146533-41-7

Basic information

• Product Name: 5-(4-Bromophenyl)-4,6-dichloropyrimidine
• Synonyms: PyriMidine, 5-(4-broMophenyl)-4,6-dichloro-;5-(4-broMophenyl)-4,6-dichloropyriMidine;potassiuM (N-propylsulfaMoyl)aMide;5-(4-Bromophenyl)-4,6-dichloro-1,3-diazine;4,6-Dichloro-5-(4-bromophenyl)pyrimidine;(4-broMophenyl)-4,6-dichloroPyriMidine;5-(4-Bromophenyl)-4,6-dichloro-Pyrimidin;5-(4-broMophenyl)-4
• CAS NO: 146533-41-7
• Molecular Formula: C₁₀H₅BrCl₂N₂
• Molecular Weight: 303.9701
• Mol File: 146533-41-7.mol

Chemical Properties

• Melting Point: 98.0 to 102.0 °C
• Boiling Point: 368.7±42.0 °C(Predicted)
• Appearance: /
• Density: 1.677±0.06 g/cm3(Predicted)
• Storage Temp.: under inert gas (nitrogen or Argon) at 2-8°C
• Solubility: Chloroform (Slightly), DMSO (Slightly)
• PKA: -4.92±0.26(Predicted)
• CAS DataBase Reference: 5-(4-Bromophenyl)-4,6-dichloropyrimidine(CAS DataBase Reference)
• NIST Chemistry Reference: 5-(4-Bromophenyl)-4,6-dichloropyrimidine(146533-41-7)
• EPA Substance Registry System: 5-(4-Bromophenyl)-4,6-dichloropyrimidine(146533-41-7)

Safety Data

• Hazardous Substances Data: 146533-41-7(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
5-(4-Bromophenyl)-4,6-dichloropyrimidine is used as a reactant for the synthesis of Macitentan, an orally active dual endothelin receptor antagonist. It plays a crucial role in the development of this medication, which is utilized for the treatment of pulmonary arterial hypertension.
Additionally, due to its versatile chemical structure, 5-(4-Bromophenyl)-4,6-dichloropyrimidine can be further utilized in the synthesis of other pharmaceutical compounds, potentially leading to the discovery of new drugs and treatments in various medical fields.

Synthesis

Dimethyl 2-(4-bromophenyl) malonate (6) A solution of methyl 2-(4-bromophenyl)acetate (5) (206.8 g, 0.9 mol) in THF (400mL), then it was added drop-wise to a suspension of sodium hydride (65.0 g,2.71 mol) in THF solution(1000mL) at room temperature, control the drip rate and the temperature was kept 25 ~ 27 , when dropping ℃ was completed, keep the temperature for 1h, then dimethyl carbonate (DMC) (325.1 g, 3.6 mol) was added, keep the reaction for 14 h. After cooling to -10 , the s ℃ olution is adjusted to pH 6~7 using hydrochloric acid (36%) then removed THF under reduced pressure, ethyl acetate (1600mL) was added to the solution, the organic phase was washed with hydrochloric acid solution (1 mol/L, 36%) saturated brine and was dried by magnesium sulfate, then it was distilled under reduced pressure to afford yellow oil. The yellow oil was solidified by cyclohexane, after mixture was filtered and driedto obtain yellow solid, then re-crystallized with ethanol- acetone (5:2) to obtain 6 as white solid (192.9 g).yield: 72.3%. M.p.77-79 , ℃ MS; 308.8 [M + Na] + , 596.7[2M+Na]+ . 5-(4-Bromophenyl) pyrimidine-4, 6-diol (7) Sodium (46.9g, 2.0mol) was slowly added into methanol (600mL) at 0 . Dimethyl ℃ – 2 - ( 4 –bromophenyl ) malonate(192.9g,0.67mol) was dissolved in methanol (380mL) added into the solution of sodium methoxide, after dropping, keep the reaction for 1h at roo was added, heated to 40 for 3.5 h. After cooling to room temperature, methanol was ℃ distilled off under reduced pressure, the solution of citric acid was added into the residue and stirred for 1 hours. The precipitated solid was suction filtered, and the solid w m temperature, then formamidineas washed with water, then dried to give a yellow solid. The crude product was added into cyclohexane (900mL) was stirred for 3h at room temperature, then the precipitated solid was suction filtered, the solid was washed with cyclohexane and dried to obtain7 as light yellow solid (149.1 g ,84.4%). M.p.178-180 ℃; MS; 269.0[M+H] + , 288.9[M + Na] + .5-(4-Bromophenyl)-4, 6-dichloropyrimidine (1) 5-(4-Bromophenyl) pyrimidine-4, 6-diol (53.4g, 0.2mol) was slowly added into POCl3 (427mL), refluxed for 8h. POCl3 was distilled off under reduced pressure, then the black viscous residue was poured into ice water (1000mL), The solution was adjusted to pH9~10 using potassium carbonate. The product was filtered off, washed with water and dried under reduced pressure to afford 5-(4-bromophenyl)-4, 6-dichloropyrimidine (1) as white solid (52.6 g, 86.5%). M. P. 101 -102 , ℃ MS: 302 [M+H] + ; 1 H -NMR (300 MHz, DMSO-d 6 ) δ 8.96(s, 1H,Ar-H), 7.72(d, J = 8.5 Hz, 2H, Ar-H), 7.39(d, J = 8.5Hz, 2H, Ar-H).

