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2-正丙基-4-甲基-6-(1’-甲基苯并咪唑-2-基)苯并咪唑 | 152628-02-9

物质功能分类

有机原料 - 杂环化合物

分子结构分类

有机化合物 - 有机杂环化合物 - 苯并咪唑类

中文名称

2-正丙基-4-甲基-6-(1’-甲基苯并咪唑-2-基)苯并咪唑

中文别名

替米沙坦中间体(双咪唑)；替米沙坦中间体2；正丙基-4-甲基-6-(1'-甲基苯并咪唑-2-基)苯并咪唑；2-正丙基-4-甲基-6-(1-甲基苯并咪唑-2-基)苯并咪唑(简称:双咪唑)；双咪唑；双咪唑[or2-正丙基-4-甲基-6-(1'-甲基苯骈咪唑-2-基)苯骈咪唑]；2-正丙基-4-甲基-6-(1'-甲基苯并咪唑-2-基)苯并咪唑；替米沙坦杂质A；2-正丙基-4-甲基-6-(1-甲基苯并咪唑-2-基)苯并咪唑

英文名称

2-n-propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)benzimidazole

英文别名

1,7'-dimethyl-2'-propyl-1H,3'H-2,5'-bibenzo[d]imidazole；2-propyl-4-methyl-6-(1-methyl-benzimidazol-2-yl)benzimidazole；4-Methyl-6-(1-methyl-1H-benzimidazol-2-yl)-2-propyl-1H-benzimidazole；4-methyl-6-(1-methylbenzimidazol-2-yl)-2-propyl-1H-benzimidazole

CAS

152628-02-9

化学式

C₁₉H₂₀N₄

mdl

MFCD03840857

分子量

304.395

InChiKey

ILXRSCZVHSZGCS-UHFFFAOYSA-N

BEILSTEIN

——

EINECS

——

物化性质

熔点：

130-135 °C(Solv: tetrahydrofuran (109-99-9))
沸点：

584.8±52.0 °C(Predicted)
密度：

1.23±0.1 g/cm3(Predicted)
溶解度：

溶于甲醇
LogP：

3.49 at 20℃ and pH6

计算性质

辛醇/水分配系数(LogP)：

4.2
重原子数：

23
可旋转键数：

3
环数：

4.0
sp3杂化的碳原子比例：

0.263
拓扑面积：

46.5
氢给体数：

1
氢受体数：

2

安全信息

海关编码：

2933990090
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：

室温、密封保存，并保持干燥。

SDS

SDS：cb72b5e09bb5daeb41dc7e37ab3fdae7

查看

Material Safety Data Sheet

Section 1. Identiﬁcation of the substance
Product Name: 2-N-Propyl-4-methyl-6-(1-methylbenzimidazole-2-yl)benzimidazole
Synonyms:

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

Section 3. Composition/information on ingredients.
Ingredient name: 2-N-Propyl-4-methyl-6-(1-methylbenzimidazole-2-yl)benzimidazole
CAS number: 152628-02-9

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.
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: C19H20N4
Molecular weight: 304.4

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.

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
2-正丙基-4-甲基-6-(1'-甲基苯并咪唑-2-基)苯并咪唑（替米沙坦EP杂质A; USP替米沙坦相关化合物A）是在替米沙坦（T017000）中发现的杂质，用作药物替米沙坦中间体。

上下游信息

上游原料

中文名称	英文名称	CAS号	化学式	分子量
——	2-methyl-4-(1-methyl-1H-benzo[d]imidazol-2-yl)aniline	——	C₁₅H₁₅N₃	237.304
——	2-methyl-4-(1-methyl-1H-benzimidazol-2-yl)-6-nitrobenzenamine	1345840-05-2	C₁₅H₁₄N₄O₂	282.302
——	2-(4-methoxy-3-methyl-5-nitrophenyl)-1-methyl-1H-benzimidazole	1345840-21-2	C₁₆H₁₅N₃O₃	297.313
——	N-[2-methyl-4-(1-methylbenzimidazole)-2-yl-6-nitrophenyl]-butanamide	1083158-66-0	C₁₉H₂₀N₄O₃	352.393

