CN101774906A - Preparation method of 3,5-dioxo-4-propyl phthalidyl cyclohexane calcium amino acid - Google Patents
Preparation method of 3,5-dioxo-4-propyl phthalidyl cyclohexane calcium amino acid Download PDFInfo
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- CN101774906A CN101774906A CN201010107681A CN201010107681A CN101774906A CN 101774906 A CN101774906 A CN 101774906A CN 201010107681 A CN201010107681 A CN 201010107681A CN 201010107681 A CN201010107681 A CN 201010107681A CN 101774906 A CN101774906 A CN 101774906A
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Abstract
The invention discloses a method for preparing 3,5-dioxo-4-propyl phthalidyl cyclohexane calcium amino acid, which comprises the following steps of: (1) carrying out hydrogenation reaction on 3,5-dihydroxy-benzoic acid methyl ester to obtain 5-methyl formate-1,3-cyclohexanedione; (2) converting the 5-methyl formate-1,3-cyclohexanedione into 3-methoxycarbonyl-5-oxocyclohexyl-1-alkene-1-acrylic ester in the presence of toluene, triethylamine and propionyl chloride; (3) converting the 3-methoxycarbonyl-5-oxocyclohexyl-1-alkene-1-acrylic ester into the 3,5-dihydroxy-benzoic acid methyl ester; (4) adding NaOH and the water into a product in the step (3), stirring the NaOH and the water, regulating the pH value of a reaction liquid to be less than 7, extracting and recrystallizing to obtain prohexadione; and (5) adding the prohexadione into sodium hydroxide water solution, and dipping calcium chloride to obtain the propyl phthalidyl cyclohexane calcium amino acid. The method shortens the synthesis routine, improves the yield rate and realizes industrialized mass production.
Description
Technical field
The present invention relates to a kind of method of plant growth retardent, relate in particular to the preparation method who transfers naphthenic acid (3,5 one dioxo, one 4 one propyl phthalidyl cyclohexane calcium amino acids), belong to the preparation field of transferring naphthenic acid.
Background technology
Transfer naphthenic acid (3,5 one dioxo, one 4 one propyl phthalidyl cyclohexane calcium amino acids, Prohexadione one caeium) at first synthetic in nineteen eighty-three by Japanese combinatorial chemistry industrial, be mainly used in the prosperous length of control cereal crop (as wheat, barley, paddy rice and peanut, flowers, lawn etc.).Transfer naphthenic acid to belong to the Plant hormones regulators,gibberellins biosynthesis inhibitor, its mechanism of action is by reducing the content of Plant hormones regulators,gibberellins, the prosperous length of control crop.
Compare with three class delayers of present widespread use, transfer naphthenic acid to crop rotation plant non-residual toxicity, environmentally safe probably replaces three class growth retardants, therefore has tempting application prospect.
In the existing synthetic method, transfer synthetic its important intermediate 5-ethyl formate-hydroresorcinol synthetic difference that mainly is of naphthenic acid.One of existing synthetic method is: with 1, resterification obtains transferring naphthenic acid (synthetic route is seen Fig. 1) behind the 3-resorcylic acid hydrogenation, and its yield has only about 65%, and is on the low side relatively.Two of existing method is: with, 3,4,5 one trimethoxybenzoic acids are raw material, and reduction obtains 1,4 one diene 1 under the liquid ammonia solution effect of sodium, 5 one dimethoxybenzoic acids promptly get 3,5 one cyclohexanediones, one 1 one ethyl formates (synthetic route is seen Fig. 2) with its acetify.Because the reaction conditions of sodium amide requires very harsh, this method has can not carry out the limitation that large-scale industrialization is produced.
Three of existing method is: ethyl maleate and acetone 1.0Mpa are generated the acetonyl ethyl maleate down, and condensation in the presence of sodium alkoxide (synthetic route is seen Fig. 3) again, there is the not high defective of whole yield in this method.
Up to now, lack that a kind of synthetic method is simple and direct, productive rate is high, but the preparation method of the accent naphthenic acid that large-scale industrialization is produced.
Summary of the invention
Technical problem to be solved by this invention is to overcome the deficiencies in the prior art, provides that a kind of synthetic method is simple and direct, productive rate is high, but the preparation method of the accent naphthenic acid that large-scale industrialization is produced.
