CN104447256A - Preparation method for intermediate (5E, 9E)-farnesyl acetone of teprenone - Google Patents
Preparation method for intermediate (5E, 9E)-farnesyl acetone of teprenone Download PDFInfo
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- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/65—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by splitting-off hydrogen atoms or functional groups; by hydrogenolysis of functional groups
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- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
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Abstract
The invention discloses a preparation method for an intermediate (5E, 9E)-farnesyl acetone of teprenone. The preparation method comprises the following steps: (1) carrying out reaction on (2E, 6E)-farnesol together with methanesulfonyl chloride and lithium chloride to obtain (2E, 6E)-farnesyl chloride; (2) carrying out reaction (2E, 6E)-farnesyl chloride together with ethyl acetoacetate and sodium ethoxide to generate (5E, 9E)-ethoxycarbonyl ethyl farnesyl acetone; and (3) decarboxylating (5E, 9E)-ethoxycarbonyl ethyl farnesyl acetone in the alkaline solution of potassium hydroxide by saponifying to obtain the (5E, 9E)-farnesyl acetone. The innovative synthesis process is used for preparing the (5E, 9E)-farnesyl acetone, the toxicity of adopted raw materials and by-products are low, and the raw materials and the by-products are easy to treat. In addition, materials react under mild reaction conditions, the preparation method is easy to operate, the yield and the purity of the (5E, 9E)-farnesyl acetone are high, and the content of isomers in (5E, 9E)-farnesyl acetone is low.
Description
Technical field
The present invention relates to the preparation method of a kind of intermediate (5E, the 9E)-Acacia acetone of medicine teprenone.Belong to pharmaceutical chemicals and intermediated chemistry synthesis technical field.
Background technology
Teprenone has another name called geranylgeranylacetone, is the gastric mucosa protective agent of terpenes, has wide spectrum antiulcer action, and the ulcer cause various factors and gastric mucosal lesions have stronger antiulcer action and the improvement result to gastric mucosal lesions.Be applied to the treatment stomach ulcer that causes of a variety of causes and chronic gastritis clinically, mucosal lesion that non-steroidal anti-inflammatory drugs brings out and treat digestive tract ulcer with acid inhibitor conbined usage; Prevention and improve the mucosal lesion, associating antacid treatment digestive tract ulcer etc. that HP infects caused mucosal lesion, prevention NSAIDs dependency gastrointestinal disorder, prevention and improve portal hypertension gastopathy.Teprenone is as gastric mucosa protective agent, and in treatment gastritis, stomach ulcer, caused by prevention various factors, mucosal lesion etc. are used, and have obtained clinically extensively accreditation and sufficient evidence.Nearest research shows; teprenone can also slow down rat tubular cell apoptosis and the interstitial fibrosis of obstructive nephropathy; slow down the Progressive symmetric erythrokeratodermia development of age related dysacusis; the new atrial fibrillation sent out of prevention and the progress slowing down paroxysmal and permanent atrial fibrillation; improve mouse brain to the hypoxic tolerance of acute anoxia, all have provide protection to the ototoxicity of antitumor drug cis-platinum, ischemic brain injury.Its mechanism of action is all relevant with induction heat shock protein(HSP), and heat-shock protein family is as a kind of protected protein of general, and its Protective effects need further further investigation.And teprenone is as the inductor of heat shock protein(HSP), after being also doomed, in clinical application, be not limited only to gastric mucosal protection, also have more wide application space.
Teprenone adopts chemical synthesis preparation, and wherein the synthesis of intermediate (5E, the 9E)-Acacia acetone of a step chemical reaction is more crucial; The product reacted as upper step and the raw material of the next step, very important.At existing disclosed technical elements, CN101343219A introduces Japanese TAKASAGO spices company (JP2004726) and reacts (5E with trans-nerolidol through Carroll, 9E) and (5Z, after 9E)-Acacia acetone mixture, in appropriate solvent, isolate (5E, 9E)-Acacia acetone of purity about 90% through deep refrigeration, mother liquor uses selenium isoversion except after desolventizing, carry out deep refrigeration, crystallization again, isolate (5E, 9E)-Acacia acetone with certain purity.Trans-nerolidol is then reacted (5E through Carroll by Shanghai 30,000 pharmaceutical Co. Ltd, 9E) and (5Z, 9E)-two kinds, Acacia acetone heterogeneous mixture, enter through rectification under vacuum again, isolate (5E, 9E) isomer, remaining mixture selenium isoversion, and then carry out a rectification under vacuum.The method due to two kinds of cis-trans-isomers boiling point difference very little, the product purity obtained is not high, and be in fact difficult to large-scale production.
The research of the new chemical synthesis process that the present invention carries out just for the foregoing reasons.Main contents comprise the brand-new synthetic route of use and carry out (5E, the synthesis of 9E)-Acacia acetone, synthetic method of the present invention has starting material and is easy to get, and reaction conditions is gentle, the features such as products therefrom (2E, 6E)-Acacia acetone yield is high, purity is high, content of isomer is low; And the raw material used and by product are easy to dirtization process, especially do not pollute environment and air.
Summary of the invention
The object of the invention is to use chemical synthesis process to prepare intermediate (5E, the 9E)-Acacia acetone of medicine teprenone.(5E, 9E) of the present invention-Acacia acetone is mainly used in the synthesis of medicine teprenone as intermediate, teprenone as medicine, primary treatment gastric mucosa disease clinically.
