(aR,3aS,4S,6S,7aR)-六氢-3a,8,8-三甲基-alpha-(2-甲基丙基)-4,6-甲桥-1,3,2-苯并二氧硼烷-2-甲胺 2,2,2-三氟乙酸盐 | 179324-87-9

• 物质功能分类: 医药中间体 - 原料药中间体
• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 异戊烯醇脂质
• 中文名称: (aR,3aS,4S,6S,7aR)-六氢-3a,8,8-三甲基-alpha-(2-甲基丙基)-4,6-甲桥-1,3,2-苯并二氧硼烷-2-甲胺 2,2,2-三氟乙酸盐
• 中文别名: AR,3AS,4S,6S,7AR)-六氢-3A,8,8-三甲基-ALPHA-(2-甲基丙基)-4,6-甲桥-1,3,2-苯并二氧硼烷-2-甲胺2,2,2-三氟乙酸盐,保特佐米(硼替佐米)中间体；(R)-六氢-三甲基-(2-甲基丙基)-甲桥-苯并二氧硼烷-甲胺-三氟乙酸盐；(R)-1-氨基-3-甲基丁基-1-硼酸蒎烷二醇酯三氟醋酸盐；(R)-1-氨基-3-甲基丁基硼酸蒎烷二醇酯三氟乙酸盐；(aR,3aS,4S,6S,7aR)-六氢-3a,8,8-三甲基-alpha-(2-甲基丙基)-4,6-甲桥-1,3,2-苯并二氧硼烷-2-甲胺2,2,2-三氟乙酸盐；(1R)-(s)-蒎二醇1-三氟乙酸铵-3-甲基丁烷-1-硼；硼替佐米中间体；(ALPHAR,3AS,4S,6S,7AR)-六氢-3A,8,8-三甲基-ALPHA-(2-甲基丙基)-4,6-甲撑-1,3,2-苯并二氧杂BOROLE-2-甲胺2,2,2-三氟乙酸酯；(R)-1-氨基-3-甲基丁基硼酸蒎烷二醇酯三氟醋酸盐；硼替佐米中间体1；硼替佐米中间体一;；硼替佐米中间体一；(aR,3aS,4S,6S,7aR)-六氢-3a,8,8-三甲基-α-(2-甲基丙基)-4,6-甲桥-1,3,2-苯并二氧硼烷-2-甲胺 2,2,2-三氟乙酸盐
• 英文名称: (1R)-3-methyl-1-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methano-1,3,2-benzodioxaborol-2-yl]butan-1-amine trifluoroacetate
• 英文别名: (R)-boroleucine-(1S,2S,3R,5S)-(+)-2,3-pinanediol ester trifluoroacetate；(aR,3aS,4S,6S,7aR)-hexahydro-3a,8,8-trimethyl-α-(2-methylpropyl)-4,6-methano-1,3,2-benzodioxaborole-2-methanamine 2,2,2-trifluoroacetate；(1S,2S,3R,5S)-pinanediol leucine boronate trifluoroacetate salt；(R)-3-methyl-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butan-1-aminium 2,2,2-trifluoroacetate；[(1R)-3-methyl-1-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02,6]decan-4-yl]butyl]azanium;2,2,2-trifluoroacetate
• CAS: 179324-87-9
• 化学式: C₂HF₃O₂*C₁₅H₂₈BNO₂
• 分子量: 379.228
• InChiKey: SRFQKJZNJYTMNI-CDVUYJLHSA-N

物化性质

• 熔点：
  157-159°C
• 溶解度：
  乙醇（微溶）、甲醇（微溶）

计算性质

• 辛醇/水分配系数(LogP)：
  3.26
• 重原子数：
  26
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.94
• 拓扑面积：
  81.8
• 氢给体数：
  2
• 氢受体数：
  8

安全信息

• 危险品运输编号：
  NONH for all modes of transport
• 危险性防范说明：
  P261,P280,P305+P351+P338
• 危险性描述：
  H302,H315,H319,H332,H335
• 储存条件：
  | 温度 | 惰性气体 | | ---- | -------- | | 2-8°C | |

SDS

Material Safety Data Sheet

---

Section 1. Identification of the substance
Product Name: (R)-Boroleucine-(1S,2S,3R,5S)-(+)-pinanediol ester trifluoroacetate
Synonyms:

---

Section 2. Hazards identification
Harmful by inhalation, in contact with skin, and if swallowed.