Technical problem to be solved by this invention is achieved through the following technical solutions:
The preparation method of 3,5 one dioxo, one 4 one propyl phthalidyl cyclohexane calcium amino acids comprises:
(1) with 3, the 5-methyl dihydroxy benzoate carries out hydrogenation reaction, obtains 5-methyl-formiate-hydroresorcinol;
(2) in the presence of toluene, triethylamine and propionyl chloride, change 5-methyl-formiate-hydroresorcinol into 3-methoxycarbonyl-5-oxygen hexamethylene-1-alkene-1-acid allyl ester;
(3) in the presence of DMAP, change 3-methoxycarbonyl-5-oxygen hexamethylene-1-alkene-1-acid allyl ester into 3,5-dioxo-4-propionyl hexahydrobenzoic acid methyl esters;
(4) to 3, add NaOH and water in 5-dioxo-4-propionyl hexahydrobenzoic acid methyl esters, stir, the pH value of transferring reaction solution is to acid, extraction, recrystallization obtains 3,5 one dioxo 1, the 4 one the third phthalidyl hexanaphthenes by sour (accent naphthenic acid);
(5) 3,5 one dioxo 1, the 4 one the third phthalidyl hexanaphthenes are dissolved in the aqueous sodium hydroxide solution by acid, drip calcium chloride, filter, washing, promptly.
In order to reach better effect, hydrogenation reaction described in the step (1) comprises: add 3 in the hydrogenation still, the 5-methyl dihydroxy benzoate, aqueous sodium hydroxide solution and water join in the autoclave pressure, add catalyzer, and ftercompction is to 2-3Mp behind the hydrogen exchange 3 times, react constant to pressure, take out reaction solution, be adjusted to the pH value to 1-3, filter with dilute hydrochloric acid.
Preferably, in the step (2), react after 5-methyl-formiate-hydroresorcinol, toluene and de-acidying agent stirred, cool to below 10 ℃, slowly drip propionyl chloride, add, 10-20 ℃ is stirred 2-15h, after the TLC monitoring fully; Filter, filtrate is used dilute hydrochloric acid successively, saturated sodium carbonate solution and water washing, and drying is filtered, and obtains containing the toluene phase of 3-methoxycarbonyl-5-oxygen hexamethylene-1-alkene-1-acid allyl ester; Wherein, described toluene can be used benzene, chloroform or 1, and 2-ethylene dichloride ring replaces; Described temperature of reaction is 40-110 ℃;
Described de-acidying agent is an organic-inorganic alkali, for example, is selected from pyridine, triethylamine, yellow soda ash, potassium primary phosphate organic-inorganic alkali such as (sodium); In addition, the aqueous solution of also available mineral alkali yellow soda ash and organic toluene are about 80 ℃, and the product of two phase reaction gained is as de-acidying agent;
Preferably, in the step (3), will contain the middle mutually DMAP of adding of toluene of 3-methoxycarbonyl-5-oxygen hexamethylene-1-alkene-1-acid allyl ester, 80 ℃ of reactions, wash with dilute hydrochloric acid, the saturated common salt water washing, separatory is behind the anhydrous magnesium sulfate drying, activated carbon decolorizing, reclaim under reduced pressure toluene obtains 3 again, 5-dioxo-4-propionyl hexahydrobenzoic acid methyl esters;
Preferably, with 3,5-dioxo-4-propionyl hexahydrobenzoic acid ethyl ester, NaOH and water stir in the step (4), and adjust pH arrives acid, ethyl acetate extraction, and recrystallization, promptly;
The inventive method is by 3, and the direct hydrogenation of 5-methyl dihydroxy benzoate has directly been obtained transferring the also important intermediate-5-ethyl formate-hydroresorcinol of acid.Synthetic route that the inventive method is brief has improved yield, can realize the industrialized production of mass-producing.
Description of drawings
The preparation method's of existing 3,5 one dioxo of Fig. 1 one 4 one propyl phthalidyl cyclohexane calcium amino acids synthetic route chart.
Existing 3,5 one dioxo of Fig. 2 one 4 one propyl phthalidyl cyclohexane calcium amino acid preparation methods' synthetic route chart.
The preparation method's of existing 3,5 one dioxo of Fig. 3 one 4 one propyl phthalidyl cyclohexane calcium amino acids synthetic route chart.
Fig. 4 the present invention 3,5 one dioxo one 4 one propyl phthalidyl cyclohexane calcium amino acid preparation methods' synthetic route chart.
Embodiment
Further describe the present invention below in conjunction with specific embodiment, advantage of the present invention and characteristics will be more clear along with description.But these embodiment only are exemplary, scope of the present invention are not constituted any restriction.It will be understood by those skilled in the art that and down can make amendment or replace without departing from the spirit and scope of the present invention, but these modifications and replacing all fall within the scope of protection of the present invention the details of technical solution of the present invention and form.
