Preparation method of (S)-1, 2, 3, 4-tetrahydro-1-naphthoic acid

Abstract

The invention discloses a preparation method of (S)-1, 2, 3, 4-tetrahydro-1-naphthoic acid, which avoids a product degradation reaction and a racemization reaction in a high-temperature process when an ethyl acetate solvent is distilled, avoids the use of a class II solvent n-hexane, and eliminates potential safety hazards in production. According to the obtained product (S)-1, 2, 3, 4-tetrahydro-1-naphthoic acid, the content of the enantiomer (R)-1, 2, 3, 4-tetrahydro-1-naphthoic acid is 0.05% or below, the chemical purity is 99.5% or above, and no n-hexane solvent is left.

Description

technical field

[0001] The invention belongs to the field of medicine and chemical industry, and in particular relates to a preparation method of an antiemetic drug, a key intermediate (S)-1,2,3,4-tetrahydro-1-naphthoic acid of palonosetron hydrochloride. Background technique

[0002] Palonosetron hydrochloride was developed by Helsinn Healthcare SA in Switzerland. It is a 5-HT3 receptor antagonist for the treatment of acute nausea and vomiting caused by chemotherapy drugs. Medications for nausea and vomiting. It was approved by the FDA in July 2003, and is now listed in many countries such as the United States, Japan, and China.

[0003] (S)-1,2,3,4-tetrahydro-1-naphthoic acid (formula I) and (R)-1,2,3,4-tetrahydro-1-naphthoic acid (formula II) are a pair Enantiomers, the two compounds can be obtained by chemical resolution from 1,2,3,4-tetrahydro-1-naphthoic acid (formula III). Among them, (S)-1,2,3,4-tetrahydro-1-naphthoic acid (formula I) is a key intermediate for the...

Examples

Embodiment 1A

[0045]12.9 kg of 1,2,3,4-tetrahydro-1-naphthoic acid, 23.8 kg of quinine, and 275 liters of 90% ethanol aqueous solution were added to the reaction vessel, and stirred evenly to obtain a mixed liquid, and the temperature was slowly raised to The mixture was completely dissolved, kept for 10 minutes, slowly cooled to 0~5℃, crystallized for 16 hours, a solid was precipitated, filtered and dried to obtain (S)-1,2,3,4-tetrahydro-1 -12.5 kg of crude naphthoic acid quinine salt.

[0046] In the reaction vessel, add 12.5 kg of the crude product of (S)-1,2,3,4-tetrahydro-1-naphthoic acid quinine salt obtained in the previous step, 175 liters of anhydrous ethanol, stir evenly, heat up to reflux, cool down To 0~5 ℃, stand for crystallization for 16 hours, there is solid precipitation, filter, oven dry to obtain 9.18 kg of fine products of (S)-1,2,3,4-tetrahydro-1-naphthoic acid quinine salt .

[0047] After the two steps of salification and recrystallization are combined, the molar yi...

Embodiment 1B

[0049] Add 12.9 kg of 1,2,3,4-tetrahydro-1-naphthoic acid, 23.8 kg of quinine, and 325 liters of anhydrous ethanol to the reaction vessel, stir well to obtain a mixed liquid, and slowly heat up until all the mixed substances are Dissolve, keep warm for 10 minutes, slowly cool down to 0~5℃, crystallize for 16 hours, there is solid precipitation, filter and dry to obtain (S)-1,2,3,4-tetrahydro-1-naphthoic acid· Crude quinine salt 15.2 kg.

[0050] Add 15.2 kg of the crude product of (S)-1,2,3,4-tetrahydro-1-naphthoic acid quinine salt obtained in the previous step, and 115 liters of 85% ethanol aqueous solution obtained in the previous step into the reaction vessel, stir evenly, slowly Slowly heat up until the mixture is completely dissolved, cool down to 0~5°C, stand for crystallization for 16 hours, a solid is precipitated, filter, and dry to obtain (S)-1,2,3,4-tetrahydro-1- Naphthoic acid quinine salt boutique 8.98 kg. After the two steps of salification and recrystallizati...

