Bibliographic Details
| Title: |
PROCESS FOR THE PREPARATION OF ARYLOXYPROPYLAMINES |
| Document Number: |
20070270483 |
| Publication Date: |
November 22, 2007 |
| Appl. No: |
11/749977 |
| Application Filed: |
May 17, 2007 |
| Abstract: |
A process for preparation of a compound of formula (I), or a salt thereof, both as individual isomer and as mixtures thereof, [chemical expression included] wherein each of A and B is independently aryl or heteroaryl optionally substituted with 1 to 4 substituents; and R and R1, which can be the same or different, are hydrogen, C1-C6 alkyl or an amino-protecting group; comprising the reaction of a compound (II) [chemical expression included] wherein A and B are as defined above, with a compound (III) [chemical expression included] wherein each of R and R1 is independently C1-C6 alkyl or an amino-protecting group; and X is a leaving group; in the presence of a basic agent; and, if desired the conversion of a compound (I) to another compound (I); and/or, if desired, the separation of an isomeric mixture of a compound (I) into the individual isomers; and/or, if desired, the conversion of a compound (I) to a salt thereof. |
| Inventors: |
MANTEGAZZA, Simone (Milano, IT); RAZZETTI, Gabriele (Giovanni, IT); RASPARINI, Marcello (Cura Carpignano, IT); ROSSI, Roberto (Pavia, IT); ALLEGRINI, Pietro (Milanese, IT) |
| Assignees: |
DIPHARMA FRANCIS S.R.L. (Baranzate, IT) |
| Claim: |
1. A process for the preparation of a compound of formula (I), or a salt thereof, as the individual isomer or a mixture thereof, [chemical expression included] wherein each of A and B is independently aryl or heteroaryl, optionally substituted by 1 to 4 substituents, wherein the substituents may be the same or different, and are selected from the group consisting of halogen, nitro, cyano, C1-C6 alkyl optionally substituted with halogen, C1-C6 alkylthio, C1-C6 alkoxy, and —N(RaRb) wherein Ra and Rb, which may be the same or different, are C1-C6 alkyl, or Ra and Rb, taken with the nitrogen atom to which Ra and Rb are linked, form a 5- or 6-membered saturated or unsaturated ring, optionally containing 1, 2 or 3 further heteroatoms selected from nitrogen and oxygen; and R and R1, which can be the same or different, are hydrogen, C1-C6 alkyl or an amino-protecting group; wherein the process comprises the steps of: (a) providing a compound (II) [chemical expression included] wherein A and B are as defined above; (b) providing a compound (III) [chemical expression included] wherein each of R and R1 is independently C1-C6 alkyl or an amino-protecting group, and X is a leaving group; and (c) reacting the compound (I) and the compound (III) with each other in the presence of a basic agent. |
| Claim: |
2. A process as claimed in to claim 1, wherein in a compound of formula (I), or in a salt thereof, A is phenyl or naphthyl optionally substituted with C1-C4 alkyl in turn optionally substituted with halogen; or with C1-C4 alkoxy; B is phenyl or thienyl; one of R and R1 is C1-C4 alkyl and the other is hydrogen, C1-C4 alkyl, or an amino-protecting group. |
| Claim: |
3. A process as claimed in claim 1, wherein the compound of formula (I) is selected from the group consisting of (+)-N-methyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine, N,N-dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine, (−)-N-methyl-3-(2-methyl-phenyloxy)-3-phenyl-propanamine, N,N-dimethyl-3-(2-methyl-phenyloxy)-3-phenyl-propanamine, N-methyl-3-(4-trifluoromethyl-phenyloxy)-3-phenyl-propanamine, N,N-dimethyl-3-(4-trifluoromethyl-phenyloxy)-3-phenyl-propanamine, N-methyl-3-(4-methoxy-phenyloxy)-3-phenyl-propanamine, N,N-dimethyl-3-(4-methoxy-phenyloxy)-3-phenyl-propanamine, phenyl N-methyl-3-(2-methyl-phenyloxy)-3-phenyl-propylcarbamate, phenyl N-methyl-3-(4-trifluoromethyl-phenyloxy)-3-phenyl-propylcarbamate, phenyl N-methyl-3-(1-naphthalenyloxy)-3-(2-thienyl)-propylcarbamate, phenyl N-methyl-3-(4-methoxy-phenyloxy)-3-phenyl-propylcarbamate, and salts salt thereof. |
| Claim: |
4. A process as claimed in claim 1, wherein the basic agent is a compound of formula E-M, wherein M is an alkali or alkaline-earth metal and E is a strong organic or inorganic base; or a compound of formula Rc—MgY or of formula (Rc)2Mg wherein Rc is C1-C6 alkyl, C5-C7 cycloalkyl, aryl or aryl-C1-C6 alkyl and Y is a halogen or a group —N(RaRb) as defined in claim 1. |
| Claim: |
