([2-chloro-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-4-yl]methyl)(imino)methyl-lambda6-sulfanone

• 分子结构分类: 有机化合物 - 有机氮化合物
• 英文名称: ([2-chloro-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-4-yl]methyl)(imino)methyl-lambda6-sulfanone
• 英文别名: [2-chloro-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-4-yl]methyl(imino)methyloxo-λ6-sulfane；[2-chloro-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-4-yl]methyl-imino-methyl-oxo-lambda6-sulfane；[2-chloro-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-4-yl]methyl-imino-methyl-oxo-λ6-sulfane
• 化学式: C₁₁H₁₇ClN₄O₂S
• 分子量: 304.801
• InChiKey: HDQVCDMIFPIMDX-OZUZKCMBSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  19
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.64
• 拓扑面积：
  87.6
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  ([2-chloro-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-4-yl]methyl)(imino)methyl-lambda6-sulfanone 在 (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride 、 四丁基溴化铵 、 potassium carbonate 、 potassium hydroxide 作用下， 以 乙醇 、 水 为溶剂， 反应 3.5h， 生成 AZD6738
  参考文献：
  名称：

  Development and Scale-up of a Route to ATR Inhibitor AZD6738

  摘要：

  AZD6738 is currently being tested in multiple phase I/II trials for the treatment of cancer. Its structure, comprising a pyrimidine core decorated with a chiral morpholine, a cyclopropyl sulfoximine, and an azaindole, make it a challenging molecule to synthesize on a large scale. We describe the evolution of the chemical processes, following the manufacture of AZD6738 from the initial scale-up through to multikilos on plant scale. During this evolution, we developed a biocatalytic process to install the sulfoxide with high enantioselectivity, followed by introduction of the cyclopropyl group first in batch, then in a continuous flow plate reactor, and finally through a series of continuous stirred tank reactors. The final plant scale process to form AZD6738 was operated on 46 kg scale with an overall yield of 18%. We discuss the impurities formed throughout the process and highlight the limitations of this route for further scale-up.

  DOI：

  10.1021/acs.oprd.9b00075
• 作为产物：
  描述：

  2,6-二氯嘧啶-4-甲酸甲酯 在 sodium periodate 、 锂硼氢 、 rhodium(II) acetate dimer 、 碘苯二乙酸 、 potassium carbonate 、 三乙胺 、 lithium iodide 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 甲醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 93.5h， 生成 ([2-chloro-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-4-yl]methyl)(imino)methyl-lambda6-sulfanone
  参考文献：
  名称：

  [EN] SUBSTITUTED PYRROLOPYRIDINES AS ATR INHIBITORS
  [FR] PYRROLOPYRIDINES SUBSTITUÉES UTILISÉES EN TANT QU'INHIBITEURS D'ATR

  摘要：

  披露包括公式(I)中的化合物，其中A、W、m、R5、R6、R7和R8的定义如下。还披露了一种使用这些化合物治疗肿瘤性疾病的方法。

  公开号：

  WO2019050889A1

文献信息

• CHEMICAL COMPOUNDS
  申请人：Foote Kevin Michael

  公开号：US20110306613A1

  公开（公告）日：2011-12-15

  There is provided pyrimidinyl compounds of Formula (I), wherein: R 2 is or pharmaceutically acceptable salts thereof, processes for their preparation, pharmaceutical compositions containing them and their use in therapy.

  提供了化合物的化学式（I）， 其中： R 2 是吗 或其药用盐，其制备方法，含有它们的药物组合物以及它们在治疗中的用途。
• [EN] SUBSTITUTED PYRROLOPYRIDINES AS ATR INHIBITORS<br/>[FR] PYRROLOPYRIDINES SUBSTITUÉES UTILISÉES EN TANT QU'INHIBITEURS D'ATR
  申请人：BLUEVALLEY PHARMACEUTICAL LLC

  公开号：WO2019050889A1

  公开（公告）日：2019-03-14

  The disclosure includes compounds of Formula (I) wherein A, W, m, R5, R6, R7, and R8, are defined herein. Also disclosed is a method for treating a neoplastic disease with these compounds.

  披露包括公式(I)中的化合物，其中A、W、m、R5、R6、R7和R8的定义如下。还披露了一种使用这些化合物治疗肿瘤性疾病的方法。
• [EN] MORPHOLINO PYRIMIDINES AND THEIR USE IN THERAPY<br/>[FR] MORPHOLINOPYRIMIDINES ET LEUR UTILISATION EN THÉRAPIE
  申请人：ASTRAZENECA AB

  公开号：WO2011154737A1

  公开（公告）日：2011-12-15

  There is provided pyrimidinyl compounds of Formula (I), wherein R2 is (1) or pharmaceutically acceptable salts thereof, processes for their preparation, pharmaceutical compositions containing them and their use in therapy.

  提供了式(I)的嘧啶基化合物，其中R2为(1)或其药学上可接受的盐，其制备方法，含有它们的制药组合物以及它们在治疗中的应用。
• Chemical Compounds
  申请人：AstraZeneca AB

  公开号：US20150164908A1

  公开（公告）日：2015-06-18

  There is provided pyrimidinyl compounds of Formula (I), wherein: R 2 is or pharmaceutically acceptable salts thereof, processes for their preparation, pharmaceutical compositions containing them and their use in therapy.

  提供了式（I）的嘧啶基化合物，其中：R2是其药学上可接受的盐，其制备方法，包含它们的药物组合物以及它们在治疗中的用途。
• Development of a Continuous Flow Sulfoxide Imidation Protocol Using Azide Sources under Superacidic Conditions
  作者：Bernhard Gutmann、Petteri Elsner、Anne O’Kearney-McMullan、William Goundry、Dominique M. Roberge、C. Oliver Kappe

  DOI：10.1021/acs.oprd.5b00217

  日期：2015.8.21

  The development of a continuous flow sulfoxide imidation protocol for a pharmaceutically relevant target molecule is described. Sulfoxide imidation is a key step in the preparation of certain ATR ldnase inhibitors. Reactions with NaN3 or TMSN3 and concentrated sulfuric acid under literature conditions provided low conversions and poor selectivities. In contrast, reactions employing fuming sulfuric acid afforded the target sulfoximine with a selectivity of similar to 90% after a reaction time of only 10-15 min at 50 degrees C. The imidation reaction using TMSN3 as reagent was successfully performed in a flow reactor utilizing CH2Cl2/H2SO4 biphasic conditions. The mixture was subsequently quenched in-line with H2O. Phase separation, neutralization, and re-extraction with an organic solvent furnished the product in excellent purity and good yields, albeit with loss of chirality.