CN102827062A - Method for preparing almotriptan malate - Google Patents
Method for preparing almotriptan malate Download PDFInfo
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- CN102827062A CN102827062A CN2012103428248A CN201210342824A CN102827062A CN 102827062 A CN102827062 A CN 102827062A CN 2012103428248 A CN2012103428248 A CN 2012103428248A CN 201210342824 A CN201210342824 A CN 201210342824A CN 102827062 A CN102827062 A CN 102827062A
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Abstract
The invention provides a method for preparing almotriptan malate, which comprises that (1) 4-(1-pyrrolidinylsulforylmenthyl)phenylhydrazine and 4-chlorobutyraldehyde are reacted with each other to obtain the corresponding phenylhydrazone, and 3-[2-(dimethylamino)ethyl]-5-(1-pyrrolidinylsulforylmenthyl)-1H-benzazole (ATP-2) is formed through cyclization under the acid condition; (2) ATP-2 is methylated under the action of formaldehyde and sodium borohydride to obtain crude almotriptan alkali (ATP-3); (3) the crude almotriptan alkali (ATP-3) is respectively salified and crystallized in fumaric acid and salicylic acid ethanol solution; and (4) the refined ATP-3 and DL-malic acid are reacted with each other in carbine to obtain the almotriptan malate. The almotriptan malate with high purity can be prepared through adopting the method; and the method has a simple synthetic technology, easily obtained raw materials, high product yield and low impurity content, and can satisfy the requirement of industrial large-scale production.
Description
Technical field
The invention belongs to the synthetic field of pharmaceutical chemistry, specifically, relate to a kind of preparation method of oxysuccinic acid LAS 31416.
Background technology
Oxysuccinic acid LAS 31416 (Almotriptan malate); Chemistry 3-[2-(dimethylin) ethyl] by name-5-(1-pyrrolidyl sulfonymethyl)-1H-indoles malate; Be teenager and grownup's Medicine for treating migraine; In September, 2000, being gone on the market by drugs approved by FDA May calendar year 2001 was used to be grown up migrainous treatment first in Spain's listing.
The oxysuccinic acid LAS 31416 is the complete synthesis brand-new compound of a kind of chemistry, and the compound method of bibliographical information is few, and nearly all synthetic route is all from p-aminophenyl methylsulfonyl pyrroles (compound I I) beginning, and then the different mode of process obtains target compound:
For example, the method for describing among the ES2084560 is the compound method of grinding the initial report of producer by former; Compound I I diazotization is obtained corresponding hydrazine, form hydrazone again, carry out Fisher without separation and close ring; And then obtain through polystep reaction such as methylate, concrete synthetic route is following:
Yet this method only provides about 20% low-yield.In addition, cause under these processing condition that a large amount of polymeric impurities forms, and make the separation time and effort consuming of LAS 31416, and productive rate is low.
Described the compound method of another kind of oxysuccinic acid LAS 31416 among the WO2006129190: with compound I I is raw material; Carry out halo to its 2nd; Further,, obtain 5-(1-pyrrolidyl-alkylsulfonyl methyl)-1H-indoles-3-ethanol with 1-triethyl siloxy-4-triethyl silyl-3-butine coupling through the catalytic Heck coupling of palladium; Obtain through polystep reaction, concrete synthetic route is following again:
Yet the preparation of 1-triethyl siloxy-4-triethyl silyl-3-butine relates to the use of n-Butyl Lithium, for large-scale industrialization production, and not only inconvenience but also dangerous.And the use of n-Butyl Lithium needs strict reaction conditions, needs the moisture content in the reaction process is carried out strictness control, and required special storage condition causes production cost to improve.
Summary of the invention
The purpose of this invention is to provide that a kind of preparation technology is simple, raw material is easy to get and the preparation method of the oxysuccinic acid LAS 31416 that product yield is high, foreign matter content is low.
