CN1093080A - The preparation method of gavaculine ethyl ester - Google Patents
The preparation method of gavaculine ethyl ester Download PDFInfo
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- CN1093080A CN1093080A CN 93120279 CN93120279A CN1093080A CN 1093080 A CN1093080 A CN 1093080A CN 93120279 CN93120279 CN 93120279 CN 93120279 A CN93120279 A CN 93120279A CN 1093080 A CN1093080 A CN 1093080A
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- ethyl ester
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Abstract
The present invention is a kind of preparation method of gavaculine ethyl ester, earlier ethyl benzoate is generated the M-NITROBENZOIC ACID ethyl ester through nitration reaction, it is dissolved in the organic solvent, and the mixture that adds sulphur and hydroborate reacts, and can get the gavaculine ethyl ester through extraction.Product purity height of the present invention, raw material is easy to get, and price is low, and is easy and simple to handle, and production process does not have waste, easy realization of large-scale production.
Description
The present invention relates to the preparation method of gavaculine ethyl ester.
The gavaculine ethyl ester is a kind of important intermediate in the chemical industry, is mainly made through esterification by gavaculine at present.The preparation method of gavaculine mainly contains three kinds: 1, produce (seeing U.S.P2878281,1959) by m-phthalic acid through Hoffmann rearrangement reaction.But the wherein difficult preparation of m-phthalic acid, the price height will concentrate the gradation crystallization method by dehydration and separate complex operation.2, under the one carbon catalysis of 10% palladium, produce (seeing J.Chem.Soc, 1962,371) by M-NITROBENZOIC ACID through sodium borohydride reduction nitro to amino.3, through the mixture of hydrazine hydrate and Graphite Powder 99 reduction nitro (Tetra Letl, 1985,26(50), 6033).These two kinds of method compartment benzaminic acid complex operations, and required M-NITROBENZOIC ACID is not easy to separate with dividing the easy structure body from it, influences quality product.In addition, directly appeared in the newspapers to amino method and led from M-NITROBENZOIC ACID ethyl ester reduction nitro, used reductive agent is respectively hydrogen (J.Org.Chem, 1961,26 under the palladium carbon catalysis, 2805), the mixture of sodium borohydride and tindichloride (Jpn.Kokal Tokkyo Koho, 1981,46845) and Ruan come nickel (Synth.Commun, 1985,15(1), 599) etc.In this several method,, caused increasing considerably of raw materials cost because used reductive agent or catalyzer cost an arm and a leg.
The purpose of this invention is to provide a kind of method for preparing the gavaculine ethyl ester, adopt this method can make highly purified product, and separation and purification is easy to operation.
The solution of the present invention is: ethyl benzoate and nitric acid carried out nitration reaction generation M-NITROBENZOIC ACID ethyl ester under strong acidic condition and-5 ℃-15 ℃, it is dissolved in the organic solvent, its solvent can be a methyl alcohol, ethanol, ether, sherwood oil, benzene, toluene, chlorobenzene, tetrahydrofuran (THF), dioxane and chloroform, the mixture that in this solution, adds sulphur and hydroborate, the weight ratio of sulphur and hydroborate is 10: 1 to 1: 10, then after reacting 2-20 hour under 20 ℃ of-80 ℃ of conditions, slough solvent, residual solids is with diluted hydrochloric acid dissolution and transfer to solution PH=1, use extracted with diethyl ether, isolate water layer and the water layer pH value is transferred to 11-14, also use extracted with diethyl ether, can get the gavaculine ethyl ester after two parts of extraction liquid underpressure distillation.
The chemical reaction of institute of the present invention foundation is expressed from the next:
Wherein M is a basic metal.
The present invention can generate the characteristics of the M-NITROBENZOIC ACID ethyl ester of higher degree during by nitric acid nitrating according to ethyl benzoate, utilize sulphur and borohydride reduction M-NITROBENZOIC ACID ethyl ester to generate the method for gavaculine ethyl ester, the product purity height, desired raw material is easy to get, price is low, and easy and simple to handle, with short production cycle, production process does not have waste, easy realization of large-scale production.
Embodiment 1
Add the 100ml vitriol oil in being furnished with the 500ml round bottom reaction flask of stirring, thermometer and dropping funnel, the water salt bath adds 60g(0.4mol after being chilled to-10 ℃) ethyl benzoate.Under agitation in-10 ℃ to+15 ℃ droppings by the solution that the 32ml vitriol oil and 32ml concentrated nitric acid are made into, drip off the back and about+10 ℃, continue reaction 30 minutes.Reaction mixture poured into leave standstill suction filtration after 1 hour in the 150g trash ice, leach thing and after washing, washing with alcohol, dry, promptly get mp.32 ℃-34 ℃ of M-NITROBENZOIC ACID ethyl esters, weight 52g, yield 66.6% in room temperature.