Embodiment 1
1,5-methyl-formiate-hydroresorcinol is synthetic
Add 3 in the hydrogenation still, 5-methyl dihydroxy benzoate 84.0g, 30% aqueous sodium hydroxide solution 67g, water 200ml joins in the autoclave pressure, add catalyzer (Ni/Al) 8g, ftercompction reacts constant to pressure to 2-3Mp behind the hydrogen exchange 3 times, takes out reaction solution, the hydrochloric acid 55g of 36%-38% is adjusted to the pH value to 1-3, filter solid, dry 80g 5-methyl-formiate-hydroresorcinol.
2,3-methoxycarbonyl-5-oxygen hexamethylene-1-alkene-1-acid allyl ester
5-methyl-formiate-hydroresorcinol 36g, toluene 120g, triethylamine 22g, react under 40-110 ℃ temperature the back that stirs, and cools to below 10 ℃, slowly drips propionyl chloride 22.0g, adds, and 10-20 ℃ is stirred 10h, after the TLC monitoring fully.Filter brown solution, add 1N HCl 50ml, wash 2 times, again with saturated sodium carbonate solution 50ml washing, water 50ml washing, behind the anhydrous magnesium sulfate drying, filter toluene liquid (directly as the next step);
3,3, the preparation of 5-dioxo-4-propionyl hexahydrobenzoic acid methyl esters
The toluene in last step mutually in, add DMAP (4-Dimethylamino pyridine) 2.4g, 80 ℃ of reaction 6h, 1NHCl 50ml washs 2 times, saturated aqueous common salt 50ml washing, separatory, behind the anhydrous magnesium sulfate drying, activated carbon decolorizing, reclaim under reduced pressure toluene obtains scarlet thick liquid 34g (directly as the next step) again.
4, transfer the preparation of naphthenic acid
3,5-dioxo-4-propionyl hexahydrobenzoic acid ethyl ester 34g, 30%NaOH 6.7g, water 25ml, 25 ℃ are stirred the 24h. hcl acidifying to the pH=1. ethyl acetate extraction, and the chloroform recrystallization gets crystal 2 0g (HPLC purity is greater than 90%).
1HNMR(CDCl3)：1.14(t，3H)，2.682.96(m，4H)，3.07(q，2H)，3.12(m，1H)
5, the preparation of 3,5 one dioxo, one 4 one propyl phthalidyl cyclohexane calcium amino acids (Prohexadione calcium)
3,5-dioxo-4-propionyl hexahydrobenzoic acid 4.2g, water 10ml adds 30%NaOH 5.3g.After the stirring and dissolving, be added dropwise to calcium chloride water (calcium chloride 2.2g and water 10mi), get Off-white solid, the dry solid 4.3g (HPLC＞98%, whole process recovery ratio about 30%) that gets of suction filtration.IR(cm
-1)：2890，1645，1560，1380。
Claims (10)
1. method for preparing 3,5 one dioxo, one 4 one propyl phthalidyl cyclohexane calcium amino acids comprises:
(1) with 3, the 5-methyl dihydroxy benzoate carries out hydrogenation reaction, obtains 5-methyl-formiate-hydroresorcinol;
(2) in the presence of toluene, triethylamine and propionyl chloride, change 5-methyl-formiate-hydroresorcinol into 3-methoxycarbonyl-5-oxygen hexamethylene-1-alkene-1-acid allyl ester;
(3) in the presence of DMAP, change 3-methoxycarbonyl-5-oxygen hexamethylene-1-alkene-1-acid allyl ester into 3,5-dioxo-4-propionyl hexahydrobenzoic acid methyl esters;
(4) to 3, add NaOH and water in 5-dioxo-4-propionyl hexahydrobenzoic acid methyl esters, stir, the pH value of transferring reaction solution is to acid, extraction, recrystallization obtains 3,5 one dioxo 1, the 4 one the third phthalidyl hexanaphthenes by sour;
(5) 3,5 one dioxo 1, the 4 one the third phthalidyl hexanaphthenes are dissolved in the aqueous sodium hydroxide solution by acid, drip calcium chloride, filter, washing, promptly.
2. in accordance with the method for claim 1, it is characterized in that, hydrogenation reaction described in the step (1) comprises: in the hydrogenation still, add 3, and the 5-methyl dihydroxy benzoate, aqueous sodium hydroxide solution and water join in the autoclave pressure, add catalyzer, ftercompction reacts constant to pressure to 2-3Mp behind the hydrogen exchange 3 times, takes out reaction solution, be adjusted to the pH value to 1-3 with dilute hydrochloric acid, filter.
