CN100484932C - Method for synthesizing 2-thenoic acetate by thiophene - Google Patents
Method for synthesizing 2-thenoic acetate by thiophene Download PDFInfo
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- CN100484932C CN100484932C CN 200510047449 CN200510047449A CN100484932C CN 100484932 C CN100484932 C CN 100484932C CN 200510047449 CN200510047449 CN 200510047449 CN 200510047449 A CN200510047449 A CN 200510047449A CN 100484932 C CN100484932 C CN 100484932C
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- oxoethanoic acid
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Abstract
This invention belongs to technique field of fine chemical industry, it relates to a preparation of composing 2-thiophene acetic acid of thiophene, mainly including: after ethanal acid is dewatered, mixed with thiophene and amorphous phosphorus in acid medium, they are reacted by effect of catalytic agent, 2-thiophene acetic acid is obtained. The used ethanal acid is technica grade ethanal acid, in the reactive process the thrown mol share ratio of thiophene and ethanal acid is 1-8:1,when the purity of ethanal acid is lower than 80%, acidity or neutral can be added to raise reaction velocity. Dehydrater addition is adjusted according to purity of ethanal acid to make water content of ethanal acid decrease to lower than 20%, dehydration time is 0.5-2h,dehydration temperature is 20-50DEG C. Thrown mol share ratio of amorphous phosphorus and ethanal acid is 0.2-1.0:1. The used catalytic agent is catalytic agent of un-protonic acid such as stannous oxide, titanium tetrabutoxide, stannic chloride, iron chloride, zinc chloride and so on, Thrown mol share ratio of catalytic agent and ethanal acid is 0.025-0.1:1.
Description
Technical field
The invention belongs to the fine chemical technology field, relate to a kind of method by thiophene Synthetic 2-thiophene acetic acid.
Background technology
The 2-thiophene acetic acid is a kind of important organic synthesis intermediate, is widely used in the synthetic of medicine and agricultural chemicals, and for example synthetic cephalosporin medicament carries out structural modification to the cephalosporin mother nucleus 7-amino-cephalosporanic acid, can improve the anti-microbial activity of medicine.
About synthesizing of 2-thiophene acetic acid, more existing reports.All be to be that raw material adopts the multistep synthesis technique with the thiophene in the synthetic method of existing report, finally obtain the target product compound.As; it is that thiophene and Acetyl Chloride 98Min. or diacetyl oxide generation acetylization reaction obtain the 2-acetyl thiophene that German PatNO.832755 is reported under the various catalyzer existence conditions; carry out the WILLGERODT reaction with ethanol, SULPHUR POWDER, ammoniacal liquor under pressurized conditions again and generate 2-thiophene ethanamide, last hydrolysis obtains the 2-thiophene acetic acid.This technology prepares 2-thiophene ethanamide by the 2-acetyl thiophene need under high pressure carry out, and adopts a large amount of excessive sulphur, and the reaction products obtained therefrom is difficult to separate, and the target product productive rate only is 20.9%.British Pat NO.1122658 is reported in POCl
3Have thiophene and N down, the dinethylformamide reaction obtains 2 thiophene carboxaldehyde, with sodium cyanide and trichloromethane reaction, the products obtained therefrom hydrogenation is obtained thiophene-2-acetonitrile then, and hydrolysis obtains the 2-thiophene acetic acid then.This method route is long, needs to use the highly toxic substance sodium cyanide, and uses the high density platinum catalyst, in security and consideration economically, is not suitable for carrying out suitability for industrialized production.US Pat NO.4287352 report obtains the 2-chloromethyl thiophene by thiophene through chloromethylation earlier, and pressurizeing under the catalysis of cobalt salt with carbon monoxide, methyl alcohol, potassium hydroxide then generates 2-thiophene acetic acid ester, makes the 2-thiophene acetic acid through hydrolysis again.This method gained intermediate product 2-chloromethyl thiophene is a kind of lachrymator, and instability can not be long time stored, and the danger of blast is arranged when airtight.US PatNO.4196299 report thiophene obtains the 2-acetyl thiophene through acetylize; and then making corresponding imines with C4-C8 Armeen or cyclammonium catalysis below 120 ℃; corresponding imines and excessive sulphur react in not being higher than 100 ℃ organic solvent and obtain 2-thiophenic sulfur acid amides, after hydrolysis, acidifying obtain the 2-thiophene acetic acid.This method reactions steps is loaded down with trivial details, the intermediates separation difficulty, and the target compound productive rate is low, is not suitable for carrying out suitability for industrialized production.
Summary of the invention
The object of the present invention is to provide a kind of technology simple, pollute for a short time, cost is low, helps realizing the 2-thiophene acetic acid production technique of suitability for industrialized production.
Technical solution of the present invention can realize according to following mode:
By the method for thiophene Synthetic 2-thiophene acetic acid, it mainly comprises the steps:
1) oxoethanoic acid is dewatered;
2) oxoethanoic acid after will dewatering mixes the back with thiophene and red phosphorus and reacts under catalyst action in acidic medium.
