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The preparation method of pim447 key intermediate

A technology for isomers and enantiomers, applied in the field of organic compound synthesis, can solve the problems of complex preparation methods and low intermediate yields, and achieve the effects of simple operation, high selectivity and few side reactions

Active Publication Date: 2022-07-22
SHANGHAI HAOHONG SCI CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] The object of the present invention is to provide the preparation of intermediate tert-butyl ((1S, 3R, 5S)-3-(3-aminopyridin-4-yl)-5-methylcyclohexyl) carbamate of PIM447 inhibitor method to solve the technical problems of low intermediate yield and complex preparation method in the prior art

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  • The preparation method of pim447 key intermediate
  • The preparation method of pim447 key intermediate
  • The preparation method of pim447 key intermediate

Examples

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Embodiment 1

[0092] Preparation of tert-butyl ((1S,3R,5S)-3-(3-aminopyridin-4-yl)-5-methylcyclohexyl)carbamate.

[0093] The preparation route of the compound of this embodiment is shown above, and the preparation method includes the following steps:

[0094] a. 140g of 5-methyl-3-(3-nitropyridin-4-yl)cyclohex-2-enone (Compound I) and 125.1g of p-methoxybenzylamine were added to 1.7L of methanol, N 2 Stir at 25 °C under protection, react for 16 h, cool down to -78 °C, add 332 mL of lithium borohydride (2N in THF) dropwise, heat up to 25 °C after the dropwise addition, and react for 1 h. Add water, stir until no bubbles are released, concentrate under reduced pressure to half of the original volume, add ethyl acetate, saturated sodium bicarbonate, and stir to separate the organic liquid. The organic liquid was washed with saturated sodium chloride, dried over sodium sulfate, and concentrated under reduced pressure to obtain compound II (isomer mixture, crude product, 176.8 g, yield 83%), w...

Embodiment 2

[0110] Preparation of PIM447

[0111]

[0112] The preparation route of the PIM447 of this embodiment is shown above, and the preparation method includes the following steps:

[0113] g. 20g tert-butyl ((1S,3R,5S)-3-(3-aminopyridin-4-yl)-5-methylcyclohexyl)carbamate (compound VIIa), 21.5g compound IX, 11.6g tert-butyl((1S,3R,5S)-3-(3-aminopyridin-4-yl)-5-methylcyclohexyl)carbamate was dissolved in 320mL N,N-dimethylformamide, N 2 16.4g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride was added at the bottom, and the reaction was carried out at 25°C for 16h. Water and ethyl acetate were added, the layers were separated, and the organic phases were combined, washed with 0.5N sodium hydroxide, water, and saturated sodium chloride, respectively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was dissolved in 152 mL of tetrahydrofuran, 608 mL of petroleum ether was added dropwise, stirred at room temperature for 1 h...

Embodiment 3

[0119] Preparation of PIM447 Isomers

[0120]

[0121] i. 5g tert-butyl((1R,3S,5R)-3-(3-aminopyridin-4-yl)-5-methylcyclohexyl)carbamate (Compound VIIb), 5.8g Compound IX, 3.13g tert-butyl((1S,3R,5S)-3-(3-aminopyridin-4-yl)-5-methylcyclohexyl)carbamate dissolved in 90mL N,N-dimethylformamide ,N 2 4.4g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride was added at the bottom, and the reaction was carried out at 25°C for 16h. Water and ethyl acetate were added, the layers were separated, and the organic phases were combined, washed with 0.5N sodium hydroxide, water, saturated sodium chloride, dried over sodium sulfate, and concentrated under reduced pressure to obtain compound XI (7.96 g, yield 89.9%).

[0122] h. Dissolve 7.96 g of compound XI in 38 mL of a dioxane solution of hydrochloric acid (4.6 N), and react at 25° C. for 1 h. It was concentrated under reduced pressure, dissolved in 13 mL of methanol, added dropwise with 270 mL of methyl tert-butyl ether,...

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Abstract

The present invention relates to the key intermediate of PIM447, namely the preparation method of compound tert-butyl ((1S, 3R, 5S)-3-(3-aminopyridine-4-yl)-5-methylcyclohexyl) carbamate, The method comprises the following steps: a. compound I is subjected to reductive amination reaction with p-methoxybenzylamine to obtain compound II; b. the mixture of compound II is subjected to acylation reaction with di-tert-butyl dicarbonate, and purified to obtain compound III; c. compound The mixture of III is subjected to a reduction reaction under the action of a reducing agent, and the mixture of compounds IVa and IVb is obtained after purification; d. The mixture of compounds IVa and IVb is de-Boc removed under acidic conditions to obtain compound V; e. The mixture of compound V is catalyzed under the action of a catalyst Compound VI is obtained by hydrogenolysis reaction; f, the mixture of compound VI is acylated with di-tert-butyl dicarbonate to obtain compound VII; g, the mixture of compound VII is separated by chiral preparative chromatography column to obtain compound VIIa. The synthetic route is as follows:

Description

technical field [0001] The invention relates to the technical field of organic compound synthesis, in particular to a preparation method of a PIM447 intermediate. Background technique [0002] PIM447 is Moloney murine leukemia (PIM) 1, 2, 3 kinase inhibitor, also known as LGH447, chemical name: N-[4-[(1R,3S,5S)-3-amino-5-methyl Cyclohexyl]-3-pyridyl]-6-(2,6-difluorophenyl)-5-fluoro-pyridine hydrochloride. PIM kinase is an important therapeutic target in tumors and autoimmune diseases. As a PIM kinase inhibitor, PIM447 has high selectivity, high metabolic stability, strong in vitro activity and in vivo activity. The literature discloses that PIM447 has good activity against acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), diffuse large B-cell lymphoma, multiple myeloma, and autoimmune diseases. [0003] The structure of the PIM447 is as follows: [0004] [0005] The PIM447 compound and its preparation method are published in J.Med.Chem.2015, 58, 8373-8...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D213/73C07D213/81
CPCC07D213/73C07D213/81C07B2200/07
Inventor 郑保富高强岳庆磊周治国梅魁袁海玲
Owner SHANGHAI HAOHONG SCI CO LTD
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