Is furnished with stirring at 1000ml, add 92.5g(0.5mol in the reaction flask of thermometer and backwash prolong) aforementioned M-NITROBENZOIC ACID ethyl ester that makes and 500ml dehydrated alcohol, start and stir, gradation at room temperature adds 27g(0.5mol gradually) POTASSIUM BOROHYDRIDE and 32g(mol) sublimed sulphur, add the back and continue reaction 16 hours at 60 ℃.Organic solvent in the intact reaction system of reduction vaporization transfers to 1 with the resistates dissolving and with its pH value lentamente with 10% hydrochloric acid, adds the 500ml ether, and the elimination insolubles is told organic layer.Water layer is transferred PH=11 with 20% sodium hydroxide solution after using the ether washing of 250ml * 2 again.With the extracted with diethyl ether of 500ml * 3, merge organic layer, use anhydrous sodium sulfate drying, the elimination insolubles, filtrate is transferred PH=3 with 20% methanesulfonic diethyl ether solution, spends the night 0 ℃ of-5 ℃ of cold putting, and leaches the crystal of separating out, drying, heavy 85g, mp.142-144 ℃, yield 65.1%.The ultimate analysis of product (calculated value) %:C, 46.24(45.98), H, 5.31(5.75), N, 4.95(5.36).The FT-IR(pressing potassium bromide troche, cm
-1): 2967.8,2844.9,1717.9,1286.9,1293.6,1048.0,778.0,754.1,537.7(meets the standard diagram that Aldrlch company proposes).
Embodiment 2
Prepare the M-NITROBENZOIC ACID ethyl ester in advance by embodiment 1.
Is being furnished with stirring, add 400ml methyl alcohol, 27g(0.5mol in the 1000ml reaction flask of thermometer and backwash prolong) POTASSIUM BOROHYDRIDE and 48g(1.5mol) sublimed sulphur, drip by 92.5g(0.5mol after 2 hours in stirring at room) solution that is made into of M-NITROBENZOIC ACID ethyl ester and 100ml methyl alcohol, add back stirring reaction 18 hours under the backwash temperature.Obtain after drying the diethyl ether solution that contains the gavaculine ethyl ester by embodiment 1 method, boil off ether, the fraction of 168 ℃ of-170 ℃/1.33kpa, n are collected in the residue underpressure distillation
20=1.5612, heavy 56g.
Embodiment 3
Prepare the M-NITROBENZOIC ACID ethyl ester in advance by embodiment 1 method.
In 500ml is furnished with the reaction flask of stirring, thermometer and backwash prolong, add 39g(0.2mol) M-NITROBENZOIC ACID ethyl ester and 200ml chloroform, under agitation add 6.4g(0.2mol) powdery sulphur, drip by 22.8g(0.6mol again) solution that is made into of sodium borohydride and 100ml ethanol, dropwised in about 1 hour, and be heated to backwash reaction 4 hours then.By embodiment 1 method reaction mixture is handled, got the gavaculine ethyl ester.
Embodiment 4
Prepare the M-NITROBENZOIC ACID ethyl ester in advance by embodiment 1 method.
In 500ml is furnished with the reaction flask of stirring, thermometer and backwash prolong, add 46.25g(0.25mol) M-NITROBENZOIC ACID ethyl ester and 250ml toluene, start and stir, gradation adds 19g(0.5mol under water-soluble cooling) sodium borohydride and 16g(0.5mol) sedimentation sulphur, add the back and continued the backwash stirring reaction 6 hours, the elimination insolubles, filtrate is washed with 20% sodium hydroxide solution, tells organic layer, use anhydrous sodium sulfate drying, slough solvent.The fraction of 170 ℃ of-172 ℃/1.33kpa is received in the residue underpressure distillation, promptly gets 32g gavaculine ethyl ester, yield 81.7%.
Claims (1)
1, a kind of preparation method of gavaculine ethyl ester, it is characterized in that under strong acidic condition and-5 ℃-15 ℃ ethyl benzoate and nitric acid carried out nitration reaction generation M-NITROBENZOIC ACID ethyl ester, it is dissolved in the organic solvent, its solvent can be a methyl alcohol, ethanol, ether, sherwood oil, benzene, toluene, chlorobenzene, tetrahydrofuran (THF), dioxane and chloroform, the mixture that in this solution, adds sulphur and hydroborate, the weight ratio of sulphur and hydroborate is 10: 1 to 1: 10, then after reacting 2-20 hour under 20 ℃ of-80 ℃ of conditions, slough solvent, residual solids is with diluted hydrochloric acid dissolution and transfer to solution PH=1, use extracted with diethyl ether, isolate water layer and the water layer pH value is transferred to 11-14, also use extracted with diethyl ether, can get the gavaculine ethyl ester after two parts of extraction liquid underpressure distillation.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN93120279A CN1036780C (en) | 1993-12-04 | 1993-12-04 | Processing method of ethyl meta-aminobenzoate |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN93120279A CN1036780C (en) | 1993-12-04 | 1993-12-04 | Processing method of ethyl meta-aminobenzoate |
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| CN1093080A true CN1093080A (en) | 1994-10-05 |
| CN1036780C CN1036780C (en) | 1997-12-24 |
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| CN93120279A Expired - Fee Related CN1036780C (en) | 1993-12-04 | 1993-12-04 | Processing method of ethyl meta-aminobenzoate |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105481707A (en) * | 2015-12-08 | 2016-04-13 | 浙江优创材料科技股份有限公司 | Preparation method of ethyl-4-dimethylaminobenzoate intermediate benzocaine |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5646845A (en) * | 1979-09-25 | 1981-04-28 | Fujiwa Kako Kk | Preparation of aromatic amino compound |
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1993
- 1993-12-04 CN CN93120279A patent/CN1036780C/en not_active Expired - Fee Related
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105481707A (en) * | 2015-12-08 | 2016-04-13 | 浙江优创材料科技股份有限公司 | Preparation method of ethyl-4-dimethylaminobenzoate intermediate benzocaine |
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| CN1036780C (en) | 1997-12-24 |
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