4-Toluenesulfonyl chloride → 2-(4-Chlorophenyl)-5-cyclopropyl-N-methyl-6-[{2-[-2-methyloxetan-3-yl]ethyl}(methylsulfonyl)amino]-2H-indazole-3-carboxamide

HRID 2272272Notes

Reaction equation

HRID 2272272 reaction equation
[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([C:17]([NH:19][CH3:20])=[O:18])=[C:15]3[C:10]([CH:11]=[C:12]([N:24]([S:30]([CH3:33])(=[O:32])=[O:31])[CH2:25][CH2:26][CH2:27][CH:28]=[CH2:29])[C:13]([CH:21]4[CH2:23][CH2:22]4)=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.[OH:34][CH2:35][CH:36]([CH:40]([OH:42])[CH3:41])[CH2:37][CH2:38]O.C[C:44](C)([O-:46])C.[K+].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[Cl-].[NH4+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([C:17]([NH:19][CH3:20])=[O:18])=[C:15]3[C:10]([CH:11]=[C:12]([N:24]([CH2:38][CH2:37][CH:36]([CH2:35][OH:34])[CH:40]([OH:42])[CH3:41])[S:30]([CH3:33])(=[O:32])=[O:31])[C:13]([CH:21]4[CH2:23][CH2:22]4)=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([C:17]([NH:19][CH3:20])=[O:18])=[C:15]3[C:10]([CH:11]=[C:12]([N:24]([CH2:25][CH2:26][CH:27]4[CH2:44][O:46][CH:28]4[CH3:29])[S:30]([CH3:33])(=[O:32])=[O:31])[C:13]([CH:21]4[CH2:23][CH2:22]4)=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1

Participants

8

Reactant 5

HCID 73974-Toluenesulfonyl chlorideHCID 25517Ammonium ChlorideHCID 14214998HCID 14214998, compoundHCID 23665647Potassium tert-butoxide2×HCID 866990012-(4-Chlorophenyl)-5-cyclopropyl-N-methyl-6-[(methylsulfonyl)(pent-4-en-1-yl)amino]-2H-indazole-3-carboxamide2×

Product 2

HCID 717690352-(4-Chlorophenyl)-5-cyclopropyl-N-methyl-6-[{2-[-2-methyloxetan-3-yl]ethyl}(methylsulfonyl)amino]-2H-indazole-3-carboxamideHCID 89846923HCID 89846923, compound

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

2-(4-Chlorophenyl)-5-cyclopropyl-6-{[4-hydroxy-3-(hydroxymethyl)pentyl](methylsulfonyl)amino}-N-methyl-2H-indazole-3-carboxamide was prepared by alkylating 2-(4-chlorophenyl)-5-cyclopropyl-N-methyl-6-[(methylsulfonyl)amino]-2H-indazole-3-carboxamide (i) with (±)-3-(hydroxymethyl)pentane-1,4-diol (prepared from (±)-3-acetyldihydrofuran-2(3H)-one as described by T. Mitsuhiro, Yanagihara, Hiroko and Y. Sachiko, Heterocycles, 1992 33, 489-492). Then, to a solution of Compound (i) (240 mg, 0.45 mmol) in anhydrous THF (35 mL) at 0° C. under argon was added potassium tert-butoxide (60 mg, 0.53 mmol) in several portions (the reaction mixture became yellow in colour) followed by a solution of p-toluenesulfonyl chloride (95 mg, 0.50 mmol) in anhydrous THF (10 mL), which was added dropwise over 10 min. The reaction was warmed to RT and monitored by TLC/LCMS and then cooled to at 0° C. whereupon more potassium tert-butoxide (80 mg, 0.71 mmol) was added. The reaction mixture was then warmed to RT and stirred for 17 h after which time, aq. saturated ammonium chloride solution was added (20 mL) and the organics extracted into Et2O (3×100 mL), dried (MgSO4) and concentrated in vacuo. Purification by automated column chromatography (Biotage SP4, Reveleris 4 g, silica gel cartridge) eluting with EtOAc:n-heptane (gradient elution, 50% to 100% v/v) and then again by automated column chromatography (Biotage SP4, SNAP KP-C18-HS 30 g, reverse phase) eluting with ACN:water (gradient elution, 0-100% v/v) gave Compound (9) as the trans isomer (mixture of enantiomeric compounds (32) and (33)) (99 mg, 43%). 1H NMR (400 MHz, CDCl3) δ 7.70 (s, 1H), 7.56-7.48 (m, 4H), 7.37 (s, 1H), 5.88-5.82 (m, 1H), 4.62-4.47 (m, 2H), 4.24-4.15 (m, 1H), 3.62 (t, J=7.9 Hz, 2H), 3.04 (s, 3H), 2.99 (d, J=4.9 Hz, 3H), 2.67-2.53 (m, 1H), 2.45-2.33 (m, 1H), 2.06-1.82 (m, 2H), 1.39 (d, J=6.1 Hz, 1.5H), 1.36 (d, J=6.1 Hz, 1.5H), 1.17-1.04 (m, 2H), 1.04-0.93 (m, 1H), 0.66-0.54 (m, 1H). ESI-MS m/z calculated for [M+H]+: 517.2. found: 517.0.

Workup

  1. additionwas added dropwise over 10 min
  2. additionwas added
  3. temperatureThe reaction mixture was then warmed to RT
  4. additionwas added (20 mL)
  5. extractionthe organics extracted into Et2O (3×100 mL)
  6. dry with materialdried (MgSO4)
  7. concentrationconcentrated in vacuo
  8. customPurification by automated column chromatography (Biotage SP4, Reveleris 4 g, silica gel cartridge)
  9. washeluting with EtOAc
  10. washn-heptane (gradient elution, 50% to 100% v/v) and then again by automated column chromatography (Biotage SP4, SNAP KP-C18-HS 30 g, reverse phase) eluting with ACN

Sources & evidence

ORD record
ord-9dc4c267933841cc8a09f9cac706fe87
Source dataset
uspto-grants-2015_09
Patent number
US09120775B2

Reaction notes

Loading…