CN107365262B - A kind of preparation method of 5,5- dimethyl -2- cyano cyclopentanone - Google Patents

A kind of preparation method of 5,5- dimethyl -2- cyano cyclopentanone Download PDF

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CN107365262B
CN107365262B CN201610308539.2A CN201610308539A CN107365262B CN 107365262 B CN107365262 B CN 107365262B CN 201610308539 A CN201610308539 A CN 201610308539A CN 107365262 B CN107365262 B CN 107365262B
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cyclopentanone
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CN107365262A (en
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沈新良
吴华龙
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Zhejiang Yulong Pharmaceutical Co ltd
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HANGZHOU UDRAGON CHEMICAL CO Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
    • C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles

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Abstract

The present invention relates to one kind 5, the preparation method of 5- dimethyl -2- cyano cyclopentanone and related intermediate 2, the preparation method of 2- dimethyl -5- (4- chlorobenzyl) cyclopentanone and its they fungicide metconazole synthesis in application, it is by isobutyrate, 1,3- dihalopropane, cyanidization agent, p-chlorobenzylchloride etc. are primary raw material, by obtained by multistep reaction preparative separation, there is process implementing convenience, high income, prospects for commercial application with higher compared with traditional handicraft.

Description

A kind of preparation method of 5,5- dimethyl -2- cyano cyclopentanone
[technical field]
The invention belongs to preparation technique of pesticide fields.More particularly it relates to one kind 2,2- dimethyl -5- (4- chlorine Benzyl) preparation method of cyclopentanone and the preparation method of related intermediate 5,5- dimethyl -2- cyano cyclopentanone, further relate to them Application in the synthesis of fungicide metconazole.
[background technique]
Metconazole, english common name: metconazole is by the development of Japanese Wu Yu chemical industrial company, and and the U.S. Cyanamide (is now the triazole bactericidal agent of the novel wide spectrum of BASF) company joint development, there are many synthesis report in relation to metconazole. 2,2- dimethyl -5- (4- chlorobenzyl) cyclopentanone is the important intermediate for synthesizing metconazole, US7166750B1, denomination of invention “process for the preparation of5-[(4-chlorophenyl)methyl]-2,2- Dimethylcyclopentanone " is related to a kind of preparation method of 2,2- dimethyl -5- (4- chlorobenzyl) cyclopentanone, technique Route is as follows:
The shortcomings that technology is process requirement by methylation reaction twice, is methylated at high cost.US6344580B1, hair Bright title " process for the preparation of2,2-dimethyl-5- (4-chlorobenzyl) Cyclopentanone and an intermediate useful therefore " is related to 2,2- dimethyl -5- (4- benzyl chloride Base) cyclopentanone another preparation method, process route is as follows:
The disadvantage is that step 3 Dieckmann Michael Diekmann condensation reaction, a cyano in two of them cyano need by plus It is finally translated into 5, the 5- dimethyl -2- cyano cyclopentanone of needs at, hydrolysis, causes yield lower, does not industrialize meaning Justice.In order to overcome disadvantage mentioned above, the present invention provide a kind of high-content, high yield 5,5- dimethyl -2- cyano cyclopentanone system Preparation Method, process implementing is convenient, has industrial applications prospect, gained correlation intermediate 2,2- dimethyl -5- (4- chlorobenzyl) Cyclopentanone is not purified to may be directly applied to being synthetically prepared for fungicide metconazole.
[summary of the invention]
[technical problems to be solved]
The object of the present invention is to provide a kind of preparation methods of 5,5- dimethyl -2- cyano cyclopentanone.
It is a further object to provide a kind of preparation methods of 2,2- dimethyl -5- (4- chlorobenzyl) cyclopentanone.
[technical solution]
The present invention is achieved through the following technical solutions.
The present invention relates to a kind of preparation methods of 5,5- dimethyl -2- cyano cyclopentanone.
