4-(6-氯嘧啶-4-基)吗啉 | 22177-92-0

• 物质功能分类: 医药中间体 - 嘧啶类化合物
• 分子结构分类: 有机化合物 - 有机氮化合物
• 中文名称: 4-(6-氯嘧啶-4-基)吗啉
• 中文别名: 4-(6-氯-4-嘧啶基)吗啉
• 英文名称: 4-(6-chloropyrimidin-4-yl)morpholine
• CAS: 22177-92-0
• 化学式: C₈H₁₀ClN₃O
• mdl: MFCD00466219
• 分子量: 199.64
• InChiKey: CFOBQJWOZVMWBR-UHFFFAOYSA-N

物化性质

• 熔点：
  149-150℃
• 沸点：
  366.0±42.0 °C(Predicted)
• 密度：
  1.320±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.2
• 重原子数：
  13
• 可旋转键数：
  1
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  38.2
• 氢给体数：
  0
• 氢受体数：
  4

安全信息

• 危险等级：
  IRRITANT
• 危险品标志：
  Xi
• 海关编码：
  2934999090
• 危险性防范说明：
  P280,P305+P351+P338
• 危险性描述：
  H302
• 储存条件：
  2-8°C，惰性气体

SDS

Material Safety Data Sheet

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Section 1. Identification of the substance
4-(6-Chloropyrimidin-4-yl)morpholine
Product Name:
Synonyms:

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Section 2. Hazards identification
Harmful by inhalation, in contact with skin, and if swallowed.
H315: Causes skin irritation
H319: Causes serious eye irritation
H335: May cause respiratory irritation
P261: Avoid breathing dust/fume/gas/mist/vapours/spray
Wear protective gloves/protective clothing/eye protection/face protection
P280:
P305+P351+P338: IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses if present
and easy to do – continue rinsing
P304+P340: IF INHALED: Remove victim to fresh air and keep at rest in a position comfortable for breathing
P405: Store locked up

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Section 3. Composition/information on ingredients.
4-(6-Chloropyrimidin-4-yl)morpholine
Ingredient name:
CAS number: 22177-92-0

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Section 4. First aid measures
Immediately wash skin with copious amounts of water for at least 15 minutes while removing
Skin contact:
contaminated clothing and shoes. If irritation persists, seek medical attention.
Eye contact: Immediately wash skin with copious amounts of water for at least 15 minutes. Assure adequate
flushing of the eyes by separating the eyelids with fingers. If irritation persists, seek medical
attention.
Inhalation: Remove to fresh air. In severe cases or if symptoms persist, seek medical attention.
Wash out mouth with copious amounts of water for at least 15 minutes. Seek medical attention.
Ingestion:

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Section 5. Fire fighting measures
In the event of a fire involving this material, alone or in combination with other materials, use dry
powder or carbon dioxide extinguishers. Protective clothing and self-contained breathing apparatus
should be worn.

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Section 6. Accidental release measures
Personal precautions: Wear suitable personal protective equipment which performs satisfactorily and meets local/state/national
standards.
Respiratory precaution: Wear approved mask/respirator
Hand precaution: Wear suitable gloves/gauntlets
Skin protection: Wear suitable protective clothing
Eye protection: Wear suitable eye protection
Methods for cleaning up: Mix with sand or similar inert absorbent material, sweep up and keep in a tightly closed container
for disposal. See section 12.
Environmental precautions: Do not allow material to enter drains or water courses.

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Section 7. Handling and storage
Handling: This product should be handled only by, or under the close supervision of, those properly qualified
in the handling and use of potentially hazardous chemicals, who should take into account the fire,
health and chemical hazard data given on this sheet.
Storage: Store in closed vessels.

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Section 8. Exposure Controls / Personal protection
Engineering Controls: Use only in a chemical fume hood.
Personal protective equipment: Wear laboratory clothing, chemical-resistant gloves and safety goggles.
General hydiene measures: Wash thoroughly after handling. Wash contaminated clothing before reuse.

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Section 9. Physical and chemical properties
Not specified
Appearance:
Boiling point: No data
Melting point: No data
Flash point: No data
Density: No data
Molecular formula: C8H10ClN3O
Molecular weight: 199.6

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Section 10. Stability and reactivity
Conditions to avoid: Heat, flames and sparks.
Materials to avoid: Oxidizing agents.
Possible hazardous combustion products: Carbon monoxide, nitrogen oxides, hydrogen chloride.

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Section 11. Toxicological information
No data.

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Section 12. Ecological information
No data.

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Section 13. Disposal consideration
Arrange disposal as special waste, by licensed disposal company, in consultation with local waste
disposal authority, in accordance with national and regional regulations.

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Section 14. Transportation information
Non-harzardous for air and ground transportation.

