Pivalic acid → (S)-1-(3-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-yl)-2,2-dimethylpropan-1-one

HRID 1483945Notes

Reaction equation

HRID 1483945 reaction equation
[C:1]([OH:7])(=O)[C:2]([CH3:5])([CH3:4])[CH3:3].N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.Cl.[NH2:31][C:32]1[C:33]2[C:43]([O:44][CH2:45][C@H:46]3[CH2:51][CH2:50][CH2:49][NH:48][CH2:47]3)=[CH:42][CH:41]=[CH:40][C:34]=2[NH:35][S:36](=[O:39])(=[O:38])[N:37]=1>O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+].CN(C=O)C>[NH2:31][C:32]1[C:33]2[C:43]([O:44][CH2:45][C@H:46]3[CH2:51][CH2:50][CH2:49][N:48]([C:1](=[O:7])[C:2]([CH3:5])([CH3:4])[CH3:3])[CH2:47]3)=[CH:42][CH:41]=[CH:40][C:34]=2[NH:35][S:36](=[O:38])(=[O:39])[N:37]=1

Participants

7

Reactant 4

HCID 6417Pivalic acidHCID 757711-HydroxybenzotriazoleHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 86714273HCID 86714273, compound

Product 1

HCID 73213588(S)-1-(3-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-yl)-2,2-dimethylpropan-1-oneYield 48.3%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 180504Ceric ammonium nitrateSolvent

Conditions

Temperature
130 °C

Procedure

Pivalic acid (71 mg, 0.692 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (117 mg, 0.865 mmol), and 1-(3-Dimethylaminopropyl)-3-ethyl carbodiimide HCl (166 mg, 10.8 mmol) were placed into a 20 mL microwave flask and diluted with anhydrous CAN (12 mL) then a solution of(S)-4-amino-5-(piperidin-3-ylmethoxy)-1H-benzo[c][1,2,6]thiadiazine 2,2-dioxide hydrochloride (Example 2a, 200 mg, 0.577 mmol) and TEA (320 uL, 2.30 mmol) in DMF (2 mL) was added. The mixture was heated with stirring in the microwave at 130° C. for 1 hour then cooled to room temperature, transferred to 250 mL round bottom flask and concentrated via rotary evaporation. The residue was purified via preparative RP HPLC (10 to 90% ACN in water). The pure fractions were collected and dried then diluted with water (6 mL) and NaHCO3 (100 mg) was added and the solution heated to 90° C. for 15 minutes until the entire compound dissolved. The solution was then cooled to 0° C. and neutralized with 1N HCl solution. The precipitate was collected and dried to provide the title compound (110 mg, 48%). 1H NMR (DMSO-d6, 400 MHz, 80° C.): 1.15 (s, 9H), 1.35 (m, 2H), 1.68 (br s, 1H), 1.85 (br s, 1H), 2.05 (br s, 1H), 2.83 (br s, 2H), 2.16 (br s, 2H), 4.06 (d, J=8 Hz, 2H), 4.12 (d, J=12 Hz, 1H), 4.20 (d, J=16 Hz, 1H), 6.60 (d, J=8 Hz, 1H), 6.76 (d, J=8 Hz, 1H), 7.44 (t, J=8 Hz, 1H), 7.78 (s, 1H), 8.37 (s, 1H), 10.93 (s, 1H). M+H=395.

Workup

  1. temperatureThe mixture was heated
  2. temperaturethen cooled to room temperature
  3. customtransferred to 250 mL round bottom flask
  4. concentrationconcentrated via rotary evaporation
  5. customThe residue was purified via preparative RP HPLC (10 to 90% ACN in water)
  6. customThe pure fractions were collected
  7. customdried
  8. additionthen diluted with water (6 mL) and NaHCO3 (100 mg)
  9. additionwas added
  10. temperaturethe solution heated to 90° C. for 15 minutes until the entire compound
  11. dissolutiondissolved
  12. temperatureThe solution was then cooled to 0° C. and neutralized with 1N HCl solution
  13. customThe precipitate was collected
  14. customdried

Sources & evidence

ORD record
ord-c80f2abbeb8847b0a1d1105ab4df862c
Source dataset
uspto-grants-2016_08
Patent number
US09420814B2

Reaction notes

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