Process for the preparation of 5-fluoro-1H-pyrazoles starting from hexafluoropropene

1. Process for the synthesis of 5-fluoro-1H-pyrazole of formula (I)

wherein R 1 represents (C 1 -C 4 )-alkyl;

comprising

reacting intermediate (3) with (C 1 -C 4 )-alkyl-CONHNH 2 to prepare 3-perfluoroethyl-4-perfluoromethyl-5-fluoro-pyrazol (intermediate (4))

 and

reacting intermediate (4) with an (C 1 -C 4 )-alkylation agent, optionally a methylation agent to prepare a compound of formula (I) (step 4).

2. Process for the synthesis of 5-fluoro-1H-pyrazole of formula (I) according to claim 1 comprising

Reacting hexafluoropropene (intermediate (1))

in the presence of a catalyst to form its dimer perfluoro-4-methyl-2-pentene (intermediate (2))

 and

isomerizing perfluoro-4-methyl-2-pentene into perfluoro-2-methyl-2-pentene (intermediate (3))

 and

reacting a compound (3) with (C 1 -C 4 )-alkyl-CONHNH 2 to prepare 3-perfluoroethyl-4-perfluoromethyl-5-fluoro-pyrazol (intermediate (4))

 and

reacting intermediate (4) with an (C 1 -C 4 )-alkylation agent, optionally a methylation agent, to prepare a compound of formula (I).

3. Process for the preparation of a compound of formula (IV)

in which

R 1 is C 1 -C 4 -alkyl; and

A 1 is C—R 2 ; and

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); preferably hydrogen, fluorine, chlorine, bromine, CN, NO 2 , 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, more preferably hydrogen, fluorine, chlorine, bromine, CN, NO 2 , methyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, methoxy, ethoxy, or pentafluoroethoxy, optionally hydrogen, fluorine, chlorine, bromine, most preferably chlorine; and

A 2 is C—R 3 or nitrogen; and

R 3 is hydrogen, methyl, fluorine or chlorine, optionally hydrogen; and

T represents one of the groups T1-T9 listed below, where the bond to the pyrazole head group is marked with an asterisk *,

 and

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 the values 0-2, optionally 0, provided that n is 0 or 1 in T5, T6 and T8 and provided n is 0 in T7; and

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, optionally with one or two, optionally with one, 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, halogenated C 1 -C 2 -alkyl and C 1 -C 2 -alkoxy substituted phenyl; preferably 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; more preferably cyclopropyl, 1-cyano-cyclopropyl or benzyl (—CH 2 —C 6 H 5 );

Comprising the process according to claim 1 .

4. Process according to claim 3 , wherein a compound of formula (IV) is a compound of formula (II)

optionally of formula (II′)

5. Process according to claim 3 , wherein a compound of formula (IV) is compound (IIa)

6. Process according to claim 3 , further comprising:

reacting compound (I) with a cyano-donor to prepare intermediate of formula (6)

wherein R 1 is (C 1 -C 4 )-alkyl; and

reacting 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 (C 1 -C 4 )-alkyl; and

reacting a compound of formula (8) or its salt (8′) with an activated form (7′) of compound (7)

wherein R 1 , A 1 , A 2 , and Q are as defined in claim 3 and LG is any leaving group, to prepare a compound of formula (II).

7. Process according to claim 3 , wherein a compound of formula (IV) is a compound of formula (III)

in which

R 1 is (C 1 -C 4 )-alkyl; and

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); optionally hydrogen, fluorine, chlorine, bromine, CN, NO 2 , 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, optionally hydrogen, fluorine, chlorine, bromine, CN, NO 2 , methyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, methoxy, ethoxy, or pentafluoroethoxy, preferably hydrogen, fluorine, chlorine, bromine, most optionally chlorine; and

A 2 is C—R 3 or nitrogen;

R 3 is hydrogen, methyl, fluorine or chlorine, optionally hydrogen; and

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, optionally with one or two, optionally with one, 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, halogenated C 1 -C 2 -alkyl and C 1 -C 2 -alkoxy substituted phenyl; optionally 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; more preferably cyclopropyl, 1-cyano-cyclopropyl or benzyl (—CH 2 —C 6 H 5 );

T represents one of the 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 the values 0-2, preferably 0, provided that n is 0 or 1 in T5, T6 and T8 and provided n is 0 in T7.

8. Process according to claim 7 , wherein a compound of formula (III) is compound of formula (III′),

optionallycompound (IIIa)

or compound (IIIb)

9. Process according to claim 7 , comprising

reacting intermediate (3) with (C 1 -C 4 )-alkyl-CONHNH 2 to prepare 3-perfluoroethyl-4-perfluoromethyl-5-fluoro-pyrazol (intermediate (4))

 and

reacting intermediate (4) with an (C 1 -C 4 )-alkylation agent, optionally a methylation agent to prepare a compound of formula (I) (Step 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; and

U represents bromine, iodine, triflate, boronic acid, boronic ester or trifluoroboronate; and

the five-membered cycles of E 1 -E 3 , carbon and nitrogen represent the 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 the values 0-2, preferably 0, 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

the five-membered cycles of E 1 -E 3 , carbon and nitrogen represent the 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 the values 0-2, preferably 0, 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).

10. Process according to claim 3 , wherein a compound of formula (IV) is a compound of formula (III″)

optionally of formula (III′″)

11. Process according to claim 10 , comprising the process according to claim 1 , either optionally 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; and

U represents bromine, iodine, triflate, boronic acid, boronic ester or trifluoroboronate; and

the five-membered cycles of E 1 -E 3 , carbon and nitrogen represent the 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 the values 0-2, preferably 0, 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

the five-membered cycles of E 1 -E 3 , carbon and nitrogen represent the 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 the values 0-2, preferably 0, 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); or optionally further comprising

reacting a compound of formula (I) and an azide-donoer to prepare intermediate (14)

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″*) (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 (optionally, methyl).

12. Process according to claim 2 , wherein R 1 is methyl.

13. Process according to claim 2 , wherein step 3 and 4 are carried out in the same solvent, optionally acetonitrile or methylene chloride, optionally methylene chloride.

14. Process according to claim 2 , wherein step 3 and 4 are carried out in the same solvent selected from the group consisting of acetonitrile or methylene chloride.