) in benzene (6.5 mL) was added 4-picoline (1.17 mL, 0.012 etol). The resulting mixture was stirred under a nitrogen atmosphere at 23"C for 30 min, treated with ethylenesulfide (0.65 mL, 0.011 mol) and stirred at 75° for 24 h. More ethylenesulfide (0.65 mL, 0.011 mol) was added and the stirring was continued at 75"C for 24 h more. The reaction mixture was cooled to 23°C and diluted with water (S mL) and ether (8 mL). The aqueous layer was separated and washed with ether (3x8 mL). The traces of organic solvents were removed under vacuum and the compound was chromatographed on ^-bondapak C-18 with water as eluting solvent to give 2.94 g (90%) ot the title compound as a colorless syrup; ir (film 2510 (SH) 1640 (pyridinium), max 1595, 1582, 1475, 1200 (sulfonate), 1031, 1010, 818 cm"1, ^Hmr no (DMSO,d&) 5: 2.29 (3H, s, CHg on pyridinium), 2.61 (s, CH3 Ph), 2.4-2.8 (4H, SH, CH3 Ph), 3.03 (2H, mCaddition of 0^0 gave at, J= 6.4 Hz, at 3.04], CHjS), 4.68 (2H, t. J«6.4 Hz, CHgW^), 7.11„7.49 (4H, 2d, 5 J=7.9 Hz, Phenyl), 8.00 (2H, d, J=6.S Hz, Bm of pyridinium), 8.89 (2H, d, J-6.5 Hz, Ho of pyridinium), uv (H20) X max: 256 (£ 4315), 222 fel7045) mp. C. Paranl trobenzyl 3- 5-( l-(4-methylpyrldinluin))ethyl-thid-6ei-fl-(.B)-hydroxyethy 1] -7-oxo-l-azabicvclo(3.2.0) 10 hept-2-ene-2-carboxylate diphenylphosphate To a cold (0°C) solution of p-nitrobenzyl (R)-hydroxyethyl]-3,7-dioxo-l-azabicyclo(3.2.0)heptane-2-carboxylate (0.522 g, 1.5 mmol) in acetonitrile (6 mL) 15 kept under a nitrogen atmosphere was added diisopropyl-ethylamine (0.314 mL, 1.8 mmol) followed by diphenyl chlorophosphate (0.373 mL, 1.9 mmol). The reaction mixture was stirred for 45 min and treated dropwise with a solution of l-(2-mercaptoethyl)-4-methylpyridinium 20 methanesulfonate (0.539 g,2.16 mmol) in acetonitrile (1.8 mL) followed by diisopropylethylamine (0.314 mL, 1.8 ramol). The reaction mixture was stirred at 0"C for 1 h, diluted with cold (0"C) water (24 mL) and poured on top of a column 1) NEc(ifr) 9 2) o.P{OP!02 4) Sfe) 91 10 15 (2.5 x 8.5 cm) of ^l-bondapak C-18. Elution of the column first with 25% acetonitrile -75% water mixture (100 mL) then with 50% acetonitrile 50% water mixture (100 mL) afforded after lyophylization of the appropriate fractions 0.91 g (83%) of the title compound ac a yellowish powder, ir (KBr) max: 3700-2800 (OH), 1770 (C=0 of ft-lactam), 1700 (C=0 of PNB ester), 1640 (pyridinium), 1595 (phenyl), 1520 (N02), 1340 (N02), 890 cm-1 (N02), 1Hmr (DMSO.Jg) 6: 1.16 (3H, d, J=6.2 Hz, CH3CH0H), 2.61 (s, CH3 on pyridinium), 3.1-3.7 (3H, m, H-6, CH2S), 3.7-4.4 (2H,m,H-5, CHgCHOH), 4.79 (2H, brt, J=6.3 Hz, CH2N+), 5.17 (d, J=4.9 Hz, OH), 5.37 (center of ABq, J=14.1 Hz, CH2 of PNB), 6.7-7.4 (10 H, m, phenyl), 7.69 (2H, d, J=8.8 Hz, Ho of PNB), 8.00 (2H, d, J=6.5 Hz, Hm of pyridinium), 8.23 (2H, d, £=8.8 Hz, Hm of PNB), 8.92 (2H, d, J=6.5 Hz, Ho of pyridinium), uv (HgO) A max : 262 (£10835), 311 (£9670) mji. Anal, calcd. for C36H36N3010SP• 1.5 H20: C 56.84, H 5.17, N 5.52, S 4.21; found C56.89, H 5.13, N 5.19, S 4.41.
D. 3-f2-( l-( 4-methylpyrldlnium) ethyl thiol -6ft- [~1-(B) -hydroxye chy1)-7-oxo-l-azablcyclo(3.2.0)hept-2-ene-2-Ccir-boxylate ch 1 10* ?i/C, H2 THT, buffer oa. 92 To a solution of p-nitrobenzyl 3-[2-(l-(4-me thy lpy rid in turn) ) -e liiy 1 thio] -6*.-11 -(R) -hydroxye thy 1 )-7-oxo-l-azabicyclo(3.2 .0)hep t-2-ene-2-carboxylate diphenylphosphate (0.t>07 g, 0.80 mmol) in wot tetra-5 hydrofuran (30 mL) was added ether (30 mL), potassium phosphate mono basic-sodium hydroxide buffer (0.15 M, 14.7 mL, pH 7.22) and 10% palladium on charcoal (0.59 g). The resulting mixture was hydrogenated under 40 psi at 23°C for 1.25 h. The organic layer was separated 10 and extracted with the buffer. (2x6 mL). The aqueous extracts were combined, filtered through a Celite pad, washed with ether (3 x 20 mL), pumped to remove traces of organic solvents and poured on top of a column (2.5 x 10 cm) of ^i-bondapak C-18. Elution of the 15 column with water and lyophylization of the appropriate fractions gave 0.136 g (49%) of the title compound as a yellowish powder-, ir (KBr) V 3700-3000 (OH), "iclx . 1770 (C=0 of /^-lactam), 1642 (pyridinium) 1592 cm (carboxylate), ^Hmr (DjO) S: 1.19 (3H, t, J=6.3 Hz, 20 CH3CH0H), 2.59 (3H, s, CRj on pyridinium), 2.84 (d, J=9.1 Hz, H-4), 2.90 (d, J=9.1 Hz, H-4), 3.0-3.6 (3H, m, CH2S, H-6), 3.86 (dd, J=9.1 Hz, J=2.6 Hz, H-5), 4.12 (m, CH3CH0H)), 4.5-4.9 (CH2N+ masked by HOD), 7.80 (2H, d, J=6.6 Hz, Hm of pyridinium), 8.58 (2H, d, J-6.6 Hz, Ho 25 of pyridinium), uv (Ho0) A : 256 (£5510), 262 (C5360) , £ max 296 (£7050) m, + 20.8° (C 0.48, HgO), T^=12.8 h (measured at a concentration of 10~4 M in a phosphate buffer pH 7.4 at 36.8°C).
Example 7 10 15 Preparation of (55) 3- I 2-(4-methylthlopyrldlnlo)-ethylthlo ]-(6S)- [(1R)-hydroxyethyl ]-7-oxo°l-azablcyclo [3.2.0 ]hopt-2-ene-2-carboxylate 4-Mercaptopyrldine (5.55 g, 50.0 mmol; Aldrlch) was dissolved In boiling abs. EtOH(50 mL). The Insoluble material was removed by filtration over Celite. The filtrate was heated to re-dlssolve, and when It cooled to ca. 50°C, methyl Iodide (3.17 mL, 51.0 mmol; Aldrtch) was added at once. The mixture was cooled to crystallize. Filtration of the solid gave 6.77 g (26.7 mmol, y.53.5%) of Che title compound as hydrlodide: *Hmr (D2O) 8: 2.70 (3H, s, -SCH3) and 7.65-7.77-8.35-8.48 ppm (4H, A2B2 type, aroraaetc Hs); lr (Nujol) vraax: 1-615, 1585 (aromatic and 780 cm"l; uv (H2O) A. 4-Mechylthlopyrldlne81 ^raax: 227 (£2.02 x 10'») and 298 nm (£1.64 x 10^).
The hydriodlde (6.33 g, 25.0 mmol) was dissolved In H2O (40 mL) and the Insoluble material was removed and washed with HjO (10 ml). To the filtrate was added at 0-5° MaOH pellet (5 g) and extracted with Et20 (3 x 25 mL), saturating the aqueous layer with NaCl. The combined organic extracts were washed with brine (it 2), dried (MgSO&) and evaporated, yielding 2.92 g (23.4 mmol, overall yield 50%) of the title compound as an oil: ^Hmr (CDCI3) 6: 2.48 (3H, s, -SCH3) and 7.03-7.13-8.38-8.48 ppm (4H, A2B2 type, aromatic-Hs); ir (film)» max: 1580 and 800 cm~l. ^Preparation of this compound was reported by King and Ware, J. Chem. Soc., 873 (1939). The procedure, described in this reference was followed. B. 4-Mathylthio-N°(2-mercaptoethy1)pyridinium methanesulfonate ^ jw_ V--V 50=60" 4-Methylthiopyridine (2.75 g, 22.0 mmol) was added slowly to methanesulfonlc acid* (0.65 mL, 10.5 mmol) by cooling in an ice-bath. To this solid was added ethylene sulfide* (0.66 mL, 11.0 mmol, Aldrich) and the mixture was heated at 50-60°C for 21 h. As reaction proceeds the solid went to solution. After cooling, the reaction mixture was dissolved in H2O (5 mL) and washed with Et20 (5x4 mL). The cloudy aqueous layer was filtered over Celite and the filtrate was purified by reverse phase silica gel column chromatography (C^g micro bondapack 10 g) eluting with H2O. Each fraction of 10 mL was collected. Fractions 2 and 3 were combined and repurified by the reverse phase column. Fraction 2 gave 1.258 g (4.48 mmol, y. 42.6%) of the title compound as a viscous oil: iHmr (DMSO-dg, CFT-20) 6: 2.32 (3H, s, MeS03 G), 2.72 (3H, s, ~SMe), 2.68 (IH, m, SH), 2.9-3.2 (3H, ra, -CH2S-), 4.59 (2K5 t, J-6.4 Hz, -CH2N©), 7.97 (2H, "d", J-7.2 Hs, aromatic-Hs) and 8.72 ppm (2H, "d", J-7.2 Hz, aromatic-Hs); ir (neat) Vmax: 1630, 1200 (br, -SO3 8), 7.83 and 770 cm"1.
