Method for preparing compounds employing solid phase synthesis and novel linker-resin

Abstract

A method is provided for preparing various intermediates and final products including MTP inhibitors employing solid phase syntheses. A new dialkoxyaryl aldehyde linker-resin of the structure ##STR1## which serves as a starting material and method for preparing same, are also provided.

What is claimed is: 
     
       1. A dialkoxyaryl aldehyde linker-resin for use in carrying out solid phase syntheses, which aldehyde linker-resin comprises a resin suitable for use as a support for carrying out solid phase syntheses and a dialkoxyaryl aldehyde containing linker attached to the resin. 
     
     
       2. The aldehyde linker-resin as defined in claim 1 which has the structure wherein ##STR124## represents a support resin.   
     
     
       3. The aldehyde linker-resin as defined in claim 1 wherein the resin ##STR125## is a polystyrene resin. 
     
     
       4. The aldehyde linker-resin as defined in claim 1 wherein the resin is a divinylbenzene cross-linked polystyrene resin, polyethylene glycol-polystyrene-based resin, polyethylene glycol-based resin or polypropylene glycol-based resin, employed in the form of beads. 
     
     
       5. A method for preparing an aldehyde linker-resin as defined in claim 1, which comprises reacting an aldehyde of the structure ##STR126## with a resin III ##STR127## where Hal is Cl, Br or I and ##STR128## represents a support resin, in the presence of a base, to form the aldehyde linker-resin. 
     
     
       6. The method as defined in claim 5 wherein the aldehyde linker-resin formed is of the structure ##STR129## 
     
     
       7. The method as defined in claim 6 wherein the resin is a divinylbenzene cross-linked polystyrene or polyethyleneglycol-polystyrene-based resin. 
     
     
       8. A method for forming an amine linker-resin intermediate of the structure ##STR130## wherein R 1  is H or alkyl, and ##STR131## represents a support resin, which comprises reacting the aldehyde linker-resin as defined in claim 2 of the structure ##STR132## with an amine of the structure H 2  N--R 1  or a salt thereof, in the presence of a dehydrating agent, and treating the reaction with a reducing agent and weak organic acid to form the amine linker-resin intermediate.   
     
     
       9. The method as defined in claim 8 wherein reaction of the aldehyde linker-resin and the amine is carried out in the presence of trimethylorthoformate, molecular sieves or titanium isopropoxide as the dehydrating agent, and the reaction is treated with sodium triacetoxyborohydride, sodium cyanoborohydride or sodium borohydride as the reducing agent. 
     
     
       10. A method for preparing a linker-resin intermediate of the structure ##STR133## wherein R 1  is H or alkyl, and Hal is Cl, Br or I, ##STR134## is a support resin, Z 1  is alkylene, alkenylene or alkynylene of up to 10 carbons, arylene or mixed arylenealkylene B is: ##STR135## B is an indenyl-type group of the structure ##STR136## wherein R 3 , R 3' , R 4'  and R 4'  may be the same or different and are independently selected from H, halogen, CF 3 , haloalkyl, alkoxy, alkyl, aryl, alkenyl, alkenyloxy, alkynyl, alkynyloxy, alkanoyl, nitro, alkylthio, alkylsulfinyl, alkylsulfonyl, carboxy, alkoxycarbonyl, aminocarbonyl, alkylcarbonyloxy, alkylcarbonylamino, cycloheteroalkyl, cycloheteroalkylalkyl, cyano, Ar, Ar-alkyl, ArO, Ar-amino, Ar-thio, Ar-sulfinyl, Ar-sulfonyl, Ar-carbonyl, Ar-carbonyloxy or Ar-carbonylamino, wherein Ar is aryl or heteroaryl and Ar may optionally include 1, 2 or 3 additional rings fused to Ar;   R 3a  and R 3a  are the same or different and are independently any of the R 3  groups except hydroxy, nitro, amino or thio; ##STR137## are the same or different and independently represent a 5 or 6 membered heteroaryl ring which may contain 1, 2, 3 or 4 heteroatoms in the ring which are independently N, S or O; and including N-oxides.   X (in the fluorenyl type ring) is a bond, or is one of the following groups: ##STR138## wherein Y 1  is O, N--R 6  or S;   n' is 0, 1 or 2;   R 6  is H, lower alkyl, aryl, --C(O)--R 11  or --C(O)--O--R 11  ;   R 7  and R 8  are the same or different and are independently H, alkyl, aryl, halogen, --O--R 12 , or   R 7  and R 8  together can be oxygen to form a ketone;   R 9 , R 10 , R 9'  and R 10'  are the same or different and are independently H, lower alkyl, aryl or --O--R 11  ;   R 9"  and R 10"  are the same or different and are independently H, lower alkyl, aryl, halogen or --O--R 11  ;   R 11  is alky or aryl;   R 12  is H, alkyl or aryl; which includes the steps of   (1) providing an amine linker-resin intermediate of the structure ##STR139## (2) treating the amine linker-resin intermediate with a halide of the structure ##STR140## where Y is Hal, Hal is Cl, Br, or F,   Z 1  is alkylene, alkenylene or alkynylene of from 1 to 10 carbons;   in the presence of a base, to form the linker-resin intermediate; or   (2a) treating the amine linker-resin intermediate of step (1) with an acid of the structure ##STR141## where Y' is OH, in the presence of a coupling agent, and an auxiliary nucleophile, to form the intermediate of the structure ##STR142## and treating the above intermediate with a dihaloalkane of the stucture   Hal.sub.1 --Z.sup.1 --Hal.sub.2     where Z 1  is as defined above, and Hal 1  and Hal 2  are independently a halogen, and a base to form the linker-resin intermediate.     
     
