CN101092387A - Method for preparing Sumatriptan Succinate - Google Patents
Method for preparing Sumatriptan Succinate Download PDFInfo
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- CN101092387A CN101092387A CN 200710069585 CN200710069585A CN101092387A CN 101092387 A CN101092387 A CN 101092387A CN 200710069585 CN200710069585 CN 200710069585 CN 200710069585 A CN200710069585 A CN 200710069585A CN 101092387 A CN101092387 A CN 101092387A
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Abstract
This invention discloses a method for preparing sumatriptan succinate. The method comprises: (1) reacting 4-chlorobutyraldehyde and sodium pyrosulfite aqueous solution, filtering and drying to obtain sodium 4-chlorobutane-1,1-disulfonate; (2) heating and reacting 4-hydrazino-N-methyl phenylmethansulfonamide and 4-chlorobutane-1,1-disulfonate in the presence of inorganic acid or organic acid catalyst, neutralizing with an alkali solution, and extracting with an organic solvent to obtain 3-(2-chloroethyl)-N-methyl-1H-indole-5-methansulfonamide; (3) adding phase transfer catalyst into 3-(2-chloroethyl)-N-methyl-1H-indole-5-methansulfonamide, reacting with dimethylamine, extracting, decolorizing, refining to obtain sumatriptan product, dissolving in a solvent under heating, adding succinic acid, reacting, and precipitating the crystal to obtain white sumatriptan succinate. The method has such advantages as short process, easy operation, high yield, low cost and stable product quality.
Description
Technical field
The utility model relates to a kind of preparation method of Sumatriptan Succinate, belongs to technical field of pharmaceutical chemistry.
Background technology
Sumatriptan Succinate chemistry 3-[2-(dimethylin) ethyl by name]-N-Methyl-1H-indole-5-Toluidrin succinate, have the structure shown in general formula I, be to make by sumatriptan (structure shown in general formula I I) and succsinic acid salify.Sumatriptan Succinate is the first triptan medicine that is used for the treatment of acute migraine, optionally shrinks the blood vessel of overdistension in the cranium brain, thereby alleviates the obstinate headache outbreak rapidly.
General formula I general formula I I
The preparation method of existing bibliographical information Sumatriptan Succinate mainly contains following several: 1. patent WO2004099141 reports, by N, N-dimethyl-3-chlorine propylamine and triethyl orthoformate make 4-(N, N dimethylamine base) butyraldehyde diethyl acetal (structure shown in general formula III) through grignard reaction
General formula III general formula I V
Obtain product with 4-diazanyl-N-methylbenzene Toluidrin hydrochloride (structure shown in general formula I V) salify after cyclization under polyphosphate (PPE) catalysis again.Total recovery is less than 15%.2. patent WO0134561 reports, compound by structure shown in 4-chlorobutyraldehyde dimethyl acetal (structure shown in general formula V) and the general formula I V obtains 3-(2-amino-ethyl)-N-Methyl-1H-indole-5-Toluidrin (structure shown in general formula VI), chemical combination through condensation, cyclization in the presence of Sodium phosphate dibasic
Salify behind the reduction methylation reaction obtains Sumatriptan Succinate to general formula V general formula VI thing VI by sodium borohydride and formaldehyde again.3. document Heterocycles; 1998; 48 (6); the 1139-1149 report; by 4-nitro-N-methylbenzene Toluidrin with Vinyl chloroformate protection amino after; become hydrazine compound through nitroreduction, diazotization, reduction reaction, hydrazine compound reacts back deprotection base with compound III again, and the decarboxylation salify obtains Sumatriptan Succinate.4. document Heterocycles 2000,53 (3), the 665-673 report, and by methyl aceto acetate and N, N-dimethyl-3-chlorine propylamine condensation obtains shown in general formula VII
General formula VII general formula VIII
The diazonium salt condensation in 3. of the compound of structure, compound VI I and method, cyclization again, deprotection base, decarboxylation salify obtain Sumatriptan Succinate.5. patent WO9902493 reports; with the 5-bromo indole is the compound that obtains structure shown in general formula VIII after the reactions such as starting raw material and oxalyl chloride, dimethylamine amidated, tetrahydrochysene lithium aluminium reducing, sodium hydride and cylite protection indole ring nitrogen, and compound VIII salify behind cyan-hydrolysis, decarboxylation, deprotection base obtains Sumatriptan Succinate.