*These reagents were- distilled prior to use.
C. (5E) p-Nitrobenzyl 3- [2-(4-Methylthiopyrldino) ethylthlo ]-(6S)~ [ (1JB-) -hydroxyethyl ]-7-oxo-l-azablcyclo [3.2.0 ]hept-2-ene-2-carboxylate chloride To a solution of (5R) p-nitrobenzyl 3,7-dioxo-(6S)- [(IR)-hydroxyethy1 ]-1-azablcyclo [3.2.0 ] heptane-(2R)-carboxylate (475 mg, 1.36 ramol) and di-isopropylethylamine (0.24 mL, 1.4 mmol) in ch3cn (5 mL) was added at 0°-5°C under a nitrogen atmosphere diphenyl chloro- co,?nb 9G phosphate (0.29 mL, 1.41 mmol). The mixture was stirred at 0°-5°, for 30 min. To this mixture was added an oily suspension of 4-raethyltluo-N-(2-mercaptoethyl)pyridinium methanesulfonate (678 mg, 1.45 mmol; 601 pure) in ch3cn (1.5 mL) followed by diisopropylethylamine (0.24 raL, 1.4 mmol). The mixture was stirred at 0°-5°C for 1 h. Immediately after addition of the base, yellowish precipitate formed. The precipitate was filtered and washed with cold ch3cn (3 mL), yielding 413 mg of yellowish solid. This was triturated from 10t MeOH in H2O (5 mL) to obtain 341 mg (0.618 mmol, y. 45.4%) of the title compound as white crystals: mp 118°-120°C; iHmr (DMS0-d6, CFT-20) 6: 1.16 (3H, d, J"6.1 Hz, r-CH3), 2.72 (3H, s, -SCH3), 3.1-3.7 (5H, m^, 3.7-4.3 (2H, m), 4.71 (2H, t, J"6.3 Hz, -CH2N), 5.15 (IH, d, J-4«9 Hz, OH), 5.20-5.35-5.40-5.55 (2H, ABq, C02CH2-Ar), 7.70 (2H, "d" J»8.8 Hz, nitrophenyl-Hs), 7.97 (2H, "dM, J™7.0 Hz, pyridinio-Hs), 8.25 (2H, "d", J»8.8 Hz, nitrophenyl-Hs), and 8.76 ppm (2H, "d", J«7.1 Hz, pyridinio-Hs); ir (Nujol) Vmax: 3250 (OH), 1775 (B-lactam), 1700 (ester) and 1625 cm"l (pyridinio); uv (abs, EtOH) >.max: 308 nm (£4.47 x 10^) ; [c*]q3° H- 24.8 (c 0.5, MeOH); Anal. calcd. for C24H26N3O6S2CI.H2O: C 50.56, H 4.95, N 7.37; found: C 50.63, H 4.72, N 6.89.
D. (5R) 3- C?-(4-Kethylthiopyrldinio)ethylthio) - (6S) -[(IS)-hydroxyethyl)-7-oxo-1-azablcyclo [3.2.0)hept -2-ene-2-carboxylate OH H2/?d-C pH 7.4 buffer co2?: I 01 10 15 20 C. 3- []2-( 3-methoxy-l-py ridlnlum) ethyl thiol -6cj.~ri '-(£)-hydroxyethyl] -7-oxo-l-azabicyclo(3.2.0)-hept-2-ene-2-carboxylafce A solution of para-nitrobenzyl 3[2-(3-methoxy-l-pyridinium chloride)ethylthio]-6ci-[l•—(R)-hydroxyethyl] -7-oxo-l-azabicyclo(3.2.0)-hept-2-ene-2-carboxylate (600 mg, 1.12 mmol) in THF (25 mL), ether (25 mL) and pH 7.4 phosphate buffer (0.1M, 25mL) was hydrogenated in a Parr shaker over 3.054 Pd/C (1.1 g) for 1 h at 40 psi. The mixture was diluted with ether and the aqueous phase was filtered through a JF52 hardened filter paper. The aqueous layer was washed with ether (2 x 20 mL), pumped under vacuum and poured on a silica gel reverse phase column. The title compound was eluted with water containing 2 and 5& acetonitrile. The appropriate fractions were combined and lyophilized to give a yellow solid that was repurified by hplc togive the penem carboxylate (150 mg, 38$); ir (nujol) ^max 1750 (s, p-lactam C=0) and 1580 cm-1 (s, carboxylate); 1Emr (DgO) 8: 8.55-8.30 (2H, m, H-2, H-6 aromatic); 8.17-7.75 (2H, m, H-3, H-4 aromatic), 4.77 (2H, t, J=5.9 Hz, CHgN®), 4.10 (IH, part of 5 lines, ,J,= 6.3 Hz, H-1'), 3.97 (3H, s, OCHg), 3.85, 3.82 (2 lines, part of dt, J=2.6 Hz, part of H-5), 3.42 (2H, t, J=5.9 Hz, CHg-S), 3.25 oa \ 10:.' (IH, dd, J=6.1 Hz, J = 2.6 Hz, H-6), 2.99-2.60 (2H, 6 lines, part of H-4) and 1.20 ppm (3M, d, J=6.4 Hz, Cll^); uv (H,.0, c 0.05) 7\: 290 (£10517), 223 (£6643); T,. c. nlaA /j (0.1 M pH 7.4 phosphate buffer, 37°C) 20 h. i 03 Example 9 Preparation of ( 5il; 6fi)-3- D?-( 3-methy 1 thiopy r Ullnio) ethyl thi o]-0-Cl-(n_)-hydroxyethyl]-7-oxo-l-axabicyc]o [3.2.olhept-2-ene-2-carboxylate SMe CH / SP A. 3-Methylthio-l-(2-mereaptoethyl)pyridinium chloride ,SMe SCI A SNe ESC?.,C3®/Ol\ Cp To a solution of 3-methylthiopyridine1 (2.00 g, 0.016 mol) in 10 mL of ether was added 15 mL. of 1 N HC1 10 and the mixture was well shaken. The aqueous phase was separated, washed with 10 mL of ether and then evaporated. The residual hydrochloride was then dried in vacuo (Pg^s^ to give a white solid. To this solid hydrochloride was added 3-methylthiopyridine (1.88 g, 0.015.mol) and 15 ethylene sulfide (0.89 mL, 0.015 mol) and the resulting mixture was heated (oil bath) at 55-65°C under Ng for 15 h. This gave a slightly turbid oil which was taken up in 125 mL of HgO and washed with CH^Clg. The aqueous solutior was concentrated to about 25 mL and then a few drops of 20 acetonitrile were added to make the mixture homogeneous.
The resulting aqueous solution was applied to a C^g reverse-phase column. Elution with MgO and subsequent evaporati on 1 04 of the relevant fractions afforded the product (2.66 g 80%) as a pale yellow, viscous oil. ir 2410 (br, -SH) cm"1; Hlnmr (^6-DMS0+D20) 6: 0.80-7.08 (m. AH, aromatic), 4.70 (t, J = 6.5 ilz, 2H, N-Cllg), 3.03 5 (skewed t, J=6.5 Hz, 2H, S-CH2), 2.64 (s, 3H, S-Me). 1Prepared by the method of J.A. Zoltewiez and C. Nisi, J. Org. Chem. 34, 765 (1969).