Embodiment 2A

[0052] 8 kg of (S)-1,2,3,4-tetrahydro-1-naphthoic acid quinine salt obtained in Example 1 was added to 25 liters of water and 40 liters of ethyl acetate, stirred, and 1 mol / l of ethyl acetate was added dropwise. Hydrochloric acid until the pH value reaches about 2.0, the layers are separated, and the organic layer is washed with 20 liters of 0.5 mol / l hydrochloric acid again. The aqueous layer was discarded, and the organic layer was used.

technical field

[0001] The invention belongs to the field of medicine and chemical industry, and in particular relates to a preparation method of an antiemetic drug, a key intermediate (S)-1,2,3,4-tetrahydro-1-naphthoic acid of palonosetron hydrochloride. Background technique

[0002] Palonosetron hydrochloride was developed by Helsinn Healthcare SA in Switzerland. It is a 5-HT3 receptor antagonist for the treatment of acute nausea and vomiting caused by chemotherapy drugs. Medications for nausea and vomiting. It was approved by the FDA in July 2003, and is now listed in many countries such as the United States, Japan, and China.

[0003] (S)-1,2,3,4-tetrahydro-1-naphthoic acid (formula I) and (R)-1,2,3,4-tetrahydro-1-naphthoic acid (formula II) are a pair Enantiomers, the two compounds can be obtained by chemical resolution from 1,2,3,4-tetrahydro-1-naphthoic acid (formula III). Among them, (S)-1,2,3,4-tetrahydro-1-naphthoic acid (formula I) is a key intermediate for the...

Examples

Embodiment 1A

[0045]12.9 kg of 1,2,3,4-tetrahydro-1-naphthoic acid, 23.8 kg of quinine, and 275 liters of 90% ethanol aqueous solution were added to the reaction vessel, and stirred evenly to obtain a mixed liquid, and the temperature was slowly raised to The mixture was completely dissolved, kept for 10 minutes, slowly cooled to 0~5℃, crystallized for 16 hours, a solid was precipitated, filtered and dried to obtain (S)-1,2,3,4-tetrahydro-1 -12.5 kg of crude naphthoic acid quinine salt.

[0046] In the reaction vessel, add 12.5 kg of the crude product of (S)-1,2,3,4-tetrahydro-1-naphthoic acid quinine salt obtained in the previous step, 175 liters of anhydrous ethanol, stir evenly, heat up to reflux, cool down To 0~5 ℃, stand for crystallization for 16 hours, there is solid precipitation, filter, oven dry to obtain 9.18 kg of fine products of (S)-1,2,3,4-tetrahydro-1-naphthoic acid quinine salt .

[0047] After the two steps of salification and recrystallization are combined, the molar yi...

Embodiment 1B

[0049] Add 12.9 kg of 1,2,3,4-tetrahydro-1-naphthoic acid, 23.8 kg of quinine, and 325 liters of anhydrous ethanol to the reaction vessel, stir well to obtain a mixed liquid, and slowly heat up until all the mixed substances are Dissolve, keep warm for 10 minutes, slowly cool down to 0~5℃, crystallize for 16 hours, there is solid precipitation, filter and dry to obtain (S)-1,2,3,4-tetrahydro-1-naphthoic acid· Crude quinine salt 15.2 kg.

[0050] Add 15.2 kg of the crude product of (S)-1,2,3,4-tetrahydro-1-naphthoic acid quinine salt obtained in the previous step, and 115 liters of 85% ethanol aqueous solution obtained in the previous step into the reaction vessel, stir evenly, slowly Slowly heat up until the mixture is completely dissolved, cool down to 0~5°C, stand for crystallization for 16 hours, a solid is precipitated, filter, and dry to obtain (S)-1,2,3,4-tetrahydro-1- Naphthoic acid quinine salt boutique 8.98 kg. After the two steps of salification and recrystallizati...

Embodiment 2A

[0052] 8 kg of (S)-1,2,3,4-tetrahydro-1-naphthoic acid quinine salt obtained in Example 1 was added to 25 liters of water and 40 liters of ethyl acetate, stirred, and 1 mol / l of ethyl acetate was added dropwise. Hydrochloric acid until the pH value reaches about 2.0, the layers are separated, and the organic layer is washed with 20 liters of 0.5 mol / l hydrochloric acid again. The aqueous layer was discarded, and the organic layer was used.

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