Processes for the preparation of 1-aryl-5-alkyl pyrazole compounds
Provided are improved processes for the preparation of 1-aryl pyrazole compounds of formula (I) and (IB): which are substituted at the 5-position of the pyrazole ring with a carbon-linked functional group. The process described are efficient and scalable and do not utilize hazardous sulfenyl halide reagents.
1. A process for preparing a 1-aryl-5-alkyl pyrazole compound of formula (IB):
wherein:
R 1b is hydrogen, cyano, halogen, R 8b , formyl, —CO 2 H, —C(O)R 8b , —C(O)OR 8b , —C(O)NR 9b R 10b or —C(S)NH 2 ;
R 2b is —S(O) m R 11b ;
R 3b is alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, halocycloalkyl, alkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, wherein each alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heterocyclyl or heteroaryl group may optionally be substituted by one or more of halogen, hydroxy, alkoxy, alkoxyalkoxy, amino, alkylamino, dialkylamino, nitro, cyano or —C(S)NH 2 ;
R 4b is hydrogen, halogen, alkyl, haloalkyl, cyano or nitro;
R 5b is hydrogen, halogen, alkyl, haloalkyl, cyano or nitro;
R 7b is hydrogen, halogen, alkyl, haloalkyl, cyano or nitro;
R 13b is hydrogen, halogen, alkyl, haloalkyl, cyano or nitro;
R 6b is halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, nitro, —C(O)R 12b , —S(O) n R 12b or SF 5 ;
W is nitrogen or C—R 13b ;
R 8b is alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, halocycloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heterocyclyl or heteroaryl;
R 9b and R 10b are independently hydrogen, alkyl, haloalkyl, hydroxy or alkoxy;
R 11b is alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl or halocycloalkyl;
R 12b is alkyl or haloalkyl;
m is 0, 1 or 2; and
n is 0, 1 or 2;
which comprises:
(i) reacting a compound of formula (IIB):
wherein
R 1b is hydrogen, cyano, halogen, R 8b , formyl, —CO 2 H, —C(O)R 8b , —C(O)OR 8b , —C(O)NR 9b R 10b or —C(S)NH 2 ;
R 2b is —S(O) m R 11b
R 4b is hydrogen, halogen, alkyl, haloalkyl, cyano or nitro;
R 5b is hydrogen, halogen, alkyl, haloalkyl, cyano or nitro;
R 6b is halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, nitro, —C(O)R 12b , S(O) n R 12b or SF 5 ;
R 7b is hydrogen, halogen, alkyl, haloalkyl, cyano or nitro;
R 8b is alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, halocycloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heterocyclyl or heteroaryl
R 11b is alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl or halocycloalkyl;
W is nitrogen or C—R 13b ;
R 13b is hydrogen, halogen, alkyl, haloalkyl, cyano or nitro; and
Q is iodo, bromo, chloro or a haloalkylsulfonate group;
with a compound of formula (IId):
wherein R 1d , R 2d and R 3d are independently alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl or heterocyclyl, wherein each alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl or heterocyclyl group may optionally be substituted with one or more halogen, hydroxy, alkoxy, alkoxyalkoxy, amino, alkylamino, dialkylamino, nitro, cyano or —C(S)NH 2 groups; in the presence of a transition metal catalyst to form the compound of formula (IB);
(ii) wherein if R 1b in the compound of formula (IB) is —C(O)OR 8b or —C(O)NR 9b R 10b , optionally converting the —C(O)OR 8b or —C(O)NR 9b R 10b groups to cyano, hydroxyalkyl, aminoalkyl, dialkylaminoalkyl, formyl, —C(O)R 8b or —C(S)NH 2 , wherein R 8b , R 9b and R 10b are as defined above for the compound of formula (IB), via functional group modification; and
(iii) optionally oxidizing the group —S(O) m R 11b where m is 0 or 1, to form the compound of formula (IB);
wherein the sequence of steps ii) and iii) may be interchanged.
2. The process of claim 1 , wherein the compound of formula (IIB) wherein Q is I, Br or Cl is prepared by reacting a compound of formula (IIIB):
wherein R 1b , R 2b , R 4b , R 5b , R 6b , R 7b and W are as defined in claim 1 for the compound of formula (IB), with a source of Br, Cl or I and a nitrite compound T-ONO, where T is hydrogen or alkyl, or a salt thereof.
3. The process of claim 1 , wherein the transition metal catalyst is a palladium catalyst.
4. The process of claim 2 , wherein T-ONO is sodium nitrite, isopentyl nitrite, or tert-Butyl nitrite.
5. The process of claim 1 , wherein Q is bromo.
6. The process of claim 1 , wherein the compound of formula (IId) is trimethylboroxine and R 3b is methyl.
7. The process of claim 1 , wherein in step (i) the compound of (IIB) is reacted with a compound of formula (IId), and wherein the process further comprises addition of a base to the reaction mixture.
8. The process of claim 7 , wherein the base is an alkali metal hydroxide or an alkali metal carbonate.
9. The process of claim 3 , wherein the palladium catalyst is selected from (Ph 3 P) 4 Pd, (Ph 3 P) 2 PdCl 2 , (CH 3 CN) 2 PdCl 2 , Pd 2 (dba) 3 , (dppf)PdCl 2 , or a palladium metal catalyst covalently linked to a polymer chain.
10. The process of claim 2 , wherein the compound of formula (IIIB) is fipronil.
11. The process of claim 4 , wherein T-ONO is sodium nitrite and the source of Br is HBr.
12. The process of claim 1 , wherein in step (i), the compound of formula (IIB) is reacted with a compound of formula (IId) in the presence of potassium carbonate.
13. The process of claim 1 , wherein in step (i), the compound of formula (IIB) is reacted with a compound of formula (IId) in the presence of n-butyl acetate.
14. The process of claim 1 , wherein:
R 4b is halogen, haloalkyl, cyano or nitro.
15. The process of claim 1 , wherein:
W is C—R 13b .
16. The process of claim 1 , wherein:
W is C—R 13 ; and
R 13b is halogen, haloalkyl, cyano or nitro.
17. The process of claim 1 , wherein:
R 4b is halogen;
W is C—R 13b ; and
R 13b is halogen.
18. The process of claim 1 , wherein:
R 4b is halogen;
W is C—R 13b ;
R 13b is halogen; and
R 6b is haloalkyl.
19. The process of claim 1 , wherein in step (i), the compound of formula (IIB) is reacted with a compound of formula (IId) in the presence of Pd 2 (dba) 3 and potassium carbonate.