US 7,553,970 B2
Process for preparing 3-heteroaryl-3-hydroxypropanoic acid derivatives
Frank Berendes, Münster (Germany); Markus Eckert, Shanghai (China); Nils Brinkmann, Leverkusen (Germany); Claus Dreisbach, Leichlingen (Germany); Ruth Meissner, Leverkusen (Germany); and Rainhard Koch, Köln (Germany)
Assigned to Lanxess Deutschland GmbH, Leverkusen (Germany)
Filed on Sep. 24, 2003, as Appl. No. 10/669,424.
Claims priority of application No. 102 44 811 (DE), filed on Sep. 26, 2002.
Prior Publication US 2004/0181058 A1, Sep. 16, 2004
Int. Cl. C07D 211/70 (2006.01); C07D 211/82 (2006.01); C07D 213/24 (2006.01); C07D 213/00 (2006.01); C07D 213/46 (2006.01); C07D 333/22 (2006.01); C07D 333/16 (2006.01); C07D 333/18 (2006.01); C07D 333/08 (2006.01); C07D 307/02 (2006.01)
U.S. Cl. 546—315  [546/334; 546/339; 546/340; 549/70; 549/78; 549/79; 549/483; 549/497] 12 Claims
 
1. A process for preparing enantiomer-enriched compounds of the formula (VI),
heteroaryl-CH(OH)—CH2—CH2—NR2R3  (VI)
in which
heteroaryl is a monocyclic aromatic radical having a total of 6 ring atoms, where one or two ring atoms, selected from the group oxygen, sulphur and nitrogen, is present and where the monocyclic aromatic radical is optionally substituted, once, twice or three times, by radicals which are selected, in each case independently of each other, from the group hydroxyl, C1-C8-alkyl, cyano, COOH, COOM, where M is an alkali metal ion or a half equivalent of an alkaline earth metal ion, COO—(C1-C4-alkyl),O—(C1-C4-alkyl), N(C1-C4-alkyl)2, NH—(C1-C4-alkyl), NO2, fluorine, chlorine, bromine, C1-C4- fluoroalkyl, CONH2 and CONH—(C1-C4-alkyl), and
R2 and R3 are, in each case independently of each other, hydrogen, C1-C8-alkyl, C4-C14-aryl or C5-C15-arylalkyl, or the two radicals R2 and R3 are together C3-C12-alkylene,
comprising:
a) reducing compounds of the formula (I)
heteroaryl-CO—CH2W  (I),
in which
heteroaryl is defined as in formula (IV), and
W is C(O)YR1n, where Y is =oxygen and n is =1 or Y is nitrogen and n is =2, or
W is CN,and
R1 are, in each case independently of each other, hydrogen, C1-C8-alkyl, C4-C10-aryl or C5-C11-arylalkyl or, when Y is nitrogen, the two radicals R1 are together C3-C5alkylene,
by contacting said compounds of the formula (I) with microorganisms selected from the group consisting of Saccharomyces cerevisiae NG 247, Saccharomyces cereviseae Y278 and Geotrichum candidum ATCC 34614;
in the presence of water having a pH range of from 3 to 11, based on 25° C.;
to yield enantiomer-enriched compound of formula (II),
heteroaryl-CH(OH)—CH2W  (II)
where, in each case,
heteroaryl and W have the meanings mentioned under formula (I), and
b) performing one of the following manipulations,
i)when W is CON(R1)2 and the R1 radicals are in each case, independently of each other, hydrogen, C1-C8-alkyl, C4-C10-aryl or C5-C11-arylalkyl, or the two R1 radicals are together C3-C5-alkylene,
reacting the enantiomer-enriched compounds of formula (II) with amines of the formula (III)
HNR2R3  (III)
in which R2 and R3 have the meaning mentioned under formula (VI), to give enantiomer-enriched compounds of the formula (IV),
heteroaryl-CH(OH)—CH2—CO—NR2R3  (IV)
in which heteroaryl, R2 and R3 have the previously mentioned meanings, or
when W is CN, aminolyizing/hydrolyzing the compounds of the formula (II) directly to yield compounds of the formula (IV), or initially hydrolyzing, partially hydrolyzing or both alcoholyzing/hydrolyzing the compounds of formula (II) to yield compounds of the formula (V)
heteroaryl-CH(OH)—CH2—CO—R4  (V)
in which heteroaryl has the meaning given under formula (I) and R4 is OR1 or NH2, where R1 has the abovementioned meaning, and amidating the compound of formula (V) to yield enantiomer-enriched compounds of the formula (IV), and
c) reducing the enantiomer-enriched compounds of the formula (IV) to yield enantiomer-enriched compounds of the formula (VI) having the abovementioned meaning.