Process for synthesis of piperidine alkaloids

Patent metadata

Field	Value
Publication number	US-9834515-B2
Application number	US-201515309873-A
Country	US
Kind code	B2
Filing date	May 5, 2015
Priority date	May 9, 2014
Publication date	Dec 5, 2017
Grant date	Dec 5, 2017

Abstract

The present invention discloses a process for synthesis of piperidine alkaloids selected from fagomine, 4-epi-fagomine and nojirimycin from tri-O-benzyl-D-glucal or tri-O-benzyl-D-galactal.

First claim

We claim:

1. A process for the preparation of piperidine alkaloids, the process comprising:
a) dissolving gluconolactone compound (1) in methanolic ammonia solution followed by stirring at room temperature in the range of 20 to 35° C. for 1 to 1.5 h to afford 5-δ-hydroxy amide (2);

b) stirring a solution of compound 2 as obtained in step (a) in DMSO and Ac 2 O at room temperature in the range of 20 to 35° C. for period in the range of 22 to 23 h followed by addition of water to afford δ-keto amide (3);

c) adding formic acid and sodium cyanoborohydride to a solution of compound 3 as obtained in step (b) in acetonitrile followed by refluxing at temperature in the range of 80 to 85° C. for period in the range of 4 to 4.5 h to afford glycolactam compound (5);

d) adding lithium aluminium hydride to a solution of compound 5 as obtained in step (c) in tetrahydrofuran followed by stirring the reaction mixture for period in the range of 3.5 to 4 h at temperature in the range of 65 to 70° C. and purification to afford protected piperidine compound (6);

e) adding palladium on active charcoal to a solution of piperidine compound 6 as obtained in step (d) in acetic acid followed by stirring the mixture for overnight for period in the range of 10 to 12 hr at room temperature in the range of 20 to 35° C. under hydrogen atmosphere to afford piperidine alkaloids (7);

f) adding Et 3 N to a solution of glycolactam (5) as obtained in step (c) in dichloromethane followed by cooling to 0° C. and further adding Boc 2 O, DMAP followed by stirring at temperature in the range of 20 to 25° C. for period in the range of 8 to 9 h to afford N-Boc protected lactam (8);

g) dissolving N-Boc protected lactam (8a) of step (d) in toluene and cooling to −76° C. under inert atmosphere and adding superhydride and ammonium chloride solution at −76° C. followed by stirring the reaction mixture for period in the range of 9 to 10 h at room temperature to afford lactamol compound 9a;

h) stirring a mixture of compound of step (e) and HCl in methanol at 70° C. for 5 h followed by basifying the reaction mixture to afford 3-deoxynojirimycin (10a);

i) dissolving N-Boc protected lactam (8a) of step (d) in dry toluene and cooled at −76° C. under inert atmosphere and adding superhydride with stirring followed by addition of TFAA, DIPEA, catalytic amount of DMAP and purification to afford Boc-iminoglycal (11a/11b); and
j) adding Boc-iminoglycal (11a) to a solution of (DHQ) 2 AQN, K 3 Fe(CN) 6 , K 2 CO 3 , K 2 OsO 2 (OH) 4 and CH 3 SO 2 NH 2 in tert-butyl alcohol and water cooled at 0° C. followed by stirring the mixture at 0° C. for 60 to 66 h to afford iminoglycal compound (12a).

2. The process as claimed in claim 1 , wherein the piperidine alkaloids are (+)-fagomine (7a), 4-epi-fagomine (7b), 3-deoxynojirimycin (10a), Boc-iminoglycal (11a/11b), iminoglycal compound (12a) and iminoglycal compound (13a).

3. The process as claimed in claim 1 , wherein the steps (a), (b) and (d) are carried out under nitrogen atmosphere.

4. The process as claimed in claim 1 , wherein the Boc-iminoglycal is tert-butyl (2R,3R)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)-3,4-dihydropyridine-1(2H)-carboxylate (11a), tert-butyl (2R,3S)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)-3,4-dihydropyridine-1(2H)-carboxylate (11b).

5. The process as claimed in claim 1 , wherein the iminoglycal compound is tert-Butyl (2R,3R,5R,6R)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)-5,6-dihydroxy-piperidine-1-carboxylate (12a) or tert-Butyl (2R,3R,5S,6S)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)-5,6-dihydroxypiperidine-1-carboxylate (13a).

6. The process as claimed in claim 1 , wherein said process may also comprise adding Boc-iminoglycal (11a) to a solution of (DHQD) 2 AQN, K 3 Fe(CN) 6 , K 2 CO 3 , K 2 OsO 2 (OH) 4 and CH 3 SO 2 NH 2 in tert-butyl alcohol and water cooled at 0° C. followed by stirring the mixture at 0° C. for 60 to 66 h to afford iminoglycal compound (13a).

Assignees

• Council Scient Ind Res

Inventors

• Bhattacharya Asish Kumar
• Chand Hemender Rami

Classifications

• C07D211/46

  having a hydrogen atom as the second substituent in position 4 · CPC title

• C07H5/04

  to nitrogen · CPC title

• C07D211/74 Primary

  Oxygen atoms · CPC title

• C07H1/00

  Processes for the preparation of sugar derivatives · CPC title

• C07H5/06

  Aminosugars · CPC title