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Preparation of duloxetine hydrochloride intermediate
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A technology of potassium salt and potassium benzoate, applied in the field of S--N, can solve problems such as being difficult to remove, increase the complexity of post-processing, and residual, and achieve the effects of avoiding residual, maintaining chirality of raw materials, and simplifying post-processing steps.
Inactive Publication Date: 2009-04-15
ZHEJIANG HUAHAI PHARMACEUTICAL CO LTD
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[0005] However, the potassium salt produced by this method is easy to be brought into the finished product, resulting in residues, which are not easy to completely remove. Therefore, in this method, potassium benzoate is first neutralized with acid to generate benzoic acid, and then extracted with a solvent. , so as to achieve the purpose of removing potassium benzoate impurities, but this increases the complexity of post-processing
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preparation example
[0019] Dissolve 100g of p-toluic acid in 500ml of water, add 42g of 99% potassium hydroxide, control the temperature below 30°C, after the addition is complete, continue to stir for 2 hours, then distill off the water to obtain white flocculent solid p-toluic acid potassium.
[0020] (Potassium o-toluate, potassium m-toluate, potassium terephthalate, and potassium p-toluenesulfonate are prepared according to the conditions of the preparation example)
Embodiment 1
[0022] At room temperature, add 50g S-(-)-N,N-dimethyl-3-(2-thienyl) 3-hydroxypropylamine, 250mlDMSO and 14.3g 50% NaH into a 500ml four-necked bottle, stir for 0.5h, Add 15.8g of potassium p-toluate, stir for 10 minutes, then add 36.7ml of 1-fluoronaphthalene dropwise, after the drop, raise the temperature to 60°C, keep it warm for 4 hours, pour it into 750ml of ice water, stir for 20min, divide it into three times with 900ml of ethyl acetate Extract and combine the organic layers. The organic layer was washed twice with saturated brine, and the organic layer was washed with anhydrous MgSO 4 Dry, filter with suction, add 32.3 g of oxalic acid at room temperature, stir at room temperature for 2 hours, filter, wash with ethyl acetate, and dry to obtain 100 g of off-white crystals. Optical rotation: [a] D 20 =80°, HPLC analysis content 97%.
[0023] Put the above solid in 500ml of absolute ethanol, heat to reflux, dissolve, cool to room temperature, filter, wash with absolute...
Embodiment 2
[0025] At room temperature, add 50g S-(-)-N,N-dimethyl-3-(2-thienyl) 3-hydroxypropylamine, 250mlDMSO and 14.3g 50% NaH into a 500ml four-necked bottle, stir for 0.5h, Add 10.5g of potassium p-toluate, stir for 10min, then add 36.7ml of 1-fluoronaphthalene dropwise, after dropping, raise the temperature to 60°C, keep it warm for 4h, pour into 750ml of ice water, stir for 20min, divide into three times with 900ml of ethyl acetate Extract and combine the organic layers. The organic layer was washed twice with saturated brine, and the organic layer was washed with anhydrous MgSO 4 Dry, filter with suction, add 32.3g of oxalic acid at room temperature, stir at room temperature for 2 hours, filter, wash with ethyl acetate, and dry to obtain 75g of off-white crystals, optical rotation: [a] D 20 =59.8°.
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Abstract
The invention discloses a method for preparing the intermediate S-(+)-N, N-dimethyl-3-(1-napthocy)-3-(2-thienyl) propylamine of duloxetinehydrochloride, and the method comprises the following steps: S-(-)-N, N-dimethyl-3-(2- thienyl)-3-hydroxyl propylamine is mixed and dissolved with sodiumhydride in an organic solvent, then sylvite compounds and 1-fluoronaphythalene are added respectively, reacting for 1 to 8 hours at the temperature of 30 to 80 DEG C, and the product is obtained by post processing; the sylvite compounds are mixtures of one or more than two of p-methyl potassium benzoate, o-methyl potassium benzoate, m-methyl potassium benzoate, potassium terephthalate, p-methyl potassium benzenesulfonate, potassium p-chlorbenzoate, potassium m-chlorbenzoate and potassium o-chlorbenzoate. The method chooses p-methyl potassium benzoate, and the like, as the sylvite, thus avoiding residue of sylvite in the product and simplifying the post processing steps. By controlling the reaction condition, the racemization is avoided effectively, thus keeping the chirality of the materials.
Description
(1) Technical field [0001] The present invention relates to a preparation method of a duloxetine intermediate, in particular to S-(+)-N,N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl)propylamine method of preparation. (2) Background technology [0002] Duloxetine is a safe and effective antidepressant developed by Eli Lilly and Company (Eilly), which is a dual reuptake inhibitor of serotonin and norepinephrine. It was approved for marketing in Europe, and was approved for marketing by the U.S. FDA in August 2004. FDA also approved it for the treatment of urinary incontinence and the treatment of peripheral nerve pain caused by diabetes. [0003] Regarding the preparation method of duloxetine, US Patent No. 5,362,886 and literature [Tetrahedron Letter, 31(49), 701-04(1990)] disclose the synthesis process of vortex and optical purity loxetine. [0004] The disclosed method employs the following steps: (s)-(-)-N,N-dimethyl-3-(2-thienyl)-3-hydroxypropylamine is dissolved together w...
Claims
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Application Information
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