Hydrochloric Acid → HCID 67229013, compound

HRID 1844312Notes

Reaction equation

HRID 1844312 reaction equation
Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.Cl.[C@H:13]12[CH2:19][C@H:16]([NH:17][CH2:18]1)[CH2:15][N:14]2[C:20]([C@@:22]1([CH2:36][CH:37]([F:39])[F:38])[CH2:26][CH2:25][C@@H:24]([NH:27][C@@H:28]2[C@H:33]([O:34][CH3:35])[CH2:32][O:31][CH2:30][CH2:29]2)[CH2:23]1)=[O:21].C(N(CC)CC)C>CS(C)=O.O1CCOCC1>[F:39][CH:37]([F:38])[CH2:36][C@:22]1([C:20]([N:14]2[CH2:15][C@@H:16]3[CH2:19][C@H:13]2[CH2:18][N:17]3[C:2]2[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=2)=[O:21])[CH2:26][CH2:25][C@@H:24]([NH:27][C@@H:28]2[C@H:33]([O:34][CH3:35])[CH2:32][O:31][CH2:30][CH2:29]2)[CH2:23]1

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 8471TriethylamineHCID 27739122-Chloro-4-(trifluoromethyl)pyrimidine2×HCID 67228981HCID 67228981, compound

Product 1

HCID 67229013HCID 67229013, compoundYield 58%

Reagents, catalysts & solvents 2

HCID 679Dimethyl SulfoxideSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

Prepared as described in example 24 using 2-chloro-4-(trifluoromethyl)pyrimidine in place of 4-chloro-6-(trifluoromethyl)pyrimidine and modifying step 9 as follows. The HCl salt of 1,5-anhydro-2,3-dideoxy-3-{[(1R,3S)-3-{[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-3-(2,2-difluoroethyl)cyclopentyl]amino}-4-O-methyl-D-erythro-pentitol (175 mg, 0.41 mmol) was placed in flask with 1,4-dioxane dioxane (3 ml). Triethylamine (0.2 ml, 1.43 mmol) was added as well as 2-chloro-4-(trifluoromethyl)pyrimidine (237 mg, 1.30 mmol). DMSO (0.3 ml) was added for solubility and the reaction was heated to 100° C. for 14.5 hours. The reaction was cooled to room temperature and partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate and the combined organics were washed with brine, dried over MgSO4, concentrated under reduced pressure and purified with the Biotage (0-100% methanol/ethyl acetate 15 column volumes) to give 1,5-anhydro-2,3-dideoxy-3-{[(1R,3S)-3-(2,2-difluoroethyl)-3-({(1S,4S)-5-[4-(trifluoromethyl)pyrimidin-2-yl]-2,5-diazabicyclo[2.2.1]hept-2-yl}carbonyl)cyclopentyl]amino}-4-O-methyl-D-erythro-pentitol as a brown foam (126 mg, 58%). LC/MS (M+H)=534.2504 exp, 534.2452 obs; 1H NMR (400 MHz, CDCl3) δ ppm 8.48-8.45 (1H), 6.79-6.78 (1H), 5.96-5.58 (1H), 5.10-4.71 (2H), 4.07-4.01 (1H), 3.93-3.87 (1H), 3.69-3.55 (4H) 3.39-3.32 (4H), 3.30-3.21 (3H), 2.77-2.66 (1H), 2.52-2.40 (1H), 2.23-1.82 (7H), 1.70-1.39 (5H)

Workup

  1. customPrepared
  2. temperatureThe reaction was cooled to room temperature
  3. custompartitioned between ethyl acetate and water
  4. extractionThe aqueous layer was extracted with ethyl acetate
  5. washthe combined organics were washed with brine
  6. dry with materialdried over MgSO4
  7. concentrationconcentrated under reduced pressure
  8. custompurified with the Biotage (0-100% methanol/ethyl acetate 15 column volumes)

Sources & evidence

ORD record
ord-9e2ee340fddb45ada03c2035175f2172
Source dataset
uspto-grants-2015_02
Patent number
US08946413B2

Reaction notes

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