Process For The Preparation Of Optically Pure Tetrahydropterins And Derivatives, And Specifically Of Optically Pure Tetrahydrofolic Acid And Derivatives Thereof, By Stereospecific Hydrogenation

Abstract

Process for the preparation of tetrahydropterin and tetrahydropterin derivatives by hydrogenating pterin and pterin derivatives with hydrogen in the presence of a hydrogenating catalyst, in which the hydrogenation is carried out in a polar reaction medium and metal complexes that are soluble in the reaction medium are employed as the hydrogenation catalysts. The process is suited to the hydrogenation, particularly asymmetric hydrogenation, of folic acid, folio acid salts, folio acid esters, folio acid ester salts or dihydroforms thereof, with the proviso that in the event of using folic acid, carboxylic acid salts thereof or dihydroforms thereof the reaction medium is aqueous, and in the event of using folic acid esters, folic acid ester salts or dihydroforms thereof the reaction medium is an alcohol. The process opens up straightforward access to achiral and chiral pterin derivatives.

1 - 28 . (canceled) 
   
   
       29 . A process for preparing tetrahydropterin of the following formula 
     
       
         
         
             
             
         
       
       or a tetrahydropterin compound of said tetrahydropterin that is substituted at the 6-, or 7- or 6- and 7-position or positions, 
       comprising hydrogenating pterin of the following formula 
     
     
       
         
         
             
             
         
       
       or a pterin compound of said pterin that is monosubstituted at the 6-, or 7- or 6- and 7-position or positions, 
       with hydrogen in a polar reaction medium in the presence of a hydrogenation catalyst that is a metal complex that is soluble in the reaction medium, wherein the catalyst has a ligand that is an achiral or chiral ditertiary diphosphine 
       or a compound of the following formulae 
     
     
       
         
         
             
             
         
       
       wherein R 111  and R 112  are each independently H or methyl. 
     
   
   
       30 . A process for preparing tetrahydropterin of the following formula 
     
       
         
         
             
             
         
       
       or a tetrahydropterin compound of said tetrahydropterin that is substituted at the 6-, or 7- or 6- and 7-position or positions, 
       comprising hydrogenating pterin of the following formula 
     
     
       
         
         
             
             
         
       
       or a pterin compound of said pterin that is monosubstituted at the 6-, or 7- or 6- and 7-position or positions, 
       with hydrogen in a polar alcoholic reaction medium in the presence of a hydrogenation catalyst that is a metal complex that is soluble in the reaction medium, wherein the catalyst has a ligand that is an achiral or chiral ditertiary diphosphine of formula IV,
   R 4 R 5 P—R 6 —PR 7 R 8   (IV) 
 
       in which 
       R 4 , R 5 , R 7  and R 8  independently of one another represent a hydrocarbon radical with 1 to 20 carbon atoms, which is unsubstituted or substituted with halogen, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, C 1 -C 6  alkoxy, C 1 -C 6  haloalkoxy, (C 6 H 5 ) 3 Si, (C 1 -C 12  alkyl) 3 Si, —NH 2 , —NH(C 1 -C 12  alkyl), —NH(phenyl), —NH(benzyl), —N(C 1 -C 2  alkyl) 2 , —N(phenyl) 2 , —N(benzyl) 2 , morpholinyl, piperidinyl, pyrrolidinyl, piperazinyl, -ammonium-X 3   − , —SO 3 M 1 , —CO 2 M 1 , —PO 3 M 1 , or —CO 2 —C 1 -C 6  alkyl, in which M 1  represents an alkali metal or hydrogen and X 3   −  is the anion of a monobasic acid; or R 4  and R 5 , and/or R 7  and R 8  together denote tetramethylene, pentmethylene, or 3-oxa-pentane-1,5-diyl, which is unsubstituted or substituted with halogen, C 1 -C 6  alkyl or C 1 -C 6  alkoxy; and R 6  is C 2 -C 4  alkylene, which is unsubstituted or substituted with C 1 -C 6  alkyl, C 1 -C 6  alkoxy, C 5  or C 6  cylcoalkyl, phenyl, napthyl, or benzyl; 1, 2 or 1,3-cycloalkylene, 1,2- or 1,3-cycloalkyenylene, 1,2- or 1,3-bicylcoalkylene or 1,2- or 1,3-bicylcoalkenylene with 4 to 10 carbon atoms, which is unsubstituted or substituted with C 1 -C 6  alkyl, phenyl, or benzyl; 1,2- or 1,3-cycloalkylene, 1,2- or 1,3-cycloalkylene, 1,2- or 1,3-bicycloalkylene or 1,2- or 1,3-bicycloalkylene with 4 to 10 carbon atoms, which is unsubstituted or substituted with C 1 -C 6  alkyl, phenyl, or benzyl, at whose 1 and/or 2 positions or at whose 3-position methylene or C 2 -C 4  alkylidene is attached; 1,4-butylene substituted in the 2,3 positions with R 9 R 10 C(O—) 2 , and which in the 1 and/or 4 positions is unsubstituted or substituted with C 1 -C 6  alkyl, phenyl, or benzyl, and where R 9  and R 10  independently of one another represent hydrogen, C 1 -C 6  alkyl, phenyl or benzyl; 3,4- or 2,4-pyrrolidinylene or methylene-4-pyrrolidine-4-yl whose nitrogen atom is substituted with hydrogen, C 1 -C 12  alkyl, phenyl, benzyl, C 1 -C 12  alkoxycarbonyl, C 1 -C 8  acyl, C 1 -C 12  alkylaminocarbonyl; or denotes 1,2-phenylene, 2-benzylene, 1,2-xylylene, 1,8-naphthylene, 2,2′-dinaphthylene or 2,2′-diphenylene, which is unsubstituted or substituted with halogen, —OH, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, phenyl, benzyl, phenyloxy or benzyloxy; or R 6  stands for a radical of the formulas 
     
