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Synthesis process of palonosetron hydrochloride hydrochloride

A technology for palonosetron hydrochloride and a synthesis process, which is applied in the field of synthesis technology of palonosetron hydrochloride, can solve problems such as low yield, and achieve the effects of high yield and simplified steps

Active Publication Date: 2017-08-25
陕西开元制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] (1) yield is too low, and the total yield of palonosetron hydrochloride (being SS type) only has 12%;

Method used

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  • Synthesis process of palonosetron hydrochloride hydrochloride
  • Synthesis process of palonosetron hydrochloride hydrochloride
  • Synthesis process of palonosetron hydrochloride hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Example 1 N-[(3,4-dihydronaphthyl-1-yl )methyl]-(S)-1-azabicyclo[2.2.2]octane-3-amine n-butanol solution

[0027] 3,4-dihydro-1-naphthylmethylamine hydrochloride (content greater than 99%, 35g, 0.18mol), 3-quinuclidone hydrochloride (content greater than 99%, 29g, 0.18mol) and toluene (300ml) was added triethylamine (45g, 0.45mol) under stirring, heated to reflux for 4h, the solvent was evaporated under reduced pressure, n-butanol (200ml) was added to the residue, cooled to 0°C, and sodium borohydride was added in batches (7.5g, 0.2mol), react at room temperature for 4h. Evaporate n-butanol under reduced pressure, add water (200ml) to the residue, extract with water-saturated n-butanol (200ml×2), combine organic phases, dry over anhydrous magnesium sulfate, filter to obtain N-[(3,4 -N-butanol solution of -dihydronaphthalen-1-yl)methyl]-(S)-1-azabicyclo[2.2.2]octane-3-amine (45g, yield 93.2%), take an appropriate amount For HPLC analysis. HPLC analysis method and ana...

Embodiment 2

[0050] Example 2 Directly in the n-butanol of N-[(3,4-dihydronaphthalene-1-yl)methyl]-(S)-1-azabicyclo[2.2.2]octane-3-amine Add catalyst to the solution for hydrogenation reduction to obtain N-[(1,2,3,4-tetrahydronaphthalene-1-yl)methyl]-(S)-1-azabicyclo[2.2.2]octane-3 -amine

[0051] Take an appropriate amount of N-[(3,4-dihydronaphthalene-1-yl)methyl]-(S)-1-azabicyclo[2.2.2]octane-3-amine in n-butanol and concentrate to About 200ml, containing N-[(3,4-dihydronaphthalene-1-yl)methyl]-(S)-1-azabicyclo[2.2.2]octane-3-amine 14g (0.05mol ), adding 5% Pd-C (2g), reacting with hydrogen at room temperature for 8h, filtering, and concentrating the filtrate to dryness under reduced pressure to obtain N-[(1,2,3,4-tetrahydronaphthalene-1-yl)methyl ]-(S)-1-Azabicyclo[2.2.2]octane-3-amine (14 g, yield 99.5%). 1 HNMR (CDCl 3 )δ:0.93(brs,1H),1.25-1.45(m,2H),1.55-1.65(m,2H),1.75-1.90(m,5H),2.41(d,J=13.4Hz,1H),2.68 -2.80(m,8H),2.84-2.92(m,2H),3.08-3.20(m,1H),7.05-7.25(m,4H).

Embodiment 3

[0052] Example 3 N-[(1,2,3,4-tetrahydronaphthalene-1-yl)methyl]-(S)-1-azabicyclo[2.2.2]octane-3-amine ring Synthetic salt to get palonosetron hydrochloride

[0053] N-[(1,2,3,4-tetrahydronaphthalen-1-yl)methyl]-(S)-1-azabicyclo[2.2.2]octane-3-amine (14g, 0.05 mol) dissolved in toluene (100ml), added triphosgene (6g, 0.02mol) at room temperature, stirred for 8h, added 46% boron trifluoride ether solution (15ml), heated to reflux for 5h, added 1mol / L hydrochloric acid (60ml ), cooled to 10°C after reflux for 1h, adjusted to pH 9 with 30% sodium hydroxide solution (about 35ml), extracted the aqueous phase with ethyl acetate (50ml×2), combined the organic phases, dried over anhydrous magnesium sulfate, and filtered , the filtrate was concentrated to dryness under reduced pressure, isopropanol (50ml) and concentrated hydrochloric acid (4g, 0.04mol) were added to the remaining light yellow syrup, stirred and crystallized, filtered, the filter cake was recrystallized with isopropano...

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Abstract

The invention discloses a synthesis process of palonosetron hydrochloride hydrochloride. The synthesis process comprises the following steps: S1, performing condensation reduction on 3,4-dihydro-1-naphthalenemethylamine hydrochloride and 3-quinuclidinone hydrochloride which serve as raw materials, thus obtaining a n-butanol solution of N-[(3,4-dihydronaphthalene-1-yl) methyl]-(S)-1-azabicyclo [2.2.2] octane-3-amine; S2, directly adding a catalyst into the n-butanol solution of the N-[(3,4-dihydronaphthalene-1-yl) methyl]-(S)-1-azabicyclo [2.2.2] octane-3-amine for hydrogenation reduction, thus obtaining N-[(1,2,3,4-tetrahydronaphthalene-1-yl) methyl]-(S)-1-azabicyclo [2.2.2] octane-3-amine; S3, performing cyclization on the N-[(1,2,3,4-tetrahydronaphthalene-1-yl) methyl]-(S)-1-azabicyclo [2.2.2] octane-3-amine to form salt, thus obtaining the palonosetron hydrochloride hydrochloride. The synthesis process provided by the invention is mild in condition, simple in step and high in yield and has advantages superior to the prior art.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a synthesis process of palonosetron hydrochloride. Background technique [0002] Palonosetron hydrochloride is a highly efficient and highly selective 5-HT3 receptor antagonist developed by MGI Pharma and Helsinn Healthcare in Switzerland. It was first approved for marketing in the United States in July 2003 and is used clinically for radiotherapy and chemotherapy. Acute and delayed nausea and vomiting. It has attracted much attention because of its high curative effect, low toxicity and side effects, long half-life, and small dosage (Palonosetron for the prevention of chemotherapy-induced nausea and vomiting: approval and efficacy, Cancer Manag Res, 2009). [0003] Yang Xinhua et al. summarized the synthetic route of palonosetron according to different raw materials and synthetic processes. Palonosetron can be converted into hydrochloride to obtain palonosetron hy...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D453/02
CPCC07D453/02
Inventor 陈云陈昊王斌
Owner 陕西开元制药有限公司
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