Process for Preparing Oxazole Intermediates

Abstract

Disclosed are compounds of formula III and a process to prepare a compound of formula III wherein R 1 , R 2 , R 3 and R 6 are defined herein, using a zinc chloride/optionally substituted oxazole adduct and an compound of formula I. Further disclosed are methods of using compounds of formula III to prepare compounds useful in the treatment of Alzheimer's disease and related conditions.

1 . A process for preparing a compound of the formula:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1  is C 1 -C 6  alkoxy or OH;  
 R 2  and R 3  are independently H, phenyl, or C 1 -C 4  alkyl; or  
 R 2  and R 3  and the carbons to which they are attached form a benzo ring, which is optionally substituted with C 1 -C 4  alkyl, C 1 -C 4  alkoxy, or dialkylamino; and  
 R 6  is C 1 -C 6  alkoxy or NR 4 R 5 ; wherein 
 R 4  and R 5  are independently C 1 -C 6  alkyl; comprising:  
 forming a reaction mixture comprising a compound of formula I:  
                     
 wherein X is Br, I, OTf, or OMs;  
 a compound of formula II:  
                     
 a catalyst and at least one solvent.  
 
 
     
     
         2 . A process according to  claim 1 , wherein the catalyst is a transition metal catalyst.  
     
     
         3 - 4 . (canceled)  
     
     
         5 . A process according to  claim 1  wherein the method is conducted in the presence of at one additional polar, aprotic solvent.  
     
     
         6 . A process according to  claim 5 , wherein the polar, aprotic solvent is tetrahydrofuran, tetramethyltetrahydrofuran, glyme, methyl t-butyl ether, or a mixture thereof.  
     
     
         7 . A process according to  claim 6 , wherein the polar, aprotic solvent is tetrahydrofuran.  
     
     
         8 . A process according to  claim 1 , wherein the reaction is performed at a temperature of from about 25° C. to about the refluxing temperature of the solvent used.  
     
     
         9 - 10 . (canceled)  
     
     
         11 . A process according to claim  10 , wherein the reaction mixture is formed by combining I, II and the catalyst, and any additional optional additives, at once or within a short time of each other.  
     
     
         12 . A process according to claim  10 , wherein the reaction mixture is formed over a period of about 0.5 hours to about 4 hours.  
     
     
         13 - 14 . (canceled)  
     
     
         15 . A process according to  claim 1 , wherein the transition metal catalyst is present in 0.01 to 20 mole percent, based on the amount of the compound of formula I.  
     
     
         16 - 17 . (canceled)  
     
     
         18 . A process according to claim  17 , wherein the reaction mixture is heated for about 24 hours.  
     
     
         19 . A process according to  claim 18 , wherein the reaction mixture is heated for about 0.5 to about 8 hours.  
     
     
         20 - 21 . (canceled)  
     
     
         22 . A process according to  claim 1 , wherein the compound of formula II is used in an excess from 1.001 to 10 equivalents, based on the compound of formula I.  
     
     
         23 - 24 . (canceled)  
     
     
         25 . A process according to  claim 1 , wherein 
 X is Br;    R 2  and R 3  are independently H, methyl or ethyl;    R 6  is NR 4 R 5 ; wherein 
 R 4  and R 5  are both C 3  alkyl; and  
   R 1  is C 1 -C 4  alkyl.    
     
     
         26 . A compound of the formula:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1  is is OH, imidazolyl, halogen, —OC(O)CH 3 , OC(O)CF 3 ;  
                     
 R 2  and R 3  are independently H or C 1 -C 4  alkyl; and 
 R 4  and R 5  are independently C 1 -C 6  alkyl.  
 
 
     
     
         27 . A compound according to  claim 26 , wherein R 2  and R 3  are independently H or methyl.  
     
     
         28 . A compound according to  claim 27 , wherein R 4  and R 5  are both C 3  alkyl.  
     
