Manufacturing process for (S)-Pregabalin

A process for preparation of a compound of general formula II, having the (S)-configuration as given in formula,

• wherein
• R3 represents hydrogen, alkyl, aryl, alkylaryl, arylalkyl, trialkylsilyl, preferably hydrogen, benzyl, mono-, di- or tri-methoxybenzyl, or other N-protective group, in particular one which together with N forms an amide or carbamate as —C(O)alkyl, —C(O)aryl, —C(O)alkylaryl, —C(O)arylalkyl, —C(O)Oalkyl, —C(O)Oaryl, —(O)COalkylaryl, —C(O)Oarylalkyl, preferably formyl, acetyl, trifluoroacetyl, —C(O)Obenzyl (Cbz) or —C(O)Otert.-butyl (BOC),
• comprising following steps:
• a) i. either enzymatic hydrolysis of compound of formula VI, wherein R2 is —CN and R1 is lower alkyl, preferably methyl, ethyl, propyl or n-butyl,
• ii. or enzymatic esterification of the compound of formula VI,
• wherein R2 is —CN and R1 is hydrogen,
• with a suitable enzyme which is capable of stereo selective esterification or hydrolysis,
• providing a chiral compound of formula V, wherein R2 is —CN, R is hydrogen and R1 is lower alkyl, preferably methyl, ethyl, propyl or n-butyl;
• b) selective reduction or hydrogenation of cyano group in the compound of formula V, in one or several separate steps, with subsequent stereo selective cyclization step forming 5-membered lactam ring of formula IV, followed by eventual esterification according to definition of the R group in compound of formula IV,
• wherein R represents hydrogen, linear or brunched C1-6-alkyl, aryl, arylalkyl, alkylaryl, trialkylsilyl, preferably hydrogen or -Me, and
• R3 is the same as defined for compound of formula II;
• c) reaction of the compound of formula IV, with a reagent containing C1-fragment, preferably CH3-nucleophilic organometallic reagent such as Me-alkali metal or Me-earth alkali metal, preferably Me—Li or MeMgCl or MeMgBr, followed by protection/activation of tert.-hydroxy group according to the definition for R4, providing a compound of formula III,
• wherein R3 is the same as defined for compound of formula II and
• R4 represents counter cation as alkali or earth alkali metal cation, preferably Li+ or MgCl/Br+, or hydrogen, trialkylsilyl, alkylaryl, arylalkyl, preferably benzyl, mono-, di- or tri-methoxybenzyl, or other O-protective group, in particular one which together with O forms an ester or carbonate as —C(O)alkyl, —C(O)aryl, —C(O)alkylaryl, —C(O)arylalkyl, —C(O)Oalkyl, —C(O)Oaryl, —C(O)Oalkylaryl, —C(O)Oarylalkyl, preferably formyl, acetyl, trifluoroacetyl, —C(O)OMe, —C(O)OEt, —C(O)Obenzyl (Cbz), or —SO2Cl or alkyl- or arylsulfonyl, preferably Mesyl, Tosyl, Nosyl or trifluoromethanesulfonyl, or thiocarbonyl derivative as —C(S)Oalkyl or —C(S)Oaryl or —C(S)imidazolyl;
• d) reductive removal of —OR4 in the compound of formula III
• ii. either directly by reductive displacement of —OR4 group with hydrogen, preferably by homogeneous or heterogeneous hydrogenation in the presence of transition metal such as Ra—Ni, Pt, Pd, Ru or Rh, or with other chemical reducing agent such as metal hydride via Sn2 displacement of —OR4 group with a hydride, or by a radical-based de-oxygenation, preferably with metal hydrides or silanes such as Et3SiH, Cl3SiH, tris(trimethylsilyl)-silane or Bu3SnH, also in the presence of NaBH4, or dialkyl phosphites or hypophosphorous acid.
• ii. or, after thermal, acid or based catalyzed elimination of H—OR4, followed by hydrogenation of the double bond in the compound of formula IIIa, wherein R3 is the same as defined for compound of formula II.

A process for preparation of a compound of general formula IV, having the (S)-configuration as given in formula,

• wherein R3 represents hydrogen, trialkylsilyl, alkyl, aryl, alkylaryl, arylalkyl, preferably hydrogen, or other N-protective group, in particular one which together with N forms an amide or carbamate as —C(O)alkyl, —C(O)aryl, —C(O)alkylaryl, —C(O)arylalkyl, —C(O)Oalkyl, —C(O)Oaryl, —(O)COalkylaryl, —C(O)Oarylalkyl, preferably formyl, acetyl, trifluoroacetyl, —C(O)Obenzyl (Cbz) or —C(O)Otert.-butyl (BOC), and
• R represents hydrogen, lower alkyl, arylalkyl, preferably hydrogen;
• comprising following steps:
• a) i. either enzymatic hydrolysis of compound of formula VI, wherein R2 is —CN and R1 is lower alkyl, preferably methyl, ethyl, propyl or n-butyl,
• ii. or enzymatic esterification of compound of formula VI, wherein R2 is —CN and R1 is hydrogen,
• with a suitable enzyme which is capable of stereo selective esterification or hydrolysis,
• providing a chiral compound of formula V, wherein R2 is —CN, R is hydrogen and R1 is lower alkyl, preferably methyl, ethyl, propyl or n-butyl;
• b) selective reduction or hydrogenation of cyano group in the compound of formula V, in one or several separate steps, followed by stereo selective cyclization step with formation of a 5-membered lactam ring and eventual esterification according to definition of the R group in the compound of formula IV.

A process for preparation of a compound of general formula III, having the (S)-configuration as given in formula,

• wherein
• R3 represents hydrogen, or other N-protective group, which together with N forms an amide or carbamate as —C(O)alkyl, —C(O)aryl, —C(O)alkylaryl, —C(O)arylalkyl, —C(O)Oalkyl, —C(O)Oaryl, —(O)COalkylaryl, —C(O)Oarylalkyl, preferably formyl, acetyl, trifluoroacetyl, —C(O)Obenzyl (Cbz) or —C(O)Otert.-butyl (BOC), and
• R4 represents counter cation as alkali or earth alkali metal cation, preferably Li+ or MgCl/Br+, or hydrogen, arylalkyl, trialkylsilyl, preferably benzyl, mono-, di- or tri-methoxybenzyl, or other O-protective group, in particular one which together with O forms an ester or carbonate as —C(O)alkyl, —C(O)aryl, —C(O)alkylaryl, —C(O)Oalkyl, —C(O)Oaryl, —C(O)Oalkylaryl, preferably formyl, acetyl, trifluoroacetyl, —C(O)Obenzyl (Cbz) or —C(O)Otert.-butyl (BOC), or —SO2Cl or alkyl- or arylsulfonyl, preferably Mesyl, Tosyl, Nosyl or trifluoromethanesulfonyl, or thiocarbonyl derivative such as —C(S)Oalkyl or —C(S)Oaryl or —C(S)imidazolyl,
• comprising following steps:
• a) reaction of the compound of formula IV,
• wherein R represents hydrogen, linear or brunched C1-6-alkyl, aryl, arylalkyl, alkylaryl, trialkylsilyl, preferably hydrogen, and
• R3 is the same as defined for compound of formula III;
• with a reagent containing C1-fragment, preferably CH3-nucleophilic organometallic reagent such as Me-alkali metal or Me-earth alkali metal, preferably Me—Li or MeMgCl or MeMgBr,
• b) followed by activation of tert.-hydroxy group according to the definition for R4.