Key intermediates for production of selective PI3K inhibitor

A technology of intermediates and inhibitors, applied in the fields of compounds containing elements of Group 3/13 of the periodic table, organic chemistry, chemical instruments and methods, etc., can solve the problems of large amount of butyllithium, low reaction temperature, and high equipment requirements , to achieve the effect of low cost, simplified reaction steps and broad market prospects

Inactive Publication Date: 2018-03-13
上海厚博生物科技有限公司
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Problems solved by technology

In the synthesis process, n-butyllithium needs to be used for substitution, and the reaction temperature is as low as -78°C. It will consume a lot of energy during the production scale-up, and the requirements for equipment are also high. At the same time, the amount of butyllithium is also large, not better

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  • Key intermediates for production of selective PI3K inhibitor
  • Key intermediates for production of selective PI3K inhibitor
  • Key intermediates for production of selective PI3K inhibitor

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Embodiment Construction

[0030] The technical solution of this patent will be further described in detail below in conjunction with specific embodiments.

[0031] see Figure 1-3 , a series of key intermediates for the production of selective PI3K inhibitors, its synthetic route is: Specifically include the following steps:

[0032] (1) Dehydration reaction of 2-amino-4-trifluoromethyl-5-bromopyridine and 2.5-hexanedione in the presence of p-toluenesulfonic acid dehydration to protect the amino group.

[0033] (2) The amino protection of 2-amino-4-trifluoromethyl-5-bromopyridine is carried out in the solvent toluene or benzene or xylene.

[0034] (3) The intermediate after amino protection is successively reacted with Grignard reagent and boronate reagent to obtain the key intermediate of pinacol borate, which is coupled with dimorpholine chlorine substituted pyrimidine by suzuki reaction, and then removed Amino protection affords 5-[2,6-bis(4-morpholinyl)-4-pyrimidinyl]-4-(trifluoromethyl)-2-pyri...

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Abstract

The invention discloses a series of key intermediates for production of a selective PI3K inhibitor. The structural formula of the key intermediates is shown in the description. The synthesis process of the key intermediates prevents complex processes, simplifies the reaction steps, utilizes easily available raw materials, utilizes mild reactions, realizes a low cost, is suitable for industrializedproduction and has a wide market prospect.

Description

technical field [0001] The invention relates to the field of pharmacy, in particular to a series of key intermediates for producing selective PI3K inhibitors. Background technique [0002] 5-[2,6-bis(4-morpholinyl)-4-pyrimidinyl]-4-(trifluoromethyl)-2-pyridinylamine is a selective PI3K inhibitor developed by pharmaceutical giant Novartis, English The name is Buparlisib, code-named BKM120 or NVP-BKM120. BKM120 has anti-proliferative activity when acting on cell lines deregulated by PI3K, including A2780, U87MG, MCF7 and DU145, with GI50 of 0.1-0.7nM (Burger MT, et al.ACS Med Chem Lett, 2011,2(10), 774–779). BKM120 induces apoptosis in multiple myeloma cells (ARP1, ARK, MM.1S, MM1.R and U266), resulting in increased G1 phase cells and decreased S phase cells. BKM120 induces apoptosis in CD138+ primary MM cells and is less toxic to CD138- stromal cells. BKM120 can cause upregulation of BimS and downregulation of XIAP. (Zheng Y, et al. J Mol Med (Berl), 2011 Dec 30.) BKM120...

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/04C07F5/02
Inventor 陈力赵跃谭学优万新锋陈晨
Owner 上海厚博生物科技有限公司
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