CN103467358B - The preparation method of Zelnorm - Google Patents
The preparation method of Zelnorm Download PDFInfo
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- CN103467358B CN103467358B CN201310356403.5A CN201310356403A CN103467358B CN 103467358 B CN103467358 B CN 103467358B CN 201310356403 A CN201310356403 A CN 201310356403A CN 103467358 B CN103467358 B CN 103467358B
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- 0 CCCCCIC(*)=N Chemical compound CCCCCIC(*)=N 0.000 description 2
- KUXQEQRPBKEDHD-UHFFFAOYSA-N CCCCCNC(C)=N Chemical compound CCCCCNC(C)=N KUXQEQRPBKEDHD-UHFFFAOYSA-N 0.000 description 1
- TUWARWGEOHQXCO-UHFFFAOYSA-N COc1ccc2[nH]cc(C=O)c2c1 Chemical compound COc1ccc2[nH]cc(C=O)c2c1 TUWARWGEOHQXCO-UHFFFAOYSA-N 0.000 description 1
Abstract
The invention provides a kind of preparation method of Zelnorm, take thiosemicarbazide as raw material, alkylated reaction is carried out with alkylating reagent, then the alkylated reaction of nitrogen is carried out with n-amylamine, again with 5-methoxy-Indole-3-aldehyde generation condensation reaction, final with toxilic acid salt-forming reaction, acquisition Zelnorm.This operational path is suitable for suitability for industrialized production, without the need to the reaction conditions of harshness, avoids the reagent using toxicity larger, improves productive rate, cost-saving.
Description
Technical field
The present invention relates to field of compound preparation, specifically, relate to the preparation method of Zelnorm.
Background technology
Zelnorm is the new class selectivity 5-HT4 acceptor portion agonist medicine that Novartis Co., Ltd of Switzerland develops first, is mainly used in treating the irritable bowel syndrome (IBS) based on constipation.
According to pertinent literature report, the synthesis technique of Zelnorm as shown in Figure 1, needs in this technique to use a large amount of methyl alcohol, especially produces the product of contaminative as contour in mercaptan in treating process and in reaction process.
Summary of the invention
The object of this invention is to provide a kind of improvement and the preparation method of environment amenable Zelnorm.
In order to realize the object of the invention, the preparation method of a kind of Zelnorm of the present invention, comprises the following steps:
1) under catalyzer existent condition, thiosemicarbazide and alkylating reagent is made in ethanol alkylated reaction to occur, synthesis S-methylamino isothiourea;
2) the S-methylamino isothiourea that obtains in step 1) and n-amylamine is made to react in ethanol, synthesis N-amyl group-N-aminoguanidine;
3) make step 2) in the N-amyl group-N-aminoguanidine that obtains and 5-methoxy-Indole-3-aldehyde there is condensation reaction in acid condition, generate Tegaserod;
4) make the Tegaserod that obtains in step 3) and toxilic acid salify in the mixed solution of ethanol and ethyl acetate, gained crystal is Zelnorm.
Wherein, the alkylating reagent used in step 1) is methyl iodide, and the mol ratio of thiosemicarbazide and methyl iodide is 1:1-1.5.
The catalyzer used in step 1) is salt of wormwood or sodium carbonate, and the mol ratio of thiosemicarbazide and catalyzer is 1:0.5-2.
The temperature of reaction of step 1) is 0-15 DEG C, and the reaction times is 8-12h, and the ethanol of use is dehydrated alcohol.
Step 2) in the mol ratio of S-methylamino isothiourea and n-amylamine be 1:1-4.
Acidic conditions described in step 3) is pH value 5-6, and the temperature of condensation reaction is 45-55 DEG C, and the reaction times is 1-2h.
Above-mentioned steps 1), 2) and 4) in use ethanol be dehydrated alcohol.
In step 4), the volume ratio of dehydrated alcohol and ethyl acetate is 1-2:1, and temperature of reaction is 50-65 DEG C, and the reaction times is 1-2h.
Step 2) in the mercaptan that produces adopt the device for absorbing tail gas filling saturated sodium hydroxide solution to absorb.
Step 4) is specially: make Tegaserod and toxilic acid salify in the mixed solution of ethanol and ethyl acetate, filter, filtrate decrease temperature crystalline, obtain Zelnorm crystal after adding activated carbon decolorizing 30min.
