CN102464580B - The preparation of halogen ethoxyacetic acid and ester thereof - Google Patents
The preparation of halogen ethoxyacetic acid and ester thereof Download PDFInfo
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- CN102464580B CN102464580B CN201010548329.3A CN201010548329A CN102464580B CN 102464580 B CN102464580 B CN 102464580B CN 201010548329 A CN201010548329 A CN 201010548329A CN 102464580 B CN102464580 B CN 102464580B
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Abstract
The preparation of 2-(2-halogen oxyethyl group) acetic acid and ester class thereof.With 2-(2-halogen oxyethyl group) ethanol for raw material, under catalyzer, oxygenant effect, there is oxidizing reaction in 10 DEG C ~ 50 DEG C and obtain 2-(2-halogen oxyethyl group) acetic acid; 2-(2-halogen oxyethyl group) acetic ester is obtained with the correspondent alcohol generation esterification of target ester under catalyst action.Present method can adopt one kettle way to carry out two-step reaction, simple to operate.This process safety, environmental protection, and yield is higher, is very suitable for industrialized production.
Description
Technical field:
The present invention relates to the preparation method of the carboxylic acid derivative of Halogen and ether, be specifically related to the preparation of halo ethoxyacetic acid and ester thereof.
Background technology:
Document Suomen Kemistilehti B (1944), it is raw material that 17-19. describes with chloroethanol, chloroethoxy methyl chloride is synthesized with under formaldehyde and hydrogen chloride gas effect, carry out cyanogenation and obtain chloroethoxy acetonitrile again with under cuprous cyanide and benzene, obtain chloroethoxy acetic acid in hydrochloric acid Water Under solution, and alcohol carries out esterification and obtains chloroethoxy acetogenin.The method reactions steps about 5 step, yield is low, about about 35%, and use in reaction process or produce the larger material of toxicity, as benzene, formaldehyde, chloroethoxy methyl chloride etc., to environment and operator very unfavorable.
Document Journal ofthe American Chemical Society, 79,4802-5; 1957, US2756240, Journalof the American Chemical Society, 26,4325-7; The report of 1961. documents volume the 5th phase " chemical research and application " calendar year 2001 the 13rd, with 2-oxo-1,4-dioxane is raw material, through ring-opening reaction, obtain corresponding 2-(2-chloroethoxy)-acetic ester, but its yield is only 56.4%, and raw material 2-oxo-1,4-dioxane commercially not easily obtains, price is very expensive, although its method of synthesizing this raw material is more, main drawback needs high temperature (500 DEG C) to react, or reactions steps is many, yield is lower by 46%.
It is raw material that document Jp04112852 describes with chloroethanol, under DMF and the effect of sodium hydrogen, carries out reacting below-30 DEG C with ethyl bromoacetate, obtains chloroethoxy acetic acid and derivative thereof, yield 75%.The method shortcoming is that the raw material sodium hydrogen used very easily is hydrolyzed in damp atmosphere, and meet water vigorous reaction, releasing hydrogen gas, easily blast etc., under therefore needing anhydrous condition, temperature lower (below-30 DEG C) is reacted, and is not suitable for industrialized production.
Document Tetrahdron 1994,50,3195 and J.Org.Chem.1998,63,2641 describe and react under catalyzer at rhodium-containing compound for raw material with ethyl diazoacetate, chloroethanol, obtain chloroethoxy acetic acid and derivative thereof, yield 80%.Use during the shortcoming of the method raw material---ethyl diazoacetate belongs to high flash point inflammable liquid, has explosivity, even also can blast during underpressure distillation, and employ noble metal as catalyzer, therefore be unfavorable for industrialized production.
Above literature method is all laboratory method, maybe needs to use poisonous or Hazardous substances, or needs harsher reaction conditions (high temperature or low temperature, anhydrous), or need use noble metal, is all unsuitable for industrialization production.
