Process for the preparation of exo-tert-butyl N-(3-azabicyclo[3.2.1]octan-8-yl)carbamate

Patent metadata

Field	Value
Publication number	US-12275709-B2
Application number	US-201917418480-A
Country	US
Kind code	B2
Filing date	Dec 24, 2019
Priority date	Dec 27, 2018
Publication date	Apr 15, 2025
Grant date	Apr 15, 2025

Abstract

The present invention relates to a process for the preparation of a compound (I) or pharmaceutically acceptable salt thereof, which is useful as the key intermediate for the synthesis of compounds for prophylaxis and treatment of a disease associated with the deposition of β-amyloid in the brain, in particular Alzheimer's disease, and other diseases such as cerebral amyloid angiopathy, hereditary cerebral hemorrhage with amyloidosis, Dutch-type (HCHWA-D), multi-infarct dementia, dementia pugilistica and Down syndrome.

First claim

The invention claimed is:

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

or a pharmaceutically acceptable salt thereof, the process consisting of:
a) the imine formation of compound (III),

via reaction of compound (II),

and hydroxylamine hydrochloride;
b) formation of compound (IV),

via reduction reaction from compound (III);
c) salt formation of compound (V),

from compound (VI) and Acid, wherein Acid is selected from:
D-glutamic acid, (R)-(−)-mandelic acid, 1-hydroxy-2-naphthoic acid, citric acid, 4-aminosalicylic acid, L-tartaric acid, hippuric acid, malonic acid, glutaric acid, oxalic acid, fumaric acid, succinic acid, 4-aminobenzoic acid, 2,5-dihydroxybenzoic acid, L-malic acid, salicylic acid, maleic acid, (1S,3R)-(−)-camphoric acid, pamoic acid, mucic acid, palmitic acid, oleic acid and lactobionic acid;
d) formation of compound (VI),

via dissociation and boc-protection of compound (V); and
e) formation of compound (I),

via de-protection of compound (VI).

2. The process of claim 1 , characterized in that the formation of the compound (IV) in b) is performed in the presence of a reducing reagent at 0° C.-70° C., wherein the reducing reagent is selected from Na, Pd/c and Raney-Ni.

3. The process according to claim 1 , characterized in that Acid used in c) is (R)-(−)-Mandelic acid, and the amount of (R)-(−)-Mandelic acid used in c) is 0.1-2.0 eq.

4. The process according to claim 1 , characterized in that the compound (VI) synthesized in d) is purified through recrystallization, which was performed in a solvent, wherein the solvent is selected from n-heptane, hexane and petroleum ether.

5. The process according to claim 1 , characterized in that the de-protection reaction in e) is performed at 20° C.-100° C.

6. A process for preparing a compound of formula (I),

or a pharmaceutically acceptable salt thereof, the process comprising:
salt formation of compound (V),

from compound (VI),

and Acid,
wherein the Acid is selected from: D-glutamic acid, (R)-(−)-mandelic acid, 1-hydroxy-2-naphthoic acid, citric acid, 4-aminosalicylic acid, L-tartaric acid, hippuric acid, malonic acid, glutaric acid, oxalic acid, fumaric acid, succinic acid, 4-aminobenzoic acid, 2,5-dihydroxybenzoic acid, L-malic acid, salicylic acid, maleic acid, (1S,3R)-(−)-camphoric acid, pamoic acid, mucic acid, palmitic acid, oleic acid and lactobionic acid.

7. The compound of formula (V),

wherein Acid is selected from: D-glutamic acid, (R)-(−)-mandelic acid, 1-hydroxy-2-naphthoic acid, citric acid, 4-aminosalicylic acid, L-tartaric acid, hippuric acid, malonic acid, glutaric acid, oxalic acid, fumaric acid, succinic acid, 4-aminobenzoic acid, 2,5-dihydroxy-benzoic acid, L-malic acid, salicylic acid, maleic acid, (1S,3R)-(−)-camphoric acid, pamoic acid, mucic acid, palmitic acid, oleic acid, and lactobionic acid.

8. A compound which is an adduct of exo-3-Benzyl-3-azabicyclo[3.2.1]octan-8-amine and (R)-(−)-mandelic acid, having formula Va

9. The process of claim 1 , wherein Acid is (R)-(−)-mandelic acid.

10. The process of claim 2 , wherein the formation of the compound (IV) is performed in the presence of Raney-Ni at 20° C.-30° C.

11. The process of claim 3 , wherein the amount of (R)-(−)-mandelic acid used in c) is 0.6 eq.

12. The process of claim 4 , wherein the solvent is n-heptane.

13. The process of claim 5 , wherein the de-protection reaction in e) is performed at 65° C.-75° C.

14. The process of claim 6 , wherein the acid is (R)-(−)-mandelic acid.

Assignees

• Hoffmann La Roche

Inventors

• Chen Weichun
• Zhang Guocai

Classifications

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• A61K31/439

  the ring forming part of a bridged ring system, e.g. quinuclidine (8-azabicyclo [3.2.1] octanes A61K31/46) · CPC title

• C07B57/00

  Separation of optically-active compounds · CPC title

• C07D221/22 Primary

  Bridged ring systems · CPC title