Process for the preparation of propionic acid derivatives

Abstract

The invention relates to a process for the preparation of a compound of formula (I) or a salt thereof.

1 . A process for the preparation of a compound of formula (I) 
       
         
           
           
               
               
           
         
         or a salt thereof, wherein a compound of formula (II) 
       
       
         
           
           
               
               
           
         
         or a salt thereof is hydrogenated 
         (e) in the presence of a catalyst comprising iridium; or 
         (f) in the presence of a catalyst comprising ruthenium and a compound of: formula (IV), 
       
       
         
           
           
               
               
           
         
         or formula (VII), 
       
       
         
           
           
               
               
           
         
         wherein 
         R 3  is alkyl, cycloalkyl or aryl; 
         R 4  is cycloalkyl, aryl or heteroaryl; 
         R 5  is cycloalkyl or aryl; 
         R 6  is cycloalkyl or aryl; 
         R 7  is cycloalkyl or aryl; 
         R 8  is cycloalkyl or aryl; and 
         R 9  is cycloalkyl or aryl. 
       
     
     
         2 . A process according to  claim 1 , wherein the catalyst comprises iridium and a compound of formula (III), 
       
         
           
           
               
               
           
         
         or formula (IX), 
       
       
         
           
           
               
               
           
         
         wherein 
         R 1  is selected from the group consisting of: hydrogen, alkyl, aryl and arylalkyl; 
         R 2  is aryl; and 
         R 10  is aryl. 
       
     
     
         3 . A process according to  claim 2 , wherein the catalyst comprises iridium and a compound of formula (III) 
       
         
           
           
               
               
           
         
       
     
     
         4 . A process according to  claim 1 , wherein the catalyst comprises iridium and a compound of formula (X) 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is selected from the group consisting of: hydrogen, alkyl, aryl and arylalkyl; and 
         R 2  is aryl. 
       
     
     
         5 . A process according to  claim 2 , wherein R 1  is selected from the group consisting of: hydrogen, iso-propyl, phenyl and benzyl. 
     
     
         6 . A process according to  claim 2 , wherein R 2  is selected from the group consisting of: phenyl, 3,5-di-methylphenyl and 3,5-di-tert-butyl-phenyl. 
     
     
         7 . A process according to  claim 2 , wherein R 10  is 3,5-di-methyl-phenyl. 
     
     
         8 . A process according to  claim 2 , wherein the compound of formula (III) is selected from the group consisting of:
 (S a ,S)-7-[4,5-Dihydro-4-benzyloxazol-2-yl]-7′-diphenylphosphino-1,1′-spirobiindane;   (S a ,S)-7-[4,5-Dihydro-4-benzyloxazol-2-yl]-7′-di(3,5-di-methylphenyl)phosphino-1,1′-spirobiindane;   (S a ,S)-7-[4,5-Dihydro-4-benzyloxazol-2-yl]-7′-di(3,5-di-tert-butylphenyl)phosphino-1,1′-spirobiindane;   (S a ,S)-7-[4,5-Dihydro-4-phenyloxazol-2-yl]-7′-di(3,5-di-tert-butylphenyl)phosphino-1,1′-spirobiindane;   (S a ,S)-7-[4,5-Dihydro-4-isopropyloxazol-2-yl]-7′-di(3,5-di-tert-butylphenyl)phosphino-1,1′-spirobiindane; and   (S a )-7-[4,5-Dihydrooxazol-2-yl]-7′-di(3,5-di-tert-butylphenyl)phosphino-1,1′-spirobiindane.   
     
     
         9 . A process according to  claim 2 , wherein the compound of formula (III) is selected from the group consisting of:
 (S a ,S)-7-[4,5-Dihydro-4-benzyloxazol-2-yl]-7′-di(3,5-di-tert-butylphenyl)phosphino-1,1′-spirobiindane;   (S a ,S)-7-[4,5-Dihydro-4-isopropyloxazol-2-yl]-7′-di(3,5-di-tert-butylphenyl)phosphino-1,1′-spirobiindane; and   (S a )-7-[4,5-Dihydrooxazol-2-yl]-7′-di(3,5-di-tert-butylphenyl)phosphino-1,1′-spirobiindane.   
     
