Sodium Carbonate → (5-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)(2-(hydroxymethyl)pyrrolidin-1-yl)methanone

HRID 877536

Reaction equation

HRID 877536 reaction equation
Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13]([N:15]3[CH2:19][CH2:18][CH:17](CO)[CH2:16]3)=[O:14])=[N:10][N:9]=2)=[C:4]([NH:22][CH:23]([CH3:25])[CH3:24])[CH:3]=1.[NH2:26][C:27]1[CH:35]=[CH:34][C:30]2[N:31]=[CH:32][S:33][C:29]=2[CH:28]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)[O:57][C:39]2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[S:33]1[C:29]2[CH:28]=[C:27]([NH:26][C:2]3[N:7]=[CH:6][C:5]([C:8]4[S:12][C:11]([C:13]([N:15]5[CH2:16][CH2:17][CH2:18][CH:19]5[CH2:39][OH:57])=[O:14])=[N:10][N:9]=4)=[C:4]([NH:22][CH:23]([CH3:24])[CH3:25])[CH:3]=3)[CH:35]=[CH:34][C:30]=2[N:31]=[CH:32]1

Participants

8

Reactant 4

HCID 10340Sodium CarbonateHCID 682886-AminobenzothiazoleHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 89691050(5-(6-Chloro-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)(3-(hydroxymethyl)pyrrolidin-1-yl)methanone

Product 1

HCID 71660460(5-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)(2-(hydroxymethyl)pyrrolidin-1-yl)methanone

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
115 °C

Procedure

To a solution of (5-(6-chloro-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)(3-(hydroxymethyl)pyrrolidin-1-yl)methanone (27a) (50 mg, 0.15 mmol) in dioxane (5 mL): H2O (1 mL), 6-amino benzothiazole (0.18 mmol, 1.2 equiv.), xanthphos (0.07 mmol, 0.5 equiv.) and Na2CO3 (0.7 mmol, 3 equiv.) were added and degassed for 10 min. To the reaction mixture Pd2(dba)3 (0.07 mmol, 0.5 equiv.) was added and degassed again for 10 min then heated at 115° C., overnight. The reaction mixture was cooled and filtered through small pad of celite. The filtrate was concentrated and the crude material was purified by column chromatography through silica gel and MeOH: CHCl3 as eluent. The material was further purified by prep HPLC to afford the title compound. 1H NMR: 400 MHz, CD3OD: δ 1.38 (d, J=6.40 Hz, 1H), 2.01-2.03 (m, 4H), 3.71-3.85 (m, 4H), 3.87-4.23 (m, 2H), 6.22 (s, 1H), 7.57 (dd, J=2.00, 8.80 Hz, 1H), 8.15 (d, J=8.80 Hz, 1H), 8.22 (m, 1H), 8.35 (bs, 1H), 9.28 (s, 1H). LC/MS: Purospher@star RP-18, 4×55 mm, 3 μm; Solvent A=10% ACN: 90% H2O: 20 mM NH4OAc; Solvent B=90% ACN: 10% H2O: 20 mM NH4COOAc; gradient 0-100% B over 1.5 min (3.2 min run time); retention time: 1.809 min; LCMS (ES-API), m/z 496.2 (M+H). HPLC: Sunfire C18 (150×4.6 mm), 3.5 micron; Solvent A=5% ACN: 95% H2O: 0.05% TFA pH=2.5; Solvent B=95% ACN: 5% H2O: 0.05% TFA pH=2.5; gradient 0-100% B over 15 min (23 min run time); Flow rate: 1.0 μL/min; Retention time: 6.317 min; Purity: 96.7%.

Workup

  1. customdegassed for 10 min
  2. customdegassed again for 10 min
  3. temperatureThe reaction mixture was cooled
  4. filtrationfiltered through small pad of celite
  5. concentrationThe filtrate was concentrated
  6. customthe crude material was purified by column chromatography through silica gel and MeOH
  7. customThe material was further purified by prep HPLC

Sources & evidence

ORD record
ord-5c60ca2741c044109a53076e4ee63ec2
Source dataset
uspto-grants-2015_03
Patent number
US08987311B2

Linked notes

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