3-氟-4-(三氟甲基)苯甲醛 | 339-72-0

• 物质功能分类: 原料药 - 抗生素类药物 - 其它抗生素类药
• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 中文名称: 3-氟-4-(三氟甲基)苯甲醛
• 中文别名: 环丝氨酸；L-环丝氨酸；左环丝氨酸；L-4-氨基-3-异噁唑烷酮；D-4-异唑基酮；草霉素PA-9
• 英文名称: L-cycloserine
• 英文别名: levcycloserine；(S)-(-)-cycloserine；(4S)-4-azaniumyl-4,5-dihydro-1,2-oxazol-3-olate
• CAS: 339-72-0
• 化学式: C₃H₆N₂O₂
• 分子量: 102.093
• InChiKey: DYDCUQKUCUHJBH-REOHCLBHSA-N

物化性质

• 熔点：
  147 °C
• 沸点：
  191.38°C (rough estimate)
• 密度：
  1.278
• 溶解度：
  H2O：可溶，50mg/mg蛋白质

计算性质

• 辛醇/水分配系数(LogP)：
  -1.5
• 重原子数：
  7
• 可旋转键数：
  0
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.67
• 拓扑面积：
  64.4
• 氢给体数：
  2
• 氢受体数：
  3

安全信息

• 危险品标志：
  Xn
• 安全说明：
  S36/37,S38
• 危险类别码：
  R5
• WGK Germany：
  2
• RTECS号：
  NY2976000
• 海关编码：
  2934999090
• 危险性防范说明：
  P280,P305+P351+P338,P310
• 危险性描述：
  H302,H315,H319,H332,H335

SDS

Name:	L-Cycloserine 99% Material Safety Data Sheet
Synonym:	L-4-Amino-3-Isoxalolidinone
CAS:	339-72-0

Section 1 - Chemical Product MSDS Name:L-Cycloserine 99% Material Safety Data Sheet
Synonym:L-4-Amino-3-Isoxalolidinone

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Section 2 - COMPOSITION, INFORMATION ON INGREDIENTS

CAS#	Chemical Name	content	EINECS#
339-72-0	L-Cycloserine	99%	206-427-0

Hazard Symbols: None Listed.
Risk Phrases: None Listed.

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Section 3 - HAZARDS IDENTIFICATION
EMERGENCY OVERVIEW
The toxicological properties of this material have not been fully investigated.
Potential Health Effects
Eye:
May cause eye irritation.
Skin:
May cause skin irritation.
Ingestion:
May cause irritation of the digestive tract. The toxicological properties of this substance have not been fully investigated.
Inhalation:
May cause respiratory tract irritation. The toxicological properties of this substance have not been fully investigated.
Chronic:
No information found.

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Section 4 - FIRST AID MEASURES
Eyes: Flush eyes with plenty of water for at least 15 minutes, occasionally lifting the upper and lower eyelids. Get medical aid.
Skin:
Get medical aid. Flush skin with plenty of water for at least 15 minutes while removing contaminated clothing and shoes. Wash clothing before reuse.
Ingestion:
Never give anything by mouth to an unconscious person. Get medical aid. Do NOT induce vomiting. If conscious and alert, rinse mouth and drink 2-4 cupfuls of milk or water.
Inhalation:
Remove from exposure and move to fresh air immediately. If not breathing, give artificial respiration. If breathing is difficult, give oxygen. Get medical aid.
Notes to Physician:

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Section 5 - FIRE FIGHTING MEASURES
General Information:
As in any fire, wear a self-contained breathing apparatus in pressure-demand, MSHA/NIOSH (approved or equivalent), and full protective gear. During a fire, irritating and highly toxic gases may be generated by thermal decomposition or combustion. Runoff from fire control or dilution water may cause pollution.
Extinguishing Media:
Use agent most appropriate to extinguish fire. Use water spray, dry chemical, carbon dioxide, or appropriate foam.

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Section 6 - ACCIDENTAL RELEASE MEASURES
General Information: Use proper personal protective equipment as indicated in Section 8.
Spills/Leaks:
Vacuum or sweep up material and place into a suitable disposal container. Clean up spills immediately, observing precautions in the Protective Equipment section. Avoid generating dusty conditions.
Provide ventilation.

