Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/04—Ortho-condensed systems

Definitions

• the present invention relates to a novel intermediate in the production of an oxoisoquinoline derivative having BTK inhibitory activity and a method for producing the intermediate.
• BTK Bruton's tyrosine kinase
• Patent Document 1 discloses 2-(3- ⁇ 2-amino-6-[1-(oxetan-3-yl)-1,2,3,6-tetrahydropyridin-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl ⁇ -2-(hydroxymethyl)phenyl)-6-cyclopropyl-8-fluoroisoquinolin-1(2H)-one (hereinafter, compound (A)): is exemplified.
• compound (A)) is extremely difficult to carry out on a semi-industrial or industrial scale. It was necessary to find a production method suitable for practical production by further improving the operability, purification efficiency, yield, etc. of the production.
• the present invention provides a novel intermediate and a process for producing oxoisoquinoline derivatives more economically and in higher yields using the intermediate. Furthermore, the process described herein allows for economical cost reduction of intermediates and results in higher yields overall, compared to currently known processes (such as those described in Patent Document 1).
• the method for producing the compound (A) provided by the present invention is as follows. (1) A production method in which compound (Ia) is oxetanylated to produce compound (Ib), which is then reacted with known compound (B) to obtain the target compound (A).
• a method for producing compound (A) in the above-mentioned production method (1) which comprises using compound (Ia) obtained by chlorinating compound (III) and then deprotecting the trifluoroacetyl group.
• a method for producing compound (A), comprising reacting compound (VII) with a brominating agent, and then reacting the resulting compound with compound (VI) in the above-mentioned production method (4), to produce compound (V).
• the present invention also provides compound (Ia), which is an intermediate for producing compound (A), and a method for producing the same, as described below.
• a method for producing compound (Ia) comprising reacting compound (VII) with a brominating agent, and then reacting the resulting compound with compound (VI) in the above-mentioned production method (9), to produce compound (V).
• the manufacturing method of the present invention using the novel manufacturing intermediates allows the target compound (A) to be manufactured more economically and in higher yields. Furthermore, the method described in this specification allows for a process that can reduce the cost of manufacturing intermediates economically compared to currently known manufacturing methods (such as those described in Patent Document 1), resulting in a higher overall yield.
• Compound (II) can also be concentrated without isolating it, and treated with aqueous ammonia to prepare compound (Ia).
• (2-2) Production of Compound (A) The target compound (A) is produced from the compound (Ia) obtained above through the aforementioned step (1).
• step (3) treating compound (IV) with trifluoroacetic anhydride to produce compound (III);
• the target compound (A) is produced through the above-mentioned step (2).
• (3-1) Preparation of Compound (III) In acetonitrile or 1,2-dichloroethane, preferably acetonitrile, compound (IV) is reacted with trifluoroacetic anhydride in the presence of an amine compound.
• the amine compound is selected from triethylamine, pyridine, and 2,6-lutidine, with 2,6-lutidine being preferred.
• the product, compound (IV) can be isolated as either the free base or the hydrochloride salt, preferably as the hydrochloride salt.
• (4-2) Production of Compound (A) The target compound (A) is produced from the compound (IV) obtained above through the aforementioned step (3).
• the reaction of the bromo compound (X) with the diaminopyrimidine (VI) is carried out in acetic acid or a mixture of acetic acid and water. When a mixture of acetic acid and water is used, the ratio of water is preferably 1% to 90%.
• the reaction temperature is 50°C to 90°C, preferably 70°C to 85°C.
• the compound (VII) used as the raw material for the above (5-1) can be produced from anise alcohol (IX), for example, as shown in the following scheme.
• anise alcohol (IX) is reacted with hydrogen bromide to form 4-methoxybenzyl bromide, which is then reacted with compound (VIII).
• the reaction of anisalcohol (IX) with hydrogen bromide is carried out in a solvent selected from toluene, dichloromethane and chloroform, with hydrogen bromide being added as an aqueous solution.
