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Sodium Carbonate → (3R)-3-methyl-4-(6-(1-((R)-S-methylsulfonimidoyl)cyclopropyl)-2-(1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)morpholine

HRID 1484042
Notes
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Reaction equation

HRID 1484042 reaction equation
CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][N:12]=[C:11]3[N:15]([S:18]([C:21]4[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=4)(=[O:20])=[O:19])[CH:16]=[CH:17][C:10]=23)O1.Cl[C:30]1[N:35]=[C:34]([N:36]2[CH2:41][CH2:40][O:39][CH2:38][C@H:37]2[CH3:42])[CH:33]=[C:32]([C:43]2([S@:46]([CH3:49])(=[NH:48])=[O:47])[CH2:45][CH2:44]2)[N:31]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.COCCOC.O.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:42][C@@H:37]1[CH2:38][O:39][CH2:40][CH2:41][N:36]1[C:34]1[CH:33]=[C:32]([C:43]2([S@:46]([CH3:49])(=[NH:48])=[O:47])[CH2:44][CH2:45]2)[N:31]=[C:30]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]3[N:15]([S:18]([C:21]4[CH:22]=[CH:23][C:24]([CH3:25])=[CH:26][CH:27]=4)(=[O:19])=[O:20])[CH:16]=[CH:17][C:10]=23)[N:35]=1
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

8

Reactant 3

HCID 10340Sodium CarbonateHCID 497589261-Tosyl-1H-pyrrolo(2,3-B)pyridine-4-boronic acid pinacol esterHCID 86660219(3R)-4-(2-chloro-6-(1-((R)-S-methylsulfonimidoyl)cyclopropyl)pyrimidin-4-yl)-3-methylmorpholine

Product 1

HCID 86660218(3R)-3-methyl-4-(6-(1-((R)-S-methylsulfonimidoyl)cyclopropyl)-2-(1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)morpholineYield 39.2%

Reagents, catalysts & solvents 4

HCID 178418476HCID 178418476, compoundCatalystHCID 80711,2-DimethoxyethaneSolventHCID 8857Ethyl AcetateSolventHCID 18180031Water 1,2-dimethoxyethaneSolvent

Conditions

Temperature
90 °C

Procedure

A solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (21.15 g, 53.11 mmol) in DME (212 ml) was added to a solution of (3R)-4-(2-chloro-6-(1-((R)—S-methylsulfonimidoyl)cyclopropyl)pyrimidin-4-yl)-3-methylmorpholine (12.55 g, 37.93 mmol) in DME:water 4:1 (55 ml). 2M aqueous sodium carbonate solution (22.76 ml, 45.52 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.666 g, 0.95 mmol) were added. The resulting solution was stirred at 90° C. for 2 hours under nitrogen. The reaction mixture was diluted with EtOAc (400 ml), and washed with water (400 ml). The organic layer was dried over MgSO4, filtered and evaporated. The residue was dissolved in DCM (100 ml) and a portion was purified by flash chromatography on silica eluting with a gradient of 0 to 5% MeOH in DCM. Pure fractions were evaporated to afford (3R)-3-methyl-4-(6-(1-((R)—S-methylsulfonimidoyl)cyclopropyl)-2-(1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)morpholine (8.42 g, 39%); 1H NMR (400 MHz, CDCl3) 1.36 (3H, d), 1.52 (2H, dd), 1.80 (2H, dd), 2.24-2.46 (3H, s), 3.10 (3H, s), 3.36 (1H, td), 3.60 (1H, td), 3.74 (1H, dd), 3.84 (1H, d), 3.99-4.18 (2H, m), 4.47 (1H, s), 6.91 (1H, s), 7.23-7.3 (3H, m, obscured by CDCl3), 7.45 (1H, d), 7.81 (1H, d), 8.08 (3H, dd), 8.51 (1H, d); m/z: (ES+) MH+, 567.4. The rest of the material was evaporated and the residue was dissolved in DCM (500 ml) and concentrated in vacuo onto silica (100 g). The resulting powder was purified by flash chromatography on silica, eluting with a gradient of 0 to 5% MeOH in DCM. Pure fractions were evaporated to dryness to afford (3R)-3-methyl-4-(6-(14(R)—S-methylsulfonimidoyl)cyclopropyl)-2-(1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)morpholine (4.00 g, 19%); 1H NMR (400 MHz, DMSO-d6) 1.19-1.31 (3H, m), 1.37-1.58 (3H, m), 1.75 (1H, ddd), 2.34 (3H, s), 3.04 (3H, d), 3.2-3.27 (1H, m), 3.46-3.54 (1H, m), 3.65 (1H, dd), 3.78 (1H, d), 3.82 (1H, s), 3.99 (1H, dd), 4.16 (1H, d), 4.54 (1H, s), 7.04 (1H, s), 7.42 (2H, d), 7.54 (1H, d), 8.01 (3H, dd), 8.10 (1H, d), 8.49 (1H, d); m/z: (ES+) MH+, 567.00.

Workup

  1. washwashed with water (400 ml)
  2. dry with materialThe organic layer was dried over MgSO4
  3. filtrationfiltered
  4. customevaporated
  5. dissolutionThe residue was dissolved in DCM (100 ml)
  6. customa portion was purified by flash chromatography on silica eluting with a gradient of 0 to 5% MeOH in DCM
  7. customPure fractions were evaporated

Sources & evidence

ORD record
ord-6c07c18542dc4609ac2bb0c9003daec3
Source dataset
uspto-grants-2016_08
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US09421213B2

Reaction notes

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