Trifluoromethanesulfonic acid → 5-chloro-pyridine-2-carboxylic acid (rel-(4aS,11bS)-2-amino-11b-methyl-4,4a,5,6,7,11b-hexahydro-3-thia-1-aza-dibenzo[a,c]cyclohepten-10-yl)-amide, 2,2,2-trifluoroacetate salt

HRID 1911035Notes

Reaction equation

HRID 1911035 reaction equation
ClC1C=CC([C:8](NC2C=CC3CCCC(CCl)=C(C)C=3C=2)=[O:9])=NC=1.NC(N)=S.Cl.[C:30]([S:33][CH2:34][C:35]1[CH2:36][CH2:37][CH2:38][C:39]2[CH:46]=[CH:45][C:44]([NH:47][C:48](=[O:56])[C:49]3[CH:54]=[CH:53][C:52]([Cl:55])=[CH:51][N:50]=3)=[CH:43][C:40]=2[C:41]=1[CH3:42])(=[NH:32])[NH2:31].[F:57][C:58]([F:64])([F:63])S(O)(=O)=O>C(O)C.C(O)(C(F)(F)F)=O>[F:57][C:58]([F:64])([F:63])[C:8]([OH:9])=[O:56].[NH2:32][C:30]1[S:33][CH2:34][C@H:35]2[CH2:36][CH2:37][CH2:38][C:39]3[CH:46]=[CH:45][C:44]([NH:47][C:48]([C:49]4[CH:54]=[CH:53][C:52]([Cl:55])=[CH:51][N:50]=4)=[O:56])=[CH:43][C:40]=3[C@@:41]2([CH3:42])[N:31]=1

Participants

7

Reactant 4

HCID 62406Trifluoromethanesulfonic acidHCID 2723790ThioureaHCID 86685429HCID 86685429, compoundHCID 86685430(2-(5-chloropicolinamido)-9-methyl-6,7-dihydro-5H-benzo[7]annulen-8-yl)methyl carbamimidothioate hydrochloride

Product 1

HCID 1317310765-chloro-pyridine-2-carboxylic acid (rel-(4aS,11bS)-2-amino-11b-methyl-4,4a,5,6,7,11b-hexahydro-3-thia-1-aza-dibenzo[a,c]cyclohepten-10-yl)-amide, 2,2,2-trifluoroacetate saltYield 36%

Reagents, catalysts & solvents 2

HCID 702EthanolSolventHCID 6422Trifluoroacetic acidSolvent

Procedure

To a solution of (E)-5-chloro-N-(8-(chloromethyl)-9-methyl-6,7-dihydro-5H-benzo[7]annulen-2-yl)picolinamide from step 3C (30 mg, 0.083 mmol) in ethanol (0.5 mL) was added thiourea (6.32 mg, 0.083 mmol). The mixture was heated to reflux for 3 h. The solvent was removed to give crude (2-(5-chloropicolinamido)-9-methyl-6,7-dihydro-5H-benzo[7]annulen-8-yl)methyl carbamimidothioate hydrochloride (36.3 mg, 0.083 mmol, 100% yield), which was used directly for the next step without purification. To a solution of the crude (2-(5-chloropicolinamido)-9-methyl-6,7-dihydro-5H-benzo[7]annulen-8-yl)methyl carbamimidothioate hydrochloride (36 mg, 0.082 mmol) in TFA (2 mL) was added trifluoromethanesulfonic acid (0.5 mL). The reaction mixture was stirred at rt for 16 h. The mixture was then concentrated and dried by azetropic distillation with toluene. The residue was then dissolved in 1.5 mL of MeOH, and a precipitate was removed by filtration. The mother liquor was purified via HPLC under standard conditions to give 5-chloro-pyridine-2-carboxylic acid (rel-(4aS,11bS)-2-amino-11b-methyl-4,4a,5,6,7,11b-hexahydro-3-thia-1-aza-dibenzo[a,c]cyclohepten-10-yl)-amide, 2,2,2-trifluoroacetate salt (16 mg, 0.030 mmol, 36% yield). LCMS (M+H)+=401.2. 1H NMR (500 MHz, methanol-d4) δ 8.72 (br. s., 1H), 8.21 (br. s., 1H), 8.08 (dd, J=8.4, 2.0 Hz, 1H), 7.90 (d, J=2.1 Hz, 1H), 7.58 (dd, J=8.1, 2.1 Hz, 1H), 7.28 (d, J=8.1 Hz, 1H), 3.22-3.10 (m, 1H), 2.99-2.80 (m, 3H), 2.57-2.40 (m, 2H), 2.10 (dd, J=14.7, 3.7 Hz, 1H), 1.90 (dd, J=14.5, 3.5 Hz, 1H), 1.87 (s, 3H), 1.64-1.52 (m, 1H)

Workup

  1. temperatureThe mixture was heated
  2. temperatureto reflux for 3 h
  3. customThe solvent was removed
  4. customto give crude (2-(5-chloropicolinamido)-9-methyl-6,7-dihydro-5H-benzo[7]annulen-8-yl)methyl carbamimidothioate hydrochloride (36.3 mg, 0.083 mmol, 100% yield), which
  5. customwas used directly for the next step without purification
  6. concentrationThe mixture was then concentrated
  7. dry with materialdried by azetropic distillation with toluene
  8. dissolutionThe residue was then dissolved in 1.5 mL of MeOH
  9. customa precipitate was removed by filtration
  10. customThe mother liquor was purified via HPLC under standard conditions

Sources & evidence

ORD record
ord-ea4bb50f4e0d4b57bb526b45fe57f386
Source dataset
uspto-grants-2013_12
Patent number
US08604024B2

Reaction notes

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