Described oxoethanoic acid is the technical grade oxoethanoic acid.Thiophene is 1～8:1 with the molfraction ratio that adds of oxoethanoic acid in the reaction process.When being lower than 80%, oxoethanoic acid purity can add acidity or neutral dewatering agent such as anhydrous magnesium sulfate, Vanadium Pentoxide in FLAKES, molecular sieve etc.Dewatering time is 0.5～2 hour, and dehydration temperaturre is 20～50 ℃.The dewatering agent add-on is adjusted according to oxoethanoic acid purity the oxoethanoic acid water content is reduced to below 20%, and dewatering time is 0.5～2h, and dehydration temperaturre is 20～50 ℃.
Described red phosphorus is 0.2～1.0:1 with the molfraction ratio that adds of oxoethanoic acid.
Catalyst system therefor is aprotic acid catalyzer such as tin protoxide, tetrabutyl titanate, tin tetrachloride, iron(ic) chloride, zinc chloride etc., and it is 0.025～0.1:1 that catalyzer adds the molfraction ratio with oxoethanoic acid.
Described acidic medium is selected organic acids such as formic acid, acetate, propionic acid, and the organic acid dosage is 0.5～2:1 with reaction raw materials total amount volume parts ratio; Reaction times is controlled in 2～20h scope, and temperature of reaction is controlled in 30～90 ℃ of scopes.
Used dewatering agent preferred acidic dewatering agent such as Vanadium Pentoxide in FLAKES, dewatering time are 1.0～1.5h, and dehydration temperaturre is 30～40 ℃, and thiophene is 3～5:1 with the molfraction ratio that adds of oxoethanoic acid, the adding the molfraction ratio and can select 0.4～0.7:1 of red phosphorus and oxoethanoic acid.
The preferred tin tetrachloride of used aprotic acid catalyzer, catalyzer adds the molfraction ratio with oxoethanoic acid can select 0.05～0.07:1, and the reaction times is 4～6h, and temperature of reaction is 60～80 ℃, and acidic medium is selected glacial acetic acid.
The present invention compares with the synthesis technique of existing 2-thiophene acetic acid and has the following advantages:
1) answer in the system and to add acid or neutral dewatering agent has been realized technical grade oxoethanoic acid Synthetic 2-thiophene acetic acid, production cost reduces greatly.
2) answer in the system and to add the selectivity that the aprotic acid catalyzer has been accelerated speed of response and improved reaction.
3) reaction conditions gentleness, catalyst levels is few, and technology is simple, the reaction yield height.
4) react all recyclable utilization again of remaining thiophene, red phosphorus, do not have the three wastes substantially and produce.
5) this synthesis technique has tangible economic benefit and environmental benefit, helps realizing suitability for industrialized production.
Embodiment
Processing step of the present invention is described by the following examples, but not limited by embodiment.
Embodiment 1:
In being equipped with the four-hole bottle of mechanical stirrer and prolong, 250ml adds 9.25g (0.1mol) 80% oxoethanoic acid, 50ml formic acid, 2.46g anhydrous magnesium sulfate, 50 ℃ of following vigorous stirring, churning time is 1h, suction filtration is removed siccative, add 42.0g (0.5mol) thiophene then successively, 1.36g (0.01mol) zinc chloride, 8.67g (0.07mol) red phosphorus, continuation is stirred 6h under 60 ℃ of conditions, suction filtration was removed unreacted red phosphorus after reaction mixture temperature dropped to room temperature, remaining thiophene and formic acid are reclaimed in the filtrate decompression distillation, products obtained therefrom is 2-thiophene acetic acid crude product, through extraction, washing, obtain 7.55g 2-thiophene acetic acid crystal behind the recrystallization, gas chromatographic detection purity reaches more than 98%, and productive rate is 53.2% (in oxoethanoic acid).
Embodiment 2:
In being equipped with the four-hole bottle of mechanical stirrer and prolong, 250ml adds 12.33g (0.1mol) 60% oxoethanoic acid, the 80ml glacial acetic acid, slowly add the 38.89g Vanadium Pentoxide in FLAKES under the agitation condition in the 1.5h, add 16.8g (0.2mol) thiophene then successively, 0.81g (0.006mol) tin protoxide, 4.96g (0.04mol) red phosphorus, continuation is stirred 4h under 80 ℃ of conditions, suction filtration was removed unreacted red phosphorus after reaction mixture temperature dropped to room temperature, remaining thiophene and glacial acetic acid are reclaimed in the filtrate decompression distillation, products obtained therefrom is 2-thiophene acetic acid crude product, through extraction, washing, obtain 6.80g2-thiophene acetic acid crystal behind the recrystallization, gas chromatographic detection purity reaches more than 98%, and productive rate is 47.9% (in oxoethanoic acid).
