146533-41-7 Usage
Description
5-(4-Bromophenyl)-4,6-dichloropyrimidine is a key intermediate with a wide range of applications in the pharmaceutical and chemical fields, characterized by its unique chemical structure that features a bromophenyl group and two chlorine atoms.
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).
Check Digit Verification of cas no
The CAS Registry Mumber 146533-41-7 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 1,4,6,5,3 and 3 respectively; the second part has 2 digits, 4 and 1 respectively.
Calculate Digit Verification of CAS Registry Number 146533-41:
(8*1)+(7*4)+(6*6)+(5*5)+(4*3)+(3*3)+(2*4)+(1*1)=127
127 % 10 = 7
So 146533-41-7 is a valid CAS Registry Number.
146533-41-7Relevant articles and documents
Preparation method of 5-(4-bromophenyl)-4,6-dichloropyrimidine
-
Paragraph 0056; 0063; 0065; 0070; 0077; 0084; 0091, (2019/01/08)
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
-
Paragraph 0013; 0022; 0027; 0032, (2019/01/14)
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.
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
Bolli, Martin H.,Boss, Christoph,Binkert, Christoph,Buchmann, Stephan,Bur, Daniel,Hess, Patrick,Iglarz, Marc,Meyer, Solange,Rein, Josiane,Rey, Markus,Treiber, Alexander,Clozel, Martine,Fischli, Walter,Weller, Thomas
, p. 7849 - 7861 (2012/10/29)
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.
