(R)-2,5-二氢-3,6-二甲氧基-2-异丙基吡嗪 | 109838-85-9

• 物质功能分类: 医药中间体 - 杂环化合物 - 吡嗪类化合物
• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 甲亚胺酸及其衍生物
• 中文名称: (R)-2,5-二氢-3,6-二甲氧基-2-异丙基吡嗪
• 中文别名: (R)-2,5-甲氧基-3-异丙基-3,6-二羟基吡嗪；(R)-2,5-贰氢-3,6-贰甲氧基-2-异丙基吡嗪；(R)-2-异丙基-3,6-二甲氧基-2,5-二氢吡嗪；(R)-2,5-二甲氧基-3-异丙基-3,6-二氢吡嗪；(R)-2,5-二氢-1,6-二甲氧基-2-异丙基吡嗪
• 英文名称: (2R)-2,5-dihydro-2-isopropyl-3,6-dimethoxypyrazine
• 英文别名: (R)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine；(R)-2-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine；(3R)-3-isopropyl-2,5-dimethoxy-3,6-dihydropyrazine；(2R)-3,6-dimethoxy-2-propan-2-yl-2,5-dihydropyrazine
• CAS: 109838-85-9
• 化学式: C₉H₁₆N₂O₂
• 分子量: 184.238
• InChiKey: FCFWEOGTZZPCTO-MRVPVSSYSA-N

物化性质

• 比旋光度：
  -102 º (c=1%, EtOH)
• 密度：
  1.028 g/mL at 20 °C (lit.)
• 闪点：
  85 °C
• 溶解度：
  溶于氯仿和乙醇
• 沸点：
  100-102°C (20 hPa)
• 稳定性/保质期：
  如果按照规格使用和储存，则不会发生分解，并且没有已知的危险反应。请避免与强氧化剂接触。

计算性质

• 辛醇/水分配系数(LogP)：
  1.4
• 重原子数：
  13
• 可旋转键数：
  3
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.78
• 拓扑面积：
  43.2
• 氢给体数：
  0
• 氢受体数：
  4

安全信息

• 安全说明：
  S23,S24/25
• WGK Germany：
  3
• 海关编码：
  2933990090
• 危险品运输编号：
  NA 1993 / PGIII
• 储存条件：
  请将贮藏器保持密封，并存放在阴凉干燥处。同时，确保工作环境具备良好通风或排气设施。

SDS

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SECTION 1: Identification of the substance/mixture and of the company/undertaking
Product identifiers
Product name : (R)-2,5-Dihydro-3,6-dimethoxy-2-isopropylpyrazine
REACH No. : A registration number is not available for this substance as the substance
or its uses are exempted from registration, the annual tonnage does not
require a registration or the registration is envisaged for a later
registration deadline.
CAS-No. : 109838-85-9
Relevant identified uses of the substance or mixture and uses advised against
Identified uses : Laboratory chemicals, Manufacture of substances

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SECTION 2: Hazards identification
Classification of the substance or mixture
Not a hazardous substance or mixture according to Regulation (EC) No. 1272/2008.
This substance is not classified as dangerous according to Directive 67/548/EEC.
Label elements
Not a hazardous substance or mixture according to EC-directives 67/548/EEC or 1999/45/EC.
Other hazards - none

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SECTION 3: Composition/information on ingredients
Substances
Synonyms : (R)-2,5-Dimethoxy-3-isopropyl-3,6-dihydropyrazine
Formula : C9H16N2O2
Molecular Weight : 184,24 g/mol
CAS-No. : 109838-85-9
No components need to be disclosed according to the applicable regulations.