     
       
         
         
             
             
         
       
       in which R 9  denotes hydrogen, C 1 -C 8  alkyl, C 1 -C 4  fluoroalkyl, unsubstituted phenyl or phenyl substituted with 1 to 3 F, Cl, Br, C 1 -C 4  alkyl, C 1 -C 4  alkoxy of fluoromethyl. 
     
   
   
       31 . A process according to  claim 29 , wherein the reaction medium is an aqueous reaction medium, and the diphosphine contains one or more water-solubilising polar substituents, which are attached either directly or via a bridging group to substituents of the phosphine group, wherein the bridging group is of formula
   —X 5 —R 41 —   wherein   X 5  is a direct bond, O, NH, Si(CH 3 ) 2 ), N(C 1 -C 4 -alkyl), NH—CO, N(C 1 -C 4 -alkyl)CO, CO—NH, CON(C 1 -C 4 -alkyl), NH—CO—O, N(C 1 -C 4 -alkyl)CO—O, O—CO—NH, O—CON(C 1 -C 4 -alkyl), NH—CO—NH, N(C 1 -C 4 -alkyl)CO—NH or N(C 1 -C 4 -alkyl)CO—N(C 1 -C 4 -alkyl), and   R 41  is a divalent hydrocarbon radical with 1 to 40 carbon atoms.   
   
   
       32 . A process for preparing tetrahydropterin of the following formula 
     
       
         
         
             
             
         
       
       or a tetrahydropterin compound of said tetrahydropterin that is substituted at the 6-, or 7- or 6- and 7-position or positions, 
       comprising hydrogenating pterin of the following formula 
     
     
       
         
         
             
             
         
       
       or a pterin compound of said pterin that is monosubstituted at the 6-, or 7- or 6- and 7-position or positions, 
       with hydrogen in a polar aqueous reaction medium in the presence of a hydrogenation catalyst that is a metal complex that is soluble in the reaction medium, wherein the catalyst has a ligand that is an achiral or chiral ditertiary diphosphine of formula XLIIIi or XLIIIii,
   (M 1 O 2 C—CH 2 CH 2 —O—CH 2 ) 3 C—NR 42 —CO—R 41   (XLIIIi) 
   (M 1 O 2 C—CH 2 CH 2 —O—CH 2 ) 3 C—NR 42 —CO-L-R 41   (XLIIIii) 
 
       in which M 1  stands for H, an alkali metal cation or an ammonium cation, R 42  denotes C 1 -C 4  alkyl or H, and R 41  is a monovalent radical of a chiral ditertiary diphosphine, wherein in formula XLIIIi a carbon or nitrogen atom of R 41  is linked to the CO group, and wherein in formula XLIIIii, L is —O—, —NH—, C 1 -C 6 -alkylene-, —N(C 1 -C 4 -alkyl)-, —O—C 1 -C 6 -alkylene-, —NH—C 1 -C 6 -alkylene- or —N(C 1 -C 4 -alkyl)-C 1 -C 6 -alkylene-. 
     
