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Preparation method of tegaserod

A technology for tegaserod and compound, applied in the field of tegaserod, can solve the problems of complicated operation, difficult to expand production, difficult to purify, etc., and achieve the effects of simple operation method, easy industrialization, and pollution reduction.

Inactive Publication Date: 2006-11-29
JIANGSU AOSAIKANG PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] According to the disclosed technology, the intermediate N-n-pentyl-N'-aminoguanidine hydroiodide is an oily substance, which is difficult to purify, so that the prepared tegaserod has poor purity and needs to be purified by column chromatography. It is cumbersome, it is difficult to expand production, and the yield is low; in addition, the color of tegaserod produced according to the disclosed technology is poor, and it is difficult to achieve the ideal white color

Method used

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  • Preparation method of tegaserod

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Preparation of 1-(5-methoxy-1H-indole-3-methylene)-3-methylthioguanidine hydroiodide

[0038] Mix and stir 17.5g (0.1mol) of 5-methoxyindole-3-aldehyde and 400mL of methanol, add 23.3g (0.1mol) of S-methylthiosemicarbazide hydroiodide in portions, and acidify with concentrated hydrochloric acid ( PH3~4), react at room temperature for 3 hours. After the reaction was completed, the solvent was distilled off, 200 mL of ethyl acetate was added to the residual solid, and 32.7 g of an off-white solid was obtained by filtration, yield: 83.9%. Analytical samples were recrystallized from ethanol.

[0039] Anal.:

[0040] Calcd (C 12 h 14 N 4 OS.HI): C, 36.9; H, 3.8; N, 14.4; S, 8.2.

[0041] Found: C, 36.2; H, 3.7; N, 14.1; S, 7.9.

Embodiment 2

[0043] Preparation of 1-(5-methoxy-1H-indole-3-methylene)-3-ethylthioguanidine hydrobromide

[0044] Mix and stir 11.5g (0.066mol) of 5-methoxyindole-3-aldehyde and 320mL of methanol, add 13.2g (0.066mol) of S-ethylthiosemicarbazide hydrobromide in portions, and acidify with concentrated hydrochloric acid ( PH3~4), react at room temperature for 3 hours. After the reaction was completed, the solvent was evaporated, 130 mL of ethyl acetate was added to the residual solid, and 19.9 g of off-white solid was obtained by filtration, yield: 84.9%. Analytical samples were recrystallized from ethanol.

[0045] Anal.:

[0046] Calcd (C 13 h 16 N 4 OS.HBr): C, 43.9; H, 4.7; N, 15.8; S, 9.0.

[0047] Found: C, 43.7; H, 4.5; N, 15.6; S, 8.7.

Embodiment 3

[0049] Preparation of 1-(5-methoxy-1H-indole-3-methylene)-3-pentylguanidine (tegaserod)

[0050] 31.2 g (0.08 mol) of 1-(5-methoxy-1H-indole-3-methylene)-3-methylthioguanidine hydroiodide, 7.0 g (0.08 mol) of n-pentylamine and methanol 160mL, heated to reflux, reacted for 6 hours, after the reaction was completed, distilled to dryness under reduced pressure, added 250ml of ethyl acetate to the residue, stirred, added 2mol / L sodium carbonate solution until the solids were completely dissolved, separated the organic phase, and used saturated Wash with sodium chloride solution until neutral, dry, add activated carbon for decolorization, filter, distill under reduced pressure until a solid precipitates, cool, and filter to obtain 21.6 g of white solid, yield: 89.7%. m.p.122~124℃.

[0051] Related substances: ≤0.1%.

[0052]HPLC conditions: chromatographic column: octadecylsilane bonded silica gel as filler, particle size 5 μm, specification 150×4.0 mm stainless steel column (Shi...

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Abstract

A process for preparing tegaserod includes such steps as reaction between 5-methoxyindole-3-aldehyde and compound II or its hydrohalate to obtain compound III or its hydrohalate, and reacting on n-pentylamine.

Description

technical field [0001] The invention relates to a preparation method of tegaserod, whose common name is Tegaserod and whose chemical name is 1-(5-methoxyl-1H-indole-3-methylene)-3-pentylguanidine. Background technique [0002] Tegaserod Maleate (Zelmac) is the first selective 5-HT developed and marketed by Novartis 4 Partial receptor agonist drugs are mainly used for the treatment of irritable bowel syndrome (IBS) mainly caused by constipation. Its structural formula is: [0003] [0004] where Pentyl is C 5 h 11 . [0005] Tegaserod (Tegaserod, I) is an indole aminoguanidine compound, and European Patent EP505322 and J.Med.Chem.1995.Vol.38.2331~2338 disclose a kind of synthetic method thereof, and the disclosed method is: 5- Methoxyindole-3-aldehyde and N-pentyl N'-aminoguanidine hydrogen iodide condensation in the system. N-n-pentyl N'-aminoguanidine hydroiodide uses thiosemicarbazide as raw material, first reacts with methyl iodide to generate S-methylthiosemicar...

Claims

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Application Information

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IPC IPC(8): C07D209/14
Inventor 宗在伟魏佳
Owner JIANGSU AOSAIKANG PHARMA CO LTD
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