CN102875538A - Method for preparing vilazodone or hydrochloride thereof - Google Patents
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Abstract
The invention relates to a method for preparing 5-(4-[4-(5-cyan-3-indolyl)-butyl]-1-piperazinyl) benzofuran-2-formamide (vilazodone) or hydrochloride thereof. The method comprises the following steps of: performing reaction between a formula-I compound and a formula-II compound 5-amino-2-formamido-benzofuran in a solvent under the action of alkaline matter, and separating and purifying products to obtain a formula-1 compound, i.e. the vilazodone; and salifying the vilazodone and hydrochloric acid in the solvent to prepare vilazodone hydrochloride. The invention also relates to a method for preparing the formula-I compound.
Description
Technical field
The present invention relates to prepare the method for Wella oxazolone or its hydrochloride.
Technical background
At present, domestic and international published several methods that prepare hydrochloric acid Wella oxazolone can be summarized as following two large classes:
1) also disclosing among patent WO2006/114202, the CN101163698A take 3-(4-piperazine butyl) indoles-5-formonitrile HCN and 5-bromobenzene and furans-2-methane amide be as intermediate, prepares the method for hydrochloric acid Wella oxazolone.Synthetic route is as follows:
The method is take 3-(4-piperazine butyl) indoles-5-formonitrile HCN and 5-bromobenzene and furans-2-methane amide be as intermediate, under three (dibenzalacetone)-two palladiums and tri-tert phosphine catalyst, carries out linked reaction, again through the acidifying salify, preparation hydrochloric acid Wella oxazolone.The method adopts expensive palladium metal complex catalyst and tri-butyl phosphine part, and preparation cost is high, is not suitable for a large amount of industrialization preparations of hydrochloric acid Wella oxazolone.
2) be take the 3-(4-R butyl among patent CN1056610C, CN155568C, CN1181067C, WO2006/114202, CN101163698A and the CN102267985A) indoles-5-formonitrile HCN and 1-(2-R ' cumarone-5-yl) piperazine is intermediate, prepare the method for Wella oxazolone, synthetic route is as follows:
Substituent R in the formula is-CH
2X(X is halogen) ,-CH
2OTs or-CHO, R ' is-COOH or-CONH
2, when R ' be-during COOH, carry out amination after the condensation, obtain the Wella oxazolone; When R ' is-CONH
2The time, condensation directly obtains the Wella oxazolone.Wella oxazolone acidifying salify obtains hydrochloric acid Wella oxazolone.
Intermediate 1-(2-R ' cumarone in this route-5-yl) piperazine is to be reacted under the alkali effect by amino cumarone and two (2-chloroethyl) amine of corresponding 2-R '-5-to obtain, and it is very low that this goes on foot reaction yield, only about 30%.
Summary of the invention
The object of the invention is to provide the preparation method of a kind of Wella oxazolone or its hydrochloride, to overcome the defective of prior art.
The preparation method of described Wella oxazolone comprises the steps:
With formula (I) compound in solvent, under the alkaline matter effect, reacted 5-24 hour under 20 ℃～150 ℃ with formula (II) compound 5-amino-1-benzofuran-2-carboxamides, preferred 8～16 hours, separating-purifying obtained the Wella oxazolone shown in the formula 1 from product;
The chemical name of its Chinese style (I) compound is 3-[(4-two (2-chloroethyl) amido) butyl]-the 5-cyanoindole;
The mol ratio of its Chinese style (I) compound and formula (II) compound is 0.8:1～1.2:1;
Described solvent be a kind of in DMF, toluene, dioxane, propyl carbinol, dimethylbenzene, tetrahydrofuran (THF), acetone, butanone, acetonitrile, the ethylene glycol monomethyl ether and more than, be preferably acetonitrile or butanone;
Described alkaline matter is conventional organic bases or the mineral alkali that uses in this area, is selected from more than a kind of the reaching in salt of wormwood, yellow soda ash, sodium bicarbonate, saleratus, triethylamine, pyridine, the diisopropylethylamine, wherein is preferably salt of wormwood or yellow soda ash;
Reaction formula is as follows:
Wherein, formula (II) compound 5-amino-1-benzofuran-2-carboxamides, but the preparation of the method among the referenced patent CN1140171A.
