CN103664682A - Synthetic method for 2-formamide cyclohexanone - Google Patents

Synthetic method for 2-formamide cyclohexanone Download PDF

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CN103664682A
CN103664682A CN201310594636.9A CN201310594636A CN103664682A CN 103664682 A CN103664682 A CN 103664682A CN 201310594636 A CN201310594636 A CN 201310594636A CN 103664682 A CN103664682 A CN 103664682A
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pimelinketone
methane amide
synthetic
acid
cyclohexanone
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CN103664682B (en
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李国防
高庆宇
马啸华
潘长伟
刘晓娟
王绍荣
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China University of Mining and Technology CUMT
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China University of Mining and Technology CUMT
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Abstract

The invention discloses a synthetic method for 2-formamide cyclohexanone with low emission and low consumption, and belongs to the technical field of medicinal chemistry and organic synthesis. According to the method, a non-oxide proton acid or salt thereof is used as a catalyst, arene is used as a solvent and a water-carrying agent, and cyclohexanone and urea are used as raw materials, so that the 2-formamide cyclohexanone can be prepared through a one-pot reaction. The screw ring synthetized through the technology provided by the invention is not needed to be cooled and separated, so that a great amount of scouring water is eliminated; besides, condensation generated water saturated by cyclohexanone, evaporated water generated during the screw ring hydrolysis and aqueous phase mother solution generated after the product is separated out are used for preparing hydrolyzing diluted acid to realize cyclic utilization, so that the loss caused by the cyclohexanone dissolution in water is eliminated, the use ratio of cyclohexanone is increased and the zero release of sewage is realized; the method is simple and convenient to operate and is suitable for industrial application.