B. p-Ni trobenzyl ( 5R,6S)-3- [2-(3-methylthiopyridinlo)ethyl thio]-6- [l-(B)-hydroxyethyl]-7-oxo-l-azabicyclo[3. 2.o] 10 hept-2-ene-2-carboxylate chloride A solution of p-nitrobenzyl (5R,6S)-6-[l-(R)-hydroxyethy ll-3,7-dioxo-l-azabicyclo£3.2.0]heptane-2-carboxylate (0.522 g, 1.50 mmol) in 7 mL of dry acetonitrile was 15 cooled at 0°C and then diisopropylethylamine (0.287 ml., 1.65 mmol) was added dropwise. To the resulting yellow-brown solution was added dropwise diphenyl chlorophosphate (0.342 mL, 1.65 mmol) and the reaction mixture was kept at 0°C for 30 min. Diisopropylethylamine (0.313 mL, 1.80 mmol) 20 was then added, followed by a solution of 3-ine thy 1 th i o-l - (2-mercaptoe thy1)pyridinium chloride (0.398 g, 1.00 iraiol ) in 0.70 mL of dry DMF. About a minute after the addition was complete a precipitate separated from the reaction 1 OS mixture and further cooling at -10"C for 10 min gave a solid orange-coloured mass. This solid was subsequently triturated with acetonitrile and the residue was collected by filtration. The residue 3 OG wus washed with acetonitrllu, then nee tone and finally dried in vacuo to give tho product (0.455 g, b5'i.) :'S a cream-colourcd solid. fhe combined filtrate was evaporated to £ive a yellou oil which was taken up in ^ a minimuEi volume of acetonitrile and cooled at 0°C for 30 min. filtration of thin mixture afforded an additional 0.139 % of the product as a li.^ht yellow solid. The combined yield was 0.594 (72>-). ir (KBr) Vr, : 3345 (br, -OH), 1770 (^-lactam CO), 1 1 iu 1680 (-C02pnb) caT ; Hrunr (dg-DMS0) 6'- 0.S3-7.96 (m, 4H, pyridinium aromatic), 8.20-7.S5 (i-3q, J=7.0 nz, 4H9 PNB aromatic) 9 5.53=4.30 (ia» 4H), 4.3-3.7 (m„ 2H), 3.6-3.25 (m, 6H), 2.66 (s, 3H, S-I-le), 1.16 (d, J=S.O Hzp yd, CHMe). 1 5 C. (^.6g)-3-:[2-(3-methylthiopvridino) ethyl thicxl -6- £1 -(R)-hydroxyethy 3,1 -7-oxo-1 -azabicyclo[ 3. 2.0]hcpt-2-ene-2-carboxylate S.-.e 20 To a nixture of p-nitrobenzyl (5R,6S)-3-[2-(3- methylthiopyridinio)ethyl thio]-6-[I-(R)-hydroxyethyl] -7-oxo-1-azabicyclo[3.2.0]-hept-2-ene-2-carboxy-latc chloride (0.55] g, 1.0 mmol) and 107. palladium on-charcoal (0.55 g) in 25 ml of phosphate buffer 25 (0.05 M, pll 7.4) was added r>mL of Ti!F and 25 mL of 107 ether. This mixture was hydrogenated (Parr) at 40 p:;j. for 1 h. The reaction mixture was then filtered through Celite and the filtercake was washed with t^O and other. The aqueous phase was separated and v/ashed v/ith additional ether (3 x). 1 0 8 After removing rcsudu.il or.'j.inic solvents in vnouo tho aqueous solution was cooled at 0 C fnd the oil was adjusted to 7.0 with saturated aqueous Nalico.j. 'Chia solution was immediately applied to a C^g revoiMJC-5 phase column. Elution with H^O and subsequent lyophilization of tho relevant fractions afforded 0.25 g of a bright yellow solid. This material vr-.c, repurified by reverse-phase hplc to ^ivc the product (0.210 g, 55/») as a liqht yellow solid, ir (i(Br)u : .112 X 10 3400 (br, -OH), 1755 (^-lactam CO), 1590 (-C02~) cm"1; 1Hnmr (Dg®) 8.60-7.76 (in, 4a, aroaatic), 4.76 (t, J=5.8 Hz, 2H, N-CH2), 4.13 (d of q, J=J'= 6.3 Hzp 1H, H-1'), 3.95 (d of t,' J=9.0 Hze J'= 2.8 Hz, 1H, H-5), 3.45-2.75 (a, 5"H), 2.59 (s, ?£, 3-ke), 1.20 15 (d, J=6.4 Hz, 3H, CHHe)i uv (H,0)l 296 (£8509), c. ma. A 273 (£13005), 231 (fT11576) na; (pH 7.4, 36.8°C) 20 h. Ex.-imnle 10 Pre or.1.r^ t ion of 3- f2-( 1 -( 2.6-dinethY"icvj.'iclini.iun)-eth.vlthiol -6«- Cl -(K)-hvdrc:. : 277 c aa ^ max (C9733), 300 (68271) mp, [«.]Q + 50.7 (C 0.48, HgO), Anal. calcd. for C10H22N2O4S•1.5 H20: C 55.51, 10 H 6.47, N 7.19; found: C 55.14, H 6.23, N 6.46.
J 1'% Example 11 Preparation of (53/ 6S)-3-(2-(2-nctSyItblo-3-methylimidazolio)ethvl-thio]-6-tl-(3) -hydroxyethyl] -7-oxo-1-azabicyclo[3.2.0]heot-2-ene-2-carboxvlate N-Me A. 2-Methylthio-3-methyl-l-(2-merca?toethy1)imidazoline trifluor©methanesulfonate SMe \ |\ f cf3so3h + ^ ksch2ch2 a ' s_me vi, / -sm, v—/ I c?*s To a solution of p-nitrobenzy1 (5R, 6S)-6- [ 1- (R) - hydroxyethyl]-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylate (1.40 g, 4.0 mmol) in 50 mL of dry acetonitrile, at O'C under Nj/ was added dropwise diisopropylethylamine (0.76 mL, 4.4 mmol) followed by diphenyl chlorophosphate (0.91 mL, 4.1 mnol). 10 After stirring the reaction mixture at room temperature for 1 h, diisopropylethylamine (0.76 mL, 4.4 mmol) was added and then a solution of 2-methylthio-3-methyl-l-(2-mercapto- ethyl)imidazolium trifluoromethanesulfonate (2.0 g, 5.9 mmol) in 5 mL of acetonitrile was added dropwise. The reaction IT> mixture was kept at room temperature for 1.5 h and was then concentrated in vacuo to give a gum. This gum was taken up in EjO and applied to a C1g reverse-phase column. Elution with HjO, then 205 acetonitrile-H^O and finally 305 acetonitrile-H20, followed by lyophilization of the appropriate 20 fractions afforded the product (0.90 g, 30%) as a light yellow solid. ir(K3r) v : 3380 (br, OH), 1770 (6-lactaraCO) — I i max cm ; Hnmr (dg-acetone) 6: 8.35 (br,s, IH), 8.24, 7.78 (A3 q, J = 8. 8 Hz, 4H, aromatic), 7.89 (br s, IH) , 7.25-6.91 (m, 10H, diphenylphosphate), 5.50, 5.25 (A3 q, J=12 Hz, 2H, benzylic), 25 4. 75-4. 27 (m, 3K) , 4.03 (s, 3H, N-Me) , 4.15-2.75 (m, 8H),. 2.59 (s, 3H, S-Me), 1.22 (d, J=6.2 Hz, 3H, -CHMe).
JIG C. (53, 6 S) — 3 — [ 2- ( 2-MethvIthio- 3-mgthvlimidazollo) gthvl thio)-6-[l-(B)-hvdroxyethyl]-7-oxo-l-azabicyclo[3.2.0]heot- 2-ene-2-carboxvlate ?-Me C02?K3 (f>0)_?0 B - M - 5 To a solution of p-nitrobenzv1 (5R, 6S)-3-[ 2- (2-methyIthio-3-methylimidazolio)ethyl thio]— 6 —[1—(R) — hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0)hept-2-ene-2- carboxylate diphenylphosphate (1.20 g, 1.56 mmol) in a mixture of 70 mL of TK?, 70 ml of ether and 31 mL of 10 phosphate buffer (0.05 M, pH 7.4) was added 1.2 g of 10% palladium-on-charcoal. This nixture was hydrogenated (Parr) at 35 psi for 55 min. The reaction mixture was then filtered through Celite and the filter caJte was washed with '^O ir.c ether. The aqueous phase was separated, cooled at 0°C and 15 the pH was adjusted to 7.0 with saturated acueous NaSCOj.
After removing residual organic solvents in vacuo the acueous solution was applied to a C1g reverse-phase column. Elution with H^O and then 8% acetonitrile-H^O and subsequent lyophilization of the .relevant fractions gave 0.25 g of a 2(1 solid. This material was repurified by reverse-phase hplc to give the product (0.114 g, 19%) as an off-white solid. ir(K3r) v : 3420 (OH), 1750 (B-lactam CO), 1590 (-CO®) cm-1; max z 'Knnr (D^O) 6: 7.58 (s, 2H), 4.52 (t, J=6 Hz, 2H), 4.28-3.82 (m, 2H) , 3.90 (s, 3H, N-Me) . 3 . 40-2.87 (m, 5H) , 2.40 25 (s, 3H, S-Me), 1.20 (d, J=6.4 Hz, 3H , -CKMe); uv (H^O) A : 297 (c 7572), 262 (e 6259), 222 (c 7955) nm. 117 Example 12 Preparation of (5g. 6j|)-3-[ 2-( 3-aminopyridinio) ethy 1 -thio]-6-f1~(?) -hydroxyethyl]-7-oxo-l-a2abicvclo(3. 2.0]-hept-2-ene-2-carboxylate 3-Aminopyridine (1.50 g, 0.016 mol) was taken up in 15 mL of IN methanolic HC1 and the resulting solution was evaporated to give the hydrochloride as an oil- To this oil was added 3-aminopyridine (1.32 g, 0.015 mol) and ethylene sulfide (0.89 ml, 0.015 jnol) and the resulting mixture was heated (oil bath) at 60-65°C under Nj for 2 h. .
Another equivalent of ethylene sulfide (0.85 ml, D.D1S mol) was added and heating was continued at 55-65°C for 65 h.
The reaction mixture was washed with CHjCl, and then taken up in H,0 (25 ml). The aqueous solution was applied to a C^g reverse-phase column which was eluted with H^O.
