CN105884607A - Preparation method of cyclopropylpropionic acid - Google Patents
Preparation method of cyclopropylpropionic acid Download PDFInfo
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- CN105884607A CN105884607A CN201410185149.1A CN201410185149A CN105884607A CN 105884607 A CN105884607 A CN 105884607A CN 201410185149 A CN201410185149 A CN 201410185149A CN 105884607 A CN105884607 A CN 105884607A
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- cyclopropyl
- ring
- propanoic acid
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Abstract
The invention relates to a synthetic method of cyclopropylpropionic acid. Technical problems of synthesis operation difficulty and expensive raw material are solved. A conventional industrial raw material cyclopropanecarboxaldehyde is used as a starting raw material and triethyl phosphonoacetate undergo a Wittig reaction to obtain 3-cyclopropyl-ethyl acrylate; 3-cyclopropyl-ethyl acrylate and sodium borohydride undergo reduction of double bonds in the presence of Lewis acid to obtain 3-cyclopropyl-ethyl propionate; and 3-cyclopropyl-ethyl propionate is hydrolyzed under an alkaline condition so as to obtain cyclopropylpropionic acid. A chemical equation is as shown in the specification.
Description
Technical field
The present invention relates to the new practicality preparation method of a kind of ring the third propanoic acid.
Background technology
Ring the third propanoic acid is a kind of useful organic synthesis intermediate, CAS:5618-03-1.This compound is frequently used in the response types such as acid amide condensation in the synthesis of storehouse compound.In document, the synthetic method to this compound rarely has report, and has respective limitation, and its synthetic route is as follows:
Route 1 (patent documentation: US 20120122888):
By using the double bond cyclization in the N-nitroso-group-N-methyl urea 4-penetenoic acid with benzyl protection to obtain cyclopropylpropionic acid benzyl ester, eventually pass the de-benzyl of hydrogenation and obtain target product.The intermediate reagent N-nitroso-group-N-methyl urea price that the document uses is extremely expensive, and when adding debenzylation, condition is difficult to control to, part three-membered ring open loop so that reaction yield is low.
Route 2(Photochemical & Photobiological
Sciences (2006), 5(11),
1000-1005):
Chromic acid oxidation hydroxyl is used to obtain.After document reaction, chromium ion is difficult to removing and makes post processing cumbersome.
Route 3(Justus
Liebigs Annalen der Chemie (1972),
759 132-57):
Use grignard reagent to obtain with carbon dioxide reaction, step simply but troublesome poeration and raw material costly.
Summary of the invention
The purpose of the present invention: be to develop a kind of simple, general ring the third propanoic acid synthetic method, mainly solves the technical problems such as expensive raw material price in the synthetic method both known, operation inconvenience.
Technical scheme: the preparation method of a kind of ring the third propanoic acid, comprises the following steps:
Using 3 footworks synthesis, the first step obtains 3-cyclopropyl-ethyl acrylate for initiation material by carrying out dimension reaction of loving and respect one's elder brother in a solvent with phosphonoacetate with regular industrial raw material ring the third formaldehyde；Second step, 3-cyclopropyl-ethyl acrylate and sodium borohydride reduce double bond under lewis acid and solvent existence condition and obtain 3-cyclopropyl-ethyl propionate；Final step reaction 3-cyclopropyl-ethyl propionate obtains ring the third propanoic acid at solvent and hydrolyzed under basic conditions；
The concrete reaction scheme of the present invention is as follows:
In above-mentioned technique, first step reaction solvent for use is oxolane and water, and reaction temperature is 0-30 DEG C；Second step reaction dissolvent is the one in methanol, ethanol or oxolane, and reaction temperature is 0-30 DEG C；Final step reaction dissolvent is the one in oxolane and water mixed liquid, ethanol and water mixed liquid, and reaction temperature is 0-30 DEG C.
Beneficial effects of the present invention: reaction process of the present invention is reasonable in design, which employs ring the third formaldehyde and does raw material, has saved synthesis cost, and route is simple, workable, and can produce on a large scale.
Detailed description of the invention
Embodiment
1
The synthesis of 3-cyclopropyl-ethyl acrylate
24.6 grams of potassium carbonate are joined in 25 milliliters of aqueous solutions.After this reaction system cooling (0 DEG C-10 DEG C); add 19 grams of phosphonoacetate; reaction is stirred 30-70 minute under same temperature (0 DEG C-10 DEG C); being added drop-wise in reaction system by the 25 milliliters of tetrahydrofuran solutions being dissolved with 5 grams of ring third formaldehyde, system is warmed to room temperature (20-30 DEG C) and reacts 16 hours.After reaction terminates, adding 25 milliliters of water in system, product extracts three times by 30 milliliters of ethyl acetate.Merging organic facies, after being dried with anhydrous sodium sulfate, filter, vacuum rotary steam obtains crude product, obtains 39.3 grams of yellow oil, productivity: 80% through column chromatography purification.
