CN1869021A - Preparation method of tegaserod - Google Patents
Preparation method of tegaserod Download PDFInfo
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- CN1869021A CN1869021A CNA2006100852242A CN200610085224A CN1869021A CN 1869021 A CN1869021 A CN 1869021A CN A2006100852242 A CNA2006100852242 A CN A2006100852242A CN 200610085224 A CN200610085224 A CN 200610085224A CN 1869021 A CN1869021 A CN 1869021A
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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
The present invention relates to Tegaserod, general Tegaserod by name, a kind of preparation method of chemistry 1-(5-methoxyl group-1H-indoles-3-methylene radical) by name-3-amyl group guanidine.
Background technology
(Tegaserod Maleate Zelmac) is first selectivity 5-HT that is gone on the market by the exploitation of Novartis company to Zelnorm
4The acceptor portion agonist medicine is mainly used in the supersensitivity irritable bowel syndrome (IBS) of treatment based on constipation.Its structural formula is:
Pentyl is C in the formula
5H
11.
Tegaserod (Tegaserod, I) be indoles aminoguanidine compounds, European patent EP 505322 and J.Med.Chem.1995.Vol.38.2331～2338 disclose its a kind of synthetic method, and disclosed method is: 5-methoxyl group indoles-3-aldehyde and N-n-pentyl N '-aminoguanidine iodine hydrohalogenic acid salt condensation makes.N-n-pentyl N '-aminoguanidine iodine hydrohalogenic acid salt is to be raw material with the thiosemicarbazide, generates the S-methylthio group for Urea,amino-iodine hydrohalogenic acid salt with iodomethane reaction earlier; Products therefrom generates N-n-pentyl-N '-aminoguanidine iodine hydrohalogenic acid salt with the n-amylamine condensation again.Its reaction formula is as follows:
According to disclosed technology, intermediate N n-pentyl-N '-aminoguanidine iodine hydrohalogenic acid salt is an oily matter, is difficult to purify, and making needs the Tegaserod purity difference that makes by column chromatography purification, and complex operation be difficult to enlarge and produce, and yield is lower; The Tegaserod shade deviation that makes according to the technology that discloses is difficult to reach ideal white in addition.
Summary of the invention
The present invention seeks to provide a kind of preparation method of Tegaserod at above-mentioned weak point, the Tegaserod purity height that the inventive method makes, color and luster is white, and working method is simple simultaneously, need not column chromatography purification, and easier industrialization has reduced the pollution to environment.
Another object of the present invention provides new intermediate (III) or its halogen acid salt (HX, X=Cl, Br, I) of a synthetic Tegaserod
R is methyl, ethyl in the formula.
A kind of preparation method of Tegaserod, its synthetic route is as follows:
(R＝CH
3，C
2H
5；X＝Cl，Br，I)
R is methyl, ethyl in the formula.X is chlorine, bromine, iodine.
To be further detailed method of the present invention below:
(a) be starting raw material with 5-methoxyl group indoles-3-aldehyde, with compound (II) or its halogen acid salt (HX, X=Cl, Br, I)
R is methyl, ethyl in the formula.
Reaction makes compound (III) or its halogen acid salt (HX, X=Cl, Br, I)
(b) compound (III) or its halogen acid salt (HX, X=Cl, Br, I)
R is methyl, ethyl in the formula.
Make Tegaserod (I) with the n-amylamine reaction.
Wherein compound (II) or its halogen acid salt (HX, X=Cl, Br, I) can be in S-methylamino thiocarbamide, S-methylamino thiocarbamide salt hydrochlorate, S-methylamino thiocarbamide hydrobromate and the S-methylamino thiocarbamide hydriodate a kind of, be preferably S-methylamino thiocarbamide hydriodate.Compound (II) structural formula is:
What wherein compound (II) or its halogen acid salt (HX, X=Cl, Br, I) can also be in S-ethylamino thiocarbamide, S-ethylamino thiocarbamide salt hydrochlorate, S-ethylamino thiocarbamide hydrobromate and the S-ethylamino thiocarbamide hydriodates is a kind of; Be preferably S-ethylamino thiocarbamide hydrobromate.
What wherein compound (III) or its halogen acid salt (HX, X=Cl, Br, I) can be in 1-(5-methoxyl group-1H-indoles-3-methylene radical)-3-methylthio group guanidine, 1-(5-methoxyl group-1H-indoles-3-methylene radical)-3-methylthio group guanidinesalt hydrochlorate, 1-(5-methoxyl group-1H-indoles-3-methylene radical)-3-methylthio group guanidine hydrobromate, 1-(5-methoxyl group-1H-indoles-3-methylene radical)-3-methylthio group guanidine hydriodates is a kind of; Be preferably 1-(5-methoxyl group-1H-indoles-3-methylene radical)-3-methylthio group guanidine hydriodate.Compound (III) structural formula is:
What wherein compound (III) or its halogen acid salt (HX, X=Cl, Br, I) can also be in 1-(5-methoxyl group-1H-indoles-3-methylene radical)-3-ethylmercapto group guanidine, 1-(5-methoxyl group-1H-indoles-3-methylene radical)-3-ethylmercapto group guanidinesalt hydrochlorate, 1-(5-methoxyl group-1H-indoles-3-methylene radical)-3-ethylmercapto group guanidine hydrobromate, 1-(5-methoxyl group-1H-indoles-3-methylene radical)-3-ethylmercapto group guanidine hydriodates is a kind of; Be preferably 1-(5-methoxyl group-1H-indoles-3-methylene radical)-3-ethylmercapto group guanidine hydrobromate.