In order to realize the object of the invention; The preparation method of a kind of oxysuccinic acid LAS 31416 of the present invention; Comprise step: 1) make the reaction of 4-(1-pyrrolidyl alkylsulfonyl methyl) phenylhydrazine and 4-chlorobutyraldehyde diethyl acetal obtain corresponding phenylhydrazone; Phenylhydrazone is not purified, and directly cyclisation forms ATP-2, i.e. 3-[2-(dimethylin) ethyl]-5-(1-pyrrolidyl sulfonymethyl)-1H-indoles under acidic conditions; 2) ATP-2 methylates under formaldehyde and Peng Qinghuana effect and obtains ATP-3, i.e. LAS 31416 alkali bullion; 3) ATP-3 bullion salify crystallization in fumaric acid and salicylic ethanolic soln respectively obtains purified ATP-3; 4) purified ATP-3 and DL-oxysuccinic acid are reacted in methyl alcohol, promptly get the oxysuccinic acid LAS 31416.Synthetic route is as shown in Figure 1.
Aforesaid preparation method; Step 1) is specially: under nitrogen protection; 4-(1-pyrrolidyl alkylsulfonyl methyl) phenylhydrazine and 4-chlorobutyraldehyde diethyl acetal are reacted under the condition of methyl alcohol and concentrated hydrochloric acid existence obtain corresponding phenylhydrazone; Directly under the acidic conditions of pH value 4.5 ± 0.5, add Sodium phosphate, dibasic then, reflux 10 ± 1h, cyclisation forms ATP-2.The mol ratio of preferred 4-(1-pyrrolidyl alkylsulfonyl methyl) phenylhydrazine and 4-chlorobutyraldehyde diethyl acetal is 1: 1-1.5 is preferably 1: 1.1.
Aforesaid preparation method, step 2) be specially: ATP-2 is dissolved in the methyl alcohol,, under 10-15 ℃, makes ATP-2 that methylation reaction takes place, obtain LAS 31416 alkali bullion then to methanol aqueous solution that wherein drips formaldehyde and sodium borohydride solution.
Aforesaid preparation method, step 3) is specially: the ATP-3 bullion respectively in fumaric acid and salicylic ethanolic soln the salify crystallization each 2 times.Preferably, earlier with ATP-3 bullion salify crystallization in the ethanolic soln of fumaric acid, place salicylic ethanolic soln salify crystallization then; Repeat aforesaid operations 1 time.
Aforesaid preparation method comprises that also the crystal to separating out carries out vacuum drying step, and vacuum drying temperature is 35 ± 5 ℃, time 3-4h.
Aforesaid preparation method, step 4) is specially: purified ATP-3 is dissolved in the methyl alcohol, then to the methanol solution that wherein drips the DL-oxysuccinic acid, behind the backflow 1h, stirs 3-4h down at 0-5 ℃, the solid of separating out is the oxysuccinic acid LAS 31416.
Aforesaid preparation method also comprises step 5), and the oxysuccinic acid LAS 31416 that promptly step 4) is obtained carries out the purified step.It is that the oxysuccinic acid LAS 31416 that step 4) obtains is placed salicylic ethanolic soln salify crystallization.And crystal vacuum-drying to separating out.Preferred vacuum drying temperature is 40 ± 5 ℃, time 4-6h.
Gained oxysuccinic acid LAS 31416 optional was further purified with gac before being converted into pharmaceutical salts, thereby obtained to meet the oxysuccinic acid LAS 31416 of medicinal standard.
