Process for the preparation of morpholine derivatives and intermediates therefore

Abstract

Processes for the preparation of a compound of formula (IIIA) or a salt thereof are disclosed.

1 . A compound of formula (I):  
     
       
         
         
             
             
         
       
     
     wherein: 
 R 1  represents C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 2-6  alkynyl-Y 1 —, aryl-Y 1 —, heteroaryl-Y 1 —, aryl-(O) t -aryl-Y 1 —, aryl-(O) t -heteroaryl-Y 1 —, heteroaryl-(O) t -aryl-Y 1 —, heteroaryl-(O) t -heteroaryl-Y 1 —, C 2-6  alkenyl-Y 1 —, aryl-O—Y 1 —, heteroaryl-O—Y 1 —, C 1-6  alkyl-SO 2 —Y 1 —, M-Y 1 —, J 2 -Y 1 —, —CN or C 3-8  cycloalkyl-Y 1 - or C 3-8  cycloalkenyl-Y 1 —, which cycloalkyl or cycloalkenyl may be optionally substituted by one or more hydroxyl or C, alkyl groups;  
 R 2  represents hydrogen or C 1-6  alkyl;  
 X represents ethylene or a group of formula CR e R f  wherein R e  and R f  independently represent hydrogen or C 1-4  alkyl or R e  and R f  may together with the carbon atom to which they are attached form a C 3-8  cycloalkyl group;  
 R 3  and R 4  independently represent hydrogen or C 1-4  alkyl;  
 Z represents a bond, CO, SO 2 , CR 9 R 6  (CH 2 ) n , (CH 2 ) n CR 9 R 6 , CHR 6 (CH 2 ) n O, CHR 6 (CH 2 ) n S, CHR 6 (CH 2 ) n OCO, CHR 6 (CH 2 ) n CO, COCHR 6 (CH 2 ) n  or SO 2 CHR 6 (CH 2 ) n ;  
 R 5  represents C 1-6  alkyl, C 2-8  alkenyl, aryl, heteroaryl, aryl-C 2-6  alkenyl- or a group of formula —Y 2 -J 1 ;  
 R 6  represents hydrogen, C 1-4  alkyl, CONR 7 R 8  or COOC 1-6  alkyl;  
 a and b represent 1 or 2, such that a+b represents 2 or 3;  
 n represents an integer from 0 to 4;  
 J 1  and J 2  independently represent a moiety of formula (K):  
                     
 wherein X 1  represents oxygen, NR 13  or sulphur, X 2  represents CH 2 , oxygen, NR 10  or sulphur, m 1  represents an integer from 1 to 3 and m 2  represents an integer from 1 to 3, provided that m 1 +m 2  is in the range from 3 to 5, also provided that when both X 1  and X 2  represent oxygen, NR 13 , NR 10  or sulphur, m 1  and m 2  must both not equal less than 2, wherein K is optionally substituted by one or more (eg. 1 or 2) —Y 3 -aryl, —Y 3 -heteroaryl, —Y 3 —CO-aryl, —COC 3-8 cycloalkyl, —Y 3 —CO-heteroaryl, —C 1-6  alkyl, —Y 3 —COOC 1-6  alkyl, —Y 3 —COC 1-6  alkyl, —Y 3 —W, —Y 3 —CO—W, —Y 3 —NR 11 R 2 , —Y 3 —CONR 11 R 12 , hydroxy, oxo, —Y 3 —SO 2 NR 11 R 12 , —Y 3 —SO 2 C 1-6  alkyl, —Y 3 —SO 2 aryl, —Y 3 —SO 2 heteroaryl, —Y 3 —NR 14 C 1-6  alkyl, —Y 3 —NR 14 SO 2 C 1-6  alkyl, —Y 3 —NR 14 CONR 11 R 12 , —Y 3 —NR 14 COOR 15  or —Y 3 —OCONR 11 R 12  groups, and is optionally fused to a monocyclic aryl or heteroaryl ring;  
 R 7 , R 8 , R 9 , R 10 , R 13 , R 14  and R 15  independently represent hydrogen or C 1-6  alkyl;  
 R 11  and R 12  independently represent hydrogen or C 1-6  alkyl or R 11  and R 12  together with the nitrogen atom to which they are attached may form a morpholine, piperidine or pyrrolidine ring;  
 M represents a C 3-8  cycloalkyl or a C 3-8  cycloalkenyl group fused to a monocyclic aryl or monocyclic heteroaryl group;  
 W represents a saturated or unsaturated, non-aromatic 5-7 membered ring containing between 1 and 3 heteroatoms selected from nitrogen, oxygen or sulphur, optionally substituted with one or more C 1-6  alkyl, halogen or hydroxy groups;  
 t represents 0 or 1.  
 Y 1l , Y   2  and Y 3  independently represent a bond or a group of formula —(CH 2 ) p CR c R d (CH 2 ) q — wherein R c  and R d  independently represent hydrogen or C 1-4  alkyl or R c  and R d  may together with the carbon atom to which they are attached form a C 3-8  cycloalkyl group, and p and q independently represent an integer from 0 to 5 wherein p+q is an integer from 0 to 5;  
 and salts and solvates thereof.  
 
