Hydrochloric Acid → 2-{2-[(4-methoxy-2,6-dimethyl-benzenesulphonyl)-methyl-amino]-ethoxy}-N-methyl-N-[3-(4-methyl-piperazin-1-yl)-cyclohexyl]-acetamide L-(+)-tartrate

HRID 222525Notes

Reaction equation

HRID 222525 reaction equation
Cl.Cl.Cl.[CH3:4][NH:5][C@H:6]1[CH2:11][CH2:10][CH2:9][C@@H:8]([N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)[CH2:7]1.[Na].[CH3:20][O:21][C:22]1[CH:27]=[C:26]([CH3:28])[C:25]([S:29]([N:32]([CH3:40])[CH2:33][CH2:34][O:35][CH2:36][C:37]([OH:39])=[O:38])(=[O:31])=[O:30])=[C:24]([CH3:41])[CH:23]=1.C[C:43]([CH3:46])([O-:45])C.[K+].Cl.[OH-:49].[Na+].C1C[O:54]CC1>C(OCC)(=O)C.O.C1(C)C=CC=CC=1>[C:43]([C@@H:46]([C@H:36]([C:37]([OH:39])=[O:38])[OH:35])[OH:54])([OH:45])=[O:49].[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH3:41])[C:25]([S:29]([N:32]([CH3:40])[CH2:33][CH2:34][O:35][CH2:36][C:37]([N:5]([CH3:4])[CH:6]2[CH2:11][CH2:10][CH2:9][CH:8]([N:12]3[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17]3)[CH2:7]2)=[O:39])(=[O:30])=[O:31])=[C:26]([CH3:28])[CH:27]=1

Participants

11

Reactant 7

HCID 313Hydrochloric AcidHCID 8028Tetrahydrofuran4×HCID 14798Sodium HydroxideHCID 5360545SodiumHCID 23665647Potassium tert-butoxideHCID 46870354{2-[(4-methoxy-2,6-dimethyl-benzenesulfonyl)-methyl-amino]-ethoxy}acetic AcidHCID 68483638methyl-[(1S,3R)-3-(4-methyl-piperazin-1-yl)cyclohexyl]-amine tri-hydrochloride

Product 1

HCID 866445082-{2-[(4-methoxy-2,6-dimethyl-benzenesulphonyl)-methyl-amino]-ethoxy}-N-methyl-N-[3-(4-methyl-piperazin-1-yl)-cyclohexyl]-acetamide L-(+)-tartrate

Reagents, catalysts & solvents 3

HCID 962WaterSolvent2×HCID 1140TolueneSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
50 °C

Procedure

3.50 kg (10.91 mol) of methyl-[(1S,3R)-3-(4-methyl-piperazin-1-yl)cyclohexyl]-amine tri-hydrochloride (F) and 4.24 kg (12.00 mol) of the sodium salt of {2-[(4-methoxy-2,6-dimethyl-benzenesulphonyl)-methyl-amino]-ethoxy}-acetic acid (E) were suspended in 17.5 L of THF and heated to 50±5° C. Then 21.43 kg (38.19 mol) potassium tert. butoxide solution in tetrahydrofuran, 5.0 L of tetrahydrofuran, 13.89 kg (83.97 mol) of 50% propanephosphonic anhydride in ethyl acetate and a further 5.0 L of tetrahydrofuran were metered in successively and the reaction mixture was stirred for approx. 1 hour at 50±5° C. After the reaction had ended 17.5 L toluene and 19.5 L water were added and the pH of the aqueous phase was adjusted to less than 2.5 with hydrochloric acid (30%). The aqueous phase was separated off, diluted with 2.0 L water and combined at 50° C. with 42 L of methylisobutylketone and a mixture of 4.45 kg (55.65 mol) sodium hydroxide solution (50%, industrial grade) and 3.5 L of water. After approx. 5 minutes' stirring at 50° C. the aqueous phase was separated off and 28.0 L solvent were distilled off in vacuo. The cloudy residue was filtered at 60° C. and the filtrate was combined with 14.0 L of methylisobutylketone. Then the solvent was eliminated completely in vacuo and product (G) was isolated.

Workup

  1. additionwere added
  2. customThe aqueous phase was separated off
  3. additiondiluted with 2.0 L water
  4. customcombined at 50° C. with 42 L of methylisobutylketone
  5. stirringAfter approx. 5 minutes' stirring at 50° C. the aqueous phase
  6. customwas separated off
  7. distillation28.0 L solvent were distilled off in vacuo
  8. filtrationThe cloudy residue was filtered at 60° C.

Sources & evidence

ORD record
ord-6edc4d8941944e56b6b6516f7bf1ea96
Source dataset
uspto-grants-2012_06
Patent number
US08207335B2

Reaction notes

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