Hydrochloric Acid → (+/-)-6-({[(3-fluoro-1-{2-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinyl)methyl]amino}methyl)-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-one

HRID 639095Notes

Reaction equation

HRID 639095 reaction equation
CC([N:5]([CH2:9][C:10]1([F:30])[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH3:28])[N:25]=3)[N:20]=[CH:19][C:18]=2[F:29])[CH2:11]1)C(=O)[O-])(C)C.Cl.[O:32]=[C:33]1[NH:38][C:37]2[N:39]=[C:40]([CH:43]=O)[CH:41]=[CH:42][C:36]=2[S:35][CH2:34]1.CCN(CC)CC.[BH4-].[Na+]>O1CCOCC1.C(Cl)Cl.CCO>[F:30][C:10]1([CH2:9][NH:5][CH2:43][C:40]2[CH:41]=[CH:42][C:36]3[S:35][CH2:34][C:33](=[O:32])[NH:38][C:37]=3[N:39]=2)[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH3:28])[N:25]=3)[N:20]=[CH:19][C:18]=2[F:29])[CH2:11]1

Participants

9

Reactant 5

HCID 313Hydrochloric AcidHCID 8471TriethylamineHCID 4311764Sodium borohydrideHCID 115935913-Oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carbaldehydeHCID 86616798HCID 86616798, compound

Product 1

HCID 59026095(+/-)-6-({[(3-fluoro-1-{2-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinyl)methyl]amino}methyl)-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-oneYield 67%

Reagents, catalysts & solvents 3

HCID 702EthanolSolventHCID 6344DichloromethaneSolventHCID 312751,4-DioxaneSolvent2×

Procedure

To a stirred solution of 1,1-dimethylethyl[(3-fluoro-1-{2-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinyl)methyl]carbamate (0.85 g, 2.0 mmole) in dioxane (50 mL) was added 4M HCl in dioxane (20 mL). After 4 h at RT, the reaction solution was concentrated to dryness under vacuum. To the amine hydrochloride salt in dry CH2Cl2 (25 mL) and dry EtOH (20 mL) at RT was added 3-oxo-3,4-dihydro-2H-pyrido[1,4]thiazine-6-carboxaldehyde (0.39 g, 2.0 mmole) and Et3N (0.84 mL, 6.0 mmole). After 24 h at RT, NaBH4 (0.01 g, 0.23 mmole) was added. After 2 h, silica gel (5 g) was added to the reaction solution and the suspension was concentrated under vacuum to a dry solid. Purification on silica (CHCl3/MeOH, 9:1 containing 5% NH4OH) afforded the title compound (0.67 g, 67%) as light yellow solid: 1H NMR (400 MHz, CD3OD) δ 8.67 (s, 1H), 8.19 (d, J=9.0 Hz, 1H), 7.77 (d, J=7.8 Hz, 1H), 7.15 (m, 2H), 4.31 (s, 2H), 4.13 (s, 3H), 3.75 (m, 2H), 3.64 (m, 2H), 3.60 (m, 4H), 3.57 (m, 4H), 2.54 (m, 2H). LC-MS (ES) m/e 501 (M+H)+.

Workup

  1. concentrationthe reaction solution was concentrated to dryness under vacuum
  2. waitAfter 24 h at RT
  3. waitAfter 2 h
  4. additionsilica gel (5 g) was added to the reaction solution
  5. concentrationthe suspension was concentrated under vacuum to a dry solid
  6. customPurification on silica (CHCl3/MeOH, 9:1 containing 5% NH4OH)

Sources & evidence

ORD record
ord-09d925bf21fe4979aadd60af275219c8
Source dataset
uspto-grants-2010_04
Patent number
US07691850B2

Reaction notes

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