The step of this method, is as follows:
In the presence of solvent and alkali, cyano -2 formula (IV) compound 5-, it is anti-that 2 methyl valeric acid ester carries out Michael Diekmann condensation It answers, obtains formula (V) compound 5,5- dimethyl -2- cyano cyclopentanone；Its reaction equation is as follows:
In formula (IV):
R is C1-C16Alkyl substituent.
A preferred embodiment of the invention, in formula (IV) R be selected from methyl, ethyl, n-propyl, isopropyl, Normal-butyl, 2- butyl, isobutyl group or tert-butyl.
According to another preferred method of implementation of the present invention, the Michael Diekmann condensation reaction is at 20~200 DEG C of temperature Lower progress.
According to another preferred method of implementation of the present invention, the solvent is selected from toluene, ethylbenzene, dimethylbenzene, front three Benzene, chlorobenzene, dichloro-benzenes, dimethylformamide, dimethyl acetamide, N-Methyl pyrrolidone, dimethyl sulfoxide, hexamethylene or first Butylcyclohexane.
According to another preferred method of implementation of the present invention, the alkali is selected from sodium methoxide, potassium methoxide, sodium ethoxide, ethyl alcohol Potassium, sodium tert-butoxide, potassium tert-butoxide, Sodamide, lithium amide.
The present invention relates to 5,5- dimethyl -2- cyano cyclopentanone (V) compounds that the preparation method is prepared to close At the use in 2,2- dimethyl -5- (4- chlorobenzyl) -5- cyano cyclopentanone or 2,2- dimethyl -5- (4- chlorobenzyl) cyclopentanone On the way.
The present invention relates to a kind of preparation methods of 2,2- dimethyl -5- (4- chlorobenzyl) cyclopentanone.The step of this method, is such as Under:
1., in alkali and organic solvent, formula (V) compound 5 that preparation method is prepared according to claim 1, 5- dimethyl -2- cyano cyclopentanone and p-chlorobenzylchloride carry out condensation reaction, obtain formula (VI) compound 2,2- dimethyl -5- (4- Chlorobenzyl) -5- cyano cyclopentanone, reaction equation is as follows:
2., in inert organic solvents, in presence of an acid, formula (VI) compound 2 1. obtained by step, 2- dimethyl- Decarboxylic reaction is hydrolyzed in 5- (4- chlorobenzyl) -5- cyano cyclopentanone, obtains formula (VII) compound 2,2- dimethyl -5- (4- chlorine Benzyl) cyclopentanone, reaction equation is as follows:
A preferred embodiment of the invention, the acid be it is one or more selected from hydrochloric acid, sulfuric acid, phosphoric acid, Hydrobromic acid, acetic acid, methane sulfonic acid or p-methyl benzenesulfonic acid acid.
According to another preferred method of implementation of the present invention, for the acid using the aqueous solution of acid, sour concentration is with weight Meter 10~100%.
According to another preferred method of implementation of the present invention, the formula (VII) compound 2,2- dimethyl -5- (4- benzyl chloride Base) cyclopentanone be applied to synthesizing fungicide metconazole.
The present invention is described in more detail below.
In order to achieve the object of the present invention.For the present invention using isobutyrate as raw material, it is led to by isobutyric acid and corresponding alcohol Cross esterification reaction and obtain, alcohol can be methanol, ethyl alcohol, propyl alcohol, isopropanol, n-butanol, 2- butanol, isobutanol, the tert-butyl alcohol, Amylalcohol, alcohol, enanthol, octanol or undecyl alcohol can also be directly commercially available from market, structural formula is as follows to eicosanol etc.:
Wherein R is any alkyl substituent, preferably C1-C16Alkyl substituent, economically consider, preferably methyl, Ethyl, n-propyl, isopropyl, normal-butyl, 2- butyl, isobutyl group or tert-butyl, the raw material and 1,3- dihalopropane formula (II) (optional 1,3- dichloropropane, 1,3- dibromopropane, 1,3- bromo-chloropropane, 1,3- diiodo propane, preferably 1,3- bromo-chloropropane, Dosage is 0.8-1.4 times of isobutyrate molar ratio, preferably 0.9-1.1 times, and reaction obtains 5-X-2 in the presence of solvent and alkali, 2 methyl valeric acid ester compounds formula (III), reaction equation is as follows:
Wherein R is any alkyl substituent, preferably C1-C16Alkyl substituent, economically consider, preferably methyl, Ethyl, n-propyl, isopropyl, normal-butyl, 2- butyl, isobutyl group or tert-butyl.Wherein X, X1 are halogen, are selected from chlorine, bromine or iodine.
