CN101538229A - Synthetic method of anti-BPH (benign prostatic hyperplasia) medicament Tamsulosin - Google Patents
Synthetic method of anti-BPH (benign prostatic hyperplasia) medicament Tamsulosin Download PDFInfo
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- CN101538229A CN101538229A CN200910134499A CN200910134499A CN101538229A CN 101538229 A CN101538229 A CN 101538229A CN 200910134499 A CN200910134499 A CN 200910134499A CN 200910134499 A CN200910134499 A CN 200910134499A CN 101538229 A CN101538229 A CN 101538229A
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Abstract
The invention relates to a synthetic method of anti-BPH (benign prostatic hyperplasia) medicament Tamsulosin. The method comprises the following steps: o-ethoxy phenoxetol is prepared into corresponding sulfonic ester which has condensation reaction with (R)-(-)-5-(2-aminopropyl)-2-metoxybenzene sulfonamide so as to obtain the Tamsulosin.
Description
The application is that application number is 200410058397.6, the applying date is on August 16th, 2004, the application people is Shenlong Singapore Private Co., Ltd, denomination of invention dividing an application for the Chinese invention patent application of " a kind of synthetic method of anti-BPH (benign prostatic hyperplasia) medicament Tamsulosin ".
Technical field
The present invention relates to the synthetic method of a kind of anti-benign prostatauxe medicine Tamsulosin (Tamsulosin).
Background technology
The chemistry of Tamsulosin is called (R)-(-)-5-[2-[[2-(2-ethoxy phenoxy group) ethyl] amido] propyl group]-2-methoxybenzenesulphoismide hydrochloride, it possesses following structural formula (1)
Tamsulosin is a kind of optionally α
1cThe antagonist of-acceptor, the early stage clinical hypertension that is used for the treatment of now is mainly used in the treatment of benign prostatauxe.It is by Japanese Yamanouchi Pharmaceutical Co., Ltd (Yamanouchi Pharmaceutical Co.Ltd.) exploitation, in 1996 in Japanese Initial Public Offering, it has patent is EP 0 034 432 (on August 26th, 1981 is open).
The Tamsulosin synthetic route that people's such as Imai EP 0 034 432 is disclosed is:
People such as Okada in people such as EP 0 257 787 (on March 2nd, 1988 open) and Niigata in US 4,731, disclosing in 478 (on March 15th, 1988 is open) utilizes R-(-)-5-(2-amine propyl group)-2-methoxybenzenesulphoismide and 1-bromo-2-(neighbour-ethoxy phenoxy group) ethane condensation to make Tamsulosin, about yield 40%, synthetic route is as follows:
William J.Wheler is in J of Labeled Compounds andRadiopharmaceuticals (I), and 171 (1988) middle announcements utilize 2-(2-ethoxy phenoxy group)-acetaldehyde and R-(-)-5 (2-amine propyl group)-2-methoxybenzenesulphoismide to make Tamsulosin through condensation, reduction.Using 5%Pd/C can reduce yield in the reaction is 32.8%; Use NaBH
3It is 57.2% that CN then can reduce yield, and synthetic route is as follows:
People such as Hoorn then disclose in WO 03/037850 A1 (on May 8th, 2003 is open) 2-methoxyl group-5-(2-oxygen propyl group)-benzsulfamide and 2-(2-ethoxy phenoxy group)-1-ethamine are made DL Tamsulosin through condensating reductive, use (+) camphor-10-sulfonic acid to make its salify then, then carrying out optical isomer splits, make Tamsulosin through four recrystallizations again, yield 8.9%.Synthetic route is as follows:
Summary of the invention
The invention relates to the novel synthesis of a kind of Tamsulosin.It is that sulphonate is made in the reaction of neighbour-ethoxy phenoxyethyl alcohol and SULPHURYL CHLORIDE, then the sulphonate of this gained and optically active amines (R)-(-)-5-(2-amine propyl group)-2-methoxybenzenesulphoismide condensation is made Tamsulosin, and synthetic route is as follows:
In detail, the inventive method comprises following two steps: (i) with neighbour-ethoxy phenoxyethyl alcohol (compound (2)) and formula RSO
2The SULPHURYL CHLORIDE reaction of Cl makes neighbour-ethoxy phenoxyethyl alcohol sulphonate (compound (3)), and wherein R is (C
1-C
6) alkyl, as methyl and ethyl, or be through halogen, nitro and/or (C
1-C
6) phenyl that replaces of alkyl (as methyl), preferably tie up to the neighbour, a, position is replaced; And (ii) compound (3) with (R)-(-)-5-(2-amine propyl group)-2-methoxybenzenesulphoismide (compound (4)) is at catalyzer and be fit in the presence of the solvent, with suitable organic amine and/or mineral alkali as acid scavenger, in 40 to 100 ℃ of following prepared in reaction Tamsulosin.