The present invention prepares the oxysuccinic acid LAS 31416 that meets medicinal standard through the optimization of processing condition.The present invention mainly investigates and has confirmed material proportion and the pH span of control in ATP-1 (being the corresponding phenylhydrazone that the reaction of 4-(1-pyrrolidyl alkylsulfonyl methyl) phenylhydrazine and 4-chlorobutyraldehyde diethyl acetal obtains) and the ATP-2 building-up process; And the stability of ATP-1 carried out preliminary investigation, and then its drying and preserving type have been confirmed; Emphasis is to refining research of LAS 31416 alkali (ATP-3); Found a yield higher; Operate comparatively simple; The effective method of purifying LAS 31416 alkali (ATP-3) adopts LAS 31416 alkali (ATP-3) the synthetic target compound oxysuccinic acid LAS 31416 behind the purifying, and quality meets the USP required standard.In order further to improve the quality of products; (chemical name of impurity D is (3-(2-(dimethylamino) ethyl)-5-((tetramethyleneimine-1-base alkylsulfonyl) methyl)-1H-indoles-1-yl) methyl alcohol to reduce single maximum contaminant D in the product; In the preparation process of amine-methylated and APT-3, produce) content; Adopt the salifiable mode of Whitfield's ointment that product has been carried out purifying once more, the refining oxysuccinic acid LAS 31416 product that obtains meeting the national regulation medicinal requirements.The highly purified LAS 31416 that adopts the inventive method to obtain, further synthesising target compound oxysuccinic acid LAS 31416, gained bullion purity can reach 99.59%, and single maximum contaminant D content is merely 0.15%, satisfies the assorted limit of list that the USP mark requires fully.Through further refining to bullion, the yield with 79% obtains oxysuccinic acid LAS 31416 elaboration, HPLC purity 99.85%, and the content of maximum single assorted D reduces to 0.02%.
Description of drawings
Fig. 1 is the synthetic route chart of oxysuccinic acid LAS 31416 in the preferred embodiment of the present invention.
Embodiment
Following examples are used to explain the present invention, but are not used for limiting scope of the present invention.If do not specialize the conventional means that used technique means is well known to those skilled in the art among the embodiment, the raw materials used commercial goods that is.
Synthesizing of embodiment 1 oxysuccinic acid LAS 31416
1.1 the preparation of 3-[2-(dimethylin) ethyl]-5-(1-pyrrolidyl sulfonymethyl)-1H-indoles
Reaction equation:
Operation steps:
In the 50L reaction kettle, add 19.3L water, 380ml concentrated hydrochloric acid and 1556.0g 4-chlorobutyraldehyde diethyl acetal, stirring at room 1 hour, subsequent use.
Under nitrogen protection, in the 100L reaction kettle that stirs, drop into the dense HCl of 4-(1-pyrrolidyl alkylsulfonyl methyl) phenylhydrazine, 4.6L water and the 700ml of 21.4L methyl alcohol, 2000g, drip the above-mentioned 4-chlorobutyraldehyde diethyl acetal solution that makes in 20 ± 5 ℃.There is yellow solid to separate out in the dropping process, dropwises, stirred 2 hours in 0-5 ℃.TLC monitoring raw material primitive reaction finishes.Centrifugal, get rid of filter to do yellow solid.
Under nitrogen protection, 32L methyl alcohol and 5L water are dropped in the 50L reaction kettle, drop into above-mentioned yellow solid that obtains and 886g disodium phosphate dihydrate, regulate pH value about 4.5 with concentrated hydrochloric acid.Heating reflux reaction 10 hours, TLC monitoring reaction finishes.Concentrating under reduced pressure adds 20L water, with washed with dichloromethane 3 times, and 5L at every turn.In water layer, add the yellow soda ash solid in batches and regulate the pH value to 9-10, with dichloromethane extraction 3 times, each 5L, merging organic phase.With saturated brine washing 3 times, each 5L uses anhydrous sodium sulfate drying at last, filters then, and concentrated filtrate gets brown jelly 1408.6g, yield 58.5%, HPLC purity 93.93%.
