Preparation of quinoline-substituted carbonate and carbamate derivatives

Abstract

The invention relates to a process for preparing quinoline-substituted carbonate and carbamate compounds, which are important intermediates in the synthesis of 6-O-substituted macrolide antibiotics. The process employs metal-catalyzed coupling reactions to provide a carbonate or carbamate of formula (I) or (II) or a substrate that can be reduced to obtain the same.

1 . A process of preparing a compound of the formula  
       R 1 —CH═CHCH 2 OC(O)—X—R 2   (I),  
     wherein R 1  is independently selected from hydrogen and quinolyl optionally substituted with one or more of: 
 (i) alkyl,  
 (ii) alkoxy,  
 (iii) aryl,  
 (iv) nitro, and  
 (v) halo;  
 R 2  is C 1 -C 10 -alkyl;  
 X is —O— or —NR 3 ;  
 R 3  is hydrogen, C 1 -C 6 -alkyl or aryl; or R 2  and R 3  taken together form an aromatic or non-aromatic ring,  
 comprising the steps of:  
 (a) preparing an intermediate selected from: 
 (i) R 1 —C≡CCH 2 OR 4 , wherein R 4  is hydrogen or a hydroxy protecting group;  
 (ii) R 1 —CH═CHC(O)OR 5 , wherein R 5  is C 1  to C 6  lower alkyl;  
 (iii) R 1 —CH═CHCH(OR 6 )(OR 7 ), wherein R 6  and R 7  are independently C 1  to C 6  alkyl;  
 (iv) R 1 —CH═CHC(O)OH;  
 (v) R 1 —CH═CHCHO; and  
 (vi) R 1 C≡C—CH 2 —OC(O)—X—R 2 ;  
 
 (b) reducing or deprotecting an intermediate obtained in step (a); and  
 (c) optionally coupling the compound obtained from step (b) with an acylating reagent.  
 
   
   
       2 . The process according to  claim 1 , wherein R 2  is isopropyl or t-butyl.  
   
   
       3 . The process according to  claim 1 , wherein the intermediate of the formula R 1 —C≡CCH 2 OR 4  is obtained by a process comprising the steps of reacting a haloquinoline with propargyl alcohol or a substituted propargyl alcohol of the formula HC≡CCH 2 OR 4 , wherein R 4  is hydrogen or a hydroxy protecting group.  
   
   
       4 . The process according to  claim 1 , wherein the intermediate of the formula R 1 —CH═CHC(O)OR 5 , is obtained by reacting a vinyl ester of the formula CH 2 ═CHC(O)OR 5 , wherein R 5  is C 1  to C 6  alkyl, with a haloquinoline.  
   
   
       5 . The process according to  claim 1 , wherein the intermediate of the formula R 1 —CH═CHC(O)OR 5 , is obtained by reacting an ester of the formula CH 3 C(O)OR 5 , wherein R 5  is C 1  to C 6  alkyl, with a quinoline carboxaldehyde.  
   
   
       6 . The process according to  claim 1 , wherein the intermediate of the formula R 1 —CH═CHCH(OR 6 )(OR 7 ), is obtained by reacting an acetal of the formula CH 2 ═CHCH(OR 6 )(OR 7 ), wherein R 6  and R 7  are independently C 1  to C 6  alkyl, with haloquinoline.  
   
   
       7 . The process according to  claim 1 , wherein the intermediate of the formula R 1 —CH═CHC(O)OH is obtained by hydrolyzing a compound of the formula R 1 —CH═CHC(O)OR 5 .  
   
   
       8 . The process according to  claim 1 , wherein the intermediate of the formula R 1 —CH═CHCHO is obtained by reducing the intermediate of formula R 1 —CH═CHCH(OR 6 )(OR 7 ).  
   
   
       9 . The process according to  claim 1 , wherein the intermediate of the formula R 1 —CH═CHCHO is obtained via condensation of acetaldehyde with quinoline carboxaldehyde.  
   
   
       10 . The process according to  claim 1 , wherein the intermediate represented by the formula R 1 —C≡CCH 2 OR 4  or R 1 —C≡C—CH 2 —OC(O)—X—R 2  obtained from step (a) is reduced by methods of catalytic semi-hydrogenation.  
   
