RU2021106928A

RU2021106928A - METHOD FOR PRODUCING 2-[(3R)-3-METHYLMORPHOLIN-4-YL]-4-(1-METHYL-1H-PYRAZOL-5-YL)-8-(1H-PYRAZOL-5-YL)-1,7- NAFTHYRIDINE

Info

Publication number: RU2021106928A
Application number: RU2021106928A
Authority: RU
Inventors: Йоханнес Платцек; Филипп РУБЕНБАУЭР; ДЕР ХАС Хендрикус Николас Себастиан ВАН; Соня Элизабет ХОГЕВЕН; УРС Маттейс Корнелис Мария ВАН; Рейнерус Герардус ГИЛИНГ; Йерун Александер ДЕККЕР
Original assignee: Байер Акциенгезельшафт; Байер Фарма Акциенгезельшафт
Priority date: 2018-08-24
Filing date: 2019-08-22
Publication date: 2022-09-26

Claims

1. Process for the preparation of a compound of formula (I)

or its tautomer of formula (Ia)

or mixtures thereof

wherein said process comprises the following successive steps: (a) reacting an intermediate of formula (IXa)

where R ¹ represents a chlorine, bromine or iodine atom or represents 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)

or a mixture of them, where

R ² and R ³ are, independently of one another, a hydrogen atom or a C ₁ -C ₆ alkyl group; or

R ² and R ³ together represent a -CH ₂ -CH ₂ - group or -CH ₂ -CH ₂ -CH ₂ -group, where the indicated -CH ₂ -CH ₂ - group or -CH ₂ -CH ₂ -CH ₂ - the group is optionally substituted one, two, three or four times with a group selected from methyl and ethyl;

or R ² and R ³ together represent a group

where * is the point of attachment to the rest of the molecule; and

R ⁴ is a group selected from tetrahydro-2H-pyran-2-yl, 1-methyl-1-methoxyethyl, 1-methyl-1-phenoxyethyl, 1-methyl-1-benzyloxyethyl; to obtain an intermediate compound of formula (VIIa) or (VIIb)

or mixtures thereof, where

R ⁴ is a group selected from tetrahydro-2H-pyran-2-yl, 1-methyl-1-methoxyethyl, 1-methyl-1-phenoxyethyl, 1-methyl-1-benzyloxyethyl; and

(b) removing the R ⁴ group from the intermediate compound of formula (VIIa) or (VIIb), thus providing a compound of formula (I), or a tautomer of formula (Ia), or a mixture thereof.

2. The method according to claim 1,

where the compound of formula (IXa) is (R)-4-(8-chloro-4-(l-methyl-1H-pyrazol-5-yl)-1,7-naphthyridin-2-yl)-3-methylmorpholine; and/or

where the compound of formula (IIIa) is a complex pinacol ester of 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-boronic acid; and/or

where the compound of formula (VIIa) is (3R)-3-methyl-4-(4-(l-methyl-1H-pyrazol-5-yl)-8-(1-(tetrahydro-2H-pyran-2-yl )-1H-pyrazol-5-yl)-1,7-naphthyridin-2-yl)morpholine.

3. The method according to claim 1 or 2,

wherein the reaction of an intermediate of formula (IXa) with a compound of formula (IIIa) or formula (IIIb) is carried out in the presence of a palladium catalyst and/or a base.

4. The method according to any one of paragraphs. 1-3, where the reaction of an intermediate compound of formula (IXa) with a compound of formula (IIIa) or (IIIb) is carried out in an organic solvent, where the solvent includes isopropyl acetate, ethyl acetate, 1,2-dimethoxyethane, 1,4-dioxane, dimethylformamide, tetrahydrofuran, 2-methyltetrahydrofuran, methanol, ethanol, 1-propanol, isopropanol, 1-butanol or 2-butanol; or wherein said reaction is carried out in a solvent mixture comprising one or more of said solvents and water.

5. The method according to any one of paragraphs. 1-4, wherein the R ⁴ group is removed from an intermediate of formula (VIIa) or (VIIb) by reacting an intermediate of formula (VIIa) or (VIIb) with an acid in a solvent or mixture of solvents.

6. The method according to any one of paragraphs. 1-5, where the intermediate compound of formula (VIIa) or (VIIb) is a compound of formula (VIIc), (VIId) or (VIIc/VIId).

7. The method according to any one of paragraphs. 1-6, wherein the intermediate of formula (VIIa), (VIIb), (VIIc), (VIId) or (VIIc/VIId) is not isolated and/or purified prior to the step of removing the R ⁴ group from the intermediate of formula (VIIa), VII(b), (VIIc), (VIId) or (VIIc/VIId).

