Palonosetron hydrochloride, and precursor compound and preparation method thereof

A technology of precursor compounds and compounds, applied in the direction of digestive system, organic chemistry, drug combination, etc., can solve the problems of safety and high cost

Inactive Publication Date: 2010-10-06
SICHUAN DIHON MEDICAL DEV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011]The above synthetic routes have their own disadvantages. The key reactions require conditions such as anhydrous, anaerobic, and ultra-low temperature reactions, and metal hydrides are used, and the reaction conditions are very demanding. It is easy to have safety problems in mass production, and the cost is high

Method used

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  • Palonosetron hydrochloride, and precursor compound and preparation method thereof
  • Palonosetron hydrochloride, and precursor compound and preparation method thereof
  • Palonosetron hydrochloride, and precursor compound and preparation method thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0029] The preparation of embodiment 1 8-chloromethyl-1-naphthoic acid compound

[0030] Mix 1-naphthoic acid (4.3kg, 25mol), paraformaldehyde (1.5kg, 50mol), acetic acid (3.25L) and concentrated hydrochloric acid (4.5L), heat to 80-85°C, and stir vigorously for 6h. After the reaction is complete, cool to room temperature, adjust the pH to 3 with sodium bicarbonate under an ice-water bath. Filter with suction, wash with water (500ml×2), and dry the obtained solid at 80°C for 10h. The crude product was recrystallized from toluene to give 8-chloromethyl-1-naphthoic acid (3.5 kg, m.p. 177-178°C). ESI-MS (positive mode) m / z: 221.4[M+1]+, 1HNMR (400MHz, CDCl3): δ8.36 (1H, d, J=7.2Hz), 8.10 (1H, d, J=8.4Hz ), 7.86 (1H, d, J = 8.4Hz), 7.63 (1H, t, J = 7.6, 8.0Hz), 7.57 (1H, t, J = 7.6, 8.0Hz), 7.38 (1H, d, J = 6.8Hz), 4.95 (2H, s).

Embodiment 2

[0031] Example 2 Preparation of 8-[(3S)-1-azabicyclo[2.2.2]octyl]-aminomethyl-1-naphthoic acid

[0032] The product 8-chloromethyl-1-naphthoic acid (3.3kg, 15mol) of embodiment 1, S-3-aminoquinuclidinine (1.89kg, 15mol) and potassium carbonate (4.1kg, 30mol) are placed in ethanol , Water mixed solvent (1 / 1 ethanol / water, 50L), reflux for 5h. Cool to room temperature, add 2L of concentrated hydrochloric acid, stir at room temperature for 2h, spin dry the solvent under reduced pressure, add 50L of ethanol, stir at room temperature for 2h, filter to remove insoluble matter. The solvent was spin-dried under reduced pressure to obtain 8-[(3S)-1-azabicyclo[2.2.2]octyl]-aminomethyl-1-naphthoic acid (4.5kg, m.p.>270°C (dec.), (c=1, CHCl3), ESI-MS (positive mode) m / z: 311.3[M+1]+, 1HNMR (400MHz, CDCl3): δ8.27 (1H, d, J=7.2Hz), 7.91 ( 1H, d, J = 8.4Hz), 7.70 (1H, d, J = 8.4Hz), 7.53 (1H, t, J = 7.6, 8.0Hz), 7.33 (1H, t, J = 7.6, 8.0Hz), 7.14(1H, d, J=6.8Hz), 4.47-4.49(m, 1H), 3.99-4...

Embodiment 3

[0033] Example 3 Preparation of 2-[(3S)-1-azabicyclo[2.2.2]octyl]-2,3-dihydro-1H-benzo[de]isoquinolin-1-one

[0034] The product 8-[(3S)-1-azabicyclo[2.2.2]octyl]-aminomethyl-1-naphthoic acid (3.1kg, 10mol), DCC (2.06kg, 10mol) of embodiment 2 Stir in 50 L of dichloromethane at room temperature for 5 h, filter and concentrate the reaction mixture to give 2-[(3S)-1-azabicyclo[2.2.2]octyl]-2,3-dihydro-1H-benzene And[de]isoquinolin-1-one (2.89kg, m.p.148-149°C, (c=1, CHCl3), ESI-MS (positive mode) m / z: 293.1[M+1]+, 1HNMR (400MHz, CDCl3): δ8.31 (1H, d, J=7.2Hz), 8.02 (1H, d, J = 8.4Hz), 7.79 (1H, d, J = 8.4Hz), 7.63 (1H, t, J = 7.6, 8.0Hz), 7.49 (1H, t, J = 7.6, 8.0Hz) , 7.31(1H, d, J=6.8Hz), 4.45-4.71(m, 3H), 3.91(m, 1H), 3.79(m, 2H), 3.38(m, 3H), 2.49(m, 1H), 1.89-2.34 (m, 4H).

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Abstract

The invention discloses a palonosetron hydrochloride, and a precursor compound and a preparation method thereof. Referring to the formula (3), the structure of the precursor compound is as follows: 8-(1-azabicyclo [2, 2, 2] capryl-3S-yl)-aminomethyl-1-naphthoic acid compound. The preparation method of the precursor compound comprises the following steps of: reacting 1-naphthoic acid or ester compound thereof with haloid acid and methylating reagent under the catalysis of Lewis acid to obtain midbody 8-chloromethyl-1-naphthoic acid; further reacting with (S)-1-azabicyclo [2, 2, 2] capryl-3-yl-amine under the alkaline condition; cyclizing in molecule to obtain 2-(1-azabicyclo [2, 2, 2] capryl-3S-yl)-2, 3-dihydro-1H-benzo [de] isoquinoline-1-ketone compounds; and further performing selectivecatalytic hydrogenation reaction to obtain the object product.

Description

technical field [0001] The present invention relates to the preparation of compound 2-(1-azabicyclo[2.2.2]oct-3S-yl)-2,3,3a,4,5,6-hexahydro-1H-benzo[de]iso Quinolin-1-one and its pharmaceutically acceptable salt, its precursor compound and its corresponding preparation method. Background technique [0002] Palonosetron hydrochloride is a selective 5-Ht3 receptor antagonist developed by Helsinn, Switzerland, with a chemical name of 2-[(3S)-1-azabicyclo[2.2.2]octyl]-2, 3,3aS, 4,5,6-hexahydro-1H-benzo[de]isoquinolin-1-one hydrochloride, see I for the molecular structure formula, this product was approved by the US FDA on July 25, 2003, For the prevention of acute and delayed nausea and vomiting associated with moderately to highly emetogenic chemotherapy. [0003] [0004] Regarding the synthetic process route of palonosetron hydrochloride, after literature research, the following routes are summarized: [0005] Route 1: With 1,8-naphthalene dioic anhydride as the startin...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D453/02A61P1/08
Inventor 李蕾蕾刘成黄衡邓兰
Owner SICHUAN DIHON MEDICAL DEV
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