EP0038869A1
Expired / Lapsed
EP
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Process for the preparation of 1-carbapenems, and intermediates for their preparation
Assignee: Merck and Co Inc
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Filing: 1980-04-30
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Granted: —
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Expires: 2000-04-30
Abstract
Abstract Processes and intermediates for the total synthesis of 1-carbapenem antibiotics (I) via intermediates (III) and (IV): wherein R is hydrogen, a pharmaceutically acceptable ester moiety or salt cation, or a readily removable blocking group; R 6 , R 7 and R 8 are, inter alia, independently selected from the group consisting of hydrogen, alkyl, alkenyl, aryl and aralkyl, and X is a conventional leaving group.
Inventors
- 👤 Burton G. Christensen
- 👤 Ronald W. Ratcliffe
Bibliographic Details
Application Number
—
Jurisdiction
EP
Data Source
google_patents
Last Synchronized
2026-11-05 17:25
CPC Classifications
C; C07; C07D; C07D205/00; C07D205/02; C07D205/06; C07D205/08; C07D477/00; C07D477/10; C07D477/12; C07D477/16; C07F; C07F7/00; C07F7/02; C07F7/08; C07F7/10; C07F9/00; C07F9/02; C07F9/547; C07F9/6561; C07F9/65611
Claims Analysis
Total Claims: 21
Claim 1
Independent Claim
290 words
A process for preparing a compound having the structural formula: and the pharmaceuticaliy acceptable salt ester and amide derivatives thereof; wherein R 6 , R and R 8 are independently selected from the group consisting of: hydrogen; substituted and unsubstituted: 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; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl; wherein the substituent or substituents relative to the above-named radicals are selected from the group consisting of: chloro, bromo, fluoro, R 1 , wherein, relative to the above listed substituents on R 6 , R 7 and R 8 , the groups R 1 and R 2 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; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl; and wherein the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group consisting of 1-4 oxygen, nitrogen or sulphur atoms and wherein the alkyl moieties associated with said heterocyclic moieties have 1-6 carbon atoms; comprising activating and treating with HSR 8 a compound of the structure: wherein R 3 is a protecting group or a pharmaceutically acceptable ester moiety; when R 6 /R 7 is hydrogen and R 7 /R 6 is CH 3 CH(OH), then R 8 is not -CH 2 CH 2 NH 2 .
Claim 2
Dependent Claim
290 words
A process for preparing a compound having the structural formula: and the pharmaceuticaliy acceptable salt ester and amide derivatives thereof; wherein R 6 , R and R 8 are independently selected from the group consisting of: hydrogen; substituted and unsubstituted: 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; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl; wherein the substituent or substituents relative to the above-named radicals are selected from the group consisting of: chloro, bromo, fluoro, R 1 , wherein, relative to the above listed substituents on R 6 , R 7 and R 8 , the groups R 1 and R 2 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; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl; and wherein the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group consisting of 1-4 oxygen, nitrogen or sulphur atoms and wherein the alkyl moieties associated with said heterocyclic moieties have 1-6 carbon atoms; comprising activating and treating with HSR 8 a compound of the structure: wherein R 3 is a protecting group or a pharmaceutically acceptable ester moiety; when R 6 /R 7 is hydrogen and R 7 /R 6 is CH 3 CH(OH), then R 8 is not -CH 2 CH 2 NH 2 .
Claim 3
Dependent Claim
17 words
A process according to Claim 1 comprising treating: with HSR 8 wherein X is a leaving group.
Claim 4
Dependent Claim
261 words
A compound selected from: wherein X is a leaving group, R 3 is hydrogen, a salt cation, a protecting group, or a pharmaceutically acceptable ester moiety; and wherein R 6 , R 7 and R 8 are independently selected from the group consisting of: hydrogen; substituted and unsubstituted: 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; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl; wherein the substituent or substituents relative to the above-named radicals are selected from the group consisting of: chloro, bromo, fluoro, R 1 , wherein, relative to the above listed substituents on R 6 , R and R 8 , the groups R 1 and R 2 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; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl; and wherein the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group consisting of 1-4 oxygen, nitrogen or sulphur atoms and wherein the alkyl moieties associated with said heterocyclic moieties have 1-6 carbon atoms; when R 6 /R 7 is hydrogen, then R 7 /R 6 is not CH 3 CH(OH).
Claim 5
Dependent Claim
261 words
A compound selected from: wherein X is a leaving group, R 3 is hydrogen, a salt cation, a protecting group, or a pharmaceutically acceptable ester moiety; and wherein R 6 , R 7 and R 8 are independently selected from the group consisting of: hydrogen; substituted and unsubstituted: 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; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl; wherein the substituent or substituents relative to the above-named radicals are selected from the group consisting of: chloro, bromo, fluoro, R 1 , wherein, relative to the above listed substituents on R 6 , R and R 8 , the groups R 1 and R 2 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; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl; and wherein the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group consisting of 1-4 oxygen, nitrogen or sulphur atoms and wherein the alkyl moieties associated with said heterocyclic moieties have 1-6 carbon atoms; when R 6 /R 7 is hydrogen, then R 7 /R 6 is not CH 3 CH(OH).
Claim 6
Dependent Claim
19 words
A compound according to Claim 3, wherein R 7 is selected from H, OCH 3 and CH 3 .
Claim 7
Dependent Claim
42 words
A compound according to Claim 4 wherein R 6 is selected from the group consisting of: substituted and unsubstituted: alkyl, alkenyl and cycloalkylalkyl wherein the substituent or substituents are selected from hydroxyl, alkoxyl having from 1-6 carbon atoms, phenoxy, amino, and carboxy.
