CN102241590B - Synthetic method of spirocyclic tetronic acid compound key intermediate - Google Patents
Synthetic method of spirocyclic tetronic acid compound key intermediate Download PDFInfo
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Abstract
The invention discloses a synthetic method of a spirocyclic tetronic acid compound key intermediate. The method comprises the following steps of: mixing a substituted phenylacetic acid compound (I) with a compound (II); heating the mixture to 50-150 DEG C; adding a carboxylic acid activation reagent; preserving heat at the temperature 50-150 DEG C and reacting fully; and performing post-treatment to obtain a spirocyclic tetronic acid compound key intermediate compound (III). The invention has the advantages that: (1) an acylation reaction is completed at one step in the preparation method, the reaction time is short, the raw material utilization ratio is high, and the energy consumption and the environmental pressure are lowered; (2) in the preparation method, the costs of raw materials are low, and an acid-binding agent or a catalyst is not invested additionally; and (3) the preparation method has a simple process, a small quantity of side reactions and high yield, and is suitable for large-scale industrial production.
Description
Technical field
The present invention relates to the fine chemical technology field, specifically relate to a kind of synthetic method of spirocyclic tetronic acid compound key intermediate.
Background technology
As everyone knows, volution compound all occupies important position with its unique structure and character in medicine and agricultural chemicals.Two plane of a loops of spirocyclic compound are mutually vertical, and under certain condition, the existence of chiral axis can consist of unsymmetric molecule or chiral molecular.For heterocyclic ring spiroring compounds, owing to mostly containing the heteroatomss such as the stronger oxygen of electronegativity, sulphur, nitrogen, Intermolecular Forces is larger, make it also may have the special property that the general organic compound such as spiral shell conjugation, spiral shell hyperconjugation or different effect does not possess, thereby become good medicine and agricultural chemicals lead compound precursor.In recent years, the scientific worker has more and more paid attention to the research in this field both at home and abroad, has synthesized novel structure, mechanism of action is unique, the compound that contains the volution skeleton, and therefrom filtered out a collection of compound with medicinal effect, the most representative is exactly the spirocyclic tetronic acid compounds.For example american documentation literature US 5262383 discloses the activity of the pest control of spirocyclic tetronic acid compounds, Chinese patent literature CN101235023 discloses this compounds new synthesis route, Chinese patent literature CN 1174676 and Chinese patent literature CN 1692099 disclose the defending insect and killing activity of the further derivative of spirocyclic tetronic acid, and Chinese patent literature CN 101511354 discloses the HIV (human immunodeficiency virus)-resistant activity of spirocyclic tetronic acid compounds.These disclosed patent documentations all utilize 1-(2-phenylacetyl oxygen (amine) base) cycloalkyl formic ether compounds to come synthesizing spiro tetronic acid compounds as key intermediate by the intramolecular condensation under alkaline condition, and the method for synthetic 1-(2-phenylacetyl oxygen (amine) base) cycloalkyl formic ether compounds is all first substituted phenylacetic acid to be made the substituted benzene Acetyl Chloride 98Min., and then reacts with 1-hydroxyl (amine) basic ring alkyl formate ester compound.Problem wherein is: 1. need in the process of preparation acyl chlorides substituted phenylacetic acid and chloride reagent are carried out redistillation after long-time back flow reaction, energy consumption is higher, and the chloride reagent need are excessive, can become more dangerous waste material after applying mechanically certain number of times.2. need to use acid binding agent such as triethylamine in acylation process, can produce a large amount of waste water, improved Environmental costs, or use more expensive catalyzer such as DMAP etc., improved material cost, all be unfavorable for suitability for industrialized production.3. the total recovery of two-step reaction is not high, is unfavorable for suitability for industrialized production yet.Therefore, need a kind of more perfect direct ester (acyl) change method of exploitation, to address the above problem.
Summary of the invention
The invention provides a kind of cost lower, the green synthesis method of the spirocyclic tetronic acid compound key intermediate that environment is more friendly.
