Naftopidil
1-[4-(2-methoxyphenyl)piperazin-1-yl]-3-naphthalen-1-yloxypropan-2-ol
C24H28N2O3, 392.49
CAS 57149-07-2
1-(4-(2-methoxyphenyl)piperazin-1-yl)-3-(naphthalen-1-yloxy)propan-2-ol
Naftopidil (INN, marketed under the brand name Flivas) is a drug used in benign prostatic hypertrophy which acts as a selective α1-adrenergic receptor antagonist or alpha blocker.[1]
PATENT
DE 2408804
CN 101671317
CN 102816136
JP 2013023467
JP 2014118360
IN 2011CH00466
US 20150353473
CN 104744405
IN 2013CH06042
IN 2012DE02071
JP 2016044182
PAPER
ChemMedChem (2009), 4(3), 393-9.
The Journal of organic chemistry (2013), 78(18), 9076-84.
e-EROS Encyclopedia of Reagents for Organic Synthesis (2014), 1-5
European journal of medicinal chemistry (2015), 96, 83-91.
Bioorganic & medicinal chemistry letters (2018), 28(9), 1534-1539.
ChemistrySelect (2019), 4(26), 7745-7750.
Green Chemistry (2019), 21(16), 4422-4433. |
PAPER
https://www.scielo.br/j/jbchs/a/q5qDxfT9mSwtL9hhQYxyhgs/?lang=en#
(S)-1-(4-(2-Methoxyphenyl)piperazin-1-yl)-3-(naphthalene1-yloxy)propan-2-ol (2b) To a solution of epoxide 8b (0.1 g, 0.5 mmol) in anhydrous 2-propanol (10 mL) was added 1-(2-methoxyphenyl) piperazine (0.096 g, 0.5 mmol) and the reaction mixture was refluxed for 32 h. After completion of reaction, the solvent was removed under reduced pressure and purification was carried out by flash column chromatography (230-400 mesh silica). The EtOAc:petroleum ether (60:40) was used as solvent system for elution, it afforded the (S)-(+)-naftopidil 2b as a yellow solid (0.156 g, 80%); mp 126-127°C; [α]D 25 +4.3o (c 1.55, MeOH);3 [α]D 25 +4.5o (c 1.5, MeOH); IR (CHCl3) νmax/cm-1 3403, 3031, 2977, 2907, 1261, 1225; 1 H NMR (300 MHz, CDCl3) d 2.58-2.70 (m, 4H, N-CH2), 2.80-2.85 (m, 2H, CH2N), 3.03-3.51 (m, 4H, NCH2), 3.51 (bs, 1H, OH), 3.75 (s, 3H, OCH3), 4.02-4.10 (m, 2H, OCH2), 4.19-4.23 (m, 1H, CH), 6.72-6.85 (m, 2H, Ar-H), 6.83-6.85 (d, 2H, J 3.9 Hz, Ar-H), 6.87-6.95 (1H, m, Ar-H), 7.14-7.29 (1H, m, Ar-H), 7.33-7.42 (3H, m, Ar-H), 7.69-7.72 (m, 1H, Ar-H), 8.19-8.22 (m, 1H, Ar-H); 13C NMR (75 MHz, CDCl3) d 50.44 (NCH2), 53.43 (NCH2), 55.17 (OCH3), 60.85 (CH2N), 65.47 (CH), 70.36 (OCH2), 104.73 (Ar), 111.03 (Ar), 118.05 (Ar), 120.39 (Ar), 120.83 (Ar), 121.78 (Ar), 122.91 (Ar), 125.07 (Ar), 125.41 (Ar), 125.67 (Ar), 126.26 (Ar), 127.32 (Ar), 134.31 (Ar), 140.87 (Ar), 152.04 (Ar), 154.21 (Ar); LC-MS m/z 393.36 (M+ + 1), 415.36 (M+ + Na); For compound 2a: [α]D 25 -10.6o (c 1, MeOH,);6 [α]D 25 -11.7o (c 1, MeOH).
