Preparation of optionally substituted dihydroisoquinolines

Patent metadata

Field	Value
Publication number	US-11958810-B2
Application number	US-201916960578-A
Country	US
Kind code	B2
Filing date	Jan 14, 2019
Priority date	Jan 23, 2018
Publication date	Apr 16, 2024
Grant date	Apr 16, 2024

Abstract

Preparation of optionally substituted dihydroisoquinolines. The present invention relates to a process for the preparation of optionally substituted dihydroi-soquinolines of the formula I.

First claim

The invention claimed is:

1. A process for preparing a compound of formula I,

wherein
R 3 , R 4 are independently selected from C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 1 -C 6 -halogenalkyl, C 2 -C 6 -halogenalkenyl and C 2 -C 6 -halogenalkynl;
R 78 is independently selected from halogen, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -halogenalkyl and C 1 -C 6 -halogenalkoxy;
o is 0, 1, 2 or 3;
Y is selected from C 1 -C 6 -alkyl, C 1 -C 6 -halogenalkyl, phenyl and benzyl, wherein phenyl and benzyl are unsubstituted or substituted by CN, NO 2 , halogen, C 1 -C 6 -halogenalkyl or C 1 -C 6 -alkoxy.
comprising one step reaction of a compound of the formula II

wherein R 3 , R 4 , o and R 78 are as defined above with a compound of formula III

wherein Y is as defined above.

2. The process as claimed in claim 1 , wherein the reaction is carried out in the presence of sulphuric acid.

3. The process as claimed in claim 1 , further comprising reacting the compound of formula I with a brominating agent to provide a compound of formula IV,

wherein
R 3 , R 4 are independently selected from C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 1 -C 6 -halogenalkyl, C 2 -C 6 -halogenalkenyl and C 2 -C 6 -halogenalkynyl;
R 78 is independently selected from halogen, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -halogenalkyl and C 1 -C 6 -halogenalkoxy;
o is 0, 1, 2 or 3;
Y is selected from C 1 -C 6 -alkyl, C 1 -C 6 -halogenalkyl, phenyl and benzyl, wherein phenyl and benzyl are unsubstituted or substituted by CN, NO 2 , halogen, C 1 -C 6 -halogenalkyl or C 1 -C 6 -alkoxy.

4. The process according to claim 3 , wherein the brominating agent is selected from the group consisting of N-bromosuccinimide (NBS), 1,3-dibromo-5,5-dimethylhydantoin (DBDMH), and a system consisting of HBr/H 2 O 2 .

5. The process according to claim 3 , wherein the brominating agent is N-bromosuccinimide (NBS).

6. The process according to claim 3 , wherein the brominating agent is 1,3-dibromo-5,5-dimethylhydantoin (DBDMH).

7. The process according to claim 3 further comprising reacting the compound of formula IV with a fluorinating agent to provide a compound of formula V,

wherein
R 3 , R 4 are independently selected from C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 1 -C 6 -halogenalkyl, C 2 -C 6 -halogenalkenyl and C 2 -C 6 -halogenalkynyl;
R 78 is independently selected from halogen, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -halogenalkyl and C 1 -C 6 -halogenalkoxy;
o is 0, 1, 2 or 3;
Y is selected from C 1 -C 6 -alkyl, C 1 -C 6 -halogenalkyl, phenyl and benzyl, wherein phenyl and benzyl are unsubstituted or substituted by CN, NO 2 , halogen, C 1 -C 6 -alkyl, C 1 -C 6 -halogenalkyl or C 1 -C 6 -alkoxy.

8. The process according to claim 7 , wherein the fluorinating agent is selected from the group consisting of NaF, CsF, KF, KHF 2 , Olah reagent, HF, a polyhydrofluoride complex of a trialkylamine and mixtures of HF in trialkylamines.

9. The process according to claim 7 further comprising reacting a compound of formula V with a metal hydroxide to provide a compound of formula VI,

wherein
R 3 , R 4 are independently selected from C 1 -C 6 -alkyl, C 1 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 1 -C 6 -halogenalkyl, C 2 -C 6 -halogenalkenyl and C 2 -C 6 -halogenalkynyl;
R 78 is independently selected from halogen, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -halogenalkyl and C 1 -C 6 -halogenalkoxy;
o is 0, 1, 2 or 3;
X is a metal ion.

10. The process according to claim 9 , further comprising reacting the compound VI with a compound of formula VIII

in which R 1 , R 2 , R 9 and R 10 are as defined above to provide a 5-substituted pyridine compound of the formula VII

wherein
R 1 is in each case independently selected from hydrogen, halogen, C 1 -C 6 -alkyl and C 1 -C 6 -halogenalkyl;
R 2 is in each case independently selected from hydrogen, halogen, C 1 -C 6 -alkyl and C 1 -C 6 -halogenalkyl;
R 3 , R 4 are independently selected from C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 1 -C 6 -halogenalkyl, C 2 -C 6 -halogenalkenyl and C 2 -C 6 -halogenalkynyl;
o is 0, 1, 2 or 3;
R 78 are independently selected from halogen, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -halogenalkyl and C 1 -C 6 -halogenalkoxy;
R 9 is in each case independently selected from CH 3 , CH 2 F and CHF 2 ;
R 10 is in each case independently selected from H, halogen, O (R 95 ), C 1 -C 6 -alkyl and C 1 -C 6 -halogenalkyl; wherein
R 95 is C 1 -C 6 -alkyl, C 1 -C 6 -halogenalkyl.

Assignees

• Basf Se

Inventors

• Mueller Bernd
• Rack Michael
• Seet Michael
• Escribano Cuesta Ana
• Lohmann Jan Klaas
• Rudolf Georg Christoph
• Nett Markus
• Hoffmann Rainer

Classifications

• C07D401/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D217/26 Primary

  Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen · CPC title