7-substituted camptothecin and camptothecin analogs and methods for producing the same

A method for the preparation of 7-substituted camptothecin compounds of formula (I) or (II):

• where
• X is H, NH2, OH, F, Cl, Br, O—C1-6 alkyl, S—C1-6 alkyl, NH—C1-6 alkyl, N(C1-6 alkyl)2, or C1-8 alkyl,
• or X is -Z-(CH2)a—N—(C1-6 alkyl)2 wherein Z is selected from the group consisting of O, NH and S, and a is an integer of 2 or 3,
• or X is —CH2NR2R3, where (a) R2 and R3 are, independently, hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl-C1-6 alkyl, C2-6 alkenyl, C1-6 alkoxy-C1-6 COR4 where R4 is hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl-C1-6 alkyl, C2-6 alkenyl, C1-6 alkoxy, C1-6 alkoxy-C1-6 alkyl, or (b) R2 and R3 taken together with the nitrogen atom to which they are attached form a saturated 3-7 membered heterocyclic ring which may contain a O, S or NR5 group, where R5 is hydrogen, C1-6 alkyl, alkyl, aryl, aryl substituted with one or more groups selected from the group consisting of C1-6 alkyl, amino, C1-6 alkylamino, C1-6 alkoxy, C1-6 alkoxy-C1-6 alkyl C1-6 alkyl C1-6 alkoxy, aryl, and aryl substituted with one or more C1-6 alkyl, or C1-6 alkoxy-C1-6 alkyl groups;
• R is C1-30 alkyl, substituted C1-30 alkyl, C1-30 alkenyl, substituted C1-30 alkenyl, C1-30 alkynyl, substituted , C1-30 alkynyl, C3-30 cycloalkyl, substituted C3-30 cycloalkyl, C6-18 aryl, substituted C6-18 aryl, C6-18 aryalkyl, (C1-30 alkyl)3 silyl or (C1-30 alkyl)i silyl C1-30 alkyl,
• Y is independently H or F, and
• n is an integer of 1 or 2,
• and salts thereof
• comprising:
• i) reacting an ortho amino cyano aromatic compound of formula (III) or (IV)
• with an organometallic reagent R-M and
• ii) condensing a resulting product with a 20(S)tricyclic ketone of formula (VII)