Process for preparing biaryl substituted 4-amino-butyric acid or derivatives thereof and their use in the production of nep inhibitors

Abstract

The invention relates to a process for producing a compound according to formula (i) or salt thereof, wherein R1 and R1′ are independently hydrogen or an amine protecting group and R2 is a carboxyl group or an ester group, comprising reacting a compound according to formula (ii) or salt thereof, wherein R1, R1′ and R2 are defined as above, with hydrogen in the presence of a transition metal catalyst and a chiral ligand, wherein the transition metal is selected from group 7, 8 or 9 of the periodic table. Furthermore, the invention relates to products obtainable by said process and to their use in the production of NEP inhibitors. Moreover, the invention relates to the use of transition metal catalyst in the preparation of NEP inhibitors or prodrugs thereof.

1 . A process for producing a compound according to formula (i), 
       
         
           
           
               
               
           
         
       
       or salt thereof, 
       wherein R1 and R1′ independently are hydrogen or an amine protecting group and R2 is a carboxyl group or an ester group, 
       comprising reacting a compound according to formula (ii) 
       
         
           
           
               
               
           
         
         or salt thereof, 
         wherein R1, R1′ and R2 are defined as above, 
         with hydrogen in the presence of a transition metal catalyst and a chiral ligand, 
         wherein the transition metal is selected from group 7, 8 or 9 of the periodic table. 
       
     
     
         2 . A process according to  claim 1 , wherein the reaction is carried out as a homogenous catalysis. 
     
     
         3 . A process according to  claim 1 , wherein the transition metal catalyst comprises rhodium or ruthenium. 
     
     
         4 . A process according to  claim 1 , wherein the transition metal catalyst comprises a dimer complex, preferably a dimer ruthenium complex. 
     
     
         5 . A process according to  claim 1 , wherein the transition metal catalyst comprises [RuI 2 (p-cymene)] 2 . 
     
     
         6 . A process according to  claim 1 , wherein the transition metal catalyst comprises Rh(nbd) 2 BF 4 . 
     
     
         7 . A process according to  claim 1 , wherein the chiral ligand is a chiral phosphine. 
     
     
         8 . A process according to  claim 1 , wherein the chiral ligand is a chiral ferrocene. 
     
     
         9 . A process according to  claim 1 , wherein the chiral ligand is a Mandyphos ligand, a Walphos ligand, a Josiphos ligand or a Solphos ligand. 
     
     
         10 . A process according to  claim 1 , wherein the chiral ligand is selected from Mandyphos SL-M001-1, Mandyphos SL-M002-1, Mandyphos SL-M004-1 Mandyphos SL-M004-2, Josiphos SL-J002-1, Josiphos SL-J003-1, Josiphos SL-J009-1, Walphos SL-W001-2, Walphos SL-W003-1, Walphos SL-W008-1 or Solphos SL-A001-1. 
     
     
         11 . A process according to claim to  3 , wherein the transition metal catalyst comprises rhodium and wherein the chiral ligand is selected from Mandyphos SL-M004-1, Josiphos SL-J003-1, Josiphos SL-J009-1, Walphos SL-W001-2, Walphos SL-W003-1, Walphos SL-W008-1 or Solphos SL-A001-1. 
     
     
         12 . A process according to  claim 11  wherein the transition metal catalyst comprises Rh(nbd) 2 BF 4 . 
     
     
         13 . A process according to  claims 11 , wherein the chiral ligand is Walphos SL-W008-1. 
     
     
         14 . A process according to  claim 3 , wherein the transition metal catalyst comprises ruthenium and wherein the chiral ligand is selected from Mandyphos SL-M001-1, Mandyphos SL-M002-1, Mandyphos SL-M004-1 Mandyphos SL-M004-2 or Josiphos SL-J002-1. 
     
     
         15 . A process according to  claim 14  wherein the transition metal catalyst comprises [RuI 2 (p-cymene)] 2 . 
     
     
         16 . A process according to  claim 14 , wherein the chiral ligand is selected from Mandyphos SL-M001-1, Mandyphos SL-M004-1 or Josiphos SL-J002-1. 
     
     
         17 . A process according to  claim 14 , wherein the chiral ligand is Mandyphos SL-M004-2. 
     
     
         18 . A process according to  claim 14 , wherein the chiral ligand is Mandyphos SL-M004-1. 
     
     
         19 . A process according to  claim 1 , wherein the molar ratio of the compound of formula (ii), or salt thereof to “active catalyst” (SIC) is 100 or higher, preferably from 1 000 to 30 000. 
     
     
         20 . A process according to  claim 1 , wherein a hydrogen pressure of from 5 bar to 25 bar is applied. 
     
