Method for producing pyrrolidine compound
The present invention provides a method suitable for industrial production of a compound of formula (V): (V) comprising a step of subjecting a compound (IV) to an asymmetric reductive amination reaction in the presence of a metal complex comprising a chiral ligand and subjecting this product to purification using salt formation with N-(4-methylbenzene-1-sulfonyl)-L-phenylalanine. (IV)
1 . A method for producing a salt of formula (V)
wherein
each R 1 is independently selected from a halogen atom and a trifluoromethanesulfonyl group;
A is an optionally further substituted 4-7 membered N-containing monocyclic saturated heterocyclyl; and
PG is a protecting group,
the process comprising subjecting a compound of formula (IV):
to an asymmetric reductive amination reaction in the presence of a metal complex comprising a chiral ligand and subjecting the resulting product to purification using salt formation with N-(4-methylbenzene-1-sulfonyl)-L-phenylalanine.
2 . The method of claim 1 , further comprising:
(a) reacting a compound of formula (II):
wherein
R 1 is independently selected from a halogen atom and a trifluoromethanesulfonyl group; and
X is a halogen atom,
with an anion of a compound of formula (III):
wherein
PG is a protecting group; and
A is an optionally further substituted 4-7 membered N-containing monocyclic saturated heterocycle;
(b) deprotecting the product of step (a);
(c) reacting the product of step (b) with a racemate of an organic acid; and
(d) introducing a protecting group to the product of step (c);
to provide the compound of formula (IV).
3 . The method of claim 1 , wherein A is selected from pyrrolidine, piperidine, and azetidine, each of which is optionally further substituted.
4 . The method of claims 1 , wherein each R 1 is independently selected from Cl, Br, I, and a trifluoromethanesulfonyl group.
5 . The method of claim 2 , wherein the organic acid is racemic tartaric acid (DL-tartaric acid).
6 . A method for producing N-(4-methylbenzene-1-sulfonyl)-L-phenylalanine salt of (2S,3S)-2-[(3-bromo-2-fluorophenyl) methyl]pyrrolidin-3-amine with a protecting group at the 1-position on the pyrrolidine, which comprises
a step comprising
Step 3a: subjecting 2-[(3-bromo-2-fluorophenyl) methyl]pyrrolidin-3-one with a protecting group at the 1-position on the pyrrolidine to an asymmetric reductive amination reaction in the presence of a metal complex comprising a chiral ligand; and
Step 3b: subjecting the product of Step 3a to purification using salt formation with N-(4-methylbenzene-1-sulfonyl)-L-phenylalanine.
7 . The method of claim 6 , further comprising
Step 1a: reacting 1-bromo-3-(bromomethyl)-2-fluorobenzene and pyrrolidin-3-one with a protecting group at the 1-position on the pyrrolidine;
Step 1b: deprotecting the product of Step 1a and reacting with DL-tartaric acid; and
Step 2: introducing a protecting group to the product of Step 1b to provide 2-[(3-bromo-2-fluorophenyl) methyl] pyrrolidin-3-one with a protecting group at the 1-position on the pyrrolidine.
8 . The method according to claim 1 , wherein the chiral ligand in the metal complex is a BINAP ligand, a phosphine ligand, a ferrocene ligand, or a cyclophane ligand.
9 . The method according to claim 1 , wherein the metal in the metal complex is ruthenium, rhodium, or iridium.
10 . The method according to claim 1 , wherein the metal complex comprising a chiral ligand is a ruthenium complex comprising a chiral BINAP ligand, or a ruthenium complex comprising a chiral cyclophane ligand.
11 . The method according to claim 1 , wherein the metal complex comprising a chiral ligand is a metal complex represented by the formula:
wherein Ligand is (S)-binap, (R)-xylyl-Phanephos or (R)-xylyl-binap.
12 . The method according to claim 1 , wherein the metal complex comprising a chiral ligand is Ru(OAc) 2 {(R)-xylyl-binap}.
13 . The method according to claim 1 , wherein the protecting group is selected from tert-butoxycarbonyl, benzyloxycarbonyl, acetyl, trityl, benzyl, 9-fluorenylmethyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, and methoxymethyl.
14 . The method according to claim 1 , wherein the protecting group is tert-butoxycarbonyl.
15 . The method according to claim 1 , wherein the purification conditions comprises recrystallization.
16 . The method according to claim 15 , wherein the crystallization comprises a salt formation with N-(4-methylbenzene-1-sulfonyl)-L-phenylalanine, which is conducted in a solvent at a temperature from 60° C. to 78° C., stirring at a temperature from 60° C. to 78° C., for about 0.5 hours, stirring at 15° C. to 35° C. for about 12 to about 48 hours, and filtering the resulting precipitate.
17 . The method according to claim 16 , further comprising recrystallizing the precipitate from a solvent selected from an alcohol, ether, or aromatic hydrocarbon.
18 . The method according to claim 17 , wherein the solvent is ethanol.
19 . The method according to claim 6 , further comprising:
Step 4: subjecting the N-(4-methylbenzene-1-sulfonyl)-L-phenylalanine salt of (2S,3S)-2-[(3-bromo-2-fluorophenyl) methyl]pyrrolidin-3-amine with a protecting group at the 1-position on the pyrrolidine to desalination and reacting with a methanesulfonylating agent;
Step 5: reacting the product of Step 4 with (3,5-difluorophenyl) boronic acid;
Step 6: subjecting the product of Step 5 to deprotection conditions; and
Step 7: subjecting the product of Step 6 to a condensation reaction with 2-hydroxy-2-methylpropanoic acid to give N-{(2S,3S)-1-(2-hydroxy-2-methylpropanoyl)-2-[(2,3′,5′-trifluoro [1,1′-biphenyl]-3-yl)methyl]pyrrolidin-3-yl} methanesulfonamide, or a hydrate thereof, or a solvate thereof.
20 . A compound which is a racemic organic acid salt of
21 . The compound of claim 20 , which is a racemic tartaric acid salt.
22 . The compound of claim 20 , which is