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Section 15. Regulatory information
No chemicals in this material are subject to the reporting requirements of SARA Title III, Section
302, or have known CAS numbers that exceed the threshold reporting levels established by SARA
Title III, Section 313.

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SECTION 16 - ADDITIONAL INFORMATION
N/A

反应信息

• 作为反应物：
  描述：

  4-(6-氯嘧啶-4-基)吗啉 在 一水合肼 作用下， 以 乙醇 为溶剂， 反应 16.0h， 以68%的产率得到4-(6-肼基-嘧啶-4-基)-吗啉
  参考文献：
  名称：

  Molidustat (BAY 85-3934) 的发现：一种用于治疗肾性贫血的小分子口服 HIF-脯氨酰羟化酶 (HIF-PH) 抑制剂

  摘要：

  缺氧诱导因子脯氨酰羟化酶（HIF-PH）的小分子抑制剂目前正在临床开发中，作为慢性肾病（CKD）相关贫血的新治疗选择。HIF-PH 的抑制模拟缺氧并导致促红细胞生成素 (EPO) 表达增加，从而增加红细胞生成。在此，我们描述了新型 2,4-二杂芳基-1,2-二氢-3 H-吡唑-3-酮类药物的发现、合成、结构-活性关系 (SAR) 和拟议的结合模式，作为口服生物可利用的 HIF- PH抑制剂贫血的治疗。对我们公司化合物库的高通量筛选确定 BAY-908 是一个有前景的热门产品。先导化合物优化计划最终鉴定出莫度司他 (BAY 85-3934)，这是一种新型小分子口服 HIF-PH 抑制剂。Molidustat 目前正在临床 III 期试验中研究作为 molidustat 钠用于治疗 CKD 患者贫血。

  DOI：

  10.1002/cmdc.201700783
• 作为产物：
  描述：

  吗啉 、 4,6-二氯嘧啶 以 水 为溶剂， 反应 16.0h， 以85%的产率得到4-(6-氯嘧啶-4-基)吗啉
  参考文献：
  名称：

  Molidustat (BAY 85-3934) 的发现：一种用于治疗肾性贫血的小分子口服 HIF-脯氨酰羟化酶 (HIF-PH) 抑制剂

  摘要：

  缺氧诱导因子脯氨酰羟化酶（HIF-PH）的小分子抑制剂目前正在临床开发中，作为慢性肾病（CKD）相关贫血的新治疗选择。HIF-PH 的抑制模拟缺氧并导致促红细胞生成素 (EPO) 表达增加，从而增加红细胞生成。在此，我们描述了新型 2,4-二杂芳基-1,2-二氢-3 H-吡唑-3-酮类药物的发现、合成、结构-活性关系 (SAR) 和拟议的结合模式，作为口服生物可利用的 HIF- PH抑制剂贫血的治疗。对我们公司化合物库的高通量筛选确定 BAY-908 是一个有前景的热门产品。先导化合物优化计划最终鉴定出莫度司他 (BAY 85-3934)，这是一种新型小分子口服 HIF-PH 抑制剂。Molidustat 目前正在临床 III 期试验中研究作为 molidustat 钠用于治疗 CKD 患者贫血。

  DOI：

  10.1002/cmdc.201700783

文献信息

• Discovery of a 3-(4-Pyrimidinyl) Indazole (MLi-2), an Orally Available and Selective Leucine-Rich Repeat Kinase 2 (LRRK2) Inhibitor that Reduces Brain Kinase Activity
  作者：Jack D. Scott、Duane E. DeMong、Thomas J. Greshock、Kallol Basu、Xing Dai、Joel Harris、Alan Hruza、Sarah W. Li、Sue-Ing Lin、Hong Liu、Megan K. Macala、Zhiyong Hu、Hong Mei、Honglu Zhang、Paul Walsh、Marc Poirier、Zhi-Cai Shi、Li Xiao、Gautam Agnihotri、Marco A. S. Baptista、John Columbus、Matthew J. Fell、Lynn A. Hyde、Reshma Kuvelkar、Yinghui Lin、Christian Mirescu、John A. Morrow、Zhizhang Yin、Xiaoping Zhang、Xiaoping Zhou、Ronald K. Chang、Mark W. Embrey、John M. Sanders、Heather E. Tiscia、Robert E. Drolet、Jonathan T. Kern、Sylvie M. Sur、John J. Renger、Mark T. Bilodeau、Matthew E. Kennedy、Eric M. Parker、Andrew W. Stamford、Ravi Nargund、John A. McCauley、Michael W. Miller

  DOI：10.1021/acs.jmedchem.7b00045

  日期：2017.4.13

  set out to develop LRRK2 inhibitors to test this hypothesis. A high throughput screen of our compound collection afforded a number of promising indazole leads which were truncated in order to identify a minimum pharmacophore. Further optimization of these indazoles led to the development of MLi-2 (1): a potent, highly selective, orally available, brain-penetrant inhibitor of LRRK2.