Summary of the invention:
The object of this invention is to provide a kind of formula I being suitable for suitability for industrialized production---the preparation method of 2-(2-halogen oxyethyl group) acetic acid and ester thereof.Can use the cheap raw material that market is easy to get, through very few step, the reaction process of short period of time, under environmental protection, safe technology condition, obtains the target product of high yield.
Technical scheme of the present invention is as follows:
The preparation method of formula I, step is as follows:
1) with 2-(2-halogen oxyethyl group) ethanol for raw material, under catalyzer, oxygenant effect, in 10 DEG C ~ 50 DEG C occur oxidizing reactions obtain 2-(2-halogen oxyethyl group) acetic acid; Described catalyzer is selected from TEMPO class material (i.e. 2,2,6,6-tetramethyl--1-piperidines oxyradical compounds); Described oxygenant is selected from perhalide, halate, halous acid salt or hypohalite;
2) step 1) products therefrom obtains 2-(2-halogen oxyethyl group) acetic ester with the correspondent alcohol generation esterification of target ester under catalyst action; Described catalyzer is selected from the vitriol oil, hydrochloric acid, thionyl chloride or 001 × 4 type resin; Described alcohol is selected from methyl alcohol, ethanol, n-propyl alcohol, 2-propyl alcohol, propyl carbinol, 2-butanols, 2-methyl isophthalic acid-propyl alcohol, the trimethyl carbinol;
Formula I
In formula, X is selected from fluorine, chlorine, bromine or iodine;
R is selected from hydrogen, methyl, ethyl, n-propyl, 2-propyl group, propyl carbinol, 2-butyl, 2-methyl isophthalic acid-propyl group or the tertiary butyl; When r is hydrogen, carry out step 2).
Carry out step 1) time, if add dihydrogen phosphate, comprise the anhydride of dihydrogen phosphate, monohydrate or dihydrate, then effect is better.Described dihydrogen phosphate preferably phosphoric acid sodium dihydrogen or potassium primary phosphate.
Step 1) preferred catalyst used is selected from 2,2,6,6-tetramethyl--1-piperidines oxyradical, 4-acetylaminohydroxyphenylarsonic acid 2,2,6,6-tetramethyl--1-piperidines oxygen or 4-hydroxyl-2,2,6,6-tetramethyl-1-piperidines oxygen; Oxygenant used is selected from sodium salt in perhalide, halate, halous acid salt, hypohalite or sylvite.
Step 1) temperature of reaction be preferably 20 DEG C ~ 40 DEG C.
Step 1) in, the preferred mol ratio of 2-(2-halogen oxyethyl group) ethanol and catalyzer is the mol ratio of 1: 0.001 ~ 0.05,2-(2-halogen oxyethyl group) ethanol and oxygenant is 1: 0.9 ~ 1.5;
Preferred mol ratio is: the mol ratio of 2-(2-halogen oxyethyl group) ethanol and catalyzer is the mol ratio of 1: 0.01 ~ 0.02,2-(2-halogen oxyethyl group) ethanol and oxygenant is 1: 1.1 ~ 1.5.
Step 2) preferred catalyst used is selected from the vitriol oil or thionyl chloride.
Following either type can be selected to complete the reaction of the present invention's two steps:
Mode one: step 1) reacted after, isolate products therefrom 2-(2-halogen oxyethyl group) acetic acid, then carry out step 2).
Mode two: adopt " one kettle way ", i.e. step 1) reacted after, not reaction product isolated, direct concentration of reaction solution, then the correspondent alcohol adding target ester dissolves, and filters, carry out step 2 with the form of the alcoholic solution of 2-(2-halogen oxyethyl group) acetic acid).This mode is easier, and does not affect quality and the yield of product, is particularly suitable for suitability for industrialized production.
The post processing mode of final product of the present invention:
The mode of available this area routine, from reaction solution, wherein extract target product extraction agent used, acetone, ethyl acetate, methylene dichloride or trichloromethane etc. can be selected, obtain the oily liquids containing formula I, after this oily liquids of underpressure distillation, required each target product can be obtained.
