Process for the preparation of (4-hydroxy-6-oxo-tetrahydropyran-2-yl) acetonitrile and derivatives
The invention relates to a process for the preparation of (4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-acetonitrile from 6-X-substituted-methyl-4-hydroxy-tetrahydro-pyran-2-one, wherein X stands for a leaving group, by reacting 6-X-substituted-methyl-4-hydroxy-tetrahydro-pyran-2-one with a cyanide ion in water and by subsequent lowering of the pH to a pH between 0 and 5. (4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-acetonitrile and other compounds obtainable from (4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-acetonitrile may suitably be used in the preparation of a pharmaceutical preparation, more in particular in the preparation of statins, more in particular in the preparation of Atorvastatine or a salt thereof, for instance its calcium salt. The invention also relates to (4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-acetonitrile and other compounds obtainable therefrom.
1. Process for the preparation of a compound of formula 1
wherein a compound of formula 2
wherein X stands for a leaving group is reacted with a cyanide ion in water and wherein the pH is subsequently lowered to a pH between 0 and 5.
2. Process according to claim 1 , wherein the cyanide ion concentration is at least 1 mole per liter.
3. Process according to claim 1 , wherein the molar ratio between the total quantity of cyanide ion and the total quantity of compound of formula 2, is between 0.5 and 10.
4. Process according to claim 1 , wherein the compound of formula 1 is first treated with a base prior to being reacted with a cyanide ion.
5. Process according to claim 4 , wherein the base is used in a molar ratio of between 0.3 and 3 as compared to the amount of compound of formula 2.
6. Process according to claim 1 , wherein the compound of formula 1 is reduced with a suitable reducing agent to form the corresponding compound of formula 3:
7. Process according to claim 1 , wherein the compound of formula 2, wherein X stands for a leaving group is prepared by an aldol condensation between acetaldehyde and an aldehyde which is substituted on the 2-position by X, wherein X is as defined above, in the presence of an aldolase and by subsequent reaction of the formed compound of formula 4,
wherein X is as defined above, with an oxidizing agent.
8. Process according to claim 7 , wherein the aldolase used is 2-deoxyribose-5-phosphate aldolase (DERA, EC 4.1.2.4) or a mutant thereof.
9. Process according to claim 1 , wherein a compound of formula 1 or a compound of formula 3 is converted into a compound of formula 6,
wherein R 1 stands for CN or CH 2 NH 2 and R 2 , R 3 and R 4 each independently stand for an alkyl, an alkenyl, a cycloalkyl, a cycloalkenyl, an aryl or an aralkyl group and wherein R 2 and R 3 may form a ring together with the C-atom to which they are bound use being made of a suitable acetal forming agent, in the presence of an acid catalyst and wherein the compound of formula 6 with R 1 stand for CN is optionally reduced with a suitable reducing agent to form the corresponding compound of formula 6 with R 1 stands for CH 2 NH 2 .
10. Process according to claim 9 , wherein a compound of formula 6, wherein R 1 stands for CN or CH 2 NH 2 and wherein R 2 , R 3 and R 4 are as defined above is subsequently hydrolysed in the presence of a base and water to form the corresponding salt of formula 7,
wherein Y stands for an alkali metal or a substituted or unsubstituted ammonium group, optionally followed by conversion of the salt of formula 7 to the corresponding acid (the compound of formula 7, wherein Y stands for H) and wherein the salt or acid of formula 7 with R 1 stands for CN is optionally reduced with a suitable reducing agent to form the corresponding salt or acid of formula 7 with R 1 stands for CH 2 NH 2 .
11. Process according to claim 10 , wherein the salt of formula 7 or the acid of formula 7 is converted into the corresponding ester of formula 8
wherein R 1 stands for CN or CH 2 NH 2 , wherein R 2 and R 3 are as defined above and wherein R 5 may represent the same groups as given above for R 2 , R 3 and R 4 , in a manner known per se.
12. Process according to claim 11 , wherein the salt of formula 7 is converted into the corresponding ester of formula 8 by contacting the salt of formula 7 in an inert solvent with an acid chloride forming agent to form the corresponding acid chloride and by contacting the formed acid chloride with an alcohol of formula R 5 OH, wherein R 5 is as defined above, in the presence of N-methyl morpholine (NMM), and wherein the salt or acid of formula 7 with R 1 stands for CN is optionally reduced with a suitable reducing agent to form the corresponding salt or acid of formula 7 with R 1 stands for CH 2 NH 2 .
13. Process according to claim 7 , wherein the compound with a nitrile group (R 1 stands for CN) is reduced with a suitable reducing agent to form the corresponding compound with an amine group (R 1 stands for CH 2 NH 2 ).
14. Process according to claim 1 , wherein the obtained compound is enantiomerically enriched.
15. Process according to claim 1 , wherein the obtained compound is further converted into statin, preferably Atorvastatin or its calcium salt in a manner known per se.