Process for the preparation of isoxazoline compounds
View Patent ↗This invention relates to processes for the preparation of antiparasitic isoxazoline compounds enriched in an enantiomer using quinine-based chiral phase transfer catalyst. The invention also relates to novel quinine-based phase transfer catalysts and to a toluene solvent form of the isoxazoline compound of the invention.
1. A crystalline solvated solid form of an isoxazoline compound of formula (I) with an aromatic solvent:
wherein:
B 1 , B 2 , B 3 , are each independently C—R or N;
each R is independently H, halogen, cyano, —NO 2 , alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkylamino, dialkylamino or alkoxycarbonyl;
R 1 is C 1 -C 3 alkyl or C 1 -C 3 haloalkyl;
Y is Y-1 or Y-2:
Q is T-NR 2 R 3 , OH, NH 2 , alkoxy, haloalkoxy, alkylamino, haloalkylamino, dialkylamino, halodialkylamino, thiol, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, or an optionally substituted 5- or 6-membered carbocyclyl, heterocyclyl or heteroaryl ring;
T is (CH 2 ) n , CH(CH 3 ), CH(CN), C(═O) or C(═S);
R 2 is H, alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, alkylcarbonyl or alkoxycarbonyl;
R 3 is H, OR 7 , NR 8 R 9 or Q 1 ; or alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl, each optionally substituted with one or more substituents independently selected from R 4 ; or
R 2 and R 3 are taken together with the nitrogen to which they are attached to form a ring containing 2 to 6 atoms of carbon and optionally one additional atom selected from the group consisting of N, S and O, said ring optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkyl, halogen, —CN, —NO 2 and alkoxy;
each R 4 is independently halogen; alkyl, cycloalkyl, alkoxy, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkyl sulfonyl, haloalkylsulfonyl, alkylamino, haloalkylamino, dialkylamino, dihaloalkylamino, cycloalkylamino, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, haloalkylcarbonyl, haloalkoxycarbonyl, haloalkylaminocarbonyl, dihaloalkylaminocarbonyl, hydroxy, —NH 2 , —CN or —NO 2 ; or Q 2 ;
each R 5 is independently halogen, alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkyl sulfonyl, haloalkylsulfonyl, alkylamino, dialkylamino, alkoxycarbonyl, —CN or —NO 2 ;
each R 6 is independently halogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkylamino, dialkylamino, —CN, —NO 2 , phenyl or pyridinyl;
R 7 is H; or alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl or cycloalkylalkyl, each optionally substituted with one of more halogen;
R 8 is H, alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, alkylcarbonyl or alkoxycarbonyl;
R 9 is H; Q 3 ; or alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl or cycloalkylalkyl, each optionally substituted with one or more substituents independently selected from R 4 ; or
R 8 and R 9 are taken together with the nitrogen to which they are attached to form a ring containing 2 to 6 atoms of carbon and optionally one additional atom selected from the group consisting of N, S and O, said ring optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkyl, halogen, —CN, —NO 2 and alkoxy;
Q 1 is a phenyl ring, a 5- or 6-membered heterocyclic ring, or an 8-, 9- or 10-membered fused bicyclic ring system optionally containing one to three heteroatoms selected from up to 1 O, up to 1 S and up to 3 N, each ring or ring system optionally substituted with one or more substituents independently selected from R 5 ;
Q 2 is independently a phenyl ring or a 5- or 6-membered heterocyclic ring, each ring optionally substituted with one or more substituents independently selected from R 6 ;
Q 3 is a phenyl ring or a 5- or 6-membered heterocyclic ring, each ring optionally substituted with one or more substituents independently selected from R 6 ; and
n is 0, 1 or 2;
wherein the asterisk represents that the carbon atom is a chiral quaternary carbon atom.
2. The crystalline solvated solid form of claim 1 , wherein:
Y is Y-2.
3. The crystalline solvated solid form of claim 1 , wherein Q is —C(O)NHCH 2 C(O)NHCH 2 CF 3 , —C(O)CH 2 S(O) 2 CH 3 , or —C(O)NHCH 2 CH 2 SCH 3 .
4. The crystalline solvated solid form of claim 1 , wherein B 1 , B 2 , B 3 , are each independently C—R; and each R is independently H, halogen or haloalkyl.
5. The crystalline solvated solid form of claim 1 , wherein R 1 is CF 3 .
6. The crystalline solvated solid form of claim 1 , wherein:
Y is Y-2;
R 1 is CF 3 ;
B 1 , B 2 , B 3 , are each independently C—R; each R is H, halogen or CF 3 ; and
Q is —C(O)NHCH 2 C(O)NHCH 2 CF 3 .
7. The crystalline solvated solid form of claim 6 , wherein B 1 is C—Cl; B 2 is C—H or C—F and B 3 is C-CF 3 .
8. The crystalline solvated solid form of claim 1 , wherein the aromatic solvent is toluene.
9. The crystalline solvated solid form of claim 6 , wherein the crystalline solvated solid form is a crystalline toluene solvate of (S)-afoxolaner having the formula:
10. The crystalline toluene solvate of claim 9 , which is characterized by an X-ray powder diffraction pattern comprising two or more of the 2-theta peaks selected from the group consisting of:
Angle
2-Theta °
4.859,
22.236,
18.838,
8.516,
25.643,
25.291,
21.859,
18.411,
19.894 and
12.746
±0.2 2-theta, as determined on a diffractometer using Cu-Kα radiation.
