(R)-巴氯芬 | 69308-37-8

• 物质功能分类: 生物化工 - 抑制剂 - 神经信号通路(Neuronal Signaling)
• 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: (R)-巴氯芬
• 中文别名: (R)-4-氨基-3-(4-氯苯基)丁酸
• 英文名称: (R)-baclofen
• 英文别名: (R)-4-amino-3-(4-chlorophenyl)butanoic acid；(-)-Baclofen；(3R)-4-azaniumyl-3-(4-chlorophenyl)butanoate
• CAS: 69308-37-8
• 化学式: C₁₀H₁₂ClNO₂
• mdl: MFCD01321057
• 分子量: 213.664
• InChiKey: KPYSYYIEGFHWSV-QMMMGPOBSA-N

物化性质

• 熔点：
  171-174°C
• 沸点：
  364.3±32.0 °C(Predicted)
• 密度：
  1.285±0.06 g/cm3(Predicted)
• 溶解度：
  超声处理可轻微溶于甲醇和水

计算性质

• 辛醇/水分配系数(LogP)：
  -1
• 重原子数：
  14
• 可旋转键数：
  4
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  63.3
• 氢给体数：
  2
• 氢受体数：
  3

ADMET

吸收、分配和排泄

• 吸收

与巴氯芬不同，阿巴氯芬的吸收不仅限于上段小肠。阿巴氯芬也可以在下段小肠和结肠中被吸收，这使得可以开发出持续释放的制剂。

Unlike baclofen, absorption of arbaclofen is not limited to the upper small intestine. Arbaclofen can also be absorbed in the lower small intestine and the colon, allowing for the development of sustained release formulations.

来源:DrugBank

吸收、分配和排泄

• 消除途径

80%的R-巴氯芬以不变的形式通过肾脏排出。

>80% of R-baclofen is renally eliminated unchanged.

来源:DrugBank

吸收、分配和排泄

• 清除

静脉注射R-巴氯芬在大鼠、猴子和狗体内的血液清除结果显示半衰期为1.6-3.4小时。在大鼠中，总血液清除率报告为0.51±0.13L/h/kg，在猴子中为0.31±0.11L/h/kg，在狗中为0.24±0.01L/h/kg。

Blood clearance of an IV bolus of R-baclofen in rats, monkeys, and dogs, resulted in a half life of 1.6-3.4hours, in one study. Total blood clearance was reported to be 0.51±0.13L/h/kg in rats, 0.31±0.11L/h/kg in monkeys, and 0.24±0.01L/h/kg in dogs. (2)

来源:DrugBank

安全信息

• 危险等级：
  6.1
• 危险性防范说明：
  P261,P305+P351+P338
• 危险性描述：
  H302,H315,H319,H335
• 储存条件：
  存储于室温下

SDS

Name:	(R)-(-)-Baclofen Material Safety Data Sheet
Synonym:
CAS:	69308-37-8

Section 1 - Chemical Product MSDS Name:(R)-(-)-Baclofen Material Safety Data Sheet
Synonym:

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Section 2 - COMPOSITION, INFORMATION ON INGREDIENTS

CAS#	Chemical Name	content	EINECS#
69308-37-8	(R)-(-)-Baclofen		unlisted

Hazard Symbols: T
Risk Phrases: 25 36/37/38 42/43

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Section 3 - HAZARDS IDENTIFICATION
EMERGENCY OVERVIEW
Toxic if swallowed. Irritating to eyes, respiratory system and skin.
May cause sensitization by inhalation and skin contact.
Potential Health Effects
Eye:
Causes eye irritation.
Skin:
Causes skin irritation. May cause skin sensitization, an allergic reaction, which becomes evident upon re-exposure to this material.
Ingestion:
Poison by ingestion.
Inhalation:
Causes respiratory tract irritation.
Chronic:
Not available.

