Dichloromethane → Cisatracurium Besylate

HRID 1808316Notes

Reaction equation

HRID 1808316 reaction equation
[CH3:1][N+:2]1([CH2:27][CH2:28][C:29]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][O:37][C:38]([CH2:40][CH2:41][N+:42]2([CH3:67])[CH:51]([CH2:52][C:53]3[CH:54]=[CH:55][C:56]([O:61][CH3:62])=[C:57]([O:59][CH3:60])[CH:58]=3)[C:50]3[CH:49]=[C:48]([O:63][CH3:64])[C:47]([O:65][CH3:66])=[CH:46][C:45]=3[CH2:44][CH2:43]2)=[O:39])=[O:30])[CH:11]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:21][CH3:22])=[C:17]([O:19][CH3:20])[CH:18]=2)[C:10]2[CH:9]=[C:8]([O:23][CH3:24])[C:7]([O:25][CH3:26])=[CH:6][C:5]=2[CH2:4][CH2:3]1.[CH:68]1[CH:69]=[CH:70][C:71]([S:74]([O-:77])(=[O:76])=[O:75])=[CH:72][CH:73]=1.[CH:78]1[CH:79]=[CH:80][C:81]([S:84]([O-:87])(=[O:86])=[O:85])=[CH:82][CH:83]=1.ClCCl.C1(S(O)(=O)=O)C=CC=CC=1>CO>[CH3:67][N@@+:42]1([CH2:41][CH2:40][C:38]([O:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][O:31][C:29]([CH2:28][CH2:27][N@+:2]2([CH3:1])[C@H:11]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([O:21][CH3:22])=[C:17]([O:19][CH3:20])[CH:18]=3)[C:10]3[CH:9]=[C:8]([O:23][CH3:24])[C:7]([O:25][CH3:26])=[CH:6][C:5]=3[CH2:4][CH2:3]2)=[O:30])=[O:39])[C@H:51]([CH2:52][C:53]2[CH:54]=[CH:55][C:56]([O:61][CH3:62])=[C:57]([O:59][CH3:60])[CH:58]=2)[C:50]2[CH:49]=[C:48]([O:63][CH3:64])[C:47]([O:65][CH3:66])=[CH:46][C:45]=2[CH2:44][CH2:43]1.[CH:68]1[CH:69]=[CH:70][C:71]([S:74]([O-:77])(=[O:76])=[O:75])=[CH:72][CH:73]=1.[CH:78]1[CH:79]=[CH:80][C:81]([S:84]([O-:87])(=[O:86])=[O:85])=[CH:82][CH:83]=1

Participants

5

Reactant 3

HCID 6344DichloromethaneHCID 7371Benzenesulfonic AcidHCID 47320Atracurium Besylate2×

Product 1

HCID 62886Cisatracurium Besylate

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Procedure

Cisatracurium besylate is disclosed in U.S. Pat. No. 5,453,510 (hereinafter U.S. '510). U.S. '510 describes the formation of (R)-tetrahydro-papaverine (compound HA) from compound (II) which is converted into a mixture of R and S diastereoisomer salts with the chiral amino acid, N-acetyl-L-leucine, resulting in the formation of a mixture of 83% of the R and 17% of the S diastereoisomer. Crystallization of the mixture from acetone affords 97% (R)-tetrahydropapaverine-N-acetyl-L-leucinate and 3% (S)-tetrahydropapaverine-N-acetyl-L-leucinate which is converted into (R)-tetrahydropapaverine base. The (R)-tetrahydropapaverine is subsequently reacted with 1,5-pentamethylene diacrylate followed by oxalic acid to afford the dioxalate salt of (1R,1′R)-2,2′-(3,11-dioxo-4,10-dioxatridecamethylene)-bis-(1,2,3,4-tetrahydro-6,7-dimethoxy-1-veratrylisoquinoline) (i.e., an isomer of compound IV). Conversion of the dioxalate salt into the free base, followed by treatment with methyl benzenesulfonate, affords an aqueous solution of (1R,1′R)-atracurium besylate. Lyophilization results in a pale yellow solid that includes a mixture of three isomers, namely, 1R-cis,1′R-cis; 1R-cis,1′R-trans; 1R-trans,1′R-trans (hereinafter referred to as the “atracurium besylate mixture”) in a ratio of about 58:34:6 respectively. The atracurium besylate mixture is subjected to preparative HPLC column chromatography on silica using a mixture of dichloromethane, methanol and benzenesulfonic acid in the ratio of 4000:500:0.25 as the eluent. The fractions containing the required isomer are collected and washed with water. The dichloromethane solution is evaporated to dryness, the residue dissolved in water and the pH of the solution adjusted to 3.5-4.0 with an aqueous solution of benzenesulfonic acid. The aqueous solution is lyophilized to afford cisatracurium besylate possessing an isomeric purity of about 99%.

Workup

  1. customLyophilization results in a pale yellow solid
  2. additiona mixture of three isomers
  3. additionThe fractions containing the required isomer
  4. customare collected
  5. washwashed with water
  6. customThe dichloromethane solution is evaporated to dryness
  7. dissolutionthe residue dissolved in water

Sources & evidence

ORD record
ord-382556f9e73e4392963819458cf862d2
Source dataset
uspto-grants-2013_01
Patent number
US08357807B2

Reaction notes

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