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Novel unsymmetrical preparation of tamsulosin hydrochloride

A tamsulosin hydrochloride, asymmetric technology, applied in the field of optically active drug synthesis, can solve the problems of large chiral raw materials, waste, waste of raw materials, etc., achieve good industrial production prospects, good diastereoselectivity, and reduce environmental pollution Effect

Inactive Publication Date: 2009-06-24
ZHEJIANG NORMAL UNIVERSITY
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  • Application Information

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Problems solved by technology

Commonly used chiral acids include camphorsulfonic acid, tartaric acid, etc. The disadvantage of this method is: 50% (S)-tamsulosin is wasted, and the resolution process has a low yield of only 30% due to repeated recrystallization. Not only waste raw materials, but also bring greater environmental pollution to the environment
The disadvantage of this method is: the chiral amine intermediate needs chemical resolution, and the resolution process wastes raw materials due to recrystallization, which is inconvenient to operate and is not conducive to the requirements of industrialization.
For example: Yamanouchi applied for a patent: EP 0257787, which uses chiral (R)-phenylethylamine as a chiral raw material. Sexual amine (structural formula is shown in formula II), finally synthesizes tamsulosin hydrochloride, at present this technique is the most important method of synthesizing tamsulosin hydrochloride, the key of this method is by using noble metal catalyst hydrogenolysis chiral (R)-phenylethylamine To obtain chiral amine (structural formula sees formula II), the shortcoming of this method is: not only can consume a large amount of chiral raw materials, increase production cost, and pollute environment
Patent applied by Narco.Pharma.Limited: WO093227, this patent uses the sodium borohydride complex of unnatural proline derivatives as a catalyst to carry out catalytic reduction of imines. This method uses expensive natural proline as a catalyst , obtain tamsulosin, but its optical purity is only 39%, which is far from meeting the requirements of industrialization

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Under the protection of nitrogen, 3.95g (16.25mmol) of 5-acetonyl-2-methoxybenzenesulfonamide was dissolved in 150ml of methanol, and 1.49g (6.5mmol) of (R)-ferrocenyl ethyl The methanol mixed solution of the amine was stirred for 6 hours to form an imine compound, which was directly poured into a high-pressure reaction axe, added Raney-Ni, heated at 50°C, and hydrogenated at 2.2MP atmospheric pressure for 48 hours. After carefully venting the excess hydrogen, filter off Raney-Ni, concentrate to remove methanol, dilute with ethyl acetate, add 20ml of aqueous solution and stir for 30 minutes, extract three times with ethyl acetate, anhydrous Na 2 SO 4 Drying, concentration and removal of solvent, the crude product was purified by silica gel column chromatography to obtain 1.6g orange solid namely: (R)-5-[2-(N-ferroceneethylamine)propyl]-2-methoxy Benzenesulfonamide. The eluent is ethyl acetate:methanol (volume ratio)=5:2. Yield: 53%, m.p.92-95°C, (c=1.0, CH 3 OH). ...

Embodiment 2

[0044] Under nitrogen protection, 3.66g (15.0mmol) of 5-acetonyl-2-methoxybenzenesulfonamide was dissolved in dry 150ml THF, and then slowly added dropwise 2.12g (8.6mmol) of (R)-diocene The THF mixed solution of iron-based ethylamine was heated to reflux and stirred for 4.5 hours to form an imine compound, and then 640mg (34.4mmol) of NaBH was added 4 , reacted at room temperature for 4h, removed THF, extracted three times with ethyl acetate, anhydrous Na 2 SO 4 Drying, concentration to remove the solvent, the crude product was purified by silica gel column chromatography to obtain 1.76g orange solid namely: (R)-5-[2-(N-ferroceneethylamine)propyl]-2-methoxy Benzenesulfonyl, the eluent is ethyl acetate: methanol (volume ratio) = 5:2. Yield: 45%, m.p.92.5-95°C. (c=1.0, CH 3 OH).