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Section 4 - FIRST AID MEASURES
Eyes: Immediately flush eyes with plenty of water for at least 15 minutes, occasionally lifting the upper and lower eyelids. Get medical aid immediately.
Skin:
Get medical aid immediately. Immediately flush skin with plenty of water for at least 15 minutes while removing contaminated clothing and shoes.
Ingestion:
Get medical aid immediately. Wash mouth out with 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. Substance is noncombustible.
Extinguishing Media:
Use extinguishing media most appropriate for the surrounding fire.

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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.

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Section 7 - HANDLING and STORAGE
Handling:
Do not breathe dust, vapor, mist, or gas. Do not get in eyes, on skin, or on clothing. Use only in a chemical fume hood.
Storage:
Store in a cool, dry place. Store in a tightly closed container.

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Section 8 - EXPOSURE CONTROLS, PERSONAL PROTECTION
Engineering Controls:
Use adequate ventilation to keep airborne concentrations low.
Exposure Limits CAS# 69308-37-8: Personal Protective Equipment Eyes: Not available.
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: Solid
Color: Not available.
Odor: Not available.
pH: Not available.
Vapor Pressure: Not available.
Viscosity: Not available.
Boiling Point: Not available.
Freezing/Melting Point: Not available.
Autoignition Temperature: Not available.
Flash Point: Not available.
Explosion Limits, lower: Not available.
Explosion Limits, upper: Not available.
Decomposition Temperature:
Solubility in water:
Specific Gravity/Density:
Molecular Formula: ClC6H4CH(CH2NH2)CH2COOH
Molecular Weight: 213.66

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Section 10 - STABILITY AND REACTIVITY
Chemical Stability:
Stable under normal temperatures and pressures.
Conditions to Avoid:
Incompatible materials.
Incompatibilities with Other Materials:
Strong oxidizing agents.
Hazardous Decomposition Products:
Hydrogen chloride, carbon monoxide, oxides of nitrogen, carbon dioxide.
Hazardous Polymerization: Will not occur.

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Section 11 - TOXICOLOGICAL INFORMATION
RTECS#:
CAS# 69308-37-8 unlisted.
LD50/LC50:
Not available.
Carcinogenicity:
(R)-(-)-Baclofen - Not listed by ACGIH, IARC, or NTP.

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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
Shipping Name: TOXIC SOLID, ORGANIC, N.O.S.*
Hazard Class: 6.1
UN Number: 2811
Packing Group: III
IMO
Shipping Name: TOXIC SOLID, ORGANIC, N.O.S.
Hazard Class: 6.1
UN Number: 2811
Packing Group: III
RID/ADR
Shipping Name: TOXIC SOLID, ORGANIC, N.O.S.
Hazard Class: 6.1
UN Number: 2811
Packing group: III

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Section 15 - REGULATORY INFORMATION

European/International Regulations
European Labeling in Accordance with EC Directives
Hazard Symbols: T
Risk Phrases:
R 25 Toxic if swallowed.
R 36/37/38 Irritating to eyes, respiratory system
and skin.
R 42/43 May cause sensitization by inhalation and
skin contact.
Safety Phrases:
S 22 Do not breathe dust.
S 26 In case of contact with eyes, rinse immediately
with plenty of water and seek medical advice.
S 28A After contact with skin, wash immediately with
plenty of water.
S 37/39 Wear suitable gloves and eye/face
protection.
WGK (Water Danger/Protection)
CAS# 69308-37-8: No information available.
Canada
CAS# 69308-37-8 is listed on Canada's DSL List.
CAS# 69308-37-8 is not listed on Canada's Ingredient Disclosure List.
US FEDERAL
TSCA
CAS# 69308-37-8 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

生物活性 - (R)-baclofen (STX 209) 是一种γ-氨基丁酸衍生物，主要用于治疗痉挛。

靶点

• GABAB受体

体内研究 (R)-Baclofen (STX209) 在 Fmr1 缺陷小鼠（背景为抗癫痫的 C57BL/6 小鼠）中抑制了诱发性发作，有效剂量为 1 mg/kg。急性腹腔注射 (R)-Baclofen (STX209) 显著减少了出现发作的小鼠比例，最小有效剂量为 1.5 mg/kg。