     
       11. The method as defined in claim 10 where ##STR143## B is a fluorenyl type group. 
     
     
       12. The method as defined in claim 10 where in step (2a) the amine linker-resin intermediate is reacted with ##STR144## in the presence of diisopropylcarbodiimide as a coupling agent. 
     
     
       13. A method is provided for preparing an MTP inhibitor of the structure ##STR145## wherein R 1  is H or alkyl, Z 1  is alkylene, alkenylene or alkynylene of up to 10 carbons, arylene or mixed arylene-alkylen, B is: ##STR146## B is an indenyl-type group of the structure ##STR147## wherein R 3 , R 3' , R 4  and R 4'  may be the same or 10 different and are independently selected from H, halogen, CF 3 , haloalkyl, alkoxy, alkyl, aryl, alkenyl, alkenyloxy, alkynyl, alkynyloxy, alkanoyl, nitro, alkylthio, alkylsulfinyl, alkylsulfonyl, carboxy, alkoxycarbonyl, aminocarbonyl, alkylcarbonyloxy, alkylcarbonylamino, cycloheteroalkyl, cycloheteroalkylalkyl, cyano, Ar, Ar-alkyl, ArO, Ar-amino, Ar-thio, Ar-sulfinyl, Ar-sulfonyl, Ar-carbonyl, Ar-carbonyloxy or Ar-carbonylamino, wherein Ar is aryl or heteroaryl and Ar may optionally include 1, 2 or 3 additional rings fused to Ar;   R 3a  and R 3b  are the same or different and are independently any of the R 3  groups except hydroxy, nitro, amino or thio; ##STR148## are the same or different and independently represent a 5 or 6 membered heteroaryl ring which may contain 1, 2, 3 or 4 heteroatoms in the ring which are independently N, S or O; and including N-oxides.   X (in the fluorenyl type ring) is a bond, or is one of the following groups: ##STR149## wherein Y 1  is O, N--R 6  or S;   n' is 0, 1 or 2;   R 6  is H, lower alkyl, aryl, --C(O)--R 11  or --C(O)--O--R 11  ;   R 7  and R 8  are the same or different and are independently H, alkyl, aryl, halogen, --O--R 12 , or   R 7  and R 8  together can be oxygen to form a ketone;   R 9 , R 10 , R 9'  and R 10'  are the same or different and are independently H, lower alkyl, aryl or --O--R 11  ;   R 9"  and R 10"  are the same or different and are independently H, lower alkyl, aryl, halogen or --O--R 11  ;   R 11  is alky or aryl;   R 12  is H, alkyl or aryl;   and D is S, O or N with the provisos that   (1) when D is S or O, R 3  is not present,   (2) when D is N, R 2  and R 3  are present, and   D, R 2  and R 3  may optionally form a ring ##STR150## which is ##STR151## wherein X 1  is ##STR152## R 5  is independently alkyl, alkenyl, alkynyl, aryl, alkoxy, aryloxy, arylalkoxy, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, polycycloalkylalkyl, cycloalkenyl, cycloheteroalkyl, heteroaryloxy, cycloalkenylalkyl, polycycloalkenyl, polycycloalkenylalkyl, heteroarylcarbonyl, arylamino, heteroarylamino, cycloalkyloxy, cycloalkylamino, all optionally substituted through available carbon atoms with 1, 2, 3 or 4 groups selected from