Process for making sarecycline hydrochloride

1. A process for preparing sarecycline hydrochloride of Formula (I)

comprising:

(a) reacting (4S,4aS,5aR,12aR)-4-(dimethylamino)-1,10,11,12a-tetrahydroxy-3, 12-dioxo-4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide of Formula II

with

(i) trifluoroacetic acid (TFA); and

(ii) N-iodosuccinimide (NIS);

to form 7-iodosancycline trifluoroacetic acid salt of Formula III

b) reacting the 7-iodosancycline trifluoroacetic acid salt of Formula (III) with

(i) N-methyl pyrrolidone (NMP);

(ii) triphenylphosphine (PPh 3 );

(iii) Bis-(Triphenyl Phosphine) palladium chloride catalyst (BTPP—PdCl 2 );

(iv) triethylsilane (Et 3 SiH); and

(v) carbon monoxide (CO);

to form 7-formylsancycline of Formula IV

c) reacting the 7-formylsancycline of Formula IV with

(i) dimethylhydroxylamine (DMHA) free base;

(ii) oxalic acid;

(iii) dimethylaminoborane (DMAB); and

(iv) acetone

to form sarecycline crude oxalate salt of Formula V

d) reacting the sarecycline crude oxalate salt of Formula V with

(i) ammonium hydroxide (NH 3 (aqueous)) or hydrochloride acid (HCl);

to form sarecycline free base of Formula VI

(e) reacting the sarecycline free base of Formula VI with

(i) ethanolic hydrochloric acid solution

to form the sarecycline hydrochloride of Formula I.

2. The process according to claim 1 , wherein step (a) further comprises

i. isopropanol; or

ii. tetrahydrofuran (THF); or

iii. isopropanol and tetrahydrofuran (THF).

3. The process according to claim 1 , wherein step (b) further comprises

i. cellulose or SiO 2 ; or

ii. sodium carbonate (Na 2 CO 3 ); or

iii. water; or

iv. sulfuric acid (H 2 SO 4 ); or

V. ethanol (EtOH); or

vi. a combination thereof.

4. The process according to claim 1 , wherein step (c) further comprises methanol (MeOH).

5. The process according to claim 1 , wherein step (d) further comprises

i. cellulose or SiO 2 ; or

ii. dichloromethane (DCM); or

iii. water; or

iv. methanol (MeOH); or

V. acetone; or

vi. a combination thereof.

6. The process according to claim 1 , wherein step (e) further comprises

i. ethanol (EtOH); or

ii. water; or

iii. hydrochloric acid (HCl); or

iv. a combination thereof.

7. The process according to claim 1 , wherein step (d) is repeated at least one time.

8. The process according to claim 1 , further comprising:

(d′) reacting the sarecycline free base of Formula VI with

(i) trifluoroacetic acid (TFA); and

(ii) tetrahydrofuran (THF)

and repeating steps (d) and (e).

9. The process according to claim 8 , wherein step (d′) further comprises

i. water; or

ii. isopropanol; or

iii. water and isopropanol.

10. The process according to claim 8 , wherein steps (d′) and (d) are repeated at least one time.