CN104529802A - Method for synthesizing N,N'-bis-substituted fluoro malonamide compound - Google Patents
Method for synthesizing N,N'-bis-substituted fluoro malonamide compound Download PDFInfo
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- CN104529802A CN104529802A CN201410767377.XA CN201410767377A CN104529802A CN 104529802 A CN104529802 A CN 104529802A CN 201410767377 A CN201410767377 A CN 201410767377A CN 104529802 A CN104529802 A CN 104529802A
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- malonamide
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Abstract
The invention discloses a method for synthesizing an N, N'-bis-substituted fluoro malonamide compound. The method comprises the following steps: carrying out reaction between primary amino-compounds and fluoro malonate which are used as raw materials under a solvent-free condition to prepare the N, N'-bis-substituted fluoro malonamide compound, or carrying out reaction between primary amine acidic salt compound and fluoro malonamide which are adopted as raw materials in the existence of solvent and acid-binding agent to prepare the N, N'-bis-substituted fluoro malonamide compound. The method is simple to operate, rapid in reaction and high in yield, the difficulty for simply and rapidly synthesizing the N,N'-bis-substituted fluoro malonamide compound can be solved, and the method is suitable for the simple preparation in a laboratory and also suitable for large-scale preparation. The prepared compound can be used for synthesizing fluorine-containing organic molecules.
Description
Technical field
The invention belongs to medicine and pesticide intermediate synthesis field, be specifically related to
a kind of method of synthesis N, N '-bis-replacement fluoro malonamide compounds.
Technical background
Fluorinated polyfunctional group organic compound is the important organic synthesis intermediate of a class, physicochemical property special because of it and coming into one's own in organic synthesis field.Amide structure is the important feature unit extensively existed in the organic molecules such as medicine, agricultural chemicals, and the existence of fluorine atom makes fluorochemicals have the advantage (Nature.1957,179:663 ~ 666) that consumption is few, toxicity is low, drug effect is high, metabolic capacity is strong than not fluorochemicals on the pharmaceutical properties such as medicine, agricultural chemicals.N, N '-bis-replacement fluoro propane diamide compound has fluorine simultaneously and replaces structure and amide structure unit, is the building block that a class has potential application foreground, can be used in the synthesis of a series of compound such as fluoro-containing pesticide and medicine.Also do not have in current document and the system synthesis of this compounds is studied, and the amides synthetic method of routine (Amino Acids & Biotic Resources.2010,32 (1): 34 ~ 38), not only complex operation, reaction time consumption is long, and productive rate is not high yet.
Summary of the invention
For the deficiency that prior art exists, the invention provides the method for the easy to be quick of a kind of synthesis N, N '-bis-replacement fluoro malonamide compounds and high yield.
For solving the problems of the technologies described above, the invention provides
a kind of method of synthesis N, N '-bis-replacement fluoro malonamide compounds, N, the structural formula of N '-bis-replacement fluoro malonamide compounds is as shown in (I), its synthesis step is as follows: with primary amine, its structural formula is as shown in formula II, with fluoromalonic acid ester, its structural formula is as shown in formula III, for raw material, the mol ratio of primary amine and fluoromalonic acid ester is 1.0 ~ 10.0:1, temperature controls between 0 DEG C ~ 50 DEG C, reaction 8 ~ 16h, prepare N, N '-bis-replacement fluoro malonamide compounds, or with primary amine acid-salt compound, its structural formula is as shown in formula IV, be raw material with fluoromalonic acid ester, the mol ratio of primary amine acid-salt compound and fluoromalonic acid ester is 1.0 ~ 10.0:1, temperature controls between 0 DEG C ~ 50 DEG C, 8 ~ 16h is reacted in organic solvent and acid binding agent, prepare N, N '-bis-replacement fluoro malonamide compounds,
In described structural formula: R
1, R
2, R
3, R
4, R
5and R
6be selected from hydrogen atom, alkyl, aromatic base, ester group, acyl group, amide group respectively, furyl, A
-be selected from the inorganic or organic acids such as chlorion, bromide anion, bisulfate ion, sulfonate radical or perchlorate.
According to the method for synthesis N, N of the present invention '-bis-replacement fluoro malonamide compounds, the mol ratio of described primary amine or primary amine acid-salt compound and fluoromalonic acid ester is: 5.0 ~ 10.0:1.
According to the method for synthesis N, N of the present invention '-bis-replacement fluoro malonamide compounds, described organic solvent is methyl alcohol, ethanol, acetonitrile, DMF or Isosorbide-5-Nitrae-dioxane, and consumption of organic solvent is 0 ~ 100 liter of/mole of ammonium salt.
According to synthesis N of the present invention, the method of N '-bis-replacement fluoro malonamide compounds, described acid binding agent is sodium carbonate, triethylamine, sodium hydroxide, salt of wormwood, potassium hydroxide or calcium hydroxide, and the add-on of acid binding agent is 1.0 ~ 3.0 moles of acid binding agents/mole ammonium salt.
Advantage of the present invention: the complex operation that (1) exists for existing synthesizing amide compounds, the problem such as the long and productive rate of reaction time consumption is low, the invention provides the method for the easy to be quick of a kind of synthesis N, N '-bis-replacement fluoro malonamide compounds and high yield.(2) according to above-mentioned synthetic method, Fluoride for Raw Material, can transform completely, and productive rate can reach 99% in most preferred reaction example for the transformation efficiency of malonic ester more than 80%.(3) synthetic method of the present invention is applicable to the simple and easy preparation in laboratory, is also applicable to amplify preparation, reacts easy, and the N of synthesis, N '-bis-replacement fluoro malonamide compounds can be used as building block molecular application in the synthesis of agricultural chemicals and medicine.
