Preparation of piperidine derivatives
AssigneeMallinckrodt Chemical, Inc.
InventorJacob Mathew
Life of this patent
Estimating the term…
Abstract
A piperidine derivative such as sufentanil is formed in a process which includes the step of condensing a piperidone with a primary amine so as to form a 4-amino-4-carboxyamino-piperidine.
Claims37
A process for preparing a piperidine derivative which comprises, condensing a piperidone with a primary amine so as to form a 4-amino-4-carboxyamino-piperidine, wherein N of said piperidone and N of the piperidine portion of said 4-amino-4-carboxyamino-piperidine is a --N--COO--(CH.sub.2).sub.n CH.sub.3, wherein n is an integer of from 0 to about 10, further including the step of hydrolyzing said --COO--(CH.sub.2).sub.n CH.sub.3 group of said 4-amino-4-carboxyamino-piperidine following the condensation reaction so as to form a piperidine hydrolysis product, wherein said piperidine hydrolysis product is condensed with a mesylate (methanesulfonyl) of the formula R--(CH.sub.2).sub.m --O--Ms, wherein R is phenyl, thienyl or 4-ethyl-4,5-dihydro-5-oxo-1H-tetrazol-1-yl, m is an integer of from 1 to about 10 and Ms is methanesulfonyl, so as to form an N-substituted R--(CH.sub.2).sub.m -piperidine product.
A process for preparing a piperidine derivative which comprises condensing a 4-amino-4-carboxyamino-piperidine with a mesylate (methanesulfonyl) of the formula R--(CH.sub.2).sub.m --O--Ms, wherein R is phenyl, thienyl or 4-ethyl-4,5-dihydro-5-oxo-1H-tetrazol-1-yl, m is an integer of from 1 to about 10 and Ms is methanesulfonyl, so as to form an N-substituted R--(CH.sub.2).sub.m -piperidine product.
A process for preparing a piperidine derivative which comprises,
- a) condensing 1-carbethoxy-4-piperidone with a primary amine so as to form 1-(carbethoxy)-4-(phenylamino)-4-piperidinecarboxanilide;
- b) hydrolyzing said 1-(carbethoxy)-4-(phenylamino)-4-piperidinecarboxanilide as to form 4-(phenylamino)-4-piperidinecarboxanilide;
- c) condensing said 4-(phenylamino)-4-piperidinecarboxanilide with a mesylate (methanesulfonyl) of the formula R--(CH.sub.2).sub.m --O--Ms wherein R is phenyl, thienyl or 4-ethyl-4,5-dihydro-5-oxo-1H-tetrazol-1-yl, m is an integer of from 1 to about 10 and Ms is methanesulfonyl, so as to form an N-substituted R--(CH.sub.2).sub.m -piperidine product;
- d) alkylating said R--(CH.sub.2).sub.m -piperidine product so as to form a tertiary amide;
- e) reducing said tertiary amide so as to form an alcohol, wherein said alcohol is N-(2-thien-2-ylethyl)-4-(phenylamino)-4-(hydroxymethyl)piperidine;
- f) alkylating said alcohol so as to form an ether;
- g) reacting said ether with CH.sub.3 CH.sub.2 COCl so as to form sufentanil;
- and
- h) converting said sufentanil to a citrate salt of sufentanil.
A process for preparing a piperidine derivative which comprises, condensing a piperidone with a primary amine so as to form a 4-amino-4-carboxyamino-piperidine, wherein N of said piperidone and N of the piperidine portion of said 4-amino-4-carboxyamino-piperidine includes a --COO--(CH.sub.2).sub.n CH.sub.3 substituent, wherein n is an integer of from 0 to about 10, wherein said condensing takes place in the presence of THF.
A compound of the formula ##STR16## wherein R.sub.1 is --CONHPh and R.sub.2 is H, R.sub.1 is --CONHPh and R.sub.2 is R--(CH.sub.2).sub.m --, R.sub.1 is --CONCH.sub.3 Ph and R.sub.2 is R--(CH.sub.2).sub.m --, R.sub.1 is --CH.sub.2 OH and R.sub.2 is R--(CH.sub.2).sub.m --, or R.sub.1 is --CH.sub.2 OCH.sub.3 and R.sub.2 is R--(CH.sub.2).sub.m --;
- and wherein Ph is phenyl, R is Ph, thienyl or 4-ethyl-4,5-dihydro-5-oxo-1H-tetrazol-1-yl and n is an integer of from 1 to about 10.
Dependencies are inferred from the claim text.