     
         10 . A process according to  claim 4 , wherein the compound of formula (X) is selected from the group consisting of:
 (S a ,R)-7-[4,5-Dihydro-4-benzyloxazol-2-yl]-7′-diphenylphosphino-1,1′-spirobiindane;   (S a ,R)-7-[4,5-Dihydro-4-benzyloxazol-2-yl]-7′-di(3,5-di-methylphenyl)phosphino-1,1′-spirobiindane;   (S a ,R)-7-[4,5-Dihydro-4-benzyloxazol-2-yl]-7′-di(3,5-di-tert-butylphenyl)phosphino-1,1′-spirobiindane;   (S a ,R)-7-[4,5-Dihydro-4-phenyloxazol-2-yl]-7′-di(3,5-di-tert-butylphenyl)phosphino-1,1′-spirobiindane; and   (S a ,R)-7-[4,5-Dihydro-4-isopropyloxazol-2-yl]-7′-di(3,5-di-tert-butylphenyl)phosphino-1,1′-spirobiindane.   
     
     
         11 . A process according to  claim 2 , wherein the catalyst is Ir(L 1 )(L 2 )Y wherein:
 Ir is iridium;   L′ is a compound of formula (III), (VIII) or (IX);   L 2  is selected from the group consisting of: cyclooctene, 1,5-cyclooctadiene, ethylene, 1,5-hexadiene and norbornadiene;   Y is selected from the group consisting of: chloride, iodide, bromide, fluoride, trifluoroacetate, tetrafluoroborate, tetrakis[3,5-bis(trifluoromethyl)phenyl]borate, tetraphenylborate, hexafluoroantimonate, hexafluorophosphate, triflate, mesylate, perchlorate, perbromate, periodate, nitrate, hydrogen sulfate and acetylacetonate; and   n is 1 or 2.   
     
     
         12 . A process according to  claim 4  wherein the catalyst is Ir(L 1 )(L 2 )Y wherein:
 Ir is iridium; 
 L′ is a compound of formula (X); 
 L 2  is selected from the group consisting of: cyclooctene, 1,5-cyclooctadiene, ethylene, 1,5-hexadiene and norbornadiene; 
 Y is selected from the group consisting of: chloride, iodide, bromide, fluoride, trifluoroacetate, tetrafluoroborate, tetrakis[3,5-bis(trifluoromethyl)phenyl]borate, tetraphenylborate, hexafluoroantimonate, hexafluorophosphate, triflate, mesylate, perchlorate, perbromate, periodate, nitrate, hydrogen sulfate and acetylacetonate; and 
 n is 1 or 2. 
 
     
     
         13 . A process according to  claim 1 , wherein the catalyst is selected from the group consisting of:
 [Ir((S,S)-7-[4,5-dihydro-4-benzyloxazol-2-yl]-7′-di(3,5-di-tert-butylphenyl)phosphino-1,1′-spirobiindane)(1,5-cyclooctadiene)][tetrakis[3,5-bis(trifluoromethyl)phenyl]borate];   [Ir((S,S)-7-[4,5-dihydro-4-benzyloxazol-2-yl]-7′-di(3,5-di-tert-butylphenyl)phosphino-1,1′-spirobiindane)(1,5-cyclooctadiene)][tetrafluoroborate];   [Ir((S,S)-7-[4,5-dihydro-4-benzyloxazol-2-yl]-7′-di(3,5-di-tert-butylphenyl)phosphino-1,1′-spirobiindane)(1,5-cyclooctadiene)][trifluoromethanesulfonate];   [Ir((S,S)-7-[4,5-dihydro-4-benzyloxazol-2-yl]-7′-di(3,5-di-tert-butylphenyl)phosphino-1,1′-spirobiindane)(1,5-cyclooctadiene)][chloride];   [Ir((S,S)-7-[4,5-dihydro-4-isopropyloxazol-2-yl]-7′-di(3,5-di-tert-butylphenyl)phosphino-1,1′-spirobiindane)(1,5-cyclooctadiene)][tetrakis[3,5-bis(trifluoromethyl)phenyl]borate]; and   [Ir((S)-7-[4,5-dihydrooxazol-2-yl]-7′-di(3,5-di-tert-butylphenyl)phosphino-1,1′-spirobiindane)(1,5-cyclooctadiene)][tetrakis[3,5-bis(trifluoromethyl)phenyl]borate].   
     
     
         14 . A process according to  claim 12 , wherein the catalyst is selected from the group consisting of:
 [Ir((S a ,R)-7-[4,5-dihydro-4-benzyloxazol-2-yl]-7′-di(3,5-di-tert-butylphenyl)phosphino-1,1′-spirobiindane)(1,5-cyclooctadiene)][tetrakis[3,5-bis(trifluoromethyl)phenyl]borate];   [Ir((S a ,R)-7-[4,5-dihydro-4-benzyloxazol-2-yl]-7′-di(3,5-di-tert-butylphenyl)phosphino-1,1′-spirobiindane)(1,5-cyclooctadiene)][tetrafluoroborate];   [Ir((S a ,R)-7-[4,5-dihydro-4-benzyloxazol-2-yl]-7′-di(3,5-di-tert-butylphenyl)phosphino-1,1′-spirobiindane)(1,5-cyclooctadiene)][trifluoromethanesulfonate]; and   [Ir((S a ,R)-7-[4,5-dihydro-4-benzyloxazol-2-yl]-7′-di(3,5-di-tert-butylphenyl)phosphino-1,1′-spirobiindane)(1,5-cyclooctadiene)][chloride].   
     
