Triethylamine → 6-fluoro-2-methyl-3-[(3S,9aS)-8-{[2-(1H-tetrazol-1-yl)pyrimidin-5-yl]acetyl}octahydropyrazino[2,1-c][1,4]oxazin-3-yl]benzonitrile

HRID 1502176Notes

Reaction equation

HRID 1502176 reaction equation
CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.FC(F)(F)C([O-])=O.[C:32]([C:34]1[C:35]([CH3:51])=[C:36]([C@@H:41]2[O:46][CH2:45][C@@H:44]3[CH2:47][NH2+:48][CH2:49][CH2:50][N:43]3[CH2:42]2)[CH:37]=[CH:38][C:39]=1[F:40])#[N:33].[N:52]1([C:57]2[N:62]=[CH:61][C:60]([CH2:63][C:64](O)=[O:65])=[CH:59][N:58]=2)[CH:56]=[N:55][N:54]=[N:53]1.C(N(CC)CC)C>CN(C=O)C>[F:40][C:39]1[C:34]([C:32]#[N:33])=[C:35]([CH3:51])[C:36]([C@@H:41]2[O:46][CH2:45][C@@H:44]3[CH2:47][N:48]([C:64](=[O:65])[CH2:63][C:60]4[CH:59]=[N:58][C:57]([N:52]5[CH:56]=[N:55][N:54]=[N:53]5)=[N:62][CH:61]=4)[CH2:49][CH2:50][N:43]3[CH2:42]2)=[CH:37][CH:38]=1

Participants

6

Reactant 4

HCID 8471TriethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 896190903-[(3S,9aS)-1,3,4,6,7,8,9,9a-octahydropyrazino[2,1-c][1,4]oxazin-8-ium-3-yl]-6-fluoro-2-methylbenzonitrile;2,2,2-trifluoroacetateHCID 89619099[2-(1H-tetrazol-1-yl)pyrimidin-5-yl]acetic acid

Product 1

HCID 716039166-fluoro-2-methyl-3-[(3S,9aS)-8-{[2-(1H-tetrazol-1-yl)pyrimidin-5-yl]acetyl}octahydropyrazino[2,1-c][1,4]oxazin-3-yl]benzonitrile

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Procedure

HATU (192 mg, 0.504 mmol) was added to a solution of (3S,9aS)-3-(3-cyano-4-fluoro-2-methylphenyl)octahydropyrazino[2,1-c][1,4]oxazin-8-ium trifluoroacetate (104 mg, 0.504 mmol) in DMF (1.5 mL). The reaction mixture was stirred at RT for 15 minutes and a solution of [2-(1H-tetrazol-1-yl)pyrimidin-5-yl]acetic acid (284 mg, 0.564 mmol) and triethylamine (0.37 ml, 2.65 mmol) in DMF (1 mL) was added. The flask was rinsed with DMF (0.5 mL). The solution was stirred at RT overnight then diluted with EtOAc and washed with dilute NaHCO3 solution, water (3×) and brine, dried (MgSO4), filtered and the solvent evaporated. The residue was purified by silica gel chromatography (24 g cartridge) using CH2Cl2 (A) and CH2Cl2:MeOH 90:10 (B) with gradient elution from 100% A to 100% B over 12 column volumes and holding at 60% A for 2 column volumes to afford the title compound: LC/MS: 505 (M+CH3CN+Na), 464 (M+H). The title compound was converted to its hydrochloride salt by dissolving in methylene chloride and adding 1 equivalent 1M HCl in ether. The suspension was stirred at RT for 30 minutes and the solvent evaporated: NMR 500 MHz (CD3OD(mixture amide rotamers) 10.03 (s, 1H); 8.87 (s, 1H); 8.86 (s, 1H); 7.94 (q, 1H); 7.31 (d t, 1H); 5.08-5.15 (m, 1H); 54.68 (d, 0.5H); 4.60 (d, 0.5H); 4.01-4.38 (m, 5.5H); 3.82 (t, 2H); 3.58-3.71 (m, 1.5H); 3.40-3.53 (m, 2.5H); 3-31-3.37 (m, 1.5H); 2.61 (br s, 3H); LC/MS 527 (M+Na+CH3CN), 505 (M+H+CH3CN), 486 (M+Na), 464 (M+H).

Workup

  1. washThe flask was rinsed with DMF (0.5 mL)
  2. stirringThe solution was stirred at RT overnight
  3. additionthen diluted with EtOAc
  4. washwashed with dilute NaHCO3 solution, water (3×) and brine
  5. dry with materialdried (MgSO4)
  6. filtrationfiltered
  7. customthe solvent evaporated
  8. customThe residue was purified by silica gel chromatography (24 g cartridge)
  9. washwith gradient elution from 100% A to 100% B over 12 column volumes

Sources & evidence

ORD record
ord-47fcaa70311e4a30bce051c2ce51543f
Source dataset
uspto-grants-2015_12
Patent number
US09206199B2

Reaction notes

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