Preparation method of high-purity palonosetron hydrochloride
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A palonosetron and high-purity technology, applied in the field of preparation of high-purity palonosetron hydrochloride, can solve the problems of low purity, low yield, unstable process and the like of palonosetron hydrochloride
Inactive Publication Date: 2018-05-29
KUNMING YUANRUI PHARMA
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[0019] The invention provides a preparation method of high-purity palonosetron hydrochloride, the purpose of which is to solve the problems
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Embodiment 1
[0092] A: Synthesis of (S)-1,2,3,4-tetralincarboxylic acid
[0093] Add 1,2,3,4-tetrahydronaphthoic acid (17.6g, 0.1mol) and quinine (32.4g, 0.1mol) into 176ml of 50% ethanol, stir at 50°C for 30min, the solution dissolves, and TLC detects the reaction Complete (PE:EA=1:2). Cool down to below 0°C and place overnight, crystallize, filter with suction, and dry. Add 100ml of ethanol to refine, crystallize below 0°C, filter with suction, dry, add 60ml of 1mol / L hydrochloric acid and 120ml of ethyl acetate, separate, dry, filter, concentrate, add n-hexane to the residue for recrystallization, and obtain a white solid 7.50 g, the yield is 42.6%, and the purity shown by HPLC is 99.81%, [α] D =-61.2° (c=1.0325, toluene).
[0094] B: Synthesis of (R)-N-((S)-3-quinyl)-1,2,3,4-tetrahydronaphthyl-1-carboxamide
[0095] Dissolve compound (S)-1,2,3,4-tetrahydronaphthoic acid (17.6g, 0.1mol) in 50ml of ethyl acetate, add oxalyl chloride (10ml, 0.12mol) under stirring, stir at room temperat...
Embodiment 2
[0103] A. Synthesis of (S)-1,2,3,4-tetrahydronaphthoic acid:
[0104] 15.6 grams, 0.1mol of 1,2,3,4-tetrahydronaphthoic acid and 29.8 grams, 0.1mol of quinine were added to 158 milliliters of 50V / V% ethanol, stirred at 50°C for 30 minutes to dissolve the solution, and detected by TLC The reaction is complete, PE:EA=1:2, lower the temperature to below 0°C and place overnight, crystallize, filter with suction, dry, then add 90 ml of ethanol to refine, crystallize below 0°C, filter with suction, dry, add 55 ml 1mol / L hydrochloric acid and 100ml ethyl acetate, separated, dried, filtered, concentrated, and the residue was recrystallized by adding n-hexane to obtain 7.21g of (S)-1,2,3,4-tetrahydronaphthoic acid as a white solid , the yield was 43.6%, and the HPLC showed that the purity was 99.82%, [α] D =-61.0° (c=1.0333, toluene)
[0105] B. Synthesis of (R)-N-((S)-3-quinyl)-1,2,3,4-tetrahydronaphthyl-1-carboxamide
[0106] Dissolve 15.6 grams, 0.1mol of compound (S)-1,2,3,4-tet...
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Abstract
The invention discloses a preparation method of high-purity palonosetron hydrochloride. A synthesis method is as follows: taking 1,2,3,4-tetrahedro-naphthoic acid as a starting raw material, taking quinine as a resolving agent to obtain chiral(S)-1,2,3,4-tetrahedro-naphthoic acid, acylating the chiral(S)-1,2,3,4-tetrahedro-naphthoic acid by using oxalyl chloride, and then reacting with (S)-3-aminoquinuclidine ammonia salt to obtain amide compound; concentrating, adding water to dilute, adding alkali to adjust pH value to obtain (R)-N-((S)-3-quinine)-1,2,3,4-tetralyl-1-formamide; performing reduction reaction on an intermediate under the existence of the sodium borohydride and boron trifluoride diethyl etherate so as to obtain (R)-N-(1-((S)-1,2,3,4-tetralyl)methyl)-3-quinine amine, continuously reacting with the triphosgene and boron trifluoride diethyl etherate, salting, extracting and regulating the pH value to obtain a crude product of the Palonosetron after the reaction is completed; and salting and refining the crude product in isopropanol so as to obtain the Palonosetron Hydrochloride with high purity. The preparation method not only solves the problem that the palonosetron hydrochloride is low in yield and unstable in process for a long time, but also adopts class-three solvent ethyl acetate to extract in the synthesis of each step, the invention is in favor of the environmental protection, and convenient for solvent recycling and cost saving, and is suitable for industrial production.
Description
technical field [0001] The invention belongs to the field of pharmaceutical synthesis and relates to a preparation method of high-purity palonosetron hydrochloride. Background technique [0002] Palonosetron hydrochloride, chemical name: 2-[1-azabicyclo(2.2.2)oct-3S-yl]-2,3,3aS,4,5,6-hexahydro-1H-benzo [de] Isoquinolin-1-one hydrochloride. On July 25, 2003, palonosetron hydrochloride developed by the Swiss HelSinn company was approved by the United States, and it was first listed in the United States two months later. Is a new type of high selectivity, high affinity 5-HT 3 Receptor antagonist, clinically used for acute and delayed nausea and vomiting caused by moderate and severe emetogenic chemotherapy drugs. It has attracted much attention because of its high curative effect, low toxicity and side effects, long half-life (about 40h), and small dosage. Its structural formula is as follows: [0003] [0004] As far as the currently published literature is concerned, ...
Claims
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