PATENT
CN 1473820
PATENT
WO 2018026371
https://patents.google.com/patent/WO2018026371A1/en
PATENT
JP-2021104982
Naftopidil monohydrochloride dihydrate and its use for the preparation of naftopidil , which is known as an ameliorating agent for dysuria associated with benign prostatic hyperplasia.
Laid-Open No. 50-12186 patcit 2: Japanese Patent Application Laid-Open No.
2013-23467 patcit 3: Indian Patent Application 466 / CHE / 2011
patcit 4: Indian Patent Application 2071 / DEL / 2012
of Naftopidil Monohydrochloride Dihydrate The naftopidil monohydrochloride dihydrate according to the present invention is preferably prepared according to the following scheme.
[Chem. 2]
[Chem. 3]
100 g of 1 -naphthol [1] was dissolved in chloromethyloxylan [2], and a sodium methoxide methanol solution was added dropwise. After completion of the reaction, the reaction was washed with water and the organic layer was concentrated to obtain 2-[(1-naphthyloxy) methyl] oxylan [3] (yield 89%).
A toluene solution of 1- (2-methoxyphenyl) piperazin [4] was added dropwise to a toluene solution of 5.0 g of 2-[(1-naphthyloxy) methyl] oxylan [3]. After completion of the reaction, the mixture was washed with water and cooled by adding hydrochloric acid. After the suspension is filtered off, it is dried and (2RS) -1- [4- (2-methoxyphenyl) piperazin-1-yl] -3- (naphthalene-1-yloxy) propan-2-ol. Hydrochloride dihydrate [5] was obtained (yield 95%).
A toluene solution of 1- (2-methoxyphenyl) piperazin [4] was added dropwise to a toluene solution of 5.0 g of 2-[(1-naphthyloxy) methyl] oxylan [3]. After completion of the reaction, the mixture was washed with water, methanol and hydrochloric acid were added to separate the liquids, and the mixture was cooled. After the suspension is filtered off, it is dried and (2RS) -1- [4- (2-methoxyphenyl) piperazin-1-yl] -3- (naphthalene-1-yloxy) propan-2-ol. Hydrochloride dihydrate [5] was obtained (yield 81%).
A toluene solution of 1- (2-methoxyphenyl) piperazin [4] was added dropwise to a toluene solution of 5.0 g of 2-[(1-naphthyloxy) methyl] oxylan [3]. After completion of the reaction, the mixture was washed with water, methanol and hydrochloric acid were added, and the mixture was cooled. After the suspension is filtered off, it is dried and (2RS) -1- [4- (2-methoxyphenyl) piperazin-1-yl] -3- (naphthalene-1-yloxy) propan-2-ol. Hydrochloride dihydrate [5] was obtained (yield 86%).
A toluene solution of 1- (2-methoxyphenyl) piperazin [4] was added dropwise to a toluene solution of 100 g of 2-[(1-naphthyloxy) methyl] oxylan [3]. After completion of the reaction, the mixture was washed with water, methanol and hydrochloric acid were added, and the mixture was cooled. After the suspension is filtered off, it is dried and (2RS) -1- [4- (2-methoxyphenyl) piperazin-1-yl] -3- (naphthalene-1-yloxy) propan-2-ol. Hydrochloride dihydrate [5] was obtained (yield 92%).
(2RS) -1- [4- (2-methoxyphenyl) piperazin-1-yl] -3- (naphthalene-1-yloxy) propan-2-ol monohydrochloride dihydrate [5 ] Toluene and sodium hydroxide aqueous solution were added to 7.0 g. The organic layer was washed with water and concentrated, and then metall and acetonitrile were added and cooled. After the suspension is filtered off, it is dried and (2RS) -1- [4- (2-methoxyphenyl) piperazin-1-yl] -3- (naphthalene-1-yloxy) propan-2-ol [ 6] was obtained (yield 82%, chemical purity 99.98%).
(2RS) -1- [4- (2-methoxyphenyl) piperazin-1-yl] -3- (naphthalene-1-yloxy) propan-2-ol monohydrochloride dihydrate [5 ] Toluene and an aqueous sodium hydroxide solution were added to 12.0 g. The organic layer was washed with water and concentrated, then metall was added and cooled. After the suspension is filtered off, it is dried and (2RS) -1- [4- (2-methoxyphenyl) piperazin-1-yl] -3- (naphthalene-1-yloxy) propan-2-ol [ 6] was obtained (yield 90%, chemical purity 99.99%).
