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Novel chemical method for preparing 6-chloro-4-(4-fluoro-2-methylphenyl) pyridine-3-amine as key intermediate of NT-814

A kind of technology of methyl phenyl, methyl phenyl boronic acid, be used in preparation compound A, preparation compound IX or compound A, the application field in preparation compound A, can solve high cost, material cannot be obtained commercially, yield is low And other issues

Pending Publication Date: 2022-07-08
康堤医疗有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, these methods usually suffer from low yield and high cost, or use materials that are not commercially available, thus affecting the overall cost of synthesizing Compound A

Method used

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  • Novel chemical method for preparing 6-chloro-4-(4-fluoro-2-methylphenyl) pyridine-3-amine as key intermediate of NT-814
  • Novel chemical method for preparing 6-chloro-4-(4-fluoro-2-methylphenyl) pyridine-3-amine as key intermediate of NT-814
  • Novel chemical method for preparing 6-chloro-4-(4-fluoro-2-methylphenyl) pyridine-3-amine as key intermediate of NT-814

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Experimental program
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Effect test

Embodiment approach

[0234] In the following, embodiments of the present invention are disclosed. The first embodiment is denoted E1, the second embodiment is denoted E2, and so on.

[0235] E1 A method for preparing compound IX:

[0236]

[0237] The method comprises the following steps i) bringing 4-chloro-5-nitropyridin-2(1H)-one (compound I) and 4-fluoro-2-methylphenylboronic acid (compound II) in the presence of a base The reaction is catalyzed by a palladium complex to provide 4-(4-fluoro-2-methylphenyl)-5-nitropyridin-2(1H)-ones of structure (III):

[0238]

[0239] E2 The method of embodiment 1, wherein the palladium complex is selected from the group consisting of palladium acetate, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium(II) dichloride, and [1,1 '-bis(diphenylphosphino)ferrocene]dichloride palladium(II), phosphine palladium complex, preferably tetrakis(triphenylphosphine) palladium.

[0240] E3 The method of any one of Embodiments 1-2, wherein the...

Embodiment 1

[0324] 4-(4-Fluoro -2 Preparation of -methylphenyl)-5-nitropyridin-2(1H)-one (compound III)

[0325]

[0326] 4-Chloro-5-nitropyridin-2(1H)-one (39.0 g, 223 mmol, available from Leapchem), (4-fluoro-2-methylphenyl)boronic acid (39.6 g, 257 mmol; available for example from commercially available from Sigma Aldrich), potassium carbonate (92.6 g, 670 mmol), and 1,4-dioxane (480 mL) were charged into a three-necked flask connected to a condenser and vacuum / nitrogen line. After being evacuated and backfilled with nitrogen 3 times, tetrakis(triphenylphosphine)palladium(0) (12.9 g, 11.2 mmol) was added under nitrogen flow and the resulting mixture was stirred at gentle reflux (99°C internal temperature) for 18 hours. The reaction mixture was cooled to room temperature and filtered. The precipitate was washed with dioxane (300 mL) and the filtrate was discarded. The precipitate was then washed with MeOH (2 x 200 mL), the filtrate was collected, concentrated in vacuo and dried...

Embodiment 2

[0328] Preparation of 2-chloro-4-(4-fluoro-2-methylphenyl)-5-nitropyridine (Compound IV)

[0329]

[0330] 4-(4-Fluoro-2-methylphenyl)-5-nitropyridin-2(1H)-one (78.0 g, 60% w / w, 0.19 mol) was suspended in a three-necked flask under nitrogen in DME (600 mL). Add POCl dropwise 3 (0.10 kg, 61 mL, 0.65 mol) (reaction was slightly exothermic, temperature rose to 40°C), then DMF (14 g, 15 mL, 0.19 mol) was added. The resulting mixture was stirred at 70°C (internal temperature) for 18 hours. The reaction mixture was cooled to room temperature and poured slowly into water (600 mL) (exothermic, cooled with ice / water bath). with solid Na 2 CO 3 The pH was neutralized and the mixture was transferred to a separatory funnel and extracted with EtOAc (2 x 600 mL). The organic layer was collected, washed with brine, washed with Na 2 SO 4 Drying, filtration and concentration in vacuo gave the title compound (46.2 g, 173 mmol, 91% w / w yield) as a brown solid in 86% purity (HPLC). ...

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Abstract

The present invention relates to a novel process for the preparation of the compound 2-(3, 5-bis (trifluoromethyl) phenyl)-N-(6-chloro-4-(4-fluoro-2-methylphenyl) pyridin-3-yl)-N, 2-dimethylpropanamide (compound IX) for the preparation of the compound 2-(3, 5-bis (trifluoromethyl) phenyl)-N-(6-chloro-4-(4-fluoro-2-methylphenyl) pyridin-3-yl)-N, 2-dimethylpropanamide (compound IX). The present invention relates to a compound (compound A) comprising 2-(4, 5-bis (trifluoromethyl) phenyl)-N-{4-(4-fluoro-2-methylphenyl)-6-[(7S), 9aS)-7-(hydroxymethyl) hexahydropyrazino [2, 1-c] [1, 4] oxazine-8 (1H)-yl]-3-pyridyl}-N, 2-dimethyl propionamide (compound A).

Description

technical field [0001] The present invention relates to a novel process for the preparation of compound IX for the preparation of compound A. The present invention also relates to compound IX prepared by said method and its use in the preparation of compound A. The present invention also relates to novel intermediates prepared by the method, including compound III, compound IV, salts of compound V, compound VII and pharmaceutically acceptable salts thereof, and their use in the preparation of compound IX or compound A . Background technique [0002] Compound A or a pharmaceutically acceptable salt thereof was first disclosed in WO 2007 / 028654. [0003] Compound A is also known as an anhydrous crystalline form. Therefore, the anhydrous crystalline form of Compound A (eg, anhydrous crystalline form 1) is described in WO2011 / 023733. [0004] Compound A or a pharmaceutically acceptable salt thereof (including its anhydrous crystalline form 1) is particularly useful in the tr...

Claims

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Application Information

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IPC IPC(8): C07D213/75
CPCC07D213/75C07D213/73C07D498/04A61K31/5383A61P15/02A61P5/24B01J23/44C07D213/76
Inventor M·施洛伊斯纳M·吉佐尼R·劳伦斯
Owner 康堤医疗有限公司
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