A kind of synthetic method of spirocyclic tetronic acid compound key intermediate, comprise: substituted phenylacetic acid compound (I) and compound (II) are mixed, be heated to 50-150 ℃, add the carboxylic acid activating reagent, then complete 50-150 ℃ of insulation reaction, aftertreatment obtains spiral ring tetronic acid compounds key intermediate compound (III);
Wherein, described substituted phenylacetic acid compound (I) structure is shown below:
In following formula, X is halogen, alkyl, haloalkyl, alkoxyl group, halogenated alkoxy or cyano group; W, Y and Z are independently hydrogen, halogen, alkyl, haloalkyl, alkoxyl group, halogenated alkoxy or cyano group respectively;
The structure of described compound (II) is shown below:
In following formula, D is oxygen, sulphur or NH; R
1For cyano group or-COOR ', wherein R ' is selected from C
1-C
4The straight or branched alkyl; R
2Be hydrogen, alkyl or alkoxyl group; N=1 or 2;
The structure of described spiral ring tetronic acid compounds key intermediate compound (III) is shown below:
In following formula, X is halogen, alkyl, haloalkyl, alkoxyl group, halogenated alkoxy or cyano group; W, Y and Z are independently hydrogen, halogen, alkyl, haloalkyl, alkoxyl group, halogenated alkoxy or cyano group respectively; D is oxygen, sulphur or NH; R
1For cyano group or-COOR ', wherein R ' is selected from C
1-C
4The straight or branched alkyl; R
2Be hydrogen, alkyl or alkoxyl group; N=1 or 2;
Reaction process is:
In formula (I), in preferred compound, X is chlorine, C
1-C
4Alkyl, C
1-C
4Haloalkyl, C
1-C
4Alkoxyl group, C
1-C
4Halogenated alkoxy or cyano group; W, Y and Z are independently hydrogen, chlorine, C respectively
1-C
4Alkyl, C
1-C
4Haloalkyl, C
1-C
4Alkoxyl group, C
1-C
4Halogenated alkoxy or cyano group; In further preferred compound, X is chlorine, methyl, trifluoromethyl, methoxyl group or cyano group; W, Y and Z are independently hydrogen, chlorine atom, methyl, trifluoromethyl, methoxyl group, oxyethyl group or cyano group respectively;
In preferred technical scheme, described substituted phenylacetic acid compound (I) is 1 with the mol ratio of compound (II): 1-1: 10, and further preferred mol ratio is 1: 1-1: 3; Described substituted phenylacetic acid compound (I) is 1 with the mol ratio of carboxylic acid activating reagent: 1-1: 10, and further preferred mol ratio is 1: 1-1: 3; Described carboxylic acid activating reagent is selected from thionyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, phosphorus tribromide, phosphorus pentabromide, tribromo oxygen phosphorus, and preferred carboxylic acid activating reagent is phosphorus oxychloride, thionyl chloride; The described reaction times is 10-120min.
Described substituted phenylacetic acid compound (I) and compound (II) all can be selected the commercially available prod.R in spirocyclic tetronic acid compound key intermediate compound (III)
1During for ester group, when namely compound (III) is 1-(2-phenylacetyl oxygen (amine) base) cycloalkyl carbamate derivatives, can be directly according to normal condition for the preparation of the spirocyclic tetronic acid compounds; If R
1During for cyano group, can make corresponding 1-(2-phenylacetyl oxygen (amine) base) cycloalkyl carbamate derivatives through simple alcoholysis reaction, step of converting is simple.
Beneficial effect of the present invention is embodied in:
(1) in this preparation method, one step of acylation reaction completes, and not with an organic solvent, the reaction times is short, and utilization rate of raw materials is high, has reduced energy consumption and environmental stress.
(2) this preparation method material cost is lower, there is no the extra input of acid binding agent or catalyzer.
(3) this preparation method technique is simple, and side reaction is few, and yield is high, is fit to large-scale industrial production.
