CN101429124B - Synthesis of (7-methoxy-1-naphthyl) ethyl acetate - Google Patents
Synthesis of (7-methoxy-1-naphthyl) ethyl acetate Download PDFInfo
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- CN101429124B CN101429124B CN2007100480418A CN200710048041A CN101429124B CN 101429124 B CN101429124 B CN 101429124B CN 2007100480418 A CN2007100480418 A CN 2007100480418A CN 200710048041 A CN200710048041 A CN 200710048041A CN 101429124 B CN101429124 B CN 101429124B
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- ethyl acetate
- naphthyl
- benzoquinones
- methoxyl group
- dihydro
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- CBMRPFJEJGWBCF-UHFFFAOYSA-N CCOC(CC(c1c2)=CCCc1ccc2OC)=O Chemical compound CCOC(CC(c1c2)=CCCc1ccc2OC)=O CBMRPFJEJGWBCF-UHFFFAOYSA-N 0.000 description 1
- VPXDDUIYFMKQBI-UHFFFAOYSA-N CCOC(Cc1cccc(cc2)c1cc2OC)=O Chemical compound CCOC(Cc1cccc(cc2)c1cc2OC)=O VPXDDUIYFMKQBI-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention discloses a method for synthesizing (7-methoxyl-1-naphthyl) acetic ether (a formula II). The method comprises the following steps: in an inert organic solvent, substituted benzoquinone is used as an aromatized dehydrogenation reagent and (7-methoxyl-3,4-dihydro-1-naphthyl) acetic ether (a formula IV) as an aromatization substrate for aromatization reaction. The method has the advantages of mild condition, full aromatization reaction, high yield and high purity.
Description
Technical field
The present invention relates to a kind of synthetic method of midbody compound, be specifically related to the synthetic method of a kind of (7-methoxyl group-1-naphthyl) ethyl acetate.
Background technology
Agomelatine, i.e. N-[2-(7-methoxyl group-1-naphthyl) ethyl] ethanamide (formula I), be a kind of melatonin receptor agonist, also be a kind of 5-HT
2CThe antagonist of acceptor has good pharmacologically active at treatment dysthymia disorders, the seasonal aspects such as fatigue, appetite disorder and obesity that constrain disorder, somnopathy, cardiovascular system diseases, digestive system, insomnia and cause owing to jet lag.
(7-methoxyl group-1-naphthyl) ethyl acetate (formula II) is the key intermediate of synthetic Agomelatine.The synthetic method of ethyl acetate (formula II) that patent documentation EP 447285 has reported a kind of (7-methoxyl group-1-naphthyl): (7-methoxyl group-3,4-dihydro-1 (2H)-naphthylene base) ethyl acetate (formula III) is in the presence of sulphur, get final product through high temperature (215 ℃) reaction, reaction formula is as follows.But aromatization is incomplete in this method, and severe reaction conditions.
Summary of the invention
Technical problem to be solved by this invention is to react not exclusively for the method that overcomes synthetic (7-methoxyl group-1-naphthyl) ethyl acetate (formula II) of prior art, and the defective of severe reaction conditions, and a kind of reaction conditions gentleness is provided, react completely, and yield and the high synthetic method of purity.
Method of the present invention comprises the steps: in the inert organic solvents, to replace benzoquinones is aromizing dehydrogenation reagent, with suc as formula (the 7-methoxyl group-3 shown in the IV, 4-dihydro-1-naphthyl) ethyl acetate is the aromizing substrate, carries out aromatization and can make suc as formula (7-methoxyl group-1-naphthyl) ethyl acetate shown in the II.
Wherein, described replacement benzoquinones can be the carbonyl position of replacement at contraposition or adjacent benzoquinones, as 1 of replacement, 4-benzoquinones and 1,2-benzoquinones, substituting group are generally chlorine or cyano group, preferable is 2,3,5,6-tetrachloro-1,4-benzoquinones, 2,3-two chloro-5,6-dicyano-1,4-benzoquinones (DDQ) and 3,4,5,6-tetrachloro-1, one or more in the 2-benzoquinones.The mole dosage of described aromizing dehydrogenation reagent and (7-methoxyl group-3,4-dihydro-1-naphthyl) ethyl acetate than preferable be 1: 1～5: 1, better is 1: 1～2: 1.What the adding mode of described (7-methoxyl group-3,4-dihydro-1-naphthyl) ethyl acetate was preferable is the dropping mode, and what the speed of dropping was preferable is 1～5 of per second, and what temperature was preferable during dropping is controlled at 10～20 ℃.Described inert organic solvents is preferable is selected from methylene dichloride, chloroform, tetracol phenixin, ethyl acetate, tetrahydrofuran (THF) and the toluene one or more.The consumption of described organic inert solvent can be 2～20 times of reactant solubilized amount.What the temperature of described reaction was preferable is 0～60 ℃, and better is 10～20 ℃.The described reaction times is detected control with TLC, till finishing with base consumption.The developping agent that TLC detects can be sherwood oil: ethyl acetate=10: 1, product Rf=0.5.