5. A process as claimed in claim 4, wherein the basic agent is selected from the group consisting of butyl-lithium, hexyl-lithium, t-butyl-lithium, phenyl lithium, ethyl-magnesium bromide, cyclohexyl-magnesium chloride, benzyl-magnesium bromide, ethyl-magnesium-diisopropylamide, dibutyl-magnesium, magnesium diisopropylamide, lithium diisopropylamide, lithium bis-trimethylsilylamide, lithium tetramethylpiperidide, potassium tert-butoxide, sodium hydride and potassium hydride. |
| Claim: |
6. A process as claimed in claim 5, wherein the basic agent is selected from the group consisting of butyl lithium, hexyl lithium and lithium diisopropylamide. |
| Claim: |
7. A process according to claim 4, wherein the reaction is carried out in the presence of a ligand. |
| Claim: |
8. A process as claimed in claim 1, wherein the leaving group is a halogen atom or a hydroxy group activated by esterification. |
| Claim: |
9. A process as claimed in claim 1, wherein the reaction is carried out in an anhydrous organic solvent. |
| Claim: |
10. A process as claimed in claim 9, wherein the solvent is selected from the group consisting of an aliphatic hydrocarbon, an aromatic hydrocarbon, petroleum ether, an ether, or a mixture of two or more than said solvents. |
| Claim: |
11. A process as claimed in claim 1, wherein the stoichiometric ratio of the compound of formula (II) to the basic agent approximately ranges from 0.5 to 10. |
| Claim: |
12. A process as claimed in claim 1, wherein the compound of formula (I) is N,N-dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine, or a salt thereof. |
| Claim: |
13. A process as claimed in claim 1, wherein the compound of formula (I) is (−)-N-methyl-3-(2-methyl-phenyloxy)-3-phenyl-propanamine, or a salt thereof. |
| Claim: |
14. A process as claimed in claim 1, wherein the compound of formula (I) is N,N-dimethyl-3-(2-methyl-phenyloxy)-3-phenyl-propanamine, or a salt thereof. |
| Claim: |
15. A process as claimed in claim 1, wherein the compound of formula (I) is N-methyl-3-(4-trifluoromethyl-phenyloxy)-3-phenyl-propanamine, or a salt thereof. |
| Claim: |
16. A process as claimed in claim 1, wherein the compound of formula (I) is N,N-dimethyl-3-(4-trifluoromethyl-phenyloxy)-3-phenyl-propanamine, or a salt thereof. |
| Claim: |
17. A process as claimed in claim 1, wherein the compound of formula (I) is N-methyl-3-(4-methoxy-phenyloxy)-3-phenyl-propanamine, or a salt thereof. |
| Claim: |
18. A process as claimed in claim 1, wherein the compound of formula (I) is N,N-dimethyl-3-(4-methoxy-phenyloxy)-3-phenyl-propanamine, or a salt thereof. |
| Claim: |
19. A process as claimed in claim 1, wherein the compound of formula (I) is phenyl N-methyl-3-(2-methyl-phenyloxy)-3-phenyl-propylcarbamate, or a salt thereof. |
| Claim: |
20. A process as claimed in claim 1, wherein the compound of formula (I) is phenyl N-methyl-3-(4-trifluoromethyl-phenyloxy)-3-phenyl-propylcarbamate, or a salt thereof. |
| Claim: |
21. A process as claimed in claim 1, wherein the compound of formula (I) is phenyl N-methyl-3-(1-naphthalenyloxy)-3-(2-thienyl)-propylcarbamate, or a salt thereof. |
| Claim: |
22. A process as claimed in claim 1, wherein the compound of formula (I) is phenyl N-methyl-3-(4-methoxy-phenyloxy)-3-phenyl-propylcarbamate, or a salt thereof. |
| Claim: |
23. A process as claimed in claim 1, wherein the compound of formula (I) is (+)-N-methyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine, or a salt thereof. |
| Claim: |
24. A process according to claim 5, wherein the reaction is carried out in the presence of a ligand. |
| Claim: |
25. A process according to claim 6, wherein the reaction is carried out in the presence of a ligand. |
| Claim: |
26. A process according to claim 1, further comprising the step of (d) converting the compound of formula (I) to another compound of formula (I). |
| Claim: |
27. A process according to claim 1, further comprising the step of (d) separating an isomeric mixture of compound (I) into individual isomers. |
| Claim: |
28. A process according to claim 26, further comprising the step of (e) separating an isomeric mixture of compound (I) into individual isomers. |
| Claim: |
29. A process according to claim 1, further comprising the step of (d) conversion of compound (I) to a salt thereof. |
| Claim: |
30. A process according to claim 26, further comprising the step of (e) conversion of compound (I) to a salt thereof. |
| Claim: |
31. A process according to claim 27, further comprising the step of (e) conversion of compound (I) to a salt thereof. |
| Claim: |
32. A process according to claim 28, further comprising the step of (f) conversion of compound (I) to a salt thereof. |
| Current U.S. Class: |
514/447 |
| Current International Class: |
61; 07 |
| Accession Number: |
edspap.20070270483 |
| Database: |
USPTO Patent Applications |
