Triethylamine → LY-2608204

HRID 559489Notes

Reaction equation

HRID 559489 reaction equation
C(Cl)(=O)C(Cl)=O.[CH:7]1([C@@H:13]2[CH2:15][C@@:14]2([C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH:28]3[CH2:30][CH2:29]3)(=[O:27])=[O:26])=[CH:21][CH:20]=2)[C:16]([OH:18])=O)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.C(N(CC)CC)C.S([O-])([O-])(=O)=O.[Na+].[Na+].[N:45]1([CH2:50][CH2:51][S:52][C:53]2[S:57][C:56]([NH2:58])=[N:55][CH:54]=2)[CH2:49][CH2:48][CH2:47][CH2:46]1>ClCCl.CN(C)C=O.O>[N:45]1([CH2:50][CH2:51][S:52][C:53]2[S:57][C:56]([NH:58][C:16]([C@:14]3([C:19]4[CH:20]=[CH:21][C:22]([S:25]([CH:28]5[CH2:29][CH2:30]5)(=[O:26])=[O:27])=[CH:23][CH:24]=4)[CH2:15][C@H:13]3[CH:7]3[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]3)=[O:18])=[N:55][CH:54]=2)[CH2:49][CH2:48][CH2:47][CH2:46]1

Participants

9

Reactant 5

HCID 8471TriethylamineHCID 24436Sodium SulfateHCID 65578Oxalyl chlorideHCID 287826785-{[2-(Pyrrolidin-1-yl)ethyl]sulfanyl}-1,3-thiazol-2-amineHCID 59378093HCID 59378093, compound

Product 1

HCID 46832368LY-2608204Yield 74%

Reagents, catalysts & solvents 3

HCID 6228DimethylformamideCatalystHCID 962WaterSolventHCID 6344DichloromethaneSolvent2×

Procedure

Oxalyl chloride (146.89 mL, 1.69 mol) is added over 15 min to a stirred solution of (1R,2S)-2-cyclohexyl-1-(4-cyclopropanesulfonyl-phenyl)-cyclopropanecarboxylic acid (295.00 g, 0.847 mol) in 10 L of anhydrous dichloromethane under an inert atmosphere. Dimethylformamide (654.61 μL, 8.5 mmol) is then added at once, and the resulting solution is stirred overnight. Volatiles are then removed under vacuum at 40° C. to afford an oil, which is dissolved in 3 L of anhydrous dichloromethane. An inert atmosphere is reestablished, and the solution is cooled to <5° C. Triethylamine (177 mL 1.27 mol) is then added dropwise over 20 minutes, leaving a dark solution. Sodium Sulfate (120.25 g, 0.847 mol) is added, followed by 5-(2-pyrrolidin-1-yl-ethylsulfanyl)-thiazol-2-ylamine (213.60 g 0.931 mole). The internal temperature rises to 20° C. The reaction mixture is stirred for 10 min in the cold, and is then allowed to warm to room temperature. After being stirred overnight, the reaction mixture is poured onto 3 L of water. The resulting mixture is stirred for a few minutes, and then the two layers are separated. The aqueous layer is extracted with 1 L dichloromethane, and the dichloromethane solutions are combined, dried over MgSO4, filtered, and concentrated under vacuum at 40° C. The resulting oil (556 g) is applied to silica gel plugs as a dichloromethane solution. Elution of the plugs with 1:12:7 2M ammonia in methanol/methyl t-butyl ether/heptane, followed by 1:19 2M ammonia (in methanol)/ethyl acetate affords a brown foam (351 g). Crystallization of 320 g of this material from methyl t-butyl ether and heptane, affords the title compound (279.4 g) as an off-white solid after drying for 2 days at 45° C. LCMS (m/e): 560 (M+H); [α]D20=−44°.

Workup

  1. customVolatiles are then removed under vacuum at 40° C.
  2. customto afford an oil, which
  3. temperaturethe solution is cooled to <5° C
  4. customleaving a dark solution
  5. customrises to 20° C
  6. stirringThe reaction mixture is stirred for 10 min in the cold, and
  7. stirringAfter being stirred overnight
  8. stirringThe resulting mixture is stirred for a few minutes
  9. customthe two layers are separated
  10. extractionThe aqueous layer is extracted with 1 L dichloromethane
  11. dry with materialdried over MgSO4
  12. filtrationfiltered
  13. concentrationconcentrated under vacuum at 40° C
  14. washElution of the plugs with 1:12:7 2M ammonia in methanol/methyl t-butyl ether/heptane

Sources & evidence

ORD record
ord-86d3254427d84888abb9c48a65516a04
Source dataset
uspto-grants-2011_11
Patent number
US08063079B2

Reaction notes

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