CN103058870A - Preparation method of ethyl 2-oxocyclopentylacetate - Google Patents
Preparation method of ethyl 2-oxocyclopentylacetate Download PDFInfo
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- CN103058870A CN103058870A CN2013100127652A CN201310012765A CN103058870A CN 103058870 A CN103058870 A CN 103058870A CN 2013100127652 A CN2013100127652 A CN 2013100127652A CN 201310012765 A CN201310012765 A CN 201310012765A CN 103058870 A CN103058870 A CN 103058870A
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Abstract
The invention relates to the field of drug synthesis, and particularly relates to a preparation method of ethyl 2-oxocyclopentylacetate. The preparation method is characterized by comprising the steps of: with diethylene adipate as a starting material, obtaining 2-oxocyclopentylacetate by adopting a one-pot method through condensation, displacement and hydrolysis deacidification, and then carrying out esterification to obtain the ethyl 2-oxocyclopentylacetate. The preparation method overcomes the shortcomings of a conventional synthetic method and has the advantages of easiness in availability of raw materials, low cost, convenient aftertreatment, short production cycle, high yield, low discharge of the three wastes (waste gas, waste water and industrial residue), suitability for large-scale production and the like.
Description
Technical field
The invention belongs to the medicine intermediate field, be specifically related to a kind of method of the 2-of preparation oxocyclopentyl ethyl acetate.
Background technology
2-oxocyclopentyl ethyl acetate is the important intermediate that preparation DP receptor antagonist draws sieve logical sequence.The main synthetic method of report is as follows both at home and abroad at present:
1) document Tetrahedron, 1981, Vol.37, No.25,4503-4508. have reported with behind cyclopentanone and the Pyrrolidine generation enamine
Again with the method for ethyl bromoacetate reaction.Process is as follows:
The method yield is lower, and uses the larger benzene of toxicity as solvent, is unfavorable for green production.
2) document J.Am.Chem.Soc.1995,117,3705-3716. have reported with cyclopentanone and have deposited at lithium diisopropyl amido (LDA)
The time and the method for ethyl bromoacetate reaction.Process is as follows:
The method cost is high, and needs-78 ℃ of low temperature and anhydrous condition, operates comparatively loaded down with trivial details.
3) patent WO2011094008A1 has reported take the cyclopentanone carboxylic acid, ethyl ester as raw material, the method that be substituted, hydrolysis decarboxylation, esterification three-step reaction obtains 2-oxocyclopentyl ethyl acetate.Process is as follows:
But the method yield lower (total recovery is 27.5%, and the substep yield is 37.9%, 75.2%, 96.4%).
4) document J.Chem.Soc., 1934,935-946. reported by diethylene adipate and prepared the cyclopentanone carboxylic acid, ethyl ester, be substituted again, hydrolysis decarboxylation, esterification altogether four-step reaction obtain the method for 2-oxocyclopentyl ethyl acetate.Process is as follows:
The total recovery of the method is that 47.7%～54.0%(substep yield is 86%, 85%, 87%, 75～85%), but the method reactions steps is many, needs repeatedly aftertreatment purifying, and the three wastes of generation are more, and expend a large amount of artificial; In addition, reaction is unfavorable for labour protection take the benzene of severe toxicity as solvent.
Summary of the invention
The objective of the invention is to seek a kind of easy to operate, efficient is high, yield good, constant product quality, eco-friendly 2-oxocyclopentyl ethyl acetate preparation method.
The present invention adopts the method for " treating different things alike ", and whole process only needs a purifying can obtain sterling, and product yield is higher than prior art.
Preparation method of the present invention comprises:
Then the cyclization in toluene with II and sodium Metal 99.5 adds the ethyl chloroacetate reaction, and reaction solution is through concentrated after washing, hydrolysis decarboxylation in acid again is through extraction, drying, concentrated, not purifiedly directly under catalyst action, carry out esterification with ethanol, obtain I through underpressure distillation again.
II wherein: sodium: the mol ratio of ethyl chloroacetate is 1: 1～2: 1～1.5.Further preferred 1: 1.2: 1.1.
Temperature of reaction is 70 ℃～115 ℃ during cyclization.Further preferred 90～100 ℃.The ring-closure reaction time is 4～10 hours.Further preferred 5～6 hours.
Wherein acid is selected from the sulfuric acid of concentrated hydrochloric acid, Hydrogen bromide or 20%～80%.Further preferred concentrated hydrochloric acid.
During hydrolysis decarboxylation, temperature of reaction is 80 ℃ and extremely refluxes.Further preferred backflow.The reaction times of hydrolysis decarboxylation is 4～8 hours.Use ethyl acetate extraction after reacting completely.
Preferably in the ethanol that contains catalytic amount sulfuric acid, react during esterification, perhaps in the ethanol of saturated hydrogenchloride, react, also can in containing the ethanol of a small amount of sulfur oxychloride, react.