Product 2-(2-halogen oxyethyl group) acetic acid and all available vapor-phase chromatography of 2-(2-halogen oxyethyl group) acetic ester of the present invention's two steps carry out qualitative or detection by quantitative.
Advantage of the present invention and beneficial effect:
1, reaction raw materials cheap, be easy to get;
2, temperature of reaction is preferably 20 DEG C ~ 40 DEG C, and reaction conditions is gentle;
3, two-step reaction can carry out at "-pot ", operates very easy;
4, obtained target product purity is high, and yield is high.Experiment confirms, 2-(the 2-halogen oxyethyl group) acetic acid prepared by present method and derivative thereof, and GC purity is all more than 96%, and yield reaches more than 75%;
5, the Hazardous substances such as poisonous, explosive that prior art is used is not used, safety, environmental protection.
Because the present invention has above advantage, therefore production cost is low, is very suitable for the fairly large production of industrialization.
Specific embodiment below further illustrates the present invention, but does not limit the present invention with this
Embodiment:
Embodiment 1
200g (1.6mol) 2-(2-chloroethoxy) ethanol is added in there-necked flask, 5g (0.032mol) 2, 2, 6, 6-tetramethyl--1-piperidines oxyradical, 80ml water, 100g (0.64mol) sodium dihydrogen phosphate dihydrate is added under stirring, be cooled to 20 ~ 25 DEG C, 218g (2.4mol) Textone being dissolved in the solution that 500ml water is made into slowly drops in above-mentioned mixed solution, control temperature is no more than 45 DEG C, drip temperature control 20-35 DEG C, be incubated 2 hours, with 400ml × 3 dichloromethane extraction, extracting solution is through anhydrous sodium sulfate drying, filter, filtrate reduced in volume is until cutout, obtain 2-(2-chloroethoxy) acetic acid 200.5g, yield 90.1%, GC purity 98.7%.
Above-mentioned concentrated 2-(2-chloroethoxy) acetic acid obtained is poured in there-necked flask, add 1500ml dehydrated alcohol, stir lower dropping vitriol oil 6.9ml (0.128mol), be warming up to 75 ~ 80 DEG C of back flow reaction after 8 hours, be cooled to 30 ~ 40 DEG C, neutralize with saturated sodium bicarbonate solution, be evaporated to cutout, extract with ethyl acetate 200ml × 3, acetic acid ethyl acetate extract is with 100ml × 3 water washing, after separatory, acetic acid ethyl acetate extract is through anhydrous sodium sulfate drying, after concentrated removing ethyl acetate, obtain oily liquids, through underpressure distillation, collect the cut of 96 ~ 98 DEG C/10mmHg, obtain 2-(2-chloroethoxy) ethyl acetate 217g, yield 90%, GC purity 99.1%.
Embodiment 2
500g (4mol) 2-(2-chloroethoxy) ethanol, 6.2g (0.04mol) 2 is added in there-necked flask, 2,6,6-tetramethyl--1-piperidines oxyradical, 400ml water, 248g (1.59mol) sodium dihydrogen phosphate dihydrate is added under stirring, be cooled to 20 DEG C ~ 25 DEG C, 491g (5.42mol) Textone being dissolved in the solution that 800ml water is made into drops in above-mentioned mixed solution, control temperature is no more than 45 DEG C, drip about temperature control 35 ~ 40 DEG C, be incubated 1 hour, be evaporated to cutout.Mixture after concentrating with 1150ml n-butanol extraction, suction filtration obtains the butanol solution of 2-(2-chloroethoxy) acetic acid.Add 1350ml propyl carbinol again, drip 10.9ml (0.2mol) vitriol oil, 115 ~ 125 DEG C of back flow reaction 9 hours, are cooled to 30 ~ 40 DEG C, neutralize with saturated solution of sodium bicarbonate, concentrating under reduced pressure is except desolventizing, and extract with ethyl acetate 1000ml × 3, acetic acid ethyl acetate extract is with 250ml × 3 water washing, after separatory, acetic acid ethyl acetate extract is with anhydrous sodium sulfate drying, and after suction filtration, concentrating under reduced pressure obtains yellow oily liquid.This oily liquids of underpressure distillation, collects 124 ~ 126 DEG C/10mmHg cut, obtains 2-(2-chloroethoxy) n-butyl acetate 645g, yield 91.1%, GC purity 98.5%.
