- Preparation method of high-purity palonosetron hydrochloride
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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.
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Paragraph 0093; 0102; 0103; 0104
(2018/08/04)
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- Method for preparing (S)-tetrahydro-1-naphthoic acid through high-efficiency resolution
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The invention relates to a preparation method of a palonosetron hydrochloride key intermediate (S)-1,2,3,4-tetrahydro-1-naphthoic acid as shown in a formula (I). The method comprises the following steps of adding a resolution agent for resolution by adopting 1,2,3,4-tetrahydro-naphthalene acid racemate as a raw material to obtain a salt (III) formed by a (S)-1,2,3,4-tetrahydro naphthalene acid and the resolution agent, and a salt (IV) formed by (R)-1,2,3,4-tetrahydro naphthalene acid and the resolution agent; carrying out salt removing on a compound III and a compound IV separately to obtain compounds (I) and (II); and carrying out racemization on the compound (II) under an alkaline condition to obtain a starting material 1,2,3,4-tetrahydro-naphthalene acid racemate and further carrying out resolution according to the steps. Therefore, the overall yield can be greatly improved, the production cost is reduced and environmental protection is facilitated. The preparation technology of the palonosetron hydrochloride key intermediate provided by the invention is different from the prior art, is safe, environmentally friendly, simple in operation and high in yield, and has relatively great practical value. The formula is as shown in the specification.
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Paragraph 0006; 0015; 0016
(2018/03/13)
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- Method for chiral preparation of (S)-tetrahydro-1-naphthoic acid and derivative thereof
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The invention relates to a method for chiral preparation of (S)-tetrahydro-1-naphthoic acid shown in a formula (V) and a derivative of (S)-tetrahydro-1-naphthoic acid. The method comprises steps as follows: (a) naphthoic acid shown in the formula (I), the derivative of naphthoic acid and (R)-2-hydroxycarboxylate shown in a formula (II) are subjected to an esterification reaction to produce naphthoate shown in a formula (III) and a derivative of naphthoate; (b) naphthoate shown in the formula (III) and the derivative of naphthoate are subjected to a hydrogenation reduction reaction in a proper solvent under the action of a metal catalyst, (S)-1,2,3,4-tetrahydronaphthalene-1-carboxylate shown in a formula (IV) and a derivative of (S)-1,2,3,4-tetrahydronaphthalene-1-carboxylate are obtained; (c) (S)-1,2,3,4-tetrahydronaphthalene-1-carboxylate shown in the formula (IV) and the derivative of (S)-1,2,3,4-tetrahydronaphthalene-1-carboxylate are hydrolyzed under the alkaline condition, and (S)-1,2,3,4-tetrahydro-1-naphthoic acid and the derivative thereof are obtained. The novel method which is different from methods in the prior art is simple to operate, green, environment-friendly, high in atom economy and suitable for industrial production and is used for chiral preparation of (S)-1,2,3,4-tetrahydro-1-naphthoic acid and the derivative thereof.
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- Process for preparing 2-(1-azabicyclo 2.2.2!oct-3-yl)-2,3,3A,4,5,6-hexahydro-1H-benz de!isoquinolin-1-one
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This invention relates to a process for preparing 2-(1-azabicyclo 2.2.2!oct-3-yl)-2,3,3a,4,5,6-tetrahydro-1H-benz de!isoquinolin-1-one, particularly 2-(1-azabicyclo 2.2.2!oct-3S-yl)-2,3,3aS,4,5,6-tetrahydro-1H-benz de!isoquinolin-1-one, and to intermediates useful in such process.
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