Evaporation of the relevant fractions gave the product (1.26 44%) as a colorless, viscous oil. ir(film) v : 3180 (NH,) 1 max a cm "; fti mr (dg-DKSO) o: 8. 19-7. 59 (m, 4H, aromatic) , 4. 59 (t, 2 Hz, 2 H, N-CH,) 3 5 (br s, 2H, -NH, ) , 3.20-2.77 *** e* eZ (m, 3H). 113 3 . p-]fi t r obe-T ry 1 (53. 6s)-3-( 3-f 3-a.ai n ony r i di n 1 o ) etby 1 - thio)-6-( 1~(B.) ~ hv i roxv e th v I) - 7-oxo- 1-ti abl cy e lo( 3 • 2 ■ 0 )- he;3t-2-ene-2-carboxYlate di-Dhecyl-Dhosohate 5 To a solution of p-nitrobenzyl (53,, 6s_)-6-( 1" (R) ~ hydr<5xye'thyl)-3,7-iiiojco-l-azabicycIo(3.2.0)heptane-2-carboxylate (0.696 g, 2.0 mmol) in 10 mL of dry acetonitr11s, at 0°C under Ng, was added dropwise dii s opropy le t'ay la-i ne (0.382 at, 2.2 mmol) followed by diphenyl chlorophosphate 10 (0.U5T mL, 2.2 caol). After stirring at 0°C for 30 ain. a solution of 3-a=ino-l-( 2-nercaptoethy1)pyridiniun chloride (O.U75 Sl 2.5 caol) in 1 ml of dry DMF vas added, folloved by additional diisopropylethylamine (0.^35 mL, 2.5 mmol). The reaction mixture vas kept at 0°C for 1.5 h and vas then 15 concentrated i_n vacuo. The resulting gum vas taien up in acetonitrile-HgO (1:1) and applied to a C^g rev»rse-phase coluan. Elution with E^O, followed by 20' acetonitrile-HjO and subsequent lyophilization of the relevant fractions afforded the product (0.730 g, 50?) as a beige-colored solid. 20 ir(X3r) v : 3330 (br, OH), 3180 (br, NH,), 1770 (3-lactan CO), D4X • . * 1690 (-C02PN3)ca ; Ennr (dg-DMSO) 6: 8.29-7-63 (a, 8 aromatic), 7-2-6.7 (b, 10H, diphenylphosphate), 5-^1, 5-18 (A3 q ,■ .J = it Hz , 2H, benzylic), U.73-U.U5 (n, 3H), 1(.2-3.8 (a, IH) , 3.6-2.6 (m, 8h), 1.15 (d, 3-6.2 Hz, 3H, CHMe). 119 C . (55. 6 S ) — 3 — C 2-( 3-Amino-ovri di nio ) e thyl ( 1~(R) -hydroxyethvl)-7-oxo-l-azabicvclo( 3-2.0)hc-pt-2-ene-2-car'bo^Ylate To a mixture of p-nitrobenzy1 (5R.. 6s)-3( 2-(3-aminopyridiaio)ethyl thio)-6= (l-(R) ~hydroxyethyl)-7-oxo-l-azabicyclo(3.2.0)hapt-2-ene-2-carboxylat e diphenylphosphate (0.730 g, 1.0 mmol) and 10? palladiun-on-charcoal (0.7 g) in 25 oL of a phosphate buffer (0.05 M, pH T-1*) was added 8 mL of TH? and 20 sL of ether. This nixture vas then hydrogenated (Parr) at b0 psi for 1 h. The resulting mixture vas filtered through a pad of Celite and the filter cake vas washed with EgO and ether. The aqueous phase was separated, washed with ether (2 x) and then residual volatiles were removed i_n vacuo. The aqueous solution was immediately applied to a C^g reverse-phase column which was eluted with HgO. Lyophilization of the relevant fractions afforded 0. li5 g of an off-white solid. This material was repurified by reverse-phase hplc to give the desired product (0.123 g, 35^) as an ivory-colored solid. ir(K3r) v : 33liO (br), 1750 (br, 8-lactam CO), 1580 (br, a 3 & X -COg ) ca'1; ' Hnar (DgO) 6: 8.07-7-59 (n, ItH, aromatic), l». 6X (t, J= 5-8 Hz, 23, W-CH2), It.lk (d of yridiniua methanesulfonate 1.14 g (15%) as a colorless syrup; ir (film) V : 2S20 (SH), 1640 (oyridinium), 11S0 (s, CH.SO ,~), 1040 mix * «J 3 (CH SO ")cai"'\ 'x-tu: (DMSO d') 6: 1.35 Jd, J=6.8 Hi, 3H, CT,CH5) , 2.30 Is, Z 3 o —,> 3H, G^so"), 2.90 (d, J-8.5 Hz, IH, SH) , 3.2-3.7 (n, CHSH) , <.52 tdd, 13 ^gera*12'9 Hz' £=8"4 Hz' CHCKjN4') , 4.37 (dd, £"*6-0 Hz, CHCH2N+) , 8.0-8.4 (m, 2H, Hm of pyridinium), 8.S-8.8 (n>, IH, Hp of pyridinium), 9.04 (dd, J=1.4 Hz, J=6.7 Hz, 2H, Ho of pyridiniun), uv (HO) X : 208 (C5267), *" 2 max 259 (E3338), Anal, calcd. for C9H15K03S2'2H20; c 37-88< H 6,71, N 4.91, S 22.47; found: C 37.49, H 6.8S, N 4.86, S 22.09 and dZ-1- (2-siercapto-^:- methylethyl) pyridinium methanesulfonate 0.32 g. (11%) as a colourless syrup; ir (film) 2S00 (SH) , 1628 (pyridinium)., 1180 (sulfonate, 1035 (sulfonate) cm 1, ]Hmr (Dmso dg) 5: 1.69 (d, £=6.8 Hz, 3H, r23CHN+). 2-3.l lcd. for CgH^NC^S.,-1. 5H2G: C 39.11, H 6.S6, N 5.07; found: C 29.13, H 5.92, H 5.20.
(SR, 6S) paranitrobenzyl 3-11- (g, S).nethyl-2- q-pyridiniun) ethy Ithio] -6- . [1- (R)-hydroxyethyl)-7-oxo-l-asabicyclo(3. 2.0)hept-2-ene-2-carboxylate diohenvlDhosohate 0H 1) NEt (iPr) ^ da —\ 2) Cl^ (OPh) . /q\. j— O \ooPN3 3) HS MS° COOPNB (PHO)2fo~ 4) NEt(iPr) ;A/ns To a cold (0°C) solution cf (SR, 6£)pazanitroben=yl 6-[l-(?p-hydroxyethyl]-3,7-dioxO-l-azabicyclo (3.2.0) hepta^e-2-oarbOKyiate (0.523 g, 1.5 mmol) in acetonitrile (6 mL) kept under a nitrogen atmosphere was added diisopropylethylamine (0.314 nL, 1.8 asaol) followed by diphenyl chlorophosphate (0.373 mL, 1.8 mmol). The reaction mixture was stirred for 30 min and treated with a solution of dt-1-(2-mercapto-2-methylethyl)pyridinium methanesulfonate (0.S39 g, 2.16 nvnol) in acetonitrile (2 nL) and diisopropylethylamine (0.314 mL, 1.8 mmol). The reaction mixture was stirred at 0*C for 1 h, diluted with cold (0*C) water (24 mL) and chrornatographed over prep bondapaX C-18 column (2.S x 8.5 cm) with 25-504 acetonitrile in water as eluting solvents to give 1.07 g (974) of the title compound as a yellowish powder after lyophilization; ir (X3r) V : 3700-3100 (OH), 1770 (C=0 of B-lactara), max 1695 (CO of PN3 ester),. 1630 (pyridinium), 1590 (phenyl), 1S18 (NO^) , 1348 (NO ) , 885 (NO,) ra"1, 'iter (DMSO d,) 6: 1.14 (d, J-6.1 Hz, 3K, A 6 © — Cf^CHO), 1.33 (d, £*6.3 Hz, 3H, CHjCHS), 4.6-5.0 (m, CH^"') , 5.14 (d, £=5.2 Hz, IH, OH), 5.37 (center of A3q, £-12.4 Hz, 2H, CH, of PNB), 6.6-7.5 (m, 10H, phenyl of phosphate), 7.69 (d, £»8.7 Kz, 2H, Ho of ?N3) , 8.0-8.4 (m, 4H, tint of PN3, Hm of pyridinium), 8.4-8.8 (si, IH, Hp of pyridinium), 9.08 (d, J-5.6 Hz, 2H, Ko of ovridiniCT), uv (HO) A : — " 2 aax 263 (E13325) , 308 (E8915). Anal, calcd. for 0,„S?-HO: C57. S2, ~3b 3b 3 iw 2 H 5.10, N 5.59, S 4.27; round: C 57.76, II 4.96, N 5. 36, S 4.35.
(SR.6S) 3- [1- (3 and S)-raethyl-2- (1-pyridinium) ethyIthio) -6-tl- (g)-hydroxyethyl)-7-oxo-l-azabicyclo(3.2.0)heot-2-ene-2-carboxvlate H §H 104 Pd/C, H2 ^ THF, ether, buffer 0< \x>0?K3 (?h0) Jo" TO a solution of (5R, 6£)paranitrobenzyl 3-fl-(H,£)methyl -2- (1-pyridiniura) ethylthio] -6.- [1- (S) -hydroxyethyl)-7-oxo-l-azabicyclo-(3.2.0)hept-2-ene-2-ca.rboxvlate diphenylphosphate (0.60 g, 0.82 mol) in wet tetrahydrofuran (33 mL) was added ether (33 mL) , potassiusi phospha mono basic-sodium hydroxide buffer (17 mL, 0.15N, pH 7.22) and 104 palladium on charcoal (0.60 g). The resulting mixture was hydrogenated for 1 h under 40 psi at 23'C. The two layers were separated and the 1 :: -I organic layer was extracted with water (3x7 ni). The aqueous layers were combined, filtered throu<;h a Celite pad, washed with ether (3 x 20 nvL) and chromatographed on prep bondapak C-18 colunn (2,5 x 9.S era) with water as eluting solvent to give 0.18 g (63%) of nixture of diastereoisoners. 5 Bie two diastereoisomers were separated by hplc (prep bondapaJc C-18) with water as eluting solvent: isomer with lower retention time, 0.068 g (23\) compound "B", ir (3C3r) V : 1770 (C=0 of B-lactam), 1633 (pyridinium), 1593 max (carboxylate)cm \ Hz, 3H, CH^CHO), 1.42 10 (d, J=»6.9 Hz, 3H, CHECKS), 2.3-3.2 (m, 3H, H-4, H-6), 3.5-3.9 (ra, IH, SCH) , 3.9-4.2 (m, 2H, H-5, Cf^CHO), 4.3-5.1 (m, CHjN*}, 7.8-8.2 (m, 2H, Ka» of pyridinium), 8.4-8.7 (m, IH, H? of pyridinium), 8.7-9.0 (ra, 2H, Ho of pyridinium uv (H O) X : 260 (E6727) , 300 (£8245) ',. [a) *3-. 39.3* (c, H,0) , T, -12.6 h ■*- max D — 2 5 -4 ~ (measured at a concentration of 10 M in phosphate buffer pH 7.4 at 1 r> 36.8"C); isomer with higher retention time, 0.081 g (284), coapound , ir (X3r) V : 1755 (C-0 of S-lactam), 1630 (pyridinium), 1590 (carboxylate) max cm"1, 'hot (D20) 5: 1.18 (d, .£=6.3 HX, 3H, CH3CHO), 1.40 (d, £='7.0 Hz, 3H, CT CHS), 2.84 (d, £=9.3 Hz, 2H, K-4), 3.26 (dd, £-2.7 H2, £-5.9 Hz, IH, H-6) , 3.4-4.2 (m, 3H, SCH, O^CHO, H-5), 4.2-S.l (m, CH^N"1") , 7.7-8.1 20 (m, 2H, Hm of pyridinium), 8.3-8.65 (m, IH",* • Hp of pyridinium) , 8.65-8.9 (ra, 2H, Hoof pyridinium), uv (HO) X : 259 (E5694), 296 (E6936), 2 max lQ)_ ' -s-96.9' (c 0.56, H,0), T, -15.6 h (measured at a concentration D - 2a. -4 of 10 M in phosphate buffer pH 7.4 at 36.8°C). i;;5 Examole 14 PREPARATION OF OH a; coo (5R,6s; 3-|2- f (S)- (l-pyridiniun) ]-l- (S)-cyclohexylthio] [1- (5?)-hydroxyethyl]-7-oxo-l-azaiicyclo(3.2.0)hepi-2-ene-2-carboxylate and OH A s"' coo 10 (5R,6£)3- 12- [ (R)- (1-pyridiniuai) ]-1- ;R)-cyclohexyIthio]-6-[1- (R) -hydroxyethyl]-7-oxo-1-azabicyclo(3.2.0)hept-2-ene-2-carboxylate. dL-1- [2-mercapto-l-cyclohexyl)pyridinium methanesulfonate SH + MaOH MsO MethanesuLfonic acid (0.6S mL, 0.01 mol) was added dropwise to pyridine (2.42 mL, 0.03 mol) with cooling. The mixture was stirred under a nitrogen atmosphere for. 10 sin, treated with tt£-cyclohexene- sulfide [1.377 g (854 pure), 0.0102 mol] and stirred at 72*C for 25 h.