The preparation method of formula (I) compound comprises the steps:
With formula (III) compound in solvent, under the reductive agent effect, under-50～20 ℃, react 1～10 hour reaction times, preferred 1.5～4 hours, separating-purifying obtained formula (I) compound: 3-[(4-two (2-chloroethyl) amido) butyl]-the 5-cyanoindole;
Wherein the mol ratio of reductive agent and formula (III) compound is 2:1～1:1;
Described solvent be a kind of in methylene dichloride, chloroform, tetrahydrofuran (THF), acetone, acetonitrile, ether, toluene, dimethylbenzene, the ethylene dichloride and more than.
Described reductive agent is two (2-methoxy ethoxy) sodium aluminates of dihydro.
Reaction formula is as follows:
The preparation method of formula (III) compound comprises the steps:
With formula (IV) compound 4-(two (2-chloroethyl) amido) butyryl chloride, in solvent, under the aluminum chloride effect, react under-20～50 ℃ with the 5-cyanoindole, 0.5～10 hour reaction times, preferred 1～3 hour, separating-purifying obtained formula (III) compound: 3-[(4-two (2-chloroethyl) amido) butyryl radicals]-5-cyanoindole hydrochloride;
The mol ratio of its Chinese style (IV) compound and 5-cyanoindole is 1.5:1～0.8:1;
It is characterized in that, described solvent be a kind of in methylene dichloride, chloroform, tetrahydrofuran (THF), acetone, acetonitrile, ether, toluene, dimethylbenzene, the ethylene dichloride and more than, preferred ethylene dichloride;
Reaction formula is as follows:
The preparation method of formula (IV) compound comprises the steps:
With formula (V) compound, in solvent, with halogenating agent, in 25～150 ℃ of lower reactions, the reaction times is 2～12 hours, preferred 2～4 hours, obtains formula (IV) compound: 4-two (2-chloroethyl) amido butyryl chloride;
Described solvent be a kind of in DMF, toluene, dioxane, dimethylbenzene, tetrahydrofuran (THF), acetone, butanone, acetonitrile, ethylene glycol monomethyl ether, methylene dichloride, the chloroform and more than, preferred methylene dichloride;
Described halogenating agent be selected from a kind of in thionyl chloride, phosphorus trichloride, phosphorus oxychloride, the oxalyl chloride and more than, preferred thionyl chloride, the mol ratio of thionyl chloride and formula (V) compound is 1:1～5:1, preferred molar ratio is 1.2:1～3:1;
Reaction formula is as follows:
The preparation method of formula (V) compound comprises the steps:
With formula (VI) compound, in solvent, under the alkaline matter effect, in 25～100 ℃ of lower reactions, the reaction times is 0.5～10 hour, preferred 2～5 hours, obtains formula (V) compound: 4-two (2-chloroethyl) amido butyric acid;
Described solvent is more than one in ethanol, methyl alcohol, acetone, tetrahydrofuran (THF), acetonitrile, isopropyl acetone, butanone or the water, is preferably the first alcohol and water;
Described alkaline matter is selected from sodium hydroxide, potassium hydroxide, and the mol ratio of alkaline matter and formula (VI) compound is 1:1～5:1, and preferred molar ratio is 2:1～3:1;
Reaction formula is as follows:
The preparation method of formula (VI) compound comprises the steps:
With formula (VII) compound in solvent, under the alkaline matter effect, under 20～150 ℃, carry out 1～24 hour reaction times with halogenating agent, preferred 3～5 hours, separating-purifying obtained formula (VI) compound: 4-two (2-chloroethyl) amido butyric acid;
Described solvent be a kind of in tetrahydrofuran (THF), methylene dichloride, chloroform, acetone, butanone, toluene, dimethylbenzene, dioxane or the acetonitrile and more than, preferred tetrahydrofuran (THF);
Described halogenating agent be selected from a kind of in phosphorus trichloride, thionyl chloride, oxalyl chloride or the phosphorus oxychloride and more than, be preferably phosphorus trichloride, the mol ratio of phosphorus trichloride and formula (VII) compound is 1:1～5:1, preferred molar ratio is 2:1～3:1;
Described alkaline matter be a kind of in pyridine, triethylamine or the diisopropylethylamine and more than;
