Process for the preparation of 5-fluorotryptophol
The present invention relates to a process for the preparation of 5-fluorotryptophol as well as a process for the preparation of (1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano-[3,4b]-indol]-4-amine using the 5-fluorotryptophol obtained by said first process. The process according to the invention provides 5-fluorotryptophol in improved yield and purity without the need for chromatographic purification of the product.
1. A process for preparing 5-fluorotryptophol comprising steps of
a) providing a mixture comprising 4-fluorophenyl-hydrazine, an activation reagent, water and at least one aprotic organic solvent selected from the group consisting of tetrahydrofuran, 2-methyltetrahydrofuran and isopropyl acetate;
b) adding to the mixture a solution of at the most about 1.1 equivalents of 2,3-dihydrofuran in at least one aprotic organic solvent selected from the group consisting of tetrahydrofuran, 2-methyltetrahydrofuran and isopropyl acetate to react with the 4-fluorophenylhydrazine to give 5-fluorotryptophol, wherein the aprotic solvent and water provided in steps a) and b) are provided in a ratio relative to each other such that a heterogeneous reaction mixture comprising a liquid organic phase and a liquid aqueous phase is formed either before or during addition step b);
c) separating the organic from the aqueous phase;
d) contacting the organic phase with an aqueous solution of at least one inorganic salt to form a heterogeneous mixture comprising a liquid organic phase and a liquid aqueous phase;
e) separating the organic phase from the aqueous phase of the heterogeneous mixture; and
f) isolating 5-fluorotryptophol from the organic phase via a precipitation step.
2. The process according to claim 1 , wherein the mixture formed in step a) is a heterogeneous mixture comprising a liquid organic phase and a liquid aqueous phase.
3. The process according to claim 1 , wherein the activation reagent is at least one protic acid or a heterogeneous Bronsted acid catalyst.
4. The process according to claim 1 , wherein the activation reagent is
a) a protic acid in an amount of at least one equivalent relative to the 4-fluorophenylhydrazine or
b) a catalytic amount of a heterogeneous Bronsted acid catalyst.
5. The process according to claim 1 , wherein the activation reagent is a protic acid that has a pK a -value in the range of −6.5 to +10.
6. The process according to claim 5 , wherein the protic acid is added to the reaction medium in the form of its addition salt with 4-fluorophenylhydrazine.
7. The process according to claim 1 , wherein the activation reagent is HCl.
8. The process according to claim 1 , wherein the activation agent is a mixture of one equivalent relative to 4-fluorophenylhydrazine of an acid selected from the group consisting of HCl, HBr, H 2 SO 4 , H 3 PO 4 and HClO 4 and an additional amount of a second acid selected from the group consisting of NH 4 Cl, NH 4 HSO 4 , (NH 4 ) 2 SO 4 , (NH 4 )H 2 PO 4 , (NH 4 ) 2 HPO 4 , and (NH 4 ) 3 PO 4 .
9. The process according to claim 8 , wherein the second acid is NH 4 Cl.
10. The process according to claim 1 , wherein the activation reagent is a catalytic amount of a heterogeneous Bronsted acid catalyst selected from the group consisting of Amberlyst-15, Amberlite-120, Indion-130, Montmorillonite K10 and Zeolite HY.
11. The process according to claim 1 , wherein the aprotic organic solvent is selected from the group consisting of isopropyl acetate and 2-methyltetrahydrofuran or mixtures thereof.
12. The process according to claim 1 , wherein water and the aprotic organic solvent are present in the heterogeneous reaction medium at a volume ratio of from about 1:3 to about 3:1.
13. The process according to claim 1 , wherein the reaction in step (b) is carried out at a temperature of at least about 50° C.
14. The process according to claim 1 , wherein phase separation step (c) is carried out at elevated temperatures in a range between 40° C. to 60° C.
15. The process according to claim 1 , wherein the formation of the heterogeneous mixture in step (d) is carried out at elevated temperatures in a range between 40° C. to 60° C.
16. The process according to claim 1 , wherein phase separation step (e) is carried out at elevated temperatures in a range between 40° C. to 60° C.
17. The process according to claim 1 , wherein isolation step (f) comprises steps of
f1) removal of the aprotic organic solvent from the organic phase obtained in step (e) to give a residue;
f2) adding to the residue obtained in step f1) water or an aqueous solution of at least one inorganic salt and an organic solvent having a water solubility at 20° C. below 5 g/l to form a heterogeneous mixture comprising a liquid aqueous phase and a liquid organic phase;
f3) separating the liquid organic phase from the heterogeneous mixture obtained in step f2); and
f4) precipitating the 5-fluorotryptophol from the liquid organic phase obtained in step f3).
18. The process according to claim 17 , wherein the organic solvent added in step f2) is toluene or benzene.
19. The process according to claim 17 , wherein the formation of the heterogeneous mixture in step f2) and/or the separation of the liquid organic phase in step f3) are/is carried out at elevated temperatures in a range from 40° C. to 60° C.
20. The process according to claim 1 , wherein in step b) relative to 4-fluorophenylhydrazine about 0.9 to 1.1 equivalent of 2,3-dihydrofuran are added to the heterogeneous reaction mixture.