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Preparation method of Bcl-2 selective inhibitor

A selected and basic technology, applied in the field of compound preparation, can solve problems such as unsuitable for industrialization, low yield, complicated operation, etc.

Active Publication Date: 2020-10-09
SHOUYAO HLDG BEIJING CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] In this method, methanesulfonyl chloride is used to prepare the activated ester for post-condensation, then sodium hydroxide is used to hydrolyze the ester group, and finally a condensation reagent is used to obtain the target product. suitable for industrialization

Method used

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  • Preparation method of Bcl-2 selective inhibitor
  • Preparation method of Bcl-2 selective inhibitor
  • Preparation method of Bcl-2 selective inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0136] Example 1: 2-((1H-pyrrole[2,3-b]pyridin-5-yl)oxy)-4-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridine Synthesis of -4-yl)benzoic acid (compound 2)

[0137]

[0138] Add compound 1 (710 g), methanol (4.2 L) and tetrahydrofuran (4.2 L) into a 20 L four-neck flask, and stir to dissolve it. A solution of lithium hydroxide (199g) and water (2L) was added dropwise, the temperature was controlled below 25°C, and the dropwise addition was complete within 1 hour. Controlled at this temperature, the reaction was continued for 3 hours. After the reaction, the temperature was controlled below 10°C, the pH was adjusted to 6 with 1N hydrochloric acid aqueous solution, the solvent was evaporated to dryness, the residue was slurried with water (2 L) and methanol (3 L) respectively, and compound 2 was obtained by suction filtration as 636 g of off-white solid. The yield is 92.4%, and the purity is 98.6%.

[0139] 1 H NMR (400MHz, CDCl 3 )δ: 9.48 (1H, s), 8.22 (1H, d, J = 2.4Hz...

Embodiment 2

[0140] Example 2: Synthesis of 4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrobenzenesulfonamide (compound 5)

[0141]

[0142] Add compounds 3 (100 g), 4 (92.4 g) and acetonitrile (2 L) into a 3 L three-necked flask, stir to dissolve, raise the temperature to 50° C. and stir for 3 hours. Spin off the solvent, add acetonitrile (1 L), beat for 2 hours, and filter with suction to obtain 107.5 g of compound 5 as a bright yellow solid, with a yield of 71.0% and a purity of 99.4%.

[0143] 1 H NMR (400MHz, DMSO-d6) δ: 8.58 (1H, t, J = 6.0Hz), 8.45 (1H, d, J = 2.0Hz), 7.81 (1H, dd, J = 9.2Hz, 2.0Hz), 7.40 (1H, d, J=9.2Hz), 7.33 (2H, s), 3.74-3.71 (4H, m), 3.54-3.47 (2H, m), 1.88-1.67 (4H, m).

Embodiment 3

[0144] Example 3: 6-(bromomethyl)-4'-chloro-2'-fluoro-3,3-dimethyl-2,3,4,5-tetrahydro-1,1'-biphenyl (compound 7) Synthesis of

[0145]

[0146] A mixture of compound 6 (100 g), carbon tetrabromide (185 g) and dichloromethane (600 mL) was stirred and dissolved, and the temperature was lowered to -10°C. Control the temperature below 10°C, add triphenylphosphine (146g) in 5 batches, and react for 1 hour. Add silica gel (200g), spin off solvent, pass flash chromatography column, use sherwood oil as eluent. The solvent was spun off, acetonitrile (250 mL) was added to make slurry for 2 hours, and the obtained solid was vacuum-dried at 30-35°C to constant weight to obtain 112 g of compound 7 as a yellow solid with a yield of 90.78% and a purity of 99.95%.

[0147] 1 H-NMR (400MHz, CDCl 3 )δ: 7.19-7.13 (2H, m), 7.10 (1H, dd, J=9.6Hz, 2.0 Hz), 3.78 (2H, s), 2.58-1.81 (4H, m), 1.53 (2H, t, J = 6.4Hz), 0.98 (6H, s).

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Abstract

The invention provides a preparation method of a Bcl-2 selective inhibitor. The present invention provides a process for the preparation of a compound of formula (I).

Description

technical field [0001] The invention discloses a preparation method of a compound which selectively inhibits the activity of Bcl-2 anti-apoptosis protein. The invention also relates to the intermediates required for the preparation of such inhibitors and to the synthesis of the required intermediates. Background technique [0002] The compound of formula (I) is a small molecule Bcl-2 inhibitor. Apoptosis plays an important role in ensuring the balance between cell proliferation and death in organisms. Disruption of this pathway leads to a variety of diseases. Anti-apoptotic Bcl-2 protein plays an important role in the regulation of apoptosis and is associated with many diseases. In various cancers and disorders of the immune system, overexpression of Bcl-2 protein is associated with resistance to chemotherapy, disease development Correlation with overall prognosis, there is therefore a need in the therapeutic field for active compounds that inhibit the anti-apoptotic prot...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04
CPCC07D471/04
Inventor 冀冲孙德广张晓军李毅王红瑞杨利民陈岩史建龙
Owner SHOUYAO HLDG BEIJING CO LTD