Reaction formula is as follows:
The preparation method of formula (VII) compound comprises the steps:
With formula (VIII) compound in solvent, under the alkaline matter effect, with two (2-hydroxyethyl) amine, in 20～150 ℃ of lower reactions, reaction times is 2～48 hours, preferred 8～12 hours, separating-purifying obtained formula (VII) compound: 4-two (2-hydroxyethyl) amido methyl-butyrate;
Wherein the mol ratio of two (2-hydroxyethyl) amine and formula (VIII) compound is 0.8:1～1.5:1, is preferably 1:1;
Described solvent be a kind of in DMF, toluene, dioxane, propyl carbinol, dimethylbenzene, tetrahydrofuran (THF), acetone, butanone, acetonitrile, the ethylene glycol monomethyl ether and more than, be preferably acetonitrile;
Described alkaline matter be selected from a kind of in sodium bicarbonate, saleratus, yellow soda ash, salt of wormwood, pyridine, triethylamine or the diisopropylethylamine and more than, be preferably yellow soda ash or salt of wormwood;
Reaction formula is as follows:
The preparation method of formula (VIII) compound comprises the steps:
In alcoholic solvent, in 10～65 ℃ of lower reactions 0.5～10 hour, described alcoholic solvent was methyl alcohol with formula (IX) compound;
Reaction formula is as follows:
With Wella oxazolone and the hydrochloric acid reaction shown in the formula 1, can obtain hydrochloric acid Wella oxazolone;
The Wella oxazolone is dissolved in the Virahol, with concentrated hydrochloric acid (37%) in 10～30 ℃, stirring reaction 0.2～5 hour filters, filtration cakes torrefaction gets hydrochloric acid Wella oxazolone;
Wherein the mol ratio of the hydrogenchloride in Wella oxazolone and the concentrated hydrochloric acid is 1:1～5:1.
Reaction formula is as follows:
Of the present invention focusing on, the ripe method of employing is prepared new intermediate (I) 3-[(4-two (2-chloroethyl) amido for the synthesis of the Wella oxazolone) butyl]-the 5-cyanoindole.This intermediate (I) is with respect to the intermediate 1-(2-R ' cumarone of bibliographical information-5-yl) piperazine (R ' be-COOH or-CONH
2) or 3-(4-piperazine butyl) difference of indoles-5-formonitrile HCN is: the sequencing of introducing two (2-chloroethyl) amine is different, because of this step reaction yield only about 30%, introducing two (2-chloroethyl) amine in the later stage can make cost significantly rise, we introduce two (2-chloroethyl) amido in advance with raw material cheap and easy to get based on this, and cost is significantly reduced.This intermediate (I) 3-[(4-two (2-chloroethyl) amido) butyl]-raw material of 5-cyanoindole is cheap and easy to get, changed the order of introducing two (2-chloroethyl) amido, can greatly reduce cost, have obvious creativeness, possess higher actual application value.
Embodiment
Embodiment 1
The preparation of 4-chloro-butyric acid methyl esters
Get 49.8g salt of wormwood in 400ml methyl alcohol, be cooled to 0～5 ℃ with ice-water bath, drip the 42.3g4-chlorobutanoylchloride, add post-heating and refluxed 4 hours, filter afterwards, the filtrate decompression distillation gets the thick product of 41.2g, is directly used in the next step.
ESI-MS[M+H]
+:137.04
1H-NMR（CDCl
3）：δ1.92-1.96（m，2H），2.31（t，2H），3.30（t，2H），3.68（s，3H）。
Embodiment 2
The preparation of 4-two (2-hydroxyethyl) amido methyl-butyrate
The 41.2g 4-chloro-butyric acid methyl esters crude product of reaction preparation was dissolved in the 400ml acetonitrile with the upper step, added two (2-hydroxyethyl) amine of 41.5g salt of wormwood and 31.5g, reflux 12 hours, cooled and filtered, the filtrate decompression distillation, residuum adds the 400ml Virahol, slowly adds 30ml(37% under the room temperature) concentrated hydrochloric acid, until the fully rear filtration of precipitation, filter cake is dissolved in the 200ml water, 3*200ml ethyl acetate extraction, organic phase anhydrous sodium sulfate drying, underpressure distillation after filtering obtains the 23.4g product.