Description

A kind of method of synthetic 2-methane amide pimelinketone
Technical field
A kind of method that the present invention relates to synthetic 2-methane amide pimelinketone, belongs to pharmaceutical chemistry and technical field of organic synthesis.
Background technology
2-methane amide pimelinketone is the important source material of hypoglycemic drug gliclazide and weedicide, existing synthetic method is as follows: method one [Journal f prakt.Chemie, Band318, Heft5,1976, S, 773～778] take pimelinketone, urea is raw material, tosic acid is made catalyzer, toluene band water synthesizing spiro (yield 91.0%).Because catalyzer tosic acid is oxidisability organic acid, in reaction process, pyroreaction especially, oxidized portion pimelinketone generates red-brown syrupy shape impurity, make the intermediate volution color of generation darker, must cool by being just hydrolyzed after water and organic solvent purifying.But adopt substep operation not only to increase Equipment Foundations input but also increased energy consumption.Separate purifying rear center body volution and be hydrolyzed to obtain product 2-methane amide pimelinketone (yield 80.0%) with dilute sulphuric acid.Chemical equation is as follows:
Although this method substep yield is higher, due to pimelinketone solubleness large (3～5%) in water, makes substep operation not only produce a large amount of waste water but also reduced the utilization ratio (pimelinketone overall utilization≤60%) of pimelinketone.Patent (a kind of preparation method of gliclazide intermediate pimelinketone-2-methane amide, application number: 201110423685.7) only the hydrolysis process of aforesaid method is improved, still have the method drawback of substep operation.
United States Patent (USP) [United States Patent, Appl.No.:777,322] and [Li Guofang, application chemical industry [J], 2010,39 (5), 641-644] all advocate one kettle way operate continuously and reduce energy consumption, but the method adopts heavy dose of (urea volatile salt quality feed ratio 2:1) volatile salt as urea high temperature polymerization inhibitor, increased the consumption of hydrolysis sulfuric acid, and the method is not mentioned the recovery technology of pimelinketone in waste water yet.Therefore still there is the defect of the not high and contaminate environment of pimelinketone utilization ratio in this technique.
Summary of the invention
For solving the method drawback of above-mentioned existing 2-methane amide pimelinketone synthesis technique, the present invention adopts new catalyst, 2-methane amide pimelinketone is synthesized in one kettle way operate continuously, in conjunction with the simple and effective method of extracting pimelinketone from waste water, the novel process that the synthetic 2-methane amide pimelinketone of a kind of high yield less energy-consumption low emission is provided, technique of the present invention is applicable to industrial applications.
The present invention realizes with following technical scheme: a kind of method of synthetic 2-methane amide pimelinketone, and take pimelinketone, urea, aromatic hydrocarbons is raw material, it is characterized in that take that non-oxidizable protonic acid or its salt are catalyzer, one kettle way is prepared 2-methane amide pimelinketone;
Described catalyzer is any of oxalic acid, phosphoric acid, polyphosphoric acid, tetra-sodium;
Further, described catalyzer is phosphoric acid, polyphosphoric acid or oxalic acid;
Described catalyzer is arbitrary ammonium salt, sodium salt or the sylvite of oxalic acid, phosphoric acid, polyphosphoric acid or tetra-sodium;
Further, described catalyzer is arbitrary ammonium salt of oxalic acid, phosphoric acid, polyphosphoric acid or tetra-sodium;
The consumption of described catalyzer is 0.001～0.005 times of pimelinketone quality;
Described aromatic hydrocarbons is benzene, toluene or dimethylbenzene, and its consumption is 0.1～1 times of pimelinketone quality.
A kind of method of synthetic 2-methane amide pimelinketone, by mass ratio, be that 1:0.1～1:0.3～0.6:0.001～0.005 pimelinketone, urea, aromatic hydrocarbons and catalyzer add reactor, in extremely anhydrous generation of 100～150 ℃ of reactions, then the 1M dilute sulphuric acid that directly adds 2.5～3.5 times of pimelinketone quality, hydrolysis volution obtains wet product 2-methane amide pimelinketone, it is dried and makes sterling at 70～100 ℃, complete one kettle way and produce;
The water mother liquor that steams water, separates after wet product 2-methane amide pimelinketone of the generation water of above-mentioned reaction process, volution hydrolytic process is collected respectively, all for preparing the 1M dilute sulphuric acid of present method hydrolysis use, carry out recycle, not only improved pimelinketone utilization ratio but also realized sewage zero-discharge;
The optimal reaction temperature of above-mentioned reaction is 120～140 ℃, and optimum reacting time is 2～5 hours.
The invention has the beneficial effects as follows: by adopting new catalyst condensation process, reduced the oxidation of pimelinketone in condensation reaction, the substep operation of former technique is formed to one kettle way successive reaction, total reaction time shortens, and energy consumption declines to a great extent; In addition, synthesizing spiro of the present invention does not need refrigerated separation to save a large amount of washing water, and the water mother liquor that is steamed water by pimelinketone saturated condensation generation water, volution hydrolysis and separate out after product is used to diluted acid recycle for preparing hydrolysis, not only improved the utilization ratio of pimelinketone but also realized sewage zero-discharge.Therefore, invented technology less energy-consumption, low emission, environmental friendliness, industrial applications promotion prospect is good.