1H-NMR (CDCl3): 6.43-6.37 (dd,J=16,8 Hz, 1 H), 5.89-5.85 (d,J=16 Hz, 1 H), 4.18-4.13 (q, 2H), 1.58-1.54
(m, 1H), 1.28-1.24 (t, 2H), 0.94-0.90 (m, 2H), 0.63-0.61 (m, 2H)。
The synthesis of 3-cyclopropyl-ethyl propionate
Being dissolved in 500 milliliters of tetrahydrofuran solutions by 20.5 grams of 3-cyclopropyl-ethyl acrylate, add 35 gram of six water and cobaltous chloride at 0 DEG C, 11.1 grams of sodium borohydrides are dividedly in some parts.System is stirred at room temperature 16 hours.Reaction adds saturated ammonium chloride solution cancellation reaction after terminating, filter out insoluble matter, extract with the tertiary ether of first, and organic layer adds anhydrous sodium sulfate and is dried, and filters, and vacuum rotary steam obtains yellow oil, obtains 15 grams of thick products, productivity: 72%.
1H-NMR (CDCl3): 4.14-4.07 (q, 4 H), 2.38-2.34
(t, 3 H), 1.52-1.46
(m, 2H), 1.24-1.21 (t, 3H), 0.75-0.60 (m, 1H),
0.41-0.37 (m, 2H), 0.04-0.01 (m, 2H)。
Embodiment
2
The synthesis of 3-cyclopropyl-ethyl propionate
Being dissolved in 500 ml methanol solution by 20.5 grams of 3-cyclopropyl-ethyl acrylate, add 35 gram of six water and cobaltous chloride at 0 DEG C, 11.1 grams of sodium borohydrides are dividedly in some parts.System is stirred at room temperature 16 hours.Reaction adds saturated ammonium chloride solution cancellation reaction after terminating, filter out insoluble matter, extract with the tertiary ether of first, and organic layer adds anhydrous sodium sulfate and is dried, and filters, and vacuum rotary steam obtains yellow oil, obtains 15.5 grams of products roughly, productivity: 75%
1H-NMR (CDCl3): 4.14-4.07 (q, 4 H), 2.38-2.34 (t, 3 H), 1.52-1.46 (m, 2H), 1.24-1.21 (t, 3H), 0.75-0.60
(m, 1H), 0.41-0.37 (m, 2H), 0.04-0.01 (m, 2H)。
Embodiment
3
The synthesis of 3-cyclopropyl-ethyl propionate
Being dissolved in 500 milliliters of ethanol solution by 20.5 grams of 3-cyclopropyl-ethyl acrylate, add 35 gram of six water and cobaltous chloride at 0 DEG C, 11.1 grams of sodium borohydrides are dividedly in some parts.System is stirred at room temperature 16 hours.Reaction adds saturated ammonium chloride solution cancellation reaction after terminating, filter out insoluble matter, extract with the tertiary ether of first, and organic layer adds anhydrous sodium sulfate and is dried, and filters, and vacuum rotary steam obtains yellow oil, obtains 15.9 grams of thick products, productivity: 76.9%.
1H-NMR (CDCl3): 4.14-4.07 (q, 4 H), 2.38-2.34 (t, 3 H), 1.52-1.46 (m, 2H), 1.24-1.21 (t, 3H), 0.75-0.60
(m, 1H), 0.41-0.37 (m, 2H), 0.04-0.01 (m, 2H)。
The synthesis of ring the third propanoic acid
16 grams of 3-cyclopropyl-ethyl propionates are dissolved in the mixed solution of 160 milliliters of ethanol and 160 milliliters of water, at 0 DEG C, add a hydronium(ion) lithium oxide 7.0 grams, at the same temperature stirring 3 hours.Reaction adds saturated ammonium chloride solution cancellation reaction after terminating, walk major part impurity with t-butyl methyl ether extraction.Aqueous phase adjusts pH value to 5 with 1 mole hydrochloride aqueous solution, extracts three times by t-butyl methyl ether 100 milliliters, and organic layer adds anhydrous sodium sulfate and is dried, and filters, and vacuum rotary steam obtains yellow oil, obtains 5.9 grams of products, productivity: 46%.
Embodiment
4
16 grams of 3-cyclopropyl-ethyl propionates are dissolved in the mixed solution of 160 milliliters of oxolanes and 160 milliliters of water, at 0 DEG C, add a hydronium(ion) lithium oxide 7.0 grams, at the same temperature stirring 3 hours.Reaction adds saturated ammonium chloride solution cancellation reaction after terminating, walk major part impurity with t-butyl methyl ether extraction.Aqueous phase is gathered around 1 mole hydrochloride aqueous solution and is adjusted pH value to 5, extracts three times by t-butyl methyl ether 100 milliliters, and organic layer adds anhydrous sodium sulfate and is dried, and filters, and vacuum rotary steam obtains yellow oil, obtains 6.4 grams of products, productivity: 50%.