ESI-MS[M+H]
+:206.14
1H-NMR（CDCl
3）：δ1.68-1.72（m，2H），2.20（t，2H），2.34（t，2H），2.52（t，4H），3.56（t，4H），3.68（s，3H）。
Embodiment 3
The preparation of 4-two (2-chloroethyl) amido methyl-butyrate
Get 20.5g 4-two (2-hydroxyethyl) amido methyl-butyrate and 30.0g pyridine and be dissolved in the 320ml tetrahydrofuran (THF), be cooled to 0～5 ℃, drip the 27.5g phosphorus trichloride, after adding, reflux 4 hours, cooled and filtered, filtrate decompression distillation, add 200ml ethyl acetate and 100ml frozen water in the residuum, it is about 7 to regulate pH with the 1N sodium hydroxide solution, separatory, and organic phase is filtered after with anhydrous sodium sulfate drying, the filtrate decompression evaporate to dryness gets the 17.4g product.
ESI-MS[M+H]
+:242.07
1H-NMR（CDCl
3）：δ1.71-1.76（m，2H），2.22（t，2H），2.33（t，2H），2.53（t，4H），3.55（t，4H），3.69（s，3H）。
Embodiment 4
The preparation of 4-two (2-chloroethyl) amido butyrates hydrochlorate
Getting 17.0g 4-two (2-chloroethyl) amido methyl-butyrate is dissolved in the 150ml methyl alcohol, add 150ml aqueous sodium hydroxide solution (1N), be heated to 50～60 ℃ of reactions, stopped heating after 3 hours, concentrating under reduced pressure is removed methyl alcohol, the residual solution ethyl acetate extraction, it is about 1.0 with 1N salt acid for adjusting pH to collect water, again concentrating under reduced pressure, residuum adds 200ml acetone stirring and crystallizing, filter, filtration cakes torrefaction gets the 17.1g white solid.
ESI-MS[M+H]
+:228.06
1H-NMR（DMSO-d6）：δ1.69-1.73（m，2H），2.24（t，2H），2.35（t，2H），2.60（t，4H），3.52（t，4H），10.41（s，1H）。
Embodiment 5
The preparation of 4-two (2-chloroethyl) amido butyryl chloride hydrochloride
Get 15.0g 4-two (2-hydroxyethyl) amido butyrates hydrochlorate in the 200ml methylene dichloride, 0～5 ℃ of lower 16.8g thionyl chloride that drips adds post-heating and refluxed 4 hours, is cooled to the room temperature evaporated under reduced pressure, gets the 16.0g crude product, is directly used in the next step.
Embodiment 6
3-[(4-two (2-chloroethyl) amido) butyryl radicals]-preparation of 5-cyanoindole hydrochloride
Get the 9.0g aluminum chloride in the 90ml ethylene dichloride, 0 ℃ of lower above-mentioned 4-two (2-chloroethyl) amido butyryl chloride hydrochloride crude product 16.0g that slowly adds, add rear continuation and stir half an hour at 0 ℃, drip afterwards the 96ml dichloroethane solution of 9.6g 5-cyanoindole, add rear answer stirring at room 2 hours, add 60g ice, 60ml concentrated hydrochloric acid, stirred 12 hours, leach precipitation, filter cake gets the 16.3g white solid with ethylene dichloride and cold water washing after the drying.
ESI-MS[M+H]
+:352.10
1H-NMR（DMSO-d6）：δ1.73-1.77（m，2H），2.35（t，2H），2.41（t，2H），2.62（t，4H），3.53（t，4H），7.13-8.10（4H），8.23（s，1H），10.62（s，1H）。
Embodiment 7
3-[(4-two (2-chloroethyl) amido) butyl]-preparation of 5-cyanoindole
Get 13.0g3-[(4-two (2-chloroethyl) amido) butyl]-5-cyanoindole hydrochloride is in the 200ml tetrahydrofuran (THF), add 7.1g yellow soda ash, hydrochloride is sloughed in stirring, filter after 2 hours, filtrate is cooled to-20 ℃, drip two (2-methoxy ethoxy) sodium aluminates (70% tetrahydrofuran solution) of 10.1g dihydro, add rear stirring at room 3 hours.Be cooled to afterwards-10 ℃, slowly add 200ml water, at room temperature stir again, after 2 hours reaction solution is neutralized to pH=7 with 1N sodium hydroxide, rear underpressure distillation, the residuum ethyl acetate extraction, collect organic phase, with filtering the filtrate decompression evaporate to dryness behind the anhydrous magnesium sulfate drying, residuum separates with silica gel column chromatography, gets 6.0g 3-[(4-two (2-chloroethyl) amido) butyl]-the 5-cyanoindole.