Tetrahydrofuran, ether, n-hexane, hexamethylene, hexahydrotoluene, toluene, ethylbenzene, diformazan can be selected in anti-solvent-applied Benzene, chlorobenzene, dichloro-benzenes, dimethylformamide, N-Methyl pyrrolidone, dimethyl sulfoxide etc., preferably tetrahydrofuran, n-hexane, Dosage is usually 1-8 times of isobutyrate weight, preferably 2-3 times.Double trimethyl silicane silicon substrate amino can be selected in the alkali of reaction Lithium, dimethylamino lithium, diethylamino lithium, lithium diisopropylamine, lithium hydride, lithium amide, Sodamide, sodium tert-butoxide, uncle Butanol potassium, sodium methoxide, sodium ethoxide, preferably dimethylamino lithium, lithium diisopropylamine, lithium amide.Reaction temperature be -50 DEG C~ 50 DEG C, -25 DEG C of preferable temperature~25 DEG C.Reaction time is generally 1-20 hours, preferably 5-10 hours.In passing through after the reaction was completed Obtaining residue with layering, decompression precipitation is 5-X-2, and it is anti-can also to be directly entered lower step for 2 methyl valeric acid ester compounds formula (III) Answer, can also further be evaporated under reduced pressure and steam product, obtain the 5-X-2 of high-content, 2 methyl valeric acid ester compounds formula (III) again with Cyanidization agent alkali metal cyanide salt (Cymag or potassium cyanide, preferably Cymag), in the presence of a phase transfer catalyst, reaction obtain 5- Cyano -2,2 methyl valeric acid ester compounds formula (IV), reaction equation is as follows:
R is any alkyl substituent, the preferably alkyl substituent of C1-C16 in formula (III), formula (IV), is economically examined Consider, preferably methyl, ethyl, n-propyl, isopropyl, normal-butyl, 2- butyl, isobutyl group or tert-butyl.X is halogen in formula (III), Selected from chlorine, bromine or iodine.The dosage of reaction cyanidization agent is the molar ratio of 5-X-2,2- methylpent acid esters Formula (III) 0.8-2.0 times, preferably 1-1.5 times, phase transfer catalyst can be used and can also not use, using can further improve reaction yield, Shorten the reaction time, can be selected trimethyl benzyl ammonium chloride, four butyl bromation amine, tetrabutyl Ammonium hydrogen sulfate, tetrabutylammonium chloride, Polyethylene glycol, the hat of cyclic crown ether class 18 6, cyclodextrin etc., preferably trimethyl benzyl ammonium chloride, four butyl bromation amine, tetrabutyl sulphur Sour hydrogen amine, tetrabutylammonium chloride, dosage 5-X-2,0.01-1 times of 2 methyl valeric acid ester compounds formula (III) weight, preferably 0.01-0.1 times.Reaction can carry out in a solvent or toluene, ethylbenzene, dimethylbenzene, front three can be selected in solvent-free middle progress, solvent Benzene, chlorobenzene, dichloro-benzenes, hexamethylene, hexahydrotoluene etc., preferably toluene, ethylbenzene, dimethylbenzene, chlorobenzene, dosage are usually 5-X-2, 0-10 times of 2 methyl valeric acid ester compounds formula (III) weight is, it is preferable to use 2-5 times.Reaction temperature is 50 DEG C -150 DEG C, preferably 80 DEG C -120 DEG C of temperature.Reaction time is generally 2-15 hours, preferably 4-10 hours.Reaction is generally cyaniding base dosage with water Anhydrous response, preferably 2-5 times can also be used in 0-10 times of weight.After the reaction was completed, added water stratification, be washed with water, depressurize it is de- Cyano -2 5-, 2 methyl valeric acid ester compounds formula (IV) are obtained after molten, then pass through Dieckmann Dick in the presence of solvent, alkali Graceful condensation reaction obtains 5,5- dimethyl -2- cyano cyclopentanone formula (V), and reaction equation is as follows:
R is any alkyl substituent, the preferably alkyl substituent of C1-C16 in formula (IV), is economically considered, preferably Methyl, ethyl, n-propyl, isopropyl, normal-butyl, 2- butyl, isobutyl group or tert-butyl.
