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Synthetic technology of darifenacin intermediate 5-(2-bromomethyl)-2,3-dihydro-1-coumarone

A technology of alkyl and carbonyl, applied in the production of bulk chemicals, organic chemistry, etc., can solve the problems of unsuitable industrialization, high cost, low yield, etc., achieve high industrial application and economic value, increase the total yield, and improve the yield high effect

Active Publication Date: 2012-10-17
ZHEJIANG JIUZHOU PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] In order to overcome the prior art 5-(2-bromoethyl)-2,3-dihydro-1-phenylpropanol preparation method needs to use serious pollution, dangerous and expensive reagents, low yield, high cost, unsuitable Due to the shortcoming of realizing industrialization, the technical scheme adopted by the present invention is to provide a new intermediate compound of daphnacin, which has the following formula b structure:

Method used

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  • Synthetic technology of darifenacin intermediate 5-(2-bromomethyl)-2,3-dihydro-1-coumarone
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  • Synthetic technology of darifenacin intermediate 5-(2-bromomethyl)-2,3-dihydro-1-coumarone

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Embodiment 1: the preparation of formula a-1 compound

[0037]

[0038] Put anhydrous aluminum trichloride (215g, 1.62mol) and 770ml of dichloromethane into the reaction bottle under the condition of -5~5℃, add acetyl chloride (95g, 1.22mol) dropwise, after the dropwise add 2, 3-Dihydrobenzofuran (97 g, 0.81 mol), continued the reaction for 2 to 2.5 hours after the dropwise addition was completed. After the reaction was completed, 1.5 L of ice water was added, the organic layer was separated, and washed successively with 400 ml of dilute hydrochloric acid and 400 ml of water. The organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated. 200ml of n-hexane was added for recrystallization, and a white solid was precipitated, which was dried to obtain 120g of the compound of formula a-1 as a white solid, with a yield of 75.9%.

[0039]

Embodiment 2

[0040] Embodiment 2: the preparation of formula b-1 compound

[0041]

[0042] Under nitrogen protection, add compound a-1 (5g, 0.025mol), sodium acetate (4.1 g, 0.05mol) and 50ml N,N-dimethylformamide, sodium iodide (0.1g, 0.6mmol), heat up to 120 °C, followed by TLC until the reaction was complete. 50 ml of ethyl acetate was added for extraction, the organic phase was washed twice with 50 ml of water, and the organic layer was concentrated to obtain 5.1 g of the compound of formula b with a yield of 92.7%.

[0043] 1 HNMR (400MHz, CDC1 3 ) δ=2.22(s,3H), δ=3.23 (t, J = 7.2 Hz, 2H), δ=4.64 (t, J = 7.2 Hz,2H), δ=5.2(s, 2H), δ=6.81 (d, J=6.8Hz,2H), δ=7.72 (d, J=6.8Hz, 1H),7.80 (s, lH) ;

[0044] MS: 243 (M + Na).

Embodiment 3

[0045] Embodiment 3: the preparation of formula b-1 compound

[0046]Under the protection of nitrogen, add compound a-1 (5g, 0.025mol), acetic acid (3g, 0.05) and 50ml tetrahydrofuran, sodium iodide (0.1g, 0.6mmol) triethylamine (5.05g, 0.05), heat up to reflux, TLC followed until the reaction was complete. Concentrate to remove tetrahydrofuran, add 50 ml of ethyl acetate for extraction, wash with 50 ml of water twice, and concentrate the organic layer to obtain 4.9 g of the compound of formula b with a yield of 89.1%.

[0047]

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Abstract

The invention relates to the technical field of heterocyclic chemistry, especially to the technical field of oxygen-containing five-membered heterocyclic chemistry. The invention specifically relates to a synthetic technology of a darifenacin intermediate 5-(2-bromomethyl)-2,3-dihydro-1-coumarone. To realize the above synthetic technology, the invention provides a novel intermediate compound, which has a structure as shown in the formular (b), wherein R is a carbonyl protective group; and R is preferably alkyl, aryl or alkyloxy. Alkyl is preferably C1-C6 straight-chain alkyl or C5-C8 annular alkane. Aryl is preferably C6-C12 aryl. Alkyloxy is preferably C1-C6 alkyloxy. The compound as shown in the formula (b) is prepared by two-step reaction of acylation and nucleophilic substitution with 2,3-dihydro coumarone as a raw material. The darifenacin intermediate 5-(2-bromomethyl)-2,3-dihydro-1-coumarone can be prepared by two-step reaction of catalytic hydrogenation and bromination of the compound as shown in the formula (b).

Description

technical field [0001] The invention relates to the technical field of heterocyclic chemistry, in particular to the technical field of oxygen-containing five-membered heterocyclic chemistry. Background technique [0002] Darifenacin, chemical name: (S)-2-[1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl]- 2,2-Diphenylacetamide is a selective muscarinic receptor antagonist developed by Pfizer of the United States. It is mainly used for the treatment of urinary incontinence. It was approved by the FDA on December 22, 2004 and listed in the United States under the trade name of Enablex , its structural formula is as follows: [0003] [0004] There are a lot of synthesis literatures of Dafenacin at present, such as U.S. Patent US5096890 and European Patent EP0388054, both adopt 5-(2-bromoethyl)-2,3-dihydro-1-phenylpropanefuran as the key intermediate, and its structural formula is as follows : [0005] [0006] Combined with references, such as Journal of Medicin...

Claims

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Application Information

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IPC IPC(8): C07D307/79
CPCY02P20/55
Inventor 廖高荣高红军李源强车大庆
Owner ZHEJIANG JIUZHOU PHARM CO LTD
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