  富含亮氨酸的重复激酶2（LRRK2）是一种大型的多结构域蛋白，除其他区域外，还包含一个激酶结构域和GTPase结构域。具有在激酶结构域中获得功能突变（例如最普遍的G2019S突变）的个体与帕金森氏病（PD）发生的风险增加相关。鉴于这种抑制LRRK2激酶活性作为影响疾病进展的潜在手段的基因验证，我们的团队着手开发LRRK2抑制剂来验证这一假设。我们化合物收集物的高通量筛选提供了许多有前途的吲唑线索，这些线索被截短以鉴定最小的药效团。这些吲唑的进一步优化导致MLi-2（1）：一种有效的，高度选择性的，口服可得的LRRK2脑渗透抑制剂。
• Design and Discovery of <i>N</i>-(2-Methyl-5′-morpholino-6′-((tetrahydro-2<i>H</i>-pyran-4-yl)oxy)-[3,3′-bipyridin]-5-yl)-3-(trifluoromethyl)benzamide (RAF709): A Potent, Selective, and Efficacious RAF Inhibitor Targeting RAS Mutant Cancers
  作者：Gisele A. Nishiguchi、Alice Rico、Huw Tanner、Robert J. Aversa、Benjamin R. Taft、Sharadha Subramanian、Lina Setti、Matthew T. Burger、Lifeng Wan、Victoriano Tamez、Aaron Smith、Yan Lou、Paul A. Barsanti、Brent A. Appleton、Mulugeta Mamo、Laura Tandeske、Ina Dix、John E. Tellew、Shenlin Huang、Lesley A. Mathews Griner、Vesselina G. Cooke、Anne Van Abbema、Hanne Merritt、Sylvia Ma、Kalyani Gampa、Fei Feng、Jing Yuan、Yingyun Wang、Jacob R. Haling、Sepideh Vaziri、Mohammad Hekmat-Nejad、Johanna M. Jansen、Valery Polyakov、Richard Zang、Vijay Sethuraman、Payman Amiri、Mallika Singh、Emma Lees、Wenlin Shao、Darrin D. Stuart、Michael P. Dillon、Savithri Ramurthy

  DOI：10.1021/acs.jmedchem.6b01862

  日期：2017.6.22

  cells. To date, many small molecule approaches are under investigation to target CRAF, yet kinase-selective and cellular potent inhibitors remain challenging to identify. Herein, we describe 14 (RAF709) [Aversa, Biaryl amide compounds as kinase inhibitors and their preparation. WO 2014151616, 2014], a selective B/C RAF inhibitor, which was developed through a hypothesis-driven approach focusing on drug-like

  RAS致癌基因已涉及超过30％的人类癌症，均代表高度未满足的医疗需求。在基因工程小鼠模型和人类肿瘤细胞中已经建立了对KRAS突变肿瘤中对CRAF激酶的精确依赖性。迄今为止，许多针对CRAF的小分子方法正在研究中，但是激酶选择性抑制剂和细胞有效抑制剂的鉴定仍然具有挑战性。在此，我们描述14（RAF709）[Aversa，联芳酰胺化合物作为激酶抑制剂及其制备方法。WO 2014151616， [2014]，一种选择性的B / C RAF抑制剂，通过假设驱动的方法开发，该方法侧重于药物样特性。在药物化学研究中遇到的一个关键挑战是在KRAS突变肿瘤细胞系中保持良好的溶解度和有效的细胞活性（pMEK的抑制和增殖）之间的平衡。我们研究了铅分子7的小分子晶体结构，并假设破坏晶体堆积会提高溶解度，从而导致从N-甲基吡啶酮转变为四氢吡喃基氧基-吡啶衍生物。在KRAS突变异种移植模型中，有14种被证明是可溶的，激酶选择性的和有效的。
• HETEROCYCLIC COMPOUND
  申请人：TAKEDA PHARMACEUTICAL COMPANY LIMITED

  公开号：US20160159773A1

  公开（公告）日：2016-06-09

  The present invention provides an agent for the prophylaxis or treatment of autoimmune diseases (e.g., psoriasis, rheumatoid arthritis, inflammatory bowel disease, Sjogren's syndrome, Behcet's disease, multiple sclerosis, systemic lupus erythematosus etc.) and the like, which has a superior Tyk2 inhibitory action. The present invention relates to a compound represented by the formula wherein each symbol is as defined in the specification, or a salt thereof.