Toluene, ethylbenzene, dimethylbenzene, trimethylbenzene, chlorobenzene, dichloro-benzenes, dimethylformamide, diformazan can be selected in anti-solvent-applied Yl acetamide, N-Methyl pyrrolidone, dimethyl sulfoxide, hexamethylene, hexahydrotoluene etc., preferably toluene, ethylbenzene, dimethylbenzene, Hexamethylene, hexahydrotoluene, dosage is usually cyano -2 5-, 2-20 times of 2 methyl valeric acid ester compounds formula (IV) weight, excellent Choosing uses 5-10 times.The alkali or alkaline earth metal alkoxy salt of the alkylol of C1-C16, preferably C1-C4 can be selected with alkali for reaction Alkylol alkali metal alkoxy salt, such as: sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, uncle Butanol lithium etc.；Also the alkali metal salt of ammonia can be selected, such as: Sodamide, potassamide, lithium amide；The alkali metal salt of hydrogen also can be selected, Such as: sodium hydride, hydrofining, lithium hydride.Economically consider, it is preferable to use sodium methoxide, sodium tert-butoxide, Sodamide.Reaction is used The dosage of alkali is usually cyano -2 5-, and 0.8-1.5 times of 2 methyl valeric acid ester compounds formula (IV) molar ratio is, it is preferable to use 0.9- 1.1 again.Reaction temperature is 20 DEG C -200 DEG C, and preferable temperature is 80 DEG C -150 DEG C.Reaction time is generally 1-8 hours, preferably 2-5 Hour.Neutralized layered shaping after the reaction was completed obtains surplus material after depressurizing precipitation as 5,5- dimethyl -2- cyano cyclopentanone Formula (V) reacts to obtain 2,2- dimethyl -5- (4- chlorobenzyl) -5- cyano ring penta again with p-chlorobenzylchloride in the presence of a base Keto-acid (VI), reaction equation is as follows:
Toluene, ethylbenzene, dimethylbenzene, trimethylbenzene, chlorobenzene, dichloro-benzenes, dimethylformamide, N- first can be selected in anti-solvent-applied Base pyrrolidones, dimethyl sulfoxide, hexamethylene, hexahydrotoluene etc. are, it is preferable to use toluene, ethylbenzene, dimethylbenzene, hexamethylene, first Butylcyclohexane, dosage are usually 0-20 times of 5,5- dimethyl -2- cyano cyclopentanone compound formula (V) weight, it is preferable to use 2- 5 times.Sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, Sodamide, sodium carbonate, sodium bicarbonate, hydrogen-oxygen can be selected with alkali in reaction Change sodium, potassium hydroxide, potassium carbonate, triethylamine, pyridine etc., it is preferable to use sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, Potassium carbonate, triethylamine, pyridine, dosage are usually the 0.8- of 5,5- dimethyl -2- cyano cyclopentanone compound formula (V) molar ratio 1.5 times, it is preferable to use 0.9-1.1 times.Reaction temperature is 20 DEG C -150 DEG C, and preferable temperature is 20 DEG C -120 DEG C.Reaction time one As be 2-8 hours, preferably 3-8 hours.After the reaction was completed through plus water stratification, be washed with water, depressurize precipitation and obtain 2,2- dimethyl- 5- (4- chlorobenzyl) -5- cyano cyclopentanone formula (VI), then hydrolysis decarboxylation obtains 2,2- dimethyl -5- (4- benzyl chloride in presence of an acid Base) cyclopentanone formula (VII), reaction equation is as follows:
Reaction with acid optional hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, acetic acid, methane sulfonic acid, p-methyl benzenesulfonic acid etc. or they One or more of mixed acid, 10%-100%, preferably 20-80% can be selected in acid concentration, and sour dosage is usually 2,2- dimethyl- 0.1-20 times, preferably 1-5 times of 5- (4- chlorobenzyl) -5- cyano cyclopentanone formula (VI) molar ratio.Reaction is general can also be in inertia It is carried out in the presence of solvent, toluene, ethylbenzene, dimethylbenzene, trimethylbenzene, chlorobenzene, dichloro-benzenes, hexamethylene, methyl cyclohexane can be selected in solvent Alkane etc. is, it is preferable to use toluene, ethylbenzene, dimethylbenzene, dosage are usually 2,2- dimethyl -5- (4- chlorobenzyl) -5- cyano cyclopentanone 0.1-10 times, preferably 2-5 times of formula (VI) weight.50 DEG C -200 DEG C of reaction temperature, preferable temperature is 80 DEG C -180 DEG C.When reaction Between generally 2-10 hours, preferably 3-8 hours.After the reaction was completed through plus water stratification, be washed with water, depressurize precipitation and obtain 2,2- bis- Methyl -5- (4- chlorobenzyl) cyclopentanone formula (VII), can be directly used for the synthesis of metconazole raw medicine, can also be evaporated under reduced pressure through high vacuum Product is steamed, 2,2- dimethyl -5- (4- chlorobenzyl) cyclopentanone formula (VII) of high-content is obtained, is used further to the conjunction of metconazole raw medicine At.
[beneficial effect]
Compared with the background technology, the present invention, first is that gained 2,2- dimethyl -5- (4- chlorobenzyl) cyclopentanone formula (VII) content >=95%, the synthesis of fungicide metconazole raw medicine can be directly used in without purification, it can also be by common vacuum distillation purification Obtain 2,2- dimethyl -5- (4- chlorobenzyl) cyclopentanone formula (VII) of higher amount, >=98%, it is used for high-content fungicide leaf bacterium The synthesis of azoles raw medicine；Second is that process implementing is convenient compared with the background technology, the present invention, high income has industrial applications prospect.
[Detailed description of the invention]
Fig. 1 is the MS spectrogram of the 5,5- dimethyl -2- cyano cyclopentanone sample of implementation 10
Fig. 2 is the 1H-NMR spectrogram of the 5,5- dimethyl -2- cyano cyclopentanone sample of implementation 10
Fig. 3 is the MS spectrogram of 2,2- dimethyl -5- (4- chlorobenzyl) cyclopentanone sample of implementation 14
Fig. 4 is the 1H-NMR spectrogram of 2,2- dimethyl -5- (4- chlorobenzyl) cyclopentanone sample of implementation 14
Specific embodiment
In the present invention, unless otherwise specified, the percentage or " % " for illustrating concentration are weight percentage；It receives Rate % is molar yield %.
Embodiment 1: putting into 52g methyl isobutyrate (0.5mol) in reaction flask, and dried n-hexane 300g, N2 gas is protected Shield is cooled to -20 DEG C, and control temperature≤- 10 DEG C instill the hexane solution 180g of the dimethylamino lithium of 15% (weight) (0.53mol), then control temperature≤- 10 DEG C and instill 1,3- bromo-chloropropane 80g (0.51mol), 3 are kept the temperature at -5 DEG C or so after dripping off Hour, 0 DEG C -10 DEG C keep the temperature 5 hours again, instill water 50g, and 15% hydrochloric acid tune PH is neutrality, and layering, 50g water washing is primary, solvent After layer air-distillation recycling design, vacuum distillation obtains product 5- chloro- 2,2 methyl valeric acid methyl esters 75g, 98% (area of G/C content Normalizing), yield 93.4%.