11. The crystalline toluene solvate of claim 9 , which is characterized by an X-ray powder diffraction pattern comprising three or more peaks selected from the group consisting of:
Angle
2-Theta °
4.859,
22.236,
18.838,
8.516,
25.643,
25.291,
21.859,
18.411,
19.894 and
12.746
±0.2 2-theta.
12. The crystalline toluene solvate of claim 9 characterized by an X-ray powder diffraction pattern substantially as shown in FIG. 8 .
13. The crystalline toluene solvate of claim 9 which is characterized by a differential scanning calorimetry (DSC) thermogram having an endotherm at a temperature of about 83° C. to about 87° C., corresponding to the toluene solvate.
14. The crystalline toluene solvate of claim 9 which is characterized by a differential scanning calorimetry (DSC) thermogram having an endotherm at a temperature of about 84.7° C., corresponding to the toluene solvate.
15. The crystalline toluene solvate of claim 9 , which is characterized by a differential scanning calorimetry thermogram substantially as shown in FIG. 7 .
16. The crystalline toluene solvate of claim 9 characterized by a thermogravimetric analysis (TGA) thermogram characterized by weight loss of about 10.5% from about about 26° C. at about 160° C.
17. The crystalline toluene solvate of claim 9 characterized by thermogravimetric analysis thermogram substantially as shown in FIG. 7 .
18. The crystalline toluene solvate of claim 9 characterized by unit cell parameters substantially equal to the following:
Cell Volume
1561.42
{acute over (Å)}3
Symmetry Cell System
Triclinic
Symmetry Space Group Name
P1
Cell Length a
8.201
{acute over (Å)}
Cell Length b
10.7031
{acute over (Å)}
Cell Length c
18.6462
{acute over (Å)}
Cell Angle α
75.6862°
Cell Angle β
84.2126°
Cell Angle γ
80.592°
Density (g/cm 3 )
1.497.
19. The crystalline toluene solvate of claim 9 characterized by unit cell parameters substantially equal to the following cell:
Cell Volume
1561.42
{acute over (Å)}3
Symmetry Cell System
Triclinic
Symmetry Space Group Name
P1
Cell Length a
8.201
{acute over (Å)}
Cell Length b
10.7031
{acute over (Å)}
Cell Length c
18.6462
{acute over (Å)}
Cell Angle α
75.6862°
Cell Angle β
84.2126°
Cell Angle γ
80.592°
Density (g/cm3)
1.497
R indices
5.5%
Absolute Structure Parameter
−0.03.
20. The crystalline toluene solvate of claim 9 characterized by having two or more of the following characteristics:
i) an X-ray powder diffraction pattern comprising at least three 2-theta values selected from the group consisting of
Angle
2-Theta °
4.859,
22.236,
18.838,
8.516,
25.643,
25.291,
21.859,
18.411,
19.894 and
12.746
±0.2 2-theta;
ii) an X-ray powder diffraction pattern substantially in accordance with the X-ray powder diffraction spectrum shown in FIG. 8 ;
iii) a differential scanning calorimetry (DSC) thermogram having an endotherm at a temperature of between about 83° C. to about 87° C.;
iv) a differential scanning calorimetry thermogram substantially as shown in FIG. 7 ; and
v) a thermogravimetric analysis (TGA) diagram substantially the same as that shown in shown in FIG. 7 .
21. The crystalline toluene solvate of claim 9 , wherein the molar ratio of (S)-afoxolaner to toluene is about 1:1.
22. The crystalline toluene solvate of claim 9 , wherein the crystalline (S)-afoxolaner toluene solvate is isolated.
23. The crystalline toluene solvate of claim 9 , wherein at least 90% of (S)-afoxolaner by weight is a crystalline toluene solvate form.
24. The crystalline toluene solvate of claim 9 , wherein at least 80% of (S)-afoxolaner by weight is a crystalline toluene solvate form.
25. The crystalline toluene solvate of claim 9 , wherein at least 70% of (S)-afoxolaner by weight is a crystalline toluene solvate form.
26. The crystalline toluene solvate of claim 9 , wherein at least 60% of (S)-afoxolaner by weight is a crystalline toluene solvate form.
27. A pesticidal or parasiticidal composition comprising the crystalline solvated solid form according to claim 1 , and at least one agriculturally or pharmaceutically acceptable carrier or excipient.
28. The pesticidal or parasiticidal composition of claim 27 , wherein the crystalline solvated solid form is a crystalline toluene solvate of (S)-afoxolaner, and wherein said crystalline toluene solvate of (S)-afoxolaner is in admixture with one or more distinct polymorphic forms of (S)-afoxolaner and/or an amorphous form of (S)-afoxolaner.
29. The pesticidal or parasiticidal composition of claim 28 , wherein at least 80% of (S)-afoxolaner is a crystalline toluene solvate form.
30. The pesticidal or parasiticidal composition of claim 28 , wherein the composition comprises at least 95% by weight of the crystalline toluene solvate of (S)-afoxolaner based on the total weight of (S)-afoxolaner in the composition.
31. The pesticidal or parasiticidal composition of claim 30 , wherein the composition comprises at least 98% by weight of the crystalline toluene solvate of (S)-afoxolaner based on the total weight of (S)-afoxolaner in the composition.