   
       11 . The process according to  claim 10 , wherein the intermediate is treated with hydrogen gas and a metal catalyst selected from palladium and platinum catalysts.  
   
   
       12 . The process according to  claim 10 , wherein the intermediate is treated with an aluminum hydride reagent and a metal catalyst selected from palladium and platinum catalysts.  
   
   
       13 . The process according to  claim 1 , wherein the intermediate of the formula R 1 —CH═CHC(O)OR 5  is reduced with an aluminum hydride reagent.  
   
   
       14 . The process according to  claim 1 , wherein the intermediate of the formula R 1 —CH═CHCHO or R 1 —CH═CHC(O)OH obtained from step (a) is reduced using a boron reducing agent or an aluminum hydride reagent.  
   
   
       15 . The process according to  claim 14 , wherein the boron reducing agent is selected from the group consisting of a borane complex reagent or a borohydride reagent.  
   
   
       16 . The process according to  claim 15 , wherein the borane complex reagent is selected from borane-dimethyl sulfide, borane-tetrahydrofuran complex, borane-pyridine complex, borane-morpholine, borane-trimethylamine complex, borane t-butylamine, borane-N,N-diisopropylethylamine, borane dimethylamine, 4-(borane-dimethylamino)pyridine, borane-4-ethylmorpholine, and borane-4-methylmorpholine.  
   
   
       17 . The process according to  claim 15 , wherein the borohydride reagent is selected from borane, borane-methyl sulfide, borane-methylsulfide 9-borabicyclononane, lithium borohydride, sodium borohydride, lithium borohydride, and potassium borohydride.  
   
   
       18 . The process according to  claim 12 ,  13  or  14  wherein the aluminum hydride reagent is selected from the group consisting of lithium aluminium hydride alone or with AlCl 3 , diisobutyl aluminum hydride, and sodium bis(2-methoxyethoxy)aluminum hydride in toluene.  
   
   
       19 . The process according to  claim 1 , wherein the compound of the formula R 1 —C═CCH 2 OC(O)—X—R 2 , is obtained by coupling an intermediate of the formula R 1 —C═CCH 2 OR with an acylating reagent.  
   
   
       20 . A process of preparing a compound of the formula:  
     
       
         
         
             
             
         
       
       X is —O— or —NR 3 —;  
       R 1  is independently selected from hydrogen and quinolyl optionally substituted with one or more substituents selected from: 
 (i) alkyl,  
 (ii) alkoxy,  
 (iii) aryl,  
 (iv) nitro, and  
 (v) halo;  
 
       R 2  is C 1 -C 10 -alkyl;  
       R 3  is hydrogen or C 1 -C 6 -alkyl; or R 2  and R 3  taken together form an aromatic or non-aromatic ring; and  
       R 8  is selected from the group consisting of: 
 (i) —CH═CH—R 11 , wherein R 11  is hydrogen or alkyl; and  
 (ii) —C≡CR 11 ;  
 comprising the steps of:  
 
       (a) reacting a compound of the formula:  
       
         
           
           
               
               
           
         
       
       wherein X 1  is a halide, with an organometallic compound of the formula R 8 -M or R 8 -M-X 1 , wherein R 8  and X 1  are as defined above and M is metal, and  
       (b) optionally hydrogenating the compound obtained in step (a), wherein R 8  is alkynyl or substituted alkynyl, to afford the corresponding compound wherein R 8  is alkenyl or substituted alkenyl.  
     
   
   
       21 . The process according to  claim 20 , wherein the metal is magnesium or lithium.  
   
   
       22 . The process according to  claim 20 , comprising the steps of reacting a compound of the formula:  
     
       
         
         
             
             
         
       
     
     wherein X 1  is a halide, with a magnesium halide compound and an alkyl lithium compound in an alcoholic solvent.  
   
   
       23 . The process of preparing a compound according to  claim 20 , wherein the quinoline carboxaldehyde is obtained by the process comprising the steps of: 
 (a) reacting a 2-halo-quinoline-3-carboxaldehyde having a formula:                          wherein X 1  is a halide, to a 2-halo-quinoline-3-carboxaldehyde acetal having a formula:                          wherein, X 1  is a halide and R 9  and R 10  are each independently C 1  to C 6  lower alkyl, by reacting with an alcohol of the formula R 9 —OH, wherein R 9  is C, to C 6  lower alkyl, or with an orthoformate of the formula HO(OR 10 ) 3 , wherein R 10  is C, to C 3  lower alkyl;    (b) dehalogenating the 2-halo-quinoline-3-carboxaldehyde acetal to form a quinoline-3-carboxaldehyde acetal having a formula:                          (c) hydrolyzing the quinoline-3-carboxaldehyde acetal.    
   
