Process for the synthesis of azetidinones

Abstract

A process is provided for preparing azetidinones useful as intermediates in the synthesis of penems and as hypocholesterolemic agents, comprising reacting a β-(substituted-amino)amide, a β-(substituted-amino)acid ester, or a β-(substituted-amino)thiolcarbonic acid ester with a silylating agent and a cyclizing agent selected from the group consisting of alkali metal carboxylates, quaternary ammonium carboxylates, quaternary ammonium hydroxides, quaternary ammonium alkoxides, quaternary ammonium aryloxides and hydrates thereof, or the reaction product of: (i) at least one quaternary ammonium halide and at least one alkali metal carboxylate; or (ii) at least one quaternary ammonium chloride, quaternary ammonium bromide, or quaternary ammonium iodide and at least one alkali metal fluoride, wherein a quaternary ammonium moiety of the cyclizing agent is unsubstituted or substituted by one to four groups independently selected from the group consisting of alkyl, arylalkyl and arylalkyl-alkyl.

1 . A process for preparing an azetidinone, comprising the step of reacting:
 (1) a β-(substituted-amino)amide, a β-(substituted-amino)-acid ester, or a β-(substituted-amino)thiolcarbonic acid ester with   (2) at least one silylating agent and   (3) at least one cyclizing agent which is
 (a) selected from the group consisting of alkali metal carboxylates, quaternary ammonium carboxylates, quaternary ammonium hydroxides, quaternary ammonium alkoxides, quaternary ammonium aryloxides and hydrates thereof, or 
 (b) the reaction product of:
 (i) at least one quaternary ammonium halide and at least one alkali metal carboxylate; or 
 (ii) at least one quaternary ammonium chloride, quaternary ammonium bromide, or quaternary ammonium iodide and at least one alkali metal fluoride, 
 
 wherein a quaternary ammonium moiety of the cyclizing agent is unsubstituted or substituted by one to four groups independently selected from the group consisting of alkyl, arylalkyl and arylalkyl-alkyl. 
   
     
     
         2 . The process according to  claim 1 , wherein the azetidinone is represented by the structural Formula (I): 
       
         
           
           
               
               
           
         
       