Embodiment 2: methyl isobutyrate (0.5mol) is replaced with (0.5mol) ethyl isobutyrate in embodiment 1, other conditions It is constant.As a result the chloro- 2,2- methylpentanoic acid ethyl ester 93g of 5-, G/C content 98% (area normalization), yield 94.6% are obtained.
Embodiment 3: methyl isobutyrate (0.5mol) is replaced with (0.5mol) isobutyl isobutyrate in embodiment 1, other Part is constant.As a result the chloro- 2,2- methylvaleric acid isobutyl ester 106g of 5-, G/C content 98% (area normalization), yield 94.0% are obtained.
Embodiment 4: methyl isobutyrate (0.5mol) (0.5mol) isobutyric acid n-propyl ester or (0.5mol) in embodiment 1 Isobutyric acid isopropyl esters replace, and other conditions are constant.As a result chloro- 2,2- methylvaleric acid n-propyl ester 99g, the 5- chloro- 2 of 5- is obtained, 2 methyl valeric acid isopropyl esters 99g, G/C content are all 98% (area normalization), and yield is all 94.0%.
Embodiment 5: dimethylamino lithium (0.53mol) is replaced with lithium diisopropylamine (0.53mol) in embodiment 1, Other conditions are constant, and it is identical to obtain result.
Embodiment 6: dimethylamino lithium (0.53mol) is replaced with lithium amide (0.53mol) in embodiment 1, other conditions It is constant, obtain 5- chloro- 2,2 methyl valeric acid methyl esters 55g, G/C content 98% (area normalization), yield 68.5%.
Embodiment 7: the chloro- 2,2- methylvaleric acid methyl ester (0.5mol) of 91g5- that investment is obtained by embodiment 1 in reaction flask, Dimethylbenzene 200g, Cymag 30g (0.60mol), water 100g, trimethyl benzyl ammonium chloride 5g, temperature rising reflux react 5 hours, GC Raw material≤2% is detected, room temperature is cooled to, is layered, 50g water washing is secondary, obtains surplus material 5- cyano -2,2- after depressurizing precipitation Methylvaleric acid methyl ester 85g, GC detection level 96% (area normalization), yield 96.4%.
Embodiment 8: in embodiment 7,5- chloro- 2,2 methyl valeric acid methyl esters (0.5mol) 5- chloro- 2,2 methyl valeric acid second Ester (0.5mol) replaces, and other conditions are constant, and obtained content and yield result is identical.
Embodiment 9: in embodiment 7,5- chloro- 2,2 methyl valeric acid methyl esters (0.5mol) 5- chloro- 2,2 methyl valeric acid is just Butyl ester (0.5mol) or 5- chloro- 2,2 methyl valeric acid isobutyl ester (0.5mol), other conditions are constant, obtain containing for corresponding product Amount and yield result are identical.