The main reactant that the present invention relates to and reagent are (2E, 6E)-farnesol, Methanesulfonyl chloride, lithium chloride, methyl aceto acetate, potassium hydroxide, dimethyl formamide, triethylamine, sal enixum, sodium bicarbonate, magnesium sulfate, dehydrated alcohol, dioxane, normal hexane, hydrochloric acid, ethyl acetate and the intermediate (2E related to, 6E)-Acacia base chlorine and (5E, 9E)-oxyethyl group carbonyl ethyl Acacia acetone.
Synthesis technique step of the present invention is as follows:
1.(2E, 6E)-farnesol and Methanesulfonyl chloride, lithium chloride be obtained by reacting (2E, 6E)-Acacia base chlorine;
2.(2E, 6E)-Acacia base chlorine and methyl aceto acetate and sodium ethylate react and generate (5E, 9E)-oxyethyl group carbonyl ethyl Acacia acetone;
3.(5E, 9E)-oxyethyl group carbonyl ethyl Acacia acetone saponification decarboxylation in potassium hydroxide basic solution obtains (5E, 9E)-Acacia acetone.
Concrete synthesis technique flow process is shown in
accompanying drawing1.
The concrete synthesis technique of the present invention is as follows:
1. the synthesis of (2E, 6E)-Acacia base chlorine
At (the 2E of charging capacity, in 6E)-farnesol, add mol ratio be 1.0 ~ 1.5 times to (2E, the triethylamine of 6E)-farnesol, continuing to add mol ratio is 1.0 ~ 1.5 times of lithium chlorides being dissolved in DMF, is cooled to-10 ~ 0 DEG C, drip the Methanesulfonyl chloride that mol ratio is 1.0 ~ 1.5 times, within 10 minutes, dropwise, temperature control 0 DEG C reaction 2-6 hour, remains without raw material; Reaction solution is poured in frozen water, with n-hexane extraction, merge organic phase; Use 5% aqueous potassium hydrogen sulfate, purified water, 5% sodium bicarbonate aqueous solution, 5% brine respectively, anhydrous magnesium sulfate dewaters, and filtrate decompression desolventizing, obtains pale yellow oily liquid body.
2. the synthesis of (5E, 9E)-oxyethyl group carbonyl ethyl Acacia acetone
In dehydrated alcohol, add the sodium ethylate that mol ratio is 1.0 ~ 3.0 times (2E, 6E)-Acacia base chlorine, be cooled to 0 DEG C, drip the methyl aceto acetate of mol ratio 1.0 ~ 3.0 times, maintain this thermotonus 20 minutes, temperature control-5 ~ 5 DEG C, drip the dioxane solution of (2E, 6E)-Acacia base chlorine; Naturally rise to room temperature, reaction 2-4 hour, remains without raw material; Add purified water, then use n-hexane extraction, the purified water of organic phase, 5% brine, anhydrous magnesium sulfate dewater, filtrate decompression desolventizing, obtain (5E, 9E)-oxyethyl group carbonyl ethyl Acacia acetone.
3. the synthesis of (5E, 9E)-Acacia acetone
In methyl alcohol, add (5E, 9E)-oxyethyl group carbonyl ethyl Acacia acetone of charging capacity, then add 4.5M potassium hydroxide solution, be warming up to-10-80 DEG C of reaction 2-4 hour, remain without raw material; Reaction solution is down to room temperature, with the hydrochloric acid of 2M, the PH of reaction solution is adjusted to 3-4; Add extraction into ethyl acetate again, organic phase is through 5% sodium hydrogen carbonate solution, purified water, 5% brine, anhydrous magnesium sulfate dehydration; Filtrate decompression desolventizing obtains (5E, 9E)-Acacia acetone, with its content of gas chromatography determination and isomer.
Wherein:
Reactant Methanesulfonyl chloride in the first step of the present invention can replace with ethyl chloride or Tosyl chloride, and mole number is identical.
Reagent methyl aceto acetate in second step of the present invention can use methyl acetoacetate, butyl-acetoacetate to replace, and mole number is identical.
Reactant sodium ethylate in the present invention the 3rd step can replace with sodium methylate, and mole number is identical.
Feature of the present invention is:
1. the synthetic method of innovation
Teprenone intermediate (5E, 9E) of the present invention-Acacia acetone synthetic method is the novel method that prior art did not adopt.
2. the synthesis technique of innovation
The technique of teprenone intermediate (5E, 9E) of the present invention-Acacia acetone synthetic method is that prior art does not have used novel process.
3. raw material used in the present invention and by product toxicity low, be easy to dirtization process.
Raw material involved in the present invention and by product all can carry out simple dirtization process as Methanesulfonyl chloride, lithium chloride, methyl aceto acetate, potassium hydroxide, dimethyl formamide, triethylamine, sal enixum, sodium bicarbonate, magnesium sulfate, dehydrated alcohol, dioxane, hydrochloric acid, ethyl acetate and pollute with regard to not producing environment, and above-mentioned substance can not to air born pollution.
4. reaction conditions gentleness of the present invention, easy handling.
Reaction conditions of the present invention is generally-10 ~ 80 DEG C, does not need high pressure, and reaction conditions is gentle, is easy to control and operation.
5. target product yield of the present invention is high, purity is high, and content of isomer is low.