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SECTION 4: First aid measures
Description of first aid measures
General advice
Consult a physician. Show this safety data sheet to the doctor in attendance.
If inhaled
If breathed in, move person into fresh air. If not breathing, give artificial respiration. Consult a physician.
In case of skin contact
Wash off with soap and plenty of water. Consult a physician.
In case of eye contact
Flush eyes with water as a precaution.
If swallowed
Do NOT induce vomiting. Never give anything by mouth to an unconscious person. Rinse mouth with
water. Consult a physician.
Most important symptoms and effects, both acute and delayed
The most important known symptoms and effects are described in the labelling (see section 2.2) and/or in
section 11
Indication of any immediate medical attention and special treatment needed
no data available

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SECTION 5: Firefighting measures
Extinguishing media
Suitable extinguishing media
For small (incipient) fires, use media such as "alcohol" foam, dry chemical, or carbon dioxide. For large
fires, apply water from as far as possible. Use very large quantities (flooding) of water applied as a mist or
spray; solid streams of water may be ineffective. Cool all affected containers with flooding quantities of
water.
Special hazards arising from the substance or mixture
Carbon oxides, nitrogen oxides (NOx)
Advice for firefighters
Wear self contained breathing apparatus for fire fighting if necessary.
Further information
Use water spray to cool unopened containers.

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SECTION 6: Accidental release measures
Personal precautions, protective equipment and emergency procedures
Use personal protective equipment. Avoid breathing vapours, mist or gas. Remove all sources of ignition.
Beware of vapours accumulating to form explosive concentrations. Vapours can accumulate in low
areas.
For personal protection see section 8.
Environmental precautions
Prevent further leakage or spillage if safe to do so. Do not let product enter drains.
Methods and materials for containment and cleaning up
Contain spillage, and then collect with an electrically protected vacuum cleaner or by wet-brushing and
place in container for disposal according to local regulations (see section 13). Keep in suitable, closed
containers for disposal.
Reference to other sections
For disposal see section 13.

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SECTION 7: Handling and storage
Precautions for safe handling
Avoid inhalation of vapour or mist.
Keep away from sources of ignition - No smoking.Take measures to prevent the build up of electrostatic
charge.
For precautions see section 2.2.
Conditions for safe storage, including any incompatibilities
Store in cool place. Keep container tightly closed in a dry and well-ventilated place. Containers which are
opened must be carefully resealed and kept upright to prevent leakage.
Specific end use(s)
Apart from the uses mentioned in section 1.2 no other specific uses are stipulated

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SECTION 8: Exposure controls/personal protection
Control parameters
Components with workplace control parameters
Exposure controls
Appropriate engineering controls
Handle in accordance with good industrial hygiene and safety practice. Wash hands before breaks and
at the end of workday.
Personal protective equipment
Eye/face protection
Safety glasses with side-shields conforming to EN166 Use equipment for eye protection tested
and approved under appropriate government standards such as NIOSH (US) or EN 166(EU).
Skin protection
Handle with gloves. Gloves must be inspected prior to use. Use proper glove removal technique
(without touching glove's outer surface) to avoid skin contact with this product. Dispose of
contaminated gloves after use in accordance with applicable laws and good laboratory practices.
Wash and dry hands.
The selected protective gloves have to satisfy the specifications of EU Directive 89/686/EEC and
the standard EN 374 derived from it.
Body Protection
impervious clothing, The type of protective equipment must be selected according to the
concentration and amount of the dangerous substance at the specific workplace.
Respiratory protection
Where risk assessment shows air-purifying respirators are appropriate use a full-face respirator
with multi-purpose combination (US) or type ABEK (EN 14387) respirator cartridges as a backup
to engineering controls. If the respirator is the sole means of protection, use a full-face supplied air
respirator. Use respirators and components tested and approved under appropriate government
standards such as NIOSH (US) or CEN (EU).
Control of environmental exposure
Prevent further leakage or spillage if safe to do so. Do not let product enter drains.