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Section 7 - HANDLING and STORAGE
Handling:
Wash thoroughly after handling. Remove contaminated clothing and wash before reuse. Use with adequate ventilation. Minimize dust generation and accumulation. Avoid contact with eyes, skin, and clothing. Keep container tightly closed. Avoid ingestion and inhalation.
Storage:
Store in a tightly closed container. Store in a cool, dry, well-ventilated area away from incompatible substances. Keep refrigerated. (Store below 4C/39F.)

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Section 8 - EXPOSURE CONTROLS, PERSONAL PROTECTION
Engineering Controls:
Facilities storing or utilizing this material should be equipped with an eyewash facility and a safety shower. Use adequate ventilation to keep airborne concentrations low.
Exposure Limits CAS# 339-72-0: Personal Protective Equipment Eyes: Wear appropriate protective eyeglasses or chemical safety goggles as described by OSHA's eye and face protection regulations in 29 CFR 1910.133 or European Standard EN166.
Skin:
Wear appropriate protective gloves to prevent skin exposure.
Clothing:
Wear appropriate protective clothing to prevent skin exposure.
Respirators:
Follow the OSHA respirator regulations found in 29 CFR 1910.134 or European Standard EN 149. Use a NIOSH/MSHA or European Standard EN 149 approved respirator if exposure limits are exceeded or if irritation or other symptoms are experienced.

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Section 9 - PHYSICAL AND CHEMICAL PROPERTIES

Physical State: Powder
Color: white
Odor: None reported.
pH: Not available.
Vapor Pressure: Not available.
Viscosity: Not available.
Boiling Point: Not available.
Freezing/Melting Point: 146 deg C
Autoignition Temperature: Not applicable.
Flash Point: Not applicable.
Explosion Limits, lower: Not available.
Explosion Limits, upper: Not available.
Decomposition Temperature:
Solubility in water: 10%
Specific Gravity/Density:
Molecular Formula: C3H6N2O2
Molecular Weight: 102.09

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Section 10 - STABILITY AND REACTIVITY
Chemical Stability:
Stable under normal temperatures and pressures.
Conditions to Avoid:
Incompatible materials, dust generation, excess heat, strong oxidants.
Incompatibilities with Other Materials:
Acids, strong oxidizing agents.
Hazardous Decomposition Products:
Nitrogen oxides, carbon monoxide, irritating and toxic fumes and gases, carbon dioxide, nitrogen.
Hazardous Polymerization: Has not been reported.

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Section 11 - TOXICOLOGICAL INFORMATION
RTECS#:
CAS# 339-72-0: NY2976000 LD50/LC50:
CAS# 339-72-0: Oral, mouse: LD50 = 2492 mg/kg.
Carcinogenicity:
L-Cycloserine - Not listed by ACGIH, IARC, or NTP.
Other:
See actual entry in RTECS for complete information.

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Section 12 - ECOLOGICAL INFORMATION

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Section 13 - DISPOSAL CONSIDERATIONS
Dispose of in a manner consistent with federal, state, and local regulations.

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Section 14 - TRANSPORT INFORMATION

IATA
Not regulated as a hazardous material.
IMO
Not regulated as a hazardous material.
RID/ADR
Not regulated as a hazardous material.

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Section 15 - REGULATORY INFORMATION

European/International Regulations
European Labeling in Accordance with EC Directives
Hazard Symbols: Not available.
Risk Phrases:
Safety Phrases:
S 24/25 Avoid contact with skin and eyes.
S 28A After contact with skin, wash immediately with
plenty of water.
S 37 Wear suitable gloves.
S 45 In case of accident or if you feel unwell, seek
medical advice immediately (show the label where
possible).
WGK (Water Danger/Protection)
CAS# 339-72-0: No information available.
Canada
None of the chemicals in this product are listed on the DSL/NDSL list.
CAS# 339-72-0 is not listed on Canada's Ingredient Disclosure List.
US FEDERAL
TSCA
CAS# 339-72-0 is not listed on the TSCA inventory.
It is for research and development use only.