• the reaction temperature is 0°C to 50°C, more preferably 15°C to 30°C.
• the product 4-methoxybenzyl bromide may be isolated once and then used in the next reaction, or may be used in the form of a solution dissolved in a reaction solvent.
• the subsequent reaction with compound (VIII) is carried out in a solvent selected from toluene, dichloromethane and chloroform, at a reaction temperature of 0°C to 50°C, preferably 15°C to 30°C.
• the product compound (VII) can be easily isolated as a solid, and is preferably used in the next step after isolation.
• the following formula (Ia): or a salt thereof is a production intermediate for producing compound (A) and is included in the present invention.
• the following is an embodiment of the invention for producing this production intermediate.
• step (6) preparing compound (III) by treating compound (IV) with trifluoroacetic anhydride;
• step (6) is carried out to produce the production intermediate (Ia).
• the production of compound (III) is as described in the above step (3-1).
• step (7) preparing compound (IV) by treating compound (V) with sodium borohydride;
• step (7) is carried out to produce the production intermediate (Ia).
• the production of compound (IV) is as described in the above step (4-1).
• step (9) reacting compound (VII) with a brominating agent, and then reacting it with diaminopyrimidine (VI) to produce compound (V);
• step (8) is carried out to produce the production intermediate (Ia).
• the compound (V) can be produced as described in the above step (5-1).
• Step 2 4-(2-amino-4-hydroxy-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-1-(4-methoxybenzyl)pyridin-1-ium bromide (V)
• 4-acetyl-1-(4-methoxybenzyl)pyridin-1-ium bromide (VII) (617 g, 1.0 Eq, 1.91 mol) was dissolved in acetic acid (1.25 L) and a solution of bromine (306 g, 98.7 mL, 1.0 Eq, 1.91 mol) in acetic acid (625 mL) was added dropwise using a dropping funnel over 10 minutes.
• Step 3 2-amino-6-(1-(4-methoxybenzyl)-1,2,3,6-tetrahydropyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-ol
• IV 4-(2-amino-4-hydroxy-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-1-(4-methoxybenzyl)pyridin-1-ium bromide (V) (843.46 g, 1.0 Eq, 1.96 mol) was suspended in a mixed solvent of methanol (1.675 L) and pyridine (5.025 L), and sodium borohydride (223.5 g, 3.0 Eq, 5.9081 mol) was added little by little while stirring at room temperature.
• Step 5 N-(4-chloro-6-(1-(2,2,2-trifluoroacetyl)-1,2,3,6-tetrahydropyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-2,2,2-trifluoroacetamide
• II 2,2,2-Trifluoro-N- ⁇ 4-hydroxy-6-[1-(2,2,2-trifluoroacetyl)-1,2,3,6-tetrahydropyridin-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-2-yl ⁇ acetamide
• III (163.3 g, 1 Eq, 385.8 mmol), acetonitrile (500 mL), and phosphorus oxychloride (354.9 g, 215.7 mL, 6 Eq, 2.315 mol) were added to a three-necked round-bottom flask equipped with a mechanical stirrer and reflux condenser, and the
• Step 6 4-chloro-6-(1,2,3,6-tetrahydropyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine
• aqueous ammonia 154 g, 196 mL, 25.0% Wt, 20 Eq, 2.26 mol
• aqueous ammonia 154 g, 196 mL, 25.0% Wt, 20 Eq, 2.26 mol
• the white solid was isolated by suction filtration through a P3 filter, washed with acetonitrile, then diethyl ether, and transferred to a 250 mL round-bottom flask with acetonitrile. The mixture was concentrated under reduced pressure at 40-50° C. Yield: 26.89 g (95% yield).
• the mixture was stirred at 90°C for at least 1 hour, and then stirred at 20°C (internal temperature) for more than 2 hours.
• the product was collected by filtration, washed with DMSO-water (1.5:3), and washed with water. The product was dried under reduced pressure at 60°C to obtain the target product.
• the compound of the present invention is useful as a production intermediate of compound (A) having a BTK inhibitory activity. By using this intermediate, it becomes possible to produce compound (A) more economically and in higher yield.

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• Nitrogen Condensed Heterocyclic Rings (AREA)

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• 2022
  • 2022-12-23 JP JP2024565529A patent/JPWO2024134859A1/ja active Pending
  • 2022-12-23 EP EP22969243.9A patent/EP4640685A1/en active Pending
  • 2022-12-23 CN CN202280102676.4A patent/CN120390749A/zh active Pending
  • 2022-12-23 WO PCT/JP2022/047526 patent/WO2024134859A1/ja not_active Ceased

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