1H-NMR(DMSO，500MZ)：1.761-1.659(m，4H)2.792-2.765(t，2H)2.861-2.864(t，2H)3.451-3.052(m，4H)4.455(s，2H)7.131-7.114(d，1H)7.206-7.173(d，1H)7.337-7.289(m，1H)7.570(s，1H)10.930(s，1H)。
1.2 the preparation of LAS 31416 alkali (ATP-3)
Reaction equation:
Operation steps:
In the 100L reaction kettle, drop into 26L methyl alcohol and 1400gATP-2; Cooling; Controlled temperature is 15 ℃, drips methanol aqueous solution (35% formaldehyde solution of 6.2L is dissolved in the 6.2L methyl alcohol) 12.4L of 18% formaldehyde simultaneously and is dissolved in the 880g sodium borohydride solution in the 12.5L water.Dropwise continued 15 ℃ of reactions 1 hour.TLC monitoring raw material primitive reaction finishes.
In reaction kettle, adding 2mol/L hydrochloric acid soln conditioned reaction liquid pH value is 3, stirs 20 minutes.Using sodium bicarbonate solid to transfer to the pH value is 6.5, and concentrating under reduced pressure boils off methyl alcohol as far as possible, with the washing of 8L ETHYLE ACETATE once.Water layer is regulated the pH value to 9-10 with the yellow soda ash solid, uses ethyl acetate extraction then 3 times, each 6L, and organic phase is with saturated brine washing 3 times, 3L at every turn.Use anhydrous sodium sulfate drying at last.Filter, concentrate, get brown oil 1.15kg, yield 75.5%.
With the above-mentioned oily matter of 3.45L anhydrous alcohol solution 1.15kg, put in the 20L reaction flask, stir.The 478g fumaric acid is dissolved in the 9.54L absolute ethyl alcohol, is added drop-wise in the reaction flask under the room temperature, refluxed 1 hour, stir cool to room temperature down, stirring at room 2 hours has solid to separate out, and filters, and solid is used a small amount of absolute ethanol washing.
The solid suspension that obtains in the mixed solution of 11.5L ETHYLE ACETATE and 11.5L water, is added 3.4L ammoniacal liquor, and regulating the pH value is alkalescence, fully stirs, and isolates organic layer.Water layer is with ethyl acetate extraction 3 times, each 5L, and combined ethyl acetate, then with saturated brine washing 3 times, each 5L uses anhydrous sodium sulfate drying at last.Filter, concentrated filtrate obtains the 919.6g solid.
The 4.6L absolute ethyl alcohol is dropped in the 10L reaction flask, add the above-mentioned solid that obtains, stir, dissolving.The 492g Whitfield's ointment is dissolved in the 1.86L absolute ethyl alcohol, is added drop-wise in the reaction flask, refluxed 1 hour, be cooled to 0-5 ℃ under stirring, keep temperature to stir 2 hours, separate out solid.Filter, solid is used a small amount of absolute ethanol washing.
The solid suspension that obtains in the mixed solution of 10L ETHYLE ACETATE and 10L water, is added 2.8L ammoniacal liquor, and regulating the pH value is alkalescence, fully stirs, and isolates organic layer.Water layer is with ethyl acetate extraction 3 times, each 5L, and combined ethyl acetate, then with saturated brine washing 3 times, each 5L, last anhydrous sodium sulfate drying filters, and filtrating concentrating obtains the 768.8g solid.
The 2.2L absolute ethyl alcohol is dropped in the 10L reaction flask, stir down and drop into the above-mentioned solid that obtains, stirring and dissolving is dissolved in the 320g fumaric acid in the 6.4L absolute ethyl alcohol, is added drop-wise in the reaction flask under the room temperature, refluxes 1 hour.Be cooled to room temperature under stirring, and at room temperature stirred 2 hours, have solid to separate out.Filter, solid is used a small amount of absolute ethanol washing.
The solid suspension that obtains in the mixed solution of 9L ETHYLE ACETATE and 9L water, is added 2.3L ammoniacal liquor, and regulating the pH value is alkalescence, fully stirs; Isolate organic layer, water layer is with ethyl acetate extraction 3 times, each 5L; Combined ethyl acetate, then with saturated brine washing 3 times, each 5L; Last anhydrous sodium sulfate drying filters, and concentrates and obtains solid 662.0g.
