Tetrahydrofuran → HCID 86653899, compound

HRID 2098441Notes

Reaction equation

HRID 2098441 reaction equation
[NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[C:17]([O:19][C@H:20]([C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[C:33](OC)[CH:32]=4)=[CH:27][CH:26]=3)[C:21]([F:24])([F:23])[F:22])[N:16]=[C:15]([NH2:39])[N:14]=2)=[CH:9][CH:8]=1)[C:3]([O-:5])=[O:4].[CH3:40][C:41]1[CH:42]=[CH:43][C:44]([S:47]([OH:50])(=[O:49])=[O:48])=[CH:45][CH:46]=1.O.C(#N)C.O.C1C[O:59][CH2:58]C1>O.O.O.S(C1C=CC(C)=CC=1)(O)(=O)=O.N[C@@H](CC1C=CC(C2C=C(O[C@H](C3C=CC(C4C=CC=C(OC)C=4)=CC=3)C(F)(F)F)N=C(N)N=2)=CC=1)C(O)=O>[OH2:4].[OH2:48].[S:47]([C:44]1[CH:45]=[CH:46][C:41]([CH3:40])=[CH:42][CH:43]=1)([OH:50])(=[O:49])=[O:48].[NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[C:17]([O:19][C@H:20]([C:25]3[CH:26]=[CH:27][C:28]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)=[CH:29][C:30]=3[O:59][CH3:58])[C:21]([F:22])([F:23])[F:24])[N:16]=[C:15]([NH2:39])[N:14]=2)=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4]

Participants

7

Reactant 4

HCID 8028TetrahydrofuranHCID 521998p-Toluenesulfonic acid monohydrateHCID 18373917Acetonitrile--water (1/1)2×HCID 86629509HCID 86629509, compound

Product 1

HCID 86653899HCID 86653899, compoundYield 93.4%

Reagents, catalysts & solvents 2

HCID 45273901HCID 45273901, compoundCatalystHCID 962WaterSolvent

Conditions

Temperature
50 °C

Procedure

(S)-2-amino-3-(4-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-methoxybiphenyl-4-yl)ethoxy)pyrimidin-4-yl)phenyl)propanoate (120.0 g, 88 w %, 105.6 g active, 196 mmol) was added to a solution of TsOH.H2O (39.8 g, 209 mmol) in a mixture of THF (240 mL) and water (48 mL). The mixture was heated to 50° C. to give a homogeneous solution. Approximately 120 mL of a mixture of ACN/water (1200/60 mL) was added and the mixture was seeded with (S)-2-amino-3-(4-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-methoxybiphenyl-4-yl)ethoxy)pyrimidin-4-yl)phenyl)propanoate tosylate dihydrate (0.63 g). After aging for 1 hour at 40° C., a nice slurry was obtained. The remaining ACN/water mixture was added slowly over 3 hours at 40° C. and the slurry was aged at 40° C. for 2 hours then slowly cooled to 20° C. and aged overnight. The solid was collected by filtration and the filter cake was washed with 5/1 ACN/THF with ˜5 vol % water (500 mL). Air drying at room temperature overnight gave 138.5 g of the product as a white solid (99.5 A %, 93.4% yield corrected for purity). Loss in the mother liquor and wash was 6.5%. KF of solid was 4.4%.

Workup

  1. customto give a homogeneous solution
  2. customa nice slurry was obtained
  3. waitthe slurry was aged at 40° C. for 2 hours
  4. temperaturethen slowly cooled to 20° C. and aged overnight
  5. filtrationThe solid was collected by filtration
  6. washthe filter cake was washed with 5/1 ACN/THF with ˜5 vol % water (500 mL)
  7. customAir drying at room temperature overnight

Sources & evidence

ORD record
ord-9027e434d0ef4882b4343b4730ad350b
Source dataset
uspto-grants-2013_05
Patent number
US08450532B2

Reaction notes

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