Preparation method of the present invention and document (J.Chem.Soc., 1934,935-946.) compare the operation more convenient, avoided repeatedly post-processing operation, whole process only needs a purifying can obtain sterling, and (adopt the method for " treating different things alike ", whole preparation process only needs 2 days to shorten half man-hour; Former method needs four-step reaction, needs just can finish in 4 days), total recovery is about 60% (document J.Chem.Soc., 1934,935-946. are 47.7%-54.0%).
The present invention compares the advantage of having more with other existing method, and is higher such as: reaction efficiency height, convenient post-treatment, yield, reduces " three wastes " discharging, and whole process only needs a purifying can obtain sterling, more meets the requirement of Green Chemistry.
Embodiment
Embodiment 1
Synthetic (I) of 2-oxocyclopentyl ethyl acetate
In the there-necked flask of 2L, add toluene 200ml, sodium (20.6g, 0.898mol), reflux under the mechanical stirring is made the fine sand shape with sodium.Be cooled to 90 ℃, add toluene 500ml, dropping was dripped off by the mixed solution of diethylene adipate (150ml, 0.749mol), dehydrated alcohol 5ml, toluene 60ml in about 1 hour, continue insulated and stirred after 6 hours, drip ethyl chloroacetate (87ml, 0.824mol), 100 ℃ of control temperature are to little boiling, dripped off in about 1 hour, and continued at about 3 hours of 100 ℃ of stirring reactions.Be cooled to room temperature, add water 300ml, then add 3mol/L hydrochloric acid (300ml) and stirring, divide and get organic layer, water layer extracts with toluene 100ml, merges organic layer, uses saturated aqueous common salt (300ml * 2) to wash, the concentrated brown liquid that to get.In the single port bottle of 1L, add aforesaid liquid, and add 400ml concentrated hydrochloric acid, reflux 6 hours, add water 300ml after concentrated, with ethyl acetate (300ml * 2) extraction, with saturated aqueous common salt (300ml * 2) washing, anhydrous sodium sulfate drying filters, the concentrated brown oil crude product that obtains.This crude product is added in the 1L single port bottle, add dehydrated alcohol 300ml, sulfuric acid 2ml, reflux 8 hours.Concentrated, add ethyl acetate 400ml dilution, use saturated NaHCO
3Solution (200ml * 2) washing, anhydrous sodium sulfate drying, suction filtration concentratedly obtains brown oil crude product 95.6g, and underpressure distillation obtains colourless liquid 76.5g, yield 60.0%, b.p.115～120 ℃/10mmHg.(document b.p.123 ℃/13mmHg).
1H-NMR(300MHz，CDCl
3)，δ(ppm)：4.06(2H，q，J=7.1Hz)，2.61～2.69(1H，m)，2.29～2.43(2H，m)，2.07～2.26(2H，m)，1.98～2.04(1H，m)，1.93～1.96(1H，m)，1.68～1.81(1H，m)，1.52～1.61(1H，m)，1.18(3H，t，J=7.1Hz).
Embodiment 2
Synthetic (I) of 2-oxocyclopentyl ethyl acetate
In the there-necked flask of 2L, add toluene 200ml, sodium (20.6g, 0.898mol), reflux under the mechanical stirring is made the fine sand shape with sodium.Be cooled to 90 ℃, add toluene 500ml, dropping was dripped off by the mixed solution of diethylene adipate (150ml, 0.749mol), dehydrated alcohol 5ml, toluene 60ml in about 1 hour, continue insulated and stirred after 6 hours, drip ethyl chloroacetate (87ml, 0.824mol), 100 ℃ of control temperature are to little boiling, dripped off in about 1 hour, and continued at about 3 hours of 100 ℃ of stirring reactions.Be cooled to room temperature, add water 300ml, then add 3mol/L hydrochloric acid (300ml) and stirring, divide and get organic layer, water layer extracts with toluene 100ml, merge organic layer, with saturated aqueous common salt (300ml * 2) washing, concentrate to get brown liquid, change in the 1L single port bottle, add 40% sulfuric acid 400ml, reflux 6 hours adds water 300ml after concentrating, extract with ethyl acetate (300ml * 2), with saturated aqueous common salt (300ml * 2) washing, anhydrous sodium sulfate drying filters, concentrate to get the brown oil crude product, change in the 1L single port bottle, add the ethanolic soln 300ml that is connected with hydrogenchloride, stirring at room 5-6 hour.Concentrated, add ethyl acetate 400ml dilution, use saturated NaHCO
3Solution (200ml * 2) washing, anhydrous sodium sulfate drying, suction filtration concentratedly obtains brown oil crude product 93.8g, and underpressure distillation obtains colourless liquid 70.5g, yield 55.3%, b.p.115～120 ℃/10mmHg.(document b.p.123 ℃/13mmHg).