There is more shortcoming in above several method, and wherein 1. method prepares compound III and must use strict anhydrous grignard reaction, and compound III boiling point height, needs molecular distillation, purification difficult; The total recovery of this route finished product is lower than 15%.Method 2. compound VI must be used expensive catalyzer sodium borohydride in reduction in the methylation reaction, and large usage quantity, and it is many to react thick product impurity, must repeatedly purify, and loss is bigger.Method is 3. 1. similar with method, has increased a few step reactions that add protecting group, deprotection base, has prolonged synthetic route, not only increased raw-material use, and the total recovery ratio method is 1. lower.Method 4. synthetic route is long, and the total cost height is not suitable for industrialization.5. method is starting raw material with the more expensive 5-bromo indole of price, and repeatedly use sodium hydride in the route, highly basic, dangerous raw material such as tetrahydrochysene lithium aluminium, sodium Metal 99.5, severe reaction conditions, and route is long, is difficult to realize the industrialization demand.
Summary of the invention
It is shorter to the purpose of this invention is to provide a kind of operational path, simple to operate, high yield and low cost, the preparation method of the Sumatriptan Succinate of constant product quality.
The present invention is a kind of preparation method of Sumatriptan Succinate, is starting raw material with 4-diazanyl-N-methylbenzene Toluidrin hydrochloride (structure shown in general formula I V), it is characterized in that carrying out according to the following steps:
1. by 4-chlorobutyraldehyde and Sodium Metabisulfite reactant aqueous solution after-filtration, drying makes 4-chlorobutane-1,1-sodium disulfonate (structure shown in general formula I X);
2. 4-diazanyl-N-methylbenzene Toluidrin hydrochloride and 4-chlorobutane-1, the 1-sodium disulfonate is in the presence of mineral acid or organic acid catalyst, after the reacting by heating, solution conditioned reaction solution with alkali is extremely neutral, obtains 3-(2-chloroethyl)-N-Methyl-1H-indole-5-Toluidrin (structure shown in general formula X) with organic solvent extraction;
3. 3-(2-chloroethyl)-N-Methyl-1H-indole-5-Toluidrin is with phase-transfer catalyst, and with the dimethylamine reaction, reaction finishes to obtain the sumatriptan crude product through organic solvent extraction;
4. the sumatriptan crude product is made with extra care with solvent and activated carbon decolorizing and is obtained the sumatriptan elaboration;
5. sumatriptan elaboration solvent heating for dissolving, add the succsinic acid salify after crystallization obtain white finished product Sumatriptan Succinate.
General formula I X general formula X
The mol ratio of 1. middle 4-chlorobutyraldehyde of described step and Sodium Metabisulfite is 1: 1～1.2.
The temperature of reaction of described step in 1. can be 10～35 ℃, and the reaction times is 0.5～1 hour.
The inorganic acid catalyst of described step in 2. can be dilute sulphuric acid or dilute hydrochloric acid, rare nitric acid etc.; Organic acid catalyst is formic acid or acetate, the aqueous solution of trifluoroacetic acid etc.
The temperature of reaction of described step in 2. can be 55～70 ℃, and the reaction times can be 2～3 hours, and the mol ratio of reactant is 4-diazanyl-N-methylbenzene Toluidrin hydrochloride: 4-chlorobutane-1,1-sodium disulfonate: acid catalyst=1: 1～1.1: 1～4.
The described step 2. solution of middle alkali can be potassium hydroxide aqueous solution or aqueous sodium hydroxide solution, ammonia soln etc.; The organic solvent of extraction is ethyl acetate or methylene dichloride, chloroform etc.
The dimethylamine of described step in 3. can be dimethylamine agueous solution or dimethylamine alcoholic solution, and concentration is 30～40%, and the molar weight of its adding is 6.5～7.5 times of 3-(2-chloroethyl)-N-Methyl-1H-indole-5-Toluidrin.
The phase-transfer catalyst of described step in 3. can be Tetrabutyl amonium bromide or benzyltriethylammoinium chloride, tetrabutylammonium iodide etc.
The temperature of reaction of described step in 3. can be 45～55 ℃, and the reaction times is 4～5 hours; The solvent of extraction can be ethyl acetate, methylene dichloride or chloroform etc.
Described step 4. and the solvent 5. can be acetone or ethyl acetate, methyl alcohol etc.
The present invention compared with prior art has following outstanding advantage and positively effect:
1, the present invention is by repetition test, and the protection form that filters out a kind of novel 4-chlorobutyraldehyde is as intermediate, i.e. 4-chlorobutane-1, and the 1-sodium disulfonate, this intermediate preparation process is simple, operation easily, purity height.Overcome the shortcoming of other protection forms of the 4-chlorobutyraldehyde that adopts in original technology; also can react generation 4-(N as the 4-chlorobutyraldehyde; the N dimethylamine base) protection form such as butyraldehyde diethyl acetal or 4-chlorobutyraldehyde dimethyl acetal; these materials are a kind of high boiling liquid; need to carry out under the high vacuum condition underpressure distillation in the suitability for industrialized production and just can obtain, complicated operation, and new intermediate of the present invention has improved the security of producing; shorten the production cycle simultaneously, saved energy consumption.