[0045] (R)-5-[2-(N-ferroceneethylamine)propyl]-2-methoxybenzenesulfonamide nuclear magnetic spectrum is: 1 HNMR (400MHz, CDCl 3 )δ: 0.97(d, J=6.4Hz, 3H), 1.30(d, J=6.4Hz, 3H), 2.57(m, 1H), 2...

Embodiment 3

[0058] Under the protection of nitrogen, dissolve 2.4g (10.0mmol) of 5-acetonyl-2-methoxybenzenesulfonamide in dry 100ml THF, and slowly add 2.3g (10.0mmol) (R)-ferrocene The THF mixed solution of ethylamine was stirred for 3 hours to form an imine compound, which was directly poured into a high-pressure reaction axe, added with Pd / C, heated at 50°C, and hydrogenated at 2.2MP atmospheric pressure for 30 hours. After carefully venting excess hydrogen, filter off Pd / C, concentrate to remove THF, dilute with ethyl acetate, add 10ml of aqueous solution and stir for 30 minutes, extract three times with ethyl acetate, anhydrous Na 2 SO 4 Drying, concentration and removal of solvent, the crude product was purified by silica gel column chromatography to obtain 2.2g orange solid namely: (R)-5-[2-(N-ferroceneethylamine)propyl]-2-methoxy Benzenesulfonamide. The eluent is ethyl acetate:methanol (volume ratio)=5:2. Yield: 48.2%, m.p.92.5-95°C. (c=1.0, CH 3 OH).

[0059] (R)-5-[2-(N-...

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Abstract

The invention relates to a method for preparing tamsulosin hydrochloride asymmetrically. (R)-ferrocenyl ethylamine and 5-acetonyl-2-methoxyl benzene sulfonamide are dissolved in solvent for condensation reaction to obtain imine compound. (R)-5-(2-(N-ferrocenyl ethylamine) propyl)-2- methoxyl benzene sulfonamide is obtained by reduction reaction of the imine compound. The (R)-5-(2-(N-ferrocenyl ethylamine) propyl)-2- methoxyl benzene sulfonamide reacts with o-2-bromine ethoxyl phenetole under the action of alkali to form (R)-5-((2-[N-(2-ethoxyl-phenoxyl) ethyl)-N-ferrocenyl ethylamine) propyl)-2-methoxyl benzene sulfonamide after treatment. The (R)-5-((2-(N-(2-ethoxyl-phenoxyl) ethyl)-N-ferrocenyl ethylamine)propyl)-2-methoxyl benzene sulfonamide generates chiral amide compound and ferrocenyl ethanol carboxylic ester under the action of anhydride, and the chiral amide compound generates the tamsulosin hydrochloride after post treatment. The preparation method has simple operation and good yield and purity, is feasible and environmental-friendly and has the prospect of industrialized production.

Description

technical field [0001] The invention relates to the field of synthesis of optically active drugs, in particular to an asymmetric preparation method of tamsulosin hydrochloride. Background technique [0002] o]propyl]-2-methoxybenzonesulfon amide (I)hydrochloride, the structural formula is shown in the right formula (I). Tamsulosin hydrochloride was first successfully developed by Yamanouchi, Japan. Tamsulosin hydrochloride is structurally a potent and highly selective a 1 - Adrenergic receptor inhibitors, which can be used in the clinical treatment of benign prostatic hyperplasia and urinary disorders caused by benign prostatic hypertrophy. Compared with similar drugs, tamsulosin hydrochloride has better curative effect and less adverse reactions such as dizziness, headache and orthostatic hypotension. Based on its good efficacy and safety, the drug has become the most commonly prescribed drug for the treatment of benign prostatic hyperplasia in the global market. Ther...

Claims

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Application Information

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IPC IPC(8): C07C311/37C07C303/40
Inventor 丁千昌李新生徐东成
Owner ZHEJIANG NORMAL UNIVERSITY
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