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Preparation method for preparing Bruton's tyrosine kinase (BTK) inhibitor

A technology of acidic conditions and compounds, applied in organic chemistry and other fields, can solve problems such as incomplete reactions

Active Publication Date: 2016-08-24
SHOUYAO HLDG BEIJING CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] This method adopts the hydrolysis method of cyano group to form amide, and the deprotection and hydrolysis of cyano group are carried out at the same time. Experiments have found that there are many problems in this method, many impurities appear, and the reaction is incomplete. Post-processing requires column chromatography to separate the product.

Method used

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  • Preparation method for preparing Bruton's tyrosine kinase (BTK) inhibitor
  • Preparation method for preparing Bruton's tyrosine kinase (BTK) inhibitor
  • Preparation method for preparing Bruton's tyrosine kinase (BTK) inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0085] Example 1: (R)-3-(5-amino-4-cyano-3-(4-phenoxyphenyl)-1H-pyrazol-1-yl)tetrahydropyrrole-1-carboxylic acid tert-butyl Preparation of ester (compound 3a)

[0086]

[0087] Add compound 1a (600g, 2.17mol), compound 2a (815g, 2.39mol), powdery cesium carbonate (1417g, 4.35mol) and N, N-methylformamide (DMF, 6L), mechanically stirred, heated to 80°C (about 1.5 hours), and sent to HPLC to monitor the reaction after 2 hours. After the reaction was completed, stop heating, cool to room temperature, then add 10L ethyl acetate and 15L water, and stir for 30 Minutes (rotating speed 200), leave standstill, separate liquid, water phase is discarded, and organic phase is stirred dry with 1kg anhydrous sodium sulfate machine, filters, and filtrate is concentrated to obtain deep reddish-brown oily matter, and this crude product is recrystallized with dioxane dioxane Once, 450 g of a light yellow powdery solid was obtained, with a yield of 46.4%.

[0088] 1 H NMR (400MHz, CDCl 3 ...

Embodiment 2

[0089] Example 2: (R)-5-amino-3-(4-phenoxyphenyl)-1-(tetrahydropyrrol-3-yl)-1H-pyrazole-4-carbonitrile hydrochloride (compound 4a ) preparation

[0090]

[0091] Compound 3a (463 g) and 6 L of dichloromethane were added to a dry 10 L three-necked flask. After dissolving, the temperature was cooled to 5° C. in an ice-water bath, and dry HCl gas was introduced for 1 hour, then stirred overnight. Suction filter, wash once with 1 L of dichloromethane, and dry in the air to obtain 385 g of light yellow powdery solid (97.0%).

[0092] 1H NMR (400MHz, DMSO): δ9.36-9.67 (2H, brs), 7.86 (2H, d, J = 8.8HZ), 7.40 (2H, t, J = 8.0Hz), 7.16 (1H, t, J =7.6Hz), 7.08(2H, d, J=8.8Hz), 7.04(2H, d, J=8.0Hz), 6.94(2H, s), 5.10-5.13(1H, m), 3.39-3.58(4H , m), 2.25-2.34 (1H, m), 2.13-2.20 (1H, m).

Embodiment 3

[0093] Example 3: (R)-5-amino-3-(4-phenoxyphenyl)-1-(tetrahydropyrrol-3-yl)-1H-pyrazole-4-carboxamide (compound 5a) preparation

[0094]

[0095] Add 3.8kg of polyphosphoric acid and 380mL of deionized water to a dry 10L three-necked flask in turn, stir and dilute, heat up to an internal temperature of 80°C, and add compound 4a (380g, 0.995mol) in batches. After the addition is complete, The internal temperature rose to 90-95°C, stirred for 8 hours, and sent to HPLC to monitor the reaction. After the reaction was completed, after the temperature dropped to room temperature, the viscous reaction liquid in the reaction bottle was poured into ice water in batches, and after pouring, While adding crushed ice, sodium hydroxide solution was added, and the addition was stopped when the pH was adjusted to 5-6. The resulting white powdery solid was filtered with suction, washed with water twice (1 L / time), and dried to obtain a light yellow foamy solid 5a (350 g , 96.8%).

[0096]...

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Abstract

The invention discloses a method for preparing a compound as shown in the formula (I). The compound as shown in the formula (I) is a small molecular Bruton's tyrosine kinase (BTK) inhibitor. It has been proved that the BTK inhibitor can inhibit chronic lymphocytic leukemia and related diseases.

Description

technical field [0001] The invention relates to the field of synthesis of medicines and medicine intermediates thereof, in particular to a preparation method of a Bruton's tyrosine kinase (BTK) kinase inhibitor. Background technique [0002] The invention provides the compound method of formula (I) compound and formula (5) compound: [0003] [0004] The compound of formula (I) is a highly selective small molecule Bruton's tyrosine kinase (Bruton's tyrosinekinase, Btk) kinase inhibitor, and is a key target for the treatment of chronic lymphocytic leukemia (CLL). Btk inhibitors, members of the Tec family of non-receptor tyrosine kinases, are key signaling enzymes expressed in all hematopoietic cell types except T lymphocytes and natural killer cells. Btk plays a crucial role in the B cell signaling pathway linking cell surface B cell receptor (B-cell receptor, BCR) stimulation to downstream intracellular responses. Btk is a key regulator of B cell development, activation...

Claims

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Application Information

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IPC IPC(8): C07D403/04C07D401/04
Inventor 杨利民孙德广殷静张传玉韩军儒冀冲张晓军杨卫民韩永信
Owner SHOUYAO HLDG BEIJING CO LTD
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