下游产品

中文名称	英文名称	CAS号	化学式	分子量
——	3'-(4-bromobenzyl)-1,7'-dimethyl-2'-propyl-1H,3'H-2,5'-bibenzo[d]imidazole	——	C₂₆H₂₅BrN₄	473.415
——	ethyl 2-(1,7'-dimethyl-2'-propyl-1H,3'H-2,5'-bibenzo[d]imidazol-3'-yl)acetate	765900-68-3	C₂₃H₂₆N₄O₂	390.485
——	3-(4-((4-methyl-6-(1-methyl-1H-benzo[d]imidazol-2-yl)-2-propyl-1H-benzo[d]imidazol-1-yl)methyl)phenyl)acrylonitrile	——	C₂₉H₂₇N₅	445.567
——	(4'-[(1,4'-dimethyl-2'-propyl-[2,6'-bi-1H-benzimidazol]-1'-yl)methyl]phenyl)-boronic acid	——	C₂₆H₂₇BN₄O₂	438.337
——	4'-[(2-n-Propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-2-hydroxymethyl-biphenyl	——	C₃₃H₃₂N₄O	500.643
4'-[(1,4'-二甲基-2'-丙基[2,6'-联-1H-苯并咪唑]-1'-基)甲基]联苯-2-甲腈	(4′-((1,7′-dimethyl-2′-propyl-1H,3′H-[2,5′-bibenzo[d]imidazol]-3′-yl)methyl)-[1,1′-biphenyl]-2-carbonitrile)	144702-27-2	C₃₃H₂₉N₅	495.627
——	4'-((1,7'-dimethyl-2'-propyl-1H,3'H-[2,5'-bibenzo[d]imidazol]-3'-yl)methyl)-[1,1'-biphenyl]-2-carbaldehyde	172525-90-5	C₃₃H₃₀N₄O	498.627
替米沙坦	Telmisartan	144701-48-4	C₃₃H₃₀N₄O₂	514.627
替米沙坦甲酯	methyl 4'-[[2-n-propyl-4-methyl-6-(1-methyl-benzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate	528560-93-2	C₃₄H₃₂N₄O₂	528.654
替米沙坦乙酯	telmisartan ethyl ester	528560-94-3	C₃₅H₃₄N₄O₂	542.681

反应信息

作为反应物：

描述：

2-正丙基-4-甲基-6-(1’-甲基苯并咪唑-2-基)苯并咪唑在盐酸、 potassium hydroxide 作用下，以甲醇、丙酮为溶剂，生成 4'-(1,4'-dimethyl-2'-propyl-1H-[2,5']dibenzimidazolyl-3'-ylmethyl)biphenyl-2-carboxylic acid methyl ester hydrochloride

参考文献：

名称：

An Efficient and Impurity-Free Process for Telmisartan: An Antihypertensive Drug

摘要：

Telmisartan (1), a substituted dibenzimidazole derivative, is an antihypertensive drug, essentially used to control blood pressure. An improved, cost-effective, and impurity-free process for telmisartan (1) suitable for large-scale production is described here by addressing various process development issues. The overall yield obtained from this newly developed process is around 50% (over five steps) compared to the literature reported process (21%, over eight steps).

DOI：

10.1021/op060200g
作为产物：

描述：

4-甲氧基-3-甲基-5-硝基苯甲醛在 sodium dithionite 、氨、双氧水、 potassium carbonate 作用下，以甲醇、乙醇、水、 N,N-二甲基甲酰胺为溶剂，反应 26.0h，生成 2-正丙基-4-甲基-6-(1’-甲基苯并咪唑-2-基)苯并咪唑

参考文献：

名称：

Highly practical and cost-efficient synthesis of telmisartan: an antihypertensive drug

摘要：

A novel and cost-efficient strategy for synthesis of an antihypertensive drug telmisartan, a substituted bis-benzimidazole derivative, is described. The key strategy is the construction of bis-benzimidazole 4 by reductive cyclization of o-nitroanilines 11 with butyl aldehyde and cyclocondensation of aromatic aldehydes 9 with o-phenylenediamine, then N-alkylation is allowed to give the target compound telmisartan after hydrolysis. The simple operation and workup procedure, along with the low production costs, make it suitable for industrial production and will benefits those with cardiovascular disease. (C) 2012 Elsevier Ltd. All rights reserved.

DOI：

10.1016/j.tet.2012.01.056
作为试剂：

描述：

4'-(bromomethyl)biphenyl-2-carbaldehyde 、 2-正丙基-4-甲基-6-(1’-甲基苯并咪唑-2-基)苯并咪唑在 2-正丙基-4-甲基-6-(1’-甲基苯并咪唑-2-基)苯并咪唑作用下，生成 4'-((1,7'-dimethyl-2'-propyl-1H,3'H-[2,5'-bibenzo[d]imidazol]-3'-yl)methyl)-[1,1'-biphenyl]-2-carbaldehyde

参考文献：

名称：

WO2006103068A1

摘要：

公开号：

点击查看最新优质反应信息

文献信息

6-Substituted benzimidazoles as new nonpeptide angiotensin II receptor antagonists: synthesis, biological activity, and structure-activity relationships

