Processes for making modulators of cystic fibrosis transmembrane conductance regulator

Patent metadata

Field	Value
Publication number	US-11465985-B2
Application number	US-201816769047-A
Country	US
Kind code	B2
Filing date	Dec 7, 2018
Priority date	Dec 8, 2017
Publication date	Oct 11, 2022
Grant date	Oct 11, 2022

Abstract

The disclosure provides processes for preparing a compound of Formula (I).

First claim

The invention claimed is:

1. A method of preparing a compound of Formula (I):

a deuterated derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:
R 1 is

and
Ring A is phenyl or

comprising:
(a) reacting 2,2,6,6-tetramethyl-piperidin-4-one or a salt thereof with chloroform and at least one base;
(b) reacting the products of the reaction in (a) with an acid to produce 5,5-dimethyl-3-methylenepyrrolidin-2-one or a salt thereof;
(c) performing an enantioselective hydrogenation of 5,5-dimethyl-3-methylenepyrrolidin-2-one or a salt thereof to produce (S)-3,5,5-trimethyl-pyrrolidin-2-one or a salt thereof;
(d) reducing (S)-3,5,5-trimethyl-pyrrolidin-2-one or a salt thereof to produce (S)-2,2,4-trimethylpyrrolidine;
(e) optionally treating (S)-2,2,4-trimethylpyrrolidine with acid to produce a salt of (S)-2,2,4-trimethylpyrrolidine; and
(f) reacting the (S)-2,2,4-trimethylpyrrolidine or salt thereof with a compound of Formula (F) or a salt thereof:

wherein:
R 1 is

Ring A is phenyl or

and
X a is chosen from halogens, and
wherein a compound of Formula (I), a deuterated derivative thereof, or a pharmaceutically acceptable salt any of the foregoing is produced.

2. The method of claim 1 , further comprising treating (S)-2,2,4-trimethylpyrrolidine with HCl to generate (S)-2,2,4-trimethylpyrrolidine hydrochloride.

3. The method of claim 1 , wherein the compound of Formula (I), deuterated derivative thereof, or pharmaceutically acceptable salt of any of the foregoing is Compound 1, a deuterated derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing:

4. The method of claim 3 , further comprising (g) reacting a compound of Formula (D-I):

or a salt thereof
wherein each X a is —F or —Cl
with Compound 12 or a salt thereof:

to produce a compound of Formula (F-I) or a salt thereof:

5. The method of claim 3 , further comprising:
reacting Compound 7 or a salt thereof

with a compound of Formula (B-I) or a salt thereof

wherein each R a is independently chosen from C 1 -C 4 alkyl; and each —X a is independently —F or —Cl;
to produce a compound of Formula (C-I) or a salt thereof:

and
hydrolyzing the —C(O)OR a group of a compound of Formula (C-I) or a salt thereof to produce a compound of Formula (D-I) or a salt thereof.

6. The method of claim 5 , further comprising decarboxylating Compound 6:

to form Compound 7 or a salt thereof:

7. A method of preparing Compound 1, a deuterated derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing:

comprising:
(a) reacting 2,2,6,6-tetramethyl-piperidin-4-one or a salt thereof with chloroform, at least one base chosen from potassium t-butoxide, potassium hydroxide, and sodium hydroxide, and at least one phase transfer catalyst chosen from tetrabutylmethylammonium chloride,
(b) reacting the products of the reaction in (a) with HCl to produce 5,5-dimethyl-3-methylenepyrrolidin-2-one or a salt thereof;
(c) performing an enantioselective hydrogenation of 5,5-dimethyl-3-methylenepyrrolidin-2-one or a salt thereof to produce (S)-3,5,5-trimethyl-pyrrolidin-2-one or a salt thereof;
(d) reducing (S)-3,5,5-trimethyl-pyrrolidin-2-one or a salt thereof to produce (S)-2,2,4-trimethylpyrrolidine;
(e) treating (S)-2,2,4-trimethylpyrrolidine with HCl to produce a HCl salt of (S)-2,2,4-trimethylpyrrolidine;
(f) decarboxylating Compound 6 or a salt thereof:

to form Compound 7 or a salt thereof:

in the presence of a base chosen from 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), aqueous sodium hydroxide, and potassium tert-butoxide or at least one acid chosen from aqueous HCl and acetic acid;
(g) reacting Compound 7 or a salt thereof with a compound of Formula (B-I) or a salt thereof:

wherein R a is methyl; and
each —X a is —Cl;

to generate a compound of Formula (C-I) or a salt thereof:

in the presence of a catalyst chosen from 1,4-diazabicyclo[2.2.2]octane (DABCO) and at least one base chosen from triethylamine, cesium carbonate, potassium carbonate, sodium carbonate, potassium tert-butoxide, potassium phosphate, DBU, and 1,1,3,3-tetramethylguanidine (TMG);
(h) hydrolyzing the —C(O)OR a group of a compound of Formula (C-I) or a salt thereof to generate a compound of Formula (D-I) or a salt thereof:

in the presence of at least one base chosen from NaOH and KOH;
(i) reacting a compound of Formula (D-I) or a salt thereof with 1,1′-carbonyldiimidazole (CDI) and subsequently reacting a product of the reaction of a compound of Formula (D-I) or a salt thereof with 1,1′-carbonyldiimidazole (CDI) with Compound 12 or a salt thereof:

in the presence of at least one base chosen from 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) to yield Compound 13 or a salt thereof:

(j) reacting Compound 13 or a salt thereof with (S)-2,2,4-trimethylpyrrolidine or a salt thereof in the presence of K 2 CO 3 to generate Compound 1 or a deuterated derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing:

Assignees

• Vertex Pharma

Inventors

• Angell Paul T
• Harrison Cristian
• Hughes Robert M
• Lewandowski Berenice
• Littler Benjamin J
• Melillo Vito
• Nugent William A
• Siesel David Andrew
• Smith David
• Studley John

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61K31/4439

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465) · CPC title

• C07D401/14 Primary

  containing three or more hetero rings · CPC title

• C07D401/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D231/20

  One oxygen atom attached in position 3 or 5 · CPC title