Acetic Acid → (S)-N1-(2-(4-(dimethylcarbamoyl)piperidin-1-yl)ethyl)-N1-methyl-N3-(4-(piperidin-1-yl)-2-(4-(1,2,3,4-tetrahydronaphthalen-1-ylcarbamoyl)pyridin-2-yl)phenyl)isophthalamide

HRID 625476Notes

Reaction equation

HRID 625476 reaction equation
[CH3:1][N:2]([CH3:11])[C:3]([CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)=[O:4].[CH3:12][N:13]([CH2:56][CH:57]=O)[C:14](=[O:55])[C:15]1[CH:54]=[CH:53][CH:52]=[C:17]([C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=[CH:23][C:22]=2[C:33]2[CH:38]=[C:37]([C:39](=[O:51])[NH:40][C@@H:41]3[C:50]4[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=4)[CH2:44][CH2:43][CH2:42]3)[CH:36]=[CH:35][N:34]=2)=[O:19])[CH:16]=1.C(O)(=O)C.[BH3-]C#N.[Na+]>C(O)C>[CH3:1][N:2]([CH3:11])[C:3]([CH:5]1[CH2:6][CH2:7][N:8]([CH2:57][CH2:56][N:13]([CH3:12])[C:14](=[O:55])[C:15]2[CH:54]=[CH:53][CH:52]=[C:17]([C:18]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([N:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)=[CH:23][C:22]=3[C:33]3[CH:38]=[C:37]([C:39](=[O:51])[NH:40][C@@H:41]4[C:50]5[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=5)[CH2:44][CH2:43][CH2:42]4)[CH:36]=[CH:35][N:34]=3)=[O:19])[CH:16]=2)[CH2:9][CH2:10]1)=[O:4]

Participants

6

Reactant 4

HCID 176Acetic AcidHCID 411689N,N-dimethylpiperidine-4-carboxamide2×HCID 5003444Sodium cyanoborohydrideHCID 86705967(S)-N1-methyl-N1-(2-oxoethyl)-N3-(4-(piperidin-1-yl)-2-(4-((1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyridin-2-yl)phenyl)isophthalamide

Product 1

HCID 56966142(S)-N1-(2-(4-(dimethylcarbamoyl)piperidin-1-yl)ethyl)-N1-methyl-N3-(4-(piperidin-1-yl)-2-(4-(1,2,3,4-tetrahydronaphthalen-1-ylcarbamoyl)pyridin-2-yl)phenyl)isophthalamide

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent

Procedure

This compound was prepared according to the procedure described for the synthesis of Example 187 using N,N-dimethylpiperidine-4-carboxamide in place of L-proline-tert-butyl ester. Into a 100-mL round-bottom flask, was placed a solution of (S)—N1-methyl-N1-(2-oxoethyl)-N3-(4-(piperidin-1-yl)-2-(4-(1,2,3,4-tetrahydronaphthalen-1-ylcarbamoyl)pyridin-2-yl)phenyl)isophthalamide (100 mg, 0.16 mmol, 1.00 equiv) in ethanol (10 mL), N,N-dimethylpiperidine-4-carboxamide (50 mg, 0.32 mmol, 2.02 equiv), acetic acid (22 mg, 0.37 mmol, 2.31 equiv). The resulting solution was stirred for 0.5 h at room temperature. To the above was added NaBH3CN (22 mg, 0.35 mmol, 2.20 equiv). The resulting solution was allowed to react, with stirring, for an additional 4 h at room temperature. The resulting mixture was concentrated under vacuum. The pH value of the solution was adjusted to 8 with sodium bicarbonate.aq. The resulting solution was extracted with 3×20 mL of ethyl acetate and the organic layers combined. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product (100 mg) was purified by Prep-HPLC with the following conditions (1#-Waters 2767-3): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH3CN (22% CH3CN up to 38% in 6 min); Detector, Waters2545 UvDector 254&270 nm 51.5 mg product was obtained. This resulted in 51.5 mg (42%) of (S)—N1-(2-(4-(dimethylcarbamoyl)piperidin-1-yl)ethyl)-N1-methyl-N3-(4-(piperidin-1-yl)-2-(4-(1,2,3,4-tetrahydronaphthalen-1-ylcarbamoyl)pyridin-2-yl)phenyl)isophthalamide as a light yellow solid. LC-MS (ES, m/z): 770[M+H]+ H-NMR (400 MHz, DMSO, ppm): 12.26 (s, 1H), 9.18˜9.16 (m, 2H), 8.90˜8.88 (d, J=3.9 Hz, 1H), 8.32˜8.25 (m, 2H), 8.02˜7.98 (t, 2H), 7.88˜7.87 (d, J=3.9 Hz, 1H), 7.71˜7.64 (m, 2H), 7.60 (s, 1H), 7.28 (s, 1H), 7.20˜7.10 (m, 4H), 5.26 (s, 1H), 3.85 (s, 11H), 3.38˜3.30 (m, 8H), 3.04 (s, 5H), 2.96 (s, 5H), 2.83˜2.78 (m, 5H), 2.00˜1.91 (m, 4H), 1.86˜1.72 (m, 9H), 1.60˜1.59 (d, J=3.3 Hz, 2H).

Workup

  1. customThis compound was prepared
  2. customInto a 100-mL round-bottom flask, was placed
  3. customto react
  4. stirringwith stirring, for an additional 4 h at room temperature
  5. concentrationThe resulting mixture was concentrated under vacuum
  6. extractionThe resulting solution was extracted with 3×20 mL of ethyl acetate
  7. dry with materialThe mixture was dried over anhydrous sodium sulfate
  8. concentrationconcentrated under vacuum
  9. customThe crude product (100 mg) was purified by Prep-HPLC with the following conditions (1#-Waters 2767-3)
  10. waitmobile phase, water with 0.05% TFA and CH3CN (22% CH3CN up to 38% in 6 min)

Sources & evidence

ORD record
ord-e0c20c6694274db98393a0f0c4ca4b2e
Source dataset
uspto-grants-2016_04
Patent number
US09301951B2

Reaction notes

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