Process for the preparation of (1R,3R)- and (1S,3S)-2,2-dihalo-3-(substituted phenyl)cyclopropanecarboxylic acids
View Patent ↗The (1R,3R)- or (1S,3S)-enantiomer of 2,2-dichloro-3-(substituted phenyl)cyclopropane-carboxylic acid is prepared in a process involving chemical resolution of a racemic mixture of a trans-2,2-dichloro-3-(substituted phenyl)cyclopropanecarboxylic acid with an enantiomeric amine, isolation of a diastereomeric amine salt and finally treatment of the salt with an acid.
1. A process for the preparation of a (1R,3R)- or a (1S,3S)-2,2-dihalo-3-(substituted phenyl)cyclopropanecarboxylic acid of Formula 1-2A or Formula 1-2B
wherein:
(A) R 1 is selected from the group consisting of H, F, Cl, Br, I, CN, NO 2 , SF 5 , (C 1 -C 3 )alkyl, and (C 1 -C 3 )haloalkyl;
(B) R 2 is selected from the group consisting of H, F, Cl, Br, I, CN, NO 2 , SF 5 , (C 1 -C 3 )alkyl, and (C 1 -C 3 )haloalkyl;
(C) R 3 is selected from the group consisting of H, F, Cl, Br, I, CN, NO 2 , SF 5 , (C 1 -C 3 )alkyl, and (C 1 -C 3 )haloalkyl;
(D) R 4 is selected from the group consisting of H, F, Cl, Br, I, CN, NO 2 , SF 5 , (C 1 -C 3 )alkyl, and (C 1 -C 3 )haloalkyl;
(E) R 5 is selected from the group consisting of H, F, Cl, Br, I, CN, NO 2 , SF 5 , (C 1 -C 3 )alkyl, and (C 1 -C 3 )haloalkyl; and
(G) X 2 is selected from the group consisting of F, Cl, Br, and I; comprising:
a) treating a racemic mixture of a trans-2,2-dihalo-3-(substituted phenyl)cyclopropane-carboxylic acid of Formula 1-1
with an enantiomeric amine of Formula 2-1 or 2-2
wherein:
X 1 is selected from the group consisting of C 1 -C 4 alkyl and benzyl;
to form a mixture;
b) isolating a diastereomeric amine salt of Formula 3-1A or Formula 3-1B,
or of Formula 3-2A or Formula 3-2B,
from the mixture; and
c) treating the isolated diastereomeric amine salt of Formula 3-1A or 3-1B, or of Formula 3-2A or 3-2B, with an acid to provide the (1R,3R)- or the (1S,3S)-2,2-dihalo-3-(substituted phenyl)cyclopropanecarboxylic acid of Formula 1-2A or Formula 1-2B.
2. The process of claim 1 wherein from about 0.4 to about 0.7 molar equivalents of the enantiomeric amine of Formula 2-1 or 2-2 is combined with the racemic mixture of the trans-2,2-dihalo-3-(substituted phenyl)cyclopropane-carboxylic acid of Formula 1-1.
3. The process of claim 1 wherein the isolating the diastereomeric amine salt of Formula 3-1A or Formula 3-1B, or of Formula 3-2A or Formula 3-2B comprises separating the diastereomeric amine salt from the crude reaction mixture by filtration or centrifugation.
4. The process of claim 1 wherein the acid may be selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and nitric acid.
5. The process of claim 1 wherein R 1 and R 5 are H.
6. The process of claim 5 wherein R 2 is selected from the group consisting of H, F, and Cl, R 3 is F or Cl, and R 4 is selected from the group consisting of F, Cl and (C 1 -C 6 )haloalkyl.
7. The process of claim 1 wherein the enantiomeric amine of Formula 2-2 is (L)-leucinamide.
8. The process of claim 1 wherein the enantiomeric amine of Formula 2-1 is (D)-phenylalanine amide.
9. The process of claim 1 wherein the enantiomeric amine of Formula 2-2 is (L)-phenylalanine amide.
10. A process for the preparation of a (1R,3R)-2,2-dichloro-3-(3-trifluoromethyl-4-fluorophenyl)cyclopropanecarboxylic acid of Formula 4-1
comprising:
a) treating a racemic mixture of trans-2,2-dichloro-3-(3-trifluoromethyl-4-fluorophenyl)cyclopropane-carboxylic acid of Formula 4-2
with an enantiomeric amine of Formula 2-2A
to form a mixture;
b) isolating a diastereomeric amine salt of Formula 4-3
from the mixture; and
c) treating the isolated diastereomeric amine salt of Formula 4-3 with an acid to provide the (1R,3R)-2,2-dichloro-3-(3-trifluoromethyl-4-fluorophenyl)cyclopropanecarboxylic acid of Formula 4-1.