   
   
       33 . A process for preparing tetrahydropterin of the following formula 
     
       
         
         
             
             
         
       
       or a tetrahydropterin compound of said tetrahydropterin that is substituted at the 6-, or 7- or 6- and 7-position or positions, 
       comprising hydrogenating pterin of the following formula 
     
     
       
         
         
             
             
         
       
       or a pterin compound of said pterin that is monosubstituted at the 6-, or 7- or 6- and 7-position or positions, 
       with hydrogen in a polar reaction medium in the presence of a hydrogenation catalyst that is a metal complex that is soluble in the reaction medium of formula XLIV, XLIVa or XLIVb,
   [X 7 Me 2 YZ]  (XLIV), 
   [X 7 Me 2 Y] + A 2   −   (XLIVa) 
   [X 7 Ru(II)X 8 X 9 ]  (XLIVb), 
 
       in which 
       Y stands for monoolefin ligands or a diene ligand; 
       X 7  represents an achiral or chiral ditertiary diphosphine, that forms a 5 to 7 membered ring with the metal atom Me 2  or Ru; 
       Me 2  denotes Ir(I) or Rh(I); 
       Z represents —Cl, —Br, or —I; and 
       A 2  is an anion of an oxy-acid, BF 4   − , B(Phenyl) 4   − , PF 6   − , SbCl 6   − , AsF 6   −  or SbF 6   − ; 
       X 8  and X 9  are the same or different and have the meaning of Z or A 2 , or X 8  has the meaning of Z or A 2  and X 9  stands for hydride. 
     
   
   
       34 . A process according to  claim 29 , wherein the reaction medium is an alcoholic reaction medium, and wherein in the ditertiary diphosphines the phosphine groups are attached (a) to various carbon atoms of a hydrocarbon chain having 2 to 4 carbon atoms, or (b) directly or via a bridging group —CR a R b — in the ortho positions of a cyclopentadienyl ring or to a cyclopentadienyl ring of a ferrocenyl, wherein R a  and R b  are the same or different and stand for H, C 1 -C 8  alkyl, C 1 -C 4  fluoroalkyl, C 5 -C 6  cycloalkyl, benzyl, or phenyl. 
   
   
       35 . A process according to  claim 32 , wherein R 42  denotes H. 
   
   
       36 . A process according to  claim 29 , wherein the pterin compound is folic acid, a folic acid salt, a folic acid ester, a folic acid ester salt or a dihydro form thereof, with the proviso that in the event of using folic acid, a carboxylic acid thereof or a dihydro form thereof, the reaction medium is aqueous, and in the event of using a folic acid ester, a folic acid ester salt or a dihydro form thereof, the reaction medium is an alcohol. 
   
   
       37 . A process according to  claim 33 , wherein the pterin compound is folic acid, a folic acid salt, a folic acid ester, a folic acid ester salt or a dihydro form thereof, with the proviso that in the event of using folic acid, a carboxylic acid thereof or a dihydro form thereof, the reaction medium is aqueous, and in the event of using a folic acid ester, a folic acid ester salt or a dihydro form thereof, the reaction medium is an alcohol. 
   
   
       38 . A process for preparing tetrahydropterin of the following formula 
     
       
         
         
             
             
         
       
       or a tetrahydropterin compound of said tetrahydropterin that is substituted at the 6-, or 7- or 6- and 7-position or positions,
 comprising hydrogenating the folic acid ester salt of formula III which is in the form of a single enantiomer or a mixture of enantiomers of formula III, 
 
     
     
       
         
         
             
             
         
       
       in which 
       HA stands for a monobasic to tribasic inorganic or organic acid, 
       x denotes an integer from 1 to 6 or a fractional number between 0 and 6, and 
       R 1  and/or R 2  are, each independently, an aliphatic radical with 1-20 carbon atoms, a cycloaliphatic radical with 3-8 carbon atoms, a cycloaliphatic-aliphatic radical with 3-8 cyclic carbon atoms and 1 to 6 carbon atoms in the aliphatic part of the radical, an aromatic hydrocarbon radical with 6-14 carbon atoms, an aromatic-aliphatic radical with 7-15 carbon atoms, a an alkyl radical with 2-16 carbon atoms in which one or more carbon atoms are each independently replaced by oxygen, sulfur, NH, or —N(C 1 -C 4  Alkyl)-, a heterocycloaliphatic radical with 3-8 ring links, a heterocycloaliphatic-aliphatic radical with 3-8 ring links and 1 to 6 carbon atoms in the aliphatic part of the radical, a heteroaromatic radical with 4 to 13 carbon atoms, a heteroaromatic-aliphatic radical with 4 to 13 cyclic carbon atoms and 1 to 6 carbon atoms in the aliphatic part of the radical, wherein the hetero part of each group means that the radical contains one or more oxygen, sulfur or nitrogen atoms in the ring,
 with hydrogen in a polar reaction medium in the presence of a hydrogenation catalyst that is a metal complex that contains a chiral ligand and that is soluble in the reaction medium, wherein the catalyst contains a ligand which is (i) triarylphosphine, (ii) tetramethylene phenylphosphine (iii) pentamethylene phenylphosphine, or (iv) a bidentate ligand with a tertiary amine group and a phosphine group or with two tertiary phosphine groups as complexing groups, wherein the bidentate ligands form together with a metal atom a five- to ten membered ring.