Novel process for the preparation of pyrazoles

A process for the production of pyrazole compounds of formula (IIA),

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• wherein
• RP is H or R1, where R1 is (C1-C4)alkyl optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, (C1-C6)alkyl, C(O)NR4R5, C(O)R6, C(O)OR7, OR8, NR9aR9b and SO2NR10aR10b;
• R2 is (C1-C4)alkyl;
• R3 is (C1-C3)alkoxy,
• wherein said process comprises the steps of
• (i) reacting a compound of formula (III),
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• where R11a and R11b are each independently (C1-C4)alkyl and R2 is (C1-C4)alkyl, with an acylating agent of the formula (IV),
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• where X is Cl or F, and Y is Cl, F or C(O)CX3, in the presence of a base and an optional activating agent;
• and
• (ii) adding in situ a hydrazine compound of formula (V)
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• where RP is H or R1, where R1 is as defined hereinbefore, and Rx=EWG,
• Ry and Rz=H;
• or Rx and Ry=H and Rz=EDG;
• or
• Rx=Ry=Rz=H when R1=EWG;
• or Rx=EWG, Ry=H and Rz=EDG,
• wherein EWG is a tri(C1-C2)alkylsilyl group and EDG is tert-butyloxycarbonyl or trifluoroacetamide.

A process for the production of pyrazole compounds of formula (IIB),

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• wherein
• RP is H or R1, where R1 is (C1-C4)alkyl or (C1-C4)alkyl((C1-C2) alkoxy);
• R2 is (C1-C4)alkyl;
• and
• R3 is (C1-C3)alkoxy,
• wherein said process comprises the steps of
• (i) reacting a compound of formula (III)
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• with an acylating agent of formula (IV) in the presence of pyridine and an optional activating agent
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• where X and Y are each independently Cl or F;
• and
• (ii) adding after about 8 hours to about 24 hours a hydrazine compound of formula (V)
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• where RP is H when
• Rx=EWG, Ry and Rz=H;
• or
• Rx and Ry=H and Rz=EDG;
• or
• Rx=Ry=Rz=H when R1=EWG;
• or
• Rx=EWG, Ry=H and Rz=EDG, where EDG is a tri(C1-C2)alkylsilyl group and EWG is tert-butyloxycarbonyl or trifluoroacetamide;
• and RP is R1, where R1 is as defined hereinbefore, when
• Rx=H, Ry=H and Rz=EWG;
• or
• Rx=EDG, Ry=H and Rz=H;
• or
• Rx=Ry=Rz=H when R1=EDG;
• or
• Rx=EDG, Ry=H and Rz=EWG, where EDG is a tri(C1-C2)alkylsilyl group and EWG is tert-butyloxycarbonyl or trifluoroacetamide.

A process for the production of compounds of formula (I)

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• or a pharmaceutically or veterinarily acceptable salt thereof, or a pharmaceutically or veterinarily acceptable solvate of either entity,
• wherein
• A is CH or N;
• R1 is H, (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl, (C1-C6)alkyl((C1-C6)alkoxy), Het, (C1-C6)alkylHet, aryl, or (C1-C6)alkylaryl, where the latter eight groups are all optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, (C1-C6)alkyl, C(O)NR4R5, C(O)R6, C(O)OR7, OR8, NR9aR9b and SO2NR10aR10b;
• R2 is (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl, (C1-C6)alkyl((C1-C6)alkoxy), Het, (C1-C6)alkylHet, aryl, or (C1-C6)alkylaryl, where the latter eight groups are all optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, (C1-C6)alkyl, C(O)NR4R5, C(O)R6, C(O)OR7, OR8, NR9aR9b and SO2NR10a R10b;
• Rt is NRpRq;
• Rp, Rq, R6, R7, R8, R10a and R10b bare each independently H or (C1-C6)alkyl;
• R9a and R9b are each independently H, (C1-C6)alkyl, or taken together with the nitrogen atom to which they are attached form an azetidinyl, pyrollidinyl or piperidinyl group;
• R4 is CO2R7, or (C1-C4)alkyl optionally substituted with OH, NR5R6, CN, CONR5R6 or CO2R7;
• or
• R4 is a pyrrolidinylsulphonyl, piperidinosulphonyl, morpholinosulphonyl, or piperazin-1-ylsulphonyl group having a substituent R10 at the 4-position of the piperazinyl group where said piperazinyl group is optionally substituted with one or two (C1-C4)alkyl, (C1-C3)alkoxy, NR7R8, or CON R7R8 groups and is optionally in the form of its 4-N-oxide;
• R10 is H or (C1-C6)alkyl;
• wherein said compounds are prepared from compounds of formula (VIII)
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• wherein R1, R2, R4 and R13 are as defined hereinbefore and said compound of formula (VIII) is prepared from the reaction of a compound of formula (VII)
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• wherein R4 and R13 are as defined hereinbefore via coupling with a compound of formula (VI)
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• wherein R1 and R2 are as defined hereinbefore and Rt is NRpRq, where Rp and Rq are each independently H or (C1-C6)alkyl and said compound of formula (VI) is prepared by nitration and hydrogenation of a compound of formula (II)
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• wherein Rt and R2 are as defined hereinbefore and RP is R1 as defined hereinbefore, and said compound of formula (II) is prepared by
• (i) reacting a compound of formula (III),
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• where R11a and R11b are each independently (C1-C6)alkyl and R2 is as defined herein before, with an acylating agent of formula (IV) in the presence of a base and an optional activating agent,
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• where X is a halogen independently selected from Cl, F or Br, and Y is a halogen, or OR12, where R12 is (C1-C6)alkyl, C(O)CX3, Het;
• or (C1-C6)alkyl(Het), where Het is pyridine or imidazole;
• and (ii) adding in situ a hydrazine compound of formula (V),
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• where RP is H or R1, where R1 is as defined hereinbefore, and Rx, Ry and Rz are each independently selected from H, an electron donating group, or an electron withdrawing group, where said electron withdrawing group or said electron donating group is labile under the conditions of the reaction.