3. in accordance with the method for claim 1, it is characterized in that, in the step (2), 5-methyl-formiate-1, react after hydroresorcinol, toluene and de-acidying agent stir, cool to below 10 ℃, slowly drip propionyl chloride, add, 10-20 ℃ is stirred 2-15h, after the TLC monitoring fully; Filter, filtrate is used dilute hydrochloric acid successively, saturated sodium carbonate solution and water washing, and drying is filtered, and obtains containing the toluene phase of 3-methoxycarbonyl-5-oxygen hexamethylene-1-alkene-1-acid allyl ester.
4. in accordance with the method for claim 3, it is characterized in that described toluene replaces with benzene, chloroform or 1,2-ethylene dichloride ring.
5. in accordance with the method for claim 3, it is characterized in that described temperature of reaction is 40-110 ℃.
6. in accordance with the method for claim 3, it is characterized in that described de-acidying agent is an organic-inorganic alkali.
7. in accordance with the method for claim 6, it is characterized in that described organic-inorganic alkali is selected from pyridine, triethylamine, yellow soda ash, potassium primary phosphate or SODIUM PHOSPHATE, MONOBASIC.
8. in accordance with the method for claim 3, it is characterized in that described organic-inorganic alkali prepares in accordance with the following methods: the aqueous solution of mineral alkali yellow soda ash and organic toluene are about 80 ℃, and the product of two phase reaction gained is as de-acidying agent.
9. in accordance with the method for claim 1, it is characterized in that, the middle mutually DMAP of adding of toluene that will contain 3-methoxycarbonyl-5-oxygen hexamethylene-1-alkene-1-acid allyl ester in the step (3), 80 ℃ of reactions are with dilute hydrochloric acid washing, saturated common salt water washing, separatory, behind the anhydrous magnesium sulfate drying, activated carbon decolorizing, reclaim under reduced pressure toluene again.
10. in accordance with the method for claim 1, it is characterized in that with 3,5-dioxo-4-propionyl hexahydrobenzoic acid ethyl ester, NaOH and water stir in the step (4), adjust pH arrives acid, ethyl acetate extraction, and recrystallization obtains transferring naphthenic acid.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104140368A (en) * | 2014-07-30 | 2014-11-12 | 江西农业大学 | Method for preparing calcium3-oxido-5-oxo-4-propionyl cyclohex-3-enecarboxylate |
| CN106957226A (en) * | 2017-03-22 | 2017-07-18 | 浙江工业大学 | A kind of preparation method of Prohexadione calcium |
| CN109680016A (en) * | 2018-10-29 | 2019-04-26 | 台州市大鹏药业有限公司 | A kind of preparation method of Prohexadione calcium |
| WO2022097115A1 (en) * | 2020-11-09 | 2022-05-12 | Hikal Limited | An improved process for preparation of prohexadione and its calcium salt |
| CN114805067A (en) * | 2022-05-19 | 2022-07-29 | 浙江科技学院 | Preparation method of prohexadione calcium intermediate |
Citations (1)
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| CN101130493A (en) * | 2007-09-06 | 2008-02-27 | 华东理工大学 | Improved method for producing prohexadione |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101130493A (en) * | 2007-09-06 | 2008-02-27 | 华东理工大学 | Improved method for producing prohexadione |
Non-Patent Citations (2)
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| 叶向阳等: "调环酸及其类似物的合成", 《农药》 * |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104140368A (en) * | 2014-07-30 | 2014-11-12 | 江西农业大学 | Method for preparing calcium3-oxido-5-oxo-4-propionyl cyclohex-3-enecarboxylate |
| CN104140368B (en) * | 2014-07-30 | 2016-05-25 | 江西农业大学 | A kind of preparation method of 3,5-dioxo-4-propiono cyclohexane-carboxylic acid calcium |
| CN106957226A (en) * | 2017-03-22 | 2017-07-18 | 浙江工业大学 | A kind of preparation method of Prohexadione calcium |
| CN109680016A (en) * | 2018-10-29 | 2019-04-26 | 台州市大鹏药业有限公司 | A kind of preparation method of Prohexadione calcium |
| WO2022097115A1 (en) * | 2020-11-09 | 2022-05-12 | Hikal Limited | An improved process for preparation of prohexadione and its calcium salt |
| CN114805067A (en) * | 2022-05-19 | 2022-07-29 | 浙江科技学院 | Preparation method of prohexadione calcium intermediate |
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Application publication date: 20100714 |