2, above-mentioned intermediate is sloughed relatively easily because of two sodium groups; with 4-chlorobutyraldehyde in the prior art other the protection forms compound compare; improved the transformation efficiency of 4-diazanyl-N-methylbenzene Toluidrin hydrochloride (structure shown in general formula I V) generation sumatriptan greatly; to prepare total recovery has brought up to more than 29%; and content in crude product reaches more than 92%; be easy to purify, be suitable for industrial amplification production.
3,3-(2-chloroethyl) in the operational path of the present invention-N-Methyl-1H-indole-5-Toluidrin (structure shown in general formula X) obtains sumatriptan with one step of dimethylamine reaction; avoided the method for reduction methylation reaction of the prior art or employing protecting group; both simplified operation; reduced the generation of impurity again; the steady quality of gained sumatriptan; and raw material is cheap and easy to get, and cost is compared with bibliographical information and can be reduced significantly.
Embodiment
Below in conjunction with embodiment the present invention is further described, but embodiment should not be construed as the scope of the present invention that limits.
Embodiment 1:
106.8g (1.0mol) 4-chlorobutyraldehyde (GC content 99.7%, commercially available) is joined in the there-necked flask of 500ml, stir also cooling, begin to drip the solution that 209.1g (1.1mol) Sodium Metabisulfite and 315ml water are made into to 20 ℃.Stirring at room 0.5 hour again after dropwising is filtered, and drying obtains the white solid 4-chlorobutane-1 of structure shown in general formula I X, 1-sodium disulfonate 289.2g (content 98.6%), yield 96.1%.
Embodiment 2:
106.8g (1.0mol) 4-chlorobutyraldehyde (GC content 99.7%, commercially available) is joined in the there-necked flask of 500ml, stir, begin to drip the solution that 190.1g (1.0mol) Sodium Metabisulfite and 290ml water are made under the room temperature.Stirring at room 0.75 hour again after dropwising is filtered, and drying obtains the white solid 4-chlorobutane-1 of structure shown in general formula I X, 1-sodium disulfonate 288.9g (content 98.4%), yield 95.8%.
Embodiment 3:
With 62.8g (208.6mmol) the 4-chlorobutane-1 of preparation among the 4-diazanyl-N-methylbenzene Toluidrin hydrochloride of 50.0g (198.7mmol) and the embodiment 1, the 1-sodium disulfonate joins in the there-necked flask of 1L, adds 5% sulfuric acid of 550ml then.Be heated to 65 ± 2 ℃ and be incubated 2 hours.Insulation finish the back with the pH of 25% aqueous sodium hydroxide solution conditioned reaction liquid to neutrality.With ethyl acetate extraction 3 times, merging organic phase washs 3 times with saturated sodium-chloride water solution, ethyl acetate is reclaimed in distillation behind anhydrous sodium sulfate drying, the about 35.0g oily matter of excess, be the crude product of 3-(2-chloroethyl)-N-Methyl-1H-indole-5-Toluidrin (structure shown in general formula X), content 93.4% (HPLC), yield 57.6%.
Embodiment 4:
With 64.1g (212.6mmol) the 4-chlorobutane-1 of preparation among the 4-diazanyl-N-methylbenzene Toluidrin hydrochloride of 50.0g (198.7mmol) and the embodiment 2, the 1-sodium disulfonate joins in the there-necked flask of 1L, adds 4.5% hydrochloric acid of 585ml then.Be heated to 60 ± 2 ℃ and be incubated 2.5 hours.Insulation finish the back with the pH of 15% ammoniacal liquor conditioned reaction liquid to neutrality.With dichloromethane extraction 3 times, merging organic phase washs 3 times with saturated sodium-chloride water solution, methylene dichloride is reclaimed in distillation behind anhydrous sodium sulfate drying, the about 34.2g oily matter of excess, be the crude product of 3-(2-chloroethyl)-N-Methyl-1H-indole-5-Toluidrin, content 94.5% (HPLC), yield 56.8%.
