Process for preparing cinacalcet

A technology of compounds and intermediates, applied in the field of preparation of active product component cinacalcet, which can solve problems such as difficult synthesis

Active Publication Date: 2012-07-04
F I S FAB ILTALIANA SINTETICI SPA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] According to Synthetic Communications, 38: 1512-1517 (2008), the above-mentioned cinacalcet synthesis involves using such as Ti(O-i-Pr) 4 and reagents such as DIBAL-H, which have to b...

Method used

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  • Process for preparing cinacalcet

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0100] Synthesis of (R)-3-(1-(naphthalen-1-yl)ethylamino)-1-(3-(trifluoromethyl)phenyl)propan-1-ol hydrochloride (IXa)

[0101]

[0102] (R)-3-(1-(naphthalen-1-yl)ethylamino)-1-(3-(trifluoromethyl)phenyl)propan-1-one hydrochloride (V) (15.95g, 39.104mmol) was suspended in cold methanol (50ml) at -10°C, followed by the slow addition of sodium borohydride solution (0.75g, 19.610mmol), 30% w / w aqueous sodium hydroxide (5.74g, 43.014mmol) and water (5ml) in order to keep the internal temperature below 0°C. The reaction mixture was stirred at 0°C for 0.5 hours and then quenched by the addition of 30% w / w aqueous hydrochloric acid to pH = 1, then water (40ml) and allowed to reach room temperature. The thick suspension thus formed was heated to 50°C, stirred for 20 minutes, then cooled to 5°C. The precipitate was filtered, washed with a 9:1 vol / vol water / methanol mixture (10 ml) and dried under vacuum at 50°C. Obtained 14.69 g (35.841 mmol) of high quality (R)-3-(1-(naphthalene...

Embodiment 2

[0104] (R)-3-Chloro-N-(1-(naphthalene-1-yl)ethyl)-3-(3-(trifluoromethyl)phenyl)propan-1-amine hydrochloride (X) synthesis

[0105]

[0106] (R)-3-(1-(naphthalen-1-yl)ethylamino)-1-(3-(trifluoromethyl)phenyl)propan-1-ol hydrochloride (IXa) (20.0 g, 48.796mmol) was suspended in toluene (140ml) at 40°C, and phosphorus oxychloride (4.3g, 28.044mmol) was added dropwise within 10 minutes. The reaction mixture was stirred at 60°C for 2 hours, then DMF (1.0 g) was added at 40°C, followed by additional phosphorus oxychloride (3.2 g, 20.870 mmol). The mixture was stirred overnight at 40°C, then MTBE (40ml) was added. Volatiles were removed and MTBE was recovered by repeated distillation under vacuum. Thereafter, a 1:1 vol / vol toluene / MTBE solution heated to 70°C was added and allowed to cool slowly to 15°C-20°C. The precipitate thus obtained was aged overnight at room temperature, then filtered and washed with a 1:1 vol / vol toluene / MTBE mixture (3 x 12 ml). After drying under va...

Embodiment 3

[0108] (R)-3-Chloro-N-(1-(naphthalene-1-yl)ethyl)-3-(3-(trifluoromethyl)phenyl)propan-1-amine hydrochloride (X) and (R, E)-N-(1-(naphthalene-1-yl)ethyl)-3-(3-(trifluoromethyl)phenyl)prop-2-en-1-amine hydrochloride (XI )Synthesis

[0109]

[0110] Method A

[0111] (R)-3-(1-(naphthalen-1-yl)ethylamino)-1-(3-(trifluoromethyl)phenyl)propan-1-ol hydrochloride (IX) (35.0g, 85.393mmol) was suspended in toluene (150ml) at 20°C, and thionyl chloride (11.2.g, 94.141mmol) was added slowly. The reaction mixture was stirred at 30°C-40°C for 4-5 hours, then the solvent was distilled off under vacuum. After several distillation / refill cycles, the residual toluene slurry was rinsed with isopropanol. The resulting isopropanol solution was refluxed for 1 hour, then cooled to 45°C and methyl tert-butyl ether (MTBE) (70ml) was added. The suspension thus obtained was stirred at 45°C for 1 hour, then cooled to 0°C and aged for 1 hour. After filtration, washing with a 3:1 vol / vol isopropan...

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PUM

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Abstract

The invention relates to a process for preparing N-[(1R)-1-(1-naphthyl)ethyl]-3-[3-(trifluoromethyl)-phenyl]propan-1-amine of formula hydrochloride salt of formula (I); i.e. Cinacalcet.HC1 and its intermediate of formula (IX).

Description

technical field [0001] The present invention relates to a process for the preparation of the active product ingredient cinacalcet, its intermediates and its pharmaceutically acceptable hydrochloride. Background technique [0002] Cinacalcet (CNC), namely N-[(1R)-1-(1-naphthyl)ethyl]-3-[3-(trifluoromethyl)-phenyl]propan-1-amine, Use in therapy as the hydrochloride salt of formula (I). [0003] [0004] In the EU as MIMPARA TM Cinacalcet hydrochloride (CNC.HCl) is marketed as a calcium mimetic that reduces parathyroid hormone secretion by activating calcium receptors. [0005] MIMPARA TM Approved for the treatment of secondary hyperparathyroidism (SHPT) (in patients with chronic kidney disease receiving dialysis) and for the treatment of primary hyperparathyroidism (PHPT) (in patients undergoing parathyroidectomy in clinically inappropriate or contraindicated patients). [0006] US Patent No. 6,011,068 discloses a class of arylalkylamines which generally include cinaca...

Claims

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Application Information

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IPC IPC(8): C07C209/74C07C211/30
CPCC07C209/74C07C211/30
Inventor N·卡托兹L·科塔卡J·弗莱托M·福尔卡托R·焦瓦内蒂G·索里亚托M·弗齐尼
Owner F I S FAB ILTALIANA SINTETICI SPA
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