Embodiment 3:
In being equipped with the four-hole bottle of mechanical stirrer and prolong, 250ml adds 9.25g (0.1mol) 80% oxoethanoic acid, the 40ml propionic acid, 3.63g molecular sieve dehydration agent, 40 ℃ of following vigorous stirring, churning time is 2h, suction filtration is removed siccative, add 50.4g (0.6mol) thiophene then successively, 2.72g (0.008mol) tetrabutyl titanate, 6.19g (0.05mol) red phosphorus, continuation is stirred 6h under 50 ℃ of conditions, suction filtration was removed unreacted red phosphorus after reaction mixture temperature dropped to room temperature, remaining thiophene and propionic acid are reclaimed in the filtrate decompression distillation, products obtained therefrom is 2-thiophene acetic acid crude product, through extraction, washing, obtain 7.04g2-thiophene acetic acid crystal behind the recrystallization, gas chromatographic detection purity reaches more than 98%, and productive rate is 49.6% (in oxoethanoic acid).
Embodiment 4:
In being equipped with the four-hole bottle of mechanical stirrer and prolong, 250ml adds 12.33g (0.1mol) 60% oxoethanoic acid, 70ml formic acid, slowly add the 38.89g Vanadium Pentoxide in FLAKES under the agitation condition in the 1.5h, add 33.6g (0.4mol) thiophene then successively, 1.20g (0.008mol) iron trichloride, 12.39g (0.1mol) red phosphorus, continuation is stirred 6h under 80 ℃ of conditions, suction filtration was removed unreacted red phosphorus after reaction mixture temperature dropped to room temperature, remaining thiophene and glacial acetic acid are reclaimed in the filtrate decompression distillation, products obtained therefrom is 2-thiophene acetic acid crude product, through extraction, washing, obtain 7.41g 2-thiophene acetic acid crystal behind the recrystallization, gas chromatographic detection purity reaches more than 98%, and productive rate is 52.2% (in oxoethanoic acid).
Embodiment 5:
In being equipped with the four-hole bottle of mechanical stirrer and prolong, 250ml adds 9.25g (0.1mol) 80% oxoethanoic acid, the 60ml glacial acetic acid, slowly add the 14.58g Vanadium Pentoxide in FLAKES under the agitation condition in the 1h, add 67.2g (0.8mol) thiophene then successively, 1.56g (0.006mol) tin tetrachloride, 6.19g (0.05mol) red phosphorus, continuation is stirred 6h under 50 ℃ of conditions, suction filtration was removed unreacted red phosphorus after reaction mixture temperature dropped to room temperature, remaining thiophene and glacial acetic acid are reclaimed in the filtrate decompression distillation, products obtained therefrom is 2-thiophene acetic acid crude product, through extraction, washing, obtain 8.17g 2-thiophene acetic acid crystal behind the recrystallization, gas chromatographic detection purity reaches more than 98%, and productive rate is 57.5% (in oxoethanoic acid).
Claims (1)
1, by the method for thiophene Synthetic 2-thiophene acetic acid, it is characterized in that, mainly comprise the steps:
1) oxoethanoic acid is dewatered;
2) oxoethanoic acid after will dewatering mixes the back with thiophene and red phosphorus and reacts under catalyst action in acidic medium;
Described oxoethanoic acid is the technical grade oxoethanoic acid; Thiophene is 1～8:1 with the molfraction ratio that adds of oxoethanoic acid in the reaction process; When being lower than 80%, oxoethanoic acid purity can add acidity or neutral dewatering agent; Dewatering time is 0.5～2 hour, and dehydration temperaturre is 20～50 ℃; Described red phosphorus is 0.2～1.0:1 with the molfraction ratio that adds of oxoethanoic acid; Catalyst system therefor is tin protoxide, tetrabutyl titanate, tin tetrachloride, iron(ic) chloride, zinc chloride, and it is 0.025～0.1:1 that catalyzer adds the molfraction ratio with oxoethanoic acid; Described acidic medium is selected organic acid, and the organic acid dosage is 0.5～2:1 with reaction raw materials total amount volume parts ratio; Reaction times is controlled in 2～20h scope, and temperature of reaction is controlled in 30～90 ℃ of scopes; Used dewatering agent is the acidic dehydration agent, and dewatering time is 1.0～1.5h, and dehydration temperaturre is 30～40 ℃, and thiophene is 3～5: 1 with the molfraction ratio that adds of oxoethanoic acid, and red phosphorus is 0.4～0.7:1 with the molfraction ratio that adds of oxoethanoic acid; Used aprotic acid catalyzer is a tin tetrachloride, and it is 0.05～0.07:1 that catalyzer adds the molfraction ratio with oxoethanoic acid, and the reaction times is 4～6h, and temperature of reaction is 60～80 ℃, and acidic medium is selected glacial acetic acid.
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Granted publication date: 20090506 Termination date: 20091119 |