Embodiment 5:
With 60.7g (204.6mmol) the 4-chlorobutane-1 of preparation among the 4-diazanyl-N-methylbenzene Toluidrin hydrochloride of 50.0g (198.7mmol) and the embodiment 1, the 1-sodium disulfonate joins in the there-necked flask of 1L, adds 6.5% acetic acid aqueous solution of 570ml then.Be heated to 58 ± 2 ℃ and be incubated 3 hours.Insulation finish the back with the pH of 15% potassium hydroxide conditioned reaction liquid to neutrality.With chloroform extraction 3 times, merge organic phase with saturated sodium-chloride water solution washing 3 times, chloroform is reclaimed in distillation behind anhydrous sodium sulfate drying, the about 35.8g oily matter of excess, be the crude product of 3-(2-chloroethyl)-N-Methyl-1H-indole-5-Toluidrin, content 92.7% (HPLC), yield 58.5%.
Embodiment 6:
The oily matter X100g (326.7mmol) that embodiment 3 is obtained adds 33% dimethylamine agueous solution 310ml, Tetrabutyl amonium bromide 2g, potassiumiodide 55g, is heated to 50 ± 2 ℃ of reactions 4.5 hours.Be chilled to room temperature ethyl acetate extraction 3 times after reaction finishes, extraction liquid washs 3 times with saturated sodium-chloride water solution, and underpressure distillation is to there being crystal to separate out.Cooled and filtered is used the ethyl acetate washing leaching cake, dry sumatriptan crude product 54.3g, content 92.5% (HPLC), the yield 52.0% of getting.
Embodiment 7:
The oily matter X 98.8g (326.5mmol) that embodiment 4 is obtained adds 33% dimethylamine alcoholic solution 330ml, benzyltriethylammoinium chloride 2g, potassiumiodide 50g, is heated to 53 ± 2 ℃ of reactions 4.75 hours.Be chilled to room temperature dichloromethane extraction 3 times after reaction finishes, extraction liquid washs 3 times with saturated sodium-chloride water solution, and underpressure distillation is to there being crystal to separate out.Cooled and filtered, with a small amount of washed with dichloromethane filter cake, dry sumatriptan crude product 52.8g, content 93.7% (HPLC), the yield 51.3% of getting.
Embodiment 8:
The oily matter X 100.8g (326.7mmol) that embodiment 5 is obtained adds 40% dimethylamine agueous solution 250ml, tetrabutylammonium iodide 2g, potassiumiodide 52.5g, is heated to 47 ± 2 ℃ of reactions 4.25 hours.Be chilled to room temperature chloroform extraction 3 times after reaction finishes, extraction liquid washs 3 times with saturated sodium-chloride water solution, and underpressure distillation is to there being crystal to separate out.Cooled and filtered is used the minimum of chloroform washing leaching cake, dry sumatriptan crude product 55.7g, content 93.1% (HPLC), the yield 53.7% of getting.
Embodiment 9:
The sumatriptan crude product 54.3g that is obtained by embodiment 6 adds acetone 520ml, refluxes 0.5 hour, adds the gac reflux decolour 1 hour.Filtered while hot, filtrate boil off 50% solvent, are chilled to 0～5 ℃.Filter, use the washing with acetone filter cake, 65 ℃ of dryings obtain 46.2g sumatriptan elaboration, content 99.5% (HPLC).
Embodiment 10:
Sumatriptan elaboration 15g by embodiment 9 obtains adds acetone 180ml, stirs reflux 15 minutes.Add the 6.0g succsinic acid, continue to reflux 1 hour.Be cooled to 10 ℃ of crystallizatioies 1.5 hours.Filter, 65 ℃ of dryings obtain the 19.5g Sumatriptan Succinate.
Embodiment 11:
Sumatriptan elaboration 15g by embodiment 9 obtains adds methyl alcohol 180ml, stirs reflux 15 minutes.Add the 6.0g succsinic acid, continue to reflux 1 hour.Be cooled to 10 ℃ of crystallizatioies 1.5 hours.Filter, 65 ℃ of dryings obtain the 18.3g Sumatriptan Succinate.
Embodiment 12:
Sumatriptan elaboration 15g by embodiment 9 obtains adds ethyl acetate 180ml, stirs reflux 15 minutes.Add the 6.0g succsinic acid, continue to reflux 1 hour.Be cooled to 10 ℃ of crystallizatioies 1.5 hours.Filter, 65 ℃ of dryings obtain the 19.8g Sumatriptan Succinate.