Embodiment 3
50g (0.4mol) 2-(2-chloroethoxy) ethanol is added in there-necked flask, 0.62g (0.004mol) 2, 2, 6, 6-tetramethyl--1-piperidines oxyradical, 16ml water, 24.8g (0.159mol) sodium dihydrogen phosphate dihydrate is added under stirring, be cooled to 20 DEG C ~ 25 DEG C, 49.1g (0.542mol) Textone being dissolved in the solution that 80ml water is made into drops in above-mentioned mixed solution, control temperature is no more than 45 DEG C, drip temperature control to 25 ~ 35 and be incubated 3 hours, concentrating under reduced pressure, add 110ml Virahol, suction filtration obtains the aqueous isopropanol of 2-(2-chloroethoxy) acetic acid.Add 130ml Virahol again, drip 1.5ml (0.02mol) sulfur oxychloride, be warming up to 65 ~ 70 DEG C of back flow reaction after 8 hours, be cooled to 30 ~ 40 DEG C, neutralize with saturated solution of sodium bicarbonate, concentrating under reduced pressure is except desolventizing, extract with ethyl acetate 750ml × 3, acetic acid ethyl acetate extract is with 150ml × 3 water washing, after separatory, acetic acid ethyl acetate extract is with anhydrous sodium sulfate drying, after suction filtration, filtrate reduced in volume obtains yellow oily liquid, oily liquids is carried out underpressure distillation, collect 98 ~ 100 DEG C/10mmHg cut, obtain 2-(2-chloroethoxy) isopropyl acetate 59.2g, yield 90%, GC purity 99.3%.
Embodiment 4
20g (0.16mol) 2-(2-chloroethoxy) ethanol, 1.25g (0.008mol) 2 is added in there-necked flask, 2,6,6-tetramethyl--1-piperidines oxyradical, 40ml water, stir the lower chlorine bleach liquor dripping 330g 5%, after dripping off, control temperature 20 ~ 35 DEG C, keeps 2 hours.After having reacted, regulate reaction solution pH to 1 ~ 2 with hydrochloric acid, concentrating under reduced pressure removing moisture, then dissolve with acetone 150ml, after suction filtration, concentrating under reduced pressure removing acetone, obtains 2-(2-chloroethoxy) acetic acid 18.9g, yield 85.3%, GC purity 96.2%.
The 2-obtained (2-chloroethoxy) acetic acid is proceeded in there-necked flask, add 200ml methyl alcohol, drip about 0.5ml (0.01mol) vitriol oil, be warming up to 65 ~ 75 DEG C of back flow reaction after 10 hours, be cooled to 30 ~ 40 DEG C, neutralize with saturated solution of sodium carbonate, concentrating under reduced pressure removing methyl alcohol, add 100ml × 3 ethyl acetate to extract, acetic acid ethyl acetate extract is with 50ml × 3 water washing, filter after separatory, filtrate reduced in volume steams to cutout, again underpressure distillation is carried out to gained oily liquids, collect the cut of 88 ~ 90 DEG C/10mmHg, obtain 2-(2-chloroethoxy) methyl acetate 18.7g, yield 85.3%, GC purity 98.8%.
Embodiment 5
20g (0.16mol) 2-(2-chloroethoxy) ethanol is added in there-necked flask, add 0.5g (0.0032mol) 2,2,6,6-tetramethyl--1-piperidines oxyradical, be cooled to 20 ~ 25 DEG C, the solution that dropping sodium periodate 37.7g (0.176mol) and 200ml water are made into, control temperature to 30 ~ 40 DEG C, keep 2 hours, after reaction terminates, concentrated removing moisture, adds 200ml acetone, elimination solid, filtrate is concentrated obtains 2-(2-chloroethoxy) acetic acid 18.2g, yield 82.1%, GC purity 98.1%.