The reaction mol ratio of 5-methoxyl group indoles-3-aldehyde and compound (II) or its halogen acid salt is 1: 0.5～1: 2.0; Be preferably 1: 0.8～1: 1.2.Temperature of reaction is-5 ℃～65 ℃, and the reaction times is 1～6 hour; Preferable reaction temperature is 20 ℃～65 ℃, and the preferred reaction time is 3～5 hours.
The reaction mol ratio of compound (III) or its halogen acid salt and n-amylamine is 1: 0.6～1: 1.8; Be preferably 1: 0.9～1: 1.1.The temperature of reaction of compound (III) or its halogen acid salt and n-amylamine is 20 ℃～65 ℃, and the reaction times is 3～10 hours.Temperature of reaction is preferably 45 ℃～65 ℃, and the reaction times is preferably 5～8 hours.
Compared with prior art it has following characteristics to the preparation method of a kind of Tegaserod of the present invention: according to the Tegaserod purity height that the inventive method makes, color and luster is white.Simultaneously working method is simple, need not column chromatography purification, makes the easier industrialization of the inventive method, and has reduced the employed toluene of prior art chromatography purification, has reduced the pollution to environment.
Further specify the present invention below by embodiment.Should correct understanding be: the preparation method in the embodiments of the invention is only used for the present invention is described and provides; rather than limitation of the present invention; so, under method prerequisite of the present invention, simple modifications of the present invention is all belonged to the scope of protection of present invention.
Embodiment
Embodiment 1:
The preparation of 1-(5-methoxyl group-1H-indoles-3-methylene radical)-3-methylthio group guanidine hydriodate
5-methoxyl group indoles-3-aldehyde 17.5g (0.1mol) and methyl alcohol 400mL are mixed stirring, and gradation adds S-methylamino thiocarbamide hydriodate 23.3g (0.1mol), with concentrated hydrochloric acid acidifying (PH3～4), and room temperature reaction 3 hours.Reaction is finished, and steaming desolventizes, and adds ethyl acetate 200mL in residual solid, filter off-white color solid 32.7g, yield: 83.9%.The analytic sample ethyl alcohol recrystallization.
Anal.：
Calcd(C
12H
14N
4OS.HI)：C，36.9；H，3.8；N，14.4；S，8.2。
Found：C，36.2；H，3.7；N，14.1；S，7.9。
Embodiment 2:
The preparation of 1-(5-methoxyl group-1H-indoles-3-methylene radical)-3-ethylmercapto group guanidine hydrobromate
5-methoxyl group indoles-3-aldehyde 11.5g (0.066mol) and methyl alcohol 320mL are mixed stirring, and gradation adds S-ethylamino thiocarbamide hydrobromate 13.2g (0.066mol), with concentrated hydrochloric acid acidifying (PH3～4), and room temperature reaction 3 hours.Reaction is finished, and steaming desolventizes, and adds ethyl acetate 130mL in residual solid, filter off-white color solid 19.9g, yield: 84.9%.The analytic sample ethyl alcohol recrystallization.
Anal.：
Calcd(C
13H
16N
4OS.HBr)：C，43.9；H，4.7；N，15.8；S，9.0。
Found：C，43.7；H，4.5；N，15.6；S，8.7。
Embodiment 3:
The preparation of 1-(5-methoxyl group-1H-indoles-3-methylene radical)-3-amyl group guanidine (Tegaserod)
With 1-(5-methoxyl group-1H-indoles-3-methylene radical)-3-methylthio group guanidine hydriodate 31.2g (0.08mol), n-amylamine 7.0g (0.08mol) and methyl alcohol 160mL, be heated to backflow, reacted 6 hours, reaction is finished, and underpressure distillation adds ethyl acetate 250ml to doing in residue, stir, add 2mol/L sodium carbonate solution to solid and all dissolve, divide and get organic phase, extremely neutral with the saturated nacl aqueous solution washing, dry, add activated carbon decolorizing, filter, underpressure distillation is to separating out solid, cooling, filter, get white solid 21.6g, yield: 89.7%.m.p.122～124℃。
Related substance :≤0.1%.
