US 12,258,343 B2
Method for preparing 2-[(3R)-3-methylmorpholin-4-yl]-4-[1-methyl-1H-pyrazol-5-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridine
Johannes Platzek, Berlin (DE); Philipp Rubenbauer, Bensheim (DE); Hendricus Nicolaas Sebastiaan Van Der Haas, Nijmegen (NL); Sonja Elisabeth Hoogeveen, Oss (NL); Matthijs Cornelis Maria Van Oers, Nijmegen (NL); Reinerus Gerardus Gieling, Beuningen (NL); and Jeroen Alexander Dekker, Ede (NL)
Assigned to BAYER AKTIENGESELLSCHAFT, Leverkusen (DE); and BAYER PHARMA AKTIENGESELLSCHAFT, Berlin (DE)
Appl. No. 17/271,141
Filed by Bayer Aktiengesellschaft, Leverkusen (DE); and Bayer Pharma Aktiengesellschaft, Berlin (DE)
PCT Filed Aug. 22, 2019, PCT No. PCT/EP2019/072467
§ 371(c)(1), (2) Date Feb. 24, 2021,
PCT Pub. No. WO2020/039025, PCT Pub. Date Feb. 27, 2020.
Claims priority of application No. 18190731 (EP), filed on Aug. 24, 2018.
Prior Publication US 2021/0253573 A1, Aug. 19, 2021
Int. Cl. C07D 471/04 (2006.01)
CPC C07D 471/04 (2013.01) [C07B 2200/13 (2013.01)] 16 Claims
OG exemplary drawing
 
1. A method for preparing a compound of formula (I)

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or its tautomer of formula (Ia)

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or a mixture thereof,
said method comprising the successive steps of:
(a) reacting an intermediate compound of formula (IXa)

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wherein
R1 is a chlorine, bromine or iodine atom or is a group selected from [(trifluoromethyl)sulfonyl]oxy, [(nonafluorobutyl)sulfonyl]oxy, (methylsulfonyl)oxy, (p-toluenesulfonyl)oxy, (phenylsulfonyl)oxy, [(4-bromophenyl)sulfonyl]oxy, [(4-nitrophenyl)sulfonyl]oxy, [(2-nitrophenyl)sulfonyl]oxy, [(4-isopropylphenyl)sulfonyl]oxy, [(2,4,6-triisopropylphenyl)sulfonyl]oxy, [(2,4,6-trimethylphenyl)sulfonyl]oxy, [(4-tert-butylphenyl)sulfonyl]oxy and [(4-methoxyphenyl)sulfonyl]oxy;
with a compound of formula (IIIa) or (IIIb)

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 or

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or a mixture thereof,
wherein
R2 and R3 are independently a hydrogen atom or a C1-C6-alkyl group;
or
R2 and R3 together represent a —CH2—CH2— group or a —CH2—CH2—CH2— group, wherein said —CH2—CH2— group or —CH2—CH2—CH2— group is optionally substituted one, two, three or four times with a group selected from methyl or ethyl;
or
R2 and R3 together represent a group

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wherein “*” represents the point of attachment to the rest of the molecule;
and
R4 is a group selected from the group consisting of tetrahydro-2H-pyran-2-yl, 1-methyl-1-methoxyethyl, 1-methyl-1-phenoxyethyl, and 1-methyl-1-benzyloxyethyl;
to give an intermediate compound of formula (VIIa) or (VIIb)

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 or

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or a mixture thereof; and
(b) removing the group R4 from the intermediate compound of formula (VIIa) or (VIIb), thus providing a compound of formula (I), or its tautomer of formula (Ia), or a mixture thereof.