Hydrochloric Acid → HCID 178445977, compound

HRID 1982335Notes

Reaction equation

HRID 1982335 reaction equation
[NH:1]([C:52]([O:54][CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)=[O:53])[C@H:2]([C:10]([NH:12][C@H:13]([C:21]([N:23]1[CH2:51][CH2:50][CH2:49][C@H:24]1[C:25]([NH:27][C@H:28]([C:36]([NH:38][C@H:39]([C:46](O)=[O:47])[CH2:40][C:41]1[N:45]=[CH:44][NH:43][CH:42]=1)=[O:37])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:26])=[O:22])[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[NH:20])[NH2:19])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].Cl.[NH2:63][C@H:64]([C@H:69]([CH2:71][C:72]([NH:74][CH2:75][CH2:76][C:77]([NH:79][C@H:80]([C:87]([NH2:89])=[O:88])[CH2:81][C:82]1[N:86]=[CH:85][NH:84][CH:83]=1)=[O:78])=[O:73])[OH:70])[CH2:65][CH:66]([CH3:68])[CH3:67].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C.O>[NH:1]([C:52]([O:54][CH2:55][C:56]1[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=1)=[O:53])[C@H:2]([C:10]([NH:12][C@H:13]([C:21]([N:23]1[CH2:51][CH2:50][CH2:49][C@H:24]1[C:25]([NH:27][C@H:28]([C:36]([NH:38][C@H:39]([C:46]([NH:63][C@H:64]([C@H:69]([CH2:71][C:72]([NH:74][CH2:75][CH2:76][C:77]([NH:79][C@H:80]([C:87]([NH2:89])=[O:88])[CH2:81][C:82]1[N:86]=[CH:85][NH:84][CH:83]=1)=[O:78])=[O:73])[OH:70])[CH2:65][CH:66]([CH3:68])[CH3:67])=[O:47])[CH2:40][C:41]1[N:45]=[CH:44][NH:43][CH:42]=1)=[O:37])[CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:26])=[O:22])[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[NH:19])[NH2:20])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:9]

Participants

9

Reactant 6

HCID 313Hydrochloric AcidHCID 79724-MethylmorpholineHCID 10868DicyclohexylcarbodiimideHCID 757711-HydroxybenzotriazoleHCID 178445942HCID 178445942, compoundHCID 178512916HCID 178512916, compound

Product 1

HCID 178445977HCID 178445977, compound

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Procedure

721 mg of Z-Arg-Arg-Pro-Phe-His-OH×3 HCl (see stage 4.4) (containing 24% by weight of NaCl), 176 mg of H-Sta-β-Ala-His-NH2, 91 mg of HOBt×H2O and 50 μl of N-methylmorpholine are dissolved in 5 ml of DMF. After cooling to 0°, 132 mg of DCCI are added and then the whole is stirred for 6 hours at 0° and left to stand overnight at room temperature. The DCH which has crystallised out is filtered off, the filtrate is concentrated to dryness and the residue is heated for 1 hour at 60° in 14 ml of methanol/glacial acetic acid/H2O (94:3:3). The solution is concentrated to 3 ml and the crude product is precipitated by the addition of 30 ml of diisopropyl ether. In order to convert it into the acetate, the product is dissolved in 5 ml of 0.05N acetic acid, a small amount of insoluble material is filtered off and the solution is filtered slowly through a column (φ=1.2 cm, length=10 cm) of weakly basic ion exchanger in the acetate form (Merck II) equilibrated in 0.05N acetic acid. The eluate is concentrated to approximately 3 ml and lyophilised. Purification is effected by means of Craig partitioning over 750 stages in the system n-pentanol/glacial acetic acid/H2O (4:1:5); K=0.13. The chromatographically pure fractions are combined, concentrated to dryness and the residue is dissolved in 3 ml of H2O and lyophilised. Z-Arg-Arg-Pro-Phe-His-Sta-β-Ala-His-NH2 (acetate form) is obtained in the form of an amorphous, water-soluble powder; Rf (D)=0.17; Rf (M)=0.30; Rf (O)=0.25.

Workup

  1. temperatureAfter cooling to 0°
  2. waitleft
  3. waitto stand overnight at room temperature
  4. customThe DCH which has crystallised out
  5. filtrationis filtered off
  6. concentrationthe filtrate is concentrated to dryness
  7. temperaturethe residue is heated for 1 hour at 60° in 14 ml of methanol/glacial acetic acid/H2O (94:3:3)
  8. concentrationThe solution is concentrated to 3 ml
  9. customthe crude product is precipitated by the addition of 30 ml of diisopropyl ether
  10. dissolutionthe product is dissolved in 5 ml of 0.05N acetic acid
  11. filtrationa small amount of insoluble material is filtered off
  12. filtrationthe solution is filtered slowly through a column (φ=1.2 cm, length=10 cm) of weakly basic ion exchanger in the acetate form (Merck II)
  13. concentrationThe eluate is concentrated to approximately 3 ml
  14. customPurification
  15. custompartitioning over 750 stages in the system n-pentanol/glacial acetic acid/H2O (4:1:5)
  16. concentrationconcentrated to dryness
  17. dissolutionthe residue is dissolved in 3 ml of H2O

Sources & evidence

ORD record
ord-9c342878524d4b92bf75e50a1d0fc157
Source dataset
uspto-grants-1986_06
Patent number
US04595677

Reaction notes

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