1,2-Dimethoxyethane → HCID 118045663, compound

HRID 595824Notes

Reaction equation

HRID 595824 reaction equation
[NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][S:10](=[O:14])(=[O:13])[CH2:9]2)=[CH:4][C:3]=1Br.[CH2:16]([NH:23][C:24]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][C:27]=1[F:35])=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.CO>[NH2:1][C:2]1[C:3]([C:29]2[CH:30]=[CH:31][C:26]([C:24]([NH:23][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[O:25])=[C:27]([F:35])[CH:28]=2)=[CH:4][C:5]([C@@H:8]2[CH2:12][CH2:11][S:10](=[O:14])(=[O:13])[CH2:9]2)=[CH:6][N:7]=1.[NH2:1][C:2]1[C:3]([C:29]2[CH:30]=[CH:31][C:26]([C:24]([NH:23][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[O:25])=[C:27]([F:35])[CH:28]=2)=[CH:4][C:5]([C@H:8]2[CH2:12][CH2:11][S:10](=[O:14])(=[O:13])[CH2:9]2)=[CH:6][N:7]=1

Participants

8

Reactant 4

HCID 80711,2-DimethoxyethaneHCID 10340Sodium CarbonateHCID 44717404[4-(Benzylcarbamoyl)-3-fluorophenyl]boronic acidHCID 118045604HCID 118045604, compound

Product 2

HCID 118045663HCID 118045663, compoundHCID 118045759HCID 118045759, compound

Reagents, catalysts & solvents 2

HCID 178418807HCID 178418807, compoundCatalystHCID 887MethanolSolvent

Conditions

Temperature
105 °C

Procedure

To a microwave reactor was charged with 3-(6-amino-5-bromopyridin-3-yl)tetrahydrothiophene 1,1-dioxide (50 mg, 0.172 mmol), 4-(benzylcarbamoyl)-3-fluorophenylboronic acid (94 mg, 0.343 mmol), 2 M aqueous Na2CO3 (0.34 mL) and PdCl2(dppf)-DCM adduct (14 mg) and DME (3 mL) were charged in a microwave vial and the mixture was purged with Argon, sealed and heated at 105° C. for 20 min. The DME layer of the reaction mixture was collected, concentrated under reduced pressure and the residue was redissolved in EtOAc (5 mL). The EtOAc solution was stripped with 1N HCl (4×1 mL) and the aqueous layers were combined, scrubbed with EtOAc (2×1 mL), then concentrated under reduced pressure and the residue was partitioned between EtOAc/sat. Na2CO3 (5 mL/1 mL), and the EtOAc extract was washed with sat. Na2CO3 (2×1 mL), brine (1 mL), dried (Na2SO4), concentrated and the residue was redissolved in acetonitrile/water (6 mL/6 mL), frozen and lyophilized yielding racemic 4-(2-amino-5-(1,1-dioxidotetrahydrothiophen-3-yl)pyridin-3-yl)-N-benzyl-2-fluorobenzamidein as light yellow powder. LCMS (m/z): 440.2 (MH+), 0.60 min; 1H NMR (CD3OD) δ ppm 7.97 (d, J=2.0 Hz, 1H), 7.84 (t, J=7.8 Hz, 1H), 7.50 (d, J=2.3 Hz, 1H), 7.31-7.44 (m, 6H), 7.22-7.30 (m, 1H), 4.61 (s, 2H), 3.55-3.70 (m, 1H), 3.47 (dd, J=13.3, 7.0 Hz, 1H), 3.33-3.39 (m, 1H), 3.08-3.25 (m, 2H), 2.53 (ddd, J=13.1, 7.4, 5.7 Hz, 1H), 2.18-2.40 (m, 1H). The racemic product was further resolved by chiral SFC (ChiralPak 5mic OJ column, 4.6×100 (mm), 5 mL/min, MeOH+0.1% DEA=50%) to afford (S)-4-(2-amino-5-(1,1-dioxidotetrahydrothiophen-3-yl)pyridin-3-yl)-N-benzyl-2-fluorobenzamide (Rt=1.7 min) and (R)-4-(2-amino-5-(1,1-dioxidotetrahydrothiophen-3-yl)pyridin-3-yl)-N-benzyl-2-fluorobenzamide (Rt=2.22 min). The absolute stereochemistry was arbitrarily assigned.

Workup

  1. additionwere charged in a microwave vial
  2. customthe mixture was purged with Argon
  3. customsealed
  4. customThe DME layer of the reaction mixture was collected
  5. concentrationconcentrated under reduced pressure
  6. dissolutionthe residue was redissolved in EtOAc (5 mL)
  7. concentrationconcentrated under reduced pressure
  8. customthe residue was partitioned between EtOAc/
  9. extractionNa2CO3 (5 mL/1 mL), and the EtOAc extract
  10. washwas washed with sat. Na2CO3 (2×1 mL), brine (1 mL)
  11. dry with materialdried (Na2SO4)
  12. concentrationconcentrated
  13. dissolutionthe residue was redissolved in acetonitrile/water (6 mL/6 mL)
  14. temperaturefrozen
  15. customlyophilized yielding racemic 4-(2-amino-5-(1,1-dioxidotetrahydrothiophen-3-yl)pyridin-3-yl)-N-benzyl-2-fluorobenzamidein as light yellow powder
  16. custom440.2 (MH+), 0.60 min

Sources & evidence

ORD record
ord-637c1a03342d400e857f620d02ad6b35
Source dataset
uspto-grants-2016_01
Patent number
US09242996B2

Reaction notes

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