     
         15 . A process according to  claim 1 , wherein the catalyst comprises ruthenium and a compound of formula (IV), (V), (VI) or (VII). 
     
     
         16 . A process according to  claim 1 , wherein R 3  is selected from the group consisting of: tert-butyl, cyclohexyl, phenyl, 2-methyl-phenyl and 3,5-di-methyl-phenyl. 
     
     
         17 . A process according to  claim 1 , wherein R 4  is selected from the group consisting of: tert-butyl, cyclohexyl, phenyl, 3,5-di-trifluoromethyl-phenyl, 4-trifluoromethyl-phenyl, 3,5-di-methyl-4-methoxy-phenyl, 1-naphtyl and 2-furyl. 
     
     
         18 . A process according to  claim 1 , wherein R 5  is selected from the group consisting of:
 phenyl, cyclohexyl, 3,5-di-methyl-4-methoxy-phenyl and 3,5-di-methyl-phenyl.   
     
     
         19 . A process according to  claim 1 , wherein R 6  is selected from the group consisting of:
 phenyl, cyclohexyl, 3,5-di-methyl-phenyl, 3,5-di-trifluoromethyl-phenyl and norbornyl.   
     
     
         20 . A process according to  claim 1 , wherein R 7  is selected from the group consisting of:
 cyclohexyl, phenyl, 3,5-di-methyl-phenyl, 3,5-di-trifluoromethyl-phenyl, 3,5-di-methyl-4-methoxy-phenyl and 2-methyl-phenyl.   
     
     
         21 . A process according to  claim 1 , wherein R 8  is cyclohexyl or phenyl. 
     
     
         22 . A process according to  claim 1 , wherein R 9  is cyclohexyl or phenyl. 
     
     
         23 . A process according to  claim 1 , wherein the compound of formula (IV), (V), (VI) or (VII) is selected from the group consisting of:
 (S)-1-[(R)-2-(Diphenylphosphino)ferrocenyl]ethyldi-tert-butylphosphine;   (S)-1-[(R)-2-(Dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphosphine;   (S)-1-[(R)-2-(Di-(4-trifluoromethylphenyl)phosphino)ferrocenyl]ethyldi-tert-butyl phosphine;   (S)-1-[(R)-2-(Di-(3,5-dimethyl-4-methoxyphenyl)phosphino)ferrocenyl]ethyldi-tert-butylphosphine;   (S)-1-[(R)-2-(Di-2-furylphosphino)ferrocenyl]ethyldi-tert-butylphosphine;   (αR,αR)-2,2′-Bis(α-N,N-dimethylaminophenylmethyl)-(S,S)-1,1′-bis(diphenylphosphino)ferrocene;   (αR,αR)-2,2′-Bis(α-N,N-dimethylaminophenylmethyl)-(S,S)-1,1′-bis[di(3,5-dimethyl-4-methoxyphenyl)phosphino]ferrocene;   (R)-1-Diphenylphosphino-2-[(S)-α-(N,N-dimethylamino)-o-diphenylphosphinophenyl)methyl]ferrocene;   (S)-1-[(S)-2-(2′-Diphenylphosphinophenyl)ferrocenyl]ethyldi(bis-3,5-trifluoromethyl phenyl)phosphine;   (R)-1-[(R)-2-(2′-Dicyclohexylphosphinophenyl)ferrocenyl]ethyldi(bis-3,5-trifluoromethylphenyl)phosphine; and   (R)-1-[(R)-2-(2′-Diphenylphosphinophenyl)ferrocenyl]ethyldi-(2-norbornyl)phosphine.   
     
     
         24 . A process according to  claim 1 , wherein the compound of formula (IV), (V), (VI) or (VII) is
 (S)-1-[(R)-2-(Diphenylphosphino)ferrocenyl]ethyldi-tert-butylphosphine; or   (S)-1-[(R)-2-(Di-(3,5-dimethyl-4-methoxyphenyl)phosphino)ferrocenyl]ethyldi-tert-butylphosphine.   
     