Gained 2-(2-chloroethoxy) acetic acid is proceeded in there-necked flask, add 200ml dehydrated alcohol, drip about 0.5ml (0.01mol) vitriol oil, reaction solution is warming up to 75 ~ 80 DEG C of back flow reaction 8 hours, with in saturated sodium bicarbonate solution and after, concentrated removing ethanol, extract with 100ml × 3 ethyl acetate, acetic acid ethyl acetate extract is with 25ml × 3 water washing, after separatory after anhydrous sodium sulfate drying, filter, filtrate is concentrated obtains oily matter, underpressure distillation is carried out to this oily matter, collect the cut of the cut of 96 ~ 98 DEG C/10mmHg, obtain 2-(2-chloroethoxy) ethyl acetate 12.7g, yield 80%, GC purity 99.2%.
Embodiment 6
67.2g (0.4mol) 2-(2-bromine oxethyl) ethanol is added in there-necked flask, 1.25g (0.008mol) 2, 2, 6, 6-tetramethyl--1-piperidines oxyradical, 16ml water, 24.8g (0.16mol) sodium dihydrogen phosphate dihydrate is added under stirring, reaction solution is cooled to 20 ~ 25 DEG C, dropping 48.8g (0.54mol) Textone is dissolved in the solution that 55ml water is made into, control temperature is no more than 45 DEG C, after dripping, reaction solution is warming up to 20 ~ 30 DEG C, be incubated 2 hours, concentrated except after anhydrating, add 600ml extraction using alcohol, suction filtration, filtrate is poured in there-necked flask, add 1.9ml (0.035mol) vitriol oil, reaction solution is warming up to 75-80 DEG C of back flow reaction 8 hours, after stopped reaction, be cooled to 30 ~ 40 DEG C, dropping saturated solution of sodium carbonate neutralizes, pressure reducing and steaming ethanol is to cutout, extract by 100ml × 3 ethyl acetate, acetic acid ethyl acetate extract is with 50ml × 3 water washing, after separatory, after anhydrous sodium sulfate drying, filter, filtrate is concentrated obtains oily matter, underpressure distillation is carried out to this oily matter, collect the cut of 100 ~ 105 DEG C/10mmHg, obtain 2-(2-bromine oxethyl) ethyl acetate 64.5g, yield 76.4%, GC purity 98%.
Claims (3)
1. the preparation method of formula I, step is as follows:
In formula, X is chlorine; R is selected from ethyl
200g 2-(2-chloroethoxy) ethanol is added in there-necked flask, 5g 2, 2, 6, 6-tetramethyl--1-piperidines oxyradical, 80ml water, 100g sodium dihydrogen phosphate dihydrate is added under stirring, be cooled to 20 ~ 25 DEG C, 218g Textone being dissolved in the solution that 500ml water is made into slowly drops in above-mentioned mixed solution, control temperature is no more than 45 DEG C, drip temperature control 20-35 DEG C, be incubated 2 hours, with 400ml × 3 dichloromethane extraction, extracting solution is through anhydrous sodium sulfate drying, filter, filtrate reduced in volume is until cutout, obtain 2-(2-chloroethoxy) acetic acid 200.5g,
Above-mentioned concentrated 2-(2-chloroethoxy) acetic acid obtained is poured in there-necked flask, adds 1500ml dehydrated alcohol, stir lower dropping vitriol oil 6.9ml; Be warming up to 75 ~ 80 DEG C of back flow reaction after 8 hours, be cooled to 30 ~ 40 DEG C, neutralize with saturated sodium bicarbonate solution, be evaporated to cutout, with ethyl acetate 200ml × 3 extract, acetic acid ethyl acetate extract with 100ml × 3 water washing, after separatory, acetic acid ethyl acetate extract is through anhydrous sodium sulfate drying, after concentrated removing ethyl acetate, obtain oily liquids, through underpressure distillation, collect the cut of 96 ~ 98 DEG C/10mmHg, obtain 2-(2-chloroethoxy) ethyl acetate 217g.