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SECTION 9: Physical and chemical properties
Information on basic physical and chemical properties
a) Appearance Form: liquid, clear
Colour: colourless
b) Odour no data available
c) Odour Threshold no data available
d) pH no data available
e) Melting point/freezing no data available
point
f) Initial boiling point and 72,0 °C at 0,7 hPa
boiling range
g) Flash point 85,0 °C - closed cup
h) Evapouration rate no data available
i) Flammability (solid, gas) no data available
j) Upper/lower no data available
flammability or
explosive limits
k) Vapour pressure no data available
l) Vapour density no data available
m) Relative density 1,028 g/mL at 20 °C
n) Water solubility no data available
o) Partition coefficient: n- no data available
octanol/water
p) Auto-ignition no data available
temperature
q) Decomposition no data available
temperature
r) Viscosity no data available
s) Explosive properties no data available
t) Oxidizing properties no data available
Other safety information
no data available

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SECTION 10: Stability and reactivity
Reactivity
no data available
Chemical stability
Stable under recommended storage conditions.
Possibility of hazardous reactions
no data available
Conditions to avoid
Heat, flames and sparks.
Incompatible materials
Strong oxidizing agents
Hazardous decomposition products
Other decomposition products - no data available
In the event of fire: see section 5

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SECTION 11: Toxicological information
Information on toxicological effects
Acute toxicity
no data available
Skin corrosion/irritation
no data available
Serious eye damage/eye irritation
no data available
Respiratory or skin sensitisation
no data available
Germ cell mutagenicity
no data available
Carcinogenicity
IARC: No component of this product present at levels greater than or equal to 0.1% is identified as
probable, possible or confirmed human carcinogen by IARC.
Reproductive toxicity
no data available
Specific target organ toxicity - single exposure
no data available
Specific target organ toxicity - repeated exposure
no data available
Aspiration hazard
no data available
Additional Information
RTECS: Not available
To the best of our knowledge, the chemical, physical, and toxicological properties have not been
thoroughly investigated.

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SECTION 12: Ecological information
Toxicity
no data available
Persistence and degradability
no data available
Bioaccumulative potential
no data available
Mobility in soil
no data available
Results of PBT and vPvB assessment
PBT/vPvB assessment not available as chemical safety assessment not required/not conducted
Other adverse effects
no data available

---

SECTION 13: Disposal considerations
Waste treatment methods
Product
This combustible material may be burned in a chemical incinerator equipped with an afterburner and
scrubber. Offer surplus and non-recyclable solutions to a licensed disposal company. Contact a licensed
professional waste disposal service to dispose of this material.
Contaminated packaging
Dispose of as unused product.

---

SECTION 14: Transport information
UN number
ADR/RID: - IMDG: - IATA: -
UN proper shipping name
ADR/RID: Not dangerous goods
IMDG: Not dangerous goods
IATA: Not dangerous goods
Transport hazard class(es)
ADR/RID: - IMDG: - IATA: -
Packaging group
ADR/RID: - IMDG: - IATA: -
Environmental hazards
ADR/RID: no IMDG Marine pollutant: no IATA: no
Special precautions for user
no data available

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SECTION 15: Regulatory information
This safety datasheet complies with the requirements of Regulation (EC) No. 1907/2006.
Safety, health and environmental regulations/legislation specific for the substance or mixture
no data available
Chemical Safety Assessment
For this product a chemical safety assessment was not carried out

---

SECTION 16: Other information
Further information
Copyright 2014 Co. LLC. License granted to make unlimited paper copies for internal use
only.
The above information is believed to be correct but does not purport to be all inclusive and shall be
used only as a guide. The information in this document is based on the present state of our knowledge
and is applicable to the product with regard to appropriate safety precautions. It does not represent any
guarantee of the properties of the product. Corporation and its Affiliates shall not be held
liable for any damage resulting from handling or from contact with the above product. See
and/or the reverse side of invoice or packing slip for additional terms and conditions of sale.