hydrogen, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, aryl, heteroaryl, arylalkyl, arylcycloalkyl, arylalkenyl, arylalkynyl, aryloxy, aryloxyalkyl, arylalkoxy, arylazo, heteroaryloxo, heteroarylalkyl, heteroarylalkenyl, heteroaryloxy, hydroxy, nitro, cyano, alkylthio, arylthio, heteroarylthio, arylthioalkyl, alkylcarbonyl, arylcarbonyl, arylaminocarbonyl, alkoxycarbonyl, aminocarbonyl, alkynylaminocarbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, alkylsulfonyl, arylsulfonylamino, heteroarylcarbonylamino, heteroarylsulfinyl, heteroarylthio, heteroarylsulfonyl, alkylsulfinyl;   R 6  is hydrogen or C 1  -C 4  alkyl or C 1  -C 4  alkenyl; all optionally substituted with 1, 2, 3 or 4 groups which may independently be any of the substituents listed in the definition of R 5  set out above; ##STR153## where J is: CHR 23 , ##STR154## R 23 , R 24  and R 25  are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, or cycloalkylalkyl;   where R 20 , R 21 , R 22  are independently hydrogen, halo, alkyl, alkenyl, alkoxy, aryloxy, aryl, arylalkyl, alkylmercapto, arylmercapto, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, hydroxy or haloalkyl; and these preferred substituents may either be directly attached or attached via an alkylene chain at an open position;   R 2  and R 3  are independently H, alkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, all optionally substituted through available carbon atoms with 1, 2, 3 or 4 groups selected from H, halogen, CF 3 , haloalkyl, hydroxy, alkoxy, alkyl, aryl, alkenyl, alkenyloxy, alkynyl, alkynyloxy, alkanoyl, nitro, alkylthio, alkylsulfinyl, alkylsulfonyl, carboxy, alkoxycarbonyl, aminocarbonyl, alkylcarbonyloxy, alkylcarbonylamino, cycloheteroalkyl, cycloheteroalkylalkyl, cyano, Ar, Ar-alkyl, ArO, Ar-amino, Ar-thio, Ar-sulfinyl, Ar-sulfonyl, Ar-carbonyl, Ar-carbonyloxy or Ar-carbonylamino (wherein Ar is aryl or heteroaryl and Ar may optionally include 1, 2 or 3 additional rings fused to Ar), cycloalkylcarbonylamino, aryloxycarbonylamino, heteroaryloxycarbonylamino, uriedo (where the uriedo nitrogens may be substituted with alkyl, aryl or heteroaryl), cyclyloheteroalkylcarbonylamino (where the heterocycle is connected to the carbonyl group via a nitrogen or carbon atom), alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, ##STR155## where J, and R 20 , R 21 , R 22  are as defined above; which method comprises   (a) providing a linker-resin intermediate of the structure ##STR156## wherein ##STR157## is a support resin, Hal is Cl, Br or I, and R 1 , and B are as defined hereinbefore,   (b) where D is S or O, reacting the linker-resin intermediate with a thioether or ether of the structure   HD--R.sub.2     where D is S or O, in the presence of a base, to form the linker-resin thioether or ether of the structure ##STR158## or (c) where D is N, reacting the linker resin intermediate with an amine ##STR159## in the presence of weak alkali base to form the linker-resin amine where D is N, and     (d) treating the linker-resin thiol, alcohol or amine with strong acid to remove the resin and form the MTP inhibitor.   
     
