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New method for preparing bepotastine by condensation under acidic condition

A condensation reaction and acidic catalyst technology, which is applied in the field of preparation of bepotastine compounds, can solve the problems of low condensation reaction yield, complex ether formation process, high cost, etc., and achieve high yield, simple operation, and no impact on configuration effect

Active Publication Date: 2012-09-19
上海右手医药科技开发有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Compared with the previous method, due to the introduction of chiral ester protecting group, the yield of resolution has been greatly improved, but the raw material 4-[(4-chlorophenyl)-2-pyridylmethoxy] of this method -1-Piperidine still uses the old method in the synthesis, and the process of forming ether is complicated. At the same time, due to the use of expensive chiral alcohol reagents, the cost is greatly increased, which is not conducive to industrialization.
[0010] There are defects in various degrees in the above-mentioned routes, such as due to the use of excessive NaH or sodium amide and other strong bases as acid-binding agents in the condensation reaction process, Greatly increased 4-[(S)-(4-chlorophenyl)-2-pyridylmethoxy]-1-piperidine or (S)-(Risk of racemization of 4-chlorophenyl)-(pyridin-2-yl)-methanol, which also creates a large base for the piperidine ring with easily leaving groups (X = Cl, Br, Ms, Ts) Elimination reaction, resulting in low condensation reaction yield and high cost
At present, there is no domestic manufacturer that can produce the bepotastine API on a large scale, and they all rely on imports to produce preparations

Method used

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  • New method for preparing bepotastine by condensation under acidic condition
  • New method for preparing bepotastine by condensation under acidic condition
  • New method for preparing bepotastine by condensation under acidic condition

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Example 1: (S)-( Preparation of 4-chlorophenyl)-(pyridin-2-yl)-methyl trichloroacetimidate:

[0033] Will (S)-( Dissolve 10.0g of 4-chlorophenyl)-(pyridin-2-yl)-methanol in 50mL of tetrahydrofuran, cool down to 0~10°C, add 0.16g of sodium hydride (60%), and dropwise add 6.57g of trichloro Acetonitrile, continue to stir for about 3 hours after dropping, TLC shows that the reaction is complete, the reaction solution is rotary evaporated to dryness, and the residue is recrystallized with dichloromethane to obtain (S)-( About 15.2 g of 4-chlorophenyl)-(pyridin-2-yl)-methyl trichloroacetimidate white solid powder (yield about 92%). Melting point: 80.0~80.5°C. 1 H-NMR: 1 H-NMR (400MHz, CDCl 3 , ppm) δ: 6.98 (s, 1H), 7.21~7.25 (m, 1H), 7.34~7.36 (d, 2H, J =8.52Hz), 7.48~7.50 (d, 2H, J =8.48Hz), 7.62~7.64 (m, 1H), 7.73~7.77 (m, 1H), 8.53 (s, 1H), 8.60~8.61 (d, 1H). ee%=98.5%, ee% value and raw material ee% value are almost unchanged, indicating that racemization does ...

Embodiment 2

[0034] Embodiment 2: Preparation of (4-chlorophenyl)-(pyridin-2-yl)-methyl trichloroacetimidate:

[0035] Dissolve 100 g of (4-chlorophenyl)-(pyridin-2-yl)-methanol in 500 mL of tetrahydrofuran, cool down to 5~15 °C, add 3.6 g of sodium hydride (60%), and dropwise add 78.8 g of three Chloroacetonitrile, after dropping, warm up to room temperature and continue to stir for about 2 hours. TLC shows that the reaction is complete. The reaction solution is concentrated to dryness, and the residue is recrystallized with dichloromethane to obtain (4-chlorophenyl)-(pyridin-2-yl )-methyl trichloroacetimidate white solid powder about 157.4g (yield about 95%). Melting point: 78.4~80.5°C. 1 H-NMR (400MHz, CDCl 3 , ppm) δ: 6.95 (s, 1H), 7.18~7.20 (m, 1H), 7.32~7.35 (d, 2H), 7.45~7.47 (d, 2H), 7.60~7.62 (m, 1H), 7.70~ 7.74 (m, 1H), 8.50 (s, 1H), 8.59~8.60 (m, 1H).

Embodiment 3

[0036] Embodiment 3: the preparation of bepotastine:

[0037] Will (S) -(4-chlorophenyl)-(pyridin-2-yl)-methyl trichloroacetimidate 10.0g was dissolved in 30mL dichloromethane, and 5.9g 4-(4-hydroxypiperidin-1-yl ) ethyl butyrate, cooled to 10°C, added 2.1g of trifluoromethanesulfonic acid, maintained the above temperature and continued to stir the reaction for 2 hours, TLC or HPLC detected that the reaction raw imide ester had completely reacted, the reaction was concentrated to remove dichloromethane, added NaOH aqueous solution was used for hydrolysis reaction, TLC showed that the intermediate was completely hydrolyzed, the pH value of the solution was adjusted to 3.5~4.0, extracted with dichloromethane, the extract was dried with anhydrous magnesium sulfate, and then concentrated under reduced pressure to dryness to obtain bepotastine 7.8 g of colored foamy solid (about 73% yield). 1 H-NMR: 1 H-NMR (400MHz, CDCl 3 , ppm) δ: 2.00 (m, 6H), 2.37 (m, 2H), 3.01 (m, 2H), 3.1...

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Abstract

The invention relates to a new method for preparing bepotastine by condensation under the acidic condition, which comprises the steps of: carrying out a condensation reaction on (s)-(4-chlorphenyl)-(pyridine-2-group)-methyl trichloroacetic imine ester or racemate of the (s)-(4-chlorphenyl)-(pyridine-2-group)-methyl trichloroacetic imine ester with 4-(4-hydroxypiperidine-1-group) ethyl butyrate under the catalysis of acid catalyst, hydrolyzing the product to obtain the bepotastine or the racemoid of the bepotastine. Compared with the prior art, alkali elimination reaction and racemization phenomenon are not caused in the condensation process of the reaction, so that the method has the advantages of being high in yield, simple and convenient in operation, and has good application prospect.

Description

technical field [0001] The invention relates to a preparation method of bepotastine compound, which belongs to the technical field of medicine synthesis. Background technique [0002] Bepostastine, also known as Bepostastine or Bepostastine, its English name is Bepostastine, and its chemical name is 4-[ (S) -(4-Chlorophenyl)-2-pyridylmethoxy]-1-piperidinebutanoic acid, the English chemical name recorded in CA is 4-[ (S) -(4-chlorophenyl)-2-pyridinylmethoxy]-1-piperidinebutanoic acid. CAS number: [125602-71-3], molecular formula: C 21 h 25 ClN 2 o 3 , molecular weight: 388.89. Structural formula: [0003] (I). [0004] Bepotastine is the active component of the clinical drug Bepotastine Besylate. Bepotastine Besylate is a histamine H1 receptor antagonist jointly developed by Japanese Tanabe Seiyaku Company and Japanese Ube Industries Company. It was released in 1998 Japan filed an application for listing, and it was approved for the treatment of allergic rhinitis ...

Claims

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Application Information

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IPC IPC(8): C07D401/12
Inventor 王海平池骋夏俊池正明段锴许关煜
Owner 上海右手医药科技开发有限公司
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