ESI-MS[M+H]
+:338.12
1H-NMR（DMSO-d6）：δ1.37-1.42（m，2H），1.58-1.62（m，2H），2.35（t，2H），2.43（t，2H），2.60（t，4H），3.51（t，4H），6.83-7.45（4H），8.50（s，1H）。
Embodiment 8
The preparation of 5-(4-[4-(5-cyano group-3-indyl)-butyl]-1-piperazinyl) benzofuran-2-carboxamides (Wella oxazolone)
Get 5.0g 3-[(4-two (2-chloroethyl) amido) butyryl radicals]-5-cyanoindole, 2.6g 5-amino-1-benzofuran-2-carboxamides and 2.0g salt of wormwood is in the 50ml propyl carbinol; reflux 48 hours; filter afterwards; the filtrate decompression distillation; residuum adds entry 20ml, and ethyl acetate 40ml stirred 1 hour; filter and collect insolubles, get the thick product 2.3g of light yellow solid.
ESI-MS[M+H]
+:442.22
1H-NMR（DMSO-d6）：δ1.51-1.53（m，2H），1.63-1.68（m，2H），2.30-2.34（m，2H），2.48-2.50（m，4H），2.71（t，2H），3.05-3.10（m，4H），7.10-8.09（m，10H），11.38（s，1H）。
Embodiment 9
The preparation of 5-(4-[4-(5-cyano group-3-indyl)-butyl]-1-piperazinyl) benzofuran-2-carboxamides hydrochloride (hydrochloric acid Wella oxazolone)
With 2.0g 5-(4-[4-(5-cyano group-3-indyl)-butyl]-1-piperazinyl) benzofuran-2-carboxamides, be dissolved in the 100ml Virahol, stir under the room temperature, drip 1.0g concentrated hydrochloric acid (37%), precipitation is rear the filtration fully, the filter cake washed with isopropyl alcohol, and 80 ℃ of vacuum-dryings are spent the night, get white powder 1.7g, HPLC purity is 99.12%.
ESI-MS[M+H]
+:442.22
1H-NMR（DMSO-d6）：δ1.68-1.76（m，2H），1,80-1.88（m，2H），2.78（t，2H），3.13-3.21（m，6H），3.53-3.56（m，2H），3.72-3.75（m，2H），7.22-8.10（m，10H），10.72（br，1H），11.42（s，1H）。
Claims (16)
1. the preparation method of Wella oxazolone, it is characterized in that, formula (I) compound in solvent, is reacted with formula (II) compound 5-amino-1-benzofuran-2-carboxamides under the alkaline matter effect, separating-purifying obtains the Wella oxazolone shown in the formula 1 from product, and reaction formula is as follows:
2. method according to claim 1, it is characterized in that, with formula (I) compound in solvent, with formula (II) compound 5-amino-1-benzofuran-2-carboxamides reaction 5-24h under 20 ℃～150 ℃, the mol ratio of its Chinese style (I) compound and formula (II) compound is 0.8:1～1.2:1 under the alkaline matter effect.Described solvent be a kind of in DMF, toluene, dioxane, propyl carbinol, dimethylbenzene, tetrahydrofuran (THF), acetone, butanone, acetonitrile, the ethylene glycol monomethyl ether and more than.Described alkaline matter be a kind of in salt of wormwood, yellow soda ash, sodium bicarbonate, saleratus, triethylamine, pyridine, the diisopropylethylamine and more than, wherein be preferably salt of wormwood or yellow soda ash.
