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Ethylmorpholine → N-[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluorobutyl]-3-azaspiro[5.5]undecane-3-carboxamide

HRID 1913319
Notes
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Reaction equation

HRID 1913319 reaction equation
[CH2:1]1[C:6]2([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][N:3]([C:12]([NH:14][C@@H:15]([CH2:19][C:20]([F:23])([F:22])[CH3:21])[C:16](O)=[O:17])=[O:13])[CH2:2]1.ON1[C:29]2[N:30]=C[CH:32]=[CH:33][C:28]=2[N:27]=N1.CCN=C=NCCCN(C)C.Cl.C(N1CCOCC1)C>C1COCC1.CN(C=O)C>[C:29]([C:28]1([NH:27][C:16]([C@@H:15]([NH:14][C:12]([N:3]2[CH2:2][CH2:1][C:6]3([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]3)[CH2:5][CH2:4]2)=[O:13])[CH2:19][C:20]([F:22])([F:23])[CH3:21])=[O:17])[CH2:32][CH2:33]1)#[N:30]
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

6

Reactant 4

HCID 7525EthylmorpholineHCID 181649HOAtHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 66661172HCID 66661172, compound2×

Product 1

HCID 24995700N-[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluorobutyl]-3-azaspiro[5.5]undecane-3-carboxamide

Reagents, catalysts & solvents

1
HCID 21974620tetrahydrofuran N,N-dimethylformamideSolvent

Conditions

Temperature
0 °C

Procedure

The crude product from example 8, (S)-2-[(3-azaspiro[5.5]undecane-3-carbonyl)amino]-4,4-difluoropentanoic acid, was dissolved in 6 ml of 2:1 THF/DMF and admixed with 161.8 mg (1.365 mmol, 1.05 eq.) of 1-amino-1-cyclopropylnitrile hydrochloride and 176.9 mg (1.3 mmol, 1 eq.) of 1-hydroxy-7-azabenzotriazole, cooled to 0° C. and admixed with 250 mg (1.3 mmol, 1 eq.) of EDCl and with 0.496 ml (3.9 mmol, 3 eq.) of N-ethylmorpholine. Subsequently, the mixture was stirred at 0° C. to RT for 2 h, THF was distilled off under reduced pressure, ethyl acetate was added and the mixture was extracted by shaking with highly dilute HCl, sat. NaHCO3 solution and sat. NaCl solution. After concentration of the organic phase, a preparative HPLC separation (Merck Hibar Purospher RP18, 250×25, Standard-Gradient of acetonitrile-water-TFA) was performed directly. Product fractions were combined and freeze-dried.

Workup

  1. distillationTHF was distilled off under reduced pressure, ethyl acetate
  2. additionwas added
  3. extractionthe mixture was extracted
  4. stirringby shaking with highly dilute HCl, sat. NaHCO3 solution and sat. NaCl solution
  5. customAfter concentration of the organic phase, a preparative HPLC separation (Merck Hibar Purospher RP18, 250×25, Standard-Gradient of acetonitrile-water-TFA)
  6. customfreeze-dried

Sources & evidence

ORD record
ord-8a144eac56634fc897234fe90f073673
Source dataset
uspto-grants-2013_12
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08609681B2

Reaction notes

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On this pageParticipantsConditionsProcedureWorkupSources & evidenceReaction notes