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Ibrutinib intermediate and preparation method thereof

A technology of ibrutinib and intermediates, applied in the field of medicinal chemistry, can solve the problems of expensive, unsuitable for industrial production and high price

Active Publication Date: 2018-11-02
JIANGSU CHUANGUO PHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

But because the starting material is not commercialized on a large scale, the price is higher, and the catalyst bis(triphenylphosphine)palladium chloride or bis(cyanophenyl)palladium chloride that needs to be used in the preparation process is also very expensive, so Not suitable for industrial production

Method used

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  • Ibrutinib intermediate and preparation method thereof
  • Ibrutinib intermediate and preparation method thereof
  • Ibrutinib intermediate and preparation method thereof

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preparation example Construction

[0081] In a preferred embodiment, the preparation of Ibrutinib key intermediate formula 5 compound 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine of the present invention method, including the following steps:

[0082]

[0083] a) The compound of formula I reacts with the active nucleophilic activator N,N-dimethylaminopyridine in the presence of a base 2 in an organic solvent 1 to obtain an active intermediate compound of formula IIa or with an active nucleophilic activator N-methylmorpholine Reaction obtains reactive intermediate formula IIb compound;

[0084] b) reacting the compound of formula IIa or the compound of formula IIb with a cyclization reagent to obtain the compound of formula 4;

[0085] c) The compound of formula 4 is ring-closed with formamide or formamidine acetate in organic solvent 2 to obtain the compound of formula 5.

[0086] In step a), the organic solvent 1 is selected from one or a combination of tetrahydrofuran, 1,4-dioxane, 2-methyltet...

Embodiment 1

[0110] The preparation of formula 2 compound 4-phenoxybenzoyl chloride

[0111] 250 mL of toluene and 50.0 g (0.23 mol) of 4-phenoxybenzoic acid were added to the reaction flask, and the temperature was lowered to 5°C. Add 41.7 g (0.35 mol) of thionyl chloride, and add 2 drops of N,N-dimethylformamide to catalyze it. The reaction solution was heated to 80° C. and stirred for 3 hours. Concentrate under reduced pressure, replace the residual liquid with toluene twice, then add 200 mL of toluene, stir evenly, and put it directly into the next reaction.

Embodiment 2

[0113] Preparation of formula 3 compound 2-[hydroxyl(4-phenoxyphenyl)methylene]malononitrile

[0114] Add 150 mL of toluene and 15.4 g (0.23 mol) of malononitrile into the reaction flask, and lower the temperature to 5°C. A toluene solution of the product of Example 1 was added. Add 60.3g (0.46mol) of N,N-diisopropylethylamine dropwise, and control the temperature at about 5°C. After the dropwise addition, the reaction solution was heated to 20° C. for 16 hours. Concentrate under reduced pressure, extract the residual solvent with ethyl acetate, wash the organic layer with 1M hydrochloric acid, and dry over sodium sulfate. Concentrate under reduced pressure to obtain 58.1 g of the compound of formula 3 with a yield of 95.1%.

[0115] 1H-NMR: δ12.18, 12.16 (1H, -OH), 7.85-7.83 (2H, m, Ph-), 7.43-7.39 (2H, t, Ph-), 7.18-7.16 (2H, t, Ph- ), 7.08-7.06 (1H, m, Ph-), 6.52 (2H, s, Ph-).

[0116] Mass(+ESI):263.17[M+H] + .

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Abstract

The invention discloses an ibrutinib intermediate and a preparation method thereof. The structure of the ibrutinib intermediate provided by the invention is shown as a formula I; the definition of R is shown as a specification and a claim. The ibrutinib intermediate can be used for preparing an ibrutinib key intermediate of 3-(4-phenoxyl phenyl)-1H-parazole[3,4-d]pyrimidine-4-amine; the preparation method comprises the steps of preparing an active intermediate of a compound shown as a formula II from a compound shown as a formula I under the effect of active nucleophilic reagents; cyclizing the compound shown as the formula II to obtain a compound 3-amino-5-(4-phenoxyl phenyl)-4-cyan-1H-parazole shown as a formula 4; performing ring closing on the compound shown as the formula 4 to obtainthe ibrutinib key intermediate. The method has the advantages that the raw materials are cheap and can be easily obtained; the use of dangerous reagents is not needed; the reaction conditions are mild; the operation is simple; the method is suitable for industrial production. (The formulas are shown in the description.).

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to an intermediate of tyrosine kinase inhibitor ibrutinib and a preparation method thereof. Background technique [0002] The chemical name of Ibrutinib is: 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine -1-yl]-1-piperidinyl]-2-propen-1-one, its structural formula is as follows: [0003] [0004] Ibrutinib is a first-in-class oral Bruton's tyrosine kinase (BTK) inhibitor, which selectively co-activates cysteine ​​residues (Cys-481) in the active site of the target protein Btk. Binding to BTK and irreversibly inhibiting BTK, thus effectively preventing the migration of tumors from B cells to lymphoid tissues adapted to the tumor growth environment. In November 2013, the US Food and Drug Administration (FDA) approved its listing for the treatment of a rare aggressive blood cancer - mantle cell lymphoma (MCL), and in July 2014 the FDA approved it for chronic...

Claims

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Application Information

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IPC IPC(8): C07C303/28C07C309/73C07D231/38C07D487/04
CPCC07C51/60C07C253/30C07C303/28C07C309/73C07D231/38C07D487/04C07C65/24C07C255/37
Inventor 胡雪峰孙猛龚浙军黄海张朋浩
Owner JIANGSU CHUANGUO PHARMA CO LTD
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