---

Section 3. Composition/information on ingredients.
Ingredient name: (R)-Boroleucine-(1S,2S,3R,5S)-(+)-pinanediol ester trifluoroacetate
CAS number: 179324-87-9

---

Section 4. First aid measures
Skin contact: Immediately wash skin with copious amounts of water for at least 15 minutes while removing
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.
Ingestion: Wash out mouth with copious amounts of water for at least 15 minutes. Seek medical attention.

---

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.

---

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.

---

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.
Store in closed vessels, under −20◦C.
Storage:

---

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.

---

Section 9. Physical and chemical properties
Appearance: Not specified
Boiling point: No data
No data
Melting point:
Flash point: No data
Density: No data
Molecular formula: C15H28BNO2.C2HF3O2
Molecular weight: 379.2

---

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 fluoride.

---

Section 11. Toxicological information
No data.

---

Section 12. Ecological information
No data.

---

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.

---

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

---

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.

---

SECTION 16 - ADDITIONAL INFORMATION
N/A

制备方法与用途

用途：(aR,3aS,4S,6S,7aR)-六氢-3a,8,8-三甲基-alpha-(2-甲基丙基)-4,6-甲桥-1,3,2-苯并二氧硼烷-2-甲胺 2,2,2-三氟乙酸盐是一种医药中间体，可用于抗肿瘤药物的合成研究。

反应信息

• 作为反应物：
  描述：

  (aR,3aS,4S,6S,7aR)-六氢-3a,8,8-三甲基-alpha-(2-甲基丙基)-4,6-甲桥-1,3,2-苯并二氧硼烷-2-甲胺 2,2,2-三氟乙酸盐 在 盐酸 、 异丁基硼酸 、 O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate 、 N-乙基异丙基胺 、 N,N-二异丙基乙胺 作用下， 以 二氯甲烷 、 水 、 乙腈 为溶剂， 反应 2.0h， 生成 硼替佐米
  参考文献：
  名称：

  [EN] AN IMPROVED PROCESS FOR THE PREPARATION OF BORONIC ACID ESTERS
  [FR] PROCÉDÉ AMÉLIORÉ POUR LA PRÉPARATION D'ESTERS D'ACIDE BORONIQUE

  摘要：

  本发明涉及一种改进的制备化合物的方法，该化合物的化学式为（I），其中PG1可以独立地选择自叔丁氧羰基（Boc）、邻苯二甲酰基、9-芴甲氧羰基（Fmoc）、三苯甲基（Trityl）、羧苄基（Cbz）、三氟乙酰基、苄基（Bn）、苄亚甲基、甲磺酰基（Mesyl）、甲苯磺酰基（Tosyl）或酰基；其固体分离和用于制备化合物的用途，特别是化合物的化学式（IV），即[(1R)-3-甲基-1-[(2S)-1-氧代-3-苯基-2-[(吡嗪羰基)氨基]丙基]氨基丁基]硼酸，其手性纯度超过99.95%，通过HPLC测量。

  公开号：

  WO2018150386A1
• 作为产物：
  描述：

  (1S,2S,3R,5S)-(+)-2,3-蒎烷二醇 在 正丁基锂 、 zinc(II) chloride 、 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 为溶剂， 反应 6.25h， 生成 (aR,3aS,4S,6S,7aR)-六氢-3a,8,8-三甲基-alpha-(2-甲基丙基)-4,6-甲桥-1,3,2-苯并二氧硼烷-2-甲胺 2,2,2-三氟乙酸盐
  参考文献：
  名称：

  肽类蛋白酶体抑制剂的系统比较突出显示了α-酮酰胺亲电试剂是一种可逆的可逆铅基序。

  摘要：

  遍在蛋白-蛋白酶体系统（UPS）已被学术界和制药业成功地靶向用于肿瘤学和免疫学领域。典型的蛋白酶体抑制剂基于肽骨架，该肽骨架具有亲电的C末端，通过它们可与活性蛋白水解位点发生反应。尽管肽部分在亚基选择性方面引起了广泛关注，但化合物的靶标特异性和生物稳定性在很大程度上由反应性战斗部决定。在这项研究中，我们已经通过结合体外，体内和结构方法对亲电子试剂进行了系统的研究，以揭示功能和化学反应性改变的含义。从而，

