Patent EA-000564-B1 (EA)
Title: A process for preparing aza cyclohexapeptides
Inventor: BELYK KEVIN M
IPC: A61P31/04
Filed: 1996-02-06
Abstract: 1. A process for preparing aza cyclohexapeptide compounds of the formula   wherein R1 is CH2CH2NH2 or CH2CONH2; R<I> is (C9-C21)-alkyl, (C9-C21)-alkenyl, (C1--C10)-alkoxyphenyl, (C1--C10)-alkoxynaphthyl or (C1--C10)-alkoxyterphenyl; R<II> is H, (C1-C4) alkyl, (C3-C4)-alkenyl, (CH2)2-4 OH, or (CH2)2-4NR<IV>R<V>; R<III> is H, (C1-C4) alkyl, (C3-C4)-alkenyl, (CH2)2-4 OH; (CH2)2-4NR<IV>R<V>; R<II> and R<III> taken together are (CH2)4, (CH2)5, (CH2)2 O(CH2)2 or (CH2)2NH(CH2)2; R<IV> is H or (C1-C4) alkyl; R<V> is H or (C1-C4) alkyl or pharmaceutically acceptable acid addition salts thereof which comprises the steps of: a) reducing Compound II of the formula   using borane complex or TiCl4/NaBH4, or ZrCl4/NaBH4 to afford Compound III of the formula   b) converting Compound III with thiophenol in the amount of 3-5 equivalents and in the presence 5-25% solution of trifluoroacetic acid in suitable solvent forming phenylsulfide to afford Compound IV of the formula   c) stereoselectively converting Compound IV to Compound I by the displacement of the phenylthio group takes place in neat ethylenediamine or with ethylenediamine dissolved in a suitable solvent at a temperature of about 10 degree C to 40 degree C. 2. The process of Claim 1 wherein the borane complex is borane complexed with dimethylsulfide, dibenzylsulfide, diphenylsulfide, THF or 1,4-oxathiane or BH2Cl with dimethylsulfide. 3. The process of Claim 1 wherein in Step b) acetonitrile is used as a solvent. 4. The process of Claim 1 wherein in Step c) the solvent is selected from water, methanol, ethanol. tetrahydrofuran, isopropanol, trifluoroethanol, acetonitrile or dichloromethane. 5. A process for preparing aza cyclohexapeptide compounds of the formula   wherein R1 is CH2CH2NH2 or CH2CONH2; R<I> is (C9-C21)-alkyl, (C9-C21)-alkenyl, (C1--C10)-alkoxyphenyl, (C1--C10)-alkoxynaphthyl, or (C1--C10)-alkoxyterphenyl; R<II> is H, (C1-C4) alkyl, (C3-C4)-alkenyl, (CH2)2-4 OH, or (CH2)2-4NR<IV>R<V>; R<III> is H, (C1-C4) alkyl, (C3-C4)-alkenyl, (CH2)2-4 OH; (CH2)2-4NR<IV>R<V>; R<II> and R<III> taken together are (CH2)4, (CH2)5, (CH2)2 O(CH2)2 or (CH2)2NH(CH2)2; R<IV> is H or (C1-C4) alkyl; R<V> is H or (C1-C4) alkyl or pharmaceutically acceptable acid addition salts thereof which comprises the steps of: a) reacting Compound II of the formula   with thiophenol in suitable solvent forming phenylsulfide to afford Compound IV-a of the formula   b) reducing Compound IV-a to afford Compound IV of the formula using borane complex or TiCl4/NaBH4, or ZrCl4/NaBH4     c) stereoselectively converting Compound IV to Compound I by the displacement of the phenylthio group takes place in neat ethylenediamine or with ethylenediamine dissolved in a suitable solvent at a temperature of about 10 degree C to 40 degree C. 6. The process of Claim 5 wherein the borane complex is borane complexed with dimethylsulfide, dibenzylsulfide, diphenylsulfide,THF or 1,4-oxathiane or BH2Cl with dimethylsulfide. 7. The process of Claim 5 wherein in Step a) acetonitrile is used as a solvent. 8. The process of Claim 5 wherein in Step c) the solvent is selected from water, methanol, ethanol. tetrahydrofuran, isopropanol, trifluoroethanol, acetonitrile or dichloromethane. 9. The process of Claim 1 wherein a compound of the formula I-1   is prepared.