Process for the preparation of 5-fluoro-1H-pyrazoles starting from hexafluoropropene
View Patent ↗A new process for the preparation of 5-fluoro-1H-pyrazoles of the general formula (I) as described herein and further reactions with this compound.
1. A process for synthesis of 5-fluoro-1H-pyrazoles of formula (I)
wherein
R 1 represents optionally halogenated (C 1 -C 4 )alkyl or optionally halogenated cyclopropyl;
comprising
preparing perfluoro-4-methyl-2-pentene (intermediate (2)) in a Step 1
by reacting hexafluoropropene (compound (1))
in the presence of a catalyst to form its dimer perfluoro-4-methyl-2-pentene; and
preparing perfluoro-2-methyl-2-pentene (intermediate (3)) in a Step 2
by isomerizing perfluoro-4-methyl-2-pentene into perfluoro-2-methyl-2-pentene; and
preparing perfluoro-2-methyl-2-penten-)3-enolate (intermediate (4)) in a Step 3
wherein Cat + refers to a positively charged organic ion, alkaline metal cation or alkaline earth metal cation,
by reacting perfluoro-2-methyl-2-pentene with water and a base; and
preparing compound of formula (I) in a Step 4 by reacting intermediate (4) in Step 4 with a hydrazine of formula (5)
R1-NH—NH 2 (5)
wherein
R 1 is optionally halogenated C 1 -C 4 -alkyl or optionally halogenated cyclopropyl.
2. A process for preparation of a compound of formula (IV)
wherein
R 1 is hydrogen, optionally halogenated C 1 -C 4 -alkyl or optionally halogenated cyclopropyl;
A 1 is C—R 2 ;
R 2 is hydrogen, fluorine, chlorine, bromine, CN, NO 2 , optionally halogenated C 1 -C 6 -alkyl, optionally halogenated C 1 -C 4 -alkoxy, optionally halogenated C 1 -C 4 -alkylsulphonyl, optionally halogenated C 1 -C 4 -alkylsulphinyl or N-cyclopropylaminocarbonyl (—C(═O)—NH—cyclopropyl); methyl, ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, methoxy, ethoxy, n-propoxy, 1-methylethoxy, fluoromethoxy, difluoromethoxy, chlorodifluoromethoxy, dichlorofluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, 2-chloro-2,2-difluoroethoxy, pentafluoroethoxy, methylsulphonyl, methylsulphinyl, trifluoromethylsulphonyl, trifluoromethylsulphinyl or N-cyclopropylaminocarbonyl;
A 2 is C—R 3 or nitrogen;
R 3 is hydrogen, methyl, fluorine or chlorine;
T represents one of T1-T9 listed below, where the bond to the pyrazole head group is marked with an asterisk *,
R 6 independently of one another represents halogen, cyano, nitro, amino or optionally substituted C 1 -C 6 -alkyl, C 1 -C 6 -alkyloxy, C 1 -C 6 -alkylcarbonyl, C 1 -C 6 -alkylsulphanyl, C 1 -C 6 -alkylsulphinyl, C 1 -C 6 -alkylsulphonyl;
n represents 0-2, provided that n is 0 or 1 in T5, T6 and T8 and provided n is 0 in T7;
Q is hydrogen, cyano, hydroxy, formyl, C 1 -C 6 -alkyl, C 3 -C 6 -alkenyl, C 3 -C 6 -alkynyl, C 3 -C 9 -cycloalkyl, C 3 -C 9 -heterocycloalkyl, C 1 -C 4 -alkoxy, C 4 -C 15 -alkylcycloalkyl, C 4 -C 15 -cycloalkylalkyl, C 1 -C 6 -hydroxyalkyl, C 6 -aryl-C 1 -C 3 -alkyl, C 5 -C 6 -heteroaryl-C 1 -C 3 -alkyl, C 1 -C 4 -aminoalkyl, aminocarbonyl-C 1 -C 4 -alkyl or C 1 -C 4 -alkyl-amino-C 1 -C 4 -alkyl which are optionally substituted with one, two, three, four or five, substituents independently selected from the group consisting of hydroxy, nitro, amino, halogen, C 1 -C 3 -alkoxy, cyano, hydroxycarbonyl, C 1 -C 4 -alkoxycarbonyl, C 1 -C 4 -alkylcarbamoyl, C 4 -C 6 -cycloalkylcarbamoyl and optionally independently with one, two or three substituents selected from the group consisting of halogen, cyano, nitro, hydroxycarbonyl, C 1 -C 2 -alkylcarbamoyl, C 1 -C 2 -alkyl, C 1 -C 2 -haloalkyl and C 1 -C 2 -alkoxy substituted phenyl;
comprising steps 1, 2, 3 and 4 of the process as described in claim 1 .