1H-NMR (CDCl3): 2.42-2.38 (t, 2 H), 1.52-1.46 (m, 2 H),
0.73-0.69 (m, 1H), 0.42-0.37 (m, 2H), 0.04-0.00 (m, 2H)。
Claims (4)
1. ring the third propanoic acid a preparation method, it is characterized in that comprising the following steps:
The first step obtains 3-cyclopropyl-ethyl acrylate for initiation material by carrying out dimension reaction of loving and respect one's elder brother in a solvent with phosphonoacetate with regular industrial raw material ring the third formaldehyde；
Second step, 3-cyclopropyl-ethyl acrylate and sodium borohydride reduce double bond under lewis acid and solvent existence condition and obtain 3-cyclopropyl-ethyl propionate；
3rd step 3-cyclopropyl-ethyl propionate hydrolyzes in the basic conditions and obtains ring the third propanoic acid.
The synthetic method of ring the third propanoic acid the most according to claim 1, is characterized in that: first step reaction temperature 0-30 DEG C, solvent is oxolane and water.
The synthetic method of ring the third propanoic acid the most according to claim 1, is characterized in that: second step reaction temperature 0-30 DEG C, solvent is the one in methanol, oxolane, ethanol.
The synthetic method of ring the third propanoic acid the most according to claim 1, is characterized in that: three-step reaction temperature 0-30 DEG C, and solvent is the one in oxolane and water mixed liquid, ethanol and water mixed liquid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410185149.1A CN105884607A (en) | 2014-05-05 | 2014-05-05 | Preparation method of cyclopropylpropionic acid |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410185149.1A CN105884607A (en) | 2014-05-05 | 2014-05-05 | Preparation method of cyclopropylpropionic acid |
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| CN105884607A true CN105884607A (en) | 2016-08-24 |
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| CN201410185149.1A Pending CN105884607A (en) | 2014-05-05 | 2014-05-05 | Preparation method of cyclopropylpropionic acid |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4093622A (en) * | 1975-05-19 | 1978-06-06 | Zoecon Corporation | Pyridine esters of cyclopropane-carboxylic acid |
| WO1999015524A1 (en) * | 1997-09-23 | 1999-04-01 | Fujisawa Pharmaceutical Co., Ltd. | Thiazole derivatives |
| US20120122888A1 (en) * | 2010-11-16 | 2012-05-17 | Abbott Laboratories | Potassium Channel Modulators |
-
2014
- 2014-05-05 CN CN201410185149.1A patent/CN105884607A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4093622A (en) * | 1975-05-19 | 1978-06-06 | Zoecon Corporation | Pyridine esters of cyclopropane-carboxylic acid |
| WO1999015524A1 (en) * | 1997-09-23 | 1999-04-01 | Fujisawa Pharmaceutical Co., Ltd. | Thiazole derivatives |
| US20120122888A1 (en) * | 2010-11-16 | 2012-05-17 | Abbott Laboratories | Potassium Channel Modulators |
Non-Patent Citations (2)
| Title |
|---|
| MINUTH, TOBIAS和BOYSEN, MIKE M. K.: "Carbohydrate-derived bis(oxazoline) ligand in the total synthesis of grenadamide", 《SYNTHESIS》 * |
| PRADEEP KUMAR等: "Enantio- and diastereocontrolled conversion of chiral epoxides to trans-cyclopropane carboxylates: application to the synthesis of cascarillic acid, grenadamide and L-(−)-CCG-II", 《ORG. BIOMOL. CHEM.》 * |
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Effective date of registration: 20170405 Address after: Jinshan District of Shanghai chemical industrial zone of Shanghai city Jinshan District 201507 (West) Yuegong Road No. 9 Applicant after: Shanghai SynTheAll Pharmaceutical Co., Ltd. Applicant after: CHANGZHOU HEQUAN PHARMACEUTICAL CO., LTD. Applicant after: Shanghai STA Pharmaceutical R & D Co., Ltd. Applicant after: Changzhou whole new drug research and Development Co., Ltd. Address before: Jinshan District of Shanghai chemical industrial zone of Shanghai city Jinshan District 201507 (West) Yuegong Road No. 9 Applicant before: Shanghai SynTheAll Pharmaceutical Co., Ltd. Applicant before: CHANGZHOU HEQUAN PHARMACEUTICAL CO., LTD. Applicant before: Shanghai STA Pharmaceutical R & D Co., Ltd. |
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Application publication date: 20160824 |