       or pharmaceutically acceptable salts or solvates of the azetidinone of Formula (I), wherein in Formula (I) above:
 X′, Y′ and Z can be the same or different and each is independently selected from the group consisting of —CH 2 —, —CH(alkyl)- and —C(alkyl) 2 -; 
 Q 1  and Q 2  can be the same or different and each is independently selected from the group consisting of H, —(C 0 -C 30  alkylene)-G, —OR 6 , —OC(O)R 6 , —OC(O)OR 9 , and —OC(O)NR 6 R 7 M; 
 Q 3 , Q 4 , and Q 5  can be the same or different and each is independently 1 to 5 substituents independently selected from the group consisting of acyl, alkyl, alkylaryl, alkylheteroaryl, alkylsulfonyl alkenyl, alkoxy, alkoxycarbonyl, alkynyl, —(C 0 -C 30  alkylene)-G, —(C 0 -C 10  alkylene)-OR 6 , —(C 0 -C 10  alkylene)-C(O)R 6 , —(C 0 -C 10  alkylene)-C(O)OR 6 , —(C 0 -C 10  alkylene)-OC(O)R 6 , —(C 0 -C 10  alkylene)-OC(O)OR 9 , —CH═CH—C(O)R 6 , —CH═CH—C(O)OR 6 , —C≡C—C(O)OR 6 , —C≡C—C(O)R 6 , —O—(C 1 -C 10  alkylene)-OR 6 , —O—(C 1 -C 10  alkylene)-C(O)R 6 , —O—(C 1 -C 10  alkylene)-C(O)OR 6 , —CN, —C(═N—CN)—NH 2 , —C(═NH)—NHR 10 , —O—(C 1 -C 10  alkylene)-C(O)NR 6 R 7 , —O—(C 0 -C 10  alkylene)-C(O)NR 6 NR 7 C(O)OR 6 , —O—(C 1 -C 10  alkylene)-C(O)(aryl)-N—N═N − , —OC(O)—(C 1 -C 10  alkylene)-C(O)OR 6 , —(C 0 -C 10  alkylene)-C(O)NR 6 R 7 , —(C 0 -C 10  alkylene)-OC(O)NR 6 R 7 , —NO 2 , —(C 0 -C 10  alkylene)-NR 6 R 7 , —O—(C 2 -C 10  alkylene)-NR 6 R 7 , —NR 6 C(O)R 7 , —NR 6 C(O)OR 9 , —NR 6 C(O)NR 7 R 8 , —NR 6 S(O) 0-2 R 9 , —N(S(O) 0-2 R 9 ) 2 , —CHNOR 6 , —C(O)NR 6 R 7 , —C(O)NR 6 NR 6 R 7 , —S(O) 0-2 NR 6 R 7 , —S(O) 0-2 R 9 , —O—C(O)—(C 1 -C 10  alkylene)-C(O)NR 6 R 7 , —OC(O)—(C 1 -C 10  alkylene)-NR 6 C(O)O-(alkylaryl), —P(O)(OR 10 ) 2 , —(C 1 -C 10  alkylene)-OSi(alkyl) 3 , —CF 3 , —OCF 3 , halo, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkoxycarbonylalkoxy, alkoxyarylalkoxy, alkoxyiminoalkyl, alkyldioyl, allyl, allyloxy, aryloxycarbonyl, aryl, arylalkyl, aryloxy, arylalkoxy, aroyl, aroyloxy, arylsulfonyl, aroylaroyloxy, aroyl, arylalkoxycarbonyl, benzoylbenzoyloxy, carboxy, cyano, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkynyl, heteroarylalkyl, heteroarylalkoxy, heteroarylsulfonyl, heteroarylthio, dioxolanyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, heterocyclylcarbonylalkoxy, hydroxy, hydroxyalkyl, and alkylsulfonyl; 
 wherein optionally one or more carbon atoms of the —(C 0 -C 30  alkylene)-radical of Q 1 , Q 2 , Q 3 , Q 4  and Q 5  is independently replaced by —O—, —C(O)—, —CH═CH—, —C≡C—, —N(alkyl)-, —N(alkylaryl)- or —NH—; 
 G is selected from the group consisting of a sugar residue, disugar residue, trisugar residue, tetrasugar residue, sugar acid, amino sugar, amino acid residue, oligopeptide residue comprising 2 to 9 amino acids, trialkylammoniumalkyl radical and —S(O) 2 —OH, 
 R 2  and R 3  can be the same or different and each is independently selected from the group consisting of hydrogen, alkyl and aryl; 
 R 6 , R 7  and R 8  can be the same or different and each is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, arylalkyl and a protecting group; and 
 each R 9  is independently alkyl, cycloalkyl, aryl or arylalkyl. 
 each R 10  is independently H or alkyl; 
 q is 0 or 1; 
 r is 0 or 1; 
 m, n and p are independently selected from 0, 1, 2, 3 or 4; provided that at least one of q and r is 1, and the sum of m, n, p, q and r is 1, 2, 3, 4, 5 or 6; and provided that when p is 0 and r is 1, the sum of m, q and n is 1, 2, 3, 4 or 5. 
 
     
     
         3 . The process according to  claim 2 , wherein the azetidinone is represented by the structural Formula (IV): 
       
         
           
           
               
               
           
         
       
     
     
         4 . The process according to  claim 1 , wherein the β-(substituted-amino)amide comprises a carbamoyl portion B—C(O)—, wherein B is a deprotonated chiral auxiliary selected from the group consisting of 
       
         
           
           
               
               
           
         
       
       wherein X is —O—, —S— or —N(alkyl)-; Y is ═O or ═S; and R 12  and R 13  are each independently selected from the group consisting of alkyl, aryl arylalkyl, and alkoxycarbonyl, or wherein one of R 12  or R 13  is as defined above and the other is hydrogen. 
     
     
         5 . The process according to  claim 4 , wherein the aryl group of R 12  or R 13  is independently selected from the group consisting of phenyl, naphthyl, benzyl, substituted phenyl, substituted naphthyl and substituted benzyl, wherein the substituents on the phenyl or naphthyl are 1-3 substituents selected from the group consisting of alkyl, alkoxy, phenyl and benzyl. 
     
     
         6 . The process according claim to  4 , wherein the β-(substituted-amino)amide comprises a carbamoyl portion B—C(O)—, where B is (R 14 )(R 15 )N—, and R 14  and R 15  are each independently selected from the group consisting of alkyl, aryl, arylalkyl. 
     
