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
Improved and single-pot process for the synthesis of macitentan, an endothelin receptor antagonist, via lithium amide-mediated nucleophilic substitution
Jagtap, Kunal M.,Niphade, Navnath C.,Gaikwad, Chandrashekhar T.,Shinde, Gorakshanath B.,Toche, Raghunath B.,Joshi, Divyesh R.,Mathad, Vijayavitthal T.
, p. 653 - 661 (2018/03/09)
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.].
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.
4-PYRIMIDINESULFAMIDE DERIVATIVE
-
, (2012/06/16)
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.