制备方法与用途

应用

(R)-2,5-二氢-3,6-二甲氧基-2-异丙基吡嗪是有机合成中间体和医药中间体，可用于实验室研发过程和化工生产过程中。

制备步骤 步骤1：N-(叔丁氧羰基)-D-缬氨酸的制备

将717g（8.53mol）NaHCO₃加入到500g（4.27mol）D-缬氨酸的6.4L水溶液中，然后分批加入932g碳酸氢二叔丁酯的6.4L THF溶液。将混合物搅拌并回流加热16小时，在真空下浓缩除去THF。向反应液中加入4.5L乙酸乙酯（EtOAc），冷却至10℃，用3.3L饱和NaHSO₄水溶液调节pH至3。分层后，用水（2L）和盐水（2L）洗涤合并的EtOAc层，并经MgSO₄干燥，在真空下浓缩得到N-(叔丁氧羰基)-D-缬氨酸924g（收率99%）。

步骤2：N-(叔丁氧羰基)-D-甘氨酸乙酸甲酯的制备

将580g（4.25mol）氯甲酸异丁酯在30分钟内分批加入到924g N-(叔丁氧羰基)-D-缬氨酸和430g Et₃N的12.3L CH₂Cl₂溶液中。随后，将甘氨酸甲酯盐酸盐（534g，4.25mol）、Et₃N（430g，4.25mol）和CH₂Cl₂（12.3L）混合物在0-5℃下搅拌30分钟，然后滴加N-(叔丁氧羰基)-D-缬氨酸。继续室温反应16小时后，用水（3×15L）和盐水（5L）洗涤、干燥，并真空浓缩得到N-(叔丁氧羰基)-D-甘氨酸乙酸甲酯1118g（收率91%）。

步骤3：(2R)-异丙基哌嗪-3,6-二酮的制备

将999g N-(叔丁氧羰基)-D-甘氨酸乙酸甲酯溶解于1，2-二氯苯（9L），在175-180℃下加热18小时，通过蒸馏除去生成的MeOH。经氮气流进一步蒸馏去除6L溶剂后，在50℃冷却并小心加入MTBE（5L）。冷却至室温后过滤，用200mL MTBE洗涤固体，并在100℃真空干燥得到(2R)-异丙基哌嗪-3,6-二酮（收率69%，372g）。

步骤4：(R)-2,5-二氢-3,6-二甲氧基-2-异丙基吡嗪的制备

将135g (2R)-异丙基哌嗪-3,6-二酮和450g 四氟硼酸三甲基酯盐（TMS）分别溶解于2L CH₂Cl₂，室温搅拌84小时。过滤所得固体，并用CH₂Cl₂洗涤后，在4°C的NaHCO₃饱和水溶液（3L）中剧烈搅拌并分批加入，同时根据需要通过添加3M NaOH水溶液维持pH在8-9之间。分离有机层并用水（2×500mL）萃取，合并有机相用盐水（500mL）洗涤、干燥，并真空浓缩。通过真空蒸馏纯化浅黄色残余油（收率93%，GC-MS进一步纯化），最终得到(R)-2,5-二氢-3,6-二甲氧基-2-异丙基吡嗪134.6g，为无色油（收率85%、ee值96%）。

用途

合成α-氨基酸的手性试剂。

反应信息

• 作为反应物：
  描述：

  (R)-2,5-二氢-3,6-二甲氧基-2-异丙基吡嗪 在 盐酸 、 lithium aluminium tetrahydride 、 正丁基锂 作用下， 以 乙醚 为溶剂， 反应 3.67h， 生成 D-缬氨酸
  参考文献：
  名称：

  Raap, J.; Wielen, C. M. van der; Lugtenburg, J., Recueil des Travaux Chimiques des Pays-Bas, 1990, vol. 109, # 4, p. 277 - 286

  摘要：

  DOI：
• 作为产物：
  描述：

  D-缬氨酸 在 碳酸氢钠 、 三乙胺 作用下， 以 四氢呋喃 、 二氯甲烷 、 水 、 邻二氯苯 为溶剂， 反应 137.5h， 生成 (R)-2,5-二氢-3,6-二甲氧基-2-异丙基吡嗪
  参考文献：
  名称：

