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Preparation method for eletriptan intermediate

An intermediate, benzyloxycarbonylpyrrolidine technology, applied in the field of medicinal chemistry, can solve the problems of unstable process, complicated operation, poor selectivity, etc., and achieves the effects of good selectivity, simple operation and reduced dosage

Active Publication Date: 2014-12-24
SHANGHAI INST OF PHARMA IND +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0010] The technical problem solved by the present invention is to overcome the high cost, complex operation and Due to defects such as unstable process and poor selectivity, a preparation of an eletriptan intermediate (R)-3-(N-benzyloxycarbonylpyrrolidin-2-ylcarbonyl)-5-bromo-1H-indole is provided method

Method used

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  • Preparation method for eletriptan intermediate
  • Preparation method for eletriptan intermediate
  • Preparation method for eletriptan intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0030] Add N-benzyloxycarbonyl-D-proline (10.0g, 40.2mmol), 20mL toluene, and 1 drop of DMF to a 100mL four-necked flask in turn, and drop oxalyl chloride (4mL, 46.6mmol) in 5mL of toluene solution at room temperature Put it into a reaction bottle, after the drop, stir at room temperature for 2 hours, concentrate the reaction solution to dryness under reduced pressure, then dissolve the oily product N-benzyloxycarbonyl prolyl chloride in 10 mL of dichloromethane, and set aside.

Embodiment 2

[0032] Add 5-bromoindole (11.8g, 60.3mmol) and 100mL of dichloromethane into a 250ml four-neck flask, cool in an ice bath to 0°C, and slowly add aluminum trichloride solid (9.7g, 72.4mmol) in batches, The internal temperature is controlled at 0-5°C, and the reaction is stirred for 1 hour. Under the condition of 0-5°C, the dichloromethane solution of N-benzyloxycarbonyl prolyl chloride obtained in Example 1 is added dropwise, and the reaction solution is kept at 0-5°C The reaction was stirred for 4h. Under ice bath, slowly drop 60mL of saturated ammonium chloride solution, filter first, and separate layers of the filtrate, wash the organic phase with saturated sodium bicarbonate and saturated brine successively, concentrate under reduced pressure, and wash the crude product with ethyl acetate and n-heptane Mixed solvent (volume ratio: 1:1) was recrystallized and purified, and dried in vacuum at 60°C for 8 hours to obtain the white solid product (R)-3-(N-benzyloxycarbonylpyrroli...

Embodiment 3

[0034] Add 5-bromoindole (11.8g, 60.3mmol) and 100mL of dichloromethane into a 250ml four-neck flask, cool to 0°C in an ice bath, slowly add zinc chloride solid (9.8g, 72.4mmol) in batches, and The temperature is controlled at 0-5°C, and the reaction is stirred for 1 hour. Under the condition of 0-5°C, the dichloromethane solution of N-benzyloxycarbonyl prolyl chloride obtained in Example 1 is added dropwise, and the reaction solution is stirred at 0-5°C. Reaction 4h. Under ice bath, slowly drop 60mL of saturated ammonium chloride solution, filter first, and separate layers of the filtrate, wash the organic phase with saturated sodium bicarbonate and saturated brine successively, concentrate under reduced pressure, and wash the crude product with ethyl acetate and n-heptane Mixed solvent (volume ratio: 1:1) was recrystallized and purified, and dried in vacuum at 60°C for 8 hours to obtain the white solid product (R)-3-(N-benzyloxycarbonylpyrrolidin-2-ylcarbonyl)-5-bromo- 1H-i...

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Abstract

The invention discloses a preparation method for an eletriptan intermediate. The preparation method comprises the following steps: in an organic solvent, and under the catalytic action of a Lewis acid, 5-bromoindole and N-benzyloxycarbonyl prolyl chloride are subjected to a reaction, wherein the reaction temperature is -20 to 20 DEG C. The preparation method has the advantages of simple operation, safety, stability, low cost, good selectivity and relatively high yield, also can reduce the amount of 5-bromoindole, and is suitable for industrialized production.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a preparation method of an eletriptan intermediate. Background technique [0002] Eletriptan Hydrobromide (trade name: Relpax), its chemical name is (R)-3-[(1-methyl-2-pyrrolidinyl)methyl]-5-[2-( Benzenesulfonyl)ethyl]-1H-indole hydrobromide, the molecular formula is C 22 h 26 N 2 o 2 S.HBr, α crystal form eletriptan hydrobromide has been listed as a drug for the treatment of migraine. The structural formula is as follows: [0003] [0004] U.S. Patent No. 5,545,644 and U.S. No. 5,607,951 disclose eletriptan and its preparation method. International patent WO0250063 discloses an improved preparation method of eletriptan, and the synthetic route is as follows: [0005] [0006] U.S. Patent US5545644 and international patent WO0250063 all disclose a kind of eletriptan key intermediate (R)-3-(N-benzyloxycarbonylpyrrolidin-2-ylcarbonyl)-5-bromo-1H-indole (II ) prepara...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/06
CPCC07D403/06
Inventor 孙辉周伟澄张顺利
Owner SHANGHAI INST OF PHARMA IND
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