Piperidine derivatives and process for their production
View Patent ↗The present invention relates to substantially pure piperidine derivative compounds of the formulae: wherein R 1 is hydrogen or hydroxy; R 2 is hydrogen; or R 1 and R 2 taken together form a second bond between the carbon atoms bearing R 1 and R 2 ; R 3 is —COOH or —COOR 4 ; R 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.
1. A process of preparing a substantially pure regioisomer of the formula:
wherein
R 3 is —COOR 4 ;
R 4 is chosen from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, 5 carbon alkyl, and 6 carbon alkyl;
A is a substituent of its ring selected from the group consisting of hydrogen, halogens, alkyl, hydroxy or alkoxy,
said process comprising:
providing a mixture of regioisomers of the formula:
recovering from the mixture of regioisomers the substantially pure regioisomer of the formula:
esterifying the substantially pure regioisomer to yield:
2. A process according to claim 1 , wherein said providing the mixture of regiolsomers comprises:
acylating a starting compound of the formula:
wherein
R 5 is —OR 6 , —N(R 6 ) 2 , and —SR 6 , and
R 6 is an alkyl with 1 to 6 carbons,
with a compound of the formula:
wherein
X is a halogen,
under conditions effective to produce a mixture of regioisomers of the formula:
hydrolyzing the first mixture of regioisomers under conditions effective to form the second mixture of regioisomers of the formula:
3. A process according to claim 2 , wherein said acylating is carried out by a Friedel-Crafts reaction using an AlCl 3 catalyst.
4. A process according to claim 1 , wherein said providing the mixture of regioisomers comprises:
acylating a starting compound of the formula:
wherein
R 5 is —OR 6 , —N(R 6 ) 2 , and —SR 6 , and
R 6 is an alkyl with 1 to 6 carbon atoms,
with a compound of the formula:
under conditions effective to produce a first mixture of regioisomers of the formula:
hydrolyzing the first mixture of regioisomers under conditions effective to form a second mixture of regioisomers of the formula:
5. A process according to claim 1 , wherein said recovering comprises:
crystallizing from the second mixture of regioisomers a substantially pure regioisomer salt of the formula:
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:
6. A process according to claim 5 , wherein X + is an alkali metal salt or an ammonium salt of the form NR 7 , R 8 , R 9 wherein R 7 , R 8 , and R 9 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.
7. A process according to claim 6 , wherein X + is cinchonidine and A is hydrogen.
8. A process of preparing a substantially pure regioisomer of the formula:
wherein
R 3 is —COOR 4 ;
R 4 is chosen from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, 5 carbon alkyl, and 6 carbon alkyl;
A is a substituent of its ring selected from the group consisting of hydrogen, halogens, alkyl, hydroxy or alkoxy,
said process comprising:
acylating a starting compound of the formula:
wherein
R 5 is OR 6 , —N(R 6 ) 2 , and —SR 6 , and
R 6 is an alkyl with 1 to 6 carbons,
with a compound of the formula:
wherein
X is a halogen,
under conditions effective to produce a first mixture of regioisomers of the formula:
and
converting the first mixture of regioisomers to the substantially pure regioisomer of formula:
9. A process of preparing a substantially pure regioisomer of the formula:
wherein
R 3 is —COOR 4 ;
R 4 is chosen from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, 5 carbon alkyl, and 6 carbon alkyl;
A is a substituent of its ring selected from the group consisting of hydrogen, halogens, alkyl, hydroxy or alkoxy,
said process comprising:
acylating a starting compound of the formula:
wherein
R 5 is —OR 6 , —N(R 6 ) 2 , and —SR 6 , and
R 6 is an alkyl with 1 to 6 carbon atoms with a compound of the formula:
under conditions effective to produce a first mixture of regioisomers of the formula:
and
converting the first mixture of regioisomers to the substantially pure regioisomer of formula:
10. A process of preparing a substantially pure regioisomer of the formula:
wherein
R 3 is —COOR 4 ;
R 4 is chosen from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, 5 carbon alkyl, and 6 carbon alkyl;
A is a substituent of its ring selected from the group consisting of hydrogen, halogens, alkyl, hydroxy or alkoxy,
said process comprising:
acylating a starting compound of the formula:
with a compound of the formula:
wherein
X 1 is a halogen, trialkyl tin, triflate, or substituents useful in organometalic coupling reactions under conditions effective to produce the substantially pure regioisomer.
11. A substantially pure regioisomer having the formula:
wherein
X is a halogen;
R 3 is —COOR 4 ;
R 4 is chosen from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, 5 carbon alkyl, and 6 carbon alkyl;
A is a substituent of its ring selected from the group consisting of hydrogen, halogens, alkyl, hydroxy or alkoxy.
12. A process of preparing a second substantially pure regiolsomer of the formula:
wherein
X is a halogen;
R 3 is —COOR 4 ;
R 4 is chosen from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, 5 carbon alkyl, and 6 carbon alkyl;
A is a substituent of its ring selected from the group consisting of hydrogen, halogens, alkyl, hydroxy or alkoxy,
said process comprising:
providing a first substantially pure regioisomer of the formula:
halogenating the first substantially pure regioisomer under conditions effective to form the second substantially pure regioisomer.