     
         7 . The process according to  claim 4 , wherein the β-(substituted-amino)amide is represented by Formula (II): 
       
         
           
           
               
               
           
         
       
       wherein B is as defined in  claim 4 ,
 X′, Y′ and Z can be the same or different and each is independently selected from the group consisting of —CH 2 —, —CH(alkyl)- and —C(alkyl) 2 -; 
 Q 1  and Q 2  can be the same or different and each is independently selected from the group consisting of H, —(C 0 -C 30  alkylene)-G, —OR 6 , —OC(O)R 6 , —OC(O)OR 9 , and —OC(O)NR 6 R 7 ; 
 Q 3 , Q 4 , and Q 5  can be the same or different and each is independently 1 to 5 substituents independently selected from the group consisting of acyl, alkyl, alkylaryl, alkylheteroaryl, alkylsulfonyl alkenyl, alkoxy, alkoxycarbonyl, alkynyl, —(C 0 -C 30  alkylene)-G, —(C 0 -C 10  alkylene)-OR 6 , —(C 0 -C 10  alkylene)-C(O)R 6 , —(C 0 -C 10  alkylene)-C(O)OR 6 , —(C 0 -C 10  alkylene)-OC(O)R 6 , —(C 0 -C 10  alkylene)-OC(O)OR 9 , —CH═CH—C(O)R 6 , —CH═CH—C(O)OR 6 , —C≡C—C(O)OR 6 , —C≡C—C(O)R 6 , —O—(C 1 -C 10  alkylene)-OR 6 , —O—(C 1 -C 10  alkylene)-C(O)R 6 , —O—(C 1 -C 10  alkylene)-C(O)OR 6 , —CN, —C(═N—CN)—NH 2 , —C(═NH)—NHR 10 , —O—(C 1 -C 10  alkylene)-C(O)NR 6 R 7 , —O—(C 0 -C 10  alkylene)-C(O)NR 6 NR 7 C(O)OR 6 , —O—(C 1 -C 10  alkylene)-C(O)(aryl)-N—N═N − , —OC(O)—(C 1 -C 10  alkylene)-C(O)OR 6 , —(C 0 -C 10  alkylene)-C(O)NR 6 R 7 , —(C 0 -C 10  alkylene)-OC(O)NR 6 R 7 , —NO 2 , —(C 0 -C 10  alkylene)-NR 6 R 7 , —O—(C 2 -C 10  alkylene)-NR 6 R 7 , —NR 6 C(O)R 7 , —NR 6 C(O)OR 9 , —NR 6 C(O)NR 7 R 8 , —NR 6 S(O) 0-2 R 9 , —N(S(O) 0-2 R 9 ) 2 , —CHNOR 6 , —C(O)NR 6 R 7 , —C(O)NR 6 NR 6 R 7 , —S(O) 0-2 NR 6 R 7 , —S(O) 0-2 R 9 , —O—C(O)—(C 1 -C 10  alkylene)-C(O)NR 6 R 7 , —OC(O)—(C 1 -C 10  alkylene)-NR 6 C(O)O-(alkylaryl), —P(O)(OR 10 ) 2 , —(C 1 -C 10  alkylene)-OSi(alkyl) 3 , —CF 3 , —OCF 3 , halo, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkoxycarbonylalkoxy, alkoxyarylalkoxy, alkoxyiminoalkyl, alkyldioyl, allyl, allyloxy, aryloxycarbonyl, aryl, arylalkyl, aryloxy, arylalkoxy, aroyl, aroyloxy, arylsulfonyl, aroylaroyloxy, aroyl, arylalkoxycarbonyl, benzoylbenzoyloxy, carboxy, cyano, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkynyl, heteroarylalkyl, heteroarylalkoxy, heteroarylsulfonyl, heteroarylthio, dioxolanyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, heterocyclylcarbonylalkoxy, hydroxy, hydroxyalkyl, and alkylsulfonyl; 
 wherein optionally one or more carbon atoms of the —(C 0 -C 30  alkylene)-radical of Q 1 , Q 2 , Q 3 , Q 4  and Q 5  is independently replaced by —O—, —C(O)—, —CH═CH—, —C≡C—, —N(alkyl)-, —N(alkylaryl)- or —NH—; 
 G is selected from the group consisting of a sugar residue, disugar residue, trisugar residue, tetrasugar residue, sugar acid, amino sugar, amino acid residue, oligopeptide residue comprising 2 to 9 amino acids, trialkylammoniumalkyl radical and —S(O) 2 —OH, 
 R 2  and R 3  can be the same or different and each is independently selected from the group consisting of hydrogen, alkyl and aryl; 
 R 6 , R 7  and R 8  can be the same or different and each is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, arylalkyl and a protecting group; and 
 each R 9  is independently alkyl, cycloalkyl, aryl or arylalkyl. 
 each R 10  is independently H or alkyl; 
 q is 0 or 1; 
 r is 0 or 1; 
 m, n and p are independently selected from 0, 1, 2, 3 or 4; provided that at least one of q and r is 1, and the sum of m, n, p, q and r is 1, 2, 3, 4, 5 or 6; and provided that when p is 0 and r is 1, the sum of m, q and n is 1, 2, 3, 4 or 5. 
 