3. A process according to claim 2 , wherein a compound of formula (IV) is a compound of formula (II),
4. A process according to claim 2 , wherein a compound of formula (IV) is compound (IIa)
5. A process according to claim 2 , further comprising:
reacting in a Step 5 compound (I) with a cyano-donor to prepare intermediate of formula (6)
wherein
R 1 is optionally halogenated C 1 -C 4 -alkyl or optionally halogenated cyclopropyl; and
reacting in a Step 6 compound (6) with an inorganic strong base in a first hydrolysis step followed by adding an inorganic acid in a second hydrolysis step to prepare intermediate of formula (7)
wherein
R 1 is optionally halogenated C 1 -C 4 -alkyl or optionally halogenated cyclopropyl; and
reacting in a Step 8 a compound of formula (8) or its salt (8′) with an activated form (7′) of compound (7)
wherein LG is any leaving group,
to prepare a compound of formula (II).
6. A process according to claim 2 , wherein a compound of formula (IV) is a compound of formula (III)
wherein
R 1 is hydrogen, optionally halogenated C 1 -C 4 -alkyl or optionally halogenated cyclopropyl;
A 1 is C—R 2 ;
R 2 is hydrogen, fluorine, chlorine, bromine, CN, NO 2 , optionally halogenated C 1 -C 6 -alkyl, optionally halogenated C 1 -C 4 -alkoxy, optionally halogenated C 1 -C 4 -alkylsulphonyl, optionally halogenated C 1 -C 4 -alkylsulphinyl or N-cyclopropylaminocarbonyl (—C(═O)—NH—cyclopropyl); methyl, ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, methoxy, ethoxy, n-propoxy, 1-methylethoxy, fluoromethoxy, difluoromethoxy, chlorodifluoromethoxy, dichlorofluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, 2-chloro-2,2-difluoroethoxy, pentafluoroethoxy, methylsulphonyl, methylsulphinyl, trifluoromethylsulphonyl, trifluoromethylsulphinyl or N-cyclopropylaminocarbonyl;
A 2 is C—R 3 or nitrogen;
R 3 is hydrogen, methyl, fluorine or chlorine;
Q is hydrogen, cyano, hydroxy, formyl or one of the groupings C 1 -C 6 -alkyl, C 3 -C 6 -alkenyl, C 3 -C 6 -alkynyl, C 3 -C 9 -cycloalkyl, C 3 -C 9 -heterocycloalkyl, C 1 -C 4 -alkoxy, C 4 -C 15 -alkylcycloalkyl, C 4 -C 15 -cycloalkylalkyl, C 1 -C 6 -hydroxyalkyl, C 6 -aryl-C 1 -C 3 -alkyl, C 5 -C 6 -heteroaryl-C 1 -C 3 -alkyl, C 1 -C 4 -aminoalkyl, aminocarbonyl-C 1 -C 4 -alkyl or C 1 -C 4 -alkyl-amino-C 1 -C 4 -alkyl which are optionally substituted with one, two, three, four or five, substituents independently selected from the group consisting of hydroxy, nitro, amino, halogen, C 1 -C 3 -alkoxy, cyano, hydroxycarbonyl, C 1 -C 4 -alkoxycarbonyl, C 1 -C 4 -alkylcarbamoyl, C 4 -C 6 -cycloalkylcarbamoyl and optionally independently with one, two or three substituents selected from the group consisting of halogen, cyano, nitro, hydroxycarbonyl, C 1 -C 2 -alkylcarbamoyl, C 1 -C 2 -alkyl, C 1 -C 2 -haloalkyl and C 1 -C 2 -alkoxy substituted phenyl;
T represents one of 5-membered heteroaromatics T1-T8 listed below, where the bond to the pyrazole head group is marked with an asterisk *,
wherein
R 6 independently of one another represents halogen, cyano, nitro, amino or optionally substituted C 1 -C 6 -alkyl, C 1 -C 6 -alkyloxy, C 1 -C 6 -alkylcarbonyl, C 1 -C 6 -alkylsulphanyl, C 1 -C 6 -alkylsulphinyl, C 1 -C 6 -alkylsulphonyl, and
n represents 0-2, provided that n is 0 or 1 in T5, T6 and T8 and provided n is 0 in T7.
