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US 6,605,723 B2Granted
Process for the preparation of ethanesul fonyl-piperidine derivatives
AssigneeHoffman-La Roche Inc.
InventorsYvo Crameri, Michelangelo Scalone, Pius Waldmeier, Ulrich Widmer
Life of this patent
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Abstract
The present invention relates to a new process for the preparation of compounds of the formulae and their pharmaceutically acceptable acid addition salts, which are NMDA (N-methyl-D-aspartate)-receptor-subtype selective blockers.
Claims16
A process for the preparation of compounds of formulae
- wherein
- R1-R4 are, independently from each other, hydrogen, halogen, hydroxy, amino, nitro, lower-alkyl-sulfonylamido, or acetamido;
- R5-R8 are, independently from each, other hydrogen, lower-alkyl, halogen, trifluoromethyl or lower-alkoxy;
- and their pharmaceutically acceptable acid addition salts;
- which process comprises
- a) reacting a protected amino acid ester (1)
- with a 4-substituted butyric acid derivative (2)
- wherein
- R9 is an amino protecting group, preferably benzyl;
- R10 and R10′ are independently a carboxylic acid protecting group;
- and
- Y represents a leaving group;
- in the presence of a base to obtain the protected alkoxycarbonylmethyl amino butyric acid derivative (3);
- b) cyclising the protected alkoxycarbonylmethyl amino butyric acid derivative (3)
- wherein the symbols are as defined above to obtain the protected alkyl 3-oxo-piperidine carboxylate salt (4);
- c) benzylating the protected alkyl 3-oxo-piperidine carboxylate salt (4)
- wherein
- AZ signifies a mineral acid or a strong organic acid to obtain the benzylated protected alkyl 3-oxo-piperidine carboxylate (5);
- d) decarboxylating the benzylated protected alkyl 3-oxo-piperidine carboxylate (5)
- wherein the symbols are as defined above;
- in presence of a strong acid to obtain the salt of formula (6);
- e) asymmetrically hydrogenating the salt of formula (6)
- wherein R9 is an amino protecting group;
- in presence of a ruthenium complex with a chiral diphosphine ligand and a chiral diamine, wherein the diphosphine has an (S) configuration and the diamine has an (R,R) configuration or the diphosphine has an (R) configuration and the diamine has an (S,S) configuration, and an organic or inorganic base, to obtain the compound of formula (7a) or (7b);
- and deprotecting the compound of formula (7a) or (7b)
- wherein the symbols are as defined above;
- or
- deprotecting the compound of formula (6);
- and
- asymmetrically hydrogenating the salt of formula (6bis)
- in presence of a ruthenium complex with a chiral diphosphine ligand and a chiral diamine, wherein the diphosphine has an (S) configuration and the diamine has an (R,R) configuration or the diphosphine has an (R) configuration and the diamine has an (S,S) configuration, and a organic or an inorganic base,
- to obtain the piperidine derivative of formula III-a or III-b;
- and
- f) reacting the piperidine derivative of formula III-a or III-b
- wherein the symbols are as defined above;
- with the reactive vinyl sulfone intermediate
- which is obtained by treating the sulfone derivative of formula II
- wherein
- R1-R4 are as defined above;
- and
- X is a leaving group;
- with a base;
- in the presence of a base to form the desired compound of formula I-a or I-b.
40 more elements
A process for the preparation of compounds of formula
- wherein
- R1-R4 are, independently from each other, hydrogen, halogen, hydroxy, amino, nitro, lower-alkyl-sulfonylamido, or acetamido;
- R5-R8 are, independently from each other, hydrogen, lower-alkyl, halogen, trifluoromethyl or lower-alkoxy;
- R9 is an amino protecting group;
- AZ signifies a mineral acid or a strong organic acid;
- which process comprises
- a) reacting a protected amino acid ester (1)
- with a 4-substituted butyric acid derivative (2)
- wherein
- R9 is an amino protecting group, preferably benzyl;
- R10 and R10′ are independently a carboxylic acid protecting group;
- and
- Y represents a leaving group;
- in the presence of a base;
- to obtain the protected alkoxycarbonylmethylamino butyric acid derivative (3);
- b) cyclising the protected alkoxycarbonylmethyl amino butyric acid derivative (3)
- wherein the symbols are as defined above to obtain the protected alkyl-3-oxo-piperidine caboxylate salt (4);
- c) benzylating the protected alkyl 3-oxo-piperidine carboxylate salt(4)
- wherein
- AZ signifies a mineral acid or a strong organic acid to obtain the benzylated protected alkyl-3-oxo-piperidine carboxylate (5);
- d) decarboxylating the benzylated protected alkyl 3-oxo-piperidine carboxylate (5)
- wherein the symbols are as defined above;
- in presence of a strong acid to obtain the compound of formula (6);
- e) deprotecting compound of formula (6) to obtain compound of formula (6bis).
21 more elements
A process for the preparation of compounds of formula
- wherein
- R1-R4 are, independently from each other, hydrogen, halogen, hydroxy, amino, nitro, lower-alkyl-sulfonylamido, or acetamido;
- R5-R8 are, independently from each, other hydrogen, lower-alkyl, halogen, trifluoromethyl or lower-alkoxy;
- and their pharmaceutically acceptable acid addition salts, which process comprises asymmetrically hydrogenating a salt of formula (6)
- wherein R9 is an amino protecting group;
- in presence of a ruthenium complex with a chiral diphosphine ligand and a chiral diamine, wherein the diphosphine has an (S) configuration and the diamine has an (R,R) configuration or the diphosphine has an (R) configuration and the diamine has an (S,S) configuration, and an organic or inorganic base,
- to obtain the compound of formula (7a) or (7b);
- and deprotecting the compound of formula (7a) or (7b)
- wherein the symbols are as defined above;
- or
- deprotecting the compound of formula (6);
- and asymmetrically hydrogenating the salt of formula (6bis)
- in presence of a ruthenium complex with a chiral diphosphine ligand and a chiral diamine, wherein the diphosphine has an (S) configuration and the diamine has an (R,R) configuration or the diphosphine has an (R) configuration and the diamine has an (S,S) configuration, and an organic or inorganic base,
- to obtain the piperidine derivative of formula III-a or III-b.
11 more elements
Compounds of formula (6)
- wherein R5-R8 are, independently from each other, hydrogen, lower-alkyl, halogen, trifluoromethyl or lower-alkoxy, BY is an amino protecting group, and AZ is a mineral acid or a strong organic acid.
Compounds of formula (6 bis)
- wherein R5-R8 are, independently from each other, hydrogen, lower-alkyl, halogen, trifluoromethyl or lower-alkoxy and AZ is a mineral acid or a strong organic acid.
Dependencies are inferred from the claim text.