Accompanying drawing and explanation thereof:
Fig. 1 is the infrared spectrum of the 2-methane amide pimelinketone that makes of technique of the present invention;
Fig. 2 is MS spectrogram and 2-methane amide pimelinketone standard MS spectrogram (SATURN gas chromatograph-mass spectrometer the carries database spectrogram) comparison diagram of the 2-methane amide pimelinketone that makes of technique of the present invention.
According to the product infrared spectrum test result shown in Fig. 1 (the Japanese JASCO FTIR2430 of company type Fourier infrared spectrograph, KBr sheet), the degree of unsaturation of 2-methane amide pimelinketone is 3, contains two carbonyls and a six-ring in molecule; 3426.8cm -1and 3199.5cm (A) -1(B) bands of a spectrum of locating are that the N-H key of primary amide stretches and anti-stretching vibration Absorption Characteristics peak; 2946.4cm -1(C), 2914.8cm -1(D), 2868.3cm -1and 2841.8cm -1(E) absorption peak of locating is to be produced by the c h bond absorption of vibrations of six-ring methylene radical; Carbonyl absorption of vibrations on six-ring produces 1708.1cm -1(F) absorption peak of locating, due to NH 2push away electronic effect, the carbonyl vibration absorption peak of acid amides drops to 1635.9cm -1(G).
Fig. 2 (on) be the MS spectrogram detecting with acetone solution product SATURN gas chromatograph-mass spectrometer (U.S. VARIANWS company), because experiment adopts FAB ion source and ion strap mass analyzer, slightly variant with standard spectrogram Fig. 2 of 2-methane amide pimelinketone (under: BP141.090440, SATURN gas chromatograph-mass spectrometer database spectrogram).Fig. 2 (on) show, 2-methane amide pimelinketone has obvious molecular ion peak m/z141M +, quasi-molecular ion peak m/z142 (M+H) +intensity is maximum, meets FAB ion source feature.The dehydration of 2-methane amide pimelinketone forms m/z123 (M-H 2o) +quasi-molecular ions, loses NH 3or OH forms m/z124 (M-NH 3) +or (M-OH) +quasi-molecular ions, de-CO forms m/z113 (M-CO) +peak.The fracture of 2-methane amide pimelinketone branch chain place loses CONH 2and de-H forms m/z96 (M-CONH 2-H) +peak.The broken ring of pimelinketone ion produces m/z69 and m/z55 quasi-molecular ions, and McLafferty rearrangement produces C nh 2no +ion (m/z58,72,86).
Embodiment
Embodiment 1
Comparative example [reference literature Journal f prakt.Chemie, Band318, Heft5,1976, S, 773～778]
190g pimelinketone, 120g urea, 1g tosic acid and 200ml toluene are joined to 2000ml three-necked bottle, back flow reaction adds 300ml water to stir cooling blowing after 10 hours, volution obtains 200g, mp:185.1～188.3 ℃, single step yield 91% after washing with water and being dried.The dry rare H of volution 200g, 470ml1M 2sO 4join 2000ml three-necked bottle heating hydrolysis complete, obtain 2-methane amide pimelinketone 102g, mp:127.3～129.6 ℃ (X-5 micro melting point apparatus mensuration, Tyke, Beijing Instrument Ltd., following example same measured method), (single step yield 80.0%), reclaims pimelinketone 71g.To consume pimelinketone (119g), calculate 2-methane amide pimelinketone (102g), total recovery 59.6%.
Embodiment 2～6 is technological operation example of the present invention.
Embodiment 2
124g pimelinketone, 42g urea, 0.6g85.0% phosphoric acid and 15g dimethylbenzene are joined to 1000ml three-necked bottle, and 138 ℃ of back flow reaction add the rare H of 320g1M after 2.5 hours 2sO 4heating hydrolysis volution, reacts complete, collects dimethylbenzene cyclohexanone mixture 77g, obtains 2-methane amide pimelinketone 58g, and mp:127.1～129.0 ℃, to consume pimelinketone (62g), total recovery 65.3%.
Embodiment 3
Dimethylbenzene cyclohexanone mixture 77g and the new pimelinketone of 62g, 42g urea, 0.6g85.0% phosphoric acid that example 2 is collected join 1000ml three-necked bottle, 135 ℃ of back flow reaction add 322g by the rare H2SO4 heating hydrolysis of the 1M volution of example 2 recycle-water preparations after 3 hours, react complete, collect dimethylbenzene cyclohexanone mixture 89g, obtain 2-methane amide pimelinketone 56.2g, mp:127.0～129.3 ℃, to consume pimelinketone (50g), total recovery 78.1%.
Embodiment 4
124g pimelinketone, 42g urea, 0.6g85.0% phosphoric acid and 15g toluene are joined to 1000ml three-necked bottle, and 136 ℃ of back flow reaction add the rare H of 320g1M after 3 hours 2sO 4heating hydrolysis volution, reacts complete, collects toluene cyclohexanone mixture 78.4g, obtains 2-methane amide pimelinketone 57.8g, and mp:127.2～129.5 ℃, to consume 60.6g pimelinketone, total recovery 66.3%.
Embodiment 5
Toluene cyclohexanone mixture 78.4g and the new pimelinketone of 60.6g, 42g urea, 0.6g85.0% phosphoric acid that example 4 is collected join 1000ml three-necked bottle, and 135 ℃ of back flow reaction add 322g by the rare H of 1M of example 4 recycle-water preparations after 3 hours 2sO 4heating hydrolysis volution, reacts complete, collects toluene cyclohexanone mixture 87.5g, obtains 2-methane amide pimelinketone 57.7g, and mp:126.7～129.1 ℃, to consume pimelinketone (51.5g), total recovery 77.9%.
Embodiment 6
36g pimelinketone, 13g urea, 0.36g ammonium phosphate and 28g toluene are joined to 500ml three-necked bottle, and 128 ℃ of back flow reaction add the rare H of 99g1M after 3 hours 2sO 4heating hydrolysis volution, reacts complete, collects toluene cyclohexanone mixture 50.3g, obtains 2-methane amide pimelinketone 12.5g, and mp:126.4～128.1 ℃, to consume 13.7g pimelinketone, total recovery 63.4%.

