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Triethylamine → (R)-(4-(1-chloropyrido[3,4-d]pyridazin-4-yl)-3-methylpiperazin-1-yl)(4,4-difluorocyclohexyl)methanone

HRID 1514388
Notes
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Reaction equation

HRID 1514388 reaction equation
[F:1][C:2]1([F:11])[CH2:7][CH2:6][CH:5]([C:8]([OH:10])=O)[CH2:4][CH2:3]1.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C.[Cl:34][C:35]1[N:40]=[N:39][C:38]([N:41]2[CH2:46][CH2:45][NH:44][CH2:43][C@H:42]2[CH3:47])=[C:37]2[CH:48]=[N:49][CH:50]=[CH:51][C:36]=12>CN(C=O)C>[Cl:34][C:35]1[N:40]=[N:39][C:38]([N:41]2[CH2:46][CH2:45][N:44]([C:8]([CH:5]3[CH2:4][CH2:3][C:2]([F:1])([F:11])[CH2:7][CH2:6]3)=[O:10])[CH2:43][C@H:42]2[CH3:47])=[C:37]2[CH:48]=[N:49][CH:50]=[CH:51][C:36]=12
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

6

Reactant 4

HCID 8471TriethylamineHCID 152842Bis(2-oxo-3-oxazolidinyl)phosphinic chlorideHCID 27791364,4-Difluorocyclohexanecarboxylic acidHCID 57657623(R)-1-chloro-4-(2-methylpiperazin-1-yl)pyrido[3,4-d]pyridazine

Product 1

HCID 57657597(R)-(4-(1-chloropyrido[3,4-d]pyridazin-4-yl)-3-methylpiperazin-1-yl)(4,4-difluorocyclohexyl)methanone

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
55 °C

Procedure

4,4-difluorocyclohexanecarboxylic acid (277 mg, 169 mmol) and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (411 mg, 1.61 mmol) were stirred in DMF (3 ml) and triethylamine (0.4 ml) for 2 minutes. The solution was added to (R)-1-chloro-4-(2-methylpiperazin-1-yl)pyrido[3,4-d]pyridazine 59 (387 mg, 1.47 mmol) and washed in with an additional 1 ml DMF. The reaction was heated at 55° C. for 1.5 hours and then stirred at RT for 17 hours. The reaction was added to saturated NaHCO3 (80 ml) and extracted three times with dichloromethane (50 ml). The combined organics were dried (MgSO4) and evaporated to give a yellow solid. The residue was chromatographed over silica with a gradient of hexane and 0-100% ethyl acetate to give (R)-(4-(1-chloropyrido[3,4-d]pyridazin-4-yl)-3-methylpiperazin-1-yl)(4,4-difluorocyclohexyl)methanone 60 as a yellow solid, 236 mg. LC/MS m/z=410 (M+H+).

Workup

  1. washwashed in with an additional 1 ml DMF
  2. additionThe reaction was added to saturated NaHCO3 (80 ml)
  3. extractionextracted three times with dichloromethane (50 ml)
  4. dry with materialThe combined organics were dried (MgSO4)
  5. customevaporated
  6. customto give a yellow solid
  7. customThe residue was chromatographed over silica with a gradient of hexane and 0-100% ethyl acetate

Sources & evidence

ORD record
ord-3b739176d1b6499d86485bc8ba11eb19
Source dataset
uspto-grants-2012_07
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08222251B2

Reaction notes

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On this pageParticipantsConditionsProcedureWorkupSources & evidenceReaction notes