Processes for the production of useful intermediates
View Patent ↗The present application relates to a new process for the asymmetric production of 3-(pyridin-4-yl)-3-hydroxy-pentanoic acid derivatives, which are useful intermediates in the manufacture of compounds that are known to show antiproliferative activity.
1. A process for the production of compounds of formula (I)
and pharmaceutically acceptable salts and esters thereof, comprising
a) reacting a compound of formula (II),
with a compound of formula (III),
and
b) further reacting in the presence of alkali- or earth alkali metal hydroxides to give the compounds of formula (I),
wherein
R and R 1 are independently, alkyl or benzyl, which benzyl is optionally substituted by one, two or three substituents including —O-alkyl; alkyl or halogen; with the proviso that:
if R is alkyl, R 1 in formula (I) may also be hydrogen or silyl, and R 1 in formula (II) may also be silyl;
R 2 is hydrogen or halogen;
X is
R 3 and R 4 are hydrogen, phenyl, alkyl or
—C(CH 3 ) 2 -phenyl;
R 5 is phenyl, benzyl or alkyl;
R 6 is hydrogen, alkyl or phenyl; and
R 7 is hydrogen, methyl or phenyl; or alternatively
R 5 and R 6 , together with the carbon atoms to which they are attached form an indan moiety and R 7 is hydrogen;
R 11 and R 12 air independently alkyl, cycloalkyl, benzyl or phenyl; and
R 13 is phenyl or alkyl.
2. The process according to claim 1 comprising
a) reacting a compound of formula (II),
with a compound of formula (III),
and
b) further reacting in the presence of alkali- or earth alkali metal hydroxides to give the compounds of formula (I),
wherein
R and R 1 are independently alkyl or benzyl, which benzyl is optionally substituted by one, two or three substituents including —O-alkyl; alkyl or halogen;
R 2 is hydrogen or halogen;
X is
R 3 and R 4 are hydrogen, phenyl, alkyl or —C(CH 3 ) 2 -phenyl;
R 5 is phenyl, benzyl or alkyl;
R 6 is hydrogen, alkyl or phenyl; and
R 7 is hydrogen, methyl or phenyl; or alternatively
R 5 and R 6 , together with the carbon atoms to which they am attached form an indan moiety and R 7 is hydrogen;
R 11 and R 12 are independently alkyl, cycloalkyl, benzyl or phenyl; and
R 13 is phenyl or alkyl.
3. A process according to claim 1 , comprising
a) reacting a compound of formula (II),
with a compound of formula (III),
and
b) further reacting in the presence of alkali- or earth alkali metal hydroxides to give the compound of formula (I),
wherein
R is alkyl; and
R 1 is hydrogen or silyl in formula (I) and silyl in formula (II);
R 2 is hydrogen or halogen:
X is
R 5 is phenyl, benzyl or alkyl;
R 6 is hydrogen, alkyl or phenyl; and
R 7 is hydrogen, methyl or phenyl.
4. The process according to claim 1 or 2 , wherein X is
wherein
R 5 is phenyl, benzyl, isopropyl, tert-butyl or methyl;
R 6 is hydrogen, methyl or phenyl; and
R 7 is hydrogen, methyl or phenyl; or alternatively
R 5 and R 6 together with the carbon atoms to which they are attached, form an indan moiety and
R 7 is hydrogen.
5. The process according to claim 4 , wherein
R 5 and R 6 are both phenyl, and
R 7 is hydrogen.
6. The process according to claim 1 or 2 , wherein the compound of formula (I-1)
is obtained by
a) reacting the compound of formula (II-1)
with the compound formula (III-1)
b) further reacting in the presence of lithium hydroxide in combination with hydrogen peroxide, to give the corresponding compound of formula (I).
7. The process according to claim 1 , wherein the compound of formula (I-2)
is obtained by
a) reacting the compound of formula (II-2)
with the compound of formula (III-2)
b) further reacting in the presence of lithium hydroxide in combination with hydrogen peroxide, to give the corresponding compound of formula (I-2).
8. The process of claim 1 , whereby the process step a) is carried out in the presence of an alkali- or earth-alkali metal amide base.
9. The process of claim 1 , whereby the process step a) is carried out in the presence of lithium hexamethyldisilazane (LHMDS).
10. The process of claim 1 , whereby the process step a) is carried out in a solvent including diethylether (Et 2 O), tetrahydrofuran (THF), tert-butyl methyl ether (TBME), pentane, hexane or heptane.
11. The process according to claim 10 , whereby the solvent of process step a) is tetrahydrofuran (THF).
12. The process of claim 1 , whereby the process step a) is carried out at temperatures between 25° C. and −120° C.
13. The process according to claim 12 , whereby the process step a) is carried out at temperatures between −60° C. and −100° C.
14. The process according to claim 12 , whereby the process step a) is carried out at temperatures between −90° C. and 100° C.
15. The process of claim 1 , whereby the process step b) is carried out in the presence of an alkali- or earth alkali metal hydroxide, alone or in combination with hydrogen peroxide.
16. The process according to claim 15 , whereby the process step b) is carried out in the presence of lithium hydroxide in combination with hydrogen peroxide.
17. The process according to claim 1 or 2 ,
wherein X is