Guanidine → HCID 178451166, compound

HRID 2289758Notes

Reaction equation

HRID 2289758 reaction equation
Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([S:13]([NH:16][C@@H:17]3[CH2:22][CH2:21][C@H:20]([C:23]([OH:25])=[O:24])[CH2:19][CH2:18]3)(=[O:15])=[O:14])=[CH:10][CH:11]=2)[C:6]([NH:26][C:27]([NH2:29])=[NH:28])=[N:5][CH:4]=1.[H-].[Na+].ClC1[C:42]2[C:37](=[CH:38]C=C(S(N[C@@H]3CC[C@H](C(OC(C)(C)C)=O)CC3)(=O)=O)C=2)[C:36](Cl)=CN=1.NC(N)=N>COCCOC.C1(C)C=CC=CC=1.CCOC(C)=O.CCCCCC.CCOC(C)=O.CC(N(C)C)=O>[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([S:13]([NH:16][C@@H:17]3[CH2:22][CH2:21][C@H:20]([C:23]([O:25][C:37]([CH3:42])([CH3:38])[CH3:36])=[O:24])[CH2:19][CH2:18]3)(=[O:14])=[O:15])=[CH:10][CH:11]=2)[C:6]([NH:26][C:27]([NH2:29])=[NH:28])=[N:5][CH:4]=1

Participants

9

Reactant 4

HCID 3520GuanidineHCID 24758Sodium hydrideHCID 178451165HCID 178451165, compoundHCID 178479409HCID 178479409, compound

Product 1

HCID 178451166HCID 178451166, compoundYield 68%

Reagents, catalysts & solvents 4

HCID 80711,2-DimethoxyethaneSolvent3×HCID 31374DimethylacetamideSolventHCID 21226206Ethyl acetate hexaneSolventHCID 21584019Toluene ethylacetateSolvent

Conditions

Temperature
60 °C

Procedure

cis-4-{[(4-Chloro-1-guanidino-7-isoquinolinyl)sulphonyl]amino}cyclohexanecarboxylic acid hydrochloride ##STR58## Guanidine hydrochloride (286 mg, 3.0 mmol) was added in one portion to a stirred suspension of NaH (56 mg, 80% dispersion by wt in mineral oil, 1.82 mmol) in DME (5 mL) and the mixture was heated at 60° C. under N2 for 30 min. A solution of t-butyl cis-4-{[(1,4-dichloro-7-isoquinolinyl)sulphonyl]amino}cyclohexanecarboxylate (346 mg, 0.75 mmol) in DME (15 mL) was added and the mixture heated at 90° C. for 2 h. A second portion of guanidine (0.75 mmol)[prepared from guanidine hydrochloride (72 mg) and NaH (22 mg)] in DME (5 mL) was added and the mixture heated at 90° C. for 1 h. DMA (10 mL) was then added to the heterogeneous reaction mixture and the now homogeneous mixture heated for an additional 6 h. The solvents were evaporated in vacuo, the residue was quenched aqueous NH4Cl (10 mL), diluted with water (150 mL) and extracted with EtOAc (2×150 mL). The combined organic extracts were washed with water (100 mL), dried (MgSO4) and evaporated in vacuo. The residue was purified by repeated column chromatography upon silica gel using (i), pentane-EtOAc (100:0 to 25:75) and then (ii), PhMe-EtOAc (50:50 to 0:100) as eluant to give t-butyl cis-4-{[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]amino}cyclohexanecarboxylate (247 mg, 0.51 mmol). [A small amount of t-butyl trans-4-{[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyllamino}cyclohexanecarboxylate (20 mg) was also isolated.]

Workup

  1. temperaturethe mixture heated at 90° C. for 2 h
  2. temperaturethe mixture heated at 90° C. for 1 h
  3. temperaturethe now homogeneous mixture heated for an additional 6 h
  4. customThe solvents were evaporated in vacuo
  5. customthe residue was quenched aqueous NH4Cl (10 mL)
  6. additiondiluted with water (150 mL)
  7. extractionextracted with EtOAc (2×150 mL)
  8. washThe combined organic extracts were washed with water (100 mL)
  9. dry with materialdried (MgSO4)
  10. customevaporated in vacuo
  11. customThe residue was purified

Sources & evidence

ORD record
ord-7c4b5870e01a4b1ab99d8812213a6d7d
Source dataset
uspto-grants-2000_07
Patent number
US06093731

Reaction notes

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