     
         29 - 31 . (canceled)  
     
     
         32 . A compound according to  claim 28 , wherein R 1  is  
       
         
           
           
               
               
           
         
       
     
     
         33 . A process for preparing compounds of the formula:  
       
         
           
           
               
               
           
         
       
       wherein 
 R 10  is —(CH 2 ) 1-2 —S(O) 0-2 —(C 1 -C 6  alkyl), —CH 2 —CH 2 —S(O) 0-2 —(C 1 -C 6  alkyl), or 
 C 1 -C 10  alkyl optionally substituted with 1, 2, or 3 groups independently selected from halogen, —F, —Cl, —Br, —I, —OH, ═O, —SH, —C≡N, —CF 3 , —C 1 -C 3  alkoxy, amino, mono- or dialkylamino, —N(R)C(O)R′—, —OC(═O)-amino and —OC(═O)-mono- or dialkylamino, or  
 C 2 -C 6  alkenyl or C 2 -C 6  alkynyl, each of which is optionally substituted with 1, 2, or 3 groups independently selected from halogen, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3  alkoxy, amino, and mono- or dialkylamino, or  
 aryl, heteroaryl, heterocyclyl, —C 1 -C 6  alkyl-aryl, —C 1 -C 6  alkyl-heteroaryl, or —C 1 -C 6  alkyl-heterocyclyl, where the ring portions of each are optionally substituted with 1, 2, 3, or 4 groups independently selected from halogen, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, −NR 105 R′ 105 , —CO 2 R, —N(R)COR′, or —N(R)SO 2 R′, —C(═O)—(C 1 -C 4 )alkyl, —SO 2 -amino, —SO 2 -mono or dialkylamino, —C(═O)-amino, —C(═O)-mono or dialkylamino, —SO 2 —(C 1 -C 4 ) alkyl, or 
 C 1 -C 6  alkoxy optionally substituted with 1, 2, or 3 groups which are independently selected from selected from halogen, or  
 C 3 -C 7  cycloalkyl optionally substituted with 1, 2, or 3 groups independently selected from halogen, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3  alkoxy, amino, —C 1 -C 6  alkyl and mono- or dialkylamino, or  
 C 1 -C 10  alkyl optionally substituted with 1, 2, or 3 groups independently selected from halogen, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF 3 , —C 1 -C 3  alkoxy, amino, mono- or dialkylamino and —C 1 -C 3  alkyl, or  
 C 2 -C 10  alkenyl or C 2 -C 10  alkynyl, each of which is optionally substituted with 1, 2, or 3 groups independently selected from halogen, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3  alkoxy, amino, C 1 -C 6  alkyl and mono- or dialkylamino; and the heterocyclyl group is optionally further substituted with oxo;  
 R and R′ independently are hydrogen, C 1 -C 10  alkyl, C 1 -C 10  alkylaryl or C 1 -C 10  alkylheteroaryl;  
 
 
 R 20  is selected from the group consisting of H; C 1 -C 6  alkyl, optionally substituted with 1, 2, or 3 substituents that are independently selected from the group consisting of C 1 -C 3  alkyl, halogen, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3  alkoxy, and —NR 1-a R 1-b ; —(CH 2 ) 0-4 -aryl; —(CH 2 ) 0-4 -heteroaryl; C 2 -C 6  alkenyl; C 2 -C 6  alkynyl; —CONR N-2 R N-3 ; —SO 2 NR N-2 R N-3 ; —CO 2 H; and —CO 2 —(C 1 -C 4  alkyl); wherein 
 R 1-a  and R 1-b  are independently —H or C 1 -C 6  alkyl;  
 
 R 30  is selected from the group consisting of H; C 1 -C 6  alkyl, optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of C 1 -C 3  alkyl, halogen, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3  alkoxy, and —NR 1-a R 1-b ; —(CH 2 ) 0-4 -aryl; —(CH 2 ) 0-4 -heteroaryl; C 2 -C 6  alkenyl; C 2 -C 6  alkynyl; —CO—NR N-2 R N-3 ; —SO 2 —NR N-2 R N3 ; —CO 2 H; and —CO—O—(C 1 -C 4  alkyl),  
 or  
 R 20 , R 30  and the carbon to which they are attached form a carbocycle of three thru seven carbon atoms, wherein one carbon atom is optionally replaced by a group selected from —O—, —S—, —SO 2 —, or —NR N-2 —; 
 R N-2  and R N-3  at each occurrence are independently selected from the group consisting of —C 1 -C 8  alkyl optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of —OH, —NH 2 , phenyl and halogen; —C 3 -C 8  cycloalkyl; —(C 1 -C 2  alkyl)-(C 3 -C 8  cycloalkyl); —(C 1 -C 6  alkyl)-O+(C 1 -C 3  alkyl); —C 2 -C 6  alkenyl; —C 2 -C 6  alkynyl; —C 1 -C 6  alkyl chain with one double bond and one triple bond; aryl; heteroaryl; heterocycloalkyl;  
 or  
 