HPLC condition: chromatographic column: with the octadecylsilane chemically bonded silica is weighting agent, granularity 5 μ m, the stainless steel column of specification 150 * 4.0mm (ShimPack CLC-ODS).Moving phase: methyl alcohol-0.05mol/L potassium dihydrogen phosphate (65: 35); Detect wavelength: 278nm.
Differentiate consistent with the Tegaserod main peak that makes according to the method that has disclosed as can be known with the HPLC method.
Embodiment 4:
The preparation of 1-(5-methoxyl group-1H-indoles-3-methylene radical)-3-amyl group guanidine (Tegaserod)
With 1-(5-methoxyl group-1H-indoles-3-methylene radical)-3-ethylmercapto group guanidine hydrobromate 18.8g (0.053mol), n-amylamine 4.6g (0.053mol) and methyl alcohol 110mL, be heated to backflow, reacted 6 hours, reaction is finished, and underpressure distillation adds ethyl acetate 190ml to doing in residue, stir, add 2mol/L sodium carbonate solution to solid and all dissolve, divide and get organic phase, extremely neutral with the saturated nacl aqueous solution washing, dry, add activated carbon decolorizing, filter, underpressure distillation is to separating out solid, cooling, filter, get white solid 13.2g, yield: 82.7%.m.p.123～124.5℃。Related substance :≤0.1%.The HPLC condition is with embodiment 3.
Embodiment 5:
The preparation of 1-(5-methoxyl group-1H-indoles-3-methylene radical)-3-methylthio group guanidine hydriodate
5-methoxyl group indoles-3-aldehyde 1.75g (0.01mol) and methyl alcohol 40mL are mixed stirring, and gradation adds S-methylamino thiocarbamide hydriodate 1.16g (0.005mol), with concentrated hydrochloric acid acidifying (PH3～4), and room temperature reaction 3 hours.Reaction is finished, and steaming desolventizes, and adds ethyl acetate 20mL in residual solid, filter off-white color solid 0.55g, yield: 28.2%.(thin-layer chromatography detects and finds that products obtained therefrom has a small amount of assorted point, TLC condition: toluene: ethanol: ammoniacal liquor=85: 15: 0.5)
Embodiment 6:
The preparation of 1-(5-methoxyl group-1H-indoles-3-methylene radical)-3-methylthio group guanidine hydriodate mixes stirring with 5-methoxyl group indoles-3-aldehyde 1.75g (0.01mol) and methyl alcohol 40mL, gradation adds S-methylamino thiocarbamide hydriodate 1.86g (0.008mol), with concentrated hydrochloric acid acidifying (PH3～4), room temperature reaction 3 hours.Reaction is finished, and steaming desolventizes, and adds ethyl acetate 20mL in residual solid, filter off-white color solid 2.37g, yield: 76.0%.
Embodiment 7:
The preparation of 1-(5-methoxyl group-1H-indoles-3-methylene radical)-3-methylthio group guanidine hydriodate
5-methoxyl group indoles-3-aldehyde 1.75g (0.01mol) and methyl alcohol 40mL are mixed stirring, and gradation adds S-methylamino thiocarbamide hydriodate 2.79g (0.012mol), with concentrated hydrochloric acid acidifying (PH3～4), and room temperature reaction 3 hours.Reaction is finished, and steaming desolventizes, and adds ethyl acetate 20mL in residual solid, filter off-white color solid 3.25g, yield: 83.4%.
Embodiment 8:
The preparation of 1-(5-methoxyl group-1H-indoles-3-methylene radical)-3-methylthio group guanidine hydriodate
5-methoxyl group indoles-3-aldehyde 1.75g (0.01mol) and methyl alcohol 40mL are mixed stirring, and gradation adds S-methylamino thiocarbamide hydriodate 3.73g (0.016mol), with concentrated hydrochloric acid acidifying (PH3～4), and room temperature reaction 3 hours.Reaction is finished, and steaming desolventizes, and adds ethyl acetate 20mL in residual solid, filter off-white color solid 3.14g, yield: 80.5%.
Embodiment 9:
The preparation of 1-(5-methoxyl group-1H-indoles-3-methylene radical)-3-methylthio group guanidine hydriodate
5-methoxyl group indoles-3-aldehyde 1.75g (0.1mol) and methyl alcohol 40mL are mixed stirring, and gradation adds S-methylamino thiocarbamide hydriodate 4.66g (0.2mol), with concentrated hydrochloric acid acidifying (PH3～4), and room temperature reaction 3 hours.Reaction is finished, and steaming desolventizes, and adds ethyl acetate 20mL in residual solid, filter off-white color solid 2.78g, yield: 71.3%.
