Methods of making 21-[4'-(nitrooxyalkyl)benzoate] corticosteroid derivatives and intermediates useful in the synthesis thereof

A method for producing a 21-[4′-(nitrooxyalkyl)benzoate] corticosteroid derivative comprising:

• (a) reacting a compound of formula (II)
• 22
• wherein:
• m is an integer from 0 to 4;
• n is an integer from 0 to 5;
• R2 is independently selected at each occurrence from the group consisting of amino, substituted amino, halogen, C1-6 alkyl, C1-6 haloalkyl, alkoxy, aryl, C1-6 alkylamino, C1-6 substituted alkylamino, and —OR7;
• R3 and R4 are independently selected at each occurrence from the group consisting of hydrogen, amino, substituted amino, halogen, C1-6 alkyl, C1-6 haloalkyl, alkoxy, aryl, C1-6 alkylamino, C1-6 substituted alkylamino, and —OR1;
• R5 and R6 are independently selected from the group consisting of hydrogen, amino, substituted amino, halogen, C1-6 alkyl, C1-6 haloalkyl, alkoxy, aryl, C1-6 alkylamino, C1-6 substituted alkylamino, and —OR7;
• R7 is independently selected at each occurrence from the group consisting of hydrogen, —C(O)R8, and —C(O)NR8R9;
• and
• R8 and R9 are independently selected at each occurrence from the group consisting of hydrogen and C1-6 alkyl;
• with acetic anhydride and nitric acid to form a compound of formula (IA)
• 23
• wherein m, n, R2, R3, R4, R5, and R6 are as above in the compound of formula (II);
• and
• (b) reacting the compound of formula (IA) with a 21-hydroxyalkyl corticosteroid and a coupling agent to produce a 21-[4′-(nitrooxyalkyl)benzoate] corticosteroid derivative.

A method for producing a 21-[4′-(nitrooxyalkyl)benzoate] corticosteroid derivative comprising:

• (a) reacting a compound of formula (II)
• 24
• wherein:
• m is an integer from 0 to 4;
• n is an integer from 0 to 5;
• R2 is independently selected at each occurrence from the group consisting of amino, substituted amino, halogen, C1-6 alkyl, C1-6 haloalkyl, alkoxy, aryl, C1-6 alkylamino, C1-6 substituted alkylamino, and —OR7;
• R3 and R4 are independently selected at each occurrence from the group consisting of hydrogen, amino, substituted amino, halogen, C1-6 alkyl, C1-6 haloalkyl, alkoxy, aryl, C1-6 alkylamino, C1-6 substituted alkylamino, and —OR7;
• R5 and R6 are independently selected from the group consisting of hydrogen, amino, substituted amino, halogen, C1-6 alkyl, C1-6 haloalkyl, alkoxy, aryl, C1-6 alkylamino, C1-6 substituted alkylamino, and —OR7;
• R7 is independently selected at each occurrence from the group consisting of hydrogen, —C(O)R8, and —C(O)NO8R9;
• and
• R8 and R9 are independently selected at each occurrence from the group consisting of hydrogen and C1-6 alkyl;
• with acetic anhydride and nitric acid to form a compound of formula (IA)
• 25
• wherein m, n, R2, R3, R4, R5, and R6 are as above in the compound of formula (II);
• (b) reacting the compound of formula (IA) with a halogenating agent to form a compound of formula (IB)
• 26
• wherein:
• X is selected from the group consisting of Cl, Br, F, and I;
• and
• m, n, R2, R3, R4, R5, and R6 are as above in the compound of formula (II);
• and
• (c) reacting the compound of formula (IB) with a 21-hydroxyalkyl corticosteroid and a base to produce a 21-[4′-(nitrooxyalkyl)benzoate] corticosteroid derivative.

A compound of formula (I)

• 27
• wherein:
• R1 is selected from the group consisting of OH, Cl, Br, F, I, and —OC(O)R10;
• m is an integer from 0 to 4;
• n is an integer from 0 to 5;
• R2 is independently selected at each occurrence from the group consisting of amino, substituted amino, halogen, C1-6 alkyl, C1-6 haloalkyl, alkoxy, aryl, C1-6 alkylamino, C1-6 substituted alkylamino, and —OR7;
• R3 and R4 are independently selected at each occurrence from the group consisting of hydrogen, amino, substituted amino, halogen, C1-6 alkyl, chloroalkyl, alkoxy, aryl, C1-6 alkylamino, C1-6 substituted alkylamino, and —OR7;
• R5 and R6 are independently selected from the group consisting of hydrogen, amino, substituted amino, halogen, C1-6 alkyl, C1-6 haloalkyl, alkoxy, aryl, C1-6 alkylamino, C1-6 substituted alkylamino, and —OR7;
• R7 is independently selected at each occurrence from the group consisting of hydrogen, —C(O)R8, and —C(O)NR1R9;
• R8 and R9 are independently selected at each occurrence from the group consisting of hydrogen and C1-6 alkyl;
• and
• R10 is selected from the group consisting of C1-6 alkyl, C1-6 chloroalkyl, alkoxy-substituted C1-6 alkyl, and aryl.

A method for producing a 21-[4′-(nitrooxyalkyl)benzoate] corticosteroid derivative comprising:

• (a) reacting a compound of formula (II)
• 28
• wherein:
• m is an integer from 0 to 4;
• n is an integer from 0 to 5;
• R2 is independently selected at each occurrence from the group consisting of amino, substituted amino, halogen, C1-6 alkyl, C1-6 haloalkyl, alkoxy, aryl, C1-6 alkylamino, C1-6 substituted alkylamino, and —OR7;
• R3 and R4 are independently selected at each occurrence from the group consisting of hydrogen, amino, substituted amino, halogen, C1-6 alkyl, C1-6 haloalkyl, alkoxy, aryl, C1-6 alkylamino, C1-6 substituted alkylamino, and
• R5 and R6 are independently selected from the group consisting of hydrogen, amino, substituted amino, halogen, C1-6 alkyl, C1-6 haloalkyl, alkoxy, aryl, C1-6 alkylamino, C1-6 substituted alkylamino, and —OR7;
• R7 is independently selected at each occurrence from the group consisting of hydrogen, —C(O)R8, and —C(O)NR8R9;
• and
• R8 and R9 are independently selected at each occurrence from the group consisting of hydrogen and C1-6 alkyl;
• with acetic anhydride and nitric acid to form a compound of formula (IA)
• 29
• wherein m, n, R2, R3, R4, Rs, and R6 are as above in the compound of formula (II);
• (b) reacting the compound of formula (IA) with an acid anhydride or an acid chloride to form a compound of formula (IC)
• 30
• wherein:
• m, n, R2, R3, R4 R5, and R6 are as above in the compound of formula (II);
• and
• R10 is selected from the group consisting of C1-6 alkyl, C1-6 chloroalkyl, alkoxy-substituted C1-6 alkyl, and aryl;
• and
• (c) reacting the compound of formula (IC) with a 21-hydroxyalkyl corticosteroid and a base to produce a 21-[4′-(nitrooxyalkyl)benzoate] corticosteroid derivative.