Detailed reactions steps and condition such as following:
Step (i)
Compound (2) is dissolved in the organic solvent, suitable solvent is by being selected from the group who is made up of chloromethane (being preferably methylene dichloride and/or trichloromethane), Narcotile (being preferably ethylene dichloride), toluene, pyridine, other similar organic solvent and composition thereof, be stirred to molten entirely, be cooled to-10 to 10 ℃ then,-5 to 5 ℃ in preferred system, more excellent is-5 to 0 ℃, drips formula RSO gradually
2The SULPHURYL CHLORIDE of Cl, wherein R is (C
1-C
6) alkyl, as methyl and ethyl, or be through halogen, nitro and/or (C
1-C
6) phenyl that replaces of alkyl (as methyl), preferably tie up to the neighbour, a, position is replaced.Finish, in 0 to 10 ℃, under preferred 0 to 5 ℃, reaction disappears until compound (2).Reaction solution is added in the frozen water gradually, separate out white solid, through filter collection, washing and dry corresponding sulphonate (compound (3)), the yield 65-90% of getting.
Step (ii)
With compound (3), add in the reaction flask as the organic amine of acid scavenger and/or mineral alkali, catalyzer and appropriate solvent, heat temperature raising is to 40-50 ℃, gradation adds compound (4), wherein as the organic amine of acid scavenger by being selected from the group who is formed by organic tertiary amine, pyridine and composition thereof, be preferably and be selected from the group who is formed by triethylamine, pyridine and composition thereof, and as the mineral alkali of acid scavenger for being selected from by KOH, NaOH, K
2CO
3, NaHCO
3, the group that formed of its analogue and composition thereof, catalyzer is by being selected from the group who is made up of the monovalence inorganic iodide, be preferably and be selected from the group who is formed by potassiumiodide (KI), sodium iodide (NaI), cupric iodide (CuI) and composition thereof, appropriate solvent is a proton-inert organic solvent, is preferably to be selected from the group who is made up of dimethyl formamide (DMF), dimethylacetal (DMA), dimethyl sulfoxide (DMSO) (DMSO), N,N-DIMETHYLACETAMIDE (DMAC), its analogue and composition thereof.Treat that compound (4) finishes, in 50-100 ℃, be preferably 50-80 ℃, more excellent is that 55-65 ℃ of following reacting by heating mixture disappears until compound (3).Be cooled to room temperature and add entry, extract, utilize to remove solvent under reduced pressure, add the organic solvent that contains HCl and (be preferably and be selected from by ethyl acetate-HCl, CH with ethyl acetate or its analogue
3OH-HCl, EtOH-HCl, (CH
3)
2The group that CHOH-HCl and composition thereof formed), separate out white solid, the various mixed solvent recrystallizations of using aqueous methanol and various aqueous alcohol, acetone then or forming with ethyl acetate, methyl tertiary butyl ether, benzene, toluene make Tamsulosin, yield 55-70%.