The present invention is by three-step reaction, and the yield of the target product (5E, 9E) obtained-Acacia acetone is higher, and total recovery is not less than 80%; Its purity is not less than 96%; Content of isomer is not more than 0.6%.This absolutely proves purity owing to strictly controlling (5E, 9E)-Acacia acetone and content of isomer, and make the purity of being synthesized the finished product teprenone raw material obtained by this intermediate higher, related substance is bright meets requirements for pharmaceuticals.
6. the present invention can large-scale production, has practicality.
figure of description
figure1 is synthesis technique flow process of the present invention
figure.
Embodiment
Now further illustrate content of the present invention by following embodiment, but range of application of the present invention is not limited to following Examples.
Embodiment 1.
1. the synthesis of (2E, 6E)-Acacia base chlorine
The triethylamine of 21.51g is added to the (2E of 43.14g, 6E)-farnesol, then the 8.23g lithium chloride being dissolved in 100mlDMF is added, be cooled to 0 DEG C, drip the Methanesulfonyl chloride of 16.56ml, within 10 minutes, dropwise, temperature control 0 DEG C reaction 2 hours, remain without raw material, reaction solution is poured in 500ml frozen water, with 3 × 100ml n-hexane extraction, merge organic phase, use 5% aqueous potassium hydrogen sulfate, purified water, 5% sodium bicarbonate aqueous solution, 5% brine respectively, anhydrous magnesium sulfate dewaters, and filtrate decompression desolventizing obtains 44.81g pale yellow oily liquid body.
2. the synthesis of (5E, 9E)-oxyethyl group carbonyl ethyl Acacia acetone
Add in 24.5g sodium ethylate in the dehydrated alcohol of 98ml, be cooled to 0 DEG C, drip 46.85g methyl aceto acetate, maintain this thermotonus 20 minutes, temperature control 0 DEG C drips the (2E that 55ml contains 43.29g, the dioxane solution of 6E)-Acacia base chlorine, dropwise, naturally rise to room temperature reaction 2 hours, remain without raw material, add 98ml purified water, then 2 × 200ml n-hexane extraction is used, the purified water of organic phase, 5% brine, anhydrous magnesium sulfate dewater, and filtrate decompression desolventizing obtains 58.02g(5E, 9E)-oxyethyl group carbonyl ethyl Acacia acetone.
3. the synthesis of (5E, 9E)-Acacia acetone
50.1g(5E is added in 185ml methyl alcohol, 9E)-oxyethyl group carbonyl ethyl Acacia acetone, add the potassium hydroxide solution 150ml of 4.53M again, be warming up to 70 DEG C of reactions 2 hours, remain without raw material, reaction solution is down to room temperature, with the hydrochloric acid of 2M, the PH of reaction solution is adjusted to 3.2, add 2 × 300ml extraction into ethyl acetate again, organic phase is through 5% sodium hydrogen carbonate solution, purified water, 5% brine, anhydrous magnesium sulfate dehydration; Filtrate decompression desolventizing obtains 37.58g(5E, 9E)-Acacia acetone, measuring content is 96.7%(GC method) and isomer 0.52%.
Embodiment 2.
1. the synthesis of (2E, 6E)-Acacia base chlorine
The triethylamine of 21.51g is added to the (2E of 43.14g, 6E)-farnesol, then the 8.23g lithium chloride being dissolved in 100mlDMF is added, be cooled to-10 DEG C, drip the Methanesulfonyl chloride of 16.56ml, within 10 minutes, dropwise, temperature control 0 DEG C reaction 2 hours, remain without raw material, reaction solution is poured in 500ml frozen water, with 3 × 100ml n-hexane extraction, merge organic phase, use 5% aqueous potassium hydrogen sulfate, purified water, 5% sodium bicarbonate aqueous solution, 5% brine respectively, anhydrous magnesium sulfate dewaters, and filtrate decompression desolventizing obtains 44.01g pale yellow oily liquid body.
2. the synthesis of (5E, 9E)-oxyethyl group carbonyl ethyl Acacia acetone
Add in 24.5g sodium ethylate in the dehydrated alcohol of 98ml, be cooled to 0 DEG C, drip 46.85g methyl aceto acetate, maintain this thermotonus 20 minutes, temperature control-5 DEG C drips the (2E that 55ml contains 43.29g, the dioxane solution of 6E)-Acacia base chlorine, dropwise, naturally room temperature reaction is risen to 2 hours, remain without raw material, add 98ml purified water, then 2 × 200ml n-hexane extraction is used, the purified water of organic phase, 5% brine, anhydrous magnesium sulfate dewaters, filtrate decompression desolventizing obtains 57.02g(5E, 9E)-oxyethyl group carbonyl ethyl Acacia acetone.
3. the synthesis of (5E, 9E)-Acacia acetone
50.1g(5E is added in 185ml methyl alcohol, 9E)-oxyethyl group carbonyl ethyl Acacia acetone, add the potassium hydroxide solution 150ml of 4.53M again, be warming up to 0 DEG C of reaction 2 hours, remain without raw material, reaction solution is down to room temperature, with the hydrochloric acid of 2M, the PH of reaction solution is adjusted to 3.2, add 2 × 300ml extraction into ethyl acetate again, organic phase is through 5% sodium hydrogen carbonate solution, purified water, 5% brine, anhydrous magnesium sulfate dehydration; Filtrate decompression desolventizing obtains 35.58g(5E, 9E)-Acacia acetone, measuring content is 97.2%(GC method) and isomer 0.48%.
