Manufacturing process for sitagliptin from L-aspartic acid

A process for preparation of a compound of formula II, having the configuration as given in the formula,

• wherein R1 represents hydroxy, alkoxy, aryloxy, alkylaryloxy, arylakyloxy, preferably methoxy, ethoxy, benzyloxy, or
• —NR6R7, wherein R6 and R7 are independently from each other hydrogen, lower alkyl, alkylaryl, arylalkyl, preferably —NH2, —NMe2, —Ndibenzyl, or in particular R6 and R7 can form together with N a 5- or 6-membered heterocyclic ring which may contain one or more heteroatoms selected from N or O and, which can be unsubstituted or substituted, preferably 4-alkyl-oxazolidin-2-one-3-yl, containing also a chiral center as 4(R)- or 4(S)-benzyl-oxazolidin-2-one-3-yl, or
• —NR8OR9, wherein R8 and R9 are independently from each other hydrogen, lower alkyl, alkylaryl, arylalkyl, preferably —NMeOMe, or in particular R8 and R9 can form together with N and O a 5- or 6-membered heterocyclic ring which may contain one or more heteroatoms selected from N or O and, which can be unsubstituted or substituted, containing also a chiral center, and
• R10 and R11 are independently from each other hydrogen, alkyl, aryl, alkylaryl, arylalkyl, preferably 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) reaction of the compound of formula IV, having the configuration as given in the formula,
• wherein R1 is the same as defined for compound of formula II, and
• i) when the dotted CN bond is a double bond, then
• R2 and R3 are void, and
• R4 is hydrogen, alkyl, aryl, alkylaryl, arylalkyl, preferably hydrogen, phenyl, benzyl, methyl, trifluoromethyl,
• or
• ii) when the dotted CN bond is a single bond, then
• R2 is hydrogen, alkyl, aryl, alkylaryl, arylalkyl, preferably 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, and
• R3 and R4 are either independently from each other hydrogen, lower alkyl, aryl, alkylaryl, arylalkyl, preferably hydrogen, phenyl, trifluoromethyl, or
• R3 and R4 are together one oxygen atom forming carbonyl function C═O,
• with a compound of formula V,
• wherein R5 is
• i) either hydrogen, in inert aprotic organic solvent, preferably chlorinated hydrocarbons as methylenechloride or dichloroethane, or aliphatic hydrocarbons, preferably hexane or heptane, in the presence of a catalyst commonly used for Friedel-Crafts reaction, preferably bortrifluoro etherate, metal halide(s) as Al-, Zn-, lanthanide- and Bi-halides,
• ii) or R5 is a metal containing group especially an alkali or earth alkali metallic radical, as e.g. lithium, sodium, potassium or a group of formula Mg-halogen (Grignard reagent), —Znhalogen, -Cer(halogen)2 or boronic acid as —B(OH)2, but preferably —Li or —MgBr or —Mg ate complex, in inert organic solvent, preferably THF,
• providing a compound of formula III, wherein R1, R10 and R11 are the same as defined for compound of formula II;
• b) reduction of the carbonyl function in benzyl position in the compound of formula III, simultaneously or in separate steps;
• c) protection or removal of N-protective group(s) as they are defined for R10 and R11 in the compound of formula II.