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| | 5-(4-Bromophenyl)-4,6-dichloropyrimidine Basic information | | Uses |
| Product Name: | 5-(4-Bromophenyl)-4,6-dichloropyrimidine | | Synonyms: | PyriMidine, 5-(4-broMophenyl)-4,6-dichloro-;5-(4-broMophenyl)-4,6-dichloropyriMidine;5-(4-Bromophenyl)-4,6-dichloro-Pyrimidin;5-(4-broMophenyl)-4;Macitentan Intermediate 1;5-(4-Bromophenyl)-4,6-dichloropyrimidine(146533-41-7);Macitentan Impurity 26;5-(4-Bromophenyl)-4,6-dichloro-1,3-diazine | | CAS: | 146533-41-7 | | MF: | C10H5BrCl2N2 | | MW: | 303.97 | | EINECS: | | | Product Categories: | 146533-41-7 | | Mol File: | 146533-41-7.mol |  |
| | 5-(4-Bromophenyl)-4,6-dichloropyrimidine Chemical Properties |
| Melting point | 98.0 to 102.0 °C | | Boiling point | 368.7±42.0 °C(Predicted) | | 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) | | form | Solid | | pka | -4.92±0.26(Predicted) | | color | Off-White | | Sensitive | Light Sensitive | | InChI | InChI=1S/C10H5BrCl2N2/c11-7-3-1-6(2-4-7)8-9(12)14-5-15-10(8)13/h1-5H | | InChIKey | WEEFLZORZXLIJE-UHFFFAOYSA-N | | SMILES | C1=NC(Cl)=C(C2=CC=C(Br)C=C2)C(Cl)=N1 |
| | 5-(4-Bromophenyl)-4,6-dichloropyrimidine Usage And Synthesis |
| Uses | 5-(4-Bromophenyl)-4,6-dichloropyrimidine is a reactant used in the synthesis of Macitentan, an orally active dual endothelin receptor antagonist. | | Description | 5 - (4-Bromophenyl)-4, 6- dichloropyrimidine is a key intermediate and has a wide range of
applications in the pharmaceutical and chemical fields. | | Uses | 5-(4-Bromophenyl)-4,6-dichloropyrimidine is a reactant used in the synthesis of Macitentan, an orally active dual endothelin receptor antagonist. | | Synthesis Reference(s) | [1] Hou, S., Chen, C., Wang, P., Sun, C.-F., Zheng, P., & Xu, S. (2016). Synthesis of 5-(4-bromophenyl) - 4, 6- dichloropyrimidine. 0. https://doi.org/10.2991/ICMMCT-16.2016.151 | | 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 ¨C 2 - ( 4
¨Cbromophenyl ) 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 ) | 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). | | References | [1] Journal of Medicinal Chemistry, 2012, vol. 55, # 17, p. 7849 - 7861
[2] Monatshefte fur Chemie, 2018, vol. 149, # 3, p. 653 - 661
[3] Bioorganic and Medicinal Chemistry, 2007, vol. 15, # 4, p. 1586 - 1605
[4] Patent: WO2004/50640, 2004, A1. Location in patent: Page 31
[5] Patent: WO2009/24906, 2009, A1. Location in patent: Page/Page column 13-14 |
| | 5-(4-Bromophenyl)-4,6-dichloropyrimidine Preparation Products And Raw materials |
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