Embodiment 10:
The preparation of 1-(5-methoxyl group-1H-indoles-3-methylene radical)-3-methylthio group guanidine hydriodate
5-methoxyl group indoles-3-aldehyde 1.75g (0.01mol) and methyl alcohol 40mL are mixed stirring, and gradation adds S-methylamino thiocarbamide hydriodate 2.33g (0.01mol), is cooled to-5 ℃, and with concentrated hydrochloric acid acidifying (PH3～4) ,-5 ℃ were reacted 6 hours.Reaction is finished, and steaming desolventizes, and adds ethyl acetate 20mL in residual solid, filter off-white color solid 1.4g, yield: 35.9%.
Embodiment 11:
The preparation of 1-(5-methoxyl group-1H-indoles-3-methylene radical)-3-methylthio group guanidine hydriodate
5-methoxyl group indoles-3-aldehyde 1.75g (0.01mol) and methyl alcohol 40mL are mixed stirring, and gradation adds S-methylamino thiocarbamide hydriodate 2.33g (0.01mol), is cooled to 10 ℃, and with concentrated hydrochloric acid acidifying (PH3～4), 10 ℃ were reacted 6 hours.Reaction is finished, and steaming desolventizes, and adds ethyl acetate 20mL in residual solid, filter off-white color solid 1.8g, yield: 46.2%.
Embodiment 12:
The preparation of 1-(5-methoxyl group-1H-indoles-3-methylene radical)-3-methylthio group guanidine hydriodate
5-methoxyl group indoles-3-aldehyde 1.75g (0.01mol) and methyl alcohol 40mL are mixed stirring, and gradation adds S-methylamino thiocarbamide hydriodate 2.33g (0.01mol), with concentrated hydrochloric acid acidifying (PH3～4), and heating reflux reaction 3 hours.Reaction is finished, and steaming desolventizes, and adds ethyl acetate 20mL in residual solid, filter off-white color solid 3.31g, yield: 84.9%.
Embodiment 13:
The preparation of 1-(5-methoxyl group-1H-indoles-3-methylene radical)-3-methylthio group guanidinesalt hydrochlorate
5-methoxyl group indoles-3-aldehyde 1.75g (0.01mol) and methyl alcohol 40mL are mixed stirring, and gradation adds S-methylamino thiocarbamide salt hydrochlorate 1.42g (0.01mol), with concentrated hydrochloric acid acidifying (PH3～4), and room temperature reaction 3 hours.Reaction is finished, and steaming desolventizes, and adds ethyl acetate 20mL in residual solid, filter off-white color solid 2.39g, yield: 80.1%.
Embodiment 14:
The preparation of 1-(5-methoxyl group-1H-indoles-3-methylene radical)-3-methylthio group guanidine hydrobromate
5-methoxyl group indoles-3-aldehyde 1.75g (0.01mol) and methyl alcohol 40mL are mixed stirring, and gradation adds S-methylamino thiocarbamide hydrobromate 1.86g (0.01mol), with concentrated hydrochloric acid acidifying (PH3～4), and room temperature reaction 3 hours.Reaction is finished, and steaming desolventizes, and adds ethyl acetate 20mL in residual solid, filter off-white color solid 2.61g, yield: 76.1%.
Embodiment 15:
The preparation of 1-(5-methoxyl group-1H-indoles-3-methylene radical)-3-ethylmercapto group guanidinesalt hydrochlorate
5-methoxyl group indoles-3-aldehyde 1.15g (6.6mmol) and methyl alcohol 32mL are mixed stirring, and gradation adds S-ethylamino thiocarbamide salt hydrochlorate 1.03g (6.6mmol), with concentrated hydrochloric acid acidifying (PH3～4), and room temperature reaction 3 hours.Reaction is finished, and steaming desolventizes, and adds ethyl acetate 13mL in residual solid, filter off-white color solid 1.62g, yield: 79.1%.
Embodiment 16:
The preparation of 1-(5-methoxyl group-1H-indoles-3-methylene radical)-3-ethylmercapto group guanidine hydriodate
5-methoxyl group indoles-3-aldehyde 1.15g (6.6mmol) and methyl alcohol 32mL are mixed stirring, and gradation adds S-ethylamino thiocarbamide hydriodate 1.63g (6.6mmol), with concentrated hydrochloric acid acidifying (PH3～4), and room temperature reaction 3 hours.Reaction is finished, and steaming desolventizes, and adds ethyl acetate 13mL in residual solid, filter off-white color solid 2.18g, yield: 82.2%.