The excess of pyridine was removed under vacuum aad the traces were codistilled with water. The residue vas mixed with water and chromato- gxaphed. through prepbondapaX C-13 column (5 x 13 cm) with 0-2fi acetonitrile in water as eluting solvent giving after lyophilization a colourless syrup 1.57 g (53%), ir (fiLn) v : 2500 (SK) , 1625 (oyridinium), 1190 max '.SO r (DHSO-d ) 5: 1.2-2.5 (n, 8H, cyclohexyl H) , 2.32 (s, 3H, 3 o CH so "), 2.82 (d, £=9.8 Hz, SH), 3.0-3.5 (m, IH, C?SH), 4.2-4.9 (m, IH, CHN ), 8.0-8.3 (m, 2H, Hm of pyridinium), 8.4-8.8 (m, IH, Hp of pyridinium), 8.9-9.3 (m, 2H, Ho Of pyridinium), uv (H^0) ^max: (£5365), 258 (C3500) .
Anal, calcd. for c12Hi9N03S2'H20: C <6-8S' H 6.88, N 4.56; found: C 46.61, H 6.46, N 4.65.
I7 B. (5R.6S)paranitrobenzyl 3-[2-[(R or S)-(l-pyridinium)]-1-(R.or S)-cyclohgxy1-thio]-6-(1- (R) -hydroxyethyl]-7-oxo-1-azabicyclo (3.2.0)hept-2-ene-2-carbo-xylate diphenylphosphate OH x) J ? S'-. 2) ClP(OPh) 0 2 3) H&"Ol MsO" COOPNB © 3) ^ MS° "COOPN3 (Ph0)„?0 4) NEt(iPr)^ r> To a cold (O'C) solution of (5R, 6£)?aranitrobenzyl 6-[l-(S)- hydroxyethyl]-3, 7-dioxo-l-azabi'cyclo(3.2.0)heptane-2-cartoxylate "(1- 37 5. 3.93 mmol) in acetonitrile (IS mL) kept under a nitrogen atmosphere was added diisopropylethylamine (0.822 mL, 4.7 mmol) and diphenyl chlorophosphate (0.979 mL, 4.7 nniol) . The resulting solution was stirred for '0 30 stiri and treated with & solution of dt-1- (2-merczpto-l-cyclohexypp/ridinium methanesulfonate (1.64 g, 5.66 raaol) in acetonitrile (4.7 mL) followed by diisopropylethylamine (0.822 mL, 4.7 mol). The reaction mixture was stirred at 0*C for 1 h, diluted with cold (O'C) water (75 nL) and chrcms-tographed on prepbondapak C-18 with 25-50% acetonitrile in water as el-Jtir.g I '3 solvent giving after lyophilization of the appropriate fractions 1.9 g (534) of the title compound, ir (K3r) V : 3700-3000 (OH), 1770 (C=0 of max • • B-lactam), 1700 (C-0 of PNB ester), 1628 (pyridinium), 1590 (phenyl), 1515 (N02),'l345 (NO,), 880 (NO,) cm"1, 'ht- (D.,0) 6: 1.13 (d, J-6.1 Hz, 3H, CHjCHO), 1.2-2.S (ro, 8H, cyclohexyl K), 2.7-3.5 (m, «H, H-4, H-6, CHS), 20 3.5-4.4 (m, 2H, CHjCHO, H-5), 4.4-5.0 (m, IH, CKNV), 5.30 (center of H3q, J-12.8 Hz, CH2 of PN3), 6.7-7.4 (m, 10H, phenyl), 7.65 (d, J-8.6 K:, 2H, Ho of PtQ) , 7.9-8.4 (ra, 4H, Hm of ?i<3, Hm of pyridiniun), 8.4-B.8 (m, IH, Hp of pyridinium), 9.0-9-4 (n, 2H, Ho of pyridinium), uv (3^0) XMx: 263 (E9038) , 309 (E6394). Anal, calcd for C39H40N3010S?"H2°: C 59.16, H 5.35, N 5.31; found: C 53.9S, H 5.15, N 5.57.
(SR,6S) 3-[2-[(R or S)-(1-pyridinium)]-l-(R or ^)-cyclohexylthio)-6-(1-(R)-hydroxyethyl]-7-oxo-l-a:abi cyclo(3.2.0)hept-2-ene-2-carboxy late To a solution of (5R,6£) paraiiitrobenzyl 3-[2-[(B, or £)-(1-pyridinium) ] -1- (R or j[)-cyclohexyl thio] -6- [1- (JO -hydroxyethyl]-7-oxo-l-aiai>icyclo(3.2.0)hept-2-ene-2-carboxylate diphenylphosphate (1.85 g, 2.34 mol) in wet tetrahydrofuran (96 mL) was added ether (96 mL), potassium phosphate monobasic-sodium hydroxide buffer (0.15M, pH 7.22, 50 mL) and 10% palladium on charcoal (1.9 g) . The resulting mixture was hydrogenated at 23° under 40 psi for 1.25 h. The organic layer was separated and washed with water (3 x 20 mL). The aqueous solutiors wens filtered through a Celite pad, washed with ether (2 x 60 mL) , pumped to remove the traces of organic solvents and chromatographed on prepbondapak C-18 column (4.5 x 9 en) with 0-S4 acetonitrile in water as eluting solvent giving after lyophilization 0.705 g (764) of a nixture of diastereoisomers. The separation of the diastereoisomers was done by hplc (prepbondapak C-18) with 44 acetonitrile in water as eluting i ::9 solvent; diastcreoisoner with lower retention time, coapound a > (0.29 31%), ir (K3r) V : 17S0 ICO of B-lactam), 1620 (sh, pyridinium), 1685 max (carboxylate) cm 'Hmr (D^O) 6: 1.21 (d, £="6.3 Hi, 3H, CS^ChG) , 1.4-2.5 (m, 8H, cyclohexyl H), 2.5-3-05 (m, 2H, H-4), 3.05-3-25 (m, IH, H-6), 3.3-3.7 (m, IH, CHS), 3.9-4.3 (m, 2H, H-5, CHjCHO), 4.3-4.8 (m, CHN''') , 7.8- 8.2 (m, 2H, Hm of pyridinium), 8.3-8.7 (m, IH, Hp of pyridinium), 8.8-9-1 (m, 2H, Ho of pyridinium), uv (H„0) X : 260 (£7123), 300 (£8685), 2 n&x fa] D23 +6.2" (£ 0.63, < Ti "16.6 h (measured at a concentration of 10 M in phosphate buffer pH 7.4 at 36.8°C); Anal, calcd. for C,„H, N,0>S ——— 20 24 2 4 •2H20: C 56.59, H 6.65, N 6.60, S 7.55; found: C 56.83, H 6.47, N 6.S9, S 7.43; diastereoisoaer wieh higher retention time, compound "3", (0-35 38%) ir (K3r) 1750 (C=0 of S-lactam) , 1622 (shpyridinium) , 1588 (carboxylate) ca"1,.,Har (DjO) 6: 1.19 (d, J=6.4 Hz, 3H, CT^GIO) , 1.3-2.5 (m, 8H, cyclohexyl H) , 2.5-3.1 (m, 2H, H-4) ,' 3.1-3. 3 (m, IH, H-6), 3.3-3.8 (ro, 23, H-5, CKS) , 4.1 (center of si, 1H^ C^GJO),. 4.25-4.7 (ra, 12, CHN ), 7.8-8.1 (m, 2K, Hm of pyridinium), 8.3-8.7 (m, IH, Hp of pyridinium), 8.75-9.0 (m, 2H, no of pyridinium), uv (H,0) X I 259 (£5992), 296 (£7646), 2 R3X 23® - , 4.87 (2H, t, J=6 Hz, -CH2-N'r) .
OH OH To a solution of (5£) allyl 3, 7-dioxo-(6£)-[ (lR^)-hydroxyethyl] - I 3 % S-6.2 (3H, m, olefinic protons), 6.6-7.4 (m, aromatic protons), 8.IS (2H, "t", 0=7 Hz, aromatic protons meta to the nitrogen), 3.63 (IH, "t", J=7 Hz, aromatic proton para to the nitrogen) and 9.07 ppm (2H, "d", £=7 Hz, aromatic protons ortho to the nitrogen); ir (film) V: 3400 (OH), 5 1770 (S-lactam), 1690 (ester), 162S (pyridinio).
