Method for preparing Tolterodine and tartrate

A technology of tolterodine and tartrate, which is applied in the field of compounds, can solve the problems of harsh reaction conditions, long synthetic process steps in industrial production, and few preparation steps, and achieve the effects of mild reaction conditions, reduced production costs, and increased yields

Active Publication Date: 2005-06-15
LUNAN PHARMA GROUP CORPORATION
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The method using the same raw material is disclosed in ZL97180147.9, but the required preparation steps are less, and the target compound can be obtained through 5 steps of reaction, but this route cannot effectively utilize the resolution of by-products, resulting in a relatively low total yield of the reaction. Low, high cost, not conducive to industrial production
[0008] The above methods all need to use LiAlH under the environment of absolute anhydrous and inert gas protection. 4 or DIBAL-H to reduce amide or ester groups, the reaction conditions are harsh, which increases the danger and operational difficulty of the reaction, making it difficult to realize large-scale industrial production of tolterodine
[0009] J.Org.Chem.1993, 63, 8067-8070 reported the route of as

Method used

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  • Method for preparing Tolterodine and tartrate
  • Method for preparing Tolterodine and tartrate
  • Method for preparing Tolterodine and tartrate

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Embodiment 1

[0032] Embodiment 1: 3-(2-hydroxyl-5-methylphenyl)-3-phenylpropylene 3, the preparation method of 5-dinitrobenzoate (4)

[0033] In a four-neck flask, add p-cresol 2 (119g, 1.1mol), trans-cinnamyl alcohol 3,5-dinitrobenzoate (344g, 1.0mol), 150mL of concentrated sulfuric acid, and heat up to 135°C- 138°C, stirred and reacted for 8 hours, cooled, adjusted the pH to neutral with 10% sodium hydroxide, extracted with ethyl acetate 80mL×2, washed the organic phase with water, washed with 5% aqueous potassium carbonate solution, and anhydrous sulfuric acid Sodium dry. After filtration, the solvent was evaporated under reduced pressure, and the residue was recrystallized with 800 mL of isopropanol to obtain 3-(2-hydroxyl-5-methylphenyl)-3-phenylpropylene 3,5-dinitrobenzene Formate (366 g, 82.8%).

Embodiment 2

[0034] Embodiment 2: the preparation method of 3-(2-hydroxyl-5-methylphenyl)-3-phenylpropylene methanesulfonate (4)

[0035] In a four-neck flask, add p-cresol 2 (119g, 1.1mol), trans-cinnamyl trifluoromethanesulfonyl ester (165g, 1.0mol), 150mL of concentrated sulfuric acid, raise the temperature to 123°C-126°C, and stir the reaction After 16 hours, cool to room temperature, adjust the pH to neutral with 10% aqueous sodium hydroxide solution, extract with 800 mL×2 ethyl acetate, wash the organic phase with water, wash with 5% potassium carbonate, and dry over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was recrystallized with 800 mL of isopropanol to obtain -(2-hydroxyl-5-methylphenyl)-3-phenylpropylene methanesulfonate (156.8 g, 84.5 %).

Embodiment 3

[0036] Example 3: Preparation of N, N-diisopropyl-3-(2-hydroxyl-5-methylphenyl)-3-phenylpropylamine 1

[0037] The product obtained in Example 1 (371 g, 0.84 mol) was dissolved in 1500 mL of toluene, mixed with 1500 g of diisopropylamine, refluxed and stirred for 38 hours, the solvent was evaporated, and the residue was added with 10% aqueous sodium hydroxide solution to adjust the pH 14, extracted with ethyl acetate, washed with water, decolorized, filtered, evaporated to remove ethyl acetate, and the oily product was N, N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3- Phenylpropylamine 1 (146 g, 68.4%).

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Abstract

A process for preparing Tuoteluoding and its tartrate includes condensation reaction between anti-styryl alcohol ester and methylphenol, direct alkalizing, extracting in organic solvent, vacuum distilling to remove solvent, purifying to obtain Tuoteluoding, condensation reaction on diisopropylamine, reacting on L-(+) tartaric acid to become salt, splitting it into (L-(+)-tartrate-R-Tuoteluoding) and (L-(+)-tartrate-S-Tuoteluoding), reaction of L-(+)-tartrate-S-Tuoteluoding on alkali, butyl lithium, or magnesium isopropyl bromide, and reacting no tartaric acid to obtain L-(+)-tartrate-R-Tuoteluoding.

Description

technical field [0001] The present invention relates to compound tolterodine [(R)-N, N-diisopropyl-3-(2-hydroxyl-5-methylphenyl)-3-phenylpropylamine] and a preparation method of tartrate thereof . Background technique [0002] Tolterodine (Tolterodine, 1) is the general name of (R)-N, N-diisopropyl-3-(2-hydroxyl-5-methylphenyl)-3-phenylpropylamine, and its structural formula is : [0003] [0004] Tolterodine 1 [0005] Tolterodine is a new type of drug for the treatment of urinary incontinence with a unique chemical structure. It is a choline M receptor antagonist, and its selectivity to the M receptor subtype of the bladder is higher than that of the salivary gland M receptor. The active metabolite is higher than the parent drug, it can competitively prevent the bladder contraction caused by carbachol, and the activity on the bladder M receptor inhibition is much higher than that on the calcium channel portal vein α-adrenergic receptors on the bladder...

Claims

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Application Information

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IPC IPC(8): C07C213/02C07C215/54
Inventor 赵志全
Owner LUNAN PHARMA GROUP CORPORATION
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