  所述Schöllkopf手性助剂的一种改进的大规模合成：（2 - [R ）-和（2小号）- 2,5-二氢-3,6-二甲氧基-2-异丙基吡嗪

  摘要：

  Schöllkopf手性助剂的合成已经大规模进行，从d-和l-缬氨酸的总收率很高。此方法避免使用剧毒的光气或三光气，低温反应和不稳定的中间体。

  DOI：

  10.1021/op049777t
• 作为试剂：
  描述：

  (R)-2,5-二氢-3,6-二甲氧基-2-异丙基吡嗪 、 2(R)-<<(1,1-Dimethylethoxy)carbonyl>amino>-2-<(3-hydroxy-4-methoxyphenyl)acetyl>-D-phenylalanine (methoxyethoxy)methyl ester 、 alkaline earth salt of/the/ methylsulfuric acid 在 (R)-2,5-二氢-3,6-二甲氧基-2-异丙基吡嗪 作用下， 生成 (R)-2-{(R)-2-tert-Butoxycarbonylamino-2-[4-methoxy-3-(3-methoxy-2-methyl-phenoxy)-phenyl]-acetylamino}-3-phenyl-propionic acid 2-methoxy-ethoxymethyl ester 、 <3-<<2-Methyl-3-methoxy-5-<4(R)-isopropyl-3,6-dimethoxy-1,4-dihydropyrazinyl>phenyl>oxy>-N-(tert-butoxycarbonyl)-(R)-4-methoxyphenylglycinyl>-D-phenylalanine (methoxyethoxy)methyl ester 、 2-methoxyethoxymethyl (2R)-2-[[(2R)-2-[3-[5-[(2R,5R)-3,6-dimethoxy-5-propan-2-yl-2,5-dihydropyrazin-2-yl]-3-methoxy-2-methylphenoxy]-4-methoxyphenyl]-2-[(2-methylpropan-2-yl)oxycarbonylamino]acetyl]amino]-3-phenylpropanoate
  参考文献：
  名称：

  Synthesis of a 14-Membered Cyclic Peptide Model of the CFG Rings of Ristocetin A and Observations on Atropdiastereoisomerism

  摘要：

  Two routes for the synthesis of a 14-membered heterodetic cyclic peptide as a model for the CFG ring system of the antibiotic ristocetin A (2) are described. The key aryl ether bonds for this molecule were constructed by using the reaction of phenoxides from (hydroxyaryl)glycine derivatives with tricarbonyl (3-methoxy-2-methylchlorobenzene) manganese hexafluorophosphate (11). This coupling reaction can be performed in the presence of protected amino acids and dipeptides without racemization of the sensitive arylglycine. Stereoselective introduction of the F-ring glycine side chain was accomplished by reaction of the aryl ether manganese complexes with Schollkopf's bislactim glycine enolate equivalent. The product(s) from this reaction were demetalated and aromatized by treatment with N-bromosuccinimide. Deprotection of the aromatized compounds followed by cycloamidation furnished two atrodiastereomeric cyclic peptides corresponding to the target molecule, the structures of which were assigned on the basis of BD-NMR NOESY experiments coupled with molecular modeling. One of the product molecules corresponds closely to the structure that has been proposed for the CFG ring system of proposed for the CFG ring of ristocetin, except for the orientation of the w(3) amide group.

  DOI：

  10.1021/jo00088a010

文献信息

• CYTOTOXIC PEPTIDES AND ANTIBODY DRUG CONJUGATES THEREOF
  申请人：PFIZER INC.

  公开号：US20130129753A1

  公开（公告）日：2013-05-23

  The present invention is directed to cytotoxic pentapeptides, to antibody drug conjugates thereof, and to methods for using the same to treat cancer.

