CN101462986A - Method for synthesizing (R)-5-(2-amino propyl)-2-methoxybenzenesulfonamide - Google Patents
Method for synthesizing (R)-5-(2-amino propyl)-2-methoxybenzenesulfonamide Download PDFInfo
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- CN101462986A CN101462986A CNA2007101725234A CN200710172523A CN101462986A CN 101462986 A CN101462986 A CN 101462986A CN A2007101725234 A CNA2007101725234 A CN A2007101725234A CN 200710172523 A CN200710172523 A CN 200710172523A CN 101462986 A CN101462986 A CN 101462986A
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Abstract
The invention relates to a method for synthesizing (R)-5-(2-aminopropyl)-2-methoxyl benzsulfamide. In the method, dihalogen anisole is used as initial raw material to react with metal. The reaction for opening ring of chiral propylene oxide or chiral epoxy chloropropane is the key reaction. Newly generated hydroxide radical reacts with substituted benzene sulfone chloride or methylsulfonyl chloride to generate leaving group to be ammonolyzed or azided and hydrolyzed or reduced into amine. (R)-5-(2-aminopropyl)-2-methoxyl benzsulfamide is prepared by protecting amido, benzene ring sulfonation, acylatation, aminolysis and deamination protection.
Description
Technical field:
The present invention relates to the synthetic field of pharmaceutical compound, relate in particular to the synthetic method of a kind of (R)-5-(2-aminopropyl)-2-methoxybenzenesulphoismide.
Background technology:
Tamsulosin hydrochloride (I) is a kind of pharmaceutically active substances of alpha-adrenergic receptor antagonist, is mainly used in the treatment of prostate gland functional disorder.(2-((2-(2-ethoxy phenoxy) ethyl) amino)-2-methoxybenzenesulphoismide belongs to benzsulfamide and sulfamyl phenylethylamine group material to its chemistry (R)-5-by name.
(R)-5-(2-aminopropyl)-2-methoxybenzenesulphoismide (II) is the key intermediate of synthetic hydrochloric acid Tamsulosin.Existing reported following several method arranged:
US 5447958 is the synthetic II of starting raw material with (-)-2-(p-methoxyphenyl)-1-methylethyl amine, synthesizes but disclose it.
EP 380144 carries out reductive amination with R (+)-1-phenyl-ethyl amine to 5-acetonyl-2-methoxybenzenesulphoismide, hydrogenolysis then, but 5-acetonyl-2-methoxybenzenesulphoismide synthetic openly.
Also disclose the synthetic of II in CA1282077 and other method, be raw material by R (+)-1-(p-methoxyphenyl) ethamine, but do not have its preparation method.
WO 2005063701 discloses with D-L-Ala and methyl-phenoxide and has carried out the method that friedel-crafts reaction is the synthetic II of committed step.But this method unavoidably has the by product of neighbour, a position, and because behind the friedel-crafts reaction, the carbonyl of carboxylic acid is converted into the ketone carbonyl, the acidity of its adjacent carbon is strengthened, so the possibility of racemization is still arranged.
Syn.Comm. (1998,1935) are synthetic (-)-2-(p-methoxyphenyl) of raw material-1-methylethyl amine with tyrosine, and route is very long, also uses expensive reagent such as methyl iodide.
Summary of the invention:
Technical problem to be solved by this invention is to provide the synthetic method of a kind of (R)-5-(2-aminopropyl)-2-methoxybenzenesulphoismide, to solve defective of the prior art.
The synthetic method of (R)-5-provided by the present invention (2-aminopropyl)-2-methoxybenzenesulphoismide, its concrete grammar step is:
Being starting raw material to the halogen phenylmethylether, by and metal function, be committed step to the reaction of chirality propylene oxide or chiral epichlorohydrin open loop, leavings group is made in the benzene sulfonyl chloride or the methylsulfonyl chloride reaction of newly-generated hydroxyl and replacement, separate or azide through ammonia then, hydrolysis or be reduced to amine, protection is amino, the phenyl ring sulfonation, acidylate, aminolysis, the deaminizating protection obtains (R)-5-(2-aminopropyl)-2-methoxybenzenesulphoismide;
Be to chlorine, to bromine or to iodine wherein to the halogen phenylmethylether; Metal is magnesium, zinc, iron, copper or nickel, and preferred metal is a magnesium; Chiral epoxy propane is the R-propylene oxide, and chiral epichlorohydrin is the S-epoxy chloropropane.
