Diisopropylethylamine → HCID 58374159, compound

HRID 1948483Notes

Reaction equation

HRID 1948483 reaction equation
[CH2:1]([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][C@@H:13]([O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[C:14]2[CH:19]=[CH:18][C:17](/[C:20](=[N:22]/[OH:23])/[NH2:21])=[CH:16][CH:15]=2)[CH2:7]1)=[O:5])[CH3:2].[C:32]1([C:38]2[C:42]([C:43]([F:46])([F:45])[F:44])=[C:41]([C:47](Cl)=O)[O:40][N:39]=2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.CCN(C(C)C)C(C)C>C(#N)C>[Si:25]([O:24][C@@H:13]([C:14]1[CH:15]=[CH:16][C:17]([C:20]2[N:21]=[C:47]([C:41]3[O:40][N:39]=[C:38]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[C:42]=3[C:43]([F:46])([F:44])[F:45])[O:23][N:22]=2)=[CH:18][CH:19]=1)[CH2:12][N:8]1[CH2:9][CH2:10][CH2:11][C@H:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:7]1)([C:28]([CH3:30])([CH3:29])[CH3:31])([CH3:27])[CH3:26]

Participants

5

Reactant 3

HCID 81531DiisopropylethylamineHCID 58374197HCID 58374197, compoundHCID 86656386HCID 86656386, compound

Product 1

HCID 58374159HCID 58374159, compoundYield 1,282%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent2×

Conditions

Temperature
3 °C

Procedure

(S)-Ethyl-1-((S)-2-(tert-butyldimethylsilyloxy)-2-(4-((Z)-N′-hydroxycarbamimidoyl)phenyl)ethyl)piperidine-3-carboxylate (32.6 g, 72 5 mmol) was dissolved in acetonitrile (145 ml) (anhydrous) and cooled to ˜3° C. with ice-bath. 3-phenyl-4-(trifluoromethyl)isoxazole-5-carbonyl chloride (19.98 g, 72.5 mmol) was dissolved in 50 mL anhydrous acetonitrile and added dropwise. The internal temperature was kept below 10° C. during addition. After addition, the reaction mixture was allowed to warm to room temperature. At 30 minutes, HPLC showed completion of the first reaction step. The reaction mixture was re-cooled to below 10° C. DIEA (18.99 ml, 109 mmol) was added slowly. After the addition, the reaction mixture was heated up to 55° C. for 17 hrs. HPLC/LCMS showed completion of the reaction. The solvents were removed by ROTAVAPOR®. The residue was stirred in 250 mL 20% EtOAc/hexanes and the DIPEA HCl salt precipitated from solution and was removed via filtration. The filtrate was concentrated and purified using a silica gel cartridge (3×330 g silica, 0-50% EtOAc/hexanes gradient). (S)-ethyl 1-((S)-2-(tert-butyldimethylsilyloxy)-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidine-3-carboxylate (43g, 64.1 mmol, 88% yield) was obtained a light yellow oil. 1H NMR (400 MHz, CDCl3) δ ppm 8.16 (2H, d), 7.68 (2H, d), 7.57 (5H, m), 4.85 (1H, m), 4.14 (2H, m), 2.95 (1H, m), 2.82 (1H, m), 2.64 (1H, dd), 2.51 (1H, m), 2.49 (1H, dd), 2.35 (1H, tt), 2.14 (1H, dt), 1.91 (1H, m), 1.66 (1H, dt), 1.57 (1H, m), 1.48 (1H, m), 1.27 (3H, t), 0.92 (9H, s), 0.11 (3H, s), −0.05 (3H, s).

Workup

  1. additionadded dropwise
  2. additionThe internal temperature was kept below 10° C. during addition
  3. additionAfter addition
  4. temperatureto warm to room temperature
  5. customcompletion of the first reaction step
  6. temperatureThe reaction mixture was re-cooled to below 10° C
  7. additionAfter the addition
  8. temperaturethe reaction mixture was heated up to 55° C. for 17 hrs
  9. customcompletion of the reaction
  10. customThe solvents were removed by ROTAVAPOR®
  11. customthe DIPEA HCl salt precipitated from solution
  12. customwas removed via filtration
  13. concentrationThe filtrate was concentrated
  14. custompurified

Sources & evidence

ORD record
ord-a72579c2a78445cbaa4ca0c146cf5579
Source dataset
uspto-grants-2013_03
Patent number
US08399451B2

Reaction notes

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