Embodiment
Proportioning according to table 1, substituted phenylacetic acid compound (I) and compound (II) are added in reactor, be heated to temperature of reaction, add the carboxylic acid activating reagent in reactor, insulation reaction is chilled to room temperature after the corresponding time subsequently, then add water washing, obtain corresponding spiral ring tetronic acid compounds key intermediate compound (III) after drying.By the reaction result of table 1 as can be known, prepare spiral ring tetronic acid compounds key intermediate compound (III) by method of the present invention and be, productive rate is higher, and content is high, and whole process saved the use of organic solvent, environmental friendliness, and cost is low.
Claims (7)
1. the synthetic method of a spirocyclic tetronic acid compound key intermediate, comprise: substituted phenylacetic acid compound (I) and compound (II) are mixed, be heated to 50-150 ℃, add the carboxylic acid activating reagent, then complete 50-150 ℃ of insulation reaction, aftertreatment obtains spiral ring tetronic acid compounds key intermediate compound (III);
Described substituted phenylacetic acid compound (I) structure is shown below:
The structure of described compound (II) is shown below:
The structure of described spiral ring tetronic acid compounds key intermediate compound (III) is shown below:
In following formula, X is chlorine, methyl, trifluoromethyl, methoxyl group or cyano group; W, Y and Z are independently hydrogen, chlorine atom, methyl, trifluoromethyl, methoxyl group, oxyethyl group or cyano group respectively; D is oxygen, sulphur or NH; R
1For cyano group or-COOR ', wherein R ' is selected from C
1-C
4The straight or branched alkyl; R
2Be hydrogen, methyl or methoxy; N=1 or 2.
2. the synthetic method of spirocyclic tetronic acid compound key intermediate according to claim 1, is characterized in that, described substituted phenylacetic acid compound (I) is 1 with the mol ratio of compound (II): 1-1: 10.
3. the synthetic method of spirocyclic tetronic acid compound key intermediate according to claim 2, is characterized in that, described mol ratio is 1: 1-1: 3.
4. the synthetic method of spirocyclic tetronic acid compound key intermediate according to claim 1, is characterized in that, described substituted phenylacetic acid compound (I) is 1 with the mol ratio of carboxylic acid activating reagent: 1-1: 10.
5. the synthetic method of spirocyclic tetronic acid compound key intermediate according to claim 4, is characterized in that, described mol ratio is 1: 1-1: 3.
6. the synthetic method of spirocyclic tetronic acid compound key intermediate according to claim 1, it is characterized in that, described carboxylic acid activating reagent is selected from thionyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, phosphorus tribromide, phosphorus pentabromide, tribromo oxygen phosphorus.
7. the synthetic method of spirocyclic tetronic acid compound key intermediate according to claim 1, is characterized in that, the described reaction times is 10-120min.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1240206A (en) * | 1999-06-17 | 2000-01-05 | 华东理工大学 | Process for preparing 1[2-(dimethyamino)-1-(4-methoxyphenyl)ethyl] cyclohexanol hydrochloridumi |
| WO2006089633A3 (en) * | 2005-02-22 | 2006-11-23 | Bayer Cropscience Ag | Spiroketal-substituted cyclic ketoenols |
| CN101235023A (en) * | 2008-03-04 | 2008-08-06 | 浙江大学 | Method for synthesizing spirodiclofen |
| CN101316585A (en) * | 2005-09-23 | 2008-12-03 | 麦它波莱克斯股份有限公司 | Process for the stereoselective preparation of (-)-halofenate and intermediates thereof |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1240206A (en) * | 1999-06-17 | 2000-01-05 | 华东理工大学 | Process for preparing 1[2-(dimethyamino)-1-(4-methoxyphenyl)ethyl] cyclohexanol hydrochloridumi |
| WO2006089633A3 (en) * | 2005-02-22 | 2006-11-23 | Bayer Cropscience Ag | Spiroketal-substituted cyclic ketoenols |
| CN101316585A (en) * | 2005-09-23 | 2008-12-03 | 麦它波莱克斯股份有限公司 | Process for the stereoselective preparation of (-)-halofenate and intermediates thereof |
| CN101235023A (en) * | 2008-03-04 | 2008-08-06 | 浙江大学 | Method for synthesizing spirodiclofen |
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