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SECTION 16 - ADDITIONAL INFORMATION
N/A

制备方法与用途

环丝氨酸

环丝氨酸属于二线抗结核药，是一种广谱抗菌药物，对许多革兰阳性菌和阴性菌具有较弱的抗菌作用。它对结核杆菌具有抑制作用，但其抗结核杆菌的效果远不如异烟肼、链霉素强。环丝氨酸通过干扰细菌细胞壁的合成来发挥抗菌作用，其用于治疗结核杆菌感染时所需的浓度为5～20mg/L，并且与其他抗结核药物之间没有交叉耐药性，因此细菌对其产生耐药性的可能性较低。

由于环丝氨酸对神经系统的毒性较大，仅在其他药物治疗无效的情况下使用。口服吸收迅速，在3～4小时内达到血药浓度峰值。一次口服0.25g的平均峰值为4mg/L，重复用药可达到更高的峰值。其血浆半衰期约为10小时，广泛分布于全身组织和体液中，包括胎儿循环、脑脊液、腹水及乳汁等，并以原形通过肾脏排泄，肾功能不全者易蓄积中毒。

环丝氨酸的主要毒性作用表现为神经系统反应，如出现严重精神症状应立即停药。该药物主要从链丝菌培养液中提取的D型和人工合成的DL型光学异构体中得到，临床应用较多的是后者，主要用于治疗结核病及对其他抗结核药物耐药的感染。

理化性质

环丝氨酸为白色或微红色晶体或粉末状物质，吸湿性强且易潮解，味微酸。其熔点在155～156℃（分解），比旋光度+115° (c=1，水，22℃)、+137° (c=5，2mol/1NaOH)。环丝氨酸易溶于水中，也能溶于乙醇，微溶于氯仿和乙醚，而不溶于一般的有机溶剂。在碱性溶液中较为稳定，在酸性和中性溶液中则容易分解。

抗菌作用

除对结核杆菌外，环丝氨酸还具有广谱抗菌作用，对多数革兰阳性与阴性细菌、立克次体以及某些原虫也有抑制效果。它与异烟肼对结核杆菌H37RV有轻度协同作用，但与链霉素既无协同也无拮抗作用。环丝氨酸作为抑菌剂，增加剂量或延长作用时间并不会出现杀菌效应。

成年人口服的剂量为每日500mg，儿童则为每公斤体重10mg，通常分两次服用。重症患者可在短期内将剂量提高到每日1g。为了确保疗效并避免不良反应，在用药期间应定期检测血药浓度，以不超过30μg/ml为宜。

制备方法

环丝氨酸可以通过两种途径制备：一种是从放线菌经发酵、提炼及精制而成；另一种是以丝氨酸甲酯的盐酸盐为原料，在五氯化磷催化下与三氯甲烷反应，脱羟基后再在氢氧化钠溶液中与羟胺反应生成环丝氨酸。

生物活性

L-Cycloserine（S）-4-Amino-3-isoxazolidone 作用于大肠杆菌和各种动物大脑，不可逆地抑制GABA5'-磷酸吡哆醛氨基转移酶，这种作用具有时间依赖性，导致γ-氨基丁酸(GABA)含量增高。GABA 是体内的一种抑制性神经递质。

靶点

3-ketodihydrosphingosine synthetase 为环丝氨酸的作用靶点。

反应信息

• 作为反应物：
  描述：

  3-氟-4-(三氟甲基)苯甲醛 在 三氧化硫 、 lithium diisopropyl amide 作用下， 生成 (S)-3-Oxo-4-(2-phenoxy-acetylamino)-isoxazolidine-2-sulfonatetetrabutyl-ammonium;
  参考文献：
  名称：

  Synthesis of phenoxyacetyl-N-sulphonyl cycloserine

  摘要：

  DOI：

  10.1016/s0040-4039(00)96496-7
• 作为产物：
  描述：

  (S)-4-aminoisoxazolidin-3-one (2S,3S)-2,3-dihydroxysuccinate 在 Amberlite IR-120 PLUS ion exchange resin (sodium form) 作用下， 以 水 为溶剂， 以64%的产率得到3-氟-4-(三氟甲基)苯甲醛
  参考文献：
  名称：

  Preparation of D-Cycloserine and 13C-Labeled D-Cycloserine

  摘要：

  D-Cycloserine (DCS), a second stage drug for the treatment of tuberculosis, is synthesized in 19.8% overall yield from DL-serine methyl ester. This synthetic route gives both enantiomers of cycloserine via a corrected and improved one pot resolution procedure using D- and L-tartaric acids. The route is used to synthesize a C-13-labeled derivative for use in biological studies.

