Two-step process for preparing 3-substituted phenylalkylamines
Processes for preparing 3-substituted phenylalkylamines comprising reacting a phenyl boronic compound with an α-β unsaturated carbonyl-containing compound via an asymmetric 1,4-addition reaction, followed by reductive alkylation. The processes may be useful in the synthesis of tapentadol.
1. A process for preparing a compound of Formula (III), the process comprising:
a) contacting a compound of Formula (I) with a compound of Formula (IV) in the presence of a transition metal catalyst and a chiral ligand to form a compound of Formula (II); and
b) contacting the compound of Formula (II) with a secondary amine having Formula (V) to form the compound of Formula (III) according to the following reaction scheme:
wherein:
R is hydrogen, alkenyl, substituted alkenyl, aryl, or substituted aryl;
R 1 is hydrogen, OR 20 , NR 20 R 21 , SR 20 R 21 , hydrocarbyl, or substituted hydrocarbyl;
R 2 is hydrocarbyl or substituted hydrocarbyl;
R 3 , R 4 , R 5 , and R 7 are independently hydrogen, OR 20 , NR 20 R 21 , SR 20 R 21 , halo, hydrocarbyl, or substituted hydrocarbyl;
R 8 is
—O—(CR 13 R 14 ) n —O—, —O—B—O—B—O—, or trihalo;
R 10 and R 11 are independently hydrocarbyl, substituted hydrocarbyl, or R 10 and R 11 together may form a ring or ring system selected from carbocyclic, heterocyclic, aryl, heteroaryl, or combinations thereof;
R 12 is hydrocarbyl or substituted hydrocarbyl;
R 13 and R 14 are independently hydrogen, hydrocarbyl, or substituted hydrocarbyl;
R 20 and R 21 are independently hydrogen, hydrocarbyl, or substituted hydrocarbyl; and
n is an integer of 1 or greater.
2. The process of claim 1 , wherein R is hydrogen, C 1 -C 10 alkenyl, substituted C 1 -C 10 alkenyl, aryl, substituted aryl, or aryl(C 1 -C 10 )alkyl; R 1 is hydrogen, alkyl, or substituted alkyl; R 2 and R 12 are independently alkyl or substituted alkyl; R 3 , R 4 , R 5 , and R 7 are independently hydrogen, alkyl, substituted alkyl, hydroxyl, alkoxy, substituted alkoxy, aryl, substituted aryl, alkylaryl, or substituted alkylaryl; R 10 and R 11 are independently alkyl or substituted alkyl; and R 13 and R 14 are independently hydrogen, alkyl, aryl, alkylaryl, or organoborane.
3. The process of claim 2 , wherein R is hydrogen or benzyl; R 1 is hydrogen; R 2 and R 12 are independently C 1 -C 10 alkyl; each of R 3 , R 4 , R 5 , and R 7 is hydrogen; and R 10 and R 11 are independently C 1 -C 10 alkyl.
4. The process of claim 1 , wherein the compound of Formula (I) is 3-hydroxyphenylboronic acid, 3-hydroxyphenyl trifluoroborate, 3-hydroxyphenylboronic acid pinacol ester, 3-hydroxyphenylboronic ester, derived from 3-hydroxyphenylboroxine, 3-benzyloxyphenylboronic acid, 3-benzyloxyphenyl trifluoroborate, 3-benzyloxyphenylboronic acid pinacol ester, 3-benzyloxyphenylboronic ester, or is derived from 3-benzyloxyphenylboroxine.
5. The process of claim 1 , wherein the compound of Formula (I) and the compound of Formula (IV) are present at a molar ratio of about 1:0.5 to about 1:6.0.
6. The process of claim 1 , wherein the transition metal catalyst comprises rhodium, palladium, or ruthenium; and the compound of Formula (I) and the transition metal catalyst are present at a molar ratio of about 1:0.0001 to about 1:0.1.
7. The process of claim 1 , wherein the chiral ligand is a bicyclic chiral diene; and the transition metal catalyst and the chiral ligand are present at a weight ratio of about 1:0.5 to about 1:2.
8. The process of claim 1 , wherein step (a) further comprises contact with a secondary or a tertiary amine; and the compound of Formula (I) and the secondary or tertiary amine are present at a molar ratio of about 1:0.01 to about 1:1.0.
9. The process of claim 8 , further comprising contact with a proton acceptor; and the compound of Formula (I) and the proton acceptor are present at a molar ratio of about 1:0.001 to about 1:2.0.
10. The process of claim 1 , wherein step (a) is conducted in the presence of a solvent chosen from a polar protic solvent, a polar aprotic solvent, a non-polar solvent, or a combination thereof; and the solvent and the compound of Formula (I) are present at a volume to weight ratio of about 1.0:1 to about 50:1; and step (a) is conducted at a temperature from about −10° C. to about 80° C.
11. The process of claim 10 , wherein the compound of Formula (II) is obtained in a yield of at least about 25%.
12. The process of claim 1 , wherein the compound of Formula (II) and the compound of Formula (V) are present at molar ratio of about 1:1 to about 1:20; step (b) is conducted in the presence of a reducing agent; and step (b) is conducted at a temperature from about −10° C. to about 80° C.
13. The process of claim 1 , wherein R is hydrogen or benzyl; R 1 is hydrogen; R 2 is ethyl; each of R 3 , R 4 , R 5 , and R 7 is hydrogen; and each of R 10 , R 11 , and R 12 is methyl.
14. The process of claim 13 , wherein the transition metal catalyst is [RhCl(C 2 H 4 ) 2 ] 2 and the chiral ligand is (1S,4S)-2,5-diphenylbicyclo[2,2,2]octa-2,5-diene.
15. The process of claim 14 , wherein the compound of Formula (III) is 3-[(1R,2R)-3-(dimethylamino)-1-ethyl-2-methylpropyl] phenol.
16. A process for preparing a compound of Formula (IIa), the process comprising contacting a compound of Formula (Ia) with a compound of Formula (IVa) in the presence of a catalyst to give the compound of Formula (IIa):
wherein:
Z is a boron containing moiety;
R is hydrogen, alkenyl, substituted alkenyl, aryl, substituted aryl, or arylalkyl;
R 3 , R 4 , R 5 , and R 7 are independently hydrogen, OR 20 , NR 20 R 21 , SR 20 R 21 , halo, hydrocarbyl, or substituted hydrocarbyl; and
R 20 and R 21 are independently hydrogen, hydrocarbyl, or substituted hydrocarbyl.
17. The process of claim 16 , wherein the transition metal catalyst comprises rhodium; and the chiral ligand is a bicyclic chiral diene.
18. The process of claim 16 , further comprising contact with an amine.
19. The process of claim 18 , further comprising contact with a proton acceptor.
20. The process of claim 16 , wherein R is hydrogen or benzyl; each of R 3 , R 4 , R 5 , and R 7 is hydrogen, and; the transition metal catalyst is [RhCl(C 2 H 4 ) 2 ] 2 ; and the chiral ligand is (1S,4S)-2,5-diphenylbicyclo[2,2,2]octa-2,5-diene.