Claims (10)

1. a method for synthetic 2-methane amide pimelinketone, take pimelinketone, urea, aromatic hydrocarbons is raw material, it is characterized in that take that non-oxidizable protonic acid or its salt are catalyzer, one kettle way is prepared 2-methane amide pimelinketone.
2. the method for synthetic 2-methane amide pimelinketone according to claim 1, is characterized in that described catalyzer is any of oxalic acid, phosphoric acid, polyphosphoric acid or tetra-sodium.
3. the method for synthetic 2-methane amide pimelinketone according to claim 2, is characterized in that described catalyzer is phosphoric acid, polyphosphoric acid or oxalic acid.
4. the method for synthetic 2-methane amide pimelinketone according to claim 1, is characterized in that described catalyzer is arbitrary ammonium salt, sodium salt or the sylvite of oxalic acid, phosphoric acid, polyphosphoric acid or tetra-sodium.
5. the method for synthetic 2-methane amide pimelinketone according to claim 4, is characterized in that described catalyzer is arbitrary ammonium salt of oxalic acid, phosphoric acid, polyphosphoric acid or tetra-sodium.
6. according to the method for the synthetic 2-methane amide pimelinketone described in claim 1-5, the consumption that it is characterized in that described catalyzer is 0.001～0.005 times of pimelinketone quality.
7. according to the method for the synthetic 2-methane amide pimelinketone described in claim 1-5, it is characterized in that described aromatic hydrocarbons is benzene, toluene or dimethylbenzene, its consumption is 0.1～1 times of pimelinketone quality.
8. the method for synthetic 2-methane amide pimelinketone according to claim 1, it is characterized in that by mass ratio being that 1:0.1～1:0.3～0.6:0.001～0.005 pimelinketone, urea, aromatic hydrocarbons and catalyzer add reactor, in extremely anhydrous generation of 100～150 ℃ of reactions, then the 1M dilute sulphuric acid that directly adds 2.5～3.5 times of pimelinketone quality, hydrolysis volution obtains wet product 2-methane amide pimelinketone, it is dried and makes sterling at 70～100 ℃, complete one kettle way and produce.
9. the method for synthetic 2-methane amide pimelinketone according to claim 8, it is characterized in that the water mother liquor that steams water, separates after wet product 2-methane amide pimelinketone of the generation water of described reaction process, volution hydrolytic process to collect respectively, all, for preparing the 1M dilute sulphuric acid of present method hydrolysis use, carry out recycle.
10. the method for synthetic 2-methane amide pimelinketone according to claim 8, the temperature of reaction that it is characterized in that described reaction is 110～140 ℃, the reaction times is 2～5 hours.
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CN104529913A (en) * 2014-12-23 2015-04-22 菏泽市方明制药有限公司 Preparation method of 6-cyclohexano-3,4-cyclohexyl-5-N-hexanolactam-4-ene
CN105218394A (en) * 2015-08-31 2016-01-06 江苏瑞克医药科技有限公司 A kind of synthesis technique improving gliclazide intermediate 2-methane amide pimelinketone yield
CN112661664A (en) * 2020-12-30 2021-04-16 安徽金鼎医药股份有限公司 Synthesis process of gliclazide intermediate 2-formamide cyclohexanone
CN114534644A (en) * 2022-02-15 2022-05-27 浙江博朗新材料有限公司 Device and method for preparing 2-formamide cyclohexanone by catalyzing spiro hydrolysis with solid acid

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104529913A (en) * 2014-12-23 2015-04-22 菏泽市方明制药有限公司 Preparation method of 6-cyclohexano-3,4-cyclohexyl-5-N-hexanolactam-4-ene
CN104529913B (en) * 2014-12-23 2018-11-30 菏泽市方明制药有限公司 The preparation method of 6- cyclohexyl -3,4- and cyclohexyl -5- nitrogen caprolactam -4- alkene
CN105218394A (en) * 2015-08-31 2016-01-06 江苏瑞克医药科技有限公司 A kind of synthesis technique improving gliclazide intermediate 2-methane amide pimelinketone yield
CN105218394B (en) * 2015-08-31 2017-03-15 江苏瑞科医药科技有限公司 A kind of synthesis technique for improving 2 Methanamide Ketohexamethylene yield of Gliclazide intermediate
CN112661664A (en) * 2020-12-30 2021-04-16 安徽金鼎医药股份有限公司 Synthesis process of gliclazide intermediate 2-formamide cyclohexanone
CN114534644A (en) * 2022-02-15 2022-05-27 浙江博朗新材料有限公司 Device and method for preparing 2-formamide cyclohexanone by catalyzing spiro hydrolysis with solid acid
CN114534644B (en) * 2022-02-15 2023-01-03 浙江博朗新材料有限公司 Device and method for preparing 2-formamide cyclohexanone by catalyzing spiro hydrolysis with solid acid

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