Patent EA-004654-B1 (EA)
Title: Processes and intermediates for preparing anti-cancer compounds
Inventor: LEHNER RICHARD SHELTON
IPC: A61K31/505
Filed: 2000-03-30
Abstract: 1. A method of preparing a compound of formula 1 or a pharmaceutically acceptable salt or solvate of said compound, wherein R<1> and R<2> are each independently selected from C1-C10 alkyl and C1-C10 alkoxy wherein said alkyl and alkoxy are optionally substituted by up to 2 substituents independently selected from hydroxy and C1-C6 alkoxy; R<15> is H or C1-C10 alkyl, which comprises treating a compound of formula 2 wherein R<15>, R<1> and R<2> are as defined above, and G is a blocking group -C(OH)R<3>R<4>; R<3>, R<4> and R<5> are each independently C1-C6 alkyl; an alkali-metal or alkaline-metal hydroxide in a solvent comprising hydroxy-substituted C1-C10 alkyl. 2. The method of claim 1 wherein said solvent is a secondary alcohol, and said alkali-metal or alkaline-metal hydroxide is selected from sodium hydroxide, lithium hydroxide, cesium hydroxide, calcium hydroxide, magnesium hydroxide and potassium hydroxide. 3. The method of claim 2 wherein said solvent is butan-2-ol or isopropanol, or a mixture of the two solvents, and said alkali-metal or alkaline-metal hydroxide is sodium hydroxide. 4. A method of preparing a compound of formula 1 R<1> and R<2> are each independently selected from C1-C10 alkyl and C1-C10 alkoxy wherein said alkyl and alkoxy are optionally substituted by up to 2 substituents independently selected from hydroxy and C1-C6 alkoxy; R<15> is H or C1-C10 alkyl, which comprises treating a compound of formula 2 5. The method of claim 4 wherein said tetra-(C1-C6 alkyl)-ammonium fluoride compound is tetra-(n-butyl)-ammonium fluoride and said aprotic solvent solvent is selected from tetrahydrofuran, diethyl ether, dimethoxyethane, toluene, dichloromethane, chloroform, and a mixture of two or more of the foregoing solvents. 6. The method of any one of the preceding claims wherein both R<1> and R<2> are 2-methoxyethoxy and R<15> is H. 7. A method of preparing an intermediate compound for use in claims 1 and 4 of formula 2: R<1> and R<2> are each independently selected from C1-C10 alkyl and C1-C10 alkoxy wherein said alkyl and alkoxy are optionally substituted by up to 2 substituents independently selected from hydroxy and C1-C6 alkoxy; R<15> is H or C1-C10 alkyl, which comprises treating a compound of formula 3 with a compound of formula 4 8. The method of claim 7 wherein the compound of formula 4 is treated in an organic solvent selected from dimethylformamide, dimethylsulfoxide, tetrahydrofuran, acetonitrile, and a mixture of two or more of the foregoing solvents. 9. The method of claim 8 wherein said solvent is acetonitrile, both R<1> and R<2> are 2-methoxyethoxy and R<15> is H. 10. The method of preparing a compound of formula 6 or 7: or their pharmaceutically acceptable salts and solvates, wherein R<6> is C1-C10 alkyl or -(CH2)mO(CH2)nCH3; R<7> is C1-C10 alkyl or -(C1-C6 alkyl) wherein the foregoing R<7> groups are optionally substituted by 1 to 3 substituents independently selected from halo, nitro, trifluoromethyl, trifluoromethoxy, (C1-C6 alkyl)sulfonyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C10 aryloxy and C6-C10arylsulfonyl; each m is independently an integer from 1 to 6, and n is an integer from 0 to 3; R<15> is H or C1-C10 alkyl; which comprises treating a compound of the formula 8 wherein R<6> and R<15> are as defined above, G<1> is -C(OH)R<3>R<4>, and R<3> and R<4> are each independently C1-C6 alkyl; with a primary or secondary alcohol of the formula R<7>-OH wherein R<7> is C1-C10 alkyl and the foregoing R<7> groups are optionally substituted by 1 to 3 substituents independently selected from halo, nitro, trifluoromethyl, trifluoromethoxy, (C1-C6 alkyl)sulfonyl, C1-C6 alkyl, C1-C6 alkoxy, C6-C10 aryloxy and C6-C10arylsulfonyl; in the presence of an alkali-metal or alkaline-metal hydroxide. 11. The method of claim 10 wherein said alkali-metal or alkaline-metal hydroxide is selected from sodium hydroxide, lithium hydroxide, cesium hydroxide, calcium hydroxide, magnesium hydroxide and potassium hydroxide. 12. The method of claim 11 wherein said alkali-metal or alkaline-metal hydroxide is sodium hydroxide, R<6> is 2-methoxyethoxy, R<15> is H, and said alcohol of formula R<7>-OH is a secondary alcohol. 13. The method of claim 1 wherein both R<1> and R<2> are 2-methoxyethoxy, and R<15> is H, said solvent is a primary alcohol, said alkali-metal or alkaline-metal hydroxide is selected from sodium hydroxide, lithium hydroxide, cesium hydroxide, calcium hydroxide, magnesium hydroxide and potassium hydroxide. 14. The method of claim 13 wherein said solvent is butan-2-ol or isopropanol, or a mixture of the two solvents, and said alkali-metal or alkaline-metal hydroxide is sodium hydroxide. 15. The method of claim 10 wherein both R<1> and R<2> are 2-methoxyethoxy, and R<15> is H, said alkali-metal or alkaline-metal hydroxide is selected from sodium hydroxide, lithium hydroxide, cesium hydroxide, calcium hydroxide, magnesium hydroxide and potassium hydroxide. 16. A compound of formula 2 R<1> and R<2> are each independently selected from C1-C10 alkyl and C1-C10 alkoxy wherein said alkyl and alkoxy are optionally substituted by up to 2 substituents independently selected from hydroxy and C1-C6 alkoxy; G is a blocking group selected from -C(OH)R<3>R<4> and -SiR<3>R<4>R<5>; R<3>, R<4> and R<5> are each independently C1-C6 alkyl; and R<15> is H or C1-C10 alkyl.