Embodiment 3
Synthetic (I) of 2-oxocyclopentyl ethyl acetate
In the there-necked flask of 2L, add toluene 200ml, sodium (17.2g, 0.749mol), mechanical stirring, reflux make sodium become the fine sand shape.Be cooled to 85 ℃, add toluene 500ml, drip the mixed solution by diethylene adipate (150ml, 0.749mol), dehydrated alcohol 5ml, toluene 60ml, dripped off in about 1 hour, continue to stir 6 hours.Be cooled to 85 ℃, drip ethyl chloroacetate (79.1ml, 0.749mol), the control temperature is no more than 100 ℃, drips off in about 1 hour, continues 85 ℃ of stir abouts 3 hours.Be cooled to room temperature, add water 300ml, then add 3mol/L hydrochloric acid (300ml) and stirring, divide and get organic layer, water layer extracts with toluene 100ml, wash with saturated aqueous common salt (300ml * 2) after merging organic layer, concentrate and obtain brown liquid, it is changed in the single port bottle of 1L, add the 400ml concentrated hydrochloric acid, reflux 6 hours adds water 300ml after concentrating, with ethyl acetate (300ml * 2) extraction, saturated aqueous common salt (300ml * 2) washing, anhydrous sodium sulfate drying filters, the concentrated brown oil crude product that obtains.This crude product is added in the 1L single port bottle, add dehydrated alcohol 300ml, add sulfuric acid 2ml, reflux 8 hours.Concentrated, add ethyl acetate 400ml dilution, use saturated NaHCO
3Solution (200ml * 2) washing, anhydrous sodium sulfate drying, suction filtration concentratedly obtains brown oil crude product 82.6g, and underpressure distillation obtains colourless liquid 67.1g, yield 52.6%, b.p.115～120 ℃/10mmHg.(document b.p.123 ℃/13mmHg).
Claims (10)
1. method for preparing 2-oxocyclopentyl ethyl acetate (I) comprises following preparation process:
Then the cyclization in toluene with II and sodium adds ethyl chloroacetate reaction, and reaction solution is concentrated after through washing, hydrolysis decarboxylation in acid again, and through extraction, drying, concentrated, not purifiedly directly under catalyst action, carry out esterification with ethanol, obtain I through underpressure distillation again.
2. the preparation method of claim 1, wherein II: sodium: the mol ratio of ethyl chloroacetate is 1: 1～2: 1～1.5.
3. the preparation method of claim 2, wherein II: sodium: the mol ratio of ethyl chloroacetate is 1: 1.2: 1.1.
4. the preparation method of claim 1, wherein temperature of reaction is 70 ℃～115 ℃ during cyclization, the reaction times is 4～10 hours.
5. the preparation method of claim 4, wherein temperature of reaction is 90～100 ℃ during cyclization, the reaction times is 5～6 hours.
6. the preparation method of claim 1, wherein acid is selected from the sulfuric acid of concentrated hydrochloric acid, Hydrogen bromide or 20～80%.
7. the preparation method of claim 6, wherein acid is concentrated hydrochloric acid.
8. the preparation method of claim 1, wherein during hydrolysis decarboxylation, temperature of reaction be 85 ℃ to refluxing; Reaction times is 4～8 hours.
9. the preparation method of claim 1, wherein the solvent of extraction is selected from ethyl acetate, methylene dichloride or toluene.
10. the preparation method of claim 1, wherein esterification is reacted in the ethanol of sulfur acid, hydrogenchloride or sulfur oxychloride.
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| CN105646209A (en) * | 2016-03-01 | 2016-06-08 | 苏州艾缇克药物化学有限公司 | Synthesizing method of ethyl 2-oxocyclopentylacetate |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101945862A (en) * | 2007-12-18 | 2011-01-12 | 艾尼纳制药公司 | Tetrahydrocyclopenta[b]indol-3-yl carboxylic acid derivatives useful in the treatment of autoimmune and inflammatory disorders |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101945862A (en) * | 2007-12-18 | 2011-01-12 | 艾尼纳制药公司 | Tetrahydrocyclopenta[b]indol-3-yl carboxylic acid derivatives useful in the treatment of autoimmune and inflammatory disorders |
Non-Patent Citations (1)
| Title |
|---|
| R.P.LINSTEAD, ET AL.: ""Fused Carbon Rings. Introduction and Part I. The Fusion of Five-membered Rings in the cis- and trans-Positions. The Synthesis of β-O：3：3-bicycloOctanones and Related Compounds."", 《J. CHEM. SOC》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105646209A (en) * | 2016-03-01 | 2016-06-08 | 苏州艾缇克药物化学有限公司 | Synthesizing method of ethyl 2-oxocyclopentylacetate |
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Application publication date: 20130424 |