Triphenylphosphine → 1-[4-(7-Chloro-1-methoxy-isoquinolin-6-yloxy)-1-trifluoromethyl-cyclohexyl]-propylamine

HRID 1948169Notes

Reaction equation

HRID 1948169 reaction equation
[NH2:1][CH:2]([C:5]1([C:12]([F:15])([F:14])[F:13])[CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]1)[CH2:3][CH3:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)C(C)C)(C)C.[Cl:44][C:45]1[CH:54]=[C:53]2[C:48]([CH:49]=[CH:50][N:51]=[C:52]2[O:55][CH3:56])=[CH:47][C:46]=1O.N(C(OCC)=O)=NC(OCC)=O>C(Cl)Cl.C1COCC1>[CH2:52]([O:55][CH3:56])[CH2:53][CH2:48][CH3:47].[CH3:4][CH2:3][CH2:2][CH2:5][CH2:6][CH2:7][CH3:8].[Cl:44][C:45]1[CH:54]=[C:53]2[C:48]([CH:49]=[CH:50][N:51]=[C:52]2[O:55][CH3:56])=[CH:47][C:46]=1[O:11][CH:8]1[CH2:9][CH2:10][C:5]([CH:2]([NH2:1])[CH2:3][CH3:4])([C:12]([F:13])([F:14])[F:15])[CH2:6][CH2:7]1

Participants

9

Reactant 5

HCID 11776TriphenylphosphineHCID 81531DiisopropylethylamineHCID 220568ethyl N-ethoxycarbonyliminocarbamateHCID 583808434-(1-Amino-propyl)-4-trifluoromethyl-cyclohexanolHCID 1361750037-Chloro-6-hydroxy-1-methoxyisoquinoline

Product 2

HCID 583808401-[4-(7-Chloro-1-methoxy-isoquinolin-6-yloxy)-1-trifluoromethyl-cyclohexyl]-propylamineYield 21.9%HCID 131730307Butylmethyl ether n-heptane

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

790 mg (3.51 mmol) of 4-(1-Amino-propyl)-4-trifluoromethyl-cyclohexanol (74) were dissolved using 8.0 ml of anhydrous THF. 1.20 g (4.56 mmol) of triphenylphosphin, 0.58 ml (3.51 mmol) of N,N-diisopropylethylamine, and 735 mg (3.51 mmol) of 7-chloro1-methoxy-isoquinolin-6-ol (81) were added and the mixture cooled to 0° C. At this temperature, 0.83 ml (5.26 mmol) of diethyl azodicarboxylate were added and the mixture stirred for 16 h at ambient temperature. Afterwards, the mixture was diluted with 20 ml of CH2Cl2 and washed successively with 20 ml of a 1N aqueous solution of NaOH, with 20 ml of a saturated aqueous solution of NH4Cl, using 20 ml of water, and with 20 ml of a saturated aqueous solution of NaCl, respectively. The organic layer was then treated with 20 ml of a 1N aqueous solution of HCl. Crude product precipitated, was filtered off and resuspended in 20 ml of a 1N aqueous solution of NaOH. This suspension was extracted three times using 20 ml of CH2Cl2. The organic layer was then dried using MgSO4 and evaporated. Chromatography of the residue on silica gel using t.-butylmethyl ether/n-heptane 1:1+1% acetic acid yielded 160 mg of the desired product as its acetate. Rt=0.79 min (Method P). Detected mass: 417.2 (M+H+).

Workup

  1. washwashed successively with 20 ml of a 1N aqueous solution of NaOH, with 20 ml of a saturated aqueous solution of NH4Cl
  2. additionThe organic layer was then treated with 20 ml of a 1N aqueous solution of HCl
  3. customCrude product precipitated
  4. filtrationwas filtered off
  5. extractionThis suspension was extracted three times
  6. customThe organic layer was then dried
  7. customevaporated

Sources & evidence

ORD record
ord-1b299d4c086e410f85e954d31ef34572
Source dataset
uspto-grants-2013_03
Patent number
US08399482B2

Reaction notes

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