Synthesis of bicyclo[2.2.2]octane derivatives

Patent metadata

Field	Value
Publication number	US-11518726-B2
Application number	US-201816754206-A
Country	US
Kind code	B2
Filing date	Oct 10, 2018
Priority date	Oct 11, 2017
Publication date	Dec 6, 2022
Grant date	Dec 6, 2022

Abstract

Provided is a process for the preparation of certain 1,4-bicyclo[2.2.2]octane derivatives. The new synthetic procedure involves treating 1,4-dimethylene cyclohexane with an oxidizing agent in the presence of a transition metal catalyst to afford an oxo-substituted bicyclo[2.2.2]octane species. This intermediate structure can then be further derivatized. The processes of this disclosure thus affords a novel and simplified means for the commercial production of a wide variety of bicyclo[2.2.2]octane derivatives.

First claim

We claim:

1. A process comprising contacting a compound of the formula

with (i) a transition metal catalyst comprising a palladium compound and (ii) an oxidizing agent;
optionally in the presence of at least one of
(I) a compound of the formula

wherein R is chosen from hydrogen; and C 1 -C 12 alkyl, optionally substituted by one or more of groups chosen from C 1 -C 6 alkoxy, halo, nitro, and cyano;
and wherein R* is chosen from hydrogen; C 1 -C 12 alkyl, optionally substituted by one or more of groups chosen from C 1 -C 6 alkoxy, halo, nitro, and cyano; and an alkali metal cation;
or
(II) a compound having at least one C 1 -C 12 alkanoyloxy moiety of the formula

wherein R is chosen from C 1 -C 12 alkyl, optionally substituted by one or more of groups chosen from C 1 -C 6 alkoxy, halo, nitro, and cyano;
to afford a compound of the formula

wherein each R 1 is independently hydrogen or a group of the formula

wherein R is C 1 -C 12 alkyl, optionally substituted by one or more of groups chosen from C 1 -C 6 alkoxy, halo, nitro, and cyano;
further comprising a step chosen from (a), (b), or (c):
(a) the step of reaction with carbon monoxide in the presence of a strong acid, followed by quenching with at least one of (i) water or (ii) an alcohol of the formula R—OH, to afford compounds of the formula

wherein R is chosen from hydrogen; and C 1 -C 12 alkyl, optionally substituted by one or more of groups chosen from C 1 -C 6 alkoxy, halo, nitro, and cyano;
optionally further comprising the step of:
contacting with hydrogen in the presence of a heterogeneous copper hydrogenation catalyst or a homogeneous hydrogenation catalyst to afford a compound of the formula

optionally followed by reductive amination to afford a compound of the formula

(b) the step of conversion to a compound of the formula:

which comprises reaction of (I) with a nitrile in the presence of an acid followed by hydrolysis to the corresponding amine;
optionally further comprising treatment of said corresponding amine with phosgene (COCl 2 ) to afford a compound of the formula:

 or
(c) the step of halogenation of (I) to afford a compound of the formula:

wherein X is halo;
optionally further comprising a step chosen from:
a. reaction with carbon monoxide in the presence of a strong acid, followed by quenching with at least one of (i) water or (ii) an alcohol of the formula R—OH, to afford compounds of the formula

wherein R is chosen from hydrogen; and C 1 -C 12 alkyl, optionally substituted by one or more of groups chosen from C 1 -C 6 alkoxy, halo, nitro, and cyano;

b. amination via treatment with ammonia to afford a compound of the formula:

 or
b. hydroformylation via treatment with carbon monoxide and hydrogen in the presence of at least one of a cobalt or ruthenium catalyst at a temperature of about 90 to 250° C. and a pressure of about 5 to 300 bar, to afford a compound of the formula:

optionally further comprising:
a. treatment with an oxidizing agent, optionally in the presence of a homogeneous and/or heterogeneous catalyst to afford a compound of the formula:

 or
b. hydrogenation in the presence of a homogeneous and/or heterogeneous catalyst to afford a compound of the formula:

2. The process of claim 1 , represented by step (a).

3. The process of claim 2 , further comprising contacting with hydrogen in the presence of a heterogeneous copper hydrogenation catalyst or a homogeneous hydrogenation catalyst to afford a compound of the formula

4. The process of claim 3 , further comprising reductive amination to afford a compound of the formula

5. The process of claim 2 , further comprising one of the following steps:
(i) formation of an ammonium salt, followed by the application of heat;
(ii) formation of an acid halide, followed by treatment with ammonia; or
(ii) formation of an anhydride, followed by treatment with ammonia;
to afford a compound of the formula

6. The process of claim 5 , further comprising hydrogenation in the presence of a catalyst, to afford a compound of the formula

7. The process of claim 1 , represented by step (b).

8. The process of claim 7 , further comprising treatment of the corresponding amine with phosgene (COCl 2 ) to afford a compound of the formula:

9. The process of claim 1 , represented by step (c).

10. The process of claim 9 , further comprising reaction with carbon monoxide in the presence of a strong acid, followed by quenching with at least one of (i) water or (ii) an alcohol of the formula R—OH, to afford compounds of the formula:

wherein R is chosen from hydrogen; and C 1 -C 12 alkyl, optionally substituted by one or more of groups chosen from C 1 -C 6 alkoxy, halo, nitro, and cyano.

11. The process of claim 9 , further comprising amination via treatment with ammonia to afford a compound of the formula:

12. The process of claim 9 , further comprising hydroformylation via treatment with carbon monoxide and hydrogen in the presence of a ruthenium catalyst at a temperature of about 90 to 250° C

Assignees

• Eastman Chem Co

Inventors

• Hu Yue Rachel
• Hembre Robert Thomas
• Tustin Gerald Charles
• Liu Zhufang
• Adams Steven J

Classifications

• C07C2602/44

  the bicyclo ring system containing eight carbon atoms · CPC title

• C07C263/10

  by reaction of amines with carbonyl halides, e.g. with phosgene · CPC title

• C07C215/20

  the carbon skeleton being saturated and containing rings · CPC title

• C07C211/19

  containing condensed ring systems · CPC title

• C07C29/60 Primary

  by elimination of -OH groups, e.g. by dehydration (C07C29/34 takes precedence) · CPC title