2. the preparation method of formula I, step is as follows:
In formula, X is chlorine; R is normal-butyl
500g 2-(2-chloroethoxy) ethanol is added in there-necked flask, 6.2g 2, 2, 6, 6-tetramethyl--1-piperidines oxyradical, 400ml water, 248g sodium dihydrogen phosphate dihydrate is added under stirring, be cooled to 20 DEG C ~ 25 DEG C, 491g Textone being dissolved in the solution that 800ml water is made into drops in above-mentioned mixed solution, control temperature is no more than 45 DEG C, drip temperature control 35 ~ 40 DEG C, be incubated 1 hour, be evaporated to cutout, mixture after concentrating with 1150ml n-butanol extraction, suction filtration obtains the butanol solution of 2-(2-chloroethoxy) acetic acid, add 1350ml propyl carbinol again, drip the 10.9ml vitriol oil, 115 ~ 125 DEG C of back flow reaction 9 hours, be cooled to 30 ~ 40 DEG C, neutralize with saturated solution of sodium bicarbonate, concentrating under reduced pressure is except desolventizing, extract with ethyl acetate 1000ml × 3, acetic acid ethyl acetate extract is with 250ml × 3 water washing, after separatory, acetic acid ethyl acetate extract is with anhydrous sodium sulfate drying, after suction filtration, concentrating under reduced pressure obtains yellow oily liquid, this oily liquids of underpressure distillation, collect 124 ~ 126 DEG C/10mmHg cut, obtain 2-(2-chloroethoxy) n-butyl acetate 645g.
3. the preparation method of formula I, step is as follows:
In formula, X is chlorine; R is sec.-propyl
50g 2-(2-chloroethoxy) ethanol is added in there-necked flask, 0.62g 2, 2, 6, 6-tetramethyl--1-piperidines oxyradical, 16ml water, 24.8g sodium dihydrogen phosphate dihydrate is added under stirring, be cooled to 20 DEG C ~ 25 DEG C, 49.1g Textone being dissolved in the solution that 80ml water is made into drops in above-mentioned mixed solution, control temperature is no more than 45 DEG C, drip temperature control to 25 ~ 35 DEG C insulation 3 hours, concentrating under reduced pressure, add 110ml Virahol, suction filtration obtains the aqueous isopropanol of 2-(2-chloroethoxy) acetic acid, add 130ml Virahol again, drip 1.5ml sulfur oxychloride, be warming up to 65 ~ 70 DEG C of back flow reaction after 8 hours, be cooled to 30 ~ 40 DEG C, neutralize with saturated solution of sodium bicarbonate, concentrating under reduced pressure is except desolventizing, extract with ethyl acetate 750ml × 3, acetic acid ethyl acetate extract is with 150ml × 3 water washing, after separatory, acetic acid ethyl acetate extract is with anhydrous sodium sulfate drying, after suction filtration, filtrate reduced in volume obtains yellow oily liquid, oily liquids is carried out underpressure distillation, collect 98 ~ 100 DEG C/10mmHg cut, obtain 2-(2-chloroethoxy) isopropyl acetate 59.2g.
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| CN103508879B (en) * | 2013-09-22 | 2015-10-21 | 江苏德峰药业有限公司 | A kind of synthetic method of haloalkoxy guanidine-acetic acid |
| CN106431831B (en) * | 2016-09-18 | 2018-12-18 | 昆明博鸿生物科技有限公司 | A kind of synthetic method of 5E- decene-1-alcohol and acetic acid 5E- ubidecarenone |
| HU231119B1 (en) * | 2018-01-12 | 2020-11-30 | Richter Gedeon Nyrt. | Process for the preparation of 4-(4-aminophenyl) morpholin-3-one |
| CN114380763A (en) * | 2020-10-16 | 2022-04-22 | 上海茂晟康慧科技有限公司 | Synthesis method of Ribosban intermediate 4- (4-aminophenyl) morpholine-3-one |
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