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A kind of preparation technology of polyfluorine-substituted aromatic heterocyclic compounds

A preparation process and a technology for heterocycles are applied in the field of pharmaceutical synthesis to achieve the effects of high stability, high yield and easy preservation

Active Publication Date: 2020-08-25
GUANGZHOU LIXIN PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The purpose of the present invention is to overcome the defects of existing synthetic routes and provide a novel preparation method for compounds shown in structure I

Method used

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  • A kind of preparation technology of polyfluorine-substituted aromatic heterocyclic compounds
  • A kind of preparation technology of polyfluorine-substituted aromatic heterocyclic compounds
  • A kind of preparation technology of polyfluorine-substituted aromatic heterocyclic compounds

Examples

Experimental program
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Effect test

preparation example Construction

[0040] Preparation of starting compound SM1:

[0041]

[0042] Compound SM1 used in this example can be prepared by the following method:

[0043] 172.32 g of compound IM1 (1.0 eq) was added to a 1 L reaction flask, and 344 ml of absolute ethanol was added thereto. 93.3g of p-toluenesulfonic acid monohydrate (1.0eq) was dissolved in 172ml of ethanol, and then added to the reaction solution under ice-bath conditions, and the dropwise addition was completed within 1h. During the dropwise addition, when a large amount of solids appeared in the reaction solution and could not be stirred, 340ml of MTBE was added and the reaction was continued for 30min. After the reaction was finished, it was filtered with suction, and the filter cake was washed with 100 ml of MTBE×5 to obtain 178 g of intermediate SM1. Intermediate 11 was reduced and salt-formed to obtain intermediate SM1, and the total yield of the two-step reaction was 74.86%. 1 H NMR (500MHz, DMSO-d 6 )δ7.75(s,2H),7.53–7...

Embodiment 1

[0047] Embodiment 1: the preparation of intermediate IM1

[0048]

[0049] 160g of compound SM1 (1.0eq) (ee value 99.8%) was suspended in 1.6L of dichloromethane, stirred at room temperature, 727ml of 0.5mol / L NaOH solution (1.1eq) was added dropwise, stirred at room temperature for 30min, the reaction solution It became clear, and the layers were separated after standing. The aqueous layer was extracted once again with 200ml of DCM. The combined organic layers were washed with 100ml of saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure at 40°C to obtain 108.28g of golden yellow oily liquid. The yield of body IM1 is 104.86% based on crude product IM1.

[0050] 1 H NMR (400MHz, CDCl 3 )δ7.11(dd, J=18.5,8.3Hz,1H),7.06-7.00(m,1H),6.97–6.91(m,1H),4.23(d,J=25.4Hz,2H),2.80(d ,J=42.4Hz,2H),2.50(t,J=11.3Hz,1H),2.38–2.25(m,1H),1.76(d,J=11.4Hz,1H),1.68-1.57(m,1H) ,1.47(s,9H),1.45-1.41(m,2H).

Embodiment 2

[0051] Embodiment 2: the preparation of intermediate IM1

[0052] Suspend 0.5 g of SM1 (1.0 eq) in 5 ml of dichloromethane, add 2.1 ml of 0.5 mol / L NaOH aqueous solution (1.0 eq) to the reaction solution, complete the addition within 3 min, and stir at room temperature for 1 h. After static separation, the DCM layer was washed with 5ml of saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure at 40°C to obtain 0.282g of intermediate IM1 as a golden oily liquid, with a yield of 98.75% based on the crude product IM1.

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Abstract

The invention discloses a preparation process of a polyfluoric substituted aromatic heterocycles compound. The preparation process of the polyfluoric substituted aromatic heterocycles compound comprises the steps of taking tert-butyl (3S, 4S)-3-amino-4-(3,4-difluorophenyl)piperidine-1-carboxylate p-toluene sulfonate as a raw material, carrying out dissociation, carrying out condensation reaction on the tert-butyl (3S, 4S)-3-amino-4-(3,4-difluorophenyl)piperidine-1-carboxylate p-toluene sulfonate and 2-fluro-4-(1-methyl-1H-pyrazole-5-yl) benzoic acid, then removing protecting group, and finallysalifying with L-malic acid to obtain 4-(1-methyl-1H-pyrazole-yl)-N-((3S,4S)-4-(3,4-difluorophenyl) piperidine-3-yl)-2-fluorobenzamide L-malate. The used raw material SM1 is solid, the stability is high, weighing and storage are facilitated, the shortcoming that in the prior art, IM1 easily becomes liquid, and is difficult to refine is overcome, an SM1 quality control standard is easily established on production, and raw material suppliers can provide pure SM1; and meanwhile, the chiral purity of the raw material SM1 is high, and the purity and integral yield of the final product are ensuredfrom the source.

Description

technical field [0001] The invention belongs to the technical field of medicine synthesis, and in particular relates to a preparation process of polyfluorine substituted aromatic biheterocyclic compounds. Background technique [0002] Akt (protein kinase B) is a serine / threonine kinase closely related to the occurrence and development of tumors. It is a member of the AGC protein kinase family and is involved in physiological processes such as cell growth, survival, proliferation, apoptosis, angiogenesis, and autophagy play an important role in. Studies have found that Akt is overexpressed in various human tumors such as gastric cancer, prostate cancer, ovarian cancer, and breast cancer. The dysfunction or abnormal activation of Akt is closely related to the occurrence, development, metastasis, and drug resistance of these tumors. Closely related, Akt is a promising anti-tumor drug target. Human Akt mainly includes three subtypes: Akt1, Akt2, Akt3, and each subtype has a hi...

Claims

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Application Information

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IPC IPC(8): C07D401/12C07C51/41C07C59/245
CPCC07D401/12Y02P20/55
Inventor 董晓武杨波胡永洲何俏军翁勤洁盛海潮陈斌辉
Owner GUANGZHOU LIXIN PHARM CO LTD
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