Atracurium EP Impurity D synthesis

Yield:1075726-91-8 32%

Reaction Conditions:

in methanol;ethyl acetate at 5 - 25; for 73 h;Purification / work up;Heating / reflux;

Steps:

9B

EXAMPLE 9B[0120] This example describes the preparation of (lR-cis)-l-[(3,4-dimethoxy- phenyl)methyl]-l,2,3,4-tetrahydro-6,7-dimethoxy-2-methyl-2-methoxycarbonylethyl- isoquinolinium iodide by crystallization of isomeric mixture. [0121] A mixture of the cis and the trans isomers of (lR)-l-[(3,4-dimethoxy- phenyl)methyl]-l,2,3,4-tetrahydro-6,7-dimethoxy-2-methyl-2-methoxycarbonylethyl- isoquinolinium iodide (1.0 g), prepared as described in example 9, was admixed with methanol (4 ml) and heated to obtain a solution. Ethyl acetate (6 ml) was added and the solution was cooled to about 25°C and stirred for 1 hour. Subsequently, the mixture was cooled to 5°C and kept at that temperature for 72 hours. The thus formed crystals were collected by filtration, washed with ethyl acetate and dried to afford (lR-cis)-l-[(3,4- dimethoxyphenyl)methyl]-l,2,3,4-tetrahydro-6,7-dimethoxy-2-methyl-2-methoxycarbonyl- ethyl-isoquinolinium iodide, 0.315 g, (32% yield or 45% yield from the cis isomer), HPLC purity 99.6 % with 0.4% of the trans isomer; m.p. 186°-188°C , [α]_D -77.9° (c=1.02, CH₂Cl₂).¹R NMR (CDCl₃): δ= 2.99 (dd, IH; J=13.8, 9.6 Hz, H₁₁), 3.12 (dd, IH, J= 18.6, 6.6 Hz, H₄), 3.22-3.40 (m, 3H, H₁₉ and H₄), 3.35 (s, 3H, NCH₃), 3.49 (s, 3H, OCH₃), 3.64 (dd, IH, J= 13.8, 4.2 Hz, H₁₁), 3.74 (s,3H, COOCH₃), 3.73-3.77 (m, IH, H₃), 3.80 (s,3H,OCH₃), 3.82 (s, 3H, OCH₃), 3.85 (s, 3H, OCH₃), 4.16 (m, 2H, H₁₈ and H₃), 4.38 (m, IH, H₁₈), 5.34 (dd, IH, J= 9.6, 4.2 Hz₁H₁), 6.10 (s, IH, H₈), 6.52 (JJ, IH, J= 8.4, 1.8 Hz, H_n), 6.64 (d, IH, J= 1.8 Hz, H₁₃), 6.66 (s, IH, H₅), 6.71 (d, IH, J= 8.4 Hz, H₁₆). ¹³C NMR (CDCl₃): δ= 23.51 (C₄), 28.57 (C₁₉), 37.90 (C₁₁), 47.20 (NCH₃), 52.83 (COOCH₃), 54.14 (C₃), 55.82 (OCH₃), 55.94 (OCH₃), 56.05 (OCH₃), 56.62 (OCH₃), 58.93 (C₁₈), 70.85 (C₁), 110.60 (C₅), 111.22 (C₁₆), 112.02 (C₈), 113.44 (C₁₃), 120.22 (C₁₀), 121.29 (C₉), 122.65 (C₁₇), 126.54 (C₁₂), 147.26 (C₆), 148.42 (C₁₄), 149.11 (C₁₅), 149.39 (C₇), and 169.96 (C₂₀). ESI⁺MS (m/z): 444.2 [M⁺].

References:

WO2008/132746,2008,A1 Location in patent:Page/Page column 28-29