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Diastereomer salts of terfenadine

A technology of diastereomer and piperidinol is applied in the field of separation of racemic components, and can solve the problems of infeasible application of chiral separation reagents on an industrial scale.

Inactive Publication Date: 2005-11-30
MERRELL DOW PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

These additional practical limitations make industrial-scale application of chiral resolution reagents even less feasible

Method used

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  • Diastereomer salts of terfenadine
  • Diastereomer salts of terfenadine
  • Diastereomer salts of terfenadine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1A

[0101] Embodiment 1A (R)-(+)-terfenadine

[0102] Racemic α-[4-(1,1-dimethylethyl)phenyl]-4-(hydroxydiphenylmethyl)-1-piperidinebutanol (terfenadine) ( 10.0 g, 21.2 mmol) and (2S, 3S)-(+)-di-p-toluoyl tartaric acid monohydrate ((+)-DPTTA) (8.60 g, 21.3 mmol) were dissolved in 90 ml of acetone. The resulting solution was cooled to room temperature (15°C to 30°C) for one day and then placed in the refrigerator for another day. The resulting crystals were collected by filtration, and the precipitated diastereomeric salts contained (+)-terfenadine and (+)-DPTTA (chemical yield 98%, diastereomeric salt excess 90% (%de)).

[0103] The salt was recrystallized twice from about 8 mL of acetone (per gram of salt) and dried in vacuo at 80°C for one day to give the purified diastereomeric salt (7.54 g, 83% chemical yield, about 100%de) . The melting point is about 125-134°C (hot stage).

[0104] IR(KBr): 2800-2200, 1720, 1610, 1265, 1105cm -1 .

[0105] [α] D 24 +20° (c=1.0, CHCl...

Embodiment 1B

[0117] Embodiment 1B (S)-(-)-terfenadine

[0118] To the crystallization mother liquor of the diastereomeric salts (R)-(+)-terfenadine and (2S,3S)-(+)-di-p-toluoyltartaric acid was added 22 ml of 1N sodium hydroxide and 80 ml of water . The resulting crystals were collected and recrystallized once from ethanol / water to give partially resolved (S)-(-)-terfenadine in 96% chemical yield.

[0119] The crystals were combined with (2R, 3R)-(-)-di-p-toluoyl tartaric acid (3.94 g, 10.2 mmol) in 75 ml of acetone in equimolar proportions, left at room temperature (15°C to 30°C) for one day, and then Put it in the refrigerator for another day. The resulting crystals were collected by filtration to give diastereomeric salts of (S)-(-)-terfenadine and (-)-di-p-toluoyltartaric acid. This salt was recrystallized once from about 8 mL of acetone (per gram of salt) and dried in vacuo at 80 °C for one day to give the purified diastereomeric salt (7.03 g, 77% chemical yield) with about 100% op...

Embodiment 2A

[0130] Embodiment 2A (R)-(+)-terfenadine

[0131] Racemic terfenadine (20 g, 42.4 mmol) and (R)-(-)-mandelic acid (6.45 g, 42.4 mmol) were dissolved in 180 mL of methanol by heating to about 60 °C . The resulting solution was cooled to room temperature (15°C to 30°C) for one day, and then placed in a 4°C refrigerator for another day. The resulting crystals were collected by vacuum filtration, and the resulting crystalline diastereomeric salts included the resolving agent and the (+)-enantiomer (chemical yield 101%, 78%de). The crystals were recrystallized twice from about 9 mL of methanol (per gram of salt) and dried in vacuo at 80°C for one day to give purified diastereomeric crystals (9.70 g, 73% chemical yield, 99%de). The melting point is about 112-118°C (hot stage).

[0132] IR(KBr): 2800-2100, 1610, 1360cm -1 .

[0133] [α] D 23 -5.9° (c=2.0, CHCl 3 )

[0134] Analysis: C 40 h 49 NO 5 :

[0135] Calculated value C: 77.01; H: 7.92; N: 2.25;

[0136] Measured...

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Abstract

A process and diastereomeric salts useful for the optical resolution of racemic alpha -[4-(1,1-dimethylethyl)phenyl]-4-(hydroxydiphenylmethyl)-1-piperidinebutanol, 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]- alpha , alpha -dimethylbenzeneacetic acid and lower alkyl 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]- alpha , alpha -dimethylbenzeneacetates. The process comprises placing into solution a chiral resolving agent, either (+) / (-)-di-paratoluoyltartaric acid or (-) / (+)-mandelic acid, in an amount equimolar to a compound corresponding to the desired enantiomer of the above compound, precipitating the resulting diastereomeric salt between the chiral resolving agent and the target enantiomer and separating the enantiomer.

Description

[0001] This application was submitted on April 10, 1995, the application number is 95193082.6, and the name of the invention is "for optical resolution of racemic α-[4-(1,1-dimethylethyl)phenyl]-4 -(Hydroxydiphenylmethyl)-1-piperidinebutanol and methods and diastereomeric salts of derivatives thereof” is a divisional application of the Chinese patent application. technical field [0002] The present invention relates to the resolution of racemic components, in particular to the resolution of racemic α-[4-(1,1-dimethylethyl)phenyl]-4-(hydroxydiphenylmethyl)- Method for 1-piperidinebutanol and some of its derived diastereomeric components. Background technique [0003] There are many efficient methods for resolving racemic compounds. For example, conventional techniques include formation of diastereoisomers followed by crystallization, differential absorption (chromatography), biochemical methods, chiral recognition, direct crysta...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07B57/00C07D211/22
CPCC07D211/22Y02P20/582
Inventor M·中村M·志贺
Owner MERRELL DOW PHARMA INC
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