Embodiment 10: 91g5- chloro- 2,2 methyl valeric acid methyl esters (0.5mol), dimethylbenzene 200g, cyaniding are put into reaction flask Sodium 30g (0.60mol), water 100g, trimethyl benzyl ammonium chloride 5g, temperature rising reflux react 5 hours, and GC detects raw material≤2%, drop It warming to room temperature, is layered, 50g water washing is secondary, cools down 50 DEG C after solvent layer reflux dewatering, it is added sodium methoxide 28g (0.50mol), Heating 110-150 DEG C insulation reaction 5 hours, during which deviate from low-boiling-point substance.Cool down after the reaction was completed, adds water 50ml, 15% hydrochloric acid tune PH value is faintly acid, layering, obtains remaining material 5 after solvent layer removed under reduced pressure, 5- dimethyl -2- cyano cyclopentanone 66.8g, and GC contains 96% (area normalization) is measured, two step total recoverys 93.5%, MS, 1H-NMR confirm its chemical structure (MS spectrogram are shown in attached drawing 1,1H- NMR spectra is shown in attached drawing 2).1H-NMR parsing such as the following table 1:
Table 1: sample1The analysis of H-NMR spectrum
Embodiment 11: the chloro- 2,2- methylvaleric acid methyl ester (0.5mol) of 5- is using the chloro- 2,2- methylvaleric acid of 5- just in embodiment 10 The chloro- 2,2- methylvaleric acid n-octyl (0.5mol) of butyl ester (0.5mol), 5- or the chloro- 2,2- methylvaleric acid isobutyl ester (0.5mol) of 5- Instead of other conditions are constant, and it is identical to obtain result.
Embodiment 12: dimethylbenzene is replaced with toluene in embodiment 10, and other conditions are constant, and it is identical to obtain result.
Embodiment 13: sodium methoxide (0.50mol) is replaced with sodium tert-butoxide (0.5mol) in embodiment 10, and other conditions are not Become, it is identical to obtain result.
Embodiment 14: gained 5,5- dimethyl -2- cyano cyclopentanone 50g (0.35mol), toluene 200g in embodiment 10, Potassium carbonate 70g (0.5mol) heats up 50 DEG C or so, instills p-chlorobenzylchloride 58g (0.35mol), insulation reaction 5 hours, adds water 100ml, layering are washed with water, and after depressurizing precipitation, obtain surplus material 2,2- dimethyl -5- (4- chlorobenzyl) -5- cyano ring penta Ketone 89g, HPLC content 95%, yield 92.3%.50% (weight) sulfuric acid 150g is added in surplus material, 140 DEG C of reactions 5 are small When, toluene 200g, water 100ml is added, extracting and demixing obtains residual dark brown oil material 2,2- diformazan after solvent layer precipitation Base -5- (4- chlorobenzyl) cyclopentanone 77g, G/C content 95% (area normalization), this step yield 95.6%.This material further subtracts Pressure distillation obtains jade-green 2,2- dimethyl -5- (4- chlorobenzyl) cyclopentanone 72g, G/C content 98% (area normalization).MS, 1H-NMR confirms its chemical structure (MS spectrogram is shown in that attached drawing 3,1H-NMR spectrogram are shown in attached drawing 4), 1H-NMR parsing such as the following table 2:
Table 2: sample1The analysis of H-NMR spectrum
Embodiment 15: putting into dimethyl sulfoxide 200g, triazole sodium 50g (0.55mol) in reaction flask, heat up 90-100 DEG C, sodium tert-butoxide 53g (0.55mol) and trimethyl thionyl bromide 95g (0.55mol) is added, instills resulting by embodiment 13 95%2,2- dimethyl -5- (4- chlorobenzyl) cyclopentanone 110g (0.44mol), 90-100 DEG C insulation reaction 2 hours, add water 200ml and toluene 200ml, 40-50 DEG C is layered, and solvent layer 50ml water washing twice, is remained after solvent layer decompression precipitation N-hexane 200g is added in excess material 140g, slightly after rising temperature for dissolving, cooling 0~5 DEG C additions seeded crystallization 5 hours, suction filtration, just oneself Alkane washing, drying obtain ecru metconazole raw medicine 120g, HPLC content 95.2% (area normalization), yield 81.2%.
Embodiment 16: in embodiment 15, used 95% 2,2- dimethyl -5- (4- chlorobenzyl) cyclopentanone (0.44mol) It is substituted with 2,2- dimethyl -5- (4- chlorobenzyl) cyclopentanone (0.44mol) of embodiment 14 resulting 98%, other conditions are not Become, as a result obtains white crystals metconazole raw medicine dry product 125g, HPLC content 96.2% (area normalization), yield 85.5%.