作者：Uwe J. Ries、Gerhard Mihm、Berthold Narr、Kai M. Hasselbach、Helmut Wittneben、Michael Entzeroth、Jacobus C. A. van Meel、Wolfgang Wienen、Norbert H. Hauel

DOI：10.1021/jm00077a007

日期：1993.12

reported nonpeptidic angiotensin II (AII) receptor antagonists DuP753 (1) and Exp 7711 (2), we have designed and investigated novel substituted benzimidazoles. Systemic variation of several substituents at the benzimidazole ring positions 4-7 led to the finding that substitution in position 6 with acylamino groups results in highly active AII antagonists. Compounds with 6-membered lactam or sultam substituents

从最近报道的非肽类血管紧张素II（AII）受体拮抗剂DuP753（1）和Exp 7711（2）开始，我们设计并研究了新型取代的苯并咪唑。苯并咪唑环位置4-7上几个取代基的系统变化导致发现，位置6被酰基氨基取代会产生高活性的AII拮抗剂。在苯并咪唑的6位上具有6元内酰胺或sultam取代基的化合物在低纳摩尔范围内显示受体活性，但当口服给予大鼠时仅具有弱活性。相反，用碱性杂环类似地取代苯并咪唑部分产生有效的AII拮抗剂，其在口服后也被很好地吸收。该系列中活性最高的化合物33（BIBR 277），被选为临床发展的候选人。在分子模型研究的基础上，提出了这种新型的AII拮抗剂与AT1受体的结合模型。
Benzimidazoles and pharmaceutical compositions containing them

申请人：Dr. Karl Thomae GmbH

公开号：US05565469A1

公开（公告）日：1996-10-15

Angiotensin-II inhibiting benzimidazoles, useful for the treatment of hypertension. Exemplary compounds are: (a) 4'-[(2-n-propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl)- methyl]-2-(1,3-thiazolidin-2,4-dione-5-methylidinyl)-biphenyl, (b) 4'-[(2-n-propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl)- methyl]-2-sulpho-biphenyl, (c) 4'-[(2-ethyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl)-be nzimidazol-1-yl)-methyl]-2-sulpho-biphenyl, (d) 4'-[(2-n-propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl)- methyl]-2-trifluoroacetylamino-biphenyl, (e) 4'-[(2-ethyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl)-be nzimidazol-1-yl)-methyl]-2-trifluoroacetylamino-biphenyl, (f) 4'-[(2-n-propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl)- methyl]-2-(4-methoxy-benzylaminocarbonylaminosulphonyl)-biphenyl, (g) 4'-[(2-n-propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl)- methyl]-2-(cyclohexylamino-carbonylaminosulphonyl)-biphenyl, (h) 4'-[(2-n-propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl)- methyl]-2-(benzoylamino-sulphonyl)-biphenyl, (i) 4'-[(2-ethyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl)-be nzimidazol-1-yl)-methyl]-2-(benzoylaminosulphfonyl)-biphenyl, (j) 4'-[(2-n-butyl-4-methyl-6-(propanesultam-1-yl)-benzimidazol-1-yl)-methyl]- 2-(benzoylaminosulphonyl)-biphenyl and (k) 4'-[(2-ethyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl)-be nzimidazol-1-yl)-methyl]-2-(cyclohexylaminocarbonylaminosulphonyl)-biphenyl .

抑制血管紧张素II的苯并咪唑类化合物，用于治疗高血压。示范性化合物包括：(a) 4'-[(2-正丙基-4-甲基-6-(1-甲基苯并咪唑-2-基)-苯并咪唑-1-基)-甲基]-2-(1,3-噻唑啉-2,4-二酮-5-甲基亚基)-联苯，(b) 4'-[(2-正丙基-4-甲基-6-(1-甲基苯并咪唑-2-基)-苯并咪唑-1-基)-甲基]-2-磺酸酯联苯，(c) 4'-[(2-乙基-4-甲基-6-(5,6,7,8-四氢咪唑[1,2-a]吡啶-2-基)-苯并咪唑-1-基)-甲基]-2-磺酸酯联苯，(d) 4'-[(2-正丙基-4-甲基-6-(1-甲基苯并咪唑-2-基)-苯并咪唑-1-基)-甲基]-2-三氟乙酰氨基联苯，(e) 4'-[(2-乙基-4-甲基-6-(5,6,7,8-四氢咪唑[1,2-a]吡啶-2-基)-苯并咪唑-1-基)-甲基]-2-三氟乙酰氨基联苯，(f) 4'-[(2-正丙基-4-甲基-6-(1-甲基苯并咪唑-2-基)-苯并咪唑-1-基)-甲基]-2-(4-甲氧基苄氨基甲酰氨基磺酰)-联苯，(g) 4'-[(2-正丙基-4-甲基-6-(1-甲基苯并咪唑-2-基)-苯并咪唑-1-基)-甲基]-2-(环己基氨基甲酰氨基磺酰)-联苯，(h) 4'-[(2-正丙基-4-甲基-6-(1-甲基苯并咪唑-2-基)-苯并咪唑-1-基)-甲基]-2-(苯甲酰氨基磺酰)-联苯，(i) 4'-[(2-乙基-4-甲基-6-(5,6,7,8-四氢咪唑[1,2-a]吡啶-2-基)-苯并咪唑-1-基)-甲基]-2-(苯甲酰氨基磺酰)-联苯，(j) 4'-[(2-正丁基-4-甲基-6-(丙磺酰胺-1-基)-苯并咪唑-1-基)-甲基]-2-(苯甲酰氨基磺酰)-联苯和(k) 4'-[(2-乙基-4-甲基-6-(5,6,7,8-四氢咪唑[1,2-a]吡啶-2-基)-苯并咪唑-1-基)-甲基]-2-(环己基氨基甲酰氨基磺酰)-联苯。
Highly Efficient and Practical Synthesis of the Key Intermediate of Telmisartan