3. method according to claim 1, it is characterized in that, the preparation method of formula (I) compound, comprise the steps: the amido with formula (III) compound 3-[(4-two (2-chloroethyl)) butyryl radicals]-the 5-cyanoindole, in solvent, with the reductive agent reduction, obtain formula (I) compound; Reaction formula is as follows:
4. method according to claim 3 is characterized in that, formula (III) compound in solvent, under the reductive agent effect, is reacted 1～10 hour reaction times under-50～20 ℃; Wherein the mol ratio of reductive agent and formula (III) compound is that the described reductive agent of 2:1～1:1. is two (2-methoxy ethoxy) sodium aluminates of dihydro.Described solvent be a kind of in methylene dichloride, chloroform, tetrahydrofuran (THF), acetone, acetonitrile, ether, toluene, dimethylbenzene, the ethylene dichloride and more than.
5. method according to claim 3, it is characterized in that, the preparation method of formula (III) compound, comprise the steps: the amido with formula (IV) compound 4-(two (2-chloroethyl)) butyryl chloride, in solvent, under the aluminum chloride effect, react with the 5-cyanoindole, separating-purifying obtains formula (III) compound: 3-[(4-two (2-chloroethyl) amido) butyryl radicals]-the 5-cyanoindole; Reaction formula is as follows:
6. method according to claim 5 is characterized in that, with formula (IV) compound 4-(two (2-chloroethyl) amido) butyryl chloride, in solvent, under the aluminum chloride effect, under-20～50 ℃, react 0.5～10 hour reaction times with the 5-cyanoindole; The mol ratio of its Chinese style (IV) compound and 5-cyanoindole is 1.5:1～0.8:1, described solvent be a kind of in methylene dichloride, chloroform, tetrahydrofuran (THF), acetone, acetonitrile, ether, toluene, dimethylbenzene, the ethylene dichloride and more than.
7. method according to claim 5, it is characterized in that the preparation method of formula (IV) compound comprises the steps: formula (V) compound in solvent, with the halogenating agent reaction, obtain formula (IV) compound: 4-(two (2-chloroethyl) amido) butyryl chloride; Reaction formula is as follows:
8. method according to claim 7 is characterized in that, with formula (V) compound, in solvent, with halogenating agent, in 25～150 ℃ of lower reactions, the reaction times is 2～12 hours.Described halogenating agent be selected from a kind of in thionyl chloride, phosphorus trichloride, phosphorus oxychloride, the oxalyl chloride and more than; The mol ratio of described halogenating agent and formula (V) compound is 1:1～5:1.Described solvent be a kind of in DMF, toluene, dioxane, dimethylbenzene, tetrahydrofuran (THF), acetone, butanone, acetonitrile, ethylene glycol monomethyl ether, methylene dichloride, the chloroform and more than.
9. method according to claim 7, it is characterized in that, the preparation method of formula (V) compound, comprise the steps: formula (VI) compound in solvent, under the alkaline matter effect, separating-purifying obtains formula (V) compound 4-two (2-chloroethyl) amido butyric acid after the hydrolysis; Reaction formula is as follows:
10. method according to claim 9 is characterized in that, with formula (VI) compound, in solvent, under the alkaline matter effect, in 25～100 ℃ of lower reactions, the reaction times is 0.5～10 hour; Described alkaline matter is selected from sodium hydroxide, potassium hydroxide, and the mol ratio of alkaline matter and formula (VI) compound is 1:1～5:1.Described solvent is more than one in ethanol, methyl alcohol, acetone, tetrahydrofuran (THF), acetonitrile, isopropyl acetone, butanone or the water.
11. method according to claim 9, it is characterized in that, the preparation method of formula (VI) compound, comprise the steps: formula (VII) compound in solvent, under the alkaline matter effect, with the halogenating agent reaction, obtain formula (VI) compound: 4-two (2-chloroethyl) amido methyl-butyrate behind the separating-purifying; Reaction formula is as follows:
12. method according to claim 11 is characterized in that, formula (VII) compound in solvent, under the alkaline matter effect, is carried out 1～24 hour reaction times under 20～150 ℃ with halogenating agent; The mol ratio of described halogenating agent and formula (VII) compound is 1:1～5:1.Described halogenating agent be selected from a kind of in phosphorus trichloride, thionyl chloride, oxalyl chloride or the phosphorus oxychloride and more than.Described alkaline matter be a kind of in pyridine, triethylamine or the diisopropylethylamine and more than.Described solvent be in tetrahydrofuran (THF), methylene dichloride, chloroform, acetone, butanone, toluene, dimethylbenzene, dioxane or the acetonitrile a kind of and more than.