Wherein leavings group is made in the hydroxyl of committed step generation and the benzene sulfonyl chloride that replaces or methylsulfonyl chloride reaction, and the solvent of reaction is methylene dichloride, tetrahydrofuran (THF), toluene, ethyl acetate or chloroform; The alkali that reacts used is mineral alkali or organic bases, and wherein mineral alkali is sodium bicarbonate, salt of wormwood, yellow soda ash, sodium hydroxide or cesium carbonate, and organic bases is triethylamine, diisopropyl ethyl amine, pyridine or piperidines, and the reaction density scope of alkali is 0.1M-10M.
Wherein the solvent separated of ammonia is the alcohol of 1-4 carbon; The solvent of azide is dimethyl formamide, methyl-sulphoxide, acetone, tetrahydrofuran (THF), ethylene dichloride or methylene dichloride.Wherein preferred solvent is methyl alcohol or ethanol.
Wherein the used solvent of hydrolysis reaction is the alcohol of 1-4 carbon; Used alkali is potassium hydroxide, sodium hydroxide, hydrazine hydrate or hydrated barta; Reduction reaction perhaps is that trialkyl phosphine reduces for aluminium lithium hydrogen, sodium borohydride, potassium boron hydrogen, lithium boron hydrogen, red aurin tricarboxylic acid, di-isopropyl aluminium hydrogen or carry out catalytic hydrogenation with the reagent of containing metal palladium and reduce.
Wherein protect amido to adopt ethanoyl, trifluoroacetyl group, propionyl, benzoyl, methyl-chloroformate, ethyl ester, sec.-propyl, the tertiary butyl or benzyl.
Wherein sulfonation reaction is reagent with the chlorsulfonic acid, and solvent is methylene dichloride, ethylene dichloride, toluene, tetrahydrofuran (THF) or ethyl acetate.
Wherein the reagent of acylation reaction is thionyl chloride, phosphorus trichloride, phosphorus pentachloride, oxalyl chloride or trichlorine phosphine oxide.
Wherein the ammonolysis reaction of acyl chlorides is that ammonia is separated reagent with the aqueous solution of ammonia or the alcoholic solution of ammonia or the tetrahydrofuran solution of ammonia, and the concentration range of ammonia is 0.1M-10M.
Wherein the reagent of deprotection reaction is alkali or acid, and wherein alkali is sodium hydroxide, potassium hydroxide, hydrated barta or lithium hydroxide; Acid is hydrochloric acid, sulfuric acid or hydrochloric acid sulfuric acid mixing acid.
Its concrete reaction scheme figure is:
Wherein, X is chlorine, bromine or iodine; Y is that leavings group is made in the benzene sulfonyl chloride or the methylsulfonyl chloride reaction of hydroxyl and replacement, and R is an amino protecting group, is ethanoyl, trifluoroacetyl group, propionyl, benzoyl, methyl-chloroformate, ethyl ester, sec.-propyl, the tertiary butyl or benzyl.
Those skilled in the art in conjunction with specific embodiments, can realize the present invention without creative work according to technique scheme.
Method of the present invention has following advantage:
1, in the inventive method, the reagent of use substantially all is common reagent, and chiral epoxy propane and epoxy chloropropane are because technology perfect in recent years, and its price also is very cheap,
2, in the inventive method, some intermediates are solids, and very easily crystallization purifying has been simplified purification process greatly,
3. in the inventive method, reaction all is classical reaction, and easy handling is beneficial to suitability for industrialized production.
Embodiment:
Following embodiment just is used to illustrate the present invention, and unrestricted the present invention.