(2RS) -1- [4- (2-Methoxyphenyl) piperazin-1-yl] -3- (naphthalene-1-yloxy) propan-2-ol monohydrochloride dihydrate [5 ] Toluene, methanol, and potassium hydroxide aqueous solution were added to 116 g. The organic layer was washed with water and concentrated, then 2-propanol was added and cooled. After the suspension is filtered off, it is dried and (2RS) -1- [4- (2-methoxyphenyl) piperazin-1-yl] -3- (naphthalene-1-yloxy) propan-2-ol [ 6] was obtained (yield 90%, chemical purity 99.98%).
A toluene solution of 1- (2-methoxyphenyl) piperazin [4] was added dropwise to a 10.0 g toluene solution of 2-[(1-naphthyloxy) methyl] oxylan [3]. After completion of the reaction, the mixture was washed with water and cooled. After the suspension is filtered off, it is dried and (2RS) -1- [4- (2-methoxyphenyl) piperazin-1-yl] -3- (naphthalene-1-yloxy) propan-2-ol [ 6] Crude crystals were obtained (yield 89%).
(2RS) -1- [4- (2-methoxyphenyl) piperazin-1-yl] -3- (naphthalene-1-yloxy) propan-2-ol [6] obtained in Comparative Example 1. Methoxyol and acetonitrile were added to 6.0 g of the crude crystals of the above, and the mixture was cooled. After the suspension is filtered off, it is dried and (2RS) -1- [4- (2-methoxyphenyl) piperazin-1-yl] -3- (naphthalene-1-yloxy) propan-2-ol [ 6] was obtained (yield 85%, chemical purity 99.96%).
(1) water and HCl content
mosquito – Le Fischer – water content value measured by the law was 7.3% to 7.5%. The amount of HCl measured by neutralization titration was 8.0% to 8.1%. Determined from these naftopidil: HCl: H 2 When calculating these molar ratios from O weight ratio of approximately 1: 1: 2. From this, it was judged that naftopidil monohydrochloride dihydrate was obtained.
(2) Powder X-ray Diffraction
The chart of the results of powder X-ray diffraction (Cu-Kα) of naftopidil monohydrochloride dihydrate was as shown in FIG. For reference, a chart of naftopidil is shown as FIG.
(3) Differential Thermal Analysis / Thermogravimetric Analysis
(TG / DTA) The chart of the results of differential thermal analysis / thermogravimetric analysis (TG / DTA) of naphthopidyl monohydrochloride dihydrate is as shown in FIG. rice field. Here, the measurement conditions were such that the heating rate was 5 ° C./min. For reference, a chart of naftopidil is shown as FIG.
References
- ^ Sakai H, Igawa T, Onita T, Furukawa M, Hakariya T, Hayashi M, Matsuya F, Shida Y, Nishimura N, Yogi Y, Tsurusaki T, Takehara K, Nomata K, Shiraishi K, Shono T, Aoki D, Kanetake H (2011). “Efficacy of naftopidil in patients with overactive bladder associated with benign prostatic hyperplasia: prospective randomized controlled study to compare differences in efficacy between morning and evening medication”. Hinyokika Kiyo. 57 (1): 7–13. PMID 21304253.
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| Clinical data | |
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| Trade names | ertv |
| AHFS/Drugs.com | International Drug Names |
| Routes of administration |
Oral |
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| CompTox Dashboard (EPA) | |
| ECHA InfoCard | 100.220.557  |
| Chemical and physical data | |
| Formula | C24H28N2O3 |
| Molar mass | 392.499 g·mol−1 |
| 3D model (JSmol) | |
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/////////////////Naftopidil, KT 611, a-Adrenergic Blocker, Antihypertensive
COC1=CC=CC=C1N2CCN(CC2)CC(COC3=CC=CC4=CC=CC=C43)O