Comparative example 1: putting into 35g isobutyronitrile (0.5mol) in reaction flask, and n-hexane 300g, N2 gas shielded is cooled to -20 DEG C, control temperature≤- 10 DEG C instill the hexane solution 180g (0.53mol) of 15% dimethylamino lithium, then control temperature ≤ -10 DEG C of instillation 1,3- bromo-chloropropane 80g (0.51mol) keep the temperature 3 hours at -5 DEG C or so after dripping off, and 0 DEG C of -10 DEG C of heat preservation 5 is small When, water 50g is instilled, 15% hydrochloric acid tune PH is neutrality, and layering 50g water washing is primary, after solvent layer air-distillation recycling design, subtracts Pressure distillation obtains the chloro- 2,2- methyl valeronitrile 71g of product 5-, G/C content 90% (area normalization), yield 87.7%.
Comparative example 2: the chloro- 2,2- methyl valeronitrile (0.5mol) of 81g 5- that investment is obtained by comparative example 1 in reaction flask, diformazan Benzene 200g, Cymag 30g (0.60mol), water 100g, trimethyl benzyl ammonium chloride 5g, temperature rising reflux react 5 hours, GC detection Raw material≤2% is cooled to room temperature, and layering, 50g water washing is secondary, obtains surplus material 5- cyano -2,2- methyl after depressurizing precipitation Valeronitrile 71g, GC detection level 89% (area normalization), yield 92.4%.
Comparative example 3: the 5- cyano -2,2- methyl valeronitrile 76g (0.5mol) that investment is obtained by comparative example 2 in reaction flask, first Benzene 200g, be added sodium tert-butoxide 49g (0.50mol), heating 110 DEG C or so insulation reaction 5 hours, during which deviate from low-boiling-point substance.Instead It should cool down after the completion, add water 50ml, 15% hydrochloric acid tune pH value is faintly acid, is layered, obtains remaining material after solvent layer removed under reduced pressure 5,5- dimethyl -2- cyano cyclopentanone 37.4g, G/C content 96% (area normalization), yield 52.3%.
It is to be understood that: although above-described embodiment contrasts detailed description to the present invention, these explanations, Only to simple declaration of the invention, rather than limiting the invention, any invention without departing from true spirit It creates, each falls within protection scope of the present invention.

Claims (5)

1. one kind 5, the preparation method of 5- dimethyl -2- cyano cyclopentanone, it is characterised in that the step of this method is as follows:
In the presence of solvent and alkali, cyano -2 formula (IV) compound 5-, 2 methyl valeric acid ester carries out Michael Diekmann condensation reaction, obtains To formula (V) compound 5,5- dimethyl -2- cyano cyclopentanone；Its reaction equation is as follows:
In formula (IV):
R is C1-C16 alkyl substituent；
The solvent is selected from toluene, ethylbenzene, dimethylbenzene, trimethylbenzene, chlorobenzene, dichloro-benzenes, dimethylformamide, dimethylacetamide Amine, N-Methyl pyrrolidone, dimethyl sulfoxide, hexamethylene or hexahydrotoluene.
2. preparation method according to claim 1, it is characterised in that R is selected from methyl, ethyl, n-propyl, different in formula (IV) Propyl, normal-butyl, 2- butyl, isobutyl group or tert-butyl.
3. preparation method according to claim 1, it is characterised in that the Michael Diekmann condensation reaction be temperature 20~ It is carried out at 200 DEG C.
4. preparation method according to claim 1, it is characterised in that the alkali be selected from sodium methoxide, potassium methoxide, sodium ethoxide, Potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, Sodamide, lithium amide.
5. preparation method described in any one of -4 claims according to claim 1, it is characterised in that formula (V) compound exists Synthesize the application in 2,2- dimethyl -5- (4- chlorobenzyl) cyclopentanone or fungicide metconazole.
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