Hydrochloric Acid → 2-[(3S)-12-[[4-(dimethylamino)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]-N-(5-fluoropyridin-2-yl)acetamide

HRID 1503906Notes

Reaction equation

HRID 1503906 reaction equation
[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([CH2:11][C@@H:12]2[CH2:23][CH2:22][C:21]3[S:20][C:19]4[N:18]=[CH:17][N:16]=[C:15]([O:24][CH:25]5[CH2:30][CH2:29][CH:28]([N:31]([CH3:39])[C:32](=O)OC(C)(C)C)[CH2:27][CH2:26]5)[C:14]=4[C:13]2=3)=[O:10])=[N:6][CH:7]=1.Cl.C=O.[BH3-]C#N.[Na+]>ClCCl.CO>[CH3:39][N:31]([CH3:32])[CH:28]1[CH2:29][CH2:30][CH:25]([O:24][C:15]2[C:14]3[C:13]4[C@H:12]([CH2:11][C:9]([NH:8][C:5]5[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=5)=[O:10])[CH2:23][CH2:22][C:21]=4[S:20][C:19]=3[N:18]=[CH:17][N:16]=2)[CH2:26][CH2:27]1

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 712FormaldehydeHCID 5003444Sodium cyanoborohydrideHCID 86695086tert-butyl N-(4-[[(3 S)-3-[[(5-fluoropyridin-2-yl)carbamoyl]methyl]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate

Product 1

HCID 681103592-[(3S)-12-[[4-(dimethylamino)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]-N-(5-fluoropyridin-2-yl)acetamideYield 13%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 6344DichloromethaneSolvent

Procedure

To a 25-mL round-bottom flask containing a solution of 23.1 (195 mg, 0.35 mmol, 1.00 equiv) in dichloromethane (15 mL) was added hydrochloric acid (12 M, 2 mL) at 0° C. under nitrogen. The resulting solution was stirred for 2 h at room temperature and concentrated under vacuum. The resulting N-(5-fluoropyridin-2-yl)-2-[(3S)-12-[[4-(methylamino)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]acetamide hydrochloride (130 mg, crude) was used in the next step directly without further purification. A solution of this material (130 mg, crude) and HCHO (37%, 1 mL) in methanol (10 mL) was stirred at room temperature for 30 min, whereupon NaBH3CN (55 mg, 0.78 mmol, 3.06 equiv) was added and the mixture stirred for an additional 2 h at room temperature. The reaction was then quenched by the addition of 20 mL of water and extracted with 3×30 mL of ethyl acetate. The combined organic layers were concentrated under vacuum. The crude product (70 mg) was purified by preparative HPLC(SHIMADZU) under the following conditions: column: Xbridge Prep C18 5 um, 19*150 mm; mobile phase: water (0.05% NH4HCO3) and CH3CN (6.0% CH3CN up to 50.0% in 25 min); UV detection at 254 and 220 nm. The fractions were collected and evaporated under reduced pressure to give the 2-[(3S)-12-[[4-(dimethylamino)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]-N-(5-fluoropyridin-2-yl)acetamide (I-38, 21.4 mg) as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.49 (s, 1H), 8.20 (m, 2H), 7.63 (m, 1H), 5.28 (m, 1H), 3.93 (t, 1H), 3.33 (m, 2H), 3.03 (m, 1H), 2.82 (m, 1H), 2.77 (m, 1H), 2.55 (m, 10H), 2.03 (m, 2H), 1.55 (m, 4H). MS: m/z 470 (M+H)+.

Workup

  1. concentrationconcentrated under vacuum
  2. customThe resulting N-(5-fluoropyridin-2-yl)-2-[(3S)-12-[[4-(methylamino)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]acetamide hydrochloride (130 mg, crude) was used in the next step directly without further purification
  3. additionwas added
  4. stirringthe mixture stirred for an additional 2 h at room temperature
  5. customThe reaction was then quenched by the addition of 20 mL of water
  6. extractionextracted with 3×30 mL of ethyl acetate
  7. concentrationThe combined organic layers were concentrated under vacuum
  8. customThe crude product (70 mg) was purified by preparative HPLC(SHIMADZU) under the following conditions
  9. waitmobile phase: water (0.05% NH4HCO3) and CH3CN (6.0% CH3CN up to 50.0% in 25 min)
  10. customThe fractions were collected
  11. customevaporated under reduced pressure

Sources & evidence

ORD record
ord-dc193ad9d9d74ee08f99ca5c95ae840f
Source dataset
uspto-grants-2015_12
Patent number
US09212190B2

Reaction notes

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