Aromatic ketones and processes for their preparation

• US 5,581,011 A
• Filed: 05/31/1995
• Issued: 12/03/1996
• Est. Priority Date: 06/24/1993
• Status: Expired due to Term

• Current Assignee: Albany Molecular Research Incorporated
• Original Assignee: Albany Molecular Research Incorporated
• Inventors: D'Ambra, Thomas E.
• Primary Examiner(s): Ivy, C. Warren
• Assistant Examiner(s): COVINGTON, RAYMOND K
• Application Number:
  US08/455,991
• Time in Patent Office: 552 Days
• Field of Search: 564/156, 564/157, 564/158, 562/450, 562/555, 560/8, 560/115, 560/159, 560/160
• US Class Current: 560/8
• CPC Class Codes: A61P 11/08 Bronchodilators
• CPC Class Codes: A61P 27/00 Drugs for disorders of the senses
• CPC Class Codes: A61P 27/14 Decongestants or antiallergics
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: C07C 59/86 containing six-membered aromatic rings and other rings
• CPC Class Codes: C07C 69/738 Esters of keto-carboxylic acids or aldehydo-carboxylic acids
• CPC Class Codes: C07D 211/20 with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
• CPC Class Codes: C07D 211/22 by oxygen atoms
• CPC Class Codes: C07D 211/32 by oxygen atoms

Abstract

The present invention relates to substantially pure piperidine derivative compounds of the formulae: ##STR1## wherein R₁ is hydrogen or hydroxy;

R₂ is hydrogen;

or R₂ and R₂ taken together form a second bond between the carbon atoms bearing R₁ and R₂ ;

R₃ is --COOH or --COOR₄ ;

R₄ has 1 to 6 carbon atoms;

A, B, and D are the substituents of their respective rings each of which may be different or the same and are hydrogen, halogens, alkyl, hydroxy, alkoxy, or other substituents.

A process of preparing such piperidine derivative compounds in substantially pure form is also disclosed.

Claims

1. A compound of the formula:

##STR42## wherein R₃ is --COOH or --COOR₄ ;

R₄ is an alkyl with 1 to 6 carbon atoms;

A is the substituents of its ring, each of which may be different or the same, and are selected from the group consisting of hydrogen, halogens, alkyl, hydroxy or alkoxy.

2. A compound according to claim 1, wherein the compound is a substantially pure regioisomer.

4. A salt according to claim 2, wherein the salt is a substantially pure regioisomer.

3. A salt having the formula:

##STR43## wherein X⁺ is a Lewis acid;

A is the substituents of its ring, each of which may be different or the same, and are selected from the group consisting of hydrogen, halogens, alkyl, hydroxy or alkoxy.

5. A process of preparing a substantially pure regioisomer of the formula:

##STR44## wherein R₃ is --COOH or --COOR₄ ;

R₄ is an alkyl with 1 to 6 carbon atoms;

A is the substituents of its ring, each of which may be different or the same, and are selected from the group consisting of hydrogen, halogens, alkyl, hydroxy or alkoxy

said process comprising;

providing a second mixture of regioisomers of the formula;

##STR45## recovering from the second mixture of regioisomers the substantially pure regioisomer.

6. A process according to claim 5, wherein said recovering comprises:

crystallizing from the second mixture of regioisomers a substantially pure regioisomer salt of the formula;

##STR46## wherein X⁺ is a Lewis acid;

isolating the substantially pure regioisomer salt; and

converting the substantially pure regioisomer salt to the substantially pure regioisomer of the formula;

##STR47##

7. A process according to claim 5, wherein X⁺ is an alkali metal salt or an ammonium salt of the form NR₇ R₈ R₉ wherein R₇, R₈, and R₉ are individually hydrogen or a straight or branched alkyl of 1 to 6 carbon atoms, or an alkyl substituted at any position with a phenyl ring or a substituted phenyl ring.

8. A process according to claim 7, wherein X⁺ is cinchonidine and A is hydrogen.

9. A process according to claim 5, wherein said providing the second mixture of regioisomers comprises:

acylating a starting compound of the formula;

##STR48## wherein R₅ is --OR₆, --N(R₆)₂, and --SR₆, and

R₆ is an alkyl with 1 to 6 carbons,

with a compound of the formula;

##STR49## wherein X is a halogen,

under conditions effective to produce a first mixture of regioisomers of the formula;

##STR50## hydrolyzing the first mixture of regioisomers under conditions effective to form the second mixture of regioisomers of the formula;

##STR51##

10. A process according to claim 9, wherein said acylating is carried out by a Friedel-Crafts reaction using an AlCl₃ catalyst.

11. A process according to claim 5, wherein said providing the second mixture of regioisomers comprises

acylating a starting compound of the formula:

##STR52## wherein R₅ is --OR₆, --N(R₆)₂, and --SR₆, and

R₆ is an alkyl with 1 to 6 carbon atoms with a compound of the formula;

##STR53## under conditions effective to produce a first mixture of regioisomers of the formula;

##STR54## hydrolyzing the first mixture of regioisomers under conditions effective to form a second mixture of regioisomers of the formula;

##STR55##

12. A process according to claim 11, wherein said recovering comprises:

crystallizing from the second mixture of regioisomers a substantially pure regioisomer salt of the formula;

##STR56## wherein X⁺ is a Lewis acid;

isolating the substantially pure regioisomer salt; and

converting the substantially pure regioisomer salt to the substantially pure regioisomer of the formula;

##STR57##

13. A process according to claim 12, wherein X⁺ is an alkali metal salt or an ammonium salt of the form NR₇ R₈ R₉ wherein R₇, R₈, and R₉ are individually hydrogen or a straight or branched alkyl of 1 to 6 carbon atoms, or an alkyl substituted at any position with a phenyl ring or a substituted phenyl ring.

14. A process according to claim 13, wherein X⁺ is cinchonidine and A is hydrogen.

15. A process of preparing a second substantially pure regioisomer of the formula:

##STR58## wherein X is a halogen;

R₃ is a --COOH or --COOR₄ ;

R₄ is an alkyl with 1 to 6 carbon atoms;

A is the substituents of its ring, each of which may be different or the same, and are selected from the group consisting of hydrogen, halogens, alkyl, hydroxy or alkoxy

said process comprising;

providing a first substantially pure regioisomer of the formula;

##STR59## and halogenating the first substantially pure regioisomer under conditions effective to form the second substantially pure regioisomer.

16. A process of preparing a substantially pure regioisomer of the formula:

##STR60## wherein R₃ is --COOH or --COOR₄

R₄ is an alkyl with 1 to 6 carbon atoms;

A is the substituents of its ring, each of which may be different or the same, and are selected from the group consisting of hydrogen, halogens, alkyl, hydroxyl or alkoxy

said process comprising;

acylating a starting compound of the formula;

##STR61## with a compound of the formula;

##STR62## wherein X₁ is a halogen, trialkyl tin, triflate, or substituents useful in organometalic coupling reactions under conditions effective to produce the substantially pure regioisomer.