7. A process according to claim 6 , wherein a compound of formula (III) is compound of formula (III′)
8. A process according to claim 6 , comprising said Steps 1 to 4 and further comprising
reacting a compound of formula (I) with an intermediate of formula (11) by nucleophilic substitution of the fluoride at the ring position of a compound of formula (I) (herein referred to as Step 9)
wherein
R 1 is optionally halogenated (C 1 -C 4 )alkyl or optionally halogenated cyclopropyl;
U represents bromine, iodine, triflate, boronic acid, boronic ester or trifluoroboronate;
five-membered cycles of E 1 -E 3 , carbon and nitrogen represent 5-membered heterocycles selected from the group consisting of
wherein
R 6 independently of one another represents halogen, cyano, nitro, amino or optionally substituted C 1 -C 6 -alkyl, C 1 -C 6 -alkyloxy, C 1 -C 6 -alkylcarbonyl, C 1 -C 6 -alkylsulphanyl, C 1 -C 6 -alkylsulphinyl, C 1 -C 6 -alkylsulphonyl, and
n represents 0-2, provided that n is 0 or 1 in T5, T6 and T8 and provided n is 0 in T7;
to prepare an intermediate of formula (12); and
reacting a compound of formula (12) and a compound of formula (13) (herein referred to as Step 10)
wherein R 1 , A 1 , A 2 , and Q are as defined for a compound of formula (III) and
U represents bromine, iodine, triflate, boronic acid, boronic ester or trifluoroboronate; and
five-membered cycles of E 1 -E 3 , carbon and nitrogen represent 5-membered heterocycles selected from the group consisting of
wherein
R 6 independently of one another represents halogen, cyano, nitro, amino or optionally substituted C 1 -C 6 -alkyl, C 1 -C 6 -alkyloxy, C 1 -C 6 -alkylcarbonyl, C 1 -C 6 -alkylsulphanyl, C 1 -C 6 -alkylsulphinyl, C 1 -C 6 -alkylsulphonyl,
n represents 0-2, provided that n is 0 or 1 in T5, T6 and T8 and provided n is 0 in T7; and
M represents bromine, iodine or triflate when U represents a boronic acid, boronic ester or trifluoroboronate; or
M represents a boronic acid, boronic ester or trifluoroboronate when U represents bromine, iodine or triflate
to prepare a compound of formula (III).
9. A process according to claim 2 , wherein a compound of formula (IV) is a compound of formula (III″)
10. A process according to claim 9 , comprising said steps 1 to 4, either optionally further comprising steps 9 and 10; or optionally further comprising
reacting a compound of formula (I) and an azide-donor to prepare intermediate (14) (herein referred to as Step 11)
wherein R 1 is as defined for a compound of formula (III); and
reacting intermediate (14) with an intermediate of formula (15) to give an intermediate (III″*) (herein referred to as Step 12)
wherein R 1 , R 6 , A 1 , and A 2 are as defined for compound (III), n is 0 or 1 and PG is any protective group of the carboxylic group such as C 1 -C 6 -alkyl.
11. A process according to claim 1 , wherein R 1 is methyl.
12. A process according to claim 1 , wherein the catalyst in Step 1 and the fluoride donor in Step 2 are identical.
13. A process according to claim 1 , wherein a solvent in Step 3 and Step 4 is identical.
14. The process according to claim 3 , wherein the compound of formula (II) is a compound of formula (II′),
15. The process according to claim 7 , wherein the compound of formula (III′) is a compound of formula (IIIa),
or a compound of formula (IIIb),
16. The process according to claim 9 , wherein the compound of formula (III″) is a compound of formula (III′″),
17. The process according to claim 2 , wherein
R 2 is hydrogen, fluorine, chlorine, bromine, CN, NO 2 , methyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, methoxy, ethoxy, or pentafluoroethoxy;
Q is C 3 -C 6 -cycloalkyl, or C 3 -C 6 -cycloalkyl which is substituted with at least one substituent selected from the group consisting of chlorine, fluorine, bromine, iodine, cyano and hydroxy, or C 6 -aryl-C 1 -C 3 -alkyl.