57149-07-2

Naftopidil was launched in Japan for the treatment of dysuria associated with benign prostatic hypertrophy (BPH). It can be prepared by a two step route starting with α-naphthol. Naftopidil is a potent postsynaptic-selective alpha-l-antagonist with a slightly higher affinity for the human prostatic than for the aortic alpha-adrenoceptor. It also shows a 5-HT1A agonistic effect, as well as a weak calcium antagonistic activity, but no alpha-2 or beta-adrenoreceptor affinity. In experiments with rats or rabbits, Naftopidil was shown to be more potent and selective for the urodynamic effect than the hypotensive effect. Aromatic or aliphatic hydroxylation are the major routes of metabolism, producing metabolites with a profile similar to the parent compound.

Off-White Solid

Boehringer Mannheim (Germany)

A α-1-Adrenergic receptor antagonist, antihypertensive.

antihypertensive, alpha-blocker, 5HT1a agonist

ChEBI: Naftopidil is a member of piperazines.

Avishot;Flivas

An α 1 -adrenoceptor antagonist with only weak antagonism at post-junctional α 2 receptors; a potent, persistent antihypertensive and vasodilator.

The general procedure for the synthesis of 1-(4-(2-methoxyphenyl)piperazin-1-yl)-3-(naphthalen-1-yloxy)propan-2-ol from 3-(1-naphthyloxy)-1,2-epoxypropane and 1-(2-methoxyphenyl)piperazine was as follows: with reference to the synthesis of Example 1 (RS)-naphthalenophenedil (HUHS1001), to a solution of 2-((1-naphthyloxy)methyl) ethylene oxide (100 mg, 0.50 mmol) to a solution of 2-(2-methoxyphenyl)piperazine (95 μL, 0.60 mmol) in ethanol (1 mL). The reaction mixture was stirred at room temperature for 1 hour. Subsequently, the reaction mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to afford (RS)-naphthodil (199 mg, 100% yield). The structure of the product was confirmed by 1H-NMR (400 MHz, CDCl3) and ESI-HRMS (cation, sodium formate).1H-NMR data were as follows: δ 2.72-2.76 (m, 4H), 2.92-2.95 (m, 2H), 3.09-3.18 (m, 4H), 3.87 (s, 3H), 4.16 (dd, J = 9.6 and 5.0 Hz, 1H), 4.24 (dd, J = 9.6 and 5.0 Hz, 1H), 4.28-4.34 (m, 1H), 6.84 (d, J = 7.8 Hz, 1H), 6.87 (d, J = 7.8 Hz, 1H), 6.91-6.98 (m, 2H), 7.00-7.04 (m, 1H), 7.39 (t , J = 8.2 Hz, 1H), 7.44 (d, J = 8.2 Hz, 1H), 7.47-7.51 (m, 2H), 7.79-7.81 (m, 1H), 8.26-8.29 (m, 1H).ESI-HRMS (cation, sodium formate) Calculated value: C24H29N2O3 ([M + H]+) m/z 393.2173 , measured value 393.2148.

[1] Patent: US2015/353473, 2015, A1. Location in patent: Paragraph 0179-0181
[2] Patent: JP6041303, 2016, B2. Location in patent: Paragraph 0064-0066
[3] Journal of Organic Chemistry, 2007, vol. 72, # 10, p. 3713 - 3722
[4] Patent: US3997666, 1976, A