     
     
         8 . The process according to  claim 7 , wherein the β-(substituted-amino)amide is represented by Formula (III): 
       
         
           
           
               
               
           
         
       
     
     
         9 . The process according  claim 1 , wherein the β-(substituted-amino)acid ester comprises a carboxylic acid ester portion R 14 —O—C(O)—, wherein R 14  is alkyl or aryl. 
     
     
         10 . The process according  claim 1 , wherein the β-(substituted-amino)thiolcarbonic acid ester comprises a thiolcarbonic acid ester portion R 14 —S—C(O)—, wherein R 14  is alkyl or aryl. 
     
     
         11 . The process according  claim 1 , wherein the silylating agent is a silylenol ether. 
     
     
         12 . The process according  claim 11 , wherein the silylating agent is selected from the group consisting of bistrimethylsilylacetamide, N-methyl-O-trimethyl silylacetamide or isopropenyloxy trimethylsilane. 
     
     
         13 . The process according to  claim 1 , wherein the alkali metal carboxylate is a carboxylate salt of an alkali metal selected from the group consisting of lithium, sodium, potassium and cesium. 
     
     
         14 . The process according to  claim 1 , wherein the alkali metal carboxylate or quaternary ammonium carboxylate comprises a carboxylate moiety selected from the group consisting of formate, acetate, propionate, butyrate, valerate, caproate, caprylate, laurate, myristate, palmitate, stearate, oleate, linoleate, linolenate, cyclohexanecarboxylate, phenylacetate, benzoate and toluate. 
     
     
         15 . The process according to  claim 14 , wherein the carboxylate moiety of the alkali metal carboxylate is acetate. 
     
     
         16 . The process according to  claim 14 , wherein the alkali metal carboxylate is potassium acetate. 
     
     
         17 . The process according to  claim 14 , wherein the carboxylate moiety of the quaternary ammonium carboxylate is acetate. 
     
     
         18 . The process according to  claim 1 , wherein the quaternary ammonium moiety of the cyclizing agent is tetra n-butylammonium. 
     
     
         19 . The process according to  claim 14 , wherein the quaternary ammonium carboxylate is tetra n-butylammonium acetate. 
     
     
         20 . The process according to  claim 1 , wherein the quaternary ammonium hydroxide is tetra n-butylammonium hydroxide. 
     
     
         21 . The process according to  claim 1 , wherein the quaternary ammonium halide comprises a halide moiety selected from the group consisting of fluoride, chloride, bromide and iodide. 
     
     
         22 . The process according to  claim 1 , wherein the cyclizing agent is the reaction product of tetra n-butylammonium bromide and potassium acetate. 
     
     
         23 . The process according to  claim 1 , wherein the cyclizing agent is the reaction product of tetra n-butylammonium bromide and cesium fluoride. 
     
     
         24 . The process according to  claim 1 , wherein the reaction product (3)(b) is formed in situ in the presence of reactants (1) and (2). 
     
     
         25 . The process according to  claim 1 , further comprising the step of forming the reaction product (3)(b) prior to reaction with reactants (1) and (2). 
     
     
         26 . The process according to  claim 1 , wherein the silylating agent is bistrimethylsilylacetamide and the cyclizing agent is tetra n-butylammonium acetate. 
     