8. The method according to any one of paragraphs. 1-7, wherein the R ⁴ group is removed from an intermediate of formula (VIIa) or (VIIb) by reacting an intermediate of formula (VIIa) or (VIIb) with aqueous hydrochloric acid in a solvent mixture of dichloromethane, methanol and water, with obtaining a crude compound of formula (I), dissolved in an acidified aqueous phase, where the pH of the resulting acidified aqueous solution is less than 3 (pH<3).

9. The method according to claim 8, where

(a) an acidified aqueous solution of the crude compound of formula (I) is extracted one or more times with solvent A, where solvent A includes dichloromethane, ethyl acetate, isopropyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, toluene or chloroform;

and/or an acidified aqueous solution of the crude compound of formula (I) is treated one or more times with a Pd scavenger;

(b) the acidified aqueous solution of the crude compound of formula (I) obtained in the previous step (a) is treated with solvent A and an aqueous base solution to obtain a biphasic system, wherein the aqueous phase of said biphasic system has a pH>12;

(c) the aqueous phase with pH>12, obtained in stage (b), is separated from the two-phase system to obtain a solution of the crude compound of formula (I) in solvent A; and optionally

(d) replacing solvent A of a solution of the crude compound of formula (I) in solvent A with solvent B, where solvent B comprises ethanol, n-propanol, n-butanol, 2-butanol or isopropanol; to obtain a solution of the crude compound of formula (I) in solvent B.

10. The method of claim 9 wherein solvent A comprises dichloromethane and wherein the aqueous base comprises aqueous potassium hydroxide and wherein solvent B comprises n-butanol.

11. The method according to any one of paragraphs. 8-10 wherein the crude compound of formula (I) is crystallized in a solvent B, preferably n-butanol, to give the polymorph B of the compound of formula (I).

12. The method according to any one of paragraphs. 1-11, which before step (a) in accordance with paragraph 1 further includes the following step:

(a) carrying out the reaction of an intermediate compound of formula (VIIIa)

where R ¹ represents a chlorine, bromine or iodine atom or represents 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; and

R ⁵ represents a chlorine, bromine or iodine atom or represents 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 (VIa)

where

or

R ² and R ³ together represent a group

where "*" represents the place of attachment to the rest of the molecule;

to obtain an intermediate compound of formula (IXa)

where

R ¹ represents a chlorine, bromine or iodine atom or represents 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.

13. The method according to p. 12, where the compound of formula (VIIIa) is (R)-8-chloro-2-(3-methylmorpholino)-1,7-naphthyridin-4-yl trifluoromethanesulfonate; and/or wherein the compound of formula (VIa) is 1-methyl-1H-pyrazole-5-boronic acid pinacol ester.

14. The method according to any one of paragraphs. 1-13, wherein the reaction of an intermediate compound of formula (VIIIa) with a compound of formula (VIa) is carried out in the presence of a palladium catalyst and/or a base.

15. Intermediate compound of formula (IXa)

where

16. Intermediate according to claim 15, which is a compound of formula (IXb)

17. Intermediate compound of formula (VIIIa)

where

R ¹ represents a chlorine, bromine or iodine atom or represents 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; and

R ⁵ represents a chlorine, bromine or iodine atom or represents 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.

18. Intermediate according to claim 17, which is a compound of formula (VIIIb)

19. The method according to any one of paragraphs. 1-14, which, before step (a) according to claim 12, further comprises the step of reacting an intermediate of formula (II)

with a compound selected from N-phenyl-bis(trifluoromethanesulfonimide), trifluoromethanesulfonic anhydride, methanesulfonic acid chloride, p-toluenesulfonyl chloride, nonafluorobutanesulfonyl chloride, nonafluorobutanesulfonyl fluoride, benzenesulfonyl chloride, 4-bromobenzenesulfonyl chloride, 4-nitrobenzenesulfonyl chloride, 2-nitrobenzenesulfonyl chloride, 4-nitrobenzenesulfonyl chloride, 2-propylbenzenesulfonyl chloride, ,6-triisopropylbenzenesulfonyl chloride, 2-mesitylenesulfonyl chloride (=2,4,6-trimethylbenzenesulfonyl chloride), 4-tert-butylbenzenesulfonyl chloride and 4-methoxybenzenesulfonyl chloride;

to obtain an intermediate compound of formula (VIIIa)

20. The method of claim 19 wherein the compound of formula (II) is (R)-8-chloro-2-(3-methylmorpholino)-1,7-naphthyridin-4-ol which is reacted with trifluoromethanesulfonic anhydride to give intermediate compound of formula (VIIIb)