  DOI：

  10.3987/com-12-12553
• 作为试剂：
  描述：

  L-蛋氨酸 在 乙二胺四乙酸 、 DL-dithiothreitol 、 磷酸吡哆醛 、 recombinant methionine γ-lyase from Citrobacter freundii 、 3-氟-4-(三氟甲基)苯甲醛 作用下， 以 aq. phosphate buffer 为溶剂， 反应 0.25h， 生成 甲硫醇 、 ammonia, α-ketobutyrate
  参考文献：
  名称：

  Pre-steady-state Kinetic and Structural Analysis of Interaction of Methionine γ-Lyase from Citrobacter freundii with Inhibitors

  摘要：

  Methionine gamma-lyase (MGL) catalyzes the gamma-elimination of l-methionine and its derivatives as well as the beta-elimination of l-cysteine and its analogs. These reactions yield alpha-keto acids and thiols. The mechanism of chemical conversion of amino acids includes numerous reaction intermediates. The detailed analysis of MGL interaction with glycine, l-alanine, l-norvaline, and l-cycloserine was performed by pre-steady-state stopped-flow kinetics. The structure of side chains of the amino acids is important both for their binding with enzyme and for the stability of the external aldimine and ketimine intermediates. X-ray structure of the MGLl-cycloserine complex has been solved at 1.6 angstrom resolution. The structure models the ketimine intermediate of physiological reaction. The results elucidate the mechanisms of the intermediate interconversion at the stages of external aldimine and ketimine formation.

  DOI：

  10.1074/jbc.m114.586511

文献信息

• The discovery of quinoline-3-carboxamides as hematopoietic prostaglandin D synthase (H-PGDS) inhibitors
  作者：David N. Deaton、Young Do、Jason Holt、Michael R. Jeune、H. Fritz Kramer、Andrew L. Larkin、Lisa A. Orband-Miller、Gregory E. Peckham、Chuck Poole、Daniel J. Price、Lee T. Schaller、Ying Shen、Lisa M. Shewchuk、Eugene L. Stewart、J. Darren Stuart、Stephen A. Thomson、Paris Ward、Joseph W. Wilson、Tianshun Xu、Jeffrey H. Guss、Caterina Musetti、Alan R. Rendina、Karen Affleck、David Anders、Ashley P. Hancock、Heather Hobbs、Simon T. Hodgson、Jonathan Hutchinson、Melanie V. Leveridge、Harry Nicholls、Ian E.D. Smith、Don O. Somers、Helen F. Sneddon、Sorif Uddin、Anne Cleasby、Paul N. Mortenson、Caroline Richardson、Gordon Saxty

  DOI：10.1016/j.bmc.2019.02.017

  日期：2019.4

  converted into the 70-fold more potent quinoline 1d (IC50 = 3,100 nM, LE = 0.49). A systematic substitution of the amine moiety of 1d, utilizing structural information and array chemistry, with modifications to improve inhibitor stability, resulted in the identification of the 300-fold more active H-PGDS inhibitor tool compound 1bv (IC50 = 9.9 nM, LE = 0.42). This selective inhibitor exhibited good murine pharmacokinetics

  为了发现比COX抑制剂更具选择性的消炎药，以减弱前列腺素信号传导，进行了基于片段的造血前列腺素D合酶筛选。将76个晶体学命中物分为相似的组，其中3-氰基喹啉1a（FP IC50 = 220,000 nM，LE = 0.43）是6，6-稠合杂环簇的有效成员。利用从其他H-PGDS片段结合模式簇的结构比较中获得的SAR洞察力，将初始命中1a转化为更有效的喹啉1d（IC50 = 3,100 nM，LE = 0.49）。利用结构信息和阵列化学方法，系统修饰1d的胺部分，并进行修饰以改善抑制剂的稳定性，结果鉴定出具有300倍活性的H-PGDS抑制剂工具化合物1bv（IC50 = 9.9 nM，LE = 0.42）。这种选择性抑制剂在肥大细胞脱粒试验中表现出良好的鼠药代动力学，剂量依赖性地减弱了PGD2的产生，应该适合于进一步研究H-PGDS生物学。
• Induced circular dichroism in chiral N-methyl amides possessing an achiral binaphthyl chromophore and its application to absolute configuration determination of aliphatic chiral amines
  作者：Toshio Fujiwara、Yuka Taniguchi、Yukiteru Katsumoto、Takeyuki Tanaka、Manabu Node、Minoru Ozeki、Masayuki Yamashita、Shinzo Hosoi

