Patent EA-002049-B1 (EA)
Title: A process for preparing certain aza cyclohexapeptides
Inventor: LEONARD WILLIAM
IPC: C07K7/56
Filed: 1997-06-10
Abstract: 1. A process for preparing aza cyclohexapeptide compounds of the formula   wherein R1 is CH2CH2NH2; 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)2-4OH, or (CH2)2-4NR<IV>R<V>; R<III> is H, C1-C4 alkyl,  C3-C4 alkenyl, (CH2)2-4OH, or (CH2)2-4NR<IV>R<V>; or R<II> and R<III> taken together are (CH2)4, (CH2)5, (CH2)2O(CH2)2 or (CH2)2NH(CH2)2; R<IV> is H or C1-C4 alkyl; R<V> is H or C1-C4 alkyl; Q is N or O; or pharmaceutically acceptable acid addition salts thereof which comprises the steps of a) reacting Compound II of the formula:   with phenylboronic acid, p-methoxyphenylboronic acid or methaneboronic acid to afford Compound III of the formula:   b) which is subsequently reduced to the amine and hydrolyzed to afford Compound IV of the formula:   c) which is reacted with thiophenol in a suitable solvent to afford Compound V of the formula;   which is stereoselectively converted to Compound I by displacement of the phenylthio group. 2 The process of Claim 1 wherein the reduction in Step (b) is accomplished using a borane complex or metal boride. 3. The process of Claim 2 wherein the metal boride is ZrCl4/NaBH4 or TiCl4/NaBH4 and the borane complex is borane complexed with dimethyl sulfide, dibenzylsulfide, diphenylsulfide,THF or 1,4-oxathiane or BH2CI with dimethylsulfide. 4. The process of Claim 1 wherein the suitable solvent in Step (c) is acetonitrile. 5. The process of Claim 1 where 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 about 40 degree C. 6. The process of Claim 5 wherein the suitable solvent is selected from water, methanol, ethanol, tetrahydrofuran, isopropanol, trifluoroethanol, acetonitrile or dichloromethane. 7. A process for preparing aza cyclohexapeptide compounds of the formula   wherein R1 is CH2CH2NH2; 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)2-4OH, or (CH2)2-4NR<IV>R<V>; R<III> is H, C1-C4 alkyl,  C3-C4 alkenyl, (CH2)2-4OH, or (CH2)2-4NR<IV>R<V>; or R<II> and R<III> taken together are (CH2)4, (CH2)5, (CH2)2O(CH2)2 or (CH2)2NH(CH2)2; R<IV> is H or C1-C4 alkyl; R<V> is H or C1-C4 alkyl; Q is N or O; or pharmaceutically acceptable acid addition salts thereof which comprises the steps of a) reacting Compound II of the formula:   with thiophenol to afford Compound VI of the formula:   b) subsequently reacting Compound VI with phenylboronic acid, p-methoxyphenylboronic acid or methaneboronic acid to afford Compound IIIa of the formula:   c) which is subsequently reduced to the amine and hydrolyzed to afford Compound V of the formula:   d) which is stereoselectively converted to Compound I by the displacement of the phenylthio group. 8. The process of Claim 7 wherein the reduction in Step (c) is accomplished using a borane complex or metal boride. 9. The process of Claim 8 wherein the metal boride is ZrCl4/NaBH4 or TiCl4/NaBH4 and the borane complex is borane complexed with dimethylsulfide, dibenzylsulfide, diphenylsulfide,THF or 1 ,4-oxathiane or BH2CI with dimethylsulfide. 10. The process of Claim 7 wherein Compound II is converted to the phenylsulfide by reaction with thiophenol in a suitable solvent. 11. The process of Claim 10 wherein the suitable solvent is acetonitrile. 12. The process of Claim 7 where 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 about 40 degree C. 13. The process of Claim 12 wherein the suitable solvent is selected from water, methanol, ethanol, tetrahydrofuran isopropanol, trifluoroethanol, acetonitri le or dichloromethane. 14. The process of Claim 1 wherein a compound of the formula   or a pharmaceutically accepaptable salt thereof is prepared. 15. The process of Claim 7 wherein a compound of the formula   or a pharmaceutically accepaptable salt thereof is prepared. 16. The process of Claim 1 wherein a compound of the formula   or a pharmaceutically accepaptable salt thereof is prepared. 17. A compound of the formula   wherein R<I> is C9-C21 alkyl, C9-C21 alkenyl, C1-C10 alkoxyphenyl, C1-C10 alkoxynaphthyl, or C1-C10 alkoxyterphenyl. 18. A compound of the formula   wherein R<I> is C9-C21 alkyl, C9-C21 alkenyl, C1-C10 alkoxyphenyl, C1-C10 alkoxynaphthyl, or C1-C10 alkoxyterphenyl.