Embodiment 1
In the 500ml exsiccant four-hole bottle, add anhydrous tetrahydro furan 250ml and magnesium powder 12g, drip the 1ml ethylene dibromide, cause the back and drip methoxyl group chlorobenzene 70g, speed is dripped in control, makes the reaction solution gentle reflux, finishes, and reflux to magnesium powder disappears.Be chilled to the 0-5 degree, drip chiral epoxy propane 29g, finish to stir and add the reaction of going out of saturated aqueous ammonium chloride collection after 2 hours, concentrate tetrahydrofuran (THF), ethyl acetate extraction, conventional aftertreatment, the product that obtains is directly used in next step reaction.
The product of previous step is dissolved in the 300ml methylene dichloride, adds triethylamine 100ml, Tosyl chloride 100g, room temperature reaction spends the night, and concentrates, and adds water and ethyl acetate extraction, obtains white solid 120g after the conventional aftertreatment.
1H?NMR(300M，CDCl
3)δ：7.62(d，J＝8.3Hz，2H)，7.24(d，J＝8.3Hz，2H)，7.21(d，J＝8.0Hz，2H)，6.72(d，J＝8.0Hz，2H)，4.70(m，1H)，3.77(s，3H)，2.85(dd，J＝6.5，14.0Hz，1H)，2.72(dd，J＝6.4，14.0Hz，1H)，2.41(s，3H)，1.29(d，J＝6.3Hz，3H).
The product of previous step is dissolved among the 300ml DMF, adds sodiumazide 35g, be heated to 100 degree reactions and spend the night, pour in the frozen water, ethyl acetate extraction, conventional aftertreatment concentrates the dried oily liquids 60g that obtains.
The product of previous step is dissolved in the 300ml methyl alcohol, adds palladium charcoal 10g, normal pressure hydrogenation, reaction finishes after-filtration, concentrate and do, directly be dissolved in the methylene dichloride, add triethylamine 100ml, drip aceticanhydride 50ml, reaction end back concentrates does, and obtains white solid, washing, the dry product 60g that gets.
The previous step product is dissolved in the methylene dichloride, add triethylamine 100ml, be chilled to the 0-5 degree, drip chlorsulfonic acid 45g, after reaction finishes, adding the saturated sodium bicarbonate solution collection goes out, the product that obtains after the conventional processing is dissolved in the thionyl chloride, reflux 30 minutes, and excessive thionyl chloride is removed in decompression, residuum is dissolved in the methylene dichloride, be chilled to the 0-5 degree, dropping ammonia 100ml, conventional aftertreatment, obtain white solid 80g, this solid and 250ml methyl alcohol, 100ml hydrochloric acid reflux, reaction finishes the back and concentrates dried, obtain the hydrochloride 50g of (R)-5-(2-aminopropyl)-2-methoxybenzenesulphoismide (II), spectroscopic data is consistent with document.
Embodiment 2
In the 1000ml exsiccant four-hole bottle, add anhydrous tetrahydro furan 500ml and magnesium powder 24g, drip the 1ml ethylene dibromide, cause the back and drip methoxyl group bromobenzene 187g, speed is dripped in control, makes the reaction solution gentle reflux, finishes, and reflux to magnesium powder disappears.Be chilled to the 0-5 degree, drip chiral epoxy propane 60g, finish to stir and add the reaction of going out of saturated aqueous ammonium chloride collection after 2 hours, concentrate tetrahydrofuran (THF), ethyl acetate extraction, conventional aftertreatment, the product that obtains is directly used in next step reaction.
The product of previous step is dissolved in the 600ml methylene dichloride, adds triethylamine 200ml, Tosyl chloride 200g, room temperature reaction spends the night, and concentrates, and adds water and ethyl acetate extraction, obtains white solid 250g after the conventional aftertreatment.
The product of previous step is dissolved among the 700ml DMSO, adds sodiumazide 80g, be heated to 100 degree reactions and spend the night, pour in the frozen water, ethyl acetate extraction, conventional aftertreatment concentrates the dried oily liquids 130g that obtains.
The product of previous step is dissolved in the 800ml methyl alcohol, adds palladium charcoal 50g, normal pressure hydrogenation, reaction finishes after-filtration, concentrate and do, directly be dissolved in the methylene dichloride, add triethylamine 200ml, drip aceticanhydride 100ml, reaction end back concentrates does, and obtains white solid, washing, the dry product 125g that gets.
