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Details for Patent: 5,589,487

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Details for Patent: 5,589,487

Title: Piperidine derivatives and process for their production
Abstract:The present invention relates to substantially pure piperidine derivative compounds of the formulae: ##STR1## wherein R.sub.1 is hydrogen or hydroxy; R.sub.2 is hydrogen; or R.sub.1 and R.sub.2 taken together form a second bond between the carbon atoms bearing R.sub.1 and R.sub.2 ; R.sub.3 is --COOH or --COOR.sub.4 ; R.sub.4 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.
Inventor(s): D'Ambra; Thomas E. (Wynantskill, NY)
Assignee: Albany Molecular Research, Inc. (Albany, NY)
Filing Date:Feb 02, 1995
Application Number:08/382,425
Claims:1. A process of preparing a piperidine derivative compound of the formula: ##STR42## wherein R.sub.1 is hydrogen or hydroxy;

R.sub.2 is hydrogen;

or R.sub.1 and R.sub.2 taken together form a second bond between the carbon atoms bearing R.sub.1 and R.sub.2 ;

R.sub.3 is --COOH or --COOR.sub.4 ;

R.sub.4 has 1 to 6 carbon atoms;

A, B, and D are the substituents of their aromatic rings, 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:

acylating a starting compound of the formula: ##STR43## with a compound of the formula: ##STR44## wherein X.sub.1 is a halogen, trialkyl tin, triflate, or substituents useful in a organometallic coupling reactions

under conditions effective to produce the substantially pure regioisomer of the formula: ##STR45## and converting the substantially pure regioisomer to the piperidine derivative compound with a piperidine compound of the formula: ##STR46##

2. A process according to claim 1 further comprising:

reducing the piperidine derivative under conditions effective to form a hydroxylated piperidine derivative of the formula: ##STR47##

3. A process according to claim 2, wherein the hydroxylated piperidine derivative has the formula: ##STR48##

4. A process according to claim 2, wherein the hydroxylated piperidine derivative has the formula: ##STR49##

5. A process according to claim 1, wherein said converting comprises:

halogenating the substantially pure regioisomer of the following formula: ##STR50## under conditions effective to form a first intermediate compound of the formula: ##STR51## wherein X is a halogen and

reacting the first intermediate compound with a piperidine compound of the formula: ##STR52## under conditions effective to form the piperidine derivative of the following formula: ##STR53##

6. A process according to claim 1, wherein said converting comprises:

reacting the substantially pure regioisomer of the following formula: ##STR54## with a piperidine compound of the formula: ##STR55## under conditions effective to form the piperidine derivative of the formula: ##STR56##

7. A process according to claim 1, wherein the piperidine derivative has the formula: ##STR57##

8. A process according to claim 1, wherein the piperidine derivative has the formula: ##STR58##

9. A process of preparing a piperidine derivative compound of the formula: ##STR59## wherein R.sub.1 is hydrogen or hydroxy;

R.sub.2 is hydrogen;

or R.sub.1 and R.sub.2 taken together form a second bond between the carbon atoms bearing R.sub.1 and R.sub.2 ;

R.sub.3 is --COOH or --COOR.sub.4 ;

R.sub.4 has 1 to 6 carbon atoms;

A, B, and D are the substituents of their aromatic rings, 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:

acylating a starting compound of the formula: ##STR60## wherein R.sub.5 is --OR.sub.6, --N(R.sub.6).sub.2, and --SR.sub.6, and

R.sub.6 is an alkyl with 1 to 6 carbon atoms

with a compound of the formula: ##STR61## under conditions effective to produce a first mixture of regioisomers of the formula: ##STR62## hydrolyzing the first mixture of regioisomers under conditions effective to form a second mixture of regioisomers of the formula: ##STR63## recovering from the second mixture of regioisomers the substantially pure regioisomer of the following formula: ##STR64## and converting the substantially pure regioisomer to the piperidine derivative compound with a piperidine compound of the formula: ##STR65##

10. A process according to claim 9, wherein said recovering comprises:

crystallizing a substantially pure regioisomer salt of the formula: ##STR66## wherein X.sup.+ is a Lewis Acid from the second mixture of regioisomers;

isolating the substantially pure regioisomer salt; and

converting the substantially pure regioisomer salt to the substantially pure regioisomer of the formula: ##STR67##

11. A process according to claim 10, wherein X.sup.+ is an alkali metal salt or an ammonium salt of the form NR.sub.7 R.sub.8 R.sub.9, wherein R.sub.7, R.sub.8, and R.sub.9 is 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.

12. A process according to claim 11 wherein X.sup.+ is cinchonidine and A is hydrogen.

13. A process according to claim 9, wherein said acylating is carried out with a catalyst containing palladium, nickel, or mixtures thereof.

14. A process according to claim 9 further comprising:

reducing the piperidine derivative under conditions effective to form a hydroxylated piperidine derivative of the formula: ##STR68##

15. A process according to claim 14, wherein the hydroxylated piperidine derivative has the formula: ##STR69##

16. A process according to claim 14, wherein the hydroxylated piperidine derivative has the formula: ##STR70##

17. A process according to claim 9, wherein said converting comprises:

halogenating the substantially pure regioisomer of the following formula: ##STR71## under conditions effective to form a first intermediate compound of the formula: ##STR72## wherein X is a halogen and

reacting the first intermediate compound with a piperidine compound of the formula: ##STR73## under conditions effective to form the piperidine derivative of the following formula: ##STR74##

18. A process according to claim 9, wherein said converting comprises:

reacting the substantially pure regioisomer of the following formula: ##STR75## with a piperidine compound of the formula: ##STR76## under conditions effective to form the piperidine derivative of the formula: ##STR77##

19. A process according to claim 9, wherein the piperidine derivative has the formula: ##STR78##

20. A process according to claim 9, wherein the piperidine derivative has the formula: ##STR79##
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