Diisopropylethylamine → HCID 23589156, compound

HRID 489905Notes

Reaction equation

HRID 489905 reaction equation
[N:1]1([CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH2:6][CH2:5][CH2:4][C@@H:3]([C:7]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[O:8])[CH2:2]1.[F:21][C:22]([F:47])([F:46])[C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[N:29]=[C:28]([C:33]1[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=1)[CH:27]=[C:26]2[C:43](O)=[O:44].O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>ClCCl>[N:9]1([C:7]([C@@H:3]2[CH2:4][CH2:5][CH2:6][N:1]([CH:15]3[CH2:20][CH2:19][N:18]([C:43]([C:26]4[C:25]5[C:30](=[CH:31][CH:32]=[C:23]([C:22]([F:21])([F:46])[F:47])[CH:24]=5)[N:29]=[C:28]([C:33]5[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:40])[F:41])=[CH:35][CH:34]=5)[CH:27]=4)=[O:44])[CH2:17][CH2:16]3)[CH2:2]2)=[O:8])[CH2:10][CH2:11][O:12][CH2:13][CH2:14]1

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 27960291-Hydroxybenzotriazole hydrateHCID 5183222HCID 5183222, compoundHCID 23589123HCID 23589123, compound

Product 1

HCID 23589156HCID 23589156, compoundYield 23%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

To a solution of (3R)-[1,4′]bipiperidinyl-3-yl-morpholin-4-yl-methanone (0.314 mmol, 100 mg) and 6-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-quinoline-4-carboxylic acid (0.346 mmol, 133 mg) in anhydrous dichloromethane was added 1-hydroxybenzotriazole hydrate (0.157 mmol, 21 mg) followed by diisopropylethylamine (0.942 mmol, 0.163 mL) then benzotriazo-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP, 0.942 mmol, 417 mg). The solution was stirred at ambient temperature for 16 hr, diluted with dichloromethane and washed with 1M potassium hydroxide solution. The aqueous layer was separated and extracted with dichloromethane (2×25 mL). The combined organic layers were dried over anhydrous sodium sulfate and evaporated to dryness under vacuum. The residue was redissolved in toluene, evaporated to dryness and purified by chromatography on a 1 mm silica gel rotor eluting with a 0 to 10% methanol in dichloromethane gradient. Final purification from residual hexamethylphosphoramide was achieved by precipitation of the hydrochloride salt (as described above in Example 6), trituration with 1M potassium hydroxide solution, filtration and rinsing with water to give the title compound (46 mg, 23%).

Workup

  1. washwashed with 1M potassium hydroxide solution
  2. customThe aqueous layer was separated
  3. extractionextracted with dichloromethane (2×25 mL)
  4. dry with materialThe combined organic layers were dried over anhydrous sodium sulfate
  5. customevaporated to dryness under vacuum
  6. dissolutionThe residue was redissolved in toluene
  7. customevaporated to dryness
  8. custompurified by chromatography on a 1 mm silica gel
  9. washrotor eluting with a 0 to 10% methanol in dichloromethane gradient
  10. customFinal purification from residual hexamethylphosphoramide
  11. customwas achieved by precipitation of the hydrochloride salt (as described above in Example 6), trituration with 1M potassium hydroxide solution, filtration
  12. washrinsing with water

Sources & evidence

ORD record
ord-c57829b1c1504e73a0691fd2fc76292f
Source dataset
uspto-grants-2005_12
Patent number
US06979741B2

Reaction notes

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