Process for preparing substituted phenylalkanes

Patent metadata

Field	Value
Publication number	US-2016009635-A1
Application number	US-201514796069-A
Country	US
Kind code	A1
Filing date	Jul 10, 2015
Priority date	Jul 10, 2014
Publication date	Jan 14, 2016
Grant date	—

Abstract

The invention provides methods for preparing substituted phenylalkanes. In particular, the processes comprise reacting a phenyl boronic compound with an α-β unsaturated carbonyl-containing compound via an asymmetric 1,4-addition reaction. The processes may be useful in the synthesis of tapentadol.

First claim

What is claimed is:

1 . A process for preparing a compound of Formula (VI), the process comprising:
a) contacting a compound of Formula (I) with a compound of Formula (VIII) in the presence of a transition metal catalyst and a chiral ligand to form a compound of Formula (IX);

b) contacting the compound of Formula (IX) with a secondary amine having Formula (X) to form a compound of Formula (V); and

c) contacting the compound of Formula (V) with an O-dealkylating agent to form the compound of Formula (VI),

wherein:
R is alkyl or alkyl substituted with other than aryl;
R 1 is hydrogen, alkyl, or substituted alkyl;
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—, 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, substituted hydrocarbyl, or boron containing moiety;
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 1 is hydrogen, alkyl, or substituted alkyl; R 2 is 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, or alkylaryl.

3 . The process of claim 2 , wherein R 1 is C 1 -C 10 alkyl; R 2 is C 1 -C 10 alkyl; R 3 , R 4 , R 5 , and R 7 are hydrogen; and R 10 , R 11 and R 12 are C 1 -C 10 alkyl.

4 . The process of claim 1 , wherein R is methyl; R 1 is hydrogen; R 2 is ethyl; each of R 3 , R 4 , R 5 , and R 7 is hydrogen; and R 10 , R 11 , and R 12 are methyl.

5 . The process of claim 1 , wherein the compound of Formula (I), the compound of Formula (VIII), and the transition metal catalyst are present at a molar ratio of about 1:0.5:0.001 to about 1:2.0:0.05; and step (a) is conducted at a temperature from about −10° C. to about 80° C.

6 . The process of claim 5 , wherein the transition metal catalyst is a transition metal complex chosen from a rhodium complex, a palladium complex, or a ruthenium complex; 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 1:0.1 to about 1:10.

7 . The process of claim 6 , wherein the compound of Formula (IX) is obtained with a diastereomeric excess of at least about 60%.

8 . The process of claim 6 , wherein step (a) further comprises contact with an amine, the amine being secondary, tertiary, chiral, or achiral.

9 . The process of claim 8 , wherein the compound of Formula (I) and the amine are present at a molar ratio of about 1:0.01 to about 1:1.0.

10 . The process of claim 9 , further comprising contact with a proton acceptor.

11 . The process of claim 10 , wherein the compound of Formula (I) and the proton acceptor are present at a molar ratio of about 1:0.01 to about 1:2.

12 . The process of claim 11 , wherein the compound of Formula (IX) is obtained with a diastereomeric excess of at least about 70%.

13 . The process of claim 1 , wherein the compound of Formula (IX) and the compound of Formula (X) are present at a molar ratio of about 1:0.5 to about 1:60; and step (b) is conducted at a temperature of about 0° C. to about 80° C.

14 . The process of claim 13 , further comprising contact with a reducing agent.

15 . The process of claim 14 , wherein the compound of Formula (IX) and the reducing agent are present at a weight ratio of about 1:0.3 to about 1:5.

16 . The process of claim 1 , wherein the O-dealkylating agent and the compound of Formula (V) are present at weight ratio of about 1:1 to about 400:1; and step (c) is conducted at a temperature of about 50° C. to about 200° C.

17 . The process of claim 1 , wherein the compound of Formula (I) is m-methoxyphenylboronic acid, 3-methoxyphenyl trifluoroborate, 3-methoxyphenylboronic acid pinacol ester, 3-methoxyphenylboronic ester, or is derived from 3-methoxyphenylboroxine; the compound of Formula (VIII) is trans-2-methyl-2-pentenal; the transition metal catalyst is [RhCl(C 2 H 4 ) 2 ] 2 ; the chiral ligand is (1S,4S)-2,5-diphenylbicyclo[2,2,2]octa-2,5-diene; the compound of Formula (X) is dimethylamine; the O-dealkylating agent is a hydrogen halide; and the compound of Formula (VI) is 3-[(1R,2R)-3-(dimethyamino)-1-ethyl-2-methylpropyl]phenol.

18 . The process of claim 17 , wherein step (a) further comprises contact with an amine and, optionally, a proton acceptor; the amine being 4-methyl morpholine.

19 . The process of claim 18 , wherein the compound of Formula (I), the compound of Formula (VII), the transition metal catalyst, the chiral ligand, the amine, and the optional proton acceptor are present at a molar ratio of 1:1.15:0.007:0.4:0.2; step (a) is conducted at a temperature of about 23° C. and under nitrogen; the compound of Formula (IX) and the compound of Formula (X) are present at a molar ratio of about 1:1; step (b) is conducted in the presence of a reducing agent, at a temperate of about 23° C., and under nitrogen; the O-dealkylating agent and the compound of Formula (V) are present at a weight ratio of about 26:1; and step (c) is conducted at a temperature of about 110° C. and under nitrogen.

20 . The process of claim 19 , wherein the compound of Formula (VI) has a yield of at least about 30%.

Assignees

• Mallinckrodt Llc

Inventors

• Liao Subo
• Mcclurg Joseph
• Trawick Bobby

Classifications

• C07C45/68

  by increase in the number of carbon atoms · CPC title

• C07C45/69

  by addition to carbon-to-carbon double or triple bonds · CPC title

• C07B2200/07

  Optical isomers · CPC title

• C07C213/08 Primary

  by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups · CPC title

• C07C45/62

  by hydrogenation of carbon-to-carbon double or triple bonds · CPC title