Processes for making modulators of cystic fibrosis transmembrane conductance regulator
The disclosure provides processes for preparing a compound of Formula (I).
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:
8. The method of claim 7 , wherein in the reaction in (b) the products of the reaction in (a) are reacted with HCl in an amount ranging from 1 to 4 molar equivalents relative to 2,2,6,6-tetramethyl-piperidin-4-one or salt thereof.