3-Aminopyridine → HCID 67121341, compound

HRID 406149Notes

Reaction equation

HRID 406149 reaction equation
[OH:1][C:2]1[C:7]2[C@@:8]3([OH:45])[C@@:21]([O:25][CH3:26])([C@H:22]([OH:24])[CH2:23][C:6]=2[CH:5]=[C:4]([CH3:46])[C:3]=1[C:47](O)=[O:48])[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:43])[C:14]([NH:30][CH:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)=[CH:15][C:16](=[O:29])[C:17]=2[C:18]=1[OH:28])[C:9]3=[O:44].[NH2:50][C:51]1[CH:52]=[N:53][CH:54]=[CH:55][CH:56]=1.O.ON1C2C=CC=CC=2N=N1>C1COCC1>[OH:1][C:2]1[C:7]2[C@@:8]3([OH:45])[C@@:21]([O:25][CH3:26])([C@H:22]([OH:24])[CH2:23][C:6]=2[CH:5]=[C:4]([CH3:46])[C:3]=1[C:47]([NH:50][C:51]1[CH:52]=[N:53][CH:54]=[CH:55][CH:56]=1)=[O:48])[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:43])[C:14]([NH:30][CH:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)=[CH:15][C:16](=[O:29])[C:17]=2[C:18]=1[OH:28])[C:9]3=[O:44]

Participants

5

Reactant 3

HCID 100093-AminopyridineHCID 27960291-Hydroxybenzotriazole hydrateHCID 67121425HCID 67121425, compound

Product 1

HCID 67121341HCID 67121341, compoundYield 9%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a solution of (6R,6aS,14aR)-1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylic acid (50 mg, 0.073 mmol) in THF (5 mL) were added 3-aminopyridine (14 mg, 0.15 mmol), polystyrene carbodiimide (130 mg, 0.147 mmol, 1.12 mmol/g), and 1-hydroxybenzotriazole hydrate (20 mg, 0.15 mmol). The reaction mixture was stirred at room temperature under nitrogen for 12 h. The reaction was quenched by adding 1N HCl solution (5 mL) and brine (25 mL). The aqueous layer was extracted with methylene chloride (2×50 mL). The organic layer was separated, dried (MgSO4), filtered and concentrated to give the crude product. The crude material was purified by preparative HPLC (10:90 acetonitrile/water to 60:40 acetonitrile/water with 0.05% TFA over 10 min, then isocratic) and lyophilized to afford (6R,6aS,14aR)-1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-N-(pyridin-3-yl)-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxamide (5 mg, 9%) as a dark red solid. To a solution of this material in anhydrous methanol at 0° C. was added 1.25 N HCl in methanol (8 μL, 0.008 mmol) and the mixture was stirred at 0° C. for 30 min. The reaction mixture was concentrated, triturated with diethyl ether, and lyophilized from acetonitrile/water to afford (6R,6aS,14aR)-1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-N-(pyridin-3-yl)-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxamide hydrochloride (5 mg, 95%) as a red-brown powder and as a mixture of diastereomers: 1H NMR (500 MHz, CD3OD) δ 9.43 (s, 1H), 8.55 (d, J=5.0 Hz, 1H), 8.43 (t, J=8.5 Hz, 1H), 8.10 (s, 1H), 7.99 (t, J=16.5 Hz, 1H), 6.70 (s, 1H), 6.17 (s, 0.4H), 6.02 (s, 0.6H), 4.94-4.83 (m, 2H), 3.72 (s, 3H), 3.67 (t, J=3.5 Hz, 1H), 3.63-3.60 (m, 1H), 3.57 (s, 3H), 3.51 (d, J=19.5 Hz, 3H), 3.47-3.37 (m, 2H), 3.26 (d, J=19.0 Hz, 1H), 3.09-2.99 (m, 1H), 2.25 (s, 3H), 1.26 (d, J=6.0 Hz, 1.8H), 1.22 (d, J=6.0 Hz, 1.2H); MS (ESI+) m/z 760 (M+H); HPLC 90.8% (AUC), tR 11.81 min.

Workup

  1. customThe reaction was quenched
  2. additionby adding 1N HCl solution (5 mL) and brine (25 mL)
  3. extractionThe aqueous layer was extracted with methylene chloride (2×50 mL)
  4. customThe organic layer was separated
  5. dry with materialdried (MgSO4)
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customto give the crude product
  9. customThe crude material was purified by preparative HPLC (10:90 acetonitrile/water to 60:40 acetonitrile/water with 0.05% TFA over 10 min

Sources & evidence

ORD record
ord-5f270c2844c244f2a99b5fb9012a7dc1
Source dataset
uspto-grants-2014_06
Patent number
US08754054B2

Reaction notes

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