Granted Patent B2

US 12,606,573 · App. 18/248,176 · Granted Apr 21, 2026

Inventor: Julian Rudolf Kuttner (Hessen, DE)

Assignee: VENATORX PHARMACEUTICALS, INC.

C07F5/025

Abstract

Claims (76)

1 . A process for preparing a compound of Formula (III):

wherein:

P 1 is a hydroxyl protecting group; and

R a , R b , and R c are independently hydrogen, fluoro, or chloro;

the process comprising reacting a compound of Formula (II)

 with an oxidizing agent.

2 . The process of claim 1 , wherein the oxidizing agent is potassium permanganate (KMnO 4 ).

3 . The process of claim 1 , wherein the process further comprises a base.

4 . The process of claim 1 , wherein the process comprises:

(i) suspending the compound of Formula (II):

 in water;

(ii) adding a base to dissolve the compound of Formula (II) in water;

(iii) adding an oxidizing agent while stirring;

(iv) stirring;

(v) adding a solvent to inactivate the excess oxidizing agent;

(vi) stirring;

(vii) filtering to get a filtrate;

(viii) acidifying the filtrate to get a slurry;

(viii) cooling the slurry; and

(ix) filtering the slurry thereby obtaining the compound of Formula (III):

5 . The process of claim 4 , wherein:

(a) the base in step (ii) is sodium hydroxide;

(b) the oxidizing agent is potassium permanganate (KMnO 4 );

(c) step (iii) is performed for about 10 h to about 20 h;

(d) the temperature is maintained at between about 20° C. and about 30° C. in step (iii);

(e) the solvent to inactivate the excess oxidizing agent is a primary or secondary alcoholic solvent;

(f) step (vi) is performed for about 10 min to about 2 h;

(g) the filtrate obtained in step (vii) is cooled to between about 0° C. and about 10° C. in step (viii) prior to acidifying;

(h) the acid used for acidifying is sulfuric acid; and/or

(i) the compound of Formula (III) is obtained by filtration.

6 . The process of claim 1 , wherein the compound of Formula (II):

is obtained by reacting a compound of Formula (I):

with a lithium reagent followed by a borate.

7 . The process of claim 6 , wherein the compound of Formula (I) is contacted with the lithium reagent to form a compound of Formula (Ia):

8 . The process of claim 6 , wherein the lithium reagent is n-BuLi.

9 . The process of claim 6 , wherein the borate is B(OiPr) 3 .

10 . The process of claim 6 , wherein the process comprises:

(i) combining a compound of Formula (I):

 and a diamine in a solvent;

(ii) stirring;

(iii) adding a lithium reagent;

(iv) stirring;

(v) adding a borate;

(vi) quenching the reaction by adding an aqueous acidic solution;

(vii) separating the layers to obtain an organic layer;

(viii) adding an aqueous basic solution to the organic layer;

(ix) separating the layers to obtain an aqueous layer;

(x) adding an acid to the aqueous layer;

(xi) cooling to obtain a suspension;

(xii) stirring;

(xiii) filtering the suspension, thereby obtaining the compound of Formula (II):

11 . The process of claim 10 , wherein:

(a) the diamine is TMEDA;

(b) the solvent use in step (i) is cyclohexane;

(c) the lithium reagent is nBuLi;

(d) the borate is B(OiPr) 3 ;

(e) the addition of the lithium reagent in step (iii) is done over about 1 h to about 6 h;

(f) the addition of the lithium reagent in step (iii) is done while the temperature is maintained between about 0° C. and about 20° C.;

(g) step (iv) is performed for about 2 h to about 3 h;

(h) the temperature is cooled to below −70° C. prior to the addition of the borate in step (v);

(i) the temperature is warmed to above −20° C. after to the addition of the borate in step (v);

(j) the aqueous acidic solution in step (vi) is a HCl solution;

(k) the aqueous basic solution in step (viii) is a NaOH solution; and/or

(l) the cooling temperature in step (xi) is about 0° C. and about 5° C.

12 . The process of claim 1 , further comprising reacting the compound of Formula (III):

with (1S,2S,3R,5S)-(+)-pinanediol in a solvent to form a compound of Formula (IV):

13 . The process of claim 12 , wherein the process comprises:

(i) mixing the compound of Formula (III), (1S,2S,3R,5S)-(+)-pinanediol, and the solvent;

(ii) heating the resulting mixture;

(iii) cooling to obtain a slurry;

(iv) filtering to obtain the compound of Formula (IV).

14 . The process of claim 13 , wherein:

(a) the solvent is n-heptane;

(b) the heating is done to reach reflux;

(c) step (ii) further comprises removing water; and/or

(d) the cooling temperature in step (iii) is below about 60° C.

Assignments (3)

Continuity (2)

References Cited (35)