The previous step product is dissolved in the methylene dichloride, add triethylamine 200ml, be chilled to the 0-5 degree, drip chlorsulfonic acid 100g, after reaction finishes, adding the saturated sodium bicarbonate solution collection goes out, the product that obtains after the conventional aftertreatment is dissolved in the thionyl chloride, reflux 30 minutes, and excessive thionyl chloride is removed in decompression, residuum is dissolved in the methylene dichloride, be chilled to the 0-5 degree, dropping ammonia 250ml, conventional aftertreatment, obtain white solid 155g, this solid and 600ml methyl alcohol, 200ml hydrochloric acid reflux, reaction finishes the back and concentrates dried, obtain the hydrochloride 105g of (R)-5-(2-aminopropyl)-2-methoxybenzenesulphoismide (II), spectroscopic data is consistent with document.
Embodiment 3
In the 500ml exsiccant four-hole bottle, add anhydrous tetrahydro furan 250ml and magnesium powder 12g, drip the 1ml ethylene dibromide, cause the back and drip methoxyl group chlorobenzene 70g, speed is dripped in control, makes the reaction solution gentle reflux, finishes, and reflux to magnesium powder disappears.Be chilled to the 0-5 degree, drip chiral epichlorohydrin 47g, finish to stir and add the reaction of going out of saturated aqueous ammonium chloride collection after 2 hours, concentrate tetrahydrofuran (THF), ethyl acetate extraction, conventional aftertreatment, the product that obtains is dissolved in the methyl alcohol, adds palladium charcoal 20g, normal pressure hydrogenation, reaction finishes after-filtration, concentrates dried next step reaction that is directly used in.
The product of previous step is dissolved in the 300ml methylene dichloride, adds triethylamine 100ml, Tosyl chloride 100g, room temperature reaction spends the night, and concentrates, and adds water and ethyl acetate extraction, obtains white solid 125g after the conventional aftertreatment.
The product of previous step is dissolved among the 300ml DMF, adds sodiumazide 35g, be heated to 100 degree reactions and spend the night, pour in the frozen water, ethyl acetate extraction, conventional aftertreatment concentrates the dried oily liquids 65g that obtains.
The product of previous step is dissolved in the 300ml methyl alcohol, adds palladium charcoal 10g, normal pressure hydrogenation, reaction finishes after-filtration, concentrate and do, directly be dissolved in the methylene dichloride, add triethylamine 100ml, drip aceticanhydride 50ml, reaction end back concentrates does, and obtains white solid, washing, the dry product 60g that gets.
The previous step product is dissolved in the methylene dichloride, add triethylamine 100ml, be chilled to the 0-5 degree, drip chlorsulfonic acid 45g, after reaction finishes, adding the saturated sodium bicarbonate solution collection goes out, the product that obtains after the conventional aftertreatment is dissolved in the thionyl chloride, reflux 30 minutes, and excessive thionyl chloride is removed in decompression, residuum is dissolved in the methylene dichloride, be chilled to the 0-5 degree, dropping ammonia 100ml, conventional aftertreatment, obtain white solid 80g, this solid and 250ml methyl alcohol, 100ml hydrochloric acid reflux, reaction finishes the back and concentrates dried, obtain the hydrochloride 50g of (R)-5-(2-aminopropyl)-2-methoxybenzenesulphoismide (II), spectroscopic data is consistent with document.
Claims (11)
1, the synthetic method of a kind of (R)-5-(2-aminopropyl)-2-methoxybenzenesulphoismide is characterized in that this method comprises the steps:
Being starting raw material to the halogen phenylmethylether, by and metal function, be committed step to the reaction of chirality propylene oxide or chiral epichlorohydrin open loop, leavings group is made in the benzene sulfonyl chloride or the methylsulfonyl chloride reaction of newly-generated hydroxyl and replacement, separate or azide through ammonia then, hydrolysis or be reduced to amine, protection is amino, the phenyl ring sulfonation, acidylate, aminolysis, the deaminizating protection obtains (R)-5-(2-aminopropyl)-2-methoxybenzenesulphoismide;
Be to chlorine, to bromine or to iodine wherein to the halogen phenylmethylether; Metal is magnesium, zinc, iron, copper or nickel; Chiral epoxy propane is the R-propylene oxide, and chiral epichlorohydrin is the S-epoxy chloropropane.
