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Dichloromethane → 4-(((5'-chloro-2'-fluoro-[2,4'-bipyridin]-6-yl)amino)methyl)tetrahydro-2H-pyran-4-carbonitrile

HRID 1963840
Notes
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Reaction equation

HRID 1963840 reaction equation
Br[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2([C:16]#[N:17])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:5]=[CH:4][CH:3]=1.[Cl:18][C:19]1[C:20](B(O)O)=[CH:21][C:22]([F:25])=[N:23][CH:24]=1.C(Cl)Cl>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].COCCOC>[Cl:18][C:19]1[C:20]([C:2]2[CH:3]=[CH:4][CH:5]=[C:6]([NH:8][CH2:9][C:10]3([C:16]#[N:17])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[N:7]=2)=[CH:21][C:22]([F:25])=[N:23][CH:24]=1
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

6

Reactant 3

HCID 6344DichloromethaneHCID 44754822(5-Chloro-2-fluoropyridin-4-yl)boronic acidHCID 581272764-((6-bromopyridin-2-yl-amino)methyl)tetrahydro-2H-pyran-4-carbonitrile2×

Product 1

HCID 581271824-(((5'-chloro-2'-fluoro-[2,4'-bipyridin]-6-yl)amino)methyl)tetrahydro-2H-pyran-4-carbonitrileYield 75%

Reagents, catalysts & solvents 2

HCID 44119782
Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)
Catalyst
HCID 80711,2-DimethoxyethaneSolvent

Conditions

Temperature
110 °C

Procedure

A mixture of 4-((6-bromopyridin-2-yl-amino)methyl)tetrahydro-2H-pyran-4-carbonitrile (Intermediate S, 410 mg, 1.384 mmol), 5-chloro-2-fluoropyridin-4-ylboronic acid (362.2 mg, 2.07 mmol), PdCl2(dppf).CH2Cl2 adduct (113 mg, 0.14 mmol), DME (5 Ml) and 2 M aqueous Na2CO2 (1.75 Ml, 3.5 mmol) was sealed and stirred at 110° C. for 20 min using microwave reactor. After cooling to room temperature the mixture was extracted with EtOAc (35 Ml), filtered and concentrated in vacuo. The crude material was purified by column chromatography [silica gel, 24 g, EtOAc/hexane=5/100 to 50/50] to provide 4-((5′-chloro-2′-fluoro-2,4′-bipyridin-6-ylamino)methyl)tetrahydro-2H-pyran-4-carbonitrile (360 mg, 75% yield). LCMS (m/z): 347 [M+H]+; retention time=0.814 min.

Workup

  1. temperatureAfter cooling to room temperature the mixture
  2. extractionwas extracted with EtOAc (35 Ml)
  3. filtrationfiltered
  4. concentrationconcentrated in vacuo
  5. customThe crude material was purified by column chromatography [silica gel, 24 g, EtOAc/hexane=5/100 to 50/50]

Sources & evidence

ORD record
ord-dbbd64427c9b4d87a58c8c4d48b3fec0
Source dataset
uspto-grants-2013_04
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08415381B2

Reaction notes

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On this pageParticipantsConditionsProcedureWorkupSources & evidenceReaction notes