2-Mercaptoethanol → N-((S)-2-amino-3-(3-chlorophenyl)propyl)-N-(4-(methoxymethyl)-5-(thiazolo[5,4-c]pyridin-2-yl)thiazol-2-yl)acetamide

HRID 2109702Notes

Reaction equation

HRID 2109702 reaction equation
[CH3:1][O:2][CH2:3][C:4]1[N:5]=[C:6]([NH:18][C:19](=[O:21])[CH3:20])[S:7][C:8]=1[C:9]1[S:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][C:16]=2[N:17]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:28][C:29]1[CH:30]=[C:31]([CH:48]=[CH:49][CH:50]=1)[CH2:32][CH:33]1[CH2:35][N@@:34]1S(C1C=CC([N+]([O-])=O)=CC=1)(=O)=O.C([O-])([O-])=O.[K+].[K+].SCCO>C(Cl)Cl.CO.CN(C=O)C>[NH2:34][C@@H:33]([CH2:32][C:31]1[CH:48]=[CH:49][CH:50]=[C:29]([Cl:28])[CH:30]=1)[CH2:35][N:18]([C:6]1[S:7][C:8]([C:9]2[S:10][C:11]3[CH:12]=[N:13][CH:14]=[CH:15][C:16]=3[N:17]=2)=[C:4]([CH2:3][O:2][CH3:1])[N:5]=1)[C:19](=[O:21])[CH3:20]

Participants

9

Reactant 5

HCID 15672-MercaptoethanolHCID 10796Cesium carbonateHCID 11430Potassium CarbonateHCID 57633920N-(4-(methoxymethyl)-5-(thiazolo[5,4-c]pyridin-2-yl)thiazol-2-yl)acetamideHCID 178526726HCID 178526726, compound

Product 1

HCID 23653700N-((S)-2-amino-3-(3-chlorophenyl)propyl)-N-(4-(methoxymethyl)-5-(thiazolo[5,4-c]pyridin-2-yl)thiazol-2-yl)acetamideYield 60.7%

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 6228DimethylformamideSolvent2×HCID 6344DichloromethaneSolvent

Conditions

Temperature
50 °C

Procedure

N-(4-(methoxymethyl)-5-(thiazolo[5,4-c]pyridin-2-yl)thiazol-2-yl)acetamide (0.120 g, 0.375 mmol), Cs2CO3 (0.244 g, 0.749 mmol), and DMF (0.0289 mL, 0.375 mmol) were added to a 50 mL round-bottomed flask. The mixture was stirred at 50° C., and a DMF solution of (S)-2-(3-chlorobenzyl)-1-(4-nitrophenylsulfonyl)aziridine (0.264 g, 0.749 mmol) was added dropwise using an addition funnel. The reaction was stirred for 1 hour, and LCMS indicated very little remaining starting material. K2CO3 (0.259 g, 1.87 mmol) and 2-mercaptoethanol (0.293 g, 3.75 mmol) were added to the reaction mixture, and the reaction was stirred again for approximately 1 hour at 25° C. The color slowly changed from dark red-brown to a more clear orange and LCMS indicated that the nosyl group had been removed. The majority of the DMF was removed under reduced pressure, and the residue was extracted with EtOAc and washed with saturated sodium bicarbonate. The organic layer was dried over sodium sulfate, filtered, and loaded onto a plug of silica gel and chromatographed using a Redi-Sep® pre-packed silica gel column (12 g), eluting with a gradient of 2% to 10% 2 M NH3.MeOH in DCM, to provide semi-pure N-((S)-2-amino-3-(3-chlorophenyl)propyl)-N-(4-(methoxymethyl)-5-(thiazolo[5,4-c]pyridin-2-yl)thiazol-2-yl)acetamide (0.111 g, 0.227 mmol, 60.7% yield). The crude material was used without further purification, but a fraction was purified using reverse phase HPLC to give pure compound N-((S)-2-amino-3-(3-chlorophenyl)propyl)-N-(4-(methoxymethyl)-5-(thiazolo[5,4-c]pyridin-2-yl)thiazol-2-yl)acetamide. LCMS (M+H) 487.8 calc. for C22H23ClN5O2S2 488.1. 1H NMR (400 MHz, CD3OD): δ ppm 9.39 (s, 1H), 8.61 (d, J=6.6 Hz, 1H), 8.16 (d, J=6.6 Hz, 1H), 7.27 (m, 2H), 7.19 (m, 2H), 4.74 (s, 2H), 3.66 (m, 1H), 3.52 (s, 3H), 3.45 (dd, J=13.8, 7.8 Hz, 1H), 2.91 (dd, J=13.9, 5.8 Hz, 1H), 2.76 (dd, J=613.9, 8.7 Hz, 1H), 1.85 (s, 3H).

Workup

  1. stirringThe reaction was stirred for 1 hour
  2. stirringthe reaction was stirred again for approximately 1 hour at 25° C
  3. customhad been removed
  4. customThe majority of the DMF was removed under reduced pressure
  5. extractionthe residue was extracted with EtOAc
  6. washwashed with saturated sodium bicarbonate
  7. dry with materialThe organic layer was dried over sodium sulfate
  8. filtrationfiltered
  9. customchromatographed
  10. washeluting with a gradient of 2% to 10% 2 M NH3

Sources & evidence

ORD record
ord-1099283f5202427b84390f8a103306e8
Source dataset
uspto-grants-2009_04
Patent number
US07514566B2

Reaction notes

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