1-Methylpiperazin-2-one → (S)-N1-methyl-N1-(2-(4-methyl-3-oxopiperazin-1-yl)ethyl)-N3-(4-(piperidin-1-yl)-2-(4-(1,2,3,4-tetrahydronaphthalen-1-ylcarbamoyl)pyridin-2-yl)phenyl)isophthalamide

HRID 625474Notes

Reaction equation

HRID 625474 reaction equation
[CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][C:3]1=[O:8].[CH3:9][N:10]([CH2:53][CH:54]=O)[C:11](=[O:52])[C:12]1[CH:51]=[CH:50][CH:49]=[C:14]([C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[CH:20][C:19]=2[C:30]2[CH:35]=[C:34]([C:36](=[O:48])[NH:37][C@@H:38]3[C:47]4[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=4)[CH2:41][CH2:40][CH2:39]3)[CH:33]=[CH:32][N:31]=2)=[O:16])[CH:13]=1.[BH3-]C#N.[Na+]>C(O)C.C(O)(=O)C.C(OCC)(=O)C>[CH3:9][N:10]([CH2:53][CH2:54][N:5]1[CH2:6][CH2:7][N:2]([CH3:1])[C:3](=[O:8])[CH2:4]1)[C:11](=[O:52])[C:12]1[CH:51]=[CH:50][CH:49]=[C:14]([C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]3)=[CH:20][C:19]=2[C:30]2[CH:35]=[C:34]([C:36](=[O:48])[NH:37][C@@H:38]3[C:47]4[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=4)[CH2:41][CH2:40][CH2:39]3)[CH:33]=[CH:32][N:31]=2)=[O:16])[CH:13]=1

Participants

7

Reactant 3

HCID 43990421-Methylpiperazin-2-one2×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 56966143(S)-N1-methyl-N1-(2-(4-methyl-3-oxopiperazin-1-yl)ethyl)-N3-(4-(piperidin-1-yl)-2-(4-(1,2,3,4-tetrahydronaphthalen-1-ylcarbamoyl)pyridin-2-yl)phenyl)isophthalamide

Reagents, catalysts & solvents 3

HCID 176Acetic AcidCatalystHCID 702EthanolSolvent2×HCID 8857Ethyl AcetateSolvent

Procedure

This compound was prepared according to the procedure described for the synthesis of Example 187 using methylpiperazin-2-one in place of L-proline-tert-butyl ester. Into a 50-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 (2 mL). This was followed by the addition of a solution of 1-methylpiperazin-2-one (18 mg, 0.16 mmol, 1.00 equiv) in ethanol (2 mL), two drop of acetic acid. To this was added NaBH3CN (20 mg, 0.32 mmol, 2.00 equiv). The resulting solution was stirred for 2 h at room temperature. The resulting solution was diluted with 50 mL of ethyl acetate. The resulting mixture was washed with 2×20 mL of brine. 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. 70 mg product was obtained. This resulted in 70 mg (61%) of (S)—N1-methyl-N1-(2-(4-methyl-3-oxopiperazin-1-yl)ethyl)-N3-(4-(piperidin-1-yl)-2-(4-(1,2,3,4-tetrahydronaphthalen-1-ylcarbamoyl)pyridin-2-yl)phenyl)isophthalamide as a yellow solid. LC-MS (ES, m/z): 728 [M+H]+ H-NMR (300 MHz, DMSO, ppm): 12.25 (s, 1H), 9.18 (d, J=8.4 Hz, 1H), 8.80 (d, J=5.1 Hz, 1H), 8.29 (d, J=13.8 Hz 2H), 7.99 (t, J=6.9 Hz, 2H), 7.86 (d, J=4.8 Hz, 1H), 7.57-7.67 (m, 3H), 7.10-7.28 (m, 5H), 5.25 (d, J=5.4 Hz, 1H), 3.92-3.85 (m, 4H), 3.30-3.54 (m, 10H), 2.78-2.95 (m, 9H), 1.99 (d, J=3.6 Hz, 2H), 1.72-1.80 (m, 6H), 1.60 (s, 2H).

Workup

  1. customThis compound was prepared
  2. customInto a 50-mL round-bottom flask, was placed
  3. washThe resulting mixture was washed with 2×20 mL of brine
  4. dry with materialThe mixture was dried over anhydrous sodium sulfate
  5. concentrationconcentrated under vacuum
  6. customThe crude product (100 mg) was purified by Prep-HPLC with the following conditions (1#-Waters 2767-3)
  7. waitmobile phase, water with 0.05% TFA and CH3CN (22% CH3CN up to 38% in 6 min)

Sources & evidence

ORD record
ord-e18578c4c66244978e7ded2de2bc01bb
Source dataset
uspto-grants-2016_04
Patent number
US09301951B2

Reaction notes

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