The 3.3L absolute ethyl alcohol is dropped in the 10L reaction flask, add the solid that obtains, stir; Dissolving, the 354g Whitfield's ointment is dissolved in the 1.34L absolute ethyl alcohol, is added drop-wise in the reaction flask under the room temperature; Refluxed 1 hour, and be cooled to 0-5 ℃ under stirring, and keep this temperature to stir 2 hours; Separate out solid in the reaction solution, filter, solid is with a small amount of absolute ethanol washing.
The solid suspension that obtains in the mixed solution of 8L ETHYLE ACETATE and 8L water, is added 2L ammoniacal liquor, and regulating the pH value is alkalescence, fully stirs; Isolate organic layer, water layer is with ethyl acetate extraction 3 times, each 5L, combined ethyl acetate; With saturated brine washing 3 times, each 5L adds the 50g gac, stirs 30 minutes then; Add anhydrous sodium sulfate drying at last, filter, concentrate and obtain solid.35 ℃ of drying under reduced pressure obtain 579.3g off-white color solid, refining back LAS 31416 yield 50.4%, HPLC purity 99.54%.
1H-NMR(DMSO，500MZ)：1.774-1.750(m，4H)2.226(s，6H)2.539-2.509(t，2H)2.828-2.797(t，2H)3.124-3.098(t，4H)4.463(s，2H)7.133-7.114(m，1H)7.175-7.172(d，1H)7.328-7.312(d，1H)7.576-7.561(d，1H)10.861(s，1H)。
1.3 the preparation of oxysuccinic acid LAS 31416 bullion
Reaction equation:
Operation steps:
In the 5L reaction flask, add ATP-3 and the 1.6L methyl alcohol of 560g, stir, dissolving, 250g is dissolved in the 1.18L methyl alcohol with the DL-oxysuccinic acid, and is added drop-wise in the reaction flask, refluxes 1 hour.Be cooled to 0-5 ℃ under stirring, keep this temperature to stir 3 hours, separate out solid, filter, filter cake washs with small amount of methanol.40 ℃ of drying under reduced pressure obtain off-white color solid 684.3g, yield: 87.3%.It is 99.59% that HPLC detects purity, and single maximum contaminant D is 0.15%.
Wherein, the chemical name of impurity D is (3-(2-(dimethylamino) ethyl)-5-((tetramethyleneimine-1-base alkylsulfonyl) methyl)-1H-indoles-1-yl) methyl alcohol, in the preparation process of amine-methylated and APT-3, produces.Its chemical structure is following:
1.4 the preparation of oxysuccinic acid LAS 31416
Operation steps:
Oxysuccinic acid LAS 31416 680g is suspended in the mixing solutions of 5L ETHYLE ACETATE and 5L water, adds 1.45L ammoniacal liquor, regulating the pH value is alkalescence, fully stirs.Isolate organic layer, water layer is with ethyl acetate extraction 3 times, each 2L, combined ethyl acetate.With saturated brine washing 3 times, each 2L uses anhydrous sodium sulfate drying at last, filters, and filtrating concentrating obtains the off-white color solid.
The above-mentioned solid that obtains is dropped in the 5L reaction flask, add the 2.4L absolute ethyl alcohol, stir, dissolving; The 260g Whitfield's ointment is dissolved in the 980ml absolute ethyl alcohol, is added drop-wise in the reaction flask, refluxed 1 hour, be cooled to 0-5 ℃ under stirring; Keep this temperature to stir 2 hours, separate out solid, filter.
Filter cake is suspended in the mixing solutions of 5L ETHYLE ACETATE and 5L water after with a small amount of absolute ethanol washing, adds 1.3L ammoniacal liquor, and regulating pH value be alkalescence, abundant stirring; Isolate organic layer, water layer is with ethyl acetate extraction 3 times, each 2L; Combined ethyl acetate, then with saturated brine washing 3 times, each 2L; Use anhydrous sodium sulfate drying at last, filter, concentrate and obtain off-white color solid 432.3g.