B. (SR) 3-((2-pyridinioethyl)thiol-(6S)~ [ (IR)-hydroxyethyl)-7-oxo-l-azabicyclo[3.2.0)hept-2-ene-2-carboxylata Pd(P After addition of anhydrous Et^O (7 iri) , the precipitate was filtered, washed with anhydrous Et^O (7 mL) and dried in. vacuo to yield 101 mg of brownish solid.' This was purified by reverse phase column chromatography (C, „ PrepPAK, 12 g. Maters Associates) eluting with H O. lo 2 20 Appropriate fractions (fr. 7-12, each 20 mL) were collected and lyo philized to obtain 53 mg (0.16 mmol, y. 64'J) of the title compound as yellowish powder. This material was contaminated with potassium diphenylphosphate and potassium 2-cthyIhexanoate: 'Hmr (020, CFT-20) 5: 0.80 £t, J-6.4 Hz, Me from ethylhexanoateJ, 1.21 (3H, d, J-6.3 Hz, l'-Me) 2-93 (211, dd, J, Hz, J = 4 Hz, 1-Ks), 3.28 (IH, dd, C, .,=6.2 H —1-5 —9 em —b-i =2 - 5 Hz, 6-H), 3.42 (2H, t, J=6 Hz, -CHS), 3.98 (IH, td, J. -—^-5 "■ a i $ Kz' "L ^"l2-5 Hz' 5"H>' 4-15 *lH' *3' J=6.2 Hz, 4.80 (2H, t, —5-6 J=6.0 Hz, -CH2N+), 7-7.5 (m, phenyl protons from diphenyl phosphate) 8.03 (2H, m, Hm of pyridinium), S.56 (IH, m, Hp of pyridinium) and 8.81 ppm (2H, "d", J=6.5 Hz, Ho of pyridinium) . i '.} 3 Example 16 Preparation of 3- [2- (N-Methyl-thiomorpholinium) ethylthiol -6a-[I'-(R)-hydroxyethyl}-7-oxo-1-azabicyclo[3.2.0]-hept-2-ene-2-carboxylate /} N 0 2 A. N-methyl-N-(2-mercaptoethy1)thioiaorpholinium methanesulfonate To precooled (ice bath) N-methylthiomorpholine* (5.00 g, 42.7 mmol) was added methanesulfonic acid (1.47 mL, 10 20.5 mmol) and ethylene sulfide (1.30 mL, 21.4 mmol). The mixture was heated at 65°C for 24 h and diluted with water (25 mL). The aqueous solution was washed with diethyl ether (3 x 25 mL), pumped under vacuum and poured over a silica gel reverse phase column; the title compound being eluted with J 5 water. The appropriate fractions were combined and evaporated to afford the thiol as an oil (4.80 g, yield 86%); ir (film) \i : 2550 cm"1 (w, SH) ; ^mr (DWSO d,)6: 3.25-2.95 (6H, m, ft A CH2N ), 3.32 (3H, s, CH^N ) , 3.20-2.65 (7H, m, CHjS, SH) and 2. 32 ppm (3H, s, CH3SC>3) .
*J.M. Lehn and J. Wagner. Tetrahedron, 26, 4227 (1970) 1) Ms OH w 2) s l :j4 B. para-Nitrobenzyl 3-[2-(N-methy1-thiomorpholinium diphenyl phosphate) ethy Ithio] -6ct- [ 1' - (R) -hydroxyethy 11 -7-oxo-1-azabicyclo[3■2.0]-hept- 2-ene-2-carboxy late OH A 3.) EtU<— 2). Cl?0(0l}>) j *8 oa o O' o: C0,?N3 4) EtN(—<)2 C02?N3 A cold (ice bath) solution of para-nitrobenzyl 6a-[1'-(R)-hydroxyethyl]-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylate (557 mg, 1.60 mmol) in CH3CN (8 mL) was treated dropwise with diisopropylethy1 amine (0.336 mL/ 1.92 mmol) and diphenylchlorophosphate (0.400 mL, 1.92 mmol) and stirred for 10 30 min. The reaction mixture was treated with N-methy1-N-(2-mercaptoethyl)thiomorpholinium methanesulfonate (393 mg, 2.29 mmol) in CH^CN (4 mL) and diisopropylethy1 amine (0.336 mL, 1.9 2 mmol) and stirred for 30 min. The solution was diluted with water (20 mL) and poured over a silica gel reversed phase 1 'j column. The desired compound was eluted with a 50% acetonitrile-water mixture. The appropriate fractions were combined, pumped under vacuum for 2 h. and lyophylized to afford the title compound (1.01 g, yield 85%): ir (nujol)v : 1760 (s, S-lactam . y JUClX C=0) and 1510 cm-1 (s, N02); Hmr (DMS0-dg) 6: 8.25 (2H, d, 20 J=8.8Hz, H-aromatic), 7.70 (2H, d, J=8.8Hz, H-aromatic), 7.33-6.84 (10 H, m, H-aromatic), 5.37 (2H, center of ABq, J=14.2 Hz, CH2) , 5.14 (IH, d, J= 4.5 Hz, OH), 4. 35-3.80, (2H, m, H-1' and H-5), 3.75-3.45 (6H, m, CH^"'') , 3.31 (3H, s, CH3N+) , 3.45-2.75 (9H, m, CH2S, H-6 and H-4) and 1.15 ppm (3H, d, J=6.2 Hz, CH3)-. a i :;5 C. 3-[2-(N-methy1-thiomorpholinium)ethylthio]-6a-[1' - ( R)-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]-heot-2-ene-2-carboxvlate eh OPf06). 10 15 20 A solution of para-nitrobenzyl 3-[2-(N-methy1-thiomorpholinium diphenylphosphate)ethylthio]-6a-[1'-(R)-hydroxyethyl]-7-oxo-l-azabicyclO[3.2.0]hept-2-ene-2-carboxylate (1.31 g, 1.76 mmol) in 0.1M pH 7.4 phosphate buffer (48.8 mL), tetrahydrofuran (20 mL) and diethyl ether (20 mL) was hydrogenated over 10§ pd/C (1.5 g) in a Parr shaker for 1 h at 40 psi. The reaction mixture was diluted with diethyl ether (40 mL) and the phases were separated. The organic phase was washed with water (2x5 mL). The aqueous phases were combined, filtered through a #52 hardened filter paper, washed with diethyl ether (2 x 20 niL) and pumped under vacuum. The aqueous solution was poured on a silica gel reverse phase column and the desired carbapenem was eluted with 5% acetonitrile-water. The appropriate fractions were combined, and lyophilized to give title compound as an amorphous solid (205 mg, 31%); ir (nujol)vmax: 1750 (s, S-lactan C=0) and 1590 cm"1 (s, C=0) ; ^r (D20) 6:4.25-3.95 (2H, m, H-1', H-5), 3. 70-3.40 (6H, m, CHjN*) , 3.35 (IH, dd, J=6.1 Hz, J=2.6 Hz, H-6), 3.08 (3H, s, CH,N+), 3.25-2.75 (8H, CH-S, H-4), and 1.24 ppra (3H, d, J=6.4 Hz, CH,); uv (H.,0, c 0.062)X : *^ fj A lIlGln 17.7 h (0.1M pH 7 phosphate buffer, 37"C) . 299 (e10 ,962) Tl/2 t a g Example 17 Preparation of (SR, 6S)-3- [2-(1-methylmorpholino)ethylthio]-6- [ (R)— 1-hydroxyethy1]-7-oxo-1-azabicyclo(3.2.0]hept-2-ene-2-carboxylate A. 1-Methvl-l-(2-mercaptoethvl)roorpholinium trifluoromethane-sulfonate £ ^ f CF3SO3H + ^ '? Me To N-methylmorpholine (3.29 mL, 0.030 mol) was added 10 dropwise trifluoromethanesulfonic acid (1.327 mL, 0.015 mol) at 10°C, followed by ethylene sulfide (0.89 mL, 0.015 mol). The resulting yellow-brown solution was heated (oil bath) at 50-60°C under N, for 13 h. Volatile material was then removed in vacuo and the residual oil was taken up in 10 mL of H20. The aqueous 15 solution was washed with diethyl ether (3x5 mL) and then residual organic solvent was removed in vacuo. The resulting aqueous solution was applied to a C^g reverse-phase column which was eluted with H^O, then 5% acetonitrile-t^O and finally 10% acetonitrile-HjO. Evaporation of the relevant fractions afforded 20 a white solid which was dried in vacuo (P^O^) to give the product (1.92 g, 41%) . ir (KBr)vm!i : 2560 (-SH) cm ^Hnmr (d,-acetone) max o «: 4.25-3.6 (m, 8H), 3.49 (s, 3H, N-Me), 3.35-2.7 (m, 5H). 1 »•» T 1 •> 4 B. p-Nitrobenzv1 (5R,6S)-3-[2-(1-methylmorpholino)ethyIthio)- ' 6-((R)-1-hydroxyethy1]-7-oxo-1-azabicyclo[3.2.0 J hept-2-ene-2-carboxvlate diphenylphosphate 5 To a solution of p-nitrobenzyl (5R,6S)-6-[(R)-1- hydroxyethyl]-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylate (0.348 g, 1.0 mmol) in 25 mL of dry acetonitrile was added drop-wise diisopropylethylamine (0,191 mL, 1.1 mmol) and then diphenyl chlorophosphate (0.228 mL, 1.1 mmol) at 0"C under N^. After 10 stirring at 0°C for 1 h diisopropylethylamine (0.226 mL, 1.3 mmol) was added to the resulting enol phosphate, followed by 1-methyl-1-(2-mercaptoethyl)morpholinium trifluoromethanesulfonate (0.373 g, 1.2 mmol). The reaction mixture was stirred at room temperature for 1.5 h and then concentrated iji vacuo. The residual material 15 was taken up in H^O and applied to a C^g reverse-phase column. Elution with HjO, then 20% acetonitrile-H.,0 and finally 30% acetonitrile-H^O followed by lyophilization of the relevant fractions gave the product (0.360 g, 40%) as an amorphous solid, ir (film) 3300 (-OH), 1770 (8-lactam CO), 1700 (-C02PN3) ca"1; 20 ^Hnmr (dg-acetone) 6: 8. 25, 7.80 (ABq, jJ=8.6 Hz, 4H, aromatic), 7.4-6.8 (m, 10H, diphenylphosphate), 5.56, 5.27 (ABq, J=14.2 Hz, 2H, benzylic), 4.42 (d of t, J=9.2 Hz, J' = 2.7 Hz, IH, H-5), 4.1-2.7 (m, 17H), 3.40 (s, 3H, N-Me) , 1.22 (d, J=6.2 Hz, 3H, -CHMe) .