Among the present invention, described suc as formula (the 7-methoxyl group-3 shown in the IV, 4-dihydro-1-naphthyl) ethyl acetate can be that method in the application for a patent for invention " synthetic method of a kind of (7-methoxyl group-3,4-dihydro-1-naphthyl) ethyl acetate " on November 9th, 2007 is prepared with reference to the applying date.Concrete steps are:
In non-protonic solvent, under the existence of organic bases, 7-methoxyl group naphthane-1-ketone and diethoxy phosphonoacetic acid ethyl ester reacted get final product.Among the present invention, Et represents ethyl.
Wherein, what the mol ratio of described 7-methoxyl group naphthane-1-ketone and diethoxy phosphonoacetic acid ethyl ester was preferable is 1: 1～1: 5, and better is 1: 1.5～1: 2.5.Described organic bases is preferable is selected from sodium methylate, sodium ethylate, sodium isopropylate, potassium tert.-butoxide and the sodium hydride one or more, and better is sodium ethylate.The consumption of described organic bases is preferable is 1～5 times of substrate 7-methoxyl group naphthane-1-ketone molar weight, and better is 1.5～2.5 times.Described non-protonic solvent is preferable is selected from tetrahydrofuran (THF), ethyl acetate, 1, and 4-dioxane and N, one or more in the dinethylformamide, the consumption of solvent are 2～20 times of reactant solubilized amount.What the temperature of described reaction was preferable is 0～150 ℃, and better is 60～80 ℃.The time of reaction is detected control by TLC, and till naphthane-1-ketone ran out of with substrate 7-methoxyl group, developping agent was a sherwood oil: ethyl acetate=10: 1, product Rf=0.5.Reaction is after column chromatography, and the molar ratio of (7-methoxyl group-3,4-dihydro-1-naphthyl) ethyl acetate (formula IV) and (7-methoxyl group-3,4-dihydro-1 (2H)-naphthylene base) ethyl acetate (formula III) can reach 8: 1～11: 1, and yield is higher, and purity is higher.
Except that specifying, agents useful for same and raw material are all commercially available to be got among the present invention.
Positive progressive effect of the present invention is: method mild condition of the present invention, aromatization is complete, yield height, purity height.
Embodiment
Mode below by embodiment further specifies the present invention, but does not therefore limit the present invention among the described scope of embodiments.
Synthesizing of embodiment 1 (7-methoxy-1-naphthyl) ethyl acetate
2,3-two chloro-5,6-dicyano-1, (DDQ, 8.12g 36mmol) are dissolved in the dry methylene chloride (100ml) the 4-benzoquinones, keep temperature to drip (7-methoxyl group-3 down for 10-15 ℃, 4-dihydro-1-naphthyl) ethyl acetate (6.6g, methylene dichloride 26.8mmol) (50ml) solution, 2 of rate of addition per seconds.Dripping Bi Shengzhi room temperature (25 ℃) stirred 1 hour.With reacting liquid filtering, filtrate is washed (50ml * 3) with saturated sodium bicarbonate solution, washing, and the salt washing, anhydrous magnesium sulfate drying, the dried solvent of concentrating under reduced pressure gets 5.9g colorless oil product, yield 90.8%, purity 98.5%.Qualification result:
1H NMR (CDCl
3, 400M) δ: 1.18 (t, J=6.8Hz, 3H), 3.88 (s, 3H), 4.08-4.13 (m, 4H), 7.20 (dd, J=2.4Hz and 8.8Hz, 1H), 7.27-7.33 (m, 2H), 7.40 (d, J=6.8Hz, 1H), 7.78 (d, J=8.0Hz, 1H), 7.86 (d, J=9.2Hz, 1H)
Synthesizing of embodiment 2 (7-methoxy-1-naphthyl) ethyl acetate
2,3,5,6-tetrachloro-1, (8.86g 36mmol) is dissolved in the dry toluene (100ml) the 4-benzoquinones, keeps temperature to drip (7-methoxyl group-3 down for 10 ℃, 4-dihydro-1-naphthyl) ethyl acetate (6.6g, toluene 26.8mmol) (50ml) solution, 2 of rate of addition per seconds.Drip and finish 10 ℃ of stirrings of maintenance temperature 2 hours.With reacting liquid filtering, filtrate is washed (50ml * 3) with saturated sodium bicarbonate solution, washing, and the salt washing, anhydrous magnesium sulfate drying, the dried solvent of concentrating under reduced pressure gets 5.7g colorless oil product, yield 87.7%, purity 97.1%.Qualification result such as embodiment 1.
Synthesizing of embodiment 3 (7-methoxy-1-naphthyl) ethyl acetate
2,3-two chloro-5,6-dicyano-1, (6.06g 26.8mmol) is dissolved in the dry chloroform (100ml) the 4-benzoquinones, keeps temperature to drip (7-methoxyl group-3 down for 0 ℃, 4-dihydro-1-naphthyl) ethyl acetate (6.6g, chloroform 26.8mmol) (50ml) solution, 5 of rate of addition per seconds.Dripping to finish keeps 0 ℃ to stir 3 hours.With reacting liquid filtering, filtrate is washed (50ml * 3) with saturated sodium bicarbonate solution, washing, and the salt washing, anhydrous magnesium sulfate drying, the dried solvent of concentrating under reduced pressure gets 5.8g colorless oil product, yield 89.2%, purity 96.5%.Qualification result such as embodiment 1.