Embodiment 3.
1. the synthesis of (2E, 6E)-Acacia base chlorine
The triethylamine of 21.51g is added to the (2E of 43.14g, 6E)-farnesol, then the 8.23g lithium chloride being dissolved in 100mlDMF is added, be cooled to 0 DEG C, drip the Methanesulfonyl chloride of 16.56ml, within 10 minutes, dropwise, temperature control 0 DEG C reaction 2 hours, remain without raw material, reaction solution is poured in 500ml frozen water, with 3 × 100ml n-hexane extraction, merge organic phase, use 5% aqueous potassium hydrogen sulfate, purified water, 5% sodium bicarbonate aqueous solution, 5% brine respectively, anhydrous magnesium sulfate dewaters, and filtrate decompression desolventizing obtains 44.55g pale yellow oily liquid body.
2. the synthesis of (5E, 9E)-oxyethyl group carbonyl ethyl Acacia acetone
Add in 24.5g sodium ethylate in the dehydrated alcohol of 98ml, be cooled to 0 DEG C, drip 46.85g methyl aceto acetate, maintain this thermotonus 20 minutes, temperature control 5 DEG C drips the (2E that 55ml contains 43.29g, the dioxane solution of 6E)-Acacia base chlorine, dropwise, naturally rise to room temperature reaction 2 hours, remain without raw material, add 98ml purified water, then 2 × 200ml n-hexane extraction is used, the purified water of organic phase, 5% brine, anhydrous magnesium sulfate dewater, and filtrate decompression desolventizing obtains 57.30g(5E, 9E)-oxyethyl group carbonyl ethyl Acacia acetone.
3. the synthesis of (5E, 9E)-Acacia acetone
50.1g(5E is added in 185ml methyl alcohol, 9E)-oxyethyl group carbonyl ethyl Acacia acetone, add the potassium hydroxide solution 150ml of 4.53M again, be warming up to 80 DEG C of reactions 2 hours, remain without raw material, reaction solution is down to room temperature, with the hydrochloric acid of 2M, the PH of reaction solution is adjusted to 3.2, add 2 × 300ml extraction into ethyl acetate again, organic phase is through 5% sodium hydrogen carbonate solution, purified water, 5% brine, anhydrous magnesium sulfate dehydration; Filtrate decompression desolventizing obtains 37.18g(5E, 9E)-Acacia acetone, measuring content is 96.4%(GC method) and isomer 0.50%.
Embodiment 4.
1. the synthesis of (2E, 6E)-Acacia base chlorine
The triethylamine of 107.5g is added to the (2E of 215.7g, 6E)-farnesol, then the 41.15g lithium chloride being dissolved in 500mlDMF is added, be cooled to 0 DEG C, drip the Methanesulfonyl chloride of 83ml, within 10 minutes, dropwise, temperature control 0 DEG C reaction 2 hours, remain without raw material, reaction solution is poured in 2500ml frozen water, with 3 × 500ml n-hexane extraction, merge organic phase, use 5% aqueous potassium hydrogen sulfate, purified water, 5% sodium bicarbonate aqueous solution, 5% brine respectively, anhydrous magnesium sulfate dewaters, and filtrate decompression desolventizing obtains 225.3g pale yellow oily liquid body.
2. the synthesis of (5E, 9E)-oxyethyl group carbonyl ethyl Acacia acetone
Add in 122.5g sodium ethylate in the dehydrated alcohol of 490ml, be cooled to 0 DEG C, drip 234g methyl aceto acetate, maintain this thermotonus 20 minutes, temperature control 0 DEG C drips the (2E that 275ml contains 216.5g, the dioxane solution of 6E)-Acacia base chlorine, dropwise, naturally room temperature reaction is risen to 2 hours, remain without raw material, add 490ml purified water, then 2 × 1000ml n-hexane extraction is used, the purified water of organic phase, 5% brine, anhydrous magnesium sulfate dewaters, filtrate decompression desolventizing obtains 288g(5E, 9E)-oxyethyl group carbonyl ethyl Acacia acetone.
3. the synthesis of (5E, 9E)-Acacia acetone
250g(5E is added in 925ml methyl alcohol, 9E)-oxyethyl group carbonyl ethyl Acacia acetone, add the potassium hydroxide solution 750ml of 4.53M again, be warming up to 75 DEG C of reactions 2 hours, remain without raw material, reaction solution is down to room temperature, with the hydrochloric acid of 2M, the PH of reaction solution is adjusted to 3.2, add 2 × 1500ml extraction into ethyl acetate again, organic phase is through 5% sodium hydrogen carbonate solution, purified water, 5% brine, anhydrous magnesium sulfate dehydration; Filtrate decompression desolventizing obtains 189.6g(5E, 9E)-Acacia acetone, measuring content is 97.0%(GC method) and isomer 0.55%.
Embodiment 5.
1. the synthesis of (2E, 6E)-Acacia base chlorine
The triethylamine of 215g is added to the (2E of 431g, 6E)-farnesol, then the 82g lithium chloride being dissolved in 100mlDMF is added, be cooled to 0 DEG C, drip the Methanesulfonyl chloride of 165ml, within 20 minutes, dropwise, temperature control 0 DEG C reaction 3 hours, remain without raw material, reaction solution is poured in 5000ml frozen water, with 3 × 1000ml n-hexane extraction, merge organic phase, use 5% aqueous potassium hydrogen sulfate, purified water, 5% sodium bicarbonate aqueous solution, 5% brine respectively, anhydrous magnesium sulfate dewaters, and filtrate decompression desolventizing obtains 450g pale yellow oily liquid body.