 R N-2 , R N-3  and the nitrogen to which they are attached form a 5, 6, or 7 membered heterocycloalkyl or heteroaryl group, wherein said heterocycloalkyl or heteroaryl group is optionally fused to a benzene, pyridine, or pyrimidine ring, and said groups are unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that at each occurrence are independently C 1 -C 6  alkyl, C 1 -C 6  alkoxy, halogen, halo C 1 -C 6  alkyl, halo C 1 -C 6  alkoxy, —CN, —NO 2 , —NH 2 , NH(C 1 -C 6  alkyl), N(C 1 -C 6  alkyl) (C 1 -C 6  alkyl), —OH, —C(O)NH 2 , —C(O)NH(C 1 -C 6  alkyl), —C(O)N(C 1 -C 6  alkyl) (C 1 -C 6  alkyl), C 1 -C 6  alkoxy C 1 -C 6  alkyl, C 1 -C 6  thioalkoxy, and C 1 -C 6  thioalkoxy C 1 -C 6  alkyl;  
 R c  is hydrogen, —(CR 245 R 250 ) 0-4 -aryl, —(CR 245 R 250 ) 0-4 -heteroaryl, —(CR 245 R 250 ) 0-4 -heterocyclyl, —(CR 245 R 250 ) 0-4 -aryl-heteroaryl, —(CR 245 R 250 ) 0-4 -aryl-heterocyclyl, —(CR 245 R 250 ) 0-4 -aryl-aryl, —(CR 245 R 250 ) 0-4 -heteroaryl-aryl, —(CR 245 R 250 ) 0-4 -heteroaryl-heterocyclyl, —(CR 245 R 250 ) 0-4 -heteroaryl-heteroaryl, —(CR 245 R 250 ) 0-4 -heterocyclyl-heteroaryl, —(CR 245 R 250 ) 0-4 -heterocyclyl-heterocyclyl, —(CR 245 R 250 ) 0-4 -heterocyclyl-aryl, —[C(R 255 )(R 260 )] 1-3 —CO—N—(R 255 ) 2 , —CH(aryl) 2 , —CH(heteroaryl) 2 , —CH(heterocyclyl) 2 , —CH(aryl)(heteroaryl), —(CH 2 ) 0-1 —CH( CH 2 ) 0-6 —OH)—(CH 2 ) 0-1 aryl, —(CH 2 ) 0-1 —CH((CH 2 ) 0-6 —OH—(CH 2 ) 0-1 -heteroaryl, —CH(-aryl or -heteroaryl)—CO—O(C 1 -C 4  alkyl), —CH(—CH 2 —OH)—CH(OH)-phenyl-NO 2 , (C 1 -C 6  alkyl)-O—(C 1 -C 6  alkyl)-OH; —CH 2 —NH—CH 2 —CH(—O—CH 2 -CH 3 ) 2 , —(CH 2 ) 0-6 —C(═NR 235 )(NR 235 R 240 ), or 
 C 1-C   10  alkyl optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of R 205 , —OC═ONR 235 R 240 , —S(═O) 0-2 (C 1 -C 6  alkyl), —SH, —NR 235 C═ONR 235 R 240 , —C═ONR 235 R 240 , and —S(═O) 2 NR 235 R 240 , or  
 —(CH 2 ) 0-3 —(C 3 -C 8 ) cycloalkyl wherein the cycloalkyl is optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of R 205 , —CO 2 H, and —CO 2 —(C 1 -C 4  alkyl), or  
 cyclopentyl, cyclohexyl, or cycloheptyl ring fused to aryl, heteroaryl, or heterocyclyl wherein one, two or three carbons of the cyclopentyl, cyclohexyl, or cycloheptyl is optionally replaced with a heteroatom independently selected from NH, NR 215 , O, or S(═O) 0-2 , and wherein the cyclopentyl, cyclohexyl, or cycloheptyl group can be optionally substituted with one or two groups that are independently R 205 , ═O, —CO—NR 235 R 240 , or —SO 2 —(C 1 -C 4  alkyl), or  
 C 2 -C 10  alkenyl or C 2 -C 10  alkynyl, each of which is optionally substituted with 1, 2, or 3 R 205  groups, wherein  
 each aryl and heteroaryl is optionally substituted with 1, 2, or 3 R 200 , and wherein each heterocyclyl is optionally substituted with 1, 2, 3, or 4 R 210 ;  
 