  DOI：

  10.1002/anie.201308984
• 作为试剂：
  描述：

  (aR,3aS,4S,6S,7aR)-六氢-3a,8,8-三甲基-alpha-(2-甲基丙基)-4,6-甲桥-1,3,2-苯并二氧硼烷-2-甲胺 2,2,2-三氟乙酸盐 、 N-(2,5-二氯苯甲酰基)甘氨酸 在 (aR,3aS,4S,6S,7aR)-六氢-3a,8,8-三甲基-alpha-(2-甲基丙基)-4,6-甲桥-1,3,2-苯并二氧硼烷-2-甲胺 2,2,2-三氟乙酸盐 作用下， 生成 2,5-dichloro-N-[2-[[3-methyl-1-(2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02,6]decan-4-yl)butyl]amino]-2-oxoethyl]benzamide
  参考文献：
  名称：

  [EN] BORONATE ESTER COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS THEREOF
  [FR] COMPOSÉS DE BORATES ESTERS ET COMPOSITIONS PHARMACEUTIQUES CONTENANT DES COMPOSÉS

  摘要：

  本发明提供了一种新型化合物，可用作蛋白酶体抑制剂。本发明还提供了包含该化合物的制药组合物以及使用该组合物治疗各种疾病的方法。

  公开号：

  WO2009154737A1

文献信息

• Design, synthesis and docking studies of novel dipeptidyl boronic acid proteasome inhibitors constructed from αα- and αβ-amino acids
  作者：Jingmiao Shi、Meng Lei、Wenkui Wu、Huayun Feng、Jia Wang、Shanshan Chen、Yongqiang Zhu、Shihe Hu、Zhaogang Liu、Cheng Jiang

  DOI：10.1016/j.bmcl.2016.03.007

  日期：2016.4

  series of novel dipeptidyl boronic acid proteasome inhibitors constructed from αα- and αβ-amino acids were designed and synthesized. Their structures were elucidated by 1H NMR, 13C NMR, LC–MS and HRMS. These compounds were evaluated for their β5 subunit inhibitory activities of human proteasome. The results showed that dipeptidyl boronic acid inhibitors composed of αα-amino acids were as active as bortezomib

  设计并合成了一系列由αα-和αβ-氨基酸构建的新型二肽基硼酸蛋白酶体抑制剂。通过1 H NMR，13 C NMR，LC-MS和HRMS阐明了它们的结构。评价这些化合物对人蛋白酶体的β5亚基抑制活性。结果表明，由αα-氨基酸组成的二肽基硼酸抑制剂的活性与硼替佐米相同。有趣的是，那些衍生自αβ-氨基酸的酶的活性完全丧失了。在所有抑制剂中，化合物22（IC 50  = 4.82 nM）对蛋白酶体活性的抑制作用最强。化合物22还是对三种具有IC 50的MM细胞系最有活性的在抑制细胞生长试验中，其值小于5 nM。分子对接研究表明，22个蛋白非常适合蛋白酶体的β5亚基活性口袋。
• [EN] METHODS FOR PREPARING BORTEZOMIB AND INTERMEDIATES USED IN ITS MANUFACTURE<br/>[FR] PROCÉDÉ DE PRÉPARATION DU BORTÉZOMIB ET INTERMÉDIAIRES UTILISÉS DANS SA PRÉPARATION
  申请人：PLIVA HRVATSKA D O O

  公开号：WO2009004350A1

  公开（公告）日：2009-01-08

  Provided herein are methods for preparing bortezomib and intermediates useful in the preparation of bortezomib. The present methods unexpectedly provide superior yields and purities, including optical purities, of bortezomib and the intermediates for the preparation of bortezomib.

  本文提供了制备硼替佐米及在制备硼替佐米过程中有用的中间体的方法。目前的方法意外地提供了硼替佐米和用于制备硼替佐米的中间体的优越产量和纯度，包括光学纯度。
• De Novo Design of Boron-Based Peptidomimetics as Potent Inhibitors of Human ClpP in the Presence of Human ClpX
  作者：Joanne Tan、Julie J. Grouleff、Yulia Jitkova、Diego B. Diaz、Elizabeth C. Griffith、Wenjie Shao、Anastasia F. Bogdanchikova、Gennady Poda、Aaron D. Schimmer、Richard E. Lee、Andrei K. Yudin

  DOI：10.1021/acs.jmedchem.9b00878

  日期：2019.7.11

  facilitate the discovery of bioactive aminoboronic acids. Herein, we have augmented this capability with a de novo library design and a virtual screening platform modified for covalent ligands. This technique has allowed us to rapidly design and identify a series of α-aminoboronic acids as the first inhibitors of human ClpXP, which is responsible for the degradation of misfolded proteins.

