Ethyl Acetate → (S)-2-{[2-(2-1H-Indazol-4-yl-acetylamino)-4-methyl-thiazole-5-carbonyl]-amino}-3-[(thiophene-2-carbonyl)-amino]-propionic acid 2-morpholin-4-yl-ethyl ester

HRID 1952661Notes

Reaction equation

HRID 1952661 reaction equation
[NH:1]1[C:9]2[C:4](=[C:5]([CH2:10][C:11]([NH:13][C:14]3[S:15][C:16]([C:20]([NH:22][C@@H:23]([CH2:27][NH:28][C:29]([C:31]4[S:32][CH:33]=[CH:34][CH:35]=4)=[O:30])[C:24]([OH:26])=[O:25])=[O:21])=[C:17]([CH3:19])[N:18]=3)=[O:12])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[N:36]1([CH2:42][CH2:43]O)[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.C(OCC)(=O)C>C1COCC1.C(OCC)(=O)C.C1COCC1.O.[Cl-].[Na+].O.OS([O-])(=O)=O.[K+]>[N:36]1([CH2:42][CH2:43][O:25][C:24](=[O:26])[C@@H:23]([NH:22][C:20]([C:16]2[S:15][C:14]([NH:13][C:11](=[O:12])[CH2:10][C:5]3[CH:6]=[CH:7][CH:8]=[C:9]4[C:4]=3[CH:3]=[N:2][NH:1]4)=[N:18][C:17]=2[CH3:19])=[O:21])[CH2:27][NH:28][C:29]([C:31]2[S:32][CH:33]=[CH:34][CH:35]=2)=[O:30])[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1

Participants

10

Reactant 4

HCID 8857Ethyl AcetateHCID 611632-MorpholinoethanolHCID 111923Propylphosphonic anhydrideHCID 51035164(S)-2-{[2-(2-1H-Indazol-4-yl-acetylamino)-4-methyl-thiazole-5-carbonyl]-amino}-3-[(thiophene-2-carbonyl)-amino]-propionic acid

Product 1

HCID 86671267(S)-2-{[2-(2-1H-Indazol-4-yl-acetylamino)-4-methyl-thiazole-5-carbonyl]-amino}-3-[(thiophene-2-carbonyl)-amino]-propionic acid 2-morpholin-4-yl-ethyl esterYield 18.2%

Reagents, catalysts & solvents 5

HCID 962WaterSolventHCID 8028TetrahydrofuranSolventHCID 516920Potassium bisulfateSolventHCID 21939870Tetrahydrofuran ethyl acetateSolventHCID 57417360Sodium chloride; waterSolvent

Procedure

A mixture of (S)-2-{[2-(2-1H-Indazol-4-yl-acetylamino)-4-methyl-thiazole-5-carbonyl]-amino}-3-[(thiophene-2-carbonyl)-amino]-propionic acid (50 mg, 0.0975 mmol), 4-morpholineethanol (1.06 mL, 8.751 mmol) and 1-propanephosphonic acid cyclic anhydride, 50 wt. % solution in ethyl acetate (0.4 mL, 0.672 mmol) in THF (2 mL) was heated at 600C for 25 h. The reaction mixture was cooled, diluted with 2/1 ethyl acetate/THF (100 mL), water (10 mL), brine (10 mL) and aqueous 1N KHSO4 (10 mL), mixed and separated the layers. The aqueous layer was extracted with 2/1 ethyl acetate/THF (2×50 mL). The organic layers were combined, washed with aqueous saturated sodium bicarbonate solution (30 mL), brine (30 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The resulting crude compound was purified by flash chromatography (ethyl acetate to 10% methanol/ethyl acetate) followed by an ether trituration to give (S)-2-{[2-(2-1H-Indazol-4-yl-acetylamino)-4-methyl-thiazole-5-carbonyl]-amino}-3-[(thiophene-2-carbonyl)-amino]-propionic acid 2-morpholin-4-yl-ethyl ester (11.1 mg, 18.2%) as a white solid. MS m/e 626.7 (M+H+).

Workup

  1. temperatureThe reaction mixture was cooled
  2. additionmixed
  3. customseparated the layers
  4. extractionThe aqueous layer was extracted with 2/1 ethyl acetate/THF (2×50 mL)
  5. washwashed with aqueous saturated sodium bicarbonate solution (30 mL), brine (30 mL)
  6. dry with materialdried over MgSO4
  7. filtrationfiltered
  8. concentrationconcentrated under reduced pressure
  9. customThe resulting crude compound was purified by flash chromatography (ethyl acetate to 10% methanol/ethyl acetate)

Sources & evidence

ORD record
ord-336300db4cbb4169bc9d0670ff5c298d
Source dataset
uspto-grants-2013_03
Patent number
US08404859B2

Reaction notes

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