1. A process for the preparation of Cisatracurium besylate (1),
wherein the process comprising the steps of:
a) reacting (R)-Tetrahydro papaverine N-acetyl-L-leucinate (5)
with tert-butyl acrylate in presence of acetic acid and aqueous ammonia
in a solvent to obtain (R)-tert-butyl 3-(1-(3,4-dimethoxy benzyl)-6,7-
dimethoxy-3,4-dihydro isoquinolin-2(1H)-yl) propanoate (4a), which
on in-situ with suitable acid to provide (R)-tert-butyl 3-(1-(3,4-
dimethoxy benzyl)-6,7-dimethoxy-3,4-dihydro isoquinolin-2(1H)-yl)
propanoate salt (4) ;
b) reacting (R)-tert-butyl 3-(1-(3,4-dimethoxy benzyl)-6,7-dimethoxy-3,4-
dihydro isoquinolin-2(1H)-yl) propanoate salt (4) with methyl
benzenesulfonate in presence of aqueous ammonia in a solvent to obtain
(1R,2R)-2-(3-tert-butoxy-3-oxopropyl)-1-(3,4-dimethoxybenzyl)-6,7-
dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinolinium
benzenesulfonate (3);
16
c) deprotecting (1R,2R)-2-(3-tert-butoxy-3-oxopropyl)-1-(3,4-
dimethoxybenzyl)-6,7-dimethoxy-2-methyl-1,2,3,4 tetrahydro
isoquinolinium benzenesulfonate (3) with trifluoroacetic acid to obtain
(1R,2R)-2-(2-carboxyethyl)-1-(3,4-dimethoxybenzyl)-6,7-dimethoxy2-methyl-1,2,3,4-tetra hydroisoquinolinium benzenesulfonate (2); and
d) reacting (1R,2R)-2-(2-carboxyethyl)-1-(3,4-dimethoxybenzyl)-6,7-
dimethoxy-2-methyl-1,2,3,4-tetra hydro Isoquinolinium
benzenesulfonate (2) with pentane-1,5-diol in presence of
benzenesulfonic acid to obtain Cisatracurium besylate (1).
2. The process as claimed in claim 1, wherein the suitable acid used in step a)
is selected from oxalic acid, acetic acid, formic acid, citric acid, malic acid,
tartaric acid and the like.
3. A process for the purification of Cisatracurium besylate (1), wherein the
process comprising the steps of:
i. dissolving crude Cisatracurium besylate (1) in one or more solvents;
and
ii. isolating pure Cisatracurium besylate (1).
4. A process for the preparation of (R)-tetrahydro papaverine N-acetyl-Lleucinate (5),
17
which comprises:
I. reacting (±)-Tetrahydro papaverine hydrochloride with N-acetyl-Lleucine in the presence of aqueous ammonia in one or more solvents to
obtain crude (R)-tetrahydro papaverine N-acetyl-L-leucinate (5); and
II. purifying crude (R)-tetrahydro papaverine N-acetyl-L-leucinate (5) to
obtain pure (R)-tetrahydro papaverine N-acetyl-L-leucinate (5).
5. The process as claimed in claim 1, wherein Cisatracurium besylate (1) so
obtained after purification is in amorphous form.
6. The process as claimed in claim 1, Cisatracurium besylate (1) obtained by
the above method is having purity greater than 99.0%, preferably greater
than 99.5% by High-performance liquid chromatography (HPLC).
7. The process as claimed in claims 1, 3 and 4, wherein the solvent used herein
are “alcoholic solvents” such as methanol, ethanol, n-propanol, isopropanol,
n-butanol, isobutanol, t-butanol, and the like; “nitrile solvents” such as
acetonitrile, propionitrile, isobutyro nitrile and the like; “polar-aprotic
solvents such as dimethylacetamide (DMA), dimethylformamide (DMF),
dimethylsulfoxide (DMSO), N-methylpyrrolidone (NMP) and the like;
“ester solvents” such as methyl acetate, ethyl acetate, isopropyl acetate, nbutyl acetate and the like; “ether solvents” such as dimethoxy methane,
tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, diethyl ether, ethylene glycol
dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl
ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether,
anisole, t-butyl methyl ether, dimethoxy ethane and the like;