   
       24 . The process according to  claim 20 , comprising the steps of: 
 (a) reacting quinoline carboxaldehyde with an acetaldehyde;    (b) reducing the compound obtained in step (a); and    (c) coupling the compound obtained in step (b) with an acylating reagent.    
   
   
       25 . A compound of selected from: 
 (a) R 1 —CH═CHC(O)OR 5 , wherein R 1  is independently selected from hydrogen and quinolyl optionally substituted with one or substituent selected from (i) alkyl, (ii) alkoxy, (iii) aryl, (iv) nitro, and (v) halo; and R 5  is C 1  to C 6  lower alkyl;    (b) R 1 —CH═CHCH(OR 6 )(OR 7 ), wherein R 6  and R 7  are independently C 1  to C 6  alkyl;    (c) R 1 —CH═CHC(O)OH;    (d) R 1 —CH═CHCHO; and    (e) R 1 —C≡C—CH 2 —OC(O)—X—R 2 ; wherein R 2  is C 1 -C 10 -alkyl; X is —O— or —NR 3 ; and R 3  is hydrogen, C 1 -C 6 -alkyl or aryl; or R 2  and R 3  taken together form an aromatic or non-aromatic ring; and    (f) R 1 —CH═CHCH 2 OH.    
   
   
       26 . A process for preparing a compound of formula  
       R 1 —CH═CHCH 2 OC(O)—X—R 2   (I),  X is —O— or —NR 3 —;    R 1  is independently selected from hydrogen and quinolyl optionally substituted with one or more substituents selected from: 
 (i) alkyl,  
 (ii) alkoxy,  
 (iii) aryl,  
 (iv) nitro, and  
 (v) halo;  
   R 2  is C 1 -C 10 -alkyl;    R 3  is hydrogen or C 1 -C 6 -alkyl; or R 2  and R 3  taken together form an aromatic or non-aromatic ring; comprising the steps of: 
 (a) preparing a compound of the formula R 1 —CH═CHCH 2 OR 4 , wherein R 4  is hydrogen or a hydroxy protecting group;  
 (b) optionally deprotecting the compound obtained in step (a); and  
 (c) reacting a compound of the formula R 1 —CH═CHCH 2 OH with an acylating agent.  
   
   
   
       27 . A process for preparing a compound of formula  
       R 1 —CH═CHCH 2 OC(O)—X—R 2   (I),  X is —O— or —NR 3 —;    R 1  is independently selected from hydrogen and quinolyl optionally substituted with one or more substituents selected from: 
 (i) alkyl,  
 (ii) alkoxy,  
 (iii) aryl,  
 (iv) nitro, and  
 (v) halo;  
   R 2  is C 1 -C 10 -alkyl;    R 3  is hydrogen or C 1 -C 6 -alkyl; or R 2  and R 3  taken together form an aromatic or non-aromatic ring; comprising the steps of: 
 (a) preparing a compound of the formula R 1 —C≡C—CH 2 —OC(O)—X—R 2 ; and  
   (b) hydrogenating the compound obtained in step (a).    
   
   
       28 . The process according to  claim 26  or  27 , wherein the acylating reagent is di-tert-butyl dicarbonate.  
   
   
       29 . A compound having the formula  
     
       
         
         
             
             
         
       
       X is —O— or —NR 3 —;  
       R 1  is independently selected from hydrogen and quinolyl optionally substituted with one or more substituents selected from: 
 (i) alkyl,  
 (ii) alkoxy,  
 (iii) aryl,  
 (iv) nitro, and  
 (v) halo;  
 
       R 2  is C 1 -C 10 -alkyl;  
       R 3  is hydrogen or C 1 -C 6 -alkyl; or R 2  and R 3  taken together form an aromatic or non-aromatic ring; and  
       R 8  is selected from the group consisting of: 
 (i) —CH═CH—R 11 , wherein R 11  is hydrogen or alkyl, and;  
 (ii) —C≡CR 11 .