反应信息

• 作为反应物：
  描述：

  (R)-巴氯芬 在 盐酸 作用下， 以 乙酸乙酯 为溶剂， 反应 1.0h， 以79%的产率得到R(+)-巴氯芬盐酸盐
  参考文献：
  名称：

  [EN] COCRYSTALS OF (R)-BACLOFEN
  [FR] COCRISTAUX DE (R)-BACLOFÈNE

  摘要：

  该发明涉及(R)-巴氯芬的新型共晶及其制备方法，特别是(R)-巴氯芬与肉桂酸、苯甲酸、水杨酸和香豆酸的共晶。还涉及含有上述共晶的药物组合物，以及利用该共晶或药物组合物治疗由于多发性硬化症、脊髓损伤或脑瘫引起的痉挛和酗酒等疾病或障碍的用途。

  公开号：

  WO2020141141A1
• 作为产物：
  描述：

  R(+)-巴氯芬盐酸盐 在 sodium hydroxide 作用下， 以 水 为溶剂， 以91%的产率得到(R)-巴氯芬
  参考文献：
  名称：

  Method of Producing Optically Active 4-Amino-3-Substituted Phenylbutanoic Acid

  摘要：

  本发明提供了生产化合物（IIa）或化合物（IIb）的方法，提供了生产化合物（IIIa）或化合物（IIIb）的方法，提供了生产化合物（Va）或其盐或化合物（Vb）或其盐的方法，提供了生产化合物（IIIa）或化合物（IIIb）的方法，此外，还提供了生产化合物（Va）或其盐或化合物（Vb）或其盐的方法，包括这些生产方法。

  公开号：

  US20090137819A1
• 作为试剂：
  描述：

  (R)-巴氯芬 、 1(S)-({[(2-fluorophenyl)oxy]carbonyl}oxy)-2-methylpropyl 2-methylpropanoate 在 (R)-巴氯芬 作用下， 生成 (ΒR)-4-氯-Β-[[[[(1S)-2-甲基-1-(2-甲基-1-氧代丙氧基)丙氧基]羰基]氨基]甲基]-苯丙酸
  参考文献：
  名称：

  METHOD OF MAKING 1-(ACYLOXY)-ALKYL CARBAMATE COMPOUNDS

  摘要：

  提供制备胺类药物的氨基甲酸酯前药的方法。还提供用于合成氨基甲酸酯前药的碳酸盐。

  公开号：

  US20140243544A1

文献信息

• A short and convenient chemoenzymatic synthesis of both enantiomers of 3-phenylGABA and 3-(4-chlorophenyl)GABA (Baclofen)
  作者：Fulvia Felluga、Valentina Gombac、Giuliana Pitacco、Ennio Valentin

  DOI：10.1016/j.tetasy.2005.02.019

  日期：2005.4

  Both enantiomers of the pharmacologically active GABA analogues 4-amino-3-phenyl and 4-amino-3-(4-chlorophenyl)butyric acid (Baclofen) with high enantiomeric excesses were synthesized by a chemoenzymatic method involving α-chymotrypsin mediated kinetic resolutions of the corresponding 3-phenyl- and 3-(4-chlorophenyl)-4-nitrobutyric acid methyl ester precursors.

