A crystal form of a key intermediate of a btk kinase inhibitor and a preparation method thereof

A technology of kinase inhibitors and intermediates, which is applied in organic chemistry methods, organic chemistry, antineoplastic drugs, etc., can solve the problems of BTK kinase inhibitor purification methods such as difficulty in scaling up, high cost, unfavorable large-scale production, etc., and achieve the production process Stable, repeatable and controllable, good crystal form stability, satisfying the effect of production, transportation and storage

Active Publication Date: 2021-04-06
SHANGHAI ZAIQI BIO TECH
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Problems solved by technology

[0006] Literature reports (R)-4-amino-1-(1-(but-2-ynoyl)pyrrolidin-3-yl)-3-(4-(2,6-difluorophenoxy)phenyl) -1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one is purified by silica gel column chromatography followed by crystallization, which makes it difficult to scale up the BTK kinase inhibitor purification method , is not conducive to large-scale production, as a human drug, impurities often have adverse effects on the human body, so high-purity drugs are an important goal of drug development, but high-purity intermediates are crucial to obtaining high-purity drugs
[0007] As the above-mentioned BTK kinase inhibitor (R)-4-amino-1-(1-(but-2-ynoyl)pyrrolidin-3-yl)-3-(4-(2,6-difluorophenoxy )Phenyl)-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one key intermediate (R)-1-(1-(tert-butoxyacyl)pyrrolidine -3-yl)-3-cyano-4-(4-(2,6-difluorophenoxy)phenyl)-1H-pyrrole-2-carboxylic acid ethyl ester Purification of intermediates by column chromatography is expensive , low efficiency, unfavorable for industrialized production, so it is urgent to develop a kind of intermediate that can be purified by crystallization and stable chemical properties, so that the novel BTK kinase inhibitor (R)-4-amino-1-(1- (But-2-ynoyl)pyrrolidin-3-yl)-3-(4-(2,6-difluorophenoxy)phenyl)-1,6-dihydro-7H-pyrrolo[2, 3-d]pyridazin-7-one purification just got easier

Method used

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  • A crystal form of a key intermediate of a btk kinase inhibitor and a preparation method thereof
  • A crystal form of a key intermediate of a btk kinase inhibitor and a preparation method thereof
  • A crystal form of a key intermediate of a btk kinase inhibitor and a preparation method thereof

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Experimental program
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Effect test

Embodiment 1

[0054] (R)-1-(1-(tert-butoxyacyl)pyrrolidin-3-yl)-3-cyano-4-(4-(2,6-difluorophenoxy)phenyl)-1H- Preparation of ethyl pyrrole-2-carboxylate

[0055] (R)-1-(1-(tert-butoxyacyl)pyrrolidin-3-yl)-3-cyano-4-bromo-1H-pyrrole-2-carboxylic acid ethyl ester (1.98g, 4.8mmol), I 2 (1.60g, 4.8mmol) and K 3 PO 4 ·3H 2 O (1.88g, 7.2mmol) in 1,4-dioxane / water (60mL / 6mL), after degassing the solution with nitrogen, then add Pd under the protection of nitrogen 2 (dba) 3 (220mg, 0.24mmol) and P(Cy) 3 (140mg, 0.48mmol), and then heated to reflux for 16h. After the reaction was completed, it was cooled to room temperature, the solid was filtered off, and the filtrate was concentrated. The residue was purified by silica gel chromatography (eluent: dichloromethane), and evaporated under reduced pressure to obtain 0.57 g of off-white solid (R)-1-(1-(tert-butoxyacyl)pyrrolidin-3-yl)- ethyl 3-cyano-4-(4-(2,6-difluorophenoxy)phenyl)-1H-pyrrole-2-carboxylate. HPLC: 99.31%, max. simple: 0.21%. ...

Embodiment 2

[0057] Take 1.0 g of the compound of formula (I) (the crude product prepared according to Example 1) and add it to a 25 mL single-necked bottle, add 2 mL of absolute ethanol, heat to reflux to dissolve, stop heating, cool and crystallize, suction filter the next day, and dry under reduced pressure After drying, 715 mg of white solid was obtained, and the yield was 71.5%. HPLC: 99.73%, max. simple: 0.04%. The X-ray diffraction spectrum of the crystalline sample is shown in image 3 . The X-ray powder diffraction pattern is characterized at 2θ values ​​of approximately 5.52, 8.62, 9.34, 11.85, 14.36, 14.52, 15.25, 17.16, 18.79, 19.02, 20.02, 20.18, 20.49, 20.79, 22.44, 23.79, 24.02, 24.29 and 28.18 peaks, and their characteristic peak positions are shown in Table 1 below. See the DSC spectrum Figure 4 , with a sharp melting endothermic peak at 97.92°C, this crystal form is defined as crystal form II. The crystalline form II contains at least 97% or more of the crystalline ...

Embodiment 3

[0062] Take 1.0g of the compound of formula (I) (the crude product prepared according to Example 1) and add it to a 25mL single-necked bottle, add 1.5mL of absolute ethanol, heat to reflux to dissolve, stop heating, cool and crystallize, the next day, suction filter and dry 868 mg of white solid was obtained, and the yield was 86.8%. The X-ray diffraction pattern and the DSC pattern of the crystalline sample are studied and compared, and the product is determined to be crystal form II.

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Abstract

The invention relates to a crystal form of a key intermediate of a BTK kinase inhibitor and a preparation method thereof, belonging to the technical field of medicine. The crystal form is (R)-1-(1-(tert-butoxyacyl)pyrrolidin-3-yl)-3-cyano-4-(4-(2,6-difluorophenoxy)benzene base)-1H-pyrrole-2-carboxylate ethyl ester crystal form II. The present invention obtains (R)-1-(1-(tert-butoxyacyl)pyrrolidin-3-yl)-3-cyano-4-(4-(2,6-difluorophenoxy)phenyl )-1H-pyrrole-2-ethyl carboxylate crystal form II has good chemical stability and crystal form stability, which is convenient for storage and transportation. BTK kinase inhibitor (R)‑4‑amino‑1‑(1‑(but‑2‑ynoyl)pyrrolidin‑3‑yl)‑3‑(4‑(2,6‑difluorophenoxy)benzene Base)-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one quality control is of great significance, and the preparation process is simple, suitable for industrial scale production.

Description

technical field [0001] The invention relates to a crystal form of a key intermediate of a BTK kinase inhibitor and a preparation method thereof, in particular to (R)-1-(1-(tert-butoxyacyl)pyrrolidin-3-yl)-3-cyano -The crystal form II of ethyl 4-(4-(2,6-difluorophenoxy)phenyl)-1H-pyrrole-2-carboxylate and a preparation method thereof belong to the technical field of medicine. Background technique [0002] Immune cells can usually be divided into T cells and B cells. The main function of B cells is to secrete various antibodies to help the body resist various foreign invasions. Bruton's tyrosine protein kinase (BTK) is one of the members of the tyrosine protein kinase subfamily and belongs to the Tec family of kinases. It is mainly expressed in hematopoietic cells and distributed in the lymphatic system, hematopoietic and blood systems. Bruton's tyrosine kinase (BTK) is a key protein kinase in the BCR signaling pathway. It can regulate the maturation and differentiation of n...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D207/34
CPCC07D207/34C07B2200/13A61P35/00
Inventor 李超孙鹏田贝贝张欣
Owner SHANGHAI ZAIQI BIO TECH
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