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4-Toluenesulfonyl chloride → 2-Chloro-4-fluoro-N-((2R,4R)-3-(2-methyl-piperidin-4-ylamino)-phenyl)-benzamide hydrochloride

HRID 1716921
Notes
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Reaction equation

HRID 1716921 reaction equation
C(OC([N:8]1[CH2:13][CH2:12][C@@H:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22](=[O:31])[C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[Cl:30])[CH:16]=2)[CH2:10][C@H:9]1[CH3:32])=O)(C)(C)C.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[Cl-].[NH4+]>C1(C)C=CC=CC=1.CO>[ClH:30].[Cl:30][C:24]1[CH:25]=[C:26]([F:29])[CH:27]=[CH:28][C:23]=1[C:22]([NH:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([NH:14][C@@H:11]2[CH2:12][CH2:13][NH:8][C@H:9]([CH3:32])[CH2:10]2)[CH:16]=1)=[O:31]
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

6

Reactant 3

HCID 73974-Toluenesulfonyl chlorideHCID 25517Ammonium ChlorideHCID 58997392(2R,4R)-4-(3-(2-Chloro-4-fluoro-benzoylamino)-phenylamino)-2-methyl-piperidine-1-carboxylic acid tert-butyl ester

Product 1

HCID 669388242-Chloro-4-fluoro-N-((2R,4R)-3-(2-methyl-piperidin-4-ylamino)-phenyl)-benzamide hydrochlorideYield 77.8%

Reagents, catalysts & solvents 2

HCID 887
Methanol
Solvent
2×
HCID 1140TolueneSolvent

Procedure

Dissolve (2R,4R)-4-(3-(2-chloro-4-fluoro-benzoylamino)-phenylamino)-2-methyl-piperidine-1-carboxylic acid tert-butyl ester (Preparation 59, 119 mg, 0.258 mmol) in toluene (5 mL). Add p-toluenesulfonyl chloride (152 mg, 0.798 mmol) and heat to 100° C. for 3 hr. Cool to room temperature and load onto an SCX column with methanol. Wash the column with methanol, flush with 2M ammonia in methanol, and concentrate in vacuo. Purify by column chromatography (0%-10% 2M NH3 in methanol/CH2Cl2) to yield an oil. Make the hydrochloride salt by sonication with one equivalent of ammonium chloride dissolved in methanol to yield 40 mg (39%) of the title compound: mass spectrum (ion spray): m/z=362.1 (M+1); 1H NMR δ (D2O/DCl, ppm) 7.78 (s, 1H), 7.49 (m, 3H), 7.21 (t, J=9.0 Hz, 18.0 Hz, 2H), 7.07 (t, J=9.0 Hz, 18.0 Hz, 1H), 3.83 (m, 1H), 3.45 (m, 1H), 3.20 (m, 1H), 2.95 (m, 1H), 2.18 (m, 2H), 1.80 (m, 1H), 1.65 (m, 1H), 1.20 (d, J=6.6 Hz, 3H); mp 182-5° C.

Workup

  1. washWash the column with methanol
  2. customflush with 2M ammonia in methanol
  3. concentrationconcentrate in vacuo
  4. customPurify by column chromatography (0%-10% 2M NH3 in methanol/CH2Cl2)
  5. customto yield an oil

Sources & evidence

ORD record
ord-c3a1eb8c382a4593ab7e8a92df9496e2
Source dataset
uspto-grants-2010_09
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US07803813B2

Reaction notes

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On this pageParticipantsProcedureWorkupSources & evidenceReaction notes