Process for preparing an intermediate to opioid receptor antagonists
AssigneeTheravance, Inc.
InventorsPierre-Jean Colson, Ying Yu, Daniel D. Long, Ioanna Stergiades
Life of this patent
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Abstract
The invention provides an efficient method for preparing 3-endo-(8-azabicyclo[3.2.1]oct-3-yl)benzamide by hydrogenation, under controlled conditions, of an amino-protected 3-(8-azabicyclo[3.2.1 ]oct-2-en-3-yl)benzamide intermediate in which the amino-protecting group is removable by catalytic hydrogenation.
Claims23
A process for preparing a compound of formula 1, having the chemical name 3-endo-(8-azabicyclo[3.2.1]oct-3-yl)benzamide, or a salt thereof:
- the process comprising:
- (a) purging a reaction vessel comprising a compound of formula 3:
- and an acid with a non-reactive gas, wherein P1 is an amino-protecting group removable by catalytic hydrogenation,
- (b) adding a palladium metal catalyst to the reaction vessel;
- (c) purging the reaction vessel with hydrogen;
- and
- (d) supplying hydrogen gas to the reaction vessel at a pressure of less than about a half atmosphere such that the total pressure in the reaction vessel is less than about one and a half atmospheres to provide a compound of formula 1 or a salt thereof.
A process for preparing a compound of formula 1, having the chemical name 3-endo-(8-azabicyclo[3.2.1]oct-3-yl)benzamide, or a salt thereof:
- the process comprising:
- (a) contacting a compound of formula 5
- wherein P1 is an amino-protecting group removable by catalytic hydrogenation and —ORx represents a sulfonate leaving group, with a compound of formula 4:
- in the presence of a palladium catalyst and a phosphine ligand to provide a compound of formula 3:
- (b) purging a reaction vessel comprising a compound of formula 3 and an acid with a non-reactive gas;
- (c) adding a palladium metal catalyst to the reaction vessel;
- (d) purging the reaction vessel with hydrogen;
- and
- (e) supplying hydrogen gas to the reaction vessel at a pressure of less than about a half atmosphere such that the total pressure in the reaction vessel is less than about one and a half atmospheres to provide a compound of formula 1 or a salt thereof.
A process for preparing a compound of formula 1, having the chemical name 3-endo-(8-azabicyclo[3.2.1]oct-3-yl)benzamide, or a salt thereof:
- the process comprising hydrogenating a compound of formula 2, having the chemical name 3-(8-azabicyclo[3.2.1]oct-2-en-3-yl)benzamide:
- or an acid salt thereof, in the presence of a palladium metal catalyst, and, when the compound of formula 2 is in the form of a free base, in the presence of an acid, to provide a compound of formula 1 or a salt thereof.
A process for preparing a compound of formula 3:
- wherein P1 is an amino-protecting group, the process comprising:
- (a) contacting a compound of formula 5
- wherein —ORx represents a sulfonate leaving group, with a compound of formula 4:
- in the presence of a palladium catalyst and a phosphine ligand to provide a compound of formula 3.
A compound of formula 2
- having the chemical name 3-(8-azabicyclo[3.2.1]oct-2-en-3-yl)benzamide.
A compound of formula 3:
- wherein P1 is an amino-protecting group.
A compound of formula 5:
- wherein P1 is benzyl and —ORx is a sulfonate leaving group.
A method of increasing the stereospecificity for the endo orientation of a sample of 3-endo-(8-azabicyclo[3.2.1]oct-3-yl)benzamide, the sample comprising more than about 10% 3-exo-(8-azabicyclo[3.2.1]oct-3-yl)benzamide, wherein 3-endo-(8-azabicyclo[3.2.1]oct-3-yl)benzamide and 3-exo-(8-azabicyclo[3.2.1]oct-3-yl)benzamide are in salt form, the process comprising:
- (a) heating a mixture of the sample of 3-endo-(8-azabicyclo[3.2.1]oct-3-yl)benzamide and an alcohol until complete dissolution is observed to provide a reaction solution;
- (b) cooling the reaction solution, adding seed crystals of 3-endo-(8-azabicyclo[3.2.1]oct-3-yl)benzamide, and stirring until a precipitate is observed;
- and
- (c) adding 2-methyl tetrahydrofuran to the reaction solution and stirring until precipitation is substantially complete to provide 3-endo-(8-azabicyclo[3.2.1]oct-3-yl)benzamide comprising less than about 2% 3-exo-(8-azabicyclo[3.2.1]oct-3-yl)benzamide.
Dependencies are inferred from the claim text.