Synthesizing of embodiment 4 (7-methoxy-1-naphthyl) ethyl acetate
3,4,5,6-tetrachloro-1, (8.86g 36mmol) is dissolved in the dry ethyl acetate (100ml) the 2-benzoquinones, keeps temperature to drip (7-methoxyl group-3 down for 5-10 ℃, 4-dihydro-1-naphthyl) ethyl acetate (1.77g, ethyl acetate 7.2mmol) (50ml) solution, 3 of rate of addition per seconds.Dripping Bi Shengzhi stirred 1 hour for 20 ℃.With reacting liquid filtering, filtrate is washed (50ml * 3) with saturated sodium bicarbonate solution, washing, and the salt washing, anhydrous magnesium sulfate drying, the concentrating under reduced pressure solvent gets 6.0g colorless oil product, yield 92.3%, purity 97.9% to doing.Qualification result such as embodiment 1.
Synthesizing of embodiment 5 (7-methoxy-1-naphthyl) ethyl acetate
2,3,5,6-tetrachloro-1, (8.86g 36mmol) is dissolved in the dry tetrahydrofuran (100ml) the 4-benzoquinones, keeps temperature to drip (7-methoxyl group-3 down for 15-20 ℃, 4-dihydro-1-naphthyl) ethyl acetate (4.43g, tetrahydrofuran (THF) 18mmol) (50ml) solution, 1 of rate of addition per second.Dripping Bi Shengzhi stirred 1 hour for 60 ℃.With reacting liquid filtering, filtrate is washed (50ml * 3) with saturated sodium bicarbonate solution, washing, and the salt washing, anhydrous magnesium sulfate drying, the dried solvent of concentrating under reduced pressure gets 6.0g colorless oil product, yield 92.3%, purity 96.9% to doing.Qualification result such as embodiment 1.
Claims (10)
1. synthetic method suc as formula (7-methoxyl group-1-naphthyl) ethyl acetate shown in the II, it is characterized in that comprising the steps: in the inert organic solvents, to replace benzoquinones is aromizing dehydrogenation reagent, with suc as formula (the 7-methoxyl group-3 shown in the IV, 4-dihydro-1-naphthyl) ethyl acetate is the aromizing substrate, carries out aromatization and gets final product; Described benzoquinones is selected from 1 of replacement, 4-benzoquinones and 1, and 2-benzoquinones, substituting group are chlorine or cyano group.
2. the method for claim 1, it is characterized in that: described replacement benzoquinones is 2,3-two chloro-5,6-dicyano-1,4-benzoquinones, 2,3,5,6-tetrachloro-1,4-benzoquinones and 3,4,5,6-tetrachloro-1, one or more in the 2-benzoquinones.
3. the method for claim 1 is characterized in that: described aromizing dehydrogenation reagent is 1: 1～5: 1 with the mole dosage ratio of (7-methoxyl group-3,4-dihydro-1-naphthyl) ethyl acetate.
4. method as claimed in claim 3 is characterized in that: described aromizing dehydrogenation reagent is 1: 1～2: 1 with the mole dosage ratio of (7-methoxyl group-3,4-dihydro-1-naphthyl) ethyl acetate.
5. the method for claim 1 is characterized in that: the adding mode of described (7-methoxyl group-3,4-dihydro-1-naphthyl) ethyl acetate is for dripping.
6. method as claimed in claim 5 is characterized in that: the speed of described dropping is 1～5 of per second.
7. method as claimed in claim 5 is characterized in that: the temperature during described the dropping is controlled at 10～20 ℃.
8. the method for claim 1, it is characterized in that: the temperature of described reaction is 0-60 ℃.
9. method as claimed in claim 8 is characterized in that: the temperature of described reaction is 10-20 ℃.
10. the method for claim 1, it is characterized in that: described inert organic solvents is selected from one or more in methylene dichloride, chloroform, tetracol phenixin, ethyl acetate, tetrahydrofuran (THF) and the toluene.
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| CN2007100480418A CN101429124B (en) | 2007-11-09 | 2007-11-09 | Synthesis of (7-methoxy-1-naphthyl) ethyl acetate |
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| CN2007100480418A CN101429124B (en) | 2007-11-09 | 2007-11-09 | Synthesis of (7-methoxy-1-naphthyl) ethyl acetate |
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| CN101429124B true CN101429124B (en) | 2011-10-26 |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5194614A (en) * | 1990-02-27 | 1993-03-16 | Adir Et Compagnie | Compounds having a naphthalene structure |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5194614A (en) * | 1990-02-27 | 1993-03-16 | Adir Et Compagnie | Compounds having a naphthalene structure |
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Granted publication date: 20111026 Termination date: 20161109 |