I C. (5?., 65) - 3- 12- (1-methylmorpholino) ethylthio) -6 - [ (R) -1-hydroxvethyl]-7-oxo-l-azabicvclo[3.2.01hept-2-ene-2-~ carboxylate 'i To a solution of p-nitrobenzyl (5R, 65) - 3-[ 2- (1- methylmorpholino) ethylthio] -6- [ (R.) -1-hydroxyethyl] - 7-oxo-1- azabicyclo[3.2.0]hept-2-ene-2-carboxylate diphenylphosphate (0.360 g, 0.49 mmol) in 13 mL of phosphate buffer (0.05 M pH 7.4) was added 0.36 g of 10% palladium-on-charcoal, 20 mL of 10 tetrahydrofuran and 20 mL of diethyl ether. This mixture was hydrogenated (Parr) at 32 psi for 1 h. The mixture was filtered through Celite and the filter pad was washed with H20 and diethyl ether. The aqueous phase was separated and the pH was adjusted to 7.0 with additional pH 7.4 phosphate buffer. 15 After removing residual organic solvents in vacuo the aqueous solution was applied to a C^g reverse-phase column. Elution with H^O and lyophilization of the relevant fractions afforded 0.130 g of an amorphous solid. This material was repurified by reverse-phase hplc to give the pure product (0.058 g, 34%) 20 as an amorohous solid. ir (KBr)v : 3420 (br, OH), 1750 . max (6 -lactam CO), 1590 (-C02~) cm ; Hnmr (D20) 6 : 4. 35-2.77 (m, 17H), 3.18 (s, 3H, N-Me), 1.23 (d, J=6.3 Hz, 3H, CHMe) ; uv (H-0)X : 300 (e6344) nm; t. ,, (pH 7.4, 36.80C) 18.5 h.
IDcLX -L/ £• i :;9 ExamDle 18 Preparation of (5R, 6S)3-[2-(1,4-dimethyl-l-piperazinium) ethylthio]-6-[1-(R)-hydroxyethyl]-7-oxo-1-azabicyclo-[3.2.0)hept-2-ene-2-carboxylate N—CH, A. 1-(2-acetylthioethv1)-1,4-dimethylpjperazinium bromide Acetone 50°C ' A solution of 2-bromo.^thyl thiolacetate *(2.20 g, 0.012 mol) and 1,4-dimethylpiperazine (1.95 mL, 0.014 mol) in acetone (4 mL) was stirred at 50°C for 65 h. After cooling to 25°C, the liquid phase was decanted from the gum which was triturated twice in diethyl ether; a hygroscopic yellowish powder, 3.2 g (90%) was obtained; ir (Nujol) v : 1685 (C=0 of • « lucLX thioester) cm ; Hmr (D-0) 5: ° ^ —v /ch ^N-CH3) , 3.18 (s, 3H, )• 2.37, 2. 39 (2s, 6H, CH3' 5,31 (d' i=6 Hz' 0K) ' 5-39 (center of ABq, J=13 Hz, CH2 of PNB), 6.6-7.4 (m, 10H, phenyl of phosphate), 7.71 (d, J=8.8 Hz, 2H, Ho of PNB), 8.26 (d, J=8.8 Hz, 25 Hm of PNB). 1 <12 D. (5a,6S)3— £ 2—(1,4-dimethy1-1-piperazinium)ethylthio]-6-(1- (R)-hydroxyethyl]-7-oxo-1-azabicyclo(3.2.0]hept-2-erie-2-carboxy late To a solution of (5R,6S)paranitrobenzyl 3-[2-(l,4-dimethyl-l-piperazinium)ethylthio)-6-[1-(R)-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate diphenylphosphate (0.47 g, 0.623 mmol) in wet tetrahydrofurarv (25 mL) was added diethyl ether (25 mL), potassium phosphate monobasic-sodium hydroxide buffer (13 mL, pH 7.22) and 10% palladium on charcoal (0.47 g). The resulting mixture was hydrogenated at 23°C under 40 psi for 1 h. The two layers were separated and the organic layer was extracted with water (2x1 mL). The aqueous layers were combined, filtered through a Celite pad, washed with diethvl-ether (2 x 15 mL) and chromatographed on PrepPak-500/C^g (Waters Associates) column (2.5 x 9.5 cm) with water as eluting solvent to give, 0.097 g (43%) after lyophylization; ir (KBr) v : ITlaJC * 3000-3700 (OH), 1750 (C=0 of B-lactam), 1585 (carboxylate)cm , Himr (D,0) 6: 1.24 (d, J=6.4Hz, 3H, CH CHOH) , 2.33 (s, 3H, —\ _ /:H3 /N C3.3> ' 3-15 (s' / 4-0-4-5 H"5' CH3CH0H) , uv x 296 (c9 476) , tal„ 61.1° (C 0.26, H.,0) , tl/2=12.4 h * max D 2. "" — 4 (measured at a concentration of 10 M in phosphate buffer pH 7.4 at 36.8°C). 1 4 0 Example 19 Preparation of (5R,6S)-3-[2-(N-methy1-thiomorpholiniun-oxide)ethylthio]-6-[1-(R)-hydroxyethyl]-7-oxo-l-azabicy-clo(3.2.0)-hept-2-ene-2-carboxylate roCPBA To a cold (-ICC) solution of (5R,6S)-3-[2-(N-methy1-thiomorpholinium)ethylthio]-6-[1-(R)-hydroxyethyl]-7-oxo-1-azabicyclo(3.2.0)-hept-2-ene-2-carboxylate (608 mg, 1.65 mmol) in a 1:1 mixture of acetonitrile-water (9 mL) was added m-chloroperbenzoic acid (334.8 mg, 1.65 mmol) in small portion over a 1 hour period. The mixture was then diluted 1 <14 with water (15 mL) and washed with diethyl ether (3 x 15 mL).
The aqueous phase was pumped under vacuum and passed through a reversed phase silica gel column (H20) to give a solid which consisted of a mixture of compounds. This mixture was separated by reversed phase HPLC and afforded fraction A 52.4 mg (yield 12%) and fraction B 23.6 mg (yield 6%) as diastereomers of the title compound; Fraction A: ir (nujol) v : 1750 (s, B-lactara C=0) • < mdx and 1580 cm"x (s, C=0); Hmr (DjO) 6: 4.26-2.91 (20 H, m, H-4, H-5, H-6, H-1', CH2S, CH2S-0, CH3"N+ and CH2N+) and 1.24 ppm (3H, d, J=6.4 Hz, CH,); uv (H,0, c 0.06) A : 302 (el0425); j jL ItlaX T 1/2:12 h (0.065 M, pH 7.4 phosphate buffer, 37°c). Fraction 3: ir (nujol) v : 1750 (s, S-lactam C=0) and 1585 cm 1 (s, C-0); .. max Hmr (D20) 6: 3.86-2.90 (17 H, m, H-4, H-5, H-6, H-1', CHjS, CH2S-0, CH2N+), 3.25 (3H, s, CH3N+) and 1.24 ppm (3H, d, J=6.4 Hz, CH,); uv (H,0, c 0.05) X : 299 (e6517); T 1/2:10.75 h (0.065 M, 3 2 max pH 7.4 buffer solution, 37°C).