     
         27 . The process according to  claim 1 , further comprising adding a second cyclizing agent which is a fluoride ion catalyst. 
     
     
         28 . The process according to  claim 1 , comprising pre-reacting reactant (1) with reactant (2). 
     
     
         29 . The process according to  claim 1 , for preparing an azetidinone represented by the structural Formula (IV): 
       
         
           
           
               
               
           
         
       
       comprising reacting:
 (1) a β-(substituted-amino)amide of the formula (III) 
 
       
         
           
           
               
               
           
         
       
       with (2) at least one silylating agent and
 (3) at least one cyclizing agent which is
 (a) selected from the group consisting of alkali metal carboxylates, quaternary ammonium carboxylates, quaternary ammonium hydroxides, quaternary ammonium alkoxides, quaternary ammonium aryloxides and hydrates thereof; or 
 (b) the reaction product of:
 (i) at least one quaternary ammonium halide and at least one alkali metal carboxylate; or 
 (ii) at least one quaternary ammonium chloride, quaternary ammonium bromide, or quaternary ammonium iodide and at least one alkali metal fluoride, 
 
 wherein a quaternary ammonium moiety of the cyclizing agent is unsubstituted or substituted by one to four groups independently selected from the group consisting of alkyl, arylalkyl and arylalkyl-alkyl. 
 
 
     
     
         30 . A process for preparing a compound represented by the Formula (IV): 
       
         
           
           
               
               
           
         
       
       comprising the step of:
 cyclizing the β-(substituted-amino)amide of formula XII 
 
       
         
           
           
               
               
           
         
       
       wherein X is —O—, —S— or —N(C 1 -C 6  alkyl); Y is ═O or ═S; and R 1  is alkyl, aryl or alkoxycarbonyl, and wherein Prot is a silyl protecting group with at least one silylating agent and at least one cyclizing agent which is:
 (a) selected from the group consisting of alkali metal carboxylates, quaternary ammonium carboxylates, quaternary ammonium hydroxides, quaternary ammonium alkoxides, quaternary ammonium aryloxides and hydrates thereof; or 
 (b) the reaction product of:
 (i) at least one quaternary ammonium halide and at least one alkali metal carboxylate; or 
 (ii) at least one quaternary ammonium chloride, quaternary ammonium bromide, or quaternary ammonium iodide and at least one alkali metal fluoride, 
 
 wherein a quaternary ammonium moiety of the cyclizing agent is unsubstituted or substituted by one to four groups independently selected from the group consisting of alkyl, arylalkyl and arylalkyl-alkyl, 
 
       to obtain the compound of Formula XI: 
       
         
           
           
               
               
           
         
       
       and
 removing the silyl protecting groups to form the compound of Formula (IV). 
 
     
     
         31 . The process according to  claim 30 , further comprising the steps of:
 reacting a chiral alcohol of Formula VIII, an imine of Formula IX and a silyl protecting agent, then condensing the silyl-protected compounds to obtain a β-(substituted-amino)amide of Formula XII, wherein X is —O—, —S— or —N(C 1 -C 6  alkyl); Y is ═O or ═S; and R 1  is alkyl, aryl or alkoxycarbonyl, and wherein Prot is a silyl protecting group:   
       
         
           
           
               
               
           
         
       
       prior to cyclizing the β-(substituted-amino)amide of Formula XII. 
     
     
         32 . The process according to  claim 30 , further comprising the steps of:
 (a) reacting p-fluorobenzoylbutyric acid of Formula V with pivaloyl chloride and acylating the product with a chiral auxiliary of Formula VI to obtain a ketone of Formula VII:   
       
         
           
           
               
               
           
         
       
       wherein X is —O—, —S— or —N(C 1 -C 6  alkyl); Y is ═O or ═S; and R 1  is alkyl, aryl or alkoxycarbonyl;
 (b) reducing the ketone of Formula VII in the presence of a chiral catalyst to an alcohol of Formula VIII: 
 
       
         
           
           
               
               
           
         
         (c) reacting the chiral alcohol of Formula VIII, an imine of formula IX and a silyl protecting agent, then condensing the silyl-protected compounds to obtain a β-(substituted-amino)amide of Formula XII, wherein Prot is a silyl protecting group: 
       
       
         
           
           
               
               
           
         
       
       prior to cyclizing the β-(substituted-amino)amide of Formula XII.