Hydrochloric Acid → HCID 67405250, compound

HRID 406404Notes

Reaction equation

HRID 406404 reaction equation
[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:19][CH:20]3[CH2:37][CH:36]4[N:22]([C:23](=[O:42])[O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH:30][CH:31]5[C:33]([C:39]([OH:41])=O)([NH:34][C:35]4=[O:38])[CH2:32]5)[CH2:21]3)=[CH:8][C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:10]2)=[CH:5][CH:4]=1.C(N=C=NCCCN(C)C)C.Cl.[CH:55]1([S:58]([NH2:61])(=[O:60])=[O:59])[CH2:57][CH2:56]1.N12CCCN=C1CCCCC2>CN(C)C1C=CN=CC=1.CCOC(C)=O.C1(C)C=CC=CC=1.ClCCl.CN(C)C=O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:19][CH:20]3[CH2:37][CH:36]4[N:22]([C:23](=[O:42])[O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH:30][CH:31]5[C:33]([C:39]([NH:61][S:58]([CH:55]6[CH2:57][CH2:56]6)(=[O:60])=[O:59])=[O:41])([NH:34][C:35]4=[O:38])[CH2:32]5)[CH2:21]3)=[CH:8][C:9]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[N:10]2)=[CH:5][CH:4]=1

Participants

9

Reactant 5

HCID 313Hydrochloric AcidHCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 811841,8-Diazabicyclo(5.4.0)undec-7-eneHCID 15765418CyclopropanesulfonamideHCID 67402106HCID 67402106, compound

Product 1

HCID 67405250HCID 67405250, compoundYield 32%

Reagents, catalysts & solvents 3

HCID 142844-(Dimethylamino)pyridineCatalystHCID 21584019Toluene ethylacetateSolventHCID 22350042dichloromethane N,N-dimethylformamideSolvent

Procedure

To a stirred suspension of the acid 22 (0.041 g, 0.072 mmol) in 3:1 dichloromethane-dimethylformamide (1.2 mL) was added N-ethyl-N′-(3-dimethylaminopropyl)-carbodiimide×HCl (0.027 g, 0.143 mmol) upon which a solution was obtained. The reaction mixture was stirred 10 min, after which 4-(dimethylamino)pyridine (0.009 g, 0.072 mmol) was added, and the reaction mixture was stirred another 40 min at room temperature. Then, a solution of the cyclopropylsulfonamide, prepared as described in WO03/053349, (0.035 g, 0.287 mmol) and 1,8-diazabicyclo[5.4.0]-undec-7-ene (0.043 ml, 0.287 mmol) was added and the tube was sealed and then put in the microwave at 100° C. for 40 minutes. The reaction mixture was then partitioned between ethyl acetate (20 mL), aq. 1 M hydrochloric acid and brine. The organic layer was pooled with the organic layer of another batch starting from 0.062 g, 0.108 mmol of the acid treated similar as above. The resulting solution was dried (Na2SO4), filtered and concentrated onto silica. The residue was purified by flash chromatography (gradient AcOEt:toluene 50:50 to 100:0+0.5% AcOH followed by AcOEt/MeOH, 9:1). Appropriate fractions were concentrated and further purified on Preparative HPLC (Column: ACE 5 C8, 100×21.2 mm, ACE-122-1020) using flow=15 mL/min, gradient 55% methanol/5% acetonitrile in aq. 10 mM ammonium acetate to 90% methanol in 10 min. Appropriate fractions were concentrated, re-dissolved in methanol, concentrated and lyophilized overnight to obtain an off-white solid. Finally this material was subjected to column chromatography (AcOEt/toluene, 1:1), to give 39 mg (32%) of the desired product 23 as a white powder: m/z=675 (M+H)+. 13C-NMR (125 MHz, CDCl3): 6.4, 6.5, 22.8, 24.0, 25.3, 28.0, 31.3, 33.4, 37.4, 43.0, 53.8, 56.2, 58.2, 63.7, 76.1, 98.9, 108.3, 115.4, 118.8, 123.3, 126.0, 127.4, 128.0, 128.9, 129.3, 129.6, 130.3, 131.2, 139.8, 151.4, 154.5, 158.5, 160.5, 161.6, 169.9, 175.6.

Workup

  1. customwas obtained
  2. stirringthe reaction mixture was stirred another 40 min at room temperature
  3. additionwas added
  4. customthe tube was sealed
  5. waitput in the microwave at 100° C. for 40 minutes
  6. customThe reaction mixture was then partitioned between ethyl acetate (20 mL), aq. 1 M hydrochloric acid and brine
  7. additiontreated similar as above
  8. dry with materialThe resulting solution was dried (Na2SO4)
  9. filtrationfiltered
  10. concentrationconcentrated onto silica
  11. customThe residue was purified by flash chromatography (gradient AcOEt:toluene 50:50 to 100:0+0.5% AcOH followed by AcOEt/MeOH, 9:1)
  12. concentrationAppropriate fractions were concentrated
  13. customfurther purified on Preparative HPLC (Column: ACE 5 C8, 100×21.2 mm, ACE-122-1020)
  14. customin 10 min
  15. concentrationAppropriate fractions were concentrated
  16. dissolutionre-dissolved in methanol
  17. concentrationconcentrated
  18. waitlyophilized overnight
  19. customto obtain an off-white solid

Sources & evidence

ORD record
ord-9478f1cc7f88484ea4a499d83a6aba98
Source dataset
uspto-grants-2014_06
Patent number
US08754105B2

Reaction notes

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