   
   
       2 . A compound of formula (I) according to  claim 1  wherein R 1  represents C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 2-6  alkynyl-Y 1 —, aryl-Y 1 —, heteroaryl-Y 1 —, aryl-(O) t -aryl-Y 1 —, aryl-(O) t -heteroaryl-Y 1 —, heteroaryl-(O) t -aryl-Y 1 —, heteroaryl-(O) t -heteroaryl-Y 1 —, C 2-6  alkenyl-Y 1 —, aryl-O-Y 1 —, heteroaryl-O—Y 1 —, C 1-6  alkyl-SO 2 —Y 1 —, M-Y 1 — or C 3-8  cycloalkyl-Y 1 — or C 3-8  cycloalkenyl-Y 1 —, which cycloalkyl or cycloalkenyl may be optionally substituted by one or more hydroxyl or C 1-6  alkyl groups; and 
 J 1  represents a moiety of formula (K):                          wherein X 1  represents oxygen, NR 13  or sulphur, X 2  represents CH 2 , oxygen, NR 10  or sulphur, ml represents an integer from 1 to 3 and m 2  represents an integer from 1 to 3, provided that ml+m 2  is in the range from 3 to 5, also provided that when both X 1  and X 2  represent oxygen, NR 13 , NR 10  or sulphur, ml and m 2  must both not equal less than 2, wherein K is optionally substituted by one or more -Y 3 -aryl, —Y 3 -heteroaryl, —Y 3 —CO-aryl, —Y 3 —CO-heteroaryl, -C 1-6  alkyl, —Y 3 —COOC 1-6  alkyl, —Y 3 —COC 1-6  alkyl, —Y 3 -W, -_3—CO—W, -_3-NR 6 R 12 , —Y 3 —CONR 6 R 12 , hydroxy, oxo, —Y 3 —SO 2 NR 11 R  2 , —Y 30    2 C,. alkyl, —Y 3 —SO 2 aryl, —Y 3 —SO 2  heteroaryl, —Y 3 —NR 14 C 1-6  alkyl, —Y 3 —NR 14 SO 2 C 1  alkyl, —Y 3 —NR 14 CONR 6 R  12 , —Y 3 —NR 14 COOR's or —Y 3 —OCONR 6 R  12  groups, and is optionally fused to a monocyclic aryl or heteroaryl ring.    
   