  本发明涉及细胞毒性五肽，其抗体药物偶联物，以及使用它们治疗癌症的方法。
• Ring-Closing Metathesis in the Synthesis of Biologically Active Peptidomimetics of Apicidin A
  作者：Prashant H. Deshmukh、Carsten Schulz-Fademrecht、Panayiotis A. Procopiou、David A. Vigushin、R. Charles Coombes、Anthony G. M. Barrett

  DOI：10.1002/adsc.200600421

  日期：2007.1.8

  macrocyclic peptidomimetics are reported, which employ iterative peptide coupling followed by high yielding ring-closing metathesis (RCM) as the key cyclization step. The target macrocyclic compounds include examples containing a (2S)-amino-8-oxodecanoic acid (Aoda) residue as analogues of apicidin A, a known potent histone deacetylase (HDAC) inhibitor. These showed modest levels of biological activity

  报道了新颖的16元大环拟肽的合成，其使用迭代肽偶联，然后高产率的闭环复分解（RCM）作为关键环化步骤。目标大环化合物包括含有（2S）-氨基-8-氧代十二烷酸（Aoda）残基作为阿皮定A的类似物的例子，阿皮定A是已知的有效组蛋白脱乙酰基酶（HDAC）抑制剂。这些显示出适度水平的作为HDAC抑制剂的生物活性。
• [EN] COMPOUNDS FOR INHIBITION OF ALPHA 4 BETA 7 INTEGRIN<br/>[FR] COMPOSÉS POUR L'INHIBITION DE L'INTÉGRINE ALPHA 4 BÊTA 7
  申请人：GILEAD SCIENCES INC

  公开号：WO2020092383A1

  公开（公告）日：2020-05-07

  The present disclosure provides a compound of Formula (I): or a pharmaceutically acceptable salt thereof as described herein. The present disclosure also provides pharmaceutical compositions comprising a compound of Formula (I), processes for preparing compounds of Formula (I), and therapeutic methods for treating inflammatory disease.

  本公开提供一种如下式（I）的化合物或其药用可接受的盐。本公开还提供包括如下式（I）化合物的药物组合物，制备如下式（I）化合物的方法，以及治疗炎症性疾病的治疗方法。
• [EN] QUINOLINE DERIVATIVES AS ALPHA4BETA7 INTEGRIN INHIBITORS<br/>[FR] DÉRIVÉS DE QUINOLÉINE UTILISÉS EN TANT QU'INHIBITEURS DE L'INTÉGRINE ALPHA4BÊTA7
  申请人：GILEAD SCIENCES INC

  公开号：WO2020092375A1

  公开（公告）日：2020-05-07

  The present disclosure provides a compound of Formula (I) or a pharmaceutically acceptable salt thereof as described herein. The present disclosure also provides pharmaceutical compositions comprising a compound of Formula (I), processes for preparing compounds of Formula (I), and therapeutic methods for treating inflammatory disease.

  本公开提供了如下所述的化合物的化学式(I)或其药用可接受的盐。本公开还提供了包含化合物的药物组合物的制备方法，制备化合物的方法以及治疗炎症性疾病的治疗方法。
• [EN] COMPOUNDS FOR THE TREATMENT OF MEDICAL DISORDERS<br/>[FR] COMPOSÉS DESTINÉS AU TRAITEMENT DE TROUBLES MÉDICAUX
  申请人：ACHILLION PHARMACEUTICALS INC

  公开号：WO2017035360A1

  公开（公告）日：2017-03-02

  Compounds, methods of use, and processes for making inhibitors of complement Factor D comprising Formula (I), or a pharmaceutically acceptable salt or composition thereof The inhibitors described herein target Factor D and inhibit or regulate the complement cascade. The inhibitors of Factor D described herein reduce the excessive activation of complement.

  化合物、使用方法和制备抑制补体因子D的方法，包括式（I）的药用盐或其组合物。本文描述的抑制剂针对因子D并抑制或调节补体级联反应。本文描述的因子D的抑制剂减少了过度激活的补体。