  本发明提供了一种用于预防或治疗自身免疫性疾病（例如牛皮癣、类风湿关节炎、炎症性肠病、干燥综合征、贝赫切特病、多发性硬化症、系统性红斑狼疮等）等的药剂，其具有优越的Tyk2抑制作用。 本发明涉及一种由下式表示的化合物 其中每个符号如规范中定义的，或其盐。
• [EN] OXADIAZOLYLTHIOPHENE DERIVATIVES USEFUL AS HISTONE DEACETYLASE INHIBITORS<br/>[FR] DÉRIVÉS D'OXADIAZOLYLTHIOPHÈNE À UTILISER EN TANT QU'INHIBITEURS DE L'HISTONE DÉSACÉTYLASE
  申请人：KARUS THERAPEUTICS LTD

  公开号：WO2019166824A1

  公开（公告）日：2019-09-06

  A compound of Formula I : (I) or a pharmaceutically acceptable salt thereof, wherein: each R' is QR1; each Q is independently selected from a bond, -C1-C10 alkylene, -C2-C10 alkenylene, -C(O)-, -C(O)O-, -C(O)N(R1)-, -C(O)N(R1)SO2- -N(R1)C(O)-, - N(R1)-, -N(SO2(R1)), -N(R1)SO2- -C(O)NR4R5-, -N(R4R5)C(O)-, -N(R4R5)- - S-, -SO-, -SO2-, -S(O)O-, -SO2N(R1)- and -O-; each R1 is independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C1-C10 haloalkyl, C1-C10 heteroalkyl, aryl, heteroaryl, C3-C10 cycloalkyl, -(C1-C10 alkylene)-C3-C10 cycloalkyl, halogen, cyano, C1-C10 alkylene- aryl, C1-C10 alkylene heteroaryl, C1-C10 heterocycloalkyl and -(C1-C10 alkylene)- C1-C10 heterocycloalkyl. The compounds are inhibitors of HDAC and therefore have potential utility in the therapy of a number of conditions including cancer and inflammation.

  一种Formula I的化合物：(I)或其药学上可接受的盐，其中：每个R'是QR1；每个Q独立地选自键，-C1-C10烷基，-C2-C10烯基，-C(O)-，-C(O)O-，-C(O)N(R1)-，-C(O)N(R1)SO2-，-N(R1)C(O)-，-N(R1)-，-N(SO2(R1))，-N(R1)SO2-，-C(O)NR4R5-，-N(R4R5)C(O)-，-N(R4R5)-，-S-，-SO-，-SO2-，-S(O)O-，-SO2N(R1)-和-O-；每个R1独立地选自H，C1-C10烷基，C2-C10烯基，C2-C10炔基，C1-C10卤代烷基，C1-C10杂原子烷基，芳基，杂芳基，C3-C10环烷基，-(C1-C10烷基)-C3-C10环烷基，卤素，氰基，C1-C10烷基-芳基，C1-C10烷基-杂原子芳基，C1-C10杂环烷基和-(C1-C10烷基)-C1-C10杂环烷基。这些化合物是HDAC的抑制剂，因此在治疗包括癌症和炎症在内的多种疾病中具有潜在用途。
• METHOD FOR THE PREPARATION OF TRIAZOLE COMPOUNDS
  申请人：Militzer Hans-Christian

  公开号：US20150087827A1

  公开（公告）日：2015-03-26

  The present invention relates to a process for preparing 1-[6-(morpholin-4-yl)pyrimidin-4-yl]-4-(1H-1,2,3-triazol-1-yl)-1H-pyrazol-5-ol (I—enol form) or 2-[6-(morpholin-4-yl)pyrimidin-4-yl]-4-(1H-1,2,3-triazol-1-yl)-1,2-dihydro-3H-pyrazol-3-one (I—keto form) and sodium 1-[6-(morpholin-4-yl)pyrimidin-4-yl]-4-(1H-1,2,3-triazol-1-yl)-1H-pyrazol-5-olate (II) from 1,2,3-triazole (III), methyl bromoacetate (IV-Me-Br) or ethyl bromoacetate (IV-Et-Br), 4,6-dichloropyrimidine (VIII), morpholine (IX) and hydrazine (XII).

  该发明涉及一种制备1-[6-(吗啉-4-基)嘧啶-4-基]-4-(1H-1,2,3-三唑-1-基)-1H-吡唑-5-醇（I—烯醇形式）或2-[6-(吗啉-4-基)嘧啶-4-基]-4-(1H-1,2,3-三唑-1-基)-1,2-二氢-3H-吡唑-3-酮（I—酮形式）和钠1-[6-(吗啉-4-基)嘧啶-4-基]-4-(1H-1,2,3-三唑-1-基)-1H-吡唑-5-醇酸盐（II）的过程，该过程从1,2,3-三唑（III）、溴乙酸甲酯（IV-Me-Br）或溴乙酸乙酯（IV-Et-Br）、4,6-二氯嘧啶（VIII）、吗啉（IX）和肼（XII）中进行。