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Synthesis of (7-methoxy-3, 4-dihydrogen-1-naphthyl) ethyl acetate

A technology of ethyl diethoxyphosphonoacetate and ethyl acetate, which is applied in the field of synthesis of intermediate compounds, can solve the problems of harsh conditions and incomplete reaction, and achieve the effects of mild conditions, complete reaction and high yield

Inactive Publication Date: 2009-05-13
SHANGHAI INST OF PHARMA IND
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0010] The technical problem to be solved by the present invention is in order to overcome prior art synthesis (7-methoxy group-3, the method condition of 4-dihydro-1-naphthyl) ethyl acetate (formula II) is comparatively harsh, and uses toxicity Larger solvent benzene, or the defect of incomplete reaction provides a kind of mild condition, does not use solvent benzene, and yield is higher, the synthetic method of complete reaction

Method used

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  • Synthesis of (7-methoxy-3, 4-dihydrogen-1-naphthyl) ethyl acetate
  • Synthesis of (7-methoxy-3, 4-dihydrogen-1-naphthyl) ethyl acetate
  • Synthesis of (7-methoxy-3, 4-dihydrogen-1-naphthyl) ethyl acetate

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Embodiment 1

[0017] Embodiment 1 (7-methoxy group-3, the synthesis of 4-dihydro-1-naphthyl) ethyl acetate

[0018] Sodium (1.38g, 60mmol) was dissolved in absolute ethanol (50ml), concentrated under reduced pressure to dry ethanol to obtain sodium ethoxide, added dry tetrahydrofuran (50ml) to dissolve, and added ethyl diethoxyphosphoroacetate (13.44g , 60mmol), stirred for 10 minutes, added 7-methoxytetralin-1-one (5.28g, 30mmol), and reacted at 65-70°C for 12 hours. The reaction solution was concentrated under reduced pressure to remove tetrahydrofuran, the residue was added with ethyl acetate (100ml) and water (50ml), the organic layer was separated, the aqueous layer was extracted once with ethyl acetate (30ml), the combined organic layers were washed with water (30ml×3) , washed with brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure to dry ethyl acetate to obtain 10.6 g of liquid product, silica gel column chromatography (petroleum ether: ethyl acetate=...

Embodiment 2

[0025] Sodium (1.38g, 60mmol) was dissolved in absolute ethanol (50ml), concentrated under reduced pressure to dry ethanol to obtain sodium ethoxide, added dry 1,4-dioxane (50ml) to dissolve, and added diethoxyphosphorus at room temperature Ethyl acetoacetate (13.44g, 60mmol) was stirred for 10 minutes, 7-methoxytetralin-1-one (5.28g, 30mmol) was added, and stirred at 70°C for 12 hours. The reaction solution was concentrated under reduced pressure to remove 1,4-dioxane, ethyl acetate (100ml) and water (50ml) were added to the residue, the organic layer was separated, the aqueous layer was extracted once with ethyl acetate (30ml), and the organic layers were combined , washed with water (30ml×3), washed with brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure to dry ethyl acetate, to obtain 10.5g of liquid product, silica gel column chromatography (petroleum ether:ethyl acetate=60:1), to obtain compound II 6.5g, colorless oil, yield 88%, purity 98...

Embodiment 3

[0027] Dissolve sodium (3.45g, 150mmol) in anhydrous methanol (150ml), concentrate under reduced pressure to dry methanol to obtain sodium methoxide, add dry ethyl acetate (150ml) to dissolve, add diethoxy ethyl phosphoacetate ( 33.6 g, 150 mmol), stirred for 10 minutes, added 7-methoxytetralin-1-one (5.28 g, 30 mmol), stirred at 80°C for 48 hours. The reaction solution was cooled to room temperature, washed with water (30ml×3), washed with brine, dried over anhydrous magnesium sulfate, and concentrated to dry ethyl acetate under reduced pressure to obtain 11.3 g of liquid product, which was subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 60: 1) Compound II 6.2g, purity 99.0%, colorless oil, yield 84%, compound III 0.6g, colorless oil, yield 8.1%, purity 98.2%, ratio of compound II to compound III 10.3 :1. . Identification result is the same as embodiment 1.

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Abstract

The invention relates to a method for synthesizing a compound of (7-methoxyl-3, 4-dihydro-1-naphthyl) acetic ether shown as a formula II. The method comprises the following steps: in an aprotic solvent, in the presence of organic alkali, 7- methoxyltetrahydronaphthalene-1-ketone and diethoxy phosphinylidyne acetic ether react to obtain the compound. The method has mild condition and full reaction, avoids the use of an toxic solvent and has high selectivity; after the reaction, the molar ratio of the (7-methoxyl-3,4-dihydro-1-naphthyl) acetic ether (a formula II) to (7-methoxyl-3,4-dihydro-1(2H)-naphthylene) acetic ether (a formula III) can reach 8 to 1-11 to 1 through column chromatography; and the yield is high; and the purity can reach over 97 percent.

Description

technical field [0001] The invention relates to a synthesis method of an intermediate compound, in particular to a synthesis method of ethyl (7-methoxy-3,4-dihydro-1-naphthyl) acetate. Background technique [0002] Agomelatine, N-[2-(7-methoxy-1-naphthyl)ethyl]acetamide (formula I), is a melatonin receptor agonist and a 5- HT 2C Receptor antagonist, has good pharmacological activity in the treatment of depression, seasonal depressive disorder, sleep disorder, cardiovascular system disease, digestive system disease, insomnia, fatigue caused by jet lag, appetite disorder and obesity . [0003] (7-methoxy-3,4-dihydro-1-naphthyl) ethyl acetate (formula II) is an intermediate for the preparation of agomelatine, and it is an excellent substrate for the aromatization reaction (7-methoxy-1-naphthyl) ethyl acetate (formula IV) can be obtained in high yield under mild conditions, and agomelatine can be prepared from formula IV through subsequent 6-step reactions. [0004] [00...

Claims

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Application Information

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IPC IPC(8): C07C69/734C07C67/333
Inventor 唐家邓李林岑均达
Owner SHANGHAI INST OF PHARMA IND
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