This solid is added in the 5L reaction flask, add 1.29L methyl alcohol, stir, dissolving.194g is dissolved in the 910ml methyl alcohol with the DL-oxysuccinic acid, is added drop-wise in the reaction solution, refluxes 1 hour.Be cooled to 0-5 ℃ under stirring, keep this temperature to stir 3 hours, separate out solid.Filter, filter cake washs with small amount of methanol, and 40 ℃ of drying under reduced pressure obtain solid 538.5g, yield: 79.2%, and HPLC purity: 99.85%.
1H-NMR(DMSO，500MZ)：1.786-1.760(m，4H)2.570-2.522(m，1H)2.750-2.709(m，1H)2.798(s，6H)3.126-3.099(t，6H)3.366-3.336(t，2H)4.307-4.282(m，1H)4.460(s，2H)7.173-7.154(m，1H)7.258(s，1H)7.450-7.434(d，1H)7.597(s，1H)。
The synthetic route of above-mentioned oxysuccinic acid LAS 31416 is as shown in Figure 1.
Though, the present invention has been done detailed description in the preceding text with general explanation and specific embodiments, on basis of the present invention, can to some modifications of do or improvement, this will be apparent to those skilled in the art.Therefore, these modifications or the improvement on the basis of not departing from spirit of the present invention, made all belong to the scope that requirement of the present invention is protected.
Claims (10)
1. the preparation method of an oxysuccinic acid LAS 31416 is characterized in that, comprises step:
1) make the reaction of 4-(1-pyrrolidyl alkylsulfonyl methyl) phenylhydrazine and 4-chlorobutyraldehyde diethyl acetal obtain corresponding phenylhydrazone, then directly under acidic conditions cyclisation form ATP-2, i.e. 3-[2-(dimethylin) ethyl]-5-(1-pyrrolidyl sulfonymethyl)-1H-indoles;
2) ATP-2 methylates under formaldehyde and Peng Qinghuana effect and obtains ATP-3, i.e. LAS 31416 alkali bullion;
3) ATP-3 bullion salify crystallization in fumaric acid and salicylic ethanolic soln respectively obtains purified ATP-3;
4) purified ATP-3 and DL-oxysuccinic acid are reacted in methyl alcohol, promptly get the oxysuccinic acid LAS 31416.
2. preparation method according to claim 1; It is characterized in that step 1) is: under nitrogen protection, make 4-(1-pyrrolidyl alkylsulfonyl methyl) phenylhydrazine and 4-chlorobutyraldehyde diethyl acetal under the condition of methyl alcohol and concentrated hydrochloric acid existence; By 1: the mol ratio of 1-1.5 reacts and obtains corresponding phenylhydrazone; Directly under the acidic conditions of pH value 4.5 ± 0.5, add Sodium phosphate, dibasic then, reflux 10 ± 1h, cyclisation forms ATP-2.
3. preparation method according to claim 1; It is characterized in that step 2) be: ATP-2 is dissolved in the methyl alcohol, then to methanol aqueous solution that wherein drips formaldehyde and sodium borohydride solution; Under 10-15 ℃, make ATP-2 that methylation reaction takes place, obtain LAS 31416 alkali bullion.
4. preparation method according to claim 1 is characterized in that, step 3) is: the ATP-3 bullion respectively in fumaric acid and salicylic ethanolic soln the salify crystallization each 2 times.
5. preparation method according to claim 4 is characterized in that, earlier with ATP-3 bullion salify crystallization in the ethanolic soln of fumaric acid, places salicylic ethanolic soln salify crystallization then, repeats this operation 1 time.
6. preparation method according to claim 5 is characterized in that, comprises that also the crystal to separating out carries out vacuum drying step, and vacuum drying temperature is 35 ± 5 ℃, time 3-4h.