     
       14. The method as defined in claim 13 wherein D is S or O and the product produced has the structure ##STR160## 
     
     
       15. The method as defined in claim 13 wherein D is N and the product produced has the structure ##STR161## 
     
     
       16. The method as defined in claim 13 wherein the product B is a fluorenyl type group. 
     
     
       17. A method for preparing a compound of the structure ##STR162## wherein R 1  is H or alkyl, Z 1  is alkylene, alkenylene or alkynylene of up to 10 carbons, arylene or mixed arylene-alkylene, ##STR163## B is an indenyl-type group of the structure ##STR164## wherein R 3 , R 3' , R 4  and R 4'  may be the same or different and are independently selected from H, halogen, CF 3 , haloalkyl, alkoxy, alkyl, aryl, alkenyl, alkenyloxy, alkynyl, alkynyloxy, alkanoyl, nitro, alkylthio, alkylsulfinyl, alkylsulfonyl, carboxy, alkoxycarbonyl, aminocarbonyl, alkylcarbonyloxy, alkylcarbonylamino, cycloheteroalkyl, cycloheteroalkylalkyl, cyano, Ar, Ar-alkyl, ArO, Ar-amino, Ar-thio, Ar-sulfinyl, Ar-sulfonyl, Ar-carbonyl, Ar-carbonyloxy or Ar-carbonylamino, wherein Ar is aryl or heteroaryl and Ar may optionally include 1, 2 or 3 additional rings fused to Ar; R 3a  and R 3a  are the same or different and are independently any of the R 3  groups except hydroxy, nitro, amino or thio; ##STR165## are the same or different and independently represent a 5 or 6 membered heteroaryl ring which may contain 1, 2, 3 or 4 heteroatoms in the ring which are independently N, S or O; and including N-oxides;   X (in the fluorenyl type ring) is a bond, or is one of the following groups: ##STR166## wherein Y 1  is O, N--R 6  or S;   n' is 0, 1 or 2;   R 6  is H, lower alkyl, aryl, --C(O)--R 11  or --C(O)--O--R 11  ;   R 7  and R 8  are the same or different and are independently H, alkyl, aryl, halogen, --O--R 12 , or   R 7  and R 8  together can be oxygen to form a ketone;   R 9 , R 10 , R 9'  and R 10'  are the same or different and are independently H, lower alkyl, aryl or --O--R 11  ;   R 9"  and R 10"  are the same or different and are independently H, lower alkyl, aryl, halogen or --O--R 11  ;   R 11  is alky or aryl;   R 12  is H, alkyl or aryl;   and Q 1  is alkyl, alkenyl, alkynyl, alkoxyl, (alkyl or aryl) 3  Si (where each alkyl or aryl group is independent), cycloalkyl, cycloalkenyl, substituted alkylamino, substituted arylalkylamino, aryl, arylalkyl, arylamino, aryloxy, heteroaryl, heteroarylamino, heteroaryloxy, arylsulfonylamino, heteroarylsulfonylamino, arylthio, arylsulfinyl, arylsulfonyl, alkylthio, alkylsulfinyl, alkylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, --PO(R 13 ) (R 14 ), (where R 13  and R 14  are independently alkyl, aryl, alkoxy, aryloxy, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylalkoxy, cycloheteroalkyl, cycloheteroalkylalkyl, cycloheteroalkoxy, or cycloheteroalkylalkoxy);   the Q 1  group may have from one to four substituents, which can be any of the R 3  groups or Q 1  groups or alkylcarbonylamino, cycloalkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, alkoxycarbonylamino, aryloxycarbonylamino, heteroaryloxylcarbonylamino, uriedo (where the uriedo nitrogens may be substituted with alkyl, aryl or heteroaryl), heterocyclylcarbonylamino (where the heterocycle is connected to the carbonyl group via a nitrogen or carbon atom), alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, ##STR167## where J is: CHR 23 , ##STR168## R 23 , R 24  and R 25  are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, or cycloalkylalkyl;   R 20 , R 21 , R 22  are independently hydrogen, halo, alkyl, alkenyl, alkoxy, aryloxy, aryl, arylalkyl, alkylmercapto, arylmercapto, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, hydroxy or haloalkyl; and these preferred substituents may either be directly attached or attached via an alkylene chain at an open position,   which comprises reacting a linker resin of the structure ##STR169## with an alkylating agent of the structure   Hal--Z.sup.1 --Q.sup.1     to form the alkylated compound ##STR170## and reacting the alkylated compound with an acid to remove the resin and form ##STR171##     
     
     
       18. The method as defined in claim 17 wherein B is a fluorenyl type group.