Mabuterol

Mabuterol
Clinical data
Other names	Mabuterolum; PB 868Cl
Identifiers
	IUPAC name 1-[4-amino-3-chloro-5-(trifluoromethyl)phenyl]-2-(tert-butylamino)ethanol;
CAS Number	56341-08-3;
PubChem CID	3995;
ChemSpider	3857;
UNII	R4K19W6S7Q;
ChEBI	CHEBI:135325;
ChEMBL	ChEMBL86749;
CompTox Dashboard (EPA)	DTXSID3048283 ;
Chemical and physical data
Formula	C13H18ClF3N2O
Molar mass	310.75 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES Clc1cc(cc(c1N)C(F)(F)F)C(O)CNC(C)(C)C;
	InChI InChI=1S/C13H18ClF3N2O/c1-12(2,3)19-6-10(20)7-4-8(13(15,16)17)11(18)9(14)5-7/h4-5,10,19-20H,6,18H2,1-3H3; Key:JSJCTEKTBOKRST-UHFFFAOYSA-N;

Mabuterol is a selective β₂ adrenoreceptor agonist.^[1]^[2]

Synthesis

The halogenation of 2-(Trifluoromethyl)aniline [88-17-5] (1) with iodine and sodium bicarbonate resulted in 2-Amino-5-Iodobenzotrifluoride [97760-97-9] (2). Protection with acetic anhydride followed by nucleophilic aromatic displacement with copper(I)cyanide gave N-[4-cyano-2-(trifluoromethyl)phenyl]acetamide [175277-96-0] (3). Hydrolysis of the nitrile and the protecting group gave 4-amino-3-(trifluoromethyl)benzoic acid [400-76-0] (4). Halogenation with chlorine gave 4-Amino-3-Chloro-5-(Trifluoromethyl)Benzoic Acid [95656-52-3] (5). Halogenation of the acid with thionyl chloride gave 4-Amino-3-chloro-5-(trifluoromethyl)benzoylchloride [63498-15-7] (6). Treatment with diethyl malonate [105-53-3] gave the acetophenone and hence 1-[4-amino-3-chloro-5-(trifluoromethyl)phenyl]ethanone [97760-76-4] (7). Halogenation with bromine in acetic acid led to 1-[4-amino-3-chloro-5-(trifluoromethyl)phenyl]-2-bromoethanone [97760-87-7] (8). Treatment with tert-butylamine [75-64-9] yielded 1-[4-amino-3-chloro-5-(trifluoromethyl)phenyl]-2-(tert-butylamino)ethenone, CID:13355601 (9). Reduction of the ketone with sodium borohydride completed the synthesis of Mabuterol (10).

References

^ Osada E, Murai T, Ishizaka Y, Sanai K (1984). "Pharmacological studies of mabuterol, a new selective beta 2-stimulant. II: Effects on the cardiovascular system and smooth muscle organs". Arzneimittel-Forschung. 34 (11A): 1641–1651. PMID 6152157.
^ Akahane K, Furukawa Y, Ogiwara Y, Haniuda M, Chiba S (July 1989). "Beta-adrenoceptor blocking effects of a selective beta 2-agonist, mabuterol, on the isolated, blood-perfused right atrium of the dog". British Journal of Pharmacology. 97 (3): 709–716. doi:10.1111/j.1476-5381.1989.tb12007.x. PMC 1854580. PMID 2474351.
^ Krüger G, Keck J, Noll K, Pieper H (1984). "Synthesis of further amino-halogen-substituted phenyl-aminoethanols". Arzneimittel-Forschung. 34 (11A): 1612–24. PMID 6152154.
^ BE 808743, Engelhardt G, Keck J, "Aminophenyl ethanolamines and oxazolidines - having analgesic, uterus spasmolytic and anti-spasmodic activity on cross-striped muscle structure", issued 1974, assigned to Thomae GmbH.
^ US 4119710, issued 1978, assigned to Boehringer Ing.
^ DE 2351281, assigned to Thomae GmbH.
^ Tu Y, Zhong J, Wang H, Pan J, Xu Z, Yang W, Luo Y (November 2016). "Synthesis of stable isotope labeled D9 -Mabuterol, D9 -Bambuterol, and D9 -Cimbuterol". Journal of Labelled Compounds & Radiopharmaceuticals. 59 (13): 546–551. doi:10.1002/jlcr.3446. PMID 27739098.

[1] Osada E, Murai T, Ishizaka Y, Sanai K (1984). "Pharmacological studies of mabuterol, a new selective beta 2-stimulant. II: Effects on the cardiovascular system and smooth muscle organs". Arzneimittel-Forschung. 34 (11A): 1641–1651. PMID 6152157.

[pmid2474351-2] Akahane K, Furukawa Y, Ogiwara Y, Haniuda M, Chiba S (July 1989). "Beta-adrenoceptor blocking effects of a selective beta 2-agonist, mabuterol, on the isolated, blood-perfused right atrium of the dog". British Journal of Pharmacology. 97 (3): 709–716. doi:10.1111/j.1476-5381.1989.tb12007.x. PMC 1854580. PMID 2474351.

[pmid6152154-3] Krüger G, Keck J, Noll K, Pieper H (1984). "Synthesis of further amino-halogen-substituted phenyl-aminoethanols". Arzneimittel-Forschung. 34 (11A): 1612–24. PMID 6152154.

[4] BE 808743, Engelhardt G, Keck J, "Aminophenyl ethanolamines and oxazolidines - having analgesic, uterus spasmolytic and anti-spasmodic activity on cross-striped muscle structure", issued 1974, assigned to Thomae GmbH.

[5] US 4119710, issued 1978, assigned to Boehringer Ing.

[6] DE 2351281, assigned to Thomae GmbH.

[pmid27739098-7] Tu Y, Zhong J, Wang H, Pan J, Xu Z, Yang W, Luo Y (November 2016). "Synthesis of stable isotope labeled D9 -Mabuterol, D9 -Bambuterol, and D9 -Cimbuterol". Journal of Labelled Compounds & Radiopharmaceuticals. 59 (13): 546–551. doi:10.1002/jlcr.3446. PMID 27739098.

[1]

[2]

[3]

[4]

[5]

[6]

[7]

Synthesis

See also

References