Method for preparing Tolterodine and tartrate

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...

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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 asymmetric synthesis of tolterodine, the product can no longer be split, but the main reaction of this route is as long as 16 steps together with the synthesis of intermediates, and the process is complicated , the yield is very low, and industrial production cannot be realized

[0010] Another method for asymmetric synthesis of tolterodine is disclosed in CN1414944A, which is easier and more efficient than the route in J.Org.Chem.1993,63,8067-8070, but the raw materials and reaction used in the method The cost of chiral reagents used in the process is relatively high, and the obtained intermediate also needs DIBAL-H or Pa / C-H 2 Etc. reduction, the reaction conditions are relatively harsh, and the synthesis process steps are still too long to be suitable for industrial production

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