Preparation method of intermediate of antitumor drug GDC-0449 (vismodegib)

A technology of intermediates and compounds, which is applied in the field of synthesis of drugs and their intermediates, can solve the problems of not very mild reaction conditions, unstable large-scale production yields, and high raw material costs, and achieve cheap raw materials, high yields, and excellent reaction conditions. mild effect

Active Publication Date: 2012-10-17
PHARMABLOCK SCIENCES (NANJING) INC
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

It mainly solves technical problems such as high raw material cost, not very mild reaction conditions, and unstab

Method used

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  • Preparation method of intermediate of antitumor drug GDC-0449 (vismodegib)
  • Preparation method of intermediate of antitumor drug GDC-0449 (vismodegib)
  • Preparation method of intermediate of antitumor drug GDC-0449 (vismodegib)

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] Preparation of Intermediate II

[0024] Synthesis of compound VII:

[0025]

[0026] Add compound VI (313.1g, 2.0mol, 1.0eq.) in 1L four-neck flask, dissolve with 5L concentrated sulfuric acid, add NaIO 4 (188.2g, 0.9mol, 0.45eq.), when the solid is completely dissolved, slowly add KI (365g, 2.2mol, 1.1eq.) at room temperature, the reaction solution is dark purple, control the reaction temperature 25-30℃, After addition, react at room temperature for 2h, after the reaction is complete. The reaction solution was slowly poured into 20 kg of crushed ice, stirred, a large amount of solids precipitated, filtered, the filter cake was washed with water and petroleum ether, and dried to obtain 410 g of compound VII as a white solid, with a yield of 72.7%. 1 HNMR (400MHz, DMSO-d 6 )δ (ppm): 13.35 (bs, 1H), 8.38 (d, J=2.0Hz, 1H), 7.91 (dd, J=8.3, 2.0Hz, 1H), 7.69 (d, J=8.3Hz, 1H) .

[0027] Synthesis of Compound VIII:

[0028]

[0029] In a 1L four-neck flask, add com...

Embodiment 2

[0040] Synthesis of compound I:

[0041]

[0042] Add compound II (81g, 400mmol, 1.0eq.) in 2L four-neck flask, 800mLDCM, add triethylamine (Et 3 N) (60g, 600mmol, 1.5eq.), then slowly add compound XII (120g, 480mmol, 1.2eq.) in an ice bath, control the temperature at 0-5°C, complete the addition, react at room temperature for 30min, and the reaction ends. Recrystallization (PE / EA) yielded 165.3 g of a white solid with a yield of 99%. Purity: 99%. 1 H NMR (400MHz, CDCl3) δ (ppm): 9.58 (bs, 1H), 8.43 (d, J = 4.7Hz, 1H), 8.03 (dd, J = 2.6, 8.7Hz, 1H), 7.90 (d, J =1.6Hz, 1H), 7.67-7.78(m, 4H), 7.60(d, J=8.0Hz, 1H), 7.51(d, J=8.8Hz, 1H), 7.23-7.24(m, 1H), 3.01 (s, 3H).

Embodiment 3

[0044] Synthesis of compound VII:

[0045]

[0046] Add compound VI (313.1g, 2.0mol, 1.0eq.) in 1L four-neck flask, dissolve with 5L concentrated sulfuric acid, add NaIO 4 (104.5g, 0.49mol, 0.25eq.), when the solid is completely dissolved, slowly add KI (248.8g, 1.50mol, 0.75eq.) at room temperature, the reaction solution is black and purple, control the reaction temperature 25-40℃ , After addition, react at room temperature for 3h, after the reaction is complete. The reaction solution was slowly poured into 18 kg of crushed ice, stirred, a large amount of solids precipitated, filtered, the filter cake was washed with water and petroleum ether, and dried to obtain 400 g of compound VII as a white solid, with a yield of 70.9%. 1 HNMR (400MHz, DMSO-d 6 )δ (ppm): 13.35 (bs, 1H), 8.38 (d, J = 2.0Hz, 1H), 7.91 (dd, J = 8.3, 2.0Hz, 1H), 7.69 (d, J = 8.3Hz, 1H) .

[0047] Synthesis of Compound VIII:

[0048]

[0049] In a 1L four-necked flask, add compound VII (331.3g, 1.1...

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Abstract

The invention relates to the field of synthesis of drug intermediates, in particular to an intermediate of antitumor drug GDC-0449 (vismodegib) and a synthesis method of the intermediate. The synthesis method is characterized by comprising the following steps: with parachlorobenzoic-acid as a raw material, firstly carrying out iodination and then carrying out a rearrangement reaction under the action of diphenylphosphoryl azide; reacting with coupled boronic acid pinacol ester; and finally carrying out coupling reaction with 2-bromopyridine; and removing protecting groups to finally obtain the intermediate of GDC-0449. The preparation method provided by the invention has the following advantages: the raw material is cheap, the reaction conditions are moderate, the yield of each reaction is high, and the total yield is high up to 54.7%; and therefore the preparation method is suitable for large-scale preparation.

Description

technical field [0001] The present invention relates to the field of synthesis of medicines and intermediates thereof, in particular to 2-chloro-N-[4-chloro-3-(2-pyridyl)phenyl]-4-(methylsulfonyl)benzamide (GDC-0449 ) intermediates and their synthetic methods. Background technique [0002] A novel targeted antineoplastic drug, Vismodegib (2-chloro-N-[4-chloro-3-(2-pyridyl)phenyl]-4-(methylsulfonyl)benzamide, GDC-0449) is hedgehog A novel small molecule inhibitor of the pathway, IC 50 It is 3nm and can effectively treat basal cell nevus syndrome and advanced basal cell carcinoma (BCC). Vismodegib was approved for marketing by the US FDA on January 30, 2012. In addition, 4-chloro-3-(2-pyridyl)aniline is a key intermediate for the synthesis of Vismodegib. [0003] For the preparation of Vismodegib (compound I), patent WO2009126863 reports related compound methods as follows: [0004] [0005] Reagents and conditions: (a) H 2 SO 4 , NaNO 2 , H 2 O, KI, yield: 73%; (b...

Claims

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Application Information

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IPC IPC(8): C07D213/38C07D213/40
CPCY02P20/55
Inventor 朱经纬毛俊杨民民吴希罕
Owner PHARMABLOCK SCIENCES (NANJING) INC
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