作者：Jianhong Zhao、Yicheng Xiong、Wu-Lin Yang、Fan Yang、Yu Jin

DOI：10.1021/acs.oprd.1c00025

日期：2021.4.16

We reported herein an efficient and practical method to access 1,7′-dimethyl-2′-propyl-2,5′-bi(1H-benzimidazole) 1, a key intermediate for the synthesis of telmisartan. The synthetic route was based on readily available o-methylaniline as the starting material, and the target product 1 was prepared through a six-step process, including amidation, formylation, cyclization, hydrolysis, amidine, and oxidation

我们在本文中报道了一种有效而实用的方法，可访问1,7'-二甲基-2'-丙基-2,5'-双（1 H-苯并咪唑）1，这是替米沙坦合成的关键中间体。合成途径基于容易获得的邻甲基苯胺作为起始原料，并且通过六步法制备目标产物1，包括酰胺化，甲酰化，环化，水解，am和氧化。制备1的总产率以100g规模为51.5％，纯度为99.91％。该方法的显着特征包括经济且容易获得的起始原料，操作简便和环境友好，这适合于工业生产。
N-Phenyl indole derivatives as AT1 antagonists with anti-hypertension activities: Design, synthesis and biological evaluation

作者：Weibo Zhu、Xiaolu Bao、He Ren、Yajing Da、Dan Wu、Fuming Li、Yijia Yan、Li Wang、Zhilong Chen

DOI：10.1016/j.ejmech.2016.03.021

日期：2016.6

synthesis, in vitro and in vivo evaluation of 6-substituted benzimidazole with 1, 4-disubsituted or 1, 5-disubsituted indole derivatives as novel angiotensin II receptor antagonists are outlined. Radioligand binding assays showed that several 6-substituted benzimidazole derivatives displayed high affinities binding to the angiotensin II type 1 receptor at the same order of magnitude to telmisartan. The

概述了以1、4-二取代或1,5-二取代的吲哚衍生物作为新型血管紧张素II受体拮抗剂的6-取代苯并咪唑的设计，合成，体外和体内评价。放射性配体结合测定表明，几种6-取代的苯并咪唑衍生物以与替米沙坦相同的数量级显示出与血管紧张素II 1型受体的高亲和力结合。对自发性高血压大鼠的生物学评估显示，2- [4-[[2-n-丙基-4-甲基-6-（1-甲基苯并咪唑-2-基）苯并咪唑-1-基]甲基] -1H-吲哚- 1-yl]苯甲酸1c可以剂量依赖性方式导致MBP显着降低。口服给药后，其最大反应降低了5 mg / kg的MBP的53 mmHg和10 mg / kg的MBP的64 mmHg，并且显着的降压作用持续了24小时以上，比氯沙坦和替米沙坦都好。旨在确定急性毒性的一项研究表明，1c的急性毒性较低，重量没有明显变化，也没有明显的不良反应。令人鼓舞的结果使1c成为一种有效且持久的抗高血压药物候选者，值得在治疗方面进行进一步研究。
一类双苯并咪唑吲哚衍生物的两种制备方法

申请人：陈志龙

公开号：CN106467521A

公开（公告）日：2017-03-01

本发明涉及一类具有降压等作用的双苯并咪唑吲哚衍生物的两种新的制备方法，解决了现有技术中存在的如反应路线长、对甲基进行溴化时产率较低、总产率低等缺点，将总产率从25％左右提高到了45％左右，具有重要的科学理论意义和应用价值，在制药领域与化学化工领域具有巨大的应用前景。