     
         21 . A process according to  claim 1  any of the preceding claims, wherein R1 and R11 are independently hydrogen or an amine protective group selected from the group consisting of C 1-6 alkyl which is mono-, di- or trisubstituted by C 6-10 aryl, wherein the aryl ring is unsubstituted or substituted by one, two or three, residues selected from the group consisting of C 1-7 alkyl, hydroxy, C 1-7 alkoxy, halogen, nitro, cyano and CF 3 ; C 6-10 aryl-C 1-7 alkyl, cumyl, phenyl-C1-C2-alkoxycarbonyl, allyl, cinnamyl, 9-fluorenylmethyloxycarbonyl (Fmoc), benzyloxymethyl (BOM), pivaloyloxymethyl (POM), trichloroethxoycarbonyl (Troc), 1-adamantyloxycarbonyl (Adoc), C 1-10 alkenyloxycarbonyl, silyl, sulfonyl, sulfenyl, succinimidyl, C 2-6 alkanoyl, C 6-10 aryl-carbonyl, C 1-6 alkoxy-carbonyl and C 6-10 aryl-C 1-6 alkoxycarbonyl. 
     
     
         22 . A process according to  claim 1 , wherein R1 is a t-butoxycarbonyl group. 
     
     
         23 . A process according to  claim 1 , wherein R2 is —COOH or —COOR3, wherein R3 is C 1-6 alkyl. 
     
     
         24 . A process according to  claim 1 , wherein a compound according to formula (ii-a), or salt thereof, is reacted: 
       
         
           
           
               
               
           
         
         wherein R1 and R1′ are independently hydrogen or an amine protecting group and R2 is a carboxyl group or an ester group. 
       
     
     
         25 . A process according to  claim 24 , wherein a compound according to formula (i-a), or salt thereof, is produced: 
       
         
           
           
               
               
           
         
         wherein R1 and R1′ are independently hydrogen or an amine protecting group and R2 is a carboxyl group or an ester group. 
       
     
     
         26 . A process according to  claim 24 , wherein a compound according to formula (i-b), or salt thereof, is produced: 
       
         
           
           
               
               
           
         
         wherein R1 and R1′ are independently hydrogen or an amine protecting group and R2 is a carboxyl group or an ester group. 
       
     
     
         27 . A process according to  claim 24 , wherein a composition comprising compounds according to formulae (i-a) and (i-b), or salts thereof, is produced and wherein the molar ratio of compounds according to formula (i-a) to compounds according to formula (i-b) is at least 88:12. 
     
     
         28 . A process according to  claim 24 , wherein a composition comprising compounds according to formulae (i-a) and (i-b), or salts thereof, is produced and wherein the molar ratio of compounds according to formula (i-b), or salts thereof, to compounds according to formula (i-a), or salts thereof, is at least 65:35. 
     
     
         29 . A process according to  claim 27 , wherein the compounds according to formula (i-a), or salts thereof, are separated from the composition by means of crystallisation. 
     
     
         30 . A process according to  claim 29 , wherein isopropylacetate and heptane are used as solvents. 
     
     
         31 . A process according to  claim 1  any of the preceding claims, wherein a compound according to formula (ii-b), or salt thereof, is reacted: 
       
         
           
           
               
               
           
         
         wherein R1 and R1′ are independently hydrogen or an amine protecting group and R2 is a carboxyl group or ester group. 
       
     
     
         32 . A process according to  claim 31 , wherein a compound according to formula (i-c), or salt thereof, is produced: 
       
         
           
           
               
               
           
         
         wherein R1 and R1′ are independently hydrogen or an amine protecting group and R2 is a carboxyl group or an ester group. 
       
     
     
         33 . A process according to  claim 31 , wherein a compound according to formula (i-d), or salt thereof, is produced: 
       
         
           
           
               
               
           
         
         wherein R1 and R1′ are independently hydrogen or an amine protecting group and R2 is a carboxyl group or an ester group. 
       
     
     
         34 . A process according to  claim 31 , wherein a composition comprising compounds according to formulae (i-c) and (i-d), or salts thereof, is produced and wherein the molar ratio of compounds according to formula (i-c), or salts thereof, to compounds according to formula (i-d), or salts thereof, is at least 88:12. 
     
     
         35 . A process according to  claim 1 , wherein the compound according to formula (i), or salt thereof, is further reacted to obtain an NEP-inhibitor or a prodrug thereof. 
     
     
         36 . A process according to  claim 1 , wherein the compound according to formula (i), or salt thereof, is further reacted to obtain an NEP-inhibitor or a prodrug thereof, comprising a γ-amino-σ-biphenyl-α-methylalkanoic acid, or acid ester, backbone. 
     
     
         37 . A process according to  claim 35 , wherein the NEP-inhibitor is N-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid or a salt or a prodrug thereof. 
     
     
         38 . A process according to  claim 35 , wherein the NEP-inhibitor prodrug is N-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester or a salt thereof. 
     
     
         39 - 43 . (canceled)