Upstream product

• 706811-25-8 5-(4-bromophenyl)-4,6-dihydroxypyrimidine 
• 149506-35-4 2-(4-bromophenyl)-malonic acid dimethyl ester 
• 41841-16-1 (4-bromo-phenyl)-acetic acid methyl ester 
• 146533-40-6 5-(p-bromophenyl)-4,6(1H,5H)-pyrimidinedione 
• 1878-68-8 2-(4-bromophenyl)-acetic acid 
• 93139-85-6 2-(4-bromophenyl)malonic acid diethyl ester 
• 14062-25-0 Ethyl 4-bromophenylacetate 

Downstream Products

• 926008-69-7 {4-[5-(4-bromophenyl)-6-chloropyrimidin-4-ylethynyl]phenyl}dimethylamine 
• 706811-26-9 2-methoxyethanesulfamic acid [6-chloro-5-(4-bromophenyl)-pyrimidin-4-yl]-amide 
• 441796-08-3 N-[5-(4-bromophenyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl]-N'-benzyl-sulfamide 
• 441796-09-4 benzylsulfamic acid {5-(4-bromophenyl)-6-[2-(5-bromopyrimidin-2-yloxy)-ethoxy]-pyrimidine-4-yl}-amide 
• 1103522-45-7 ACT-132577 
• 1393813-42-7 N-5-(4-bromophenyl)-6-chloro-4-pyrimidinyl-N‘-propylsulfamide 
• 2211059-05-9 2‐((6‐amino‐5‐(4‐bromophenyl)pyrimidin‐4‐yl)oxy)ethan‐1‐ol 
• 1642873-04-8 2-((5-(4-bromophenyl)-6-chloropyrimidin-4-yl)oxy)ethan-1-ol 
• 887366-72-5 1-benzyloxypropanesulfamic acid [6-chloro-5-(4-bromophenyl)-pyrimidin-4-yl]-amide 
• 1433875-21-8 ACT-080803 

Relevant articles and documents

Improved and single-pot process for the synthesis of macitentan, an endothelin receptor antagonist, via lithium amide-mediated nucleophilic substitution

Abstract: An improved, simple, efficient, and telescoped synthesis of macitentan, an endothelin receptor antagonist, starting from 5-(4-bromophenyl)-4,6-dichloropyrimidine in an overall yield of around 62% is described. Graphical abstract: [Figure not available: see fulltext.].

Preparation method of 5-(4-bromophenyl)-4,6-dichloropyrimidine

The invention belongs to the technical field of pharmaceutical chemistry synthesis, and relates to a preparation method of 5-(4-bromophenyl)-4,6-dichloropyrimidine. The preparation method comprises the following steps: carrying out catalytic esterification on bromophenylacetic acid to prepare methyl p-bromophenylacetate, then carrying out a reaction with dimethyl carbonate to synthesize 2-(4-bromophenyl)-malonic acid-1,3-diethyl ester, carrying out cyclization by using formamidine hydrochloride to obtain 5-(4-bromophenyl)-4,6-dihydroxy pyrimidine, and then carrying out chlorination to obtain the product 5-(4-bromophenyl)-4,6-dichloropyrimidine. In the preparation process of the intermediate 1, a solid acid is adopted as a catalyst, so that the synthesis process and a post-treatment step are simplified. The solid acid is easy to separate and can be repeatedly used, so that resources are saved, and production cost is reduced. In a process of preparing the intermediate 2, sodium methoxideis adopted as an alkali to replace sodium hydride or amino sodium used in the prior art, so that production safety is improved, and production cost is reduced. Meanwhile, the intermediate 3 is prepared by adopting a one-pot method, so that operation steps are reduced.