   
       3 . A compound of formula (I) according to  claim 1  wherein R 1  represents C1 alkyl, C 2 ” alkenyl, C 2  alkynyl, aryl-Y 1 —, heteroaryl-Y 1 —, aryl-(O) t -aryl-Y 1 —, aryl-(O) t -heteroaryl-Y 1 —, heteroaryl-(O) t -aryl-Y 1 —, heteroaryl-(O) t -heteroaryl-Yi-, C 2   6  alkenyl-Y 1 —, aryl-O—Y 1 —, heteroaryl-O—Y 1 —, C 1  alkyl-SO 2 —Y 1 —, M-Yl- or C3. cycloalkyl-Yl- or C. cycloalkenyl-Y 1 —, which cycloalkyl or cycloalkenyl may be optionally substituted by one or more hydroxyl or C 1 , alkyl groups; 
 Z represents a bond, CO, CR 9 R 6 (CH 2 ) n , CHR 6 (CH 2 ) n0  , CHR 6 (CH 2 ),S, CHR 6 (CH 2 ) n OCO, CHR 6 (CH 2 ) n ,CO; and    J 1  represents a moiety of formula (K):                          wherein X 1  represents oxygen, nitrogen, NR 13  or sulphur, x 2  represents CH 2 , oxygen, nitrogen, NR 10  or sulphur, m 1  represents an integer from 1 to 3, m 2  represents an integer from 1 to 3, provided that mI+m 2  is in the range from 3 to 5, also provided that when X 2  represents oxygen, nitrogen, NR 10  or sulphur, mland m 2  must both not equal less than 2, wherein K is optionally substituted by one or more -Y 3 -aryl, —Y 3 -heteroaryl, —Y 3 —CO-aryl, —Y 3 —CO-heteroaryl, -Con alkyl, —Y 3 —COOC 1-6  alkyl, —Y 3 —COC 1-6  alkyl, -y3-W, -y3—CO—W, -Y 3 - NR 6 R  2 , —Y 3 —CONR 11 R 2 , hydroxy, oxo, —Y 10    2 NR 6 R 12   1 -Y 6 —SO 2 C 1  alkyl, —Y 3 —SO 2 aryl, -Y 3  So 2  heteroaryl, —Y 3 —NR 14 C 1 . alkyl, —Y 3 —NR 14 SO 2 CI6 alkyl, —Y 3 —NR 14 CONR 6 R 12 , -Y 3 - NR 14 COOR 15  or —Y 3 —OCONR 1 R 12  groups, and is optionally fused to a monocyclic aryl or heteroaryl ring.    
   
   
       4 . A compound of formula (I) according to any one of claims  1  to 3 wherein RI represents aryl-Y 1 -.  
   
   
       5 . A compound of formula (I) according to  claim 4  wherein R 1  represents optionally substituted phenyl-Y 1 - in which phenyl may be optionally substituted.  
   
   
       6 . A compound of formula (I) according to any one of claims  1  to 5 wherein Y 1 represents -CH 2 -.  
   
   
       7 . A compound of formula (I) according to claim I wherein X represents methylene.  
   
   
       8 . A compound of formula (I) according to  claim 1  wherein a and b both represent 1.  
   
   
       9 . A compound of formula (I) according to claim I or  claim 3  wherein Z represents a bond, CO, CHR 6 (CH 2 ) n , CHR 6 (CH 2 ) n0  or CHR 6 (CH 2 ) n CO.  
   
   
       10 . A compound of formula (I) according to  claim 9  wherein Z represents CH 2 .  
   
   
       11 . A compound of formula (I) according to claim I wherein R 6  represents phenyl optionally substituted with one or more halogen atoms.  
   
   
       12 . A compound of formula (I) according to  claim 11  wherein R 11  represents 3,4- dichlorophenyl.  
   
   
       13 . A compound of formula (I) according to any one of claims  1  to 12 as described in Examples 1 to 240 or a salt or solvate of any one thereof.  
   
   
       14 . A compound of formula (I) according to  claim 13  which is 2-[3- (Aminosulfonyl)phenyl]-N-[(2S)-4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl]acetamide or a solvate thereof.  
   
