Process-scale synthesis of a plasma kallikrein inhibitor

Patent metadata

Field	Value
Publication number	US-12503443-B2
Application number	US-202017632585-A
Country	US
Kind code	B2
Filing date	Aug 5, 2020
Priority date	Aug 6, 2019
Publication date	Dec 23, 2025
Grant date	Dec 23, 2025

Abstract

Disclosed are methods of preparing Compound I, and salts thereof. The methods of preparing Compound I are suitable for use on process scale.

First claim

We claim:

1 . A method, comprising the step of:
combining compound C, or a salt thereof, and compound F, or a salt thereof, under conditions sufficient to produce compound D, or a salt thereof, wherein: compound C is represented by:

compound F is represented by:

and compound D is represented by:

wherein:
the conditions sufficient to produce compound D comprise an amide-coupling reagent, and a base A;
the amide-coupling reagent is propylphosphonic anhydride (T3P), N,N′-di (isopropyl) carbodiimide, N,N′-di (cyclohexyl) carbodiimide, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide, or ethyl 2-cyano-2-(hydroxyimino) acetate;
the base A is triethylamine, pyridine, diisopropylethylamine, diisopropylmethylamine, imidazole, pyrimidine, N-methylmorpholine, quinuclidine, or 1,4-diazabicyclo [2.2.2]octane (DABCO); and
compound C is used in an amount of at least 1 kg.

2 . The method of claim 1 , wherein the amide-coupling reagent is propylphosphonic anhydride (T3P).

3 . The method of claim 1 , wherein the base A is pyridine.

4 . The method of claim 1 , wherein the conditions sufficient to produce compound D further comprise a solvent A.

5 . The method of claim 4 , wherein the solvent A is a polar aprotic solvent.

6 . The method of claim 5 , wherein the solvent A is dichloromethane, tetrahydrofuran, acetone, acetonitrile, or ethyl acetate.

7 . The method of claim 1 , wherein compound C is present as an acid salt; and
the method further comprises the step of combining the acid salt of compound C with an aqueous base B, thereby forming the free base of compound C; wherein the step of combining the acid salt of compound C with the aqueous base B occurs before combining compound C and compound F.

8 . The method of claim 7 , wherein the acid salt of compound C is a hydrochloride salt, a hydrobromide salt, a hydroiodide salt, or an oxalic acid salt.

9 . The method of claim 1 , further comprising (a) combining compound B, or a salt thereof, and

to form a reaction mixture A, then (b) combining the reaction mixture A with a reducing agent under conditions sufficient to form compound C, or a salt thereof, wherein:
compound B is represented by:

10 . The method of claim 9 , wherein the reducing agent is LiAlH 4 or NaBH 4 .

11 . The method of claim 9 , further comprising contacting compound C with an acid A to form an acid salt of compound C.

12 . The method of claim 11 , wherein the acid A is hydrochloric acid, hydrobromic acid, hydroiodic acid, or oxalic acid; and the acid salt of compound Cis a hydrochloride salt, a hydrobromide salt, a hydroiodide salt, or an oxalic acid salt.

13 . The method of claim 9 , wherein compound B is present as an acid salt; and
the method further comprises the step of combining the salt of compound B with an organic base C, thereby forming the free base of compound B; wherein the step of combining the salt of compound B with the organic base C occurs before combining compound B and

14 . The method of claim 9 , further comprising (a) combining compound A and an acid B under conditions sufficient to form compound B, or a salt thereof; wherein:
compound A is represented by:

15 . The method of claim 14 , wherein the acid B is hydrochloric acid, hydrobromic acid, or hydroiodic acid.

16 . The method of claim 14 , wherein compound B is formed as an acid salt.

17 . The method of claim 1 , further comprising (e) combining compound D and a deprotecting reagent to form a reaction mixture B, then (d) exposing the reaction mixture B to conditions sufficient to form Compound I as a free base; wherein:
Compound I is represented by:

18 . The method of claim 17 , further comprising:
i) providing a first freebase mixture of Compound I as a free base in an organic solvent D, thereby forming a freebase mixture; ii) combining the freebase mixture with a reagent solution A comprising an acid D and an organic solvent E under conditions sufficient to form a reaction mixture C comprising a salt of Compound I; and iii) isolating a crystalline salt of Compound I from the reaction mixture C comprising the salt of Compound I.

19 . The method of claim 18 , wherein the crystalline salt is a hydrochloride salt.

20 . The method of claim 18 , wherein the crystalline salt is a bis (hydrochloride) salt.

21 . The method of claim 1 , wherein compound C is used in an amount of at least 5 kg, at least 10 kg, at least 15 kg, at least 20 kg, at least 25 kg, at least 30 kg, at least 35 kg, at least 40 kg, at least 45 kg, at least 50 kg, at least 55 kg, or at least 60 kg.

22 . The method of claim 1 , wherein compound C is used in an amount of at least 50 kg.

Assignees

• Biocryst Pharm Inc

Inventors

• El-Kattan Yahya
• Babu Yarlagadda S

Classifications

• C07C2602/02

  the rings having only two atoms in common · CPC title

• A61K31/415

  1,2-Diazoles · CPC title

• C07C255/58

  containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton · CPC title

• C07C253/30 Primary

  by reactions not involving the formation of cyano groups · CPC title

• C07D231/14 Primary

  with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms · CPC title