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A kind of preparation method of ceritinib and its intermediate

A technology for ceritinib and a compound, which is applied in the field of preparation of ceritinib, can solve the problems of complicated purification operation, high reaction temperature, difficult industrial expansion of production, etc., and achieves improved reaction yield, mild reaction conditions, and avoidance of heavy metals residual effect

Active Publication Date: 2018-09-18
CHIA TAI TIANQING PHARMA GRP CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] In this synthetic method, the following problems exist in the condensation reaction of formula 3 compound and formula 4 compound to prepare formula 5 compound: 1) used palladium acetate, xantphos and Cs 2 CO 3 The price is expensive; 2) palladium acetate is easy to cause heavy metal residues; 3) the reaction is irradiated with microwaves to 150 ° C, the reaction temperature is high, and the microwave heating method is difficult to be used for industrial expansion production; 4) the product must be purified by silica gel chromatography, which makes the purification operation complicated , high cost of industrialization

Method used

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  • A kind of preparation method of ceritinib and its intermediate
  • A kind of preparation method of ceritinib and its intermediate
  • A kind of preparation method of ceritinib and its intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] Embodiment 1: the synthesis of formula III compound

[0040]

[0041] Dissolve the compound of formula I (117g, 0.603mol) and the compound of formula II (100g, 0.502mol) in 1500mL of chloroform, add diisopropylethylamine (78g, 0.60mol) at room temperature, and heat to reflux for 2 hours . After the reaction was detected by TLC, it was concentrated to dryness to obtain 300 g of a brown solid. Then add 600mL of methanol, stir well at 10°C, and filter with suction to obtain 152g of light yellow compound of formula III, the HPLC purity is greater than 98%, and the yield is 85%. 1 H-NMR (300MHz, CDCl 3 )δ:11.56(s,1H),9.26(s,1H),8.26(d,1H),8.03(d,1H),7.76(m,1H),7.48(m,1H),3.21(m,1H ),1.33(d,6H).MS:379.0[M+Na] + ,355.0[M-H] - .

Embodiment 2

[0042] Embodiment 2: the synthesis of formula V-Boc compound

[0043]

[0044] The compound of formula III (60g, 0.168mol) and the compound of formula IV-Boc (64.5g, 0.185mol) were dissolved in 1800mL of absolute ethanol, heated to 60°C for 8 hours, after the reaction was detected by TLC, concentrated to dryness to obtain a brown color solid. Recrystallization with PE:EA=3:1 gave 91 g of the compound of formula V-Boc as a yellow solid, with an HPLC purity greater than 98% and a yield of 81%.1 H-NMR (300MHz, CDCl 3 )δ:11.58(s,1H),9.21(s,1H),8.15(m,3H),7.87(d,1H),7.64(d,1H),7.46(m,1H),6.73(m,1H ),4.28(m,1H),4.14(m,2H),3.28(m,1H),2.82(m,3H),1.93(m,2H),1.72(m,2H),1.51(m,3H) ,1.39(m,10H),1.28(m,11H).MS:669.3[M+H] + ,691.3[M+Na] + .

Embodiment 3

[0045] Embodiment 3: the synthesis of formula VI-Boc compound

[0046]

[0047] A mixture of formula V-Boc compound (20g, 0.030mol), reduced iron powder (8.1g, 0.145mol), ammonium chloride (15.5g, 0.290mol) dissolved in 600mL ethanol and water (V:V=2:1) The solution was heated to reflux for 1 h. After the reaction was detected by TLC, it was filtered, and the filtrate was concentrated to dryness to obtain 16.5 g of a gray-green solid. The HPLC purity was greater than 98%, and the yield was 86%. 1 H-NMR (300MHz, CDCl 3 )δ:9.49(s,1H),8.70(d,1H),8.13(s,1H),7.91(m,2H),7.64(d,1H),7.41(m,1H),7.28(m,1H ),6.72(m,1H),4.56(m,1H),4.27(m,2H),3.30(m,1H),2.84(m,3H),2.23(m,3H),1.93(m,2H) ,1.75(m,2H),1.52(m,2H),1.39(m,10H),1.34(m,11H).MS:639.3[M+H] + ,661.3[M+Na] + .

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Abstract

The invention specifically relates to a preparation method for ceritinib and an intermediate of ceritinib, belonging to the technical field of pharmaceutical chemistry. The method comprises the following steps: with 2,4-dichloro-5-nitropyrimidine as a raw material, carrying out a two-step condensation reaction so as to obtain a compound as shown in a formula V which is described in the specification; and subjecting the compound as shown in the formula V to reduction, chlorination and removal of a protective group R so as to obtain ceritinib. The method substantially improves reaction yield; reaction conditions are mild; the obtained product, i.e., ceritinib, does not need column chromatographic purification; and the method is suitable for industrial production and avoids heavy metal residuals.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular, the invention relates to a preparation method of Ceritinib and an intermediate thereof. Background technique [0002] Ceritinib is an anaplastic lymphoma enzyme (ALK) tyrosine kinase inhibitor developed by Novartis Pharmaceuticals, which was approved by the FDA in April 2014 for use after treatment with crizotinib The treatment of patients with metastatic NSCLC who have disease progression or intolerance, the trade name is Zykadia. The chemical name of ceritinib is 5-chloro-N4-[2-[(1-methylethyl)sulfonyl]phenyl]-N2-[5-methyl-2-(1-methylethoxy base)-4-(4-piperidinyl)phenyl]-2,4-pyrimidinediamine, the structure is as follows: [0003] [0004] A variety of preparation methods of ceritinib are disclosed in the prior art, wherein CN101616895A discloses that 2,4,5-trichloropyrimidine (formula 1) is used as a raw material, and 2-(isopropylsulfonyl ) aniline (formula 2) condensati...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/12C07D239/42
CPCY02P20/55
Inventor 李锐刘飞王冬冬王善春王鹏
Owner CHIA TAI TIANQING PHARMA GRP CO LTD
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