  DOI：10.1016/j.tetasy.2012.06.013

  日期：2012.7

  Induced circular dichroism (ICD) was observed in binaphthyl N-methyl amides of chiral primary amines. The CD spectra showed split curves centered at 225 nm. A good correlation was found between the sign of the exciton chirality of the binaphthyl derivative and the absolute configuration of the original amine. Furthermore, the screw sense of the two naphthyl groups in the most stable conformer obtained

  在手性伯胺的联萘基N-甲基酰胺中观察到诱导的圆二色性（ICD）。CD光谱显示出以225nm为中心的分裂曲线。在联萘衍生物的激子手性征与原始胺的绝对构型之间发现良好的相关性。此外，通过分子力学（MM）计算获得的最稳定构象异构体中两个萘基的螺丝感与激子手性所预期的一致，这表明基于MM计算的方法可用于确定未知的绝对构型脂族手性胺。通过测定天然产物d-和l-环丝氨酸的绝对构型证明了本方法的实际应用。
• Synthesen des 4-Amino-3-isoxazolidinons (Cycloserin) und einiger Analoga
  作者：Pl. A. Plattner、A. Boller、H. Frick、A. Fürst、B. Hegedüs、H. Kirchensteiner、St. Majnoni、R. Schläpfer、H. Spiegelberg

  DOI：10.1002/hlca.19570400536

  日期：——

  Stereospecific syntheses of cycloserine (D-4-amino-3-isoxazolidinone) are described. The same synthetic methods lead to some 5-substituted 4-amino-3-isoxazolidinones. The stereochemical relationship of these compounds to the parent amino acids is discussed.

  描述了环丝氨酸（D-4-氨基-3-异恶唑烷酮）的立体特异性合成。相同的合成方法导致一些5-取代的4-氨基-3-异恶唑烷酮。讨论了这些化合物与母体氨基酸的立体化学关系。
• Combinatorial chemistry of natural products: Solid phase synthesis of D- and L-cycloserine derivatives
  作者：Mikhail F. Gordeev、Gary W. Luehr、Hon C. Hui、Eric M. Gordon、Dinesh V. Patel

  DOI：10.1016/s0040-4020(98)00997-1

  日期：1998.12

  An efficient methodology for a solid phase synthesis of D- and L-cycloserine derivatives is described. Fmoc-D-cycloserine 4 and its L-enantiomer 5 prepared by a selective amine acylation of bis-silylated parent compounds are immobilized on Sasrin or 2-chlorotrityl linker resins using Mitsunobu-type reaction or direct tritylation, respectively. The resulting Fmoc-cycloserine resins 7, 10, and 11 are

  描述了一种固相合成D-和L-环丝氨酸衍生物的有效方法。通过双甲硅烷基化的母体化合物的选择性胺酰化制备的Fmoc-D-环丝氨酸4及其L-对映异构体5分别通过Mitsunobu型反应或直接三苯甲基化固定在Sasrin或2-氯三苯甲基连接基树脂上。将所得的Fmoc-环丝氨酸树脂7、10和11在DMF或DCM中用哌啶脱保护，以生成固定的环丝氨酸试剂，其伯氨基暴露于各种合成转化中。描述了在反应板上平行的D-环丝氨酸文库合成的例子。
• 一种环丝氨酸的生产工艺
  申请人：安徽悦康凯悦制药有限公司

  公开号：CN105646385A

  公开（公告）日：2016-06-08

  本发明属于化学合成领域，具体涉及一种环丝氨酸的生产工艺，本发明采用的合成工艺为三步，以D-丝氨酸为起始物料，通过酯化、氯代、环合三步反应得环丝氨酸，工艺过程简单，收率高、纯度高。本发明在酯化反应时用乙酸乙酯代替乙醚、环合反应条件后不加8-羟基喹啉进行粗品的制备，避免了易制毒试剂乙醚及危险品8-羟基喹啉的使用，同时，本发明合成路线短、成本低；所得产品收率稳定、质量可控。

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