Claims (10)
1, a kind of preparation method of Sumatriptan Succinate is a starting raw material with 4-diazanyl-N-methylbenzene Toluidrin hydrochloride, it is characterized in that carrying out according to the following steps:
1. by 4-chlorobutyraldehyde and Sodium Metabisulfite reactant aqueous solution after-filtration, drying makes 4-chlorobutane-1, the 1-sodium disulfonate;
2. 4-diazanyl-N-methylbenzene Toluidrin hydrochloride and 4-chlorobutane-1, the 1-sodium disulfonate is in the presence of mineral acid or organic acid catalyst, after the reacting by heating, solution conditioned reaction solution with alkali is extremely neutral, obtains 3-(2-chloroethyl)-N-Methyl-1H-indole-5-Toluidrin with organic solvent extraction;
3. 3-(2-chloroethyl)-N-Methyl-1H-indole-5-Toluidrin is with phase-transfer catalyst, and with the dimethylamine reaction, reaction finishes to obtain the sumatriptan crude product through organic solvent extraction;
4. the sumatriptan crude product is made with extra care with solvent and activated carbon decolorizing and is obtained the sumatriptan elaboration;
5. sumatriptan elaboration solvent heating for dissolving, add the succsinic acid salify after crystallization obtain white finished product Sumatriptan Succinate.
2,, it is characterized in that the mol ratio of 1. middle 4-chlorobutyraldehyde of described step and Sodium Metabisulfite is 1: 1～1.2 by the preparation method of the described a kind of Sumatriptan Succinate of claim 1.
3, by the preparation method of the described a kind of Sumatriptan Succinate of claim 1, it is characterized in that the temperature of reaction during described step 1. is 10～35 ℃, the reaction times is 0.5～1 hour.
4, by the preparation method of the described a kind of Sumatriptan Succinate of claim 1, it is characterized in that the inorganic acid catalyst during described step 2. is dilute sulphuric acid or dilute hydrochloric acid, rare nitric acid; Organic acid catalyst is formic acid or acetate, the aqueous solution of trifluoroacetic acid.
5, press the preparation method of the described a kind of Sumatriptan Succinate of claim 1, it is characterized in that the temperature of reaction during described step 2. is 55～70 ℃, reaction times is 2～3 hours, the mol ratio of reactant is 4-diazanyl-N-methylbenzene Toluidrin hydrochloride: 4-chlorobutane-1,1-sodium disulfonate: acid catalyst=1: 1～1.1: 1～4.
6,, it is characterized in that molten potassium hydroxide aqueous solution or aqueous sodium hydroxide solution, the ammonia soln of can be of alkali during described step 2. by the preparation method of the described a kind of Sumatriptan Succinate of claim 1; The organic solvent of extraction is ethyl acetate or methylene dichloride, chloroform.
7, press the preparation method of the described a kind of Sumatriptan Succinate of claim 1, it is characterized in that the dimethylamine during described step 3. is dimethylamine agueous solution or dimethylamine alcoholic solution, concentration is 30～40%, and the molar weight of its adding is 6.5～7.5 times of 3-(2-chloroethyl)-N-Methyl-1H-indole-5-Toluidrin.
8, by the preparation method of the described a kind of Sumatriptan Succinate of claim 1, it is characterized in that the phase-transfer catalyst during described step 3. is Tetrabutyl amonium bromide or benzyltriethylammoinium chloride, tetrabutylammonium iodide.
9, by the preparation method of the described a kind of Sumatriptan Succinate of claim 1, it is characterized in that the temperature of reaction during described step 3. is 45～55 ℃, the reaction times is 4～5 hours; The solvent of extraction is ethyl acetate, methylene dichloride or chloroform.
10, by the preparation method of the described a kind of Sumatriptan Succinate of claim 1, it is characterized in that described step 4. and the solvent 5. be acetone or ethyl acetate, methyl alcohol.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102212027A (en) * | 2011-05-04 | 2011-10-12 | 苏州莱克施德药业有限公司 | Preparation method for sumatriptan |
| CN102432519A (en) * | 2011-11-21 | 2012-05-02 | 山东新华制药股份有限公司 | Preparation method of 3-(2-aminoethyl)-N-methyl-1H-indole-5-methanesulfonamide |
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| GB9013845D0 (en) * | 1990-06-21 | 1990-08-15 | Glaxo Group Ltd | Process |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102212027A (en) * | 2011-05-04 | 2011-10-12 | 苏州莱克施德药业有限公司 | Preparation method for sumatriptan |
| CN102212027B (en) * | 2011-05-04 | 2012-12-12 | 苏州莱克施德药业有限公司 | Preparation method for sumatriptan |
| CN102432519A (en) * | 2011-11-21 | 2012-05-02 | 山东新华制药股份有限公司 | Preparation method of 3-(2-aminoethyl)-N-methyl-1H-indole-5-methanesulfonamide |
| CN102432519B (en) * | 2011-11-21 | 2013-12-11 | 山东新华制药股份有限公司 | Preparation method of 3-(2-aminoethyl)-N-methyl-1H-indole-5-methanesulfonamide |
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