Embodiment 17:
The preparation of 1-(5-methoxyl group-1H-indoles-3-methylene radical)-3-amyl group guanidine (Tegaserod)
With 1-(5-methoxyl group-1H-indoles-3-methylene radical)-3-methylthio group guanidinesalt hydrochlorate 2.31g (0.008mol), n-amylamine 0.7g (0.008mol) and methyl alcohol 16mL, be heated to backflow, reacted 6 hours, reaction is finished, underpressure distillation adds ethyl acetate 25ml to doing in residue, stir, adding 2mol/L sodium carbonate solution to solid all dissolves, divide and get organic phase, extremely neutral with the saturated nacl aqueous solution washing, drying, filter, underpressure distillation is to separating out solid, and cooling is filtered, get white solid 2.04g, yield: 84.7%.
m.p.121～123℃。
Embodiment 18:
The preparation of 1-(5-methoxyl group-1H-indoles-3-methylene radical)-3-amyl group guanidine (Tegaserod)
With 1-(5-methoxyl group-1H-indoles-3-methylene radical)-3-methylthio group guanidine hydrobromate 2.74g (0.008mol), n-amylamine 0.7g (0.008mol) and methyl alcohol 16mL, be heated to backflow, reacted 6 hours, reaction is finished, underpressure distillation adds ethyl acetate 25ml to doing in residue, stir, adding 2mol/L sodium carbonate solution to solid all dissolves, divide and get organic phase, extremely neutral with the saturated nacl aqueous solution washing, drying, filter, underpressure distillation is to separating out solid, and cooling is filtered, get white solid 1.94g, yield: 80.6%.
m.p.121.5～123.5℃。
Embodiment 19:
The preparation of 1-(5-methoxyl group-1H-indoles-3-methylene radical)-3-amyl group guanidine (Tegaserod)
With 1-(5-methoxyl group-1H-indoles-3-methylene radical)-3-ethylmercapto group guanidinesalt hydrochlorate 1.65g (0.0053mol), n-amylamine 0.46g (0.0053mol) and methyl alcohol 11mL, be heated to backflow, reacted 6 hours, reaction is finished, and underpressure distillation adds ethyl acetate 19ml to doing in residue, stir, add 2mol/L sodium carbonate solution to solid and all dissolve, divide and get organic phase, extremely neutral with the saturated nacl aqueous solution washing, dry, add activated carbon decolorizing, filter, underpressure distillation is to separating out solid, cooling, filter, get white solid 1.18g, yield: 74.0%.m.p.122.5～124.5℃。
Embodiment 20:
The preparation of 1-(5-methoxyl group-1H-indoles-3-methylene radical)-3-amyl group guanidine (Tegaserod)
With 1-(5-methoxyl group-1H-indoles-3-methylene radical)-3-ethylmercapto group guanidine hydriodate 2.13g (0.0053mol), n-amylamine 0.46g (0.0053mol) and methyl alcohol 11mL, be heated to backflow, reacted 6 hours, reaction is finished, and underpressure distillation adds ethyl acetate 19ml to doing in residue, stir, add 2mol/L sodium carbonate solution to solid and all dissolve, divide and get organic phase, extremely neutral with the saturated nacl aqueous solution washing, dry, add activated carbon decolorizing, filter, underpressure distillation is to separating out solid, cooling, filter, get white solid 1.41g, yield: 88.4%.m.p.122～124℃。
Embodiment 21:
The preparation of 1-(5-methoxyl group-1H-indoles-3-methylene radical)-3-amyl group guanidine (Tegaserod)
With 1-(5-methoxyl group-1H-indoles-3-methylene radical)-3-methylthio group guanidine hydriodate 3.12g (0.008mol), n-amylamine 0.42g (0.0048mol) and methyl alcohol 16mL, be heated to backflow, reacted 6 hours, reaction is finished, underpressure distillation adds ethyl acetate 25ml to doing in residue, stir, adding 2mol/L sodium carbonate solution to solid all dissolves, divide and get organic phase, extremely neutral with the saturated nacl aqueous solution washing, drying, filter, underpressure distillation is to separating out solid, and cooling is filtered, get white solid 0.5g, yield: 34.6%.
Embodiment 22:
The preparation of 1-(5-methoxyl group-1H-indoles-3-methylene radical)-3-amyl group guanidine (Tegaserod)
With 1-(5-methoxyl group-1H-indoles-3-methylene radical)-3-methylthio group guanidine hydriodate 3.12g (0.008mol), n-amylamine 0.42g (0.0072mol) and methyl alcohol 16mL, be heated to backflow, reacted 6 hours, reaction is finished, underpressure distillation adds ethyl acetate 25ml to doing in residue, stir, adding 2mol/L sodium carbonate solution to solid all dissolves, divide and get organic phase, extremely neutral with the saturated nacl aqueous solution washing, drying, filter, underpressure distillation is to separating out solid, and cooling is filtered, get white solid 1.84g, yield: 84.9%.
Embodiment 23:
The preparation of 1-(5-methoxyl group-1H-indoles-3-methylene radical)-3-amyl group guanidine (Tegaserod)
With 1-(5-methoxyl group-1H-indoles-3-methylene radical)-3-methylthio group guanidine hydriodate 3.12g (0.008mol), n-amylamine 0.42g (0.0088mol) and methyl alcohol 16mL, be heated to backflow, reacted 6 hours, reaction is finished, underpressure distillation as for, in residue, add ethyl acetate 25ml, stir, adding 2mol/L sodium carbonate solution to solid all dissolves, divide and get organic phase, extremely neutral with the saturated nacl aqueous solution washing, drying, filter, underpressure distillation is to separating out solid, and cooling is filtered, get white solid 2.00g, yield: 83.0%.