2. the synthesis of (5E, 9E)-oxyethyl group carbonyl ethyl Acacia acetone
Add in 245g sodium ethylate in the dehydrated alcohol of 1000ml, be cooled to 0 DEG C, drip 46.85g methyl aceto acetate, maintain this thermotonus 20 minutes, temperature control 0 DEG C drips the (2E that 550ml contains 433g, the dioxane solution of 6E)-Acacia base chlorine, dropwise, naturally room temperature reaction is risen to 2 hours, remain without raw material, add 1000ml purified water, then 2 × 2000ml n-hexane extraction is used, the purified water of organic phase, 5% brine, anhydrous magnesium sulfate dewaters, filtrate decompression desolventizing obtains 584g(5E, 9E)-oxyethyl group carbonyl ethyl Acacia acetone.
3. the synthesis of (5E, 9E)-Acacia acetone
501g(5E is added in 1850ml methyl alcohol, 9E)-oxyethyl group carbonyl ethyl Acacia acetone, add the potassium hydroxide solution 1500ml of 4.53M again, be warming up to 75 DEG C of reactions 2 hours, remain without raw material, reaction solution is down to room temperature, with the hydrochloric acid of 2M, the PH of reaction solution is adjusted to 3.5, add 2 × 3000ml extraction into ethyl acetate again, organic phase is through 5% sodium hydrogen carbonate solution, purified water, 5% brine, anhydrous magnesium sulfate dehydration; Filtrate decompression desolventizing obtains 388g(5E, 9E)-Acacia acetone, measuring content is 96.6%(GC method) and isomer 0.56%.
Embodiment 6.
1. the synthesis of (2E, 6E)-Acacia base chlorine
The triethylamine of 215g is added to the (2E of 431g, 6E)-farnesol, then the 82g lithium chloride being dissolved in 100mlDMF is added, be cooled to 0 DEG C, drip the Methanesulfonyl chloride of 165ml, within 20 minutes, dropwise, temperature control-5 DEG C reaction 3 hours, remain without raw material, reaction solution is poured in 5000ml frozen water, with 3 × 1000ml n-hexane extraction, merge organic phase, use 5% aqueous potassium hydrogen sulfate, purified water, 5% sodium bicarbonate aqueous solution, 5% brine respectively, anhydrous magnesium sulfate dewaters, and filtrate decompression desolventizing obtains 442g pale yellow oily liquid body.
2. the synthesis of (5E, 9E)-oxyethyl group carbonyl ethyl Acacia acetone
Add in 245g sodium ethylate in the dehydrated alcohol of 1000ml, be cooled to 0 DEG C, drip 46.85g methyl aceto acetate, maintain this thermotonus 20 minutes, temperature control 5 DEG C drips the (2E that 550ml contains 433g, the dioxane solution of 6E)-Acacia base chlorine, dropwise, naturally room temperature reaction is risen to 3 hours, remain without raw material, add 1000ml purified water, then 2 × 2000ml n-hexane extraction is used, the purified water of organic phase, 5% brine, anhydrous magnesium sulfate dewaters, filtrate decompression desolventizing obtains 592g(5E, 9E)-oxyethyl group carbonyl ethyl Acacia acetone.
3. the synthesis of (5E, 9E)-Acacia acetone
501g(5E is added in 1850ml methyl alcohol, 9E)-oxyethyl group carbonyl ethyl Acacia acetone, add the potassium hydroxide solution 1500ml of 4.53M again, be warming up to 75 DEG C of reactions 2 hours, remain without raw material, reaction solution is down to room temperature, with the hydrochloric acid of 2M, the PH of reaction solution is adjusted to 3.5, add 2 × 3000ml extraction into ethyl acetate again, organic phase is through 5% sodium hydrogen carbonate solution, purified water, 5% brine, anhydrous magnesium sulfate dehydration; Filtrate decompression desolventizing obtains 394g(5E, 9E)-Acacia acetone, measuring content is 96.9%(GC method) and isomer 0.58%.
Embodiment 7.
1. the synthesis of (2E, 6E)-Acacia base chlorine
The triethylamine of 1075g is added to the (2E of 2150g, 6E)-farnesol, then the 412g lithium chloride being dissolved in 5000mlDMF is added, be cooled to 0 DEG C, drip the Methanesulfonyl chloride of 830ml, within 30 minutes, dropwise, temperature control 0 DEG C reaction 3 hours, remain without raw material, reaction solution is poured in 25L frozen water, with 3 × 5L n-hexane extraction, merge organic phase, use 5% aqueous potassium hydrogen sulfate, purified water, 5% sodium bicarbonate aqueous solution, 5% brine respectively, anhydrous magnesium sulfate dewaters, and filtrate decompression desolventizing obtains 2.25kg pale yellow oily liquid body.
2. the synthesis of (5E, 9E)-oxyethyl group carbonyl ethyl Acacia acetone
Add in 1225g sodium ethylate in the dehydrated alcohol of 5L, be cooled to 0 DEG C, drip 2.35kg methyl aceto acetate, maintain this thermotonus 30 minutes, temperature control 0 DEG C drips the (2E that 2.75L contains 2.20kg, the dioxane solution of 6E)-Acacia base chlorine, dropwise, naturally rise to room temperature reaction 3 hours, remain without raw material, add 5L purified water, then 2 × 10L n-hexane extraction is used, the purified water of organic phase, 5% brine, anhydrous magnesium sulfate dewater, and filtrate decompression desolventizing obtains 3.1kg(5E, 9E)-oxyethyl group carbonyl ethyl Acacia acetone.
