Water → AFN-1252 tosylate monohydrate

HRID 2383083Notes

Reaction equation

HRID 2383083 reaction equation
C(Cl)Cl.[CH3:4][N:5]([CH2:21][C:22]1[O:23][C:24]2[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=2[C:26]=1[CH3:27])[C:6](=[O:20])/[CH:7]=[CH:8]/[C:9]1[CH:10]=[N:11][C:12]2[NH:13][C:14](=[O:19])[CH2:15][CH2:16][C:17]=2[CH:18]=1.[CH3:32][C:33]1[CH:34]=[CH:35][C:36]([S:39]([OH:42])(=[O:41])=[O:40])=[CH:37][CH:38]=1.O.O>CO.CCCCCCC>[OH2:19].[S:39]([C:36]1[CH:37]=[CH:38][C:33]([CH3:32])=[CH:34][CH:35]=1)([OH:42])(=[O:41])=[O:40].[CH3:4][N:5]([CH2:21][C:22]1[O:23][C:24]2[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=2[C:26]=1[CH3:27])[C:6](=[O:20])/[CH:7]=[CH:8]/[C:9]1[CH:10]=[N:11][C:12]2[NH:13][C:14](=[O:19])[CH2:15][CH2:16][C:17]=2[CH:18]=1

Participants

7

Reactant 4

HCID 962WaterHCID 6344DichloromethaneHCID 521998p-Toluenesulfonic acid monohydrateHCID 10407120AFN-1252

Product 1

HCID 25029351AFN-1252 tosylate monohydrateYield 187.5%

Reagents, catalysts & solvents 2

HCID 887MethanolSolvent2×HCID 8900HeptaneSolvent

Conditions

Temperature
37.5 °C

Procedure

A 22-L three-necked round-bottomed flask with a mechanical stirrer, a thermocouple, a reflux condenser and a nitrogen inlet was flushed with N2. The flask was charged with DCM (12 L, 16 v) and (E)-N-methyl-N-((3-methylbenzofuran-2-yl)methyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide (0.75 kg, 1.999 mol, 1.0 eq.). To the suspension, MeOH (1 L, 1.33 eq) was added and resulting suspension was heated to IT=35-40° C. When IT=35° C., a solution of TsOH.H2O (0.38 kg, 1.999 mol. 1 eq.) in methanol (0.5 L, 0.67 v) was added over 10 min while maintaining IT=35-40° C. After the addition was complete a clear solution was formed which was then filtered through 0.45 μm filter paper. The filtrate was divided in to two halves and transferred into two 22-L three-necked round-bottomed flasks with a mechanical stirrer, a thermocouple, a reflux condenser and a nitrogen inlet. Each solution was stirred at IT=35-40° C. and water (32 g, 2 mol, 1 eq.) was added. The clear solutions were then diluted with heptane (6 L, 8 v) over 15 min while maintaining IT=35-40° C. The resulting suspensions were allowed cooled to IT=20-25° C. over 3 h and allowed to stir at the same temperature for 18 h. The solid was collected by filtration using a Buchnner funnel with a cloth filter and 20-L glass receiver under vacuum. The solids were washed with heptane (3×2.7 v). The damp solid was dried under vacuum at 30-35° C. with a slow N2 bleed for 72 h to a constant weight to give 1.06 kg of the desired product as a white solid. The material was analyzed and the results indicated 98.3% area HPLC purity with 7.7 ppm Pd. This material was used for ball milling.

Workup

  1. customA 22-L three-necked round-bottomed flask with a mechanical stirrer, a thermocouple, a reflux condenser and a nitrogen inlet was flushed with N2
  2. customresulting suspension
  3. temperaturewhile maintaining IT=35-40° C
  4. additionAfter the addition
  5. customwas formed which
  6. filtrationwas then filtered through 0.45 μm
  7. filtrationfilter paper
  8. customtransferred into two 22-L three-necked round-bottomed flasks with a mechanical stirrer
  9. additionwas added
  10. temperaturewhile maintaining IT=35-40° C
  11. temperatureThe resulting suspensions were allowed cooled to IT=20-25° C. over 3 h
  12. filtrationThe solid was collected by filtration
  13. filtrationfilter
  14. washThe solids were washed with heptane (3×2.7 v)
  15. dry with materialThe damp solid was dried under vacuum at 30-35° C. with a slow N2
  16. waitbleed for 72 h to a constant weight

Sources & evidence

ORD record
ord-25227db22cd44f06b24537a1e3d51b9f
Source dataset
uspto-grants-2012_09
Patent number
US08263613B2

Reaction notes

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