13. method according to claim 11, it is characterized in that, the preparation method of formula (VII) compound, comprise the steps: formula (VIII) compound in solvent, under the alkaline matter effect, with the reaction of two (2-hydroxyethyl) amine, separating-purifying obtains formula (VII) compound: 4-two (2-hydroxyethyl) amido methyl-butyrate from product; Reaction formula is as follows:
14. method according to claim 13 is characterized in that, in solvent, under the alkaline matter effect, with two (2-hydroxyethyl) amine, in 20～150 ℃ of lower reactions, the reaction times is 2～48 hours with formula (VIII) compound; Wherein the mol ratio of two (2-hydroxyethyl) amine and formula (VIII) compound is 0.8:1～1.5:1.Described alkaline matter be selected from a kind of in sodium bicarbonate, saleratus, yellow soda ash, salt of wormwood, pyridine, triethylamine or the diisopropylethylamine and more than.Described solvent be a kind of in DMF, toluene, dioxane, propyl carbinol, dimethylbenzene, tetrahydrofuran (THF), acetone, butanone, acetonitrile, the ethylene glycol monomethyl ether and more than.
15. the preparation method of hydrochloric acid Wella oxazolone is characterized in that, comprises claim of right1～32 each described method and following steps: with formula 1 described Wella oxazolone, in solvent, add concentrated hydrochloric acid (37%), obtain hydrochloric acid Wella oxazolone.
16. method according to claim 15 is characterized in that, comprise the steps: the Wella oxazolone is dissolved in the Virahol, with concentrated hydrochloric acid (37%) in 10～30 ℃, stirring reaction 0.2～5 hour.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013156935A1 (en) * | 2012-04-16 | 2013-10-24 | Ranbaxy Laboratories Limited | Process for the preparation of crystalline vilazodone hydrochloride |
| CN105017233A (en) * | 2014-04-23 | 2015-11-04 | 天津药物研究院 | Vilazodone hydrochloride crystal as well as preparation method, drug composition and application thereof |
| US9533949B2 (en) | 2012-09-12 | 2017-01-03 | Apotex Pharmachem Inc. | Processes for the preparation of 3-alkyl indoles |
| RU2711636C1 (en) * | 2019-04-04 | 2020-01-17 | Зайдин Магомедович Джамбулатов | N,N-(di-γ-CHLOROPROPYL)AMINOACETIC ACID, HAVING BACTERICIDAL ACTIVITY |
| CN110922401A (en) * | 2018-09-19 | 2020-03-27 | 广东东阳光药业有限公司 | Preparation method of quininone derivative |
| CN111574381A (en) * | 2020-04-17 | 2020-08-25 | 杭州盛弗泰新材料科技有限公司 | Method for preparing 2-chloroethylamine hydrochloride |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013156935A1 (en) * | 2012-04-16 | 2013-10-24 | Ranbaxy Laboratories Limited | Process for the preparation of crystalline vilazodone hydrochloride |
| US9533949B2 (en) | 2012-09-12 | 2017-01-03 | Apotex Pharmachem Inc. | Processes for the preparation of 3-alkyl indoles |
| CN105017233A (en) * | 2014-04-23 | 2015-11-04 | 天津药物研究院 | Vilazodone hydrochloride crystal as well as preparation method, drug composition and application thereof |
| CN110922401A (en) * | 2018-09-19 | 2020-03-27 | 广东东阳光药业有限公司 | Preparation method of quininone derivative |
| CN110922401B (en) * | 2018-09-19 | 2022-07-26 | 广东东阳光药业有限公司 | Preparation method of quinuclidone derivative |
| RU2711636C1 (en) * | 2019-04-04 | 2020-01-17 | Зайдин Магомедович Джамбулатов | N,N-(di-γ-CHLOROPROPYL)AMINOACETIC ACID, HAVING BACTERICIDAL ACTIVITY |
| CN111574381A (en) * | 2020-04-17 | 2020-08-25 | 杭州盛弗泰新材料科技有限公司 | Method for preparing 2-chloroethylamine hydrochloride |
| CN111574381B (en) * | 2020-04-17 | 2023-01-10 | 杭州盛弗泰新材料科技有限公司 | Method for preparing 2-chloroethylamine hydrochloride |
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