3. the synthesis of (5E, 9E)-Acacia acetone
2.5kg(5E is added in 9.25L methyl alcohol, 9E)-oxyethyl group carbonyl ethyl Acacia acetone, add the potassium hydroxide solution 7500ml of 4.53M again, be warming up to 80 DEG C of reactions 3 hours, remain without raw material, reaction solution is down to room temperature, with the hydrochloric acid of 2M, the PH of reaction solution is adjusted to 3.5, add 2 × 15L extraction into ethyl acetate again, organic phase is through 5% sodium hydrogen carbonate solution, purified water, 5% brine, anhydrous magnesium sulfate dehydration; Filtrate decompression desolventizing obtains 1.93kg(5E, 9E)-Acacia acetone, measuring content is 96.4%(GC method) and isomer 0.56%.
Embodiment 8.
1. the synthesis of (2E, 6E)-Acacia base chlorine
The triethylamine of 1075g is added to the (2E of 2150g, 6E)-farnesol, then the 412g lithium chloride being dissolved in 5000mlDMF is added, be cooled to 0 DEG C, drip the Methanesulfonyl chloride of 830ml, within 30 minutes, dropwise, temperature control-5 DEG C reaction 4 hours, remain without raw material, reaction solution is poured in 25L frozen water, with 3 × 5L n-hexane extraction, merge organic phase, use 5% aqueous potassium hydrogen sulfate, purified water, 5% sodium bicarbonate aqueous solution, 5% brine respectively, anhydrous magnesium sulfate dewaters, and filtrate decompression desolventizing obtains 2.08kg pale yellow oily liquid body.
2. the synthesis of (5E, 9E)-oxyethyl group carbonyl ethyl Acacia acetone
Add in 1225g sodium ethylate in the dehydrated alcohol of 5L, be cooled to 0 DEG C, drip 2.35kg methyl aceto acetate, maintain this thermotonus 30 minutes, temperature control 5 DEG C drips the (2E that 2.75L contains 2.20kg, the dioxane solution of 6E)-Acacia base chlorine, dropwise, naturally rise to room temperature reaction 3 hours, remain without raw material, add 5L purified water, then 2 × 10L n-hexane extraction is used, the purified water of organic phase, 5% brine, anhydrous magnesium sulfate dewater, and filtrate decompression desolventizing obtains 3.18kg(5E, 9E)-oxyethyl group carbonyl ethyl Acacia acetone.
3. the synthesis of (5E, 9E)-Acacia acetone
2.5kg(5E is added in 9.25L methyl alcohol, 9E)-oxyethyl group carbonyl ethyl Acacia acetone, add the potassium hydroxide solution 1500ml of 4.53M again, be warming up to 80 DEG C of reactions 4 hours, remain without raw material, reaction solution is down to room temperature, with the hydrochloric acid of 2M, the PH of reaction solution is adjusted to 3.5, add 2 × 15L extraction into ethyl acetate again, organic phase is through 5% sodium hydrogen carbonate solution, purified water, 5% brine, anhydrous magnesium sulfate dehydration; Filtrate decompression desolventizing obtains 2.02kg(5E, 9E)-Acacia acetone, measuring content is 96.3%(GC method) and isomer 0.51%.
Embodiment 9.
1. the synthesis of (2E, 6E)-Acacia base chlorine
The triethylamine of 2150g is added to the (2E of 4310g, 6E)-farnesol, then the 823g lithium chloride being dissolved in 10LDMF is added, be cooled to 0 DEG C, drip the Methanesulfonyl chloride of 1656ml, within 30 minutes, dropwise, temperature control 0 DEG C reaction 6 hours, remain without raw material, reaction solution is poured in 50L frozen water, with 3 × 10L n-hexane extraction, merge organic phase, use 5% aqueous potassium hydrogen sulfate, purified water, 5% sodium bicarbonate aqueous solution, 5% brine respectively, anhydrous magnesium sulfate dewaters, and filtrate decompression desolventizing obtains 4510g pale yellow oily liquid body.
2. the synthesis of (5E, 9E)-oxyethyl group carbonyl ethyl Acacia acetone
Add in 2450g sodium ethylate in the dehydrated alcohol of 10L, be cooled to 0 DEG C, drip 4700g methyl aceto acetate, maintain this thermotonus 30 minutes, temperature control 0 DEG C drips the (2E that 5.5L contains 4300g, the dioxane solution of 6E)-Acacia base chlorine, dropwise, naturally rise to room temperature reaction 4 hours, remain without raw material, add 10L purified water, then 2 × 20L n-hexane extraction is used, the purified water of organic phase, 5% brine, anhydrous magnesium sulfate dewater, and filtrate decompression desolventizing obtains 5.963kg(5E, 9E)-oxyethyl group carbonyl ethyl Acacia acetone.