Embodiment 24:
The preparation of 1-(5-methoxyl group-1H-indoles-3-methylene radical)-3-amyl group guanidine (Tegaserod)
With 1-(5-methoxyl group-1H-indoles-3-methylene radical)-3-methylthio group guanidine hydriodate 3.12g (0.008mol), n-amylamine 0.42g (0.0144mol) and methyl alcohol 16mL, be heated to backflow, reacted 6 hours, reaction is finished, underpressure distillation adds ethyl acetate 25ml to doing in residue, stir, adding 2mol/L sodium carbonate solution to solid all dissolves, divide and get organic phase, extremely neutral with the saturated nacl aqueous solution washing, drying, filter, underpressure distillation is to separating out solid, and cooling is filtered, get white solid 1.74g, yield: 72.3%.
Embodiment 25:
The preparation of 1-(5-methoxyl group-1H-indoles-3-methylene radical)-3-amyl group guanidine (Tegaserod)
With 1-(5-methoxyl group-1H-indoles-3-methylene radical)-3-methylthio group guanidine hydriodate 3.12g (0.008mol), n-amylamine 0.7g (0.008mol) and methyl alcohol 16mL, 20 ℃ were reacted 10 hours, reaction is finished, underpressure distillation is to doing, in residue, add ethyl acetate 25ml, stir, add 2mol/L sodium carbonate solution to solid and all dissolve, divide and get organic phase, to neutral, drying adds activated carbon decolorizing with the saturated nacl aqueous solution washing, filter, underpressure distillation is to separating out solid, and cooling is filtered, get white solid 1.40g, yield: 58.1%.
Embodiment 26:
The preparation of 1-(5-methoxyl group-1H-indoles-3-methylene radical)-3-amyl group guanidine (Tegaserod)
With 1-(5-methoxyl group-1H-indoles-3-methylene radical)-3-methylthio group guanidine hydriodate 3.12g (0.008mol), n-amylamine 0.7g (0.008mol) and methyl alcohol 16mL, 45 ℃ were reacted 8 hours, reaction is finished, underpressure distillation is to doing, in residue, add ethyl acetate 25ml, stir, add 2mol/L sodium carbonate solution to solid and all dissolve, divide and get organic phase, to neutral, drying adds activated carbon decolorizing with the saturated nacl aqueous solution washing, filter, underpressure distillation is to separating out solid, and cooling is filtered, get white solid 2.02g, yield: 83.9%.
Embodiment 27:
The preparation of 1-(5-methoxyl group-1H-indoles-3-methylene radical)-3-amyl group guanidine (Tegaserod)
With 1-(5-methoxyl group-1H-indoles-3-methylene radical)-3-methylthio group guanidine hydriodate 3.12g (0.008mol), n-amylamine 0.7g (0.008mol) and methyl alcohol 16mL, 65 ℃ of back flow reaction 3 hours, reaction is finished, underpressure distillation is to doing, in residue, add ethyl acetate 25ml, stir, add 2mol/L sodium carbonate solution to solid and all dissolve, divide and get organic phase, to neutral, drying adds activated carbon decolorizing with the saturated nacl aqueous solution washing, filter, underpressure distillation is to separating out solid, and cooling is filtered, get white solid 1.45g, yield: 60.2%.
Embodiment 28:
The preparation of 1-(5-methoxyl group-1H-indoles-3-methylene radical)-3-amyl group guanidine maleic acid salt (Zelnorm)
The Tegaserod 5.20g (0.017mol) that will make by embodiment 3, toxilic acid 2.04g (0.017mol), methyl alcohol 200ml stirs, and it is clear to add thermosol.Filtered while hot, filtrate is cooled to room temperature, separates out solid, filters, and uses methanol wash, and vacuum-drying 3 hours gets 6.15g white finished product, yield 85.0%.184～185 ℃ of fusing points.
(a) HPLC content (normalization method): 99.8%, chromatographic condition is the same.
(b) ultimate analysis
Measuring unit: Nanjing University modern analysis center
Instrument: Foss Heraeus elemental analyser
Method: sample is through combustion decomposition, and quantitatively conversion detects, and obtains the percentage composition of C, H, N again through data processing.
Measurement result:
Table 1 Zelnorm results of elemental analyses
| Element | Theoretical value (%) | Finished product (%) | ||
| Measured value | Mean value | |||
| C | 57.55 | 57.43 | 57.48 | 57.46 |
| H | 6.52 | 6.59 | 6.67 | 6.63 |
| N | 16.78 | 16.65 | 16.57 | 16.61 |
Conclusion: the difference of the C of Zelnorm finished product, H, N content measured value and theoretical value is less than 0.3%.