The chemical structural formula of the Zelnorm adopting the inventive method to prepare is as follows:
Preferably, the preparation method of Zelnorm of the present invention comprises the steps:
The first step is using thiosemicarbazide as raw material, and using methyl iodide as alkylating reagent, salt of wormwood makes reaction carry out completely as catalyzer.Temperature of reaction is 0-15 DEG C, and the reaction times is 8-12h.Concrete reaction formula is as follows:
Second step is the synthesis of N-amyl group-N-aminoguanidine.The reaction solution the first step be obtained by reacting boils off solvent gained solid and adds in dehydrated alcohol, reacts heat up with n-amylamine, and this step reaction produces mercaptan gases and adopts saturated sodium hydroxide solution to absorb.TLC endpoint detection, the mol ratio of S-methylamino isothiourea and n-amylamine is 1:1-1.5.Temperature of reaction is 55-60 DEG C, and the reaction times is 5-8h.Concrete reaction formula is as follows:
3rd step is the synthesis of Tegaserod.5-methoxy-Indole-3-aldehyde is directly joined in upper step reaction solution, adds salt acid for adjusting pH to acid.Temperature of reaction is 25-50 DEG C, and the reaction times is 1-2h.Concrete reaction formula is as follows:
4th step is the synthesis of Zelnorm.Upper step reaction solution is boiled off solvent, adds water dissolution, be extracted with ethyl acetate, toxilic acid is dissolved in ethanol, add in ethyl acetate solution, add activated carbon decolorizing 30min and filter, filtrate decrease temperature crystalline.Concrete reaction formula is as follows:
5th step is refining.Upper step crystalline solid filtered, gained solid adds in the mixed solvent of ethanol and ethyl acetate, 50-65 DEG C of dissolving, decrease temperature crystalline.Gained solid, 60-70 DEG C of air blast is dried.
The preparation method of Zelnorm of the present invention is applicable to suitability for industrialized production, the solvent (using ethanol to replace the methyl alcohol that toxicity is larger) that technique nontoxicity after improvement is larger, and decreasing operation steps, raw material is easy to get, and last treating process have employed mixed solvent, add the solubleness of Zelnorm, decrease the consumption of refining solvent, improve productive rate, cost-saving, good impurity removing effect, and environmentally friendly.
Accompanying drawing explanation
Fig. 1 is the preparation technology of existing Zelnorm.
Fig. 2 is the schematic diagram of Zelnorm building-up reactions of the present invention.
Embodiment
Following examples for illustration of the present invention, but are not used for limiting the scope of the invention.If do not specialize, the conventional means that technique means used in embodiment is well known to those skilled in the art, is raw materials usedly commercial goods.
The synthesis of embodiment 1 Zelnorm
Comprise the following steps:
(1) synthesis of S-methylamino isothiourea
In 50L reactor, add 20kg dehydrated alcohol under ice-water bath, stir, progressively add thiosemicarbazide 5kg.Measure methyl iodide 9.3kg, add in reactor, slowly add salt of wormwood 7.5kg in batches, after reacting about 20min, have a large amount of white solid to separate out, and with bubble formation.After continuing reaction 8h, TLC detection reaction is complete, stopped reaction.
Gained reaction solution underpressure distillation 70 DEG C is boiled off solvent.This walks yield: 90%.
(2) synthesis of N-amyl group-N-aminoguanidine
The reaction product the first step being boiled off solvent adds in dehydrated alcohol, adds 3.8L n-amylamine wherein, and being warming up to 60 DEG C has gas (mercaptan) to produce, and adopts saturated sodium hydroxide solution to absorb tail gas.TLC endpoint detection, reacts completely after 5.5h.This walks yield 89%.
(3) synthesis of Tegaserod
5-methoxy-Indole-3-aldehyde is directly joined in upper step reaction solution, adds salt acid for adjusting pH to 5-6.Temperature of reaction is 25-50 DEG C, and the reaction times is 1-2h.
(4) synthesis of Zelnorm
Upper step reaction solution is boiled off solvent, adds water dissolution, be extracted with ethyl acetate, toxilic acid is dissolved in ethanol, add in ethyl acetate solution, add activated carbon decolorizing 30min and filter, filtrate decrease temperature crystalline.
This step obtains drying solid: 16.2kg.
(5) refining
Upper step crystalline solid is filtered, in gained solid, adds the dehydrated alcohol of 60L and the mixed solvent (the two volume ratio is 2:1) of ethyl acetate, 40-50 DEG C of dissolving, decrease temperature crystalline.Gained solid, 60-70 DEG C of air blast is dried.This step obtains drying solid: 15.2kg.Yield: 93%.
The synthesis of embodiment 2 Zelnorm
Operate equally by embodiment 1, only change the salt of wormwood used in the first step reactions steps into sodium carbonate 5.8kg, reaction 12h, other conditions are constant, TLC endpoint detection, and the first step yield is 85%, all the other step reaction conditions are constant, and products therefrom is similar to the finished product of embodiment 1.
The synthesis of embodiment 3 Zelnorm
Operate equally by embodiment 1, only the dehydrated alcohol used in step (5) and ethyl acetate volume ratio are become 1:1 from 2:1, mixed solvent add-on is 90L.The product content of products therefrom is similar to embodiment 1.
The synthesis of embodiment 4 Zelnorm
Operate equally by embodiment 1, only the dehydrated alcohol used in step (5) and ethyl acetate (volume ratio 2:1) are become anhydrous methanol, the add-on of anhydrous methanol is 180L, and temperature is 60-65 DEG C, other conditions are constant, and the product content of products therefrom is similar to embodiment 1.