3. the synthesis of (5E, 9E)-Acacia acetone
5kg(5E is added in 18.5L methyl alcohol, 9E)-oxyethyl group carbonyl ethyl Acacia acetone, add the potassium hydroxide solution 15L of 4.53M again, be warming up to 80 DEG C of reactions 4 hours, remain without raw material, reaction solution is down to room temperature, with the hydrochloric acid of 2M, the PH of reaction solution is adjusted to 3.5, add 2 × 30L extraction into ethyl acetate again, organic phase is through 5% sodium hydrogen carbonate solution, purified water, 5% brine, anhydrous magnesium sulfate dehydration; Filtrate decompression desolventizing obtains 3.98kg(5E, 9E)-Acacia acetone, measuring content is 97.1%(GC method) and isomer 0.58%.
Embodiment 10.
1. the synthesis of (2E, 6E)-Acacia base chlorine
The triethylamine of 2150g is added to the (2E of 4310g, 6E)-farnesol, then the 823g lithium chloride being dissolved in 10LDMF is added, be cooled to 0 DEG C, drip the Methanesulfonyl chloride of 1656ml, within 30 minutes, dropwise, temperature control-5 DEG C reaction 6 hours, remain without raw material, reaction solution is poured in 50L frozen water, with 3 × 10L n-hexane extraction, merge organic phase, use 5% aqueous potassium hydrogen sulfate, purified water, 5% sodium bicarbonate aqueous solution, 5% brine respectively, anhydrous magnesium sulfate dewaters, and filtrate decompression desolventizing obtains 4500g pale yellow oily liquid body.
2. the synthesis of (5E, 9E)-oxyethyl group carbonyl ethyl Acacia acetone
Add in 2450g sodium ethylate in the dehydrated alcohol of 10L, be cooled to 0 DEG C, drip 4700g methyl aceto acetate, maintain this thermotonus 30 minutes, temperature control-5 DEG C drips the (2E that 5.5L contains 4300g, the dioxane solution of 6E)-Acacia base chlorine, dropwise, naturally rise to room temperature reaction 4 hours, remain without raw material, add 10L purified water, then 2 × 20L n-hexane extraction is used, the purified water of organic phase, 5% brine, anhydrous magnesium sulfate dewater, and filtrate decompression desolventizing obtains 5.86kg(5E, 9E)-oxyethyl group carbonyl ethyl Acacia acetone.
3. the synthesis of (5E, 9E)-Acacia acetone
5kg(5E is added in 18.5L methyl alcohol, 9E)-oxyethyl group carbonyl ethyl Acacia acetone, add the potassium hydroxide solution 15L of 4.53M again, be warming up to 80 DEG C of reactions 4 hours, remain without raw material, reaction solution is down to room temperature, with the hydrochloric acid of 2M, the PH of reaction solution is adjusted to 3.5, add 2 × 30L extraction into ethyl acetate again, organic phase is through 5% sodium hydrogen carbonate solution, purified water, 5% brine, anhydrous magnesium sulfate dehydration; Filtrate decompression desolventizing obtains 3.63kg(5E, 9E)-Acacia acetone, measuring content is 97.0%(GC method) and isomer 0.50%.
Embodiment 11.
1. the synthesis of (2E, 6E)-Acacia base chlorine
2150g triethylamine is added to the (2E of 4314g, 6E)-farnesol, then the 823g lithium chloride being dissolved in 10LDMF is added, be cooled to 0 DEG C, drip the ethyl chloride of 2738g, 10min dropwises, temperature control 0 DEG C reaction 4 hours, TLC monitors, and remains without raw material, reaction solution is poured in 50L frozen water, with 3 × 10L n-hexane extraction, merge organic phase, use 5% aqueous potassium hydrogen sulfate, purified water, 5% sodium bicarbonate aqueous solution, 5% brine respectively, anhydrous magnesium sulfate dewaters, and filtrate decompression desolventizing obtains 4452g pale yellow oily liquid body.
2. the synthesis of (5E, 9E)-oxyethyl group carbonyl ethyl Acacia acetone
2450g sodium ethylate is added in 10L dehydrated alcohol, be cooled to 0 DEG C, drip 4685g methyl aceto acetate, maintain this thermotonus 20 minutes, temperature control 0 DEG C drips 5.5L and contains 4329g(2E, the dioxane solution of 6E)-Acacia base chlorine, dropwise, naturally rise to room temperature reaction 4 hours, TLC monitors, remain without raw material, add 10L purified water, then use 2 × 20L n-hexane extraction, the purified water of organic phase, 5% brine, anhydrous magnesium sulfate dewater, filtrate decompression desolventizing obtains 5750g(5E, 9E)-oxyethyl group carbonyl ethyl Acacia acetone.
3. the synthesis of (5E, 9E)-Acacia acetone
5010g(5E is added in 18.5L methyl alcohol, 9E)-oxyethyl group carbonyl ethyl Acacia acetone, add the potassium hydroxide solution 15L of 4.53M again, be warming up to 75 DEG C of reactions 2 hours, TLC monitors, and remains without raw material, reaction solution is down to room temperature, with the hydrochloric acid of 2N, the PH of reaction solution is adjusted to 3.5, then adds 2 × 30L extraction into ethyl acetate, organic phase is through 5% sodium hydrogen carbonate solution, purified water, 5% brine, anhydrous magnesium sulfate dehydration; Filtrate decompression desolventizing obtains 3838g(5E, 9E)-Acacia acetone, content 96.5%, isomer 0.50%.
Embodiment 12.