S '3 5 Example 20 Preparation of (5R,6S)-3-[2-(1,4,4-Trimethy1-1-piperazinium)-ethylthio]-6-(IR-hydroxyethyl]-7-oxo-1-azabicyclo(3.2.0)heot-2-ene-2-carboxvlate chloride , Clc COO A. 1-(2-acetvlthioethvl)-1,4,4-trimethvloiperazinium bromjdeiodica , 0 \/ \/ - - S. / \ „ - Kel V N V ' Br , I O N + N— ' Br \ V CH CS \ / \ CH Is \_ / /-oa. 5S-60°c ' A suspension of 1-(2-acetylthioethyl)-1,4-dimethyl- piperazinium bromide (1.48 g, 5.0 mmol) in isopropyl alcohol (10 mL) was treated with methyliodide (0.373 mL, 6.0 mmol) and heated at 55-60°C for 30 h. The solvents were evaporated under reduced pressuji the residue was triturated in hexane and the solid was filtered, 1.85 g. The solid was dissolved in hot water (8 mL) and the solution was diluted with acetone until turbidity (70-80 mL). Two successive crystallizations gave 1.5 g, mp 220-5°C dec., 683 of the title comoound; ir (K3r)v : 1692 cm 1 (C=0); ^Hmr (D,0) 6: 2.40 (s, 2H, max 2 CH3COO), 3.37 (s, N-CH3), 3.39 (s, N-CH3), 3.99 (s); uv (H20)Xmax: 226 (e 1314 4) . Anal, calcd for C^Hj ^OSBrl: C 30.08, H 5.51, N 6.38; found: C 30.48, H 5.53, N 6.86. 1 'J c 3. 1- (2-mgrcaotoethy1) -1. 4, 4-triroe th v 1 pipe ra; injur, btschlori.de A mixture of 1-(2-acctylthiocthy1 ) - I,4,4-trimethy1-piperazinium bromideiodide (1.84 g, 4.19 mmol) and 6N hydrochloric '> acid (15 mL) was heated at 57°C under a nitrogen atmosphere for 2.5 h. The solution was concentrated under reduced pressure to dryness. The solid was suspended in water (10 mL) and the well-stirred suspension was treated with permutit S-1 Cl~ until a solution was obtained. The solution was pour.ed on a column'(1.2 x I*1 60 cm) of permutit S-1 CI . The column was eluted with water (1.5 mL/min). The appropriate fractions were combined and lyophilized to give a white powder, 0.93 g, mp 190-191°C, 85%; ir (nujol)v : ^ ~ IuaX 2460 (SH) ; ^Hmr (D20) 5: 3.4 (s, N-CH-j) , 3.45 (s, N-CH-j) , 4.07 (s). Anal, calcd for CgH^NjSClj- 0. 75 H-jO: C 39.34, H 8.62, N 10.20, I r' S 11.67; found: C 39 . 48, H 8.39, N 10.55, S 11.15. 14 7 (5R, 6S) pa rani trobenzy 1 3- [ 2 - (1, 4 , 4- trime thy 1- 1-piperazir.ium) - ethy ithio j- 6-(IR-hydroxyethy1J -7-oxo-l-azabicyclo(3.2.0)hept' 2-ene-2-carboxvlate bischloride 2) CI?(0?h)j CH Permutit S-1 CI 0 3) NZt(i?r) CODPK3 To a cold (5°C) solution of (5R,6S) paranitrobenzyl 6- [iR-hvdrcxyethy1]- 3,7-dioxo-l-azabicyclo(3.2.0)heptane-2R-carboxylate (0.94 g, 2.7 rsnol) in acetonitrile (3 mL) kept under a nitrogen atmosphere was added diisopropylethylamine (0 . 557 mL, 3.2 mmol) arc diphenyl chlorophosphate (0.663 mL, 3.2 mmol). The reaction mixture was stirred at 5°C for 30 min and treated with diisopropy lethylamine (0.599 mL, 3.44 mmol) and an aqueous solution (4 mL) of l-(2-mercaptoethy1)-1,4,4-trimethylpiperazinium bischloride (0.90 g, 3.44 mmol). After 1.25 h, diisopropylethylamine (0.1 mL, 0.57 nr.iol) was aaced and the stirring was continued for 2 h. A part of the acetonitrile was eliminated under reduced pressure and the resulting red mixture was chromatographed on PreoPak -500/C,„ (Water Associates) * • J, o column with 25-75% acetonitrile in water as eluting solvent to give a yellowish powder (1.4 g) after lyophylization. The powder was solubilized in water and the solution was passed on a column (1.2 x 58 cm) of permutit S-1 Cl using water an eluting solvent. Lyophylization of the appropriate fractions gave 1.17 g of a powder that was repurified on a column of PrepPak -500/C^g. Lyophylization of the appropriate fractions gave a yellowish powder, 0.80 g (53%); ir (K3r)v : 3400 (br, OH), 1770 (C=0 of the B-lactam), 1690 max , (C=0 of ?N3 ester), 1605 (aromatic), 1515 (NC>2) , 134 5 ca-"1; 1Hmr (D20) c: 1.26 (d, J=6.3 Hz, 3H, CHjCHOH), 3.39 (s, NCH3), 4.00 (s), 5.37 (br, s, CH2 of PN3), 7.60 (d, J=8.6 Hz, 2H, Ho of-PNB), 8.20 (d, J = 3. 7 Hz, 2H, Hm of PN3) ; uv (H 20) : 276 U1209 4), 306 (* 10752) . Anal, calcd. for C25K36N40,SC12"2H20: C 46.51, H 6.56, " N- c.CS. S 4.97, Cl 10.98; found: C 46.31, H 6.IS, N S.57, S 5.3£, Cl 11.37. 1 4 8 D. (5R,6S)- 3-[2-(1,4,4-trimethy1-1-piperazinium)ethylthio]-6-(lR-hydroxve thy1J-7-oxo-l-azabicvclo(3.2.0)hept-2-ene-2-carbo>:vlate chloride A mixture of (5R,6S) paranitrobenzyl 3—[2—(1,4,4 — trinethy1-1-piperazinium)ethylthio] -6-[lR-hvdroxyethy1]-7-oxo-1-azibicyclo(3.2.0)hept-2-ene-2-carboxylate bischloride (0.40 g, 0.63 mmol), phosphate buffer (30 mL, 0.05M, pH 7.0), tetrahydrofuran (10 mL), ether (30 mL) and 10% palladium on charcoal (0.40 9) was hydrogenated at 23°C under 35 psi for 1 h. The two phases were separated. The organic phase was extracted with water (10 rJL) . The aqueous phases were filtered on a Celite pad, washed with ether . (10 mL) , concentrated under vacuum to 10 mL and chromatographed cr. PrePak-50 0/Ccolumn (2.2 x 11 cm) with water as eluting solvent to give 70 mg (25%) after Ivonhylization; ir (KBr)v : 3400 (br, OH) -i f 1755 (C=0 of the S-lactam) , 1585 (carboxylate) cm ; Krar (D^O) c" : 1.24 (3 H, d, J = 6.3 Hz, CH-jCHOH) , 3.36 (s, NCH3) , 3.93 (s); uv (F^O) Xmax: 296 <£7937)' [°^d3 35-9° (c' 0-30, HjO), T1/2= 9.3 h (measured at a concentration of To-4 M in phosphate buffer pH 7.4 at 36.8°C). 1 <1 0

Claims (12)

CLAIMS:
1. A process for the preparation of a carbapenem derivative of the formula R8 » S-A-R COOR" 14 Q 1 whoroin R is hydroqen and P. is selected from hy
2. A process according to Claim 1, wherein the base is a non-nucleophilic tertiary amine or a tri (C^-C^j) alkyl-amine.
3. A process according to Claim 2,wherein the base is a non-nucleophilic tertiary amine.
4. A process according to Claim 1, 2 or 3,wherein the reaction is carried out at a temperature of -15°C up to room temperature.
5. A process according to Claim 4,wherein the reaction is carried out at a temperature in the range of I roni to
6. A process according to Claim 1, 2, 3, 4 or 5, wherein the inert solvent is selected from acctonitrilc, a mixture of acetonitrile, dimethylformamide, tetrahydrofuran, a mixture of tetrahydrofuran and water, a mixture of acetonitrile and water and acetone.
7. A process for the preparation of a quaternary amine thiol compound of the formula wherein A is cyclopentylene, cyclohexylene or R10 I -C R11 12 13 in which R , R , R and R are each independently hydrogen 9 14 or C^-C4 alkyl, X is a counter anion and R represents a substituted or unsubstituted mono, bi- or polycyclic aromatic or non-aromatic heterocyclic radical containinq at least one nitrogen in the ring and attached to A through a ring nitrogen, thereby forming a quaternary ammonium group, which process comprises reacting a sulfide of the formula 1 "-.S wherein R^°, R^, R^2 and R^3 are each independently hydrogen or C^-C4 a-lkvl with a strong acid and either (a) a heteroaromatic amine of the formula wherein represents a substituted or unsubstituted mono-, bi- or polycyclic aromatic heterocyclic radical containing at least one nitrogen in the ring capable of being quaternized and bonded to a carbon atom Io of substituent A or (b) a heterocyclic amine of the formula wherein represents a substituted or unsubstituted mono-, bi- or polycyclic i r> non-aromatic heterocyclic radical containing at least one nitrogen in the ring capable of being quaternized by substituent R1® and bonded to a carbon atom of substituent A and R^ represents either (a) an optionally substituted aliphatic, cycloaliphatic, cvcloaliphatic-aliphatic, aryl, araliphatic, heteroaryl, heteroaraliphatic, hetero-2() cyclyl or heterocyclyl-aliphatic radical or (b) a divalent phenylene or alkylene group joined to the ring so as to form a bridged polycyclic group. ) 1 5 <>
8. A proccss according to Claim 7, wherri n the reaction is carried out at a temperature in the range of from -20°C to 10(fc.
9. A process according to Claim 7 or Claim f>, wherein the s !. rori'i .icid ihydroch.lor i c, hydrobromic, methanesulfonic , toiuenesulfonic or trifluoromethanesulfonic. I
10. I 0 . A process according to Claim 7, 8 or 9, wherein the re action is carried out in the presence of a non-polar organic solvent.
11. A process according to Claim 10, wherein the non-polar organic solvent is methylene chloride, benzene, xylene or toluene. 10
12. A process-; according to Claim 7, 8, 9, 10 or II, wherein, when the amine and sulfide reagents are liquids or when the amine reagent it; a :jolid, the sulfide reagent is liuuid and the solid amine is soluble in the liquid sulfide reagent, the reaction i carried out without additional r.olvent. I r> l .1. A quaternary amine thiol compound of the formula 14 HS — A — R x6 VII wherein A is cyclopentylene, cyclohexylene or R10 R12 I I — C C — R11 R13 in which R^", R^, R*2 and R^3 are each independently hydrogen 20 or C1-C4 alkyl, X® is a counter anion and represents a substituted or unsubstituted mono, bi- or polycyclic aromatic or non-aromatic heterocyclic radical containing at least one nitrogen in the ring and attached to A through a ring nitrogen, thereby forming a quaternary ammonium group.;i r. 7;14. A process according to Claim 1, substantially as described in any of the applicable Examples in the foregoing description.;lb. A process according to Claim 7, substantially as 5 described in any of the applicable Examples in the foregoing description.;16. A process according to Claim 1, modified by the inclusion of an additional step, in which process 14;R comprises initially an N-methyl-thiomorpholinium;10 radical, and the initially obtained derivative of formula;I is converted into the corresponding compound answering;14;to formula I wherein R comprises an N-methyl-thiomorpholinium oxide radical, by oxidation with m-chloroperbenzoic acid, the procedure being that of the '-r> foregoing Example 19 op ananalogous procedure equivalent thereto.;17. A carbapenem derivative prepared by a process according to amy of claims 1 to 6 or Claim 14.;18. A quaternary ammonium thiol compound prepared by a process according to any of Claims 7 to 12 or Claim 15. 20 19. A sulfoxide compound prepared by the process of;Claim 16.;20. A pharmaceutical composition comprising a carbapenem derivative as claimed in Claim 17 and a pharmaceutically acceptable carrier or diluent. 25 21. A pharmaceutical composition according to Claim;20, substantially as hereinbefore described.;Relorence has been directed in pursuance ol SutirjCc/wA section 14 ut the Patents Act, l')b4 , to psiLeril No. 54769.;y. r. kelly & co.;* AGENTS TOR THE APPLICANTS
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