(c) the infrared absorption spectrometry result of Zelnorm finished product
| Absorption peak wave number (cm -1) | Oscillatory type | Group | Absorption peak strength |
| 3500～2500 | The O-H stretching vibration | -COOH | S, wide |
| 3315，3159 | The N-H stretching vibration | -NH | m，s |
| 2995 | =C-H stretching vibration | ＝C-H | m |
| 2956，2934，2830 | -C-H stretching vibration | -C-H | m，m，m |
| 1670，1628 | The C=O stretching vibration | -COOH | s，s |
| The C=N stretching vibration | Imines | ||
| The C=C stretching vibration | Ethylene linkage | ||
| 1615，1487 | The C=C stretching vibration | The phenyl ring skeleton | s，s |
| 1582，794 | The C-N flexural vibration | ＝C-NH | s，m |
| 1379 | The C-H flexural vibration | -CH 3 | m |
| 1359 | The C-N stretching vibration | Ar-NH- | s |
| 1264，1075 | The C-O-C stretching vibration | ArOCH 3 | s，s |
| 860 | The C-H out-of-plane deformation vibration | 1,2, the 4-trisubstituted benzene | m |
(d) hydrogen of Zelnorm spectrum measurement result
| Chemical shift (ppm) | Proton number | Peak shape | Ownership | Relevant chemical shift of proton (ppm) | Remarks |
| 0.89 | 3H | t | H 20 | 1.33 | J＝5.0Hz |
| 1.33 | 4H | d | H 19，H 18 | 0.89，1.58 | |
| 1.58 | 2H | dd | H 17 | 1.33，3.30 | J＝10.0Hz |
| 3.30 | 4H | t | H 16 | 1.58，7.76 | J=5.0Hz, wherein 2H can be by D 2The O exchange |
| 3.83 | 3H | s | H 10 | / | |
| 6.10 | 2H | s | H 22，H 23 | / | |
| 6.87 | 1H | dd | H 3 | 7.36 | J 1＝5.0Hz，J 2＝10.0Hz |
| 7.36 | 1H | d | H 4 | 6.87 | J＝10.0Hz |
| 7.66 | 2H | s | H 1 | / | Wherein 1H can be by D 2The O exchange |
| 7.76 | 1H | s | H 15 | 3.30 | Can be by D 2The O exchange |
| 7.85 | 1H | s | H 8 | / | |
| 8.38 | 1H | s | H 11 | / | |
| 10.80～11.30 | 1H | w | COOH | / | Can be by D 2The O exchange |
| 11.58 | 1H | w | COOH | / | Can be by D 2The O exchange |
(e) carbon of Zelnorm spectrum measurement result
| Chemical shift (ppm) | Carbon type | Relevant chemical shift of proton (ppm) | Long-range relevant chemical shift of proton (ppm) | Ownership |
| 13.92 | Uncle C | 0.89 | 1.33 | C 20 |
| 21.86 | Secondary C | 1.33 | 0.89，1.33，1.58 | C 19 |
| 28.29 | Secondary C | 1.33 | 0.89，1.33，1.58，3.30 | C 18 |
| 28.35 | Secondary C | 1.58 | 1.33，3.30 | C 17 |
| 40.90 | Secondary C | 3.30 | 1.33，1.58 | C 16 |
| 55.24 | Uncle C | 3.83 | / | C 10 |
| 103.96 | Uncle C | 7.66 | 6.87 | C 1 |
| 110.42 | Season C | / | 7.85，8.38 | C 7 |
| 112.66 | Uncle C | 6.87，7.36 | 7.66 | C 3，C 4 |
| 124.57 | Season C | / | 7.36，7.85，8.38 | C 6 |
| 131.81 | Season C | / | 6.87，7.66，7.85 | C 5 |
| 131.98 | Uncle C | 7.85 | 8.38 | C 8 |
| 136.09 | Uncle C | 6.10 | 6.10 | C 22，C 23 |
| 144.99 | Uncle C | 8.38 | 7.85 | C 11 |
| 153.51 | Season C | / | 3.30 | C 13 |
| 154.65 | Season C | / | 3.83，6.87，7.36，7.66 | C 2 |
| 167.56 | Season C | / | 6.10 | C 21，C 24 |
Claims (8)
1. method for preparing Tegaserod shown in the structural formula (I):
It is characterized in that may further comprise the steps:
(a) be starting raw material with 5-methoxyl group indoles-3-aldehyde, with compound (II) or its halogen acid salt (HX, X=Cl, Br, I)
R is CH in the formula
3, C
2H
5
Reaction makes compound (III) or its halogen acid salt (HX, X=Cl, Br, I)
R is CH in the formula
3, C
2H
5
(b) compound (III) or its halogen acid salt (HX, X=Cl, Br, I)
R is CH in the formula
3, C
2H
5
Make Tegaserod (I) with the n-amylamine reaction.