1. the synthesis of (2E, 6E)-Acacia base chlorine
2151g triethylamine is added to the (2E of 4314g, 6E)-farnesol, then the 823g lithium chloride being dissolved in 10LDMF is added, be cooled to 0 DEG C, drip the Tosyl chloride of 4060g, within 10 minutes, dropwise, temperature control 0 DEG C reaction 4 hours, TLC monitors, and remains without raw material, reaction solution is poured in 50L frozen water, with 3 × 10L n-hexane extraction, merge organic phase, use 5% aqueous potassium hydrogen sulfate, purified water, 5% sodium bicarbonate aqueous solution, 5% brine respectively, anhydrous magnesium sulfate dewaters, and filtrate decompression desolventizing obtains 4492g pale yellow oily liquid body.
2. the synthesis of (5E, 9E)-oxyethyl group carbonyl ethyl Acacia acetone
2450g sodium ethylate is added in 10L dehydrated alcohol, be cooled to 0 DEG C, drip 4685g methyl aceto acetate, maintain this thermotonus 20 minutes, temperature control 0 DEG C drips 5.5L and contains 4329g(2E, the dioxane solution of 6E)-Acacia base chlorine, dropwise, naturally rise to room temperature reaction 4 hours, TLC monitors, remain without raw material, add 10L purified water, then use 2 × 20L n-hexane extraction, the purified water of organic phase, 5% brine, anhydrous magnesium sulfate dewater, filtrate decompression desolventizing obtains 577g(5E, 9E)-oxyethyl group carbonyl ethyl Acacia acetone.
3. the synthesis of (5E, 9E)-Acacia acetone
5010g(5E is added in 18.5L methyl alcohol, 9E)-oxyethyl group carbonyl ethyl Acacia acetone, add the potassium hydroxide solution 15L of 4.53M again, be warming up to 75 DEG C of reactions 2 hours, TLC monitors, and remains without raw material, reaction solution is down to room temperature, with the hydrochloric acid of 2N, the PH of reaction solution is adjusted to 3.5, then adds 2 × 30L extraction into ethyl acetate, organic phase is through 5% sodium hydrogen carbonate solution, purified water, 5% brine, anhydrous magnesium sulfate dehydration; Filtrate decompression desolventizing obtains 3810g(5E, 9E)-Acacia acetone, content 97.0%, isomer 0.49%.
Claims (4)
1. a preparation method for teprenone intermediate (5E, 9E)-Acacia acetone, is characterized in that: its synthesis technique is as follows:
(1) synthesis of (2E, 6E)-Acacia base chlorine
At (the 2E of charging capacity, in 6E)-farnesol, add mol ratio be 1.0 ~ 1.5 times to (2E, the triethylamine of 6E)-farnesol, continuing to add mol ratio is 1.0 ~ 1.5 times of lithium chlorides being dissolved in DMF, is cooled to-10 ~ 0 DEG C, drip the Methanesulfonyl chloride that mol ratio is 1.0 ~ 1.5 times, within 10 minutes, dropwise, temperature control 0 DEG C reaction 2-6 hour, remains without raw material; Reaction solution is poured in frozen water, with n-hexane extraction, merge organic phase; Use 5% aqueous potassium hydrogen sulfate, purified water, 5% sodium bicarbonate aqueous solution, 5% brine respectively, anhydrous magnesium sulfate dewaters, and filtrate decompression desolventizing, obtains pale yellow oily liquid body;
(2) synthesis of (5E, 9E)-oxyethyl group carbonyl ethyl Acacia acetone
In dehydrated alcohol, add the sodium ethylate that mol ratio is 1.0 ~ 3.0 times (2E, 6E)-Acacia base chlorine, be cooled to 0 DEG C, drip the methyl aceto acetate of mol ratio 1.0 ~ 3.0 times, maintain this thermotonus 20 minutes, temperature control-5 ~ 5 DEG C, drip the dioxane solution of (2E, 6E)-Acacia base chlorine; Naturally rise to room temperature, reaction 2-4 hour, remains without raw material; Add purified water, then use n-hexane extraction, the purified water of organic phase, 5% brine, anhydrous magnesium sulfate dewater, filtrate decompression desolventizing, obtain (5E, 9E)-oxyethyl group carbonyl ethyl Acacia acetone;
(3) synthesis of (5E, 9E)-Acacia acetone
。
2. teprenone intermediate (5E according to claim 1, the preparation method of 9E)-Acacia acetone, it is characterized in that: the reactant Methanesulfonyl chloride in the first step of the present invention can replace with ethyl chloride or Tosyl chloride, and mole number is identical.
3. teprenone intermediate (5E according to claim 1, the preparation method of 9E)-Acacia acetone, it is characterized in that: the reagent methyl aceto acetate in second step of the present invention can use methyl acetoacetate, butyl-acetoacetate to replace, and mole number is identical.
4. the preparation method of teprenone intermediate (5E, 9E) according to claim 1-Acacia acetone, is characterized in that: the reactant sodium ethylate in the present invention the 3rd step can replace with sodium methylate, and mole number is identical.
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| CN108034283A (en) * | 2017-12-15 | 2018-05-15 | 淮海工学院 | A kind of seven methine cyanine dyes of Pegylation benzindole and its preparation method and application |
| CN112010744A (en) * | 2019-05-29 | 2020-12-01 | 武汉臻智生物科技有限公司 | Farnesyl acetone and preparation method thereof |
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| CN103052619A (en) * | 2010-09-01 | 2013-04-17 | 科约特制药公司 | Methods for treating neurodegenerative diseases |
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