Claim 8
Dependent Claim
37 words
A compound according to Claims 4 or 5 wherein R 6 is selected from the group consisting of alkyl, cycloalkylalkyl, alkyl substituted by one or more hydroxyl groups, or cycloalkylalkyl substituted by one or more hydroxyl groups.
Claim 9
Dependent Claim
14 words
A compound according to Claims 4, 5 or 6 wherein R 7 is hydrogen.
Claim 10
Dependent Claim
19 words
A compound according to Claims 3, 4, 5, 6, or 7 wherein R6 is selected from: φ = phenyl
Claim 11
Dependent Claim
19 words
A compound according to Claim 3 wherein X is chloro, bromo, iodo, phenylsulfonyloxy, p-toluylsulfonyloxy, p-nitrophenylsulfonyloxy, methylsulfonyloxy, trifluoromethylsulfonyloxy, diphenylphosphoryl, bis(trichloroethyl)phosphoryl.
Claim 12
Dependent Claim
80 words
A compound according to Claims 3, 4 or 7 selected from: H, wherein: y = 0 or 1; X = OH, NH 2 ; SH; n 0 or 1; R = substituted or unsubstituted: alkyl, alkenyl or alkynyl having 1-6 carbon atoms wherein the substituent is R 1 ; R 1° = alkoxyl, carboxyl, CF 3 , OH, H, linear or branched alkyl bearing 1 or more hydroxyl groups, amino, aminoalkyl, Cl, F, Br, alkylthio, amidino, guanidino, oximino, phenyloxy, phenylthio,
Claim 13
Dependent Claim
200 words
A process according to Claims 1 or 2 wherein R 8 is selected from: 1.) aliphatic (including carbocyclic) groups having 1-10 carbon atoms selected from: alkyl, cycloalkyl, alkenyl, cycloalkenyl and alkynyl; 2.) substituted aliphatic groups having 1-10 carbon atoms selected from: alkyl, cycloalkyl, alkenyl, cycloalkenyl and alkynyl; wherein the substituents are selected from: chloro, bromo, fluoro, R 1 , 3.) aryl and substituted aryl; wherein the aryl is phenyl and wherein the substituents are defined above under 2.); 4.) heteroaryl and substituted heteroaryl having 1-4 O, N or S atoms; and wherein the substituents are defined above under 2.); 5.) arylaliphatic, wherein aryl is phenyl, which are selected from the aliphatic groups defined under 1.) which are substituted by phenyl or substituted phenyl; wherein such substituents on phenyl are defined under 2.), above; 6.) heteroarylaliphatic and heterocyclylaliphatic; wherein the aliphatic moiety is defined under 1.), above; the substituted and unsubstituted heteroaryl and heterocyclic moieties have 1-4 O, N or S atoms; wherein such substituents are defined under 2.),above; 7.) substituted and unsubstituted alkyl-heteroatom-alkyl having 4-12 carbon atoms; wherein the heteroatom is selected from: O, S, NR° (R° is H, substituted or unsubstituted alkyl); wherein such substituents are defined under 2.),above.
Claim 14
Dependent Claim
14 words
A process according to Claim 11, subparagraph 1.); wherein R 8 is selected from:
Claim 15
Dependent Claim
106 words
A process according to Claim 11, subparagraph 2.); wherein R 8 is selected from: n = 2-6; R 1 = H, n=1-6; X=O, NH, NR 1 , R 1 =H, CH 3 n-2-6 n=2-6; R 1 =CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , n=2-6; R 1 /R 2 =CH 3 , CH 2 CH 3 ; CH 3 ,CH 3 ; CH 2 CH 3 ,CH 2 CH 3 R 1 =H, CH 3 , n-3-5 R 1 and R 2 are independently chosen from H and CH 3 n=1, R 2 /R 1 =H,H; CH 3 ,H
Claim 16
Dependent Claim
14 words
A process according to Claim 11, subparagraph 3.); wherein R 8 is selected from:
Claim 17
Dependent Claim
25 words
A process according to Claim 11, subparagraph 4.), wherein R 8 is: X=N,O Y=H X=S Y=H, Cl, OCH 2 CH 3 R=H, CH3 X=NH, S
Claim 18
Dependent Claim
12 words
A process according to Claim 11, subparagraph 5.); wherein R 8 is:
Claim 19
Dependent Claim
150 words
A process according to Claim 11, sub paragraph 6.); wherein R 8 is: R 1 = OCH 2 CH 3 X = O, S, NH X = O, S, NH X = O, S, NH X = O, S, NH X = O, S, NH R 1 =H, CH 3 m = 1-3 n = 1-3 R 2 =H, CH 3 , R 1 =H, CH 3 , NH 2 R 1 = H, CH 3 R 1 =H, CH 3 X = O, S, NH R 1 = H, CH 3 R 1 = H, CH 3 R 1 = H, CH 3 X = O, NH, NCH 3 R 1 = H, CH 3 R 1 = H, CH 3 R 1 = H, CH 3 R 1 = H, CH 3 R 1 = H, CH 3 X = 0, S, NH X = O, S, NH
Claim 20
Dependent Claim
12 words
A process according to Claim 11, subparagraph 7.); wherein R 8 is:
Claim 21
Dependent Claim
20 words
A process according to Claim 1 or 2 for preparing: φ = phenyl (R - phenyl, m-aminomethylphenyl, o-, p-, m-hydroxyphenyl)
References Cited (Backward Citations)
EP0007973A1
Cited
EP0017970A1
Cited
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