936563-87-0

Usage

Biological Activity

pci-32765 is an inhibitor of bruton tyrosine kinase (btk) with ic50 value of 0.5nm [1].pci-32765 is a covalent and irreversible inhibitor of btk through bonding to cys-481 in the atp binding domain. pci-32765 inhibits phosphorylation of btk in a b cells (ic50 of 11nm) as well as the downstream substrates phosphoinositide phospholipase cγ (plc γ) and erk in cell assays. pci-32765 has in vivo efficacy in b cell lymphoma. in cll cells, pci-32765 induces cells apoptosis through inhibiting the expression of bcr-dependent udp-glucose ceramide glucosyltransferase [1].pci-32765 is oral effective in vivo. it induces lymphocytosis during the first weeks of therapy in patients with cll. it is also efficacious in autoimmune disease. in the mrl-fas lupus model, pci-32765 inhibits collagen-induced arthritis as well as autoantibody production and development of kidney disease. it also diminished fcγriii-induced production of pro-inflammatory cytokines [1].

references

[1] burger ja, buggy jj. bruton tyrosine kinase inhibitor ibrutinib (pci-32765). leuk lymphoma. 2013 nov;54(11):2385-91.

Upstream product

• 814-68-6 acryloyl chloride 
• 330792-69-3 2-[(4-phenoxy-phenyl)-methoxy-methylene]-malononitrile 
• 330792-68-2 2-[hydroxy-(4-phenoxy-phenyl)-methylene]-malononitrile 
• 330786-24-8 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine 
• 2215-77-2 4-Phenoxybenzoic acid 
• 2380-63-4 4-Aminopyrazolo<3,4-d>pyrimidin 
• 151266-23-8 4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidine 
• 1022150-12-4 (R)-3-(4-phenoxyphenyl)-1-(piperidine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-4-amine 
• 1022150-11-3 (3R)‐4‐amino‐3‐(4-phenoxyphenyl)‐1‐(1‐tert-butoxycarbonylpiperidine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine 
• 85275-45-2 N-tert-butoxycarbonyl-3-piperidinol 
• 5305-40-8 2,6-dichloro-pyrimidine carbaldehyde 
• 101-55-3 4-Bromodiphenyl ether 
• 79-10-7 acrylic acid 
• 25268-16-0 Dichloro-methyl-(4-phenoxy-phenyl)-silane 

Relevant academic research and scientific papers

A synthetic method of ibutinib

The present invention provides a preparation method of ibutinib and its application, by optimizing the feeding ratio and reaction conditions, increasing the purification step of the intermediate, and the use of inorganic alkali instead of organic base as an acid binding agent, significantly reducing the impurity content of ibutinib synthetic intermediates and final products, especially the content of isomer impurities, to ensure the quality of drugs and clinical drug safety provides a strong guarantee.

Purification method of ibrutinib crystal form A

The invention discloses a purification method of an ibrutinib crystal form A. According to the method, the purification of the ibrutinib crystal form A is realized by utilizing crystal form conversion. The method comprises the following steps: dissolving a crude product of the ibrutinib crystal form A, adding a seed crystal E to obtain an ibrutinib crystal form E, dissolving the crystal form E, and crystallizing to obtain the ibrutinib crystal form A with higher purity. The purification method of the ibrutinib crystal form A is simple in process and high in yield, and the purification problem that impurities in the ibrutinib crystal form A are difficult to remove is solved.

Tunable Methacrylamides for Covalent Ligand Directed Release Chemistry

Targeted covalent inhibitors are an important class of drugs and chemical probes. However, relatively few electrophiles meet the criteria for successful covalent inhibitor design. Here we describe α-substituted methacrylamides as a new class of electrophiles suitable for targeted covalent inhibitors. While typically α-substitutions inactivate acrylamides, we show that hetero α-substituted methacrylamides have higher thiol reactivity and undergo a conjugated addition-elimination reaction ultimately releasing the substituent. Their reactivity toward thiols is tunable and correlates with the pKa/pKb of the leaving group. In the context of the BTK inhibitor ibrutinib, these electrophiles showed lower intrinsic thiol reactivity than the unsubstituted ibrutinib acrylamide. This translated to comparable potency in protein labeling, in vitro kinase assays, and functional cellular assays, with improved selectivity. The conjugate addition-elimination reaction upon covalent binding to their target cysteine allows functionalizing α-substituted methacrylamides as turn-on probes. To demonstrate this, we prepared covalent ligand directed release (CoLDR) turn-on fluorescent probes for BTK, EGFR, and K-RasG12C. We further demonstrate a BTK CoLDR chemiluminescent probe that enabled a high-throughput screen for BTK inhibitors. Altogether we show that α-substituted methacrylamides represent a new and versatile addition to the toolbox of targeted covalent inhibitor design.