  由于硼具有调节酶功能的能力，硼酸已引起合成化学和药物化学家的关注。最近，我们证明了含硼的两性构件可以促进生物活性氨基硼酸的发现。在此，我们通过从头开始的文库设计和针对共价配体进行了修改的虚拟筛选平台来增强了此功能。这项技术使我们能够快速设计和鉴定一系列α-氨基硼酸作为人类ClpXP的第一种抑制剂，这是导致错误折叠的蛋白质降解的原因。
• Benzoisothiazolone Organo/Copper-Cocatalyzed Redox Dehydrative Construction of Amides and Peptides from Carboxylic Acids using (EtO)₃P as the Reductant and O₂ in Air as the Terminal Oxidant
  作者：Lanny S. Liebeskind、Pavankumar Gangireddy、Matthew G. Lindale

  DOI：10.1021/jacs.6b03168

  日期：2016.6.1

  Carboxylic acids and amine/amino acid reactants can be converted to amides and peptides at neutral pH within 5-36 h at 50 °C using catalytic quantities of a redox-active benzoisothiazolone and a copper complex. These catalytic "oxidation-reduction condensation" reactions are carried out open to dry air using O2 as the terminal oxidant and a slight excess of triethyl phosphite as the reductant. Triethyl

  使用催化量的具有氧化还原活性的苯并异噻唑酮和铜络合物，羧酸和胺/氨基酸反应物可以在 50°C 下在 5-36 小时内在中性 pH 值下转化为酰胺和肽。这些催化“氧化-还原缩合”反应在干燥空气中进行，使用O 2 作为末端氧化剂和稍微过量的亚磷酸三乙酯作为还原剂。磷酸三乙酯是容易去除的副产物。这些易于运行的催化反应为 CN 键的酰化构建提供了实用且经济的方法。
• Design, synthesis, in vitro and in vivo evaluation, and structure-activity relationship (SAR) discussion of novel dipeptidyl boronic acid proteasome inhibitors as orally available anti-cancer agents for the treatment of multiple myeloma and mechanism studies
  作者：Meng Lei、Huayun Feng、Enhe Bai、Hui Zhou、Jia Wang、Jingmiao Shi、Xueyuan Wang、Shihe Hu、Zhaogang Liu、Yongqiang Zhu

  DOI：10.1016/j.bmc.2018.06.020

  日期：2018.8

  A series of novel dipeptidyl boronic acid inhibitors of 20S proteasome were designed and synthesized. Aliphatic groups at R1 position were designed for the first time to fully understand the SAR (structure–activity relationship). Among the screened compounds, novel inhibitor 5c inhibited the CT-L (chymotrypsin-like) activity with IC50 of 8.21 nM and the MM (multiple myeloma) cells RPMI8226, U266B and

  设计并合成了一系列新型的20S蛋白酶体二肽基硼酸抑制剂。首次设计R 1位置的脂族基团以充分了解SAR（结构-活性关系）。在筛选的化合物中，新型抑制剂5c抑制CT-L（胰凝乳蛋白酶样）活性，IC 50为8.21 nM，而MM（多发性骨髓瘤）细胞RPMI8226，U266B和ARH77增殖，IC 50为8.99、6.75和9.10 nM。与化合物MLN2238（市售MLN9708的生物活性形式）相比，它们分别显示出相似的体外活性。为了研究口服药物的可用性，化合物5c用酶促IC 50为6.74 nM酯化其前药6a，RPMI8226，U266B和ARH77细胞增殖IC 50分别为2.59、4.32和3.68 nM。此外，前药6a表现出良好的药代动力学特性，口服生物利用度为24.9％，与MLN9708相似（27.8％）。此外，在人ARH77异种移植小鼠模型中，化合物6a显示出良好的微粒体稳定性，并比