Embodiment
Embodiment 1
Neighbour-ethoxy phenoxyethyl alcohol-methanesulfonate ester
Neighbour-ethoxy phenoxyethyl alcohol 50.0 grams (0.28 mole) and 197 gram pyridines are added in the reaction flasks, be stirred to and be chilled to-5 to 0 ℃ after molten entirely.Gradually add methylsulfonyl chloride 53.1 grams (0.46 mole) down in stirring, dropping temperature is controlled at-5 to 0 ℃, finishes, and in 0 to 5 ℃ was reacted 3 to 4 hours.Reaction is finished, and in stirring down reaction solution is gradually joined in 350 milliliters of frozen water, adds temperature and is controlled at 0 to 5 ℃, separates out white solid gradually.The filter collection, filter cake is washed till the non-pyridine smell with 150 ml waters washing three times, and drying gets 61.9 gram target compounds.Yield 85.0%, purity 99.83% (HPLC).
Embodiment 2
(R)-(-)-and 5-[2-[(2-ethoxy phenoxy group) ethyl] amido]-propyl group-2-methoxybenzenesulphoismide hydrochloride (Tamsulosin)
With neighbour-ethoxy phenoxyethyl alcohol-methanesulfonate ester 27.7 grams (0.11 mole), R-(-)-5-(2-amine propyl group)-2-methoxybenzenesulphoismide 20.0 grams (0.082 mole), NaHCO
37.5 gram (0.09 mole), potassiumiodide (KI) 1.36 grams and dimethyl formamide (DMF) place reaction flask for 80 milliliters, and logical nitrogen is warming up to 55 to 65 ℃ of reactions 11 hours.Reaction is finished, and is cooled to room temperature, adds 600 milliliters in water and uses ethyl acetate to extract three times for 500 milliliters, and the combined ethyl acetate extracting solution with 100 ml waters washing secondary, with anhydrous magnesium sulfate drying, removes ethyl acetate under reduced pressure, and residuum is dissolved in the ethanol, filtered while hot.Filtrate is cooled to room temperature, and dripping EtOH-HCl to pH value gradually is 2, separates out white solid.Use the aqueous ethanol recrystallization, separate out white crystals,, get 20.4 gram target compounds, yield 56.9% through filter collection, washing with alcohol, drying.
Claims (6)
1. the method for synthetic neighbour-ethoxy phenoxyethyl alcohol sulphonate, it may further comprise the steps: with the neighbour-ethoxy phenoxyethyl alcohol and the formula RSO of formula (2)
2The SULPHURYL CHLORIDE of Cl to 10 ℃ of reactions down, forms the neighbour-ethoxy phenoxyethyl alcohol sulphonate of formula (3) in temperature-10:
Wherein R is the C1-C6 alkyl, or through the phenyl of halogen, nitro and/or the replacement of C1-C6 alkyl.
2. according to the method for claim 1, wherein reaction lies in temperature-5 and carries out under 5 ℃.
3. according to the method for claim 2, wherein reaction lies under 0 to 5 ℃ of the temperature and carries out.
4. according to the method for claim 1, wherein reaction lies under the solvent existence and carries out.
5. according to the method for claim 4, wherein solvent system is selected from the group who is made up of chloromethane, Narcotile, benzene, substituted benzene, pyridine and composition thereof.
6. according to the method for claim 5, wherein solvent system is selected from the group who is made up of methylene dichloride, trichloromethane, ethylene dichloride, benzene, toluene and composition thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200910134499A CN101538229A (en) | 2004-08-16 | 2004-08-16 | Synthetic method of anti-BPH (benign prostatic hyperplasia) medicament Tamsulosin |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200910134499A CN101538229A (en) | 2004-08-16 | 2004-08-16 | Synthetic method of anti-BPH (benign prostatic hyperplasia) medicament Tamsulosin |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2004100583976A Division CN100545148C (en) | 2004-08-16 | 2004-08-16 | A kind of synthetic method of anti-BPH (benign prostatic hyperplasia) medicament Tamsulosin |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101538229A true CN101538229A (en) | 2009-09-23 |
Family
ID=41121650
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN200910134499A Pending CN101538229A (en) | 2004-08-16 | 2004-08-16 | Synthetic method of anti-BPH (benign prostatic hyperplasia) medicament Tamsulosin |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101538229A (en) |
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2004
- 2004-08-16 CN CN200910134499A patent/CN101538229A/en active Pending
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Application publication date: 20090923 |