Preparation of

The invention relates to a preparation process of. Specific examples of compound formula I (5 - amino -3 - (4 - phenoxyphenyl) - 1H - pyrazole -4 - carbonitrile) and compound formula II ((S)-1 - (3 - hydroxypiperidine -1 - yl) prop -2 - (-1 - phenoxypheny

Preparation method of ibrutinib

The invention relates to a preparation method of ibrutinib and an intermediate thereof, belonging to the field of medicinal chemistry. According to the preparation method, the ibrutinib can be obtained through condensation, condensation, substitution, substitution and Suzuki reaction by taking a low-cost material flow as a starting material; and the method is low in cost, free of light delay reaction, high in yield, good in selectivity, short in route, few in generated three wastes and suitable for industrial large-scale production.

Preparation method of ibrutinib intermediate

The invention relates to a preparation method of ibrutinib and an intermediate thereof, belonging to the field of medicinal chemistry. According to the preparation method, ibrutinib can be obtained through condensation, cyclization, substitution, Suzuki reaction and acylation reaction by taking a low-cost material flow as a starting material. The method is low in cost, free of light delay reaction, high in yield, good in selectivity, short in route, few in generated three wastes and suitable for industrial large-scale production.

PROCESSES AND INTERMEDIATES FOR PREPARING A BTK INHIBITOR

Disclosed is a process for the preparation of certain intermediates, e.g. process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, in an enantioenriched form, which intermediate and processes are useful in the preparation of a BTK inhibitor, such as ibrutinib.

Continuous low-cost preparation method of ibrutinib

The invention discloses a continuous low-cost preparation method of ibrutinib, belonging to the technical field of medicine synthesis. The method comprises the following steps: 1) carrying out a Mitsunobu reaction on a raw material, DIAD and triphenylphosphine to obtain an intermediate; 2) removing a Boc protecting group from a reaction solution, extracting unreacted 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine, and feeding and applying the unreacted 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine indiscriminately; 3) adding dichloromethane into a water phase obtained afterraw material extraction in the step 2), adjusting a pH value by using an aqueous sodium hydroxide solution, separating out an organic phase, carrying out drying by using anhydrous sodium sulfate, anddirectly adding triethylamine and acryloyl chloride for an acylation reaction; and 4) conducting washing, removing impurities, and performing evaporating to remove solvents to obtain ibrutinib. The preparation method of the invention overcomes the defects of large residual quantity of raw materials, excessive use of triphenylphosphine oxide, high cost and the like in the prior art, has the advantages of high comprehensive yield, low production cost, environment friendliness and continuity, and is suitable for industrial production.

Synthetic method of high-purity ibrutinib

The invention relates to a synthetic method of high-purity ibrutinib, and belongs to the technical field of pharmaceutical chemicals. The synthetic method of ibrutinib comprises the following steps: firstly, reacting an acyl halide derivative III with an alkaline compound IV, and further reacting with a formula II to obtain high-purity ibrutinib. The synthetic method of ibrutinib can effectively reduce related substance impurities V, is simple and convenient to operate, mild in reaction and high in purity, and is convenient for industrial scale-up production.

Synthesis method of ibrutinib

The invention relates to the technical field of medicine synthesis, in particular to a synthesis method of ibrutinib. In the prior art, the purity and yield of synthesized ibrutinib are not high enough, the product quality is influenced by low purity, and raw material waste and high industrial production cost are caused by low yield. Based on the above problems, the invention provides a synthesismethod of ibrutinib. The method comprises the following steps of: preparing a high-purity intermediate M3, carrying out acylation reaction on the high-purity intermediate M3 and acryloyl chloride under alkaline conditions, and carrying out a series of purification steps to obtain high-purity and high-yield ibrutinib, thereby enhancing the product quality and greatly lowering the raw material wasteand industrial production cost.