7. preparation method according to claim 1 is characterized in that, step 4) is: purified ATP-3 is dissolved in the methyl alcohol; Then to the methanol solution that wherein drips the DL-oxysuccinic acid; Behind the backflow 1h, stir 3-4h down at 0-5 ℃, the solid of separating out is the oxysuccinic acid LAS 31416.
8. according to each described preparation method of claim 1-7, it is characterized in that, comprise that also the oxysuccinic acid LAS 31416 that step 4) is obtained carries out the purified step.
9. preparation method according to claim 8 is characterized in that, it is that the oxysuccinic acid LAS 31416 that step 4) obtains is placed salicylic ethanolic soln salify crystallization, and the crystal vacuum-drying to separating out.
10. preparation method according to claim 9 is characterized in that, vacuum drying temperature is 40 ± 5 ℃, time 4-6h.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103353494A (en) * | 2013-07-04 | 2013-10-16 | 山东省医药工业研究所 | HPLC (high performance liquid chromatography) detection method of related substances in almotriptan malate |
| CN103520126A (en) * | 2013-10-11 | 2014-01-22 | 扬子江药业集团四川海蓉药业有限公司 | Almotriptan tablet and preparation method thereof |
| CN106478484A (en) * | 2016-08-31 | 2017-03-08 | 重庆华森制药股份有限公司 | A kind of method preparing Almogran key intermediate |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN85106225A (en) * | 1983-12-06 | 1987-02-18 | 格拉克索公司 | The preparation method of indole derivatives and the application in medical treatment thereof |
| WO2006129190A1 (en) * | 2005-06-03 | 2006-12-07 | Glenmark Pharmaceuticals Limited | Process for the preparation of almotriptan |
| WO2010113183A2 (en) * | 2009-04-03 | 2010-10-07 | Msn Laboratories Limited | Process for the preparation of 1-[[[3-[2-(dimethylamino)ethyl]-1h-indol-5-yl]methyl]sulfonyl] pyrrolidine and its pharmaceutically acceptable salts |
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2012
- 2012-09-17 CN CN2012103428248A patent/CN102827062A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN85106225A (en) * | 1983-12-06 | 1987-02-18 | 格拉克索公司 | The preparation method of indole derivatives and the application in medical treatment thereof |
| WO2006129190A1 (en) * | 2005-06-03 | 2006-12-07 | Glenmark Pharmaceuticals Limited | Process for the preparation of almotriptan |
| WO2010113183A2 (en) * | 2009-04-03 | 2010-10-07 | Msn Laboratories Limited | Process for the preparation of 1-[[[3-[2-(dimethylamino)ethyl]-1h-indol-5-yl]methyl]sulfonyl] pyrrolidine and its pharmaceutically acceptable salts |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103353494A (en) * | 2013-07-04 | 2013-10-16 | 山东省医药工业研究所 | HPLC (high performance liquid chromatography) detection method of related substances in almotriptan malate |
| CN103353494B (en) * | 2013-07-04 | 2014-12-31 | 山东省医药工业研究所 | HPLC (high performance liquid chromatography) detection method of related substances in almotriptan malate |
| CN103520126A (en) * | 2013-10-11 | 2014-01-22 | 扬子江药业集团四川海蓉药业有限公司 | Almotriptan tablet and preparation method thereof |
| CN103520126B (en) * | 2013-10-11 | 2016-06-22 | 扬子江药业集团四川海蓉药业有限公司 | A kind of Almotriptan tablet and preparation method thereof |
| CN106478484A (en) * | 2016-08-31 | 2017-03-08 | 重庆华森制药股份有限公司 | A kind of method preparing Almogran key intermediate |
| CN106478484B (en) * | 2016-08-31 | 2017-11-10 | 重庆华森制药股份有限公司 | A kind of method for preparing almotriptan key intermediate |
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Application publication date: 20121219 |