Synthetic method for macitentan drug intermediate

The invention discloses a synthetic method for a macitentan drug intermediate. The synthetic method for the macitentan drug intermediate comprises the following raw material components: 20-30 parts ofanhydrous methanol, 6-8 parts of 4-bromophenylacetic acid, 8-10 parts of sulfonyl chloride, 20-40 parts of sodium methoxide, 10-15 parts of dimethyl carbonate, 5-10 parts of formamidine hydrochloride, 60-80 parts of phosphorus oxychloride (newly evaporated) and 1-2 parts of N,N-dimethylaniline. According to the provided synthetic scheme, synthetic raw materials are simple, the purity of the obtained product is higher than that of like products, and the requirement for keeping synthesizing macitentan can be met.

AN IMPROVED PROCESS FOR THE PREPARATION OF MACITENTAN

The present invention relates to an improved process for the preparation of macitentan and pharmaceutical acceptable salts thereof. Further present invention also relates to methylene chloride solvate of macitentan and their use in the preparation of pure macitentan.

4-PYRIMIDINESULFAMIDE DERIVATIVE

The invention relates to the compound of structural formula (I) and the salts thereof. Said compound is useful as endothelin receptor antagonist. The invention further relates to a process for preparing said compound.

The discovery of N -[5-(4-bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy] ethoxy]-4-pyrimidinyl]- N ′-propylsulfamide (macitentan), an orally active, potent dual endothelin receptor antagonist

Starting from the structure of bosentan (1), we embarked on a medicinal chemistry program aiming at the identification of novel potent dual endothelin receptor antagonists with high oral efficacy. This led to the discovery of a novel series of alkyl sulfamide substituted pyrimidines. Among these, compound 17 (macitentan, ACT-064992) emerged as particularly interesting as it is a potent inhibitor of ETA with significant affinity for the ET B receptor and shows excellent pharmacokinetic properties and high in vivo efficacy in hypertensive Dahl salt-sensitive rats. Compound 17 successfully completed a long-term phase III clinical trial for pulmonary arterial hypertension.

4-PYRIMIDINESULFAMIDE DERIVATIVE

The invention relates to the compound of structural formula (I) and the salts thereof. Said compound is useful as endothelin receptor antagonist. The invention further relates to a process for preparing said compound.

4-Amino-5-aryl-6-arylethynylpyrimidines: Structure-activity relationships of non-nucleoside adenosine kinase inhibitors

A series of non-nucleoside adenosine kinase (AK) inhibitors is reported. These inhibitors originated from the modification of 5-(3-bromophenyl)-7-(6-morpholin-4-ylpyridin-3-yl)pyrido[2,3-d]pyrimidin-4-ylamine (ABT-702). The identification of a linker that would approximate the spatial arrangement found between the pyrimidine ring and the aryl group at C(7) in ABT-702 was a key element in this modification. A search of potential linkers led to the discovery of an acetylene moiety as a suitable scaffold. It was hypothesized that the aryl acetylenes, ABT-702, and adenosine bound to the active site of AK (closed form) in a similar manner with respect to the orientation of the heterocyclic base. Although potent acetylene analogs were discovered based on this assumption, an X-ray crystal structure of 5-(4-dimethylaminophenyl)-6-(6-morpholin-4-ylpyridin-3-ylethynyl)pyrimidin-4-ylamine (16a) revealed a binding orientation contrary to adenosine. In addition, this compound bound tightly to a unique open conformation of AK. The structure-activity relationships and unique ligand orientation and protein conformation are discussed.

NOVEL SULFAMIDES

The invention relates to novel sulfamic acid amides and their use as active ingredients in the preparation of pharmaceutical compositions. The invention also concerns related aspects including pharmaceutical compositions containing one or more of those compounds and especially their use as endothelin receptor antagonists.

PYRIMIDINE-SULFAMIDES AND THEIR USE AS ENDOTHELIAN RECEPTOR ANTAGONIST

The invention relates to novel sulfamic acid amides of General Formula (I) and their use as active ingredients in the preparation of pharmaceutical compositions. The invention also concerns related aspects including processes for the preparation of the compounds, pharmaceutical compositions containing one or more of those compounds and especially their use as endothelin receptor antagonists. [ADD FORMULA]