  具有高对映体过量的药理活性GABA类似物4-氨基-3-苯基和4-氨基-3-（4-氯苯基）丁酸（Baclofen）的两种对映体均通过化学酶法合成，涉及α-胰凝乳蛋白酶介导的动力学拆分。相应的3-苯基-和3-（4-氯苯基）-4-硝基丁酸甲酯前体。
• [EN] DIFLUOROMETHOXYLATION AND TRIFLUOROMETHOXYLATION COMPOSITIONS AND METHODS FOR SYNTHESIZING SAME<br/>[FR] COMPOSITIONS DE DIFLUOROMÉTHOXYLATION ET DE TRIFLUOROMÉTHOXYLATION ET LEURS PROCÉDÉS DE SYNTHÈSE
  申请人：UNIV NEW YORK STATE RES FOUND

  公开号：WO2019168874A1

  公开（公告）日：2019-09-06

  The present invention provides a compound having the structure (I), a processing of making the compound; and a process of using the compound as a reagent for the difluoromethoxylation and trifluoromethoxylation of arenes or heteroarenes.

  本发明提供了一种具有结构（I）的化合物，制备该化合物的方法；以及将该化合物用作芳烃或杂环芳烃的二氟甲氧基化和三氟甲氧基化试剂的方法。
• Chemoenzymatic enantioselective synthesis of baclofen
  作者：Robert Chênevert、Michel Desjardins

  DOI：10.1139/v94-294

  日期：1994.11.1

  We report two different chemoenzymatic enantioselective syntheses of baclofen based on the distinction between enantiotopic ester groups in compounds bearing a prochiral centre. In the first approach, the key step is the highly stereoselective enzymatic hydrolysis of dimethyl 3-(4-chlorophenyl)glutarate by chymotrypsin in an aqueous medium. In the second approach, the key step is the enzyme-catalyzed esterification of 2-(4-chloropheny 1)-1,3-propanediol by acetic anhydride in the presence of a lipase in an organic medium.

  我们报告了基于含有一个非手性中心的化合物中对映异构酯基团之间的区别，实现巴氯芬的两种不同的化学酶选择性合成方法。在第一种方法中，关键步骤是在水介质中由胰蛋白酶高度立体选择性地水解二甲基3-(4-氯苯基)戊二酸酯。在第二种方法中，关键步骤是在有机介质中，通过酶催化的方式，乙酸酐存在下，利用脂肪酶对2-(4-氯苯基)-1,3-丙二醇进行酯化。
• Enantioselective Synthesisof (-)-(<i>R</i>)-Baclofen and Analoguesvia Rhodium-Catalysed Conjugate Addition of Boronic Acids
  作者：Günter Helmchen、Oliver Meyer、Jean-Michel Becht

  DOI：10.1055/s-2003-40847

  日期：——

  Highly enantioselective syntheses of the antispastic drug (-)-(R)-Baclofen and analogues have been achieved by using rhodium-catalysed asymmetric 1,4-additions of arylboronic acids to 4-amino-but-2,3-enoic acid derivatives.

  通过使用铑催化的不对称1,4-加成反应，将芳基硼酸加成到4-氨基-丁-2,3-烯酸衍生物上，成功实现了高度对映选择性的抗痉挛药物(-)-(R)-巴氯芬及其类似物的合成。
• Enantioselective synthesis of β-substituted butyric acid derivatives via orthoester Claisen rearrangement of enzymatically resolved allylic alcohols: application to the synthesis of (R)-(−)-baclofen
  作者：Elisabetta Brenna、Nicola Caraccia、Claudio Fuganti、Daniela Fuganti、Piero Grasselli

  DOI：10.1016/s0957-4166(97)00538-7

  日期：1997.11

  A three step synthesis of (R)-(−)-baclofen is described. The key step is the orthoester Claisen rearrangement of enantiopure allylic alcohol , affording γ,δ-unsaturated ester (S,E)-(+)-6 with high stereoselectivity. This latter derivative is converted into (R)-(−)-baclofen through a high yield one-pot reaction.

  描述了（R）-（-）-baclofen的三步合成。关键步骤是对映体纯烯丙基醇的原酸酯Claisen重排，得到具有高立体选择性的γ，δ-不饱和酯（S，E）-（+）-6 。后者的衍生物通过高产率的一锅法反应转化为（R）-（-）-巴洛克芬。