As seen from the above embodiment, sodium carbonate and salt of wormwood all can be used in the present invention as catalyzer, but the catalytic activity of salt of wormwood is greater than sodium carbonate (embodiment 2), and therefore catalyzer is more preferably salt of wormwood.Use methyl alcohol to replace the mixed solvent of ethanol and ethyl acetate, need a large amount of methyl alcohol as solvent, easily to environment, and it is larger for the harm of operator, change the mixed solvent of ethanol and ethyl acetate into, effectively can reduce solvent load, cost-saving.
Although above the present invention is described in detail with a general description of the specific embodiments, on basis of the present invention, can make some modifications or improvements it, this will be apparent to those skilled in the art.Therefore, these modifications or improvements without departing from theon the basis of the spirit of the present invention, all belong to the scope of protection of present invention.
Claims (3)
1. a preparation method for Zelnorm, is characterized in that, comprises the following steps:
1) under catalyzer existent condition, thiosemicarbazide and alkylating reagent is made in ethanol alkylated reaction to occur, synthesis S-methylamino isothiourea;
2) make step 1) in the S-methylamino isothiourea that obtains and n-amylamine react in ethanol, synthesis N-amyl group-N-aminoguanidine;
3) make step 2) in the N-amyl group-N-aminoguanidine that obtains and 5-methoxy-Indole-3-aldehyde there is condensation reaction in acid condition, generate Tegaserod;
4) make step 3) in the Tegaserod that obtains and toxilic acid salify in the mixed solution of ethanol and ethyl acetate, gained crystal is Zelnorm;
Step 1) in use alkylating reagent be methyl iodide, the mol ratio of thiosemicarbazide and methyl iodide is 1:1-1.5;
Step 1) in use catalyzer be salt of wormwood, the mol ratio of thiosemicarbazide and catalyzer is 1:0.5-2;
Step 1), 2) and 4) in use ethanol be dehydrated alcohol;
Step 1) temperature of reaction be 0-15 DEG C, the reaction times is 8-12h;
Step 2) in the mol ratio of S-methylamino isothiourea and n-amylamine be 1:1-4; Temperature of reaction is 55 ~ 60 DEG C, and the reaction times is 5-8h;
Step 3) described in acidic conditions be pH value 5-6, the temperature of condensation reaction is 45-55 DEG C, and the reaction times is 1-2h;
Step 4) in the volume ratio of dehydrated alcohol and ethyl acetate be 1-2:1, temperature of reaction is 50-65 DEG C, and the reaction times is 1-2h.
2. method according to claim 1, is characterized in that, step 2) in the mercaptan that produces adopt the device for absorbing tail gas filling saturated sodium hydroxide solution to absorb.
3. method according to claim 1, it is characterized in that, step 4) be specially: make Tegaserod and toxilic acid salify in the mixed solution of ethanol and ethyl acetate, filter after adding activated carbon decolorizing 30min, filtrate decrease temperature crystalline, obtains Zelnorm crystal.
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| CN113845464B (en) * | 2021-10-28 | 2023-05-02 | 西安交通大学 | Indolyl guanidine compound and preparation method and application thereof |
| CN113801052B (en) * | 2021-10-28 | 2023-06-27 | 西安交通大学 | Indolylguanidine compound containing aromatic acid ester, and preparation method and application thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0505322A1 (en) * | 1991-03-22 | 1992-09-23 | Sandoz Ltd. | Aminoguanidines |
| CN1763018A (en) * | 2005-09-30 | 2006-04-26 | 天津药物研究院 | Oxazolidinone analog compound |
| CN1869021A (en) * | 2006-06-06 | 2006-11-29 | 江苏奥赛康药业有限公司 | Preparation method of tegaserod |
| WO2008095903A1 (en) * | 2007-02-07 | 2008-08-14 | Chemo Ibérica, S.A. | New addition salt of n-amino-n'-pentylguanidine, the process for its preparation and use thereof for obtaining tegaserod |
-
2013
- 2013-08-15 CN CN201310356403.5A patent/CN103467358B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0505322A1 (en) * | 1991-03-22 | 1992-09-23 | Sandoz Ltd. | Aminoguanidines |
| CN1763018A (en) * | 2005-09-30 | 2006-04-26 | 天津药物研究院 | Oxazolidinone analog compound |
| CN1869021A (en) * | 2006-06-06 | 2006-11-29 | 江苏奥赛康药业有限公司 | Preparation method of tegaserod |
| WO2008095903A1 (en) * | 2007-02-07 | 2008-08-14 | Chemo Ibérica, S.A. | New addition salt of n-amino-n'-pentylguanidine, the process for its preparation and use thereof for obtaining tegaserod |
Non-Patent Citations (2)
| Title |
|---|
| 万嵘,等.马来酸替加色罗的合成工艺改进.《中国药物化学杂志》.2003,第13卷(第1期),第40-41页. * |
| 汪洪湖,等.替加色罗制备工艺的改进.《安徽医药》.2011,第15卷(第3期),第289页. * |
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