 R 200  at each occurrence is independently selected from —OH, —NO 2 , halogen, —CO 2 H, C≡N, —(CH 2 ) 0-4 —CO—NR 220 R 225 , —(CH 2 ) 0-4 —CO—(C 1 -C 12  alkyl), —(CH 2 ) 0-4 —CO—(C 2 -C 12  alkenyl), —(CH 2 ) 0-4 —CO—(C 2 -C 12  alkynyl), —(CH 2 ) 0-4 —CO—(C 3 -C 7  cycloalkyl), —(CH 2 ) 0-4 —CO-aryl, —(CH 2 ) 0-4 —CO-heteroaryl, —(CH 2 ) 0-4 —CO-heterocyclyl, —(CH 2 ) 0-4 —CO—O—R 215 , —(CH 2 ) 0-4 —SO 2 —NR 220 R 225 , —(CH 2 ) 0-4 —SO—(C 1 -C 8  alkyl), —(CH 2 ) 0-4 —SO 2— (C 1 -C 12  alkyl), —(CH 2 ) 0-4 —SO 2 —(C 3 -C 7  cycloalkyl), —(CH 2 ) 0-4 —N(H or R 215 )—CO—O—R 215 , —(CH 2 ) 0-4 −N(H or R 215 )—CO—N(R 215 ) 2 , —(CH 2 ) 0-4 —N—CS—N(R 215 ) 2 , —(CH 2 ) 0-4 —N(—H or R 215 )—CO—R 220 , —(CH 2 ) 0-4 —NR 220 R 225 , —(CH 2 ) 0-4 —O—CO—(C 1 -C 6  alkyl), —(CH 2 ) 0-4 —O—P(O)—(OR 240 ) 2 , —(CH 2 ) 0-4 —O—C—N(R 215 ) 2 , —(CH 2 ) 0-4 —O—CS—N(R 215 ) 2 , —(CH 2 ) 0-4 —O—(R 215 ), —(CH 2 ) 0-4 —O—(R 215 )—COOH, —(CH 2 ) 0-4 —S—(R 215 ), —(CH 2 ) 0-4 —O—(C 1 -C 6  alkyl optionally substituted with 1, 2, 3, or 5 —F), C 3 -C 7  cycloalkyl, —(CH 2 ) 0-4 —N(H or R 215 )−SO 2 —R 220 , —(CH 2 ) 0-4 —C 3 -C 7  cycloalkyl, or 
 C 1 -C 10  alkyl optionally substituted with 1, 2, or 3 R 205  groups, or  
 C 2 -C 10  alkenyl or C 2 -C 10  alkynyl, each of which is optionally substituted with 1 or 2 R 205  groups, wherein  
 the aryl and heteroaryl groups at each occurrence are optionally substituted with 1, 2, or 3 groups that are independently R 205 , R 210 , or 
 C 1 -C 6  alkyl substituted with 1, 2, or 3 groups that are independently R 205  or R 210 , and wherein  
 
 the heterocyclyl group at each occurrence is optionally substituted with 1, 2, or 3 groups that are independently R 210 ;  
 
 R 205  at each occurrence is independently selected from C 1 -C 6  alkyl, halogen, —OH, —O-phenyl, —SH, —C≡N, —CF 3 , C 1 -C 6  alkoxy, NH 2 , NH(C 1 -C 6  alkyl) or N—(C 1 -C 6  alkyl) (C 1 -C 6  alkyl);  
 R 210  at each occurrence is independently selected from halogen, C 1 -C 6  alkoxy, C 1 -C 6  haloalkoxy, —NR 220 R 225 , OH, C≡N, —CO—(C 1 -C 4  alkyl), SO 2 —NR 235 R 240 , —CO—NR 235 R 240 , —SO 2 —(C 1 -C 4  alkyl), ═O, or C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl or C 3 -C 7  cycloalkyl, 
 each of which is optionally substituted with 1, 2, or 3 R 205  groups;  
 
 R 215  at each occurrence is independently selected from C 1 -C 6  alkyl, —(CH 2 ) 0-2 -(aryl), C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 7  cycloalkyl, and (CH 2 ) 0-2 -(heteroaryl), —(CH 2 ) 0-2 -(heterocyclyl), wherein 
 the aryl group at each occurrence is optionally substituted with 1, 2, or 3 groups that are independently R 205  or R 210 , and wherein  
 the heterocyclyl and heteroaryl groups at each occurrence are optionally substituted with 1, 2, or 3 R 210 ;  
 
