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 1911035ノート

反応式

HRID 1911035 の反応式
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

参加物

7

反応物 4

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

生成物 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 salt収率 36%

試薬・触媒・溶媒 2

HCID 702Ethanol溶媒HCID 6422Trifluoroacetic acid溶媒

実験手順

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)

後処理

  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

出典と根拠

ORDレコード
ord-ea4bb50f4e0d4b57bb526b45fe57f386
出典データセット
uspto-grants-2013_12
特許番号
US08604024B2

反応ノート

読み込み中…