     
         25 . A process according to  claim 1 , wherein the catalyst is Ru(L 3 )(L 4 )(L 5 ) m Y p  wherein:
 Ru is ruthenium;   L 3  is a compound of formula (IV), (V), (VI) or (VII);   L 4  is η 5 -2,4-dimethylpentadienyl, cyclopentadienyl or η 5 -2,3,4-trimethylpenta-dienyl;   L 5  is selected from the group consisting of: halide, acetonitrile, diethyl ether, water, acetone, tetrahydrofuran, dioxane, pyridine, imidazole and thiophene;   Y is selected from the group consisting of: tetrakis[3,5-bis(trifluoromethyl)phenyl]borate, hexafluoroantimonate, hexafluorophosphate, triflate, mesylate, hydrogen sulfate and perchlorate;   m is 0 or 1; and   p is 0 or 1.   
     
     
         26 . A process according to  claim 1 , wherein the catalyst is selected from the group consisting of:
 [Ru(η 5 -2,4-dimethylpentadienyl)((S)-1-[(R)-2-(diphenylphosphino)ferrocenyl]ethyldi-tert-butylphosphine)(acetonitrile)][tetrafluoroborate];   [Ru(rη 5 -2,4-dimethylpentadienyl)((S)-1-[(R)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphosphine)(acetonitrile)][tetrafluoroborate];   [Ru(η 5 -2,4-dimethylpentadienyl)((S)-1-[(R)-2-(di-(4-trifluoromethylphenyl)phosphino)ferrocenyl]ethyldi-tert-butylphosphine)(acetonitrile)][tetrafluoroborate];   [Ru(η 5 -2,4-dimethylpentadienyl)((S)-1-[(R)-2-(di-(3,5-dimethyl-4-methoxyphenyl)phosphino)ferrocenyl]ethyldi-tert-butylphosphine)(acetonitrile)][tetrafluoroborate];   [Ru(η 5 -2,4-dimethylpentadienyl)((S)-1-[(R)-2-(di-2-furylphosphino)ferrocenyl]ethyldi-tert-butylphosphine)(acetonitrile)][tetrafluoroborate];   [Ru(η 5 -2,4-dimethylpentadienyl)((αR,αR)-2,2′-bis(α-N,N-dimethylaminophenylmethyl)-(S,S)-1,1′-bis(diphenylphosphino)ferrocene) (acetonitrile)][tetrafluoroborate];   [Ru(η 5 -2,4-dimethylpentadienyl)((αR,αR)-2,2′-bis(α-N,N-dimethylaminophenylmethyl)-(S,S)-1,1′-bis[di(3,5-dimethyl-4-methoxyphenyl)phosphino]ferrocene)(acetonitrile)][tetrafluoroborate];   [RuI(η 5 -2,4-dimethylpentadienyl)((R)-1-diphenylphosphino-2-[(S)-α-(N,N-dimethylamino)-o-diphenylphosphinophenyl)methyl]ferrocene)];   [Ru(η 5 -2,4-dimethylpentadienyl)((S)-1-[(S)-2-(2′-diphenylphosphinophenyl) ferrocenyl]ethyldi(bis-3,5-trifluoromethylphenyl)phosphine) (acetonitrile)][tetrafluoroborate];   [Ru(η 5 -2,4-dimethylpentadienyl)((R)-1-[(R)-2-(2′-dicyclohexylphosphinophenyl) ferrocenyl]ethyldi(bis-3,5-trifluoromethylphenyl)phosphine) (acetonitrile)][tetrafluoroborate]; and   [Ru(η 5 -2,4-dimethylpentadienyl)((R)-1-[(R)-2-(2′-diphenylphosphinophenyl) ferrocenyl]ethyldi-(2-norbornyl)phosphine) (acetonitrile)][tetrafluoroborate].   
     
     
         27 . A process according to  claim 1 , wherein the catalyst is
 [Ru(η 5 -2,4-dimethylpentadienyl)((S)-1-[(R)-2-(diphenylphosphino)ferrocenyl]ethyldi-tert-butylphosphine)(acetonitrile)][tetrafluoroborate]; or   [Ru(η 5 -2,4-dimethylpentadienyl)((S)-1-[(R)-2-(di-(3,5-dimethyl-4-methoxyphenyl)phosphino)ferrocenyl]ethyldi-tert-butylphosphine)(acetonitrile)][tetrafluoroborate].   
     
     
         28 . A compound of formula (I) as defined in  claim 1  or a salt thereof obtained by a process according to  claim 1 . 
     
     
         29 . A process according to  claim 4 , wherein R 1  is selected from the group consisting of:
 hydrogen, iso-propyl, phenyl and benzyl.   
     
     
         30 . A process according to any one of  claim 4 , wherein R 2  is selected from the group consisting of: phenyl, 3,5-di-methylphenyl and 3,5-di-tert-butyl-phenyl.