   
       15 . A pharmaceutical composition comprising a compound of formula (I) as defined in any one of claims  1  to 14 or a pharmaceutically acceptable salt or solvate thereof in admixture with one or more pharmaceutically acceptable diluents or carriers.  
   
   
       16 . A compound of formula (I) as defined in any one of, claims  1  to 14 or a pharmaceutically acceptable salt or solvate thereof for use as a pharmaceutical.  
   
   
       17 . Use of a compound of formula (I) as defined in any one of claims 1 to 14 or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for the treatment of inflammatory diseases.  
   
   
       18 . A method of treatment or prophylaxis of inflammatory diseases eg. asthma which comprises administering to a patient an effective amount of a compound of formula (I) as defined in any one of claims  1  to 14 or a pharmaceutically acceptable salt or solvate thereof.  
   
   
       19 . A process for preparing a compound of formula (I) according to any one of  claims 1  to  14  which comprises: 
 (a) acylation of a compound of formula (II)                          wherein R 2 , R 3 , R 4 , R 5 , X, Z, a and b are as defined in  claim 1 , with a compound of formula R 1 COOH or an activated derivative thereof, wherein R 1  is as defined in  claim 1;  or    (b) reacting a compound of formula (III)                          wherein RI, R 2 , R 3 , R 4 , X, a and b are as defined in  claim 1 , with a compound of formula L′-Z-R 5 , wherein Z and R 1  are as defined in  claim 1  and L 1  represents a suitable leaving group; or    (c) deprotecting a compound of formula (I) which is protected; or    (d) interconversion of other compounds of formula (I).    
   
   
       20 . A process for preparing a compound of formula (I) according to any one of  claims 1  to  14  which comprises: 
 (e) forming a compound of formula (I) wherein R 1  representsheteroaryl-Y 1 —, aryl-(O) t - heteroaryl-Y 1 — or heteroaryl-(O) t -heteroaryl-Y 1 — (wherein said Y 1  group is attached to heteroaryl via a heterocyclic nitrogen atom) and R 2  represents hydrogen which comprises reacting a compound of formula (IV)                          or a protected derivative thereof wherein R 3 , R 4 , Rs, X, Y 1 , Z, a and b are as defined in  claim 1 , L 2  represents a suitable leaving group, such as a halogen atom eg. bromine and PI represents a solid phase resin bound protecting group, with a heterocyclic compound 5 defined by the R 1  groups heteroaryl, aryl-(O) t -heteroaryl or heteroaryl-(O) t -heteroaryl above wherein said heteroaryl group contains at least one NH atom, followed by removal of the solid phase resin bound protecting group; or    (f) forming a compound of formula (I) wherein Z represents CR 9 R 6 (CH 2 ) n  and R 9  represents hydrogen which comprises reacting a compound of formula (111) or a protected 10 derivative thereof with a compound of formula R 6 CO(CH 2 ) n R 5 , followed by reduction of the resultant imine; or    (g) forming a compound of formula (I) wherein Z represents CO by reacting a compound of formula (III) or a protected derivative thereof with a compound of formula R 5 COOH or an activated derivative thereof.    
   
   
       21 . A compound of formula (II)  
     
       
         
         
             
             
         
       
     
     wherein R 2 , R 3 , R 4 , Rs, X, Z, a and b are as defined in  claim 1  or a protected derivative thereof, or a salt or solvate thereof.  
   
   
       22 . A compound of formula (III)  
     
       
         
         
             
             
         
       
     
     wherein R′, R 2 , R 3 , R 4 , X, a and b are as defined in  claim 1  or a protected derivative thereof, or a salt or solvate thereof.  
   
   
       23 . A compound of formula (IV)  
     
       
         
         
             
             
         
       
     
     wherein R 3,  R 4 , R 5 , X, Y 1 , Z, a and b are as defined in  claim 1 , L 2  represents a suitable leaving group, such as a halogen atom eg. bromine and P 1  represents a solid phase resin bound protecting group, or a salt or solvate thereof.