2. according to the preparation method of the described a kind of Tegaserod of claim 1, its compound (II) or its halogen acid salt (HX, X=Cl, Br, I) be a kind of in S-methylamino thiocarbamide, S-methylamino thiocarbamide salt hydrochlorate, S-methylamino thiocarbamide hydrobromate, S-methylamino thiocarbamide hydriodate, S-ethylamino thiocarbamide, S-ethylamino thiocarbamide salt hydrochlorate, S-ethylamino thiocarbamide hydrobromate and the S-ethylamino thiocarbamide hydriodate, compound (II) or its halogen acid salt are preferably S-methylamino thiocarbamide hydriodate, S-ethylamino thiocarbamide hydrobromate.
3. according to the preparation method of the described a kind of Tegaserod of claim 1, its compound (III) or its halogen acid salt (HX, X=Cl, Br, I) are a kind of in 1-(5-methoxyl group-1H-indoles-3-methylene radical)-3-methylthio group guanidine, 1-(5-methoxyl group-1H-indoles-3-methylene radical)-3-methylthio group guanidinesalt hydrochlorate, 1-(5-methoxyl group-1H-indoles-3-methylene radical)-3-methylthio group guanidine hydrobromate, 1-(5-methoxyl group-1H-indoles-3-methylene radical)-3-methylthio group guanidine hydriodate; Be preferably 1-(5-methoxyl group-1H-indoles-3-methylene radical)-3-methylthio group guanidine hydriodate.
4. according to the preparation method of the described a kind of Tegaserod of claim 1, its compound (III) or its halogen acid salt (HX, X=Cl, Br, I) are a kind of in 1-(5-methoxyl group-1H-indoles-3-methylene radical)-3-ethylmercapto group guanidine, 1-(5-methoxyl group-1H-indoles-3-methylene radical)-3-ethylmercapto group guanidinesalt hydrochlorate, 1-(5-methoxyl group-1H-indoles-3-methylene radical)-3-ethylmercapto group guanidine hydrobromate, 1-(5-methoxyl group-1H-indoles-3-methylene radical)-3-ethylmercapto group guanidine hydriodate; Be preferably 1-(5-methoxyl group-1H-indoles-3-methylene radical)-3-ethylmercapto group guanidine hydrobromate.
5. the preparation method of a kind of Tegaserod according to claim 1 is characterized in that the reaction mol ratio of 5-methoxyl group indoles-3-aldehyde and compound (II) or its halogen acid salt (HX, X=Cl, Br, I) is 1: 0.5～1: 2.0; Be preferably 1: 0.8～1: 1.2.
6. the preparation method of a kind of Tegaserod according to claim 1 is characterized in that the temperature of reaction of 5-methoxyl group indoles-3-aldehyde and compound (II) or its halogen acid salt (HX, X=Cl, Br, I) is-5 ℃～65 ℃, and the reaction times is 1～6 hour; Preferable reaction temperature is 20 ℃～65 ℃, and the preferred reaction time is 3～5 hours.
7. the preparation method of a kind of Tegaserod according to claim 1 is characterized in that compound (III) or its halogen acid salt (HX, X=Cl, Br, I) and the reaction mol ratio of n-amylamine are 1: 0.6～1: 1.8; Be preferably 1: 0.9～1: 1.1.
8. the preparation method of a kind of Tegaserod according to claim 1 is characterized in that compound (III) or its halogen acid salt (HX, X=Cl, Br, I) and the temperature of reaction of n-amylamine are 20 ℃～65 ℃, and the reaction times is 3～10 hours; Temperature of reaction is preferably 45 ℃～65 ℃, and the reaction times is preferably 5～8 hours.
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| CNB2006100852242A CN100412059C (en) | 2006-06-06 | 2006-06-06 | Preparation method of tegaserod |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008055994A1 (en) * | 2006-11-09 | 2008-05-15 | Generics [Uk] Limited | Novel process |
| CN103467358A (en) * | 2013-08-15 | 2013-12-25 | 蚌埠丰原医药科技发展有限公司 | Preparation method for tegaserod maleate |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| HUT64023A (en) * | 1991-03-22 | 1993-11-29 | Sandoz Ag | Process for producing aminoguanidine derivatives and pharmaceutical compositions comprising such compounds |
| WO2004085393A1 (en) * | 2003-03-25 | 2004-10-07 | Hetero Drugs Limited | Novel crystalline forms of tegaserod maleate |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008055994A1 (en) * | 2006-11-09 | 2008-05-15 | Generics [Uk] Limited | Novel process |
| CN103467358A (en) * | 2013-08-15 | 2013-12-25 | 蚌埠丰原医药科技发展有限公司 | Preparation method for tegaserod maleate |
| CN103467358B (en) * | 2013-08-15 | 2015-09-02 | 蚌埠丰原医药科技发展有限公司 | The preparation method of Zelnorm |
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| Publication number | Publication date |
|---|---|
| CN100412059C (en) | 2008-08-20 |
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