 R 220  and R 225  at each occurrence are independently selected from —H, —C 3 -C 7  cycloalkyl, —(C 1 -C 2  alkyl)-(C 3 -C 7  cycloalkyl), —(C 1 -C 6  alkyl)-O—(C 1 -C 3  alkyl), —C 2 -C 6  alkenyl, —C 2 -C 6  alkynyl, —C 1 -C 6  alkyl chain with one double bond and one triple bond, -aryl, -heteroaryl, and -heterocyclyl, or 
 —C 1 -C 10  alkyl optionally substituted with —OH, —NH 2  or halogen, wherein  
 the aryl, heterocyclyl and heteroaryl groups at each occurrence are optionally substituted with 1, 2, or 3 R 270  groups  
 
 R 235  and R 240  at each occurrence are independently H, or C 1 -C 6  alkyl;  
 R 245  and R 25 o at each occurrence are independently selected from —H, C 1 -C 4  alkyl, C 1 -C 4  alkylaryl, C 1 -C 4  alkylheteroaryl, C 1 -C 4  hydroxyalkyl, C 1 -C 4  alkoxy, C 1 -C 4  haloalkoxy, —(CH 2 ) 0-4 —C 3 -C 7  cycloalkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, and phenyl; or  
 R 245  and R 250  are taken together with the carbon to which they are attached to form a carbocycle of 3, 4, 5, 6, or 7 carbon atoms, where one carbon atom is optionally replaced by a heteroatom selected from —O—, —S—, —SO 2 —, and —NR 220 —;  
 R 255  and R 260  at each occurrence are independently selected from —H, —(CH 2 ) 1-2 —S(O) 0-2 —(C 1 -C 6  alkyl), (C 1 -C 4  alkyl)-aryl, —(C 1 -C 4  alkyl)-heteroaryl, —(C 1 -C 4  alkyl)-heterocyclyl, -aryl, -heteroaryl, -heterocyclyl, —(CH 2 ) 1-4 —R 265 —(CH 2 ) 0-4 -aryl, —(CH 2 ) 1-4 —R 265 —(CH 2 ) 0-4 -heteroaryl, —(CH 2 ) 1-4 —R 265 —(CH 2 ) 0-4 -heterocyclyl, or 
 C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl or —(CH 2 ) 0-4 —C 3 -C 7  cycloalkyl, each of which is optionally substituted with 1, 2, or 3 R 205  groups, wherein  
 each aryl or phenyl is optionally substituted with 1, 2, or 3 groups that are independently R 205 , R 210 , or 
 C 1 -C 6  alkyl substituted with 1, 2, or 3 groups that are independently R 205  or R 210 , and wherein  
 
 each heterocyclyl is optionally substituted with 1, 2, 3, or 4 R 210 ;  
 
 R 265  at each occurrence is independently —O—, —S— or —N(C 1 -C 6  alkyl)-;  
 R 270  at each occurrence is independently R 205 , halogen C 1 -C 6  alkoxy, C 1 -C 6  haloalkoxy, NR 235 R 240 , —OH, —C≡N, —CO—(C 1 -C 4  alkyl), _SO 2 NR 235 R 240 , —CO—NR 235 R 240 , —SO 2 —(C 1 -C 4  alkyl), ═O, or 
 C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl or —(CH 2 ) 0-4 -C 3 -C 7  cycloalkyl, each of which is optionally substituted with 1, 2, or 3 R 205  groups;  
 
 comprising 
 forming a reaction mixture comprising a compound of formula III  
                     
 wherein  
 
 R 1  is OH, imidazolyl, halogen or  
                     
 R 2  and R 3  are independently H, phenyl, or C 1 -C 4  alkyl; or  
 R 2  and R 3  and the carbons to which they are attached form a benzene ring; and  
 R 6  is C 1 -C 6  alkoxy or NR 4 R 5 ; wherein  
 R 4  and R 5  are independently C 1 -C 6  alkyl; 
 and a compound of formula VIII  
                     
 
 in a solvent.  
 
     
     
         34 . (canceled)  
     
     
         35 . A process according to  claim 33  wherein the reaction mixture comprises a base which is pyridine, collidine, di-tertiarybutyl pyridine, triethylamine, diisopropylethylamine, dimethylamino pyridine, or lutidine.  
     
     
         36 . A process according to  claim 35 , wherein the reaction mixture further comprises an additive which is 1, 2, or 3 of the following: 
 EDCI, HOBT, benzotriazole, HOAT, HATU, or DCC.