2. synthetic method according to claim 1 is characterized in that described metal is a magnesium.
3, synthetic method according to claim 1 is characterized in that: leavings group is made in hydroxyl that committed step generates and the benzene sulfonyl chloride that replaces or methylsulfonyl chloride reaction, and the solvent of reaction is methylene dichloride, tetrahydrofuran (THF), toluene, ethyl acetate or chloroform; The alkali that reacts used is mineral alkali or organic bases, wherein mineral alkali is sodium bicarbonate, salt of wormwood, yellow soda ash, sodium hydroxide or cesium carbonate, organic bases is triethylamine, diisopropyl ethyl amine, pyridine or piperidines, and the reaction density of alkali in reaction solution is 0.1M-10M.
4, synthetic method according to claim 1 is characterized in that: the solvent that ammonia is separated is the alcohol of 1-4 carbon; The solvent of azide is dimethyl formamide, methyl-sulphoxide, acetone, tetrahydrofuran (THF), ethylene dichloride or methylene dichloride.
5, synthetic method according to claim 4 is characterized in that the solvent that ammonia is separated is methyl alcohol or ethanol.
6, synthetic method according to claim 1 is characterized in that: the used solvent of hydrolysis reaction is the alcohol of 1-4 carbon; Used alkali is potassium hydroxide, sodium hydroxide, hydrazine hydrate or hydrated barta; Reduction reaction perhaps is that trialkyl phosphine reduces for aluminium lithium hydrogen, sodium borohydride, potassium boron hydrogen, lithium boron hydrogen, red aurin tricarboxylic acid, di-isopropyl aluminium hydrogen or carry out catalytic hydrogenation with the reagent of containing metal palladium and reduce.
7, synthetic method according to claim 1 is characterized in that: the protection amido adopts ethanoyl, trifluoroacetyl group, propionyl, benzoyl, methyl-chloroformate, ethyl ester, sec.-propyl, the tertiary butyl or benzyl.
8, synthetic method according to claim 1 is characterized in that: sulfonation reaction is reagent with the chlorsulfonic acid, and solvent is methylene dichloride, ethylene dichloride, toluene, tetrahydrofuran (THF) or ethyl acetate.
9, synthetic method according to claim 1 is characterized in that: the reagent of acylation reaction is thionyl chloride, phosphorus trichloride, phosphorus pentachloride, oxalyl chloride or trichlorine phosphine oxide.
10, synthetic method according to claim 1 is characterized in that: the ammonolysis reaction of acyl chlorides is that ammonia is separated reagent with the aqueous solution of ammonia or the alcoholic solution of ammonia or the tetrahydrofuran solution of ammonia, and the concentration range of ammonia is 0.1M-10M.
11. synthetic method according to claim 1 is characterized in that: deprotection reaction reagent is alkali or acid, and wherein alkali is sodium hydroxide, potassium hydroxide, hydrated barta or lithium hydroxide; Acid is hydrochloric acid, sulfuric acid or hydrochloric acid sulfuric acid mixing acid.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106380396A (en) * | 2016-08-15 | 2017-02-08 | 浙江康峰化工有限公司 | A method of removing chlorosulfonic acid in pentachlorobenzoyl chloride production |
| CN109942434A (en) * | 2019-03-26 | 2019-06-28 | 山东世纪阳光科技有限公司 | A kind of production method of large red-based g |
-
2007
- 2007-12-18 CN CN2007101725234A patent/CN101462986B/en not_active Expired - Fee Related
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106380396A (en) * | 2016-08-15 | 2017-02-08 | 浙江康峰化工有限公司 | A method of removing chlorosulfonic acid in pentachlorobenzoyl chloride production |
| CN109942434A (en) * | 2019-03-26 | 2019-06-28 | 山东世纪阳光科技有限公司 | A kind of production method of large red-based g |
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