Embodiment
Following instance for further describing the N in the present invention, the synthetic method of N '-bis-replacement fluoro malonamide compounds, reaction expression is as follows:
Or
The present invention is only limitted to following instance absolutely not.Raw material amine in claim limited range or ammonium salt and fluoromalonic acid ester all can prepare corresponding N, N '-bis-replacement fluoro malonamide compounds according to method provided by the invention.
Embodiment 1
In the reactor, add 731 milligrams of (10mmol) n-Butyl Amine 99s and 300 milligrams of (2mmol) fluoromalonic acid dimethyl esters, stir under room temperature condition.Reaction thin-layer chromatography is monitored, and after 16 hours, monitoring result shows that fluoromalonic acid dimethyl ester has reacted, filtered with after 10 milliliters of cold ethanol dispersions by reaction mixture, white solid crude product recrystallization in methyl alcohol, obtains N, N '-dibutyl fluoro Malonamide 462 milligrams, yield 99%.Product through NMR analysis confirmation,
1h NMR (CDCl
3, 500MHz, δ/ppm): 6.82 (br, 2H), 5.18 (d, J=48.0Hz, 1H), 3.31 (dd, J=13.5,7.0Hz, 4H), 1.55-1.49 (m, 4H), 1.39-1.31 (m, 4H), 0.93 (t, J=7.5Hz, 6H).
Embodiment 2
In the reactor, 170 milligrams of (2mmol) cyclopentamine, 178 milligrams of (1mmol) diethyl fluoromalonate are added, stirring reaction 12 hours under room temperature condition.Mixture is directly separated by column chromatography, obtains N, N '-bicyclopentyl fluoro Malonamide 204 milligrams, yield 80%.Product through NMR analysis confirmation,
1h NMR (CDCl
3, 500MHz, δ/ppm): 6.77 (br, 2H), 5.12 (d, J=48.0Hz, 1H), 4.24-4.17 (m, 2H), 2.01-1.95 (m, 4H), 1.69-1.60 (m, 8H), 1.47-1.39 (m, 4H).
Embodiment 3
In the reactor, add 107 milligrams of (1mmol) benzylamines and 150 milligrams of (1mmol) fluoromalonic acid dimethyl esters, stir 16 hours under room temperature condition.Reaction mixture is directly separated by column chromatography, obtains N, N '-dibenzyl fluoro Malonamide 129 milligrams, yield 46%.Product through NMR analysis confirmation,
1h NMR (CDCl
3, 500MHz, δ/ppm): 7.36-7.26 (m, 10H), 7.11 (br, 2H), 5.29 (d, J=47.5Hz, 1H), 4.54-4.45 (m, 4H).
Embodiment 4
In the reactor, add 675 milligrams of (10mmol) methylamine hydrochlorides, 300 milligrams of (2mmol) diethyl fluoromalonate, 1.06 grams of (10mmol) sodium carbonate and 10 milliliters of ethanol, stirring reaction 10 hours under 50 DEG C of conditions.Filter, successively with cold ethanol and petroleum ether filter cake, white solid crude product recrystallization in methyl alcohol, obtains N, N '-dimethyl fluoro Malonamide 222 milligrams, yield 75%.Product through NMR analysis confirmation,
1h NMR (DMSO-d
6, 500MHz, δ/ppm): 8.26 (br, 2H), 5.20 (d, J=48.5Hz, 1H), 2.63 (d, J=5.0Hz, 6H).
Embodiment 5
In the reactor, 1.40 grams of (10mmol) propylamine hydrobromates, 356 milligrams of (2mmol) diethyl fluoromalonate, 3.03 grams of (30mmol) triethylamines and 30 milliliters of acetonitriles are added.Stirred at ambient temperature reacts 16 hours.Filter, boil off solvent, residual mixture is directly separated by column chromatography, obtains N, N '-dipropyl fluoro Malonamide 400 milligrams, yield 99%.Product through NMR analysis confirmation,
1h NMR (CDCl
3, 500MHz, δ/ppm): 6.91 (br, 2H), 5.19 (d, J=50Hz, 1H), 3.27 (dd, J=14,7.0Hz, 4H), 1.59-1.52 (m, 4H), 0.93 (t, J=7.5Hz, 6H).
Embodiment 6
In the reactor, add 815 milligrams of (10mmol) ethylamine hydrochlorides, 750 milligrams of (5mmol) fluoromalonic acid dimethyl esters, 2.02 grams of (20mmol) triethylamines and 10 ml methanol, stirring reaction 10 hours under 50 DEG C of conditions.Filter, use petroleum ether filter cake, white solid crude product recrystallization in methyl alcohol, obtains N, N '-diethyl fluoro Malonamide 710 milligrams, yield 81%.Product through NMR analysis confirmation,
1h NMR (DMSO-d
6, 500MHz, δ/ppm): 8.29 (br, 2H), 5.17 (d, J=48.5Hz, 1H), 3.15-3.10 (m, 4H), 1.03 (t, J=7.0Hz, 6H).
Embodiment 7
In the reactor, 1.5 grams of (16mmol) chaff amine, 1.25 grams of (7mmol) diethyl fluoromalonate, 10 milliliters of ethanol are added, stirred at ambient temperature 16 hours.Be spin-dried for solvent, filter, by petroleum ether 4 times, white solid crude product recrystallization in methyl alcohol, obtains N, N '-two furfuryl fluoro Malonamide 1.95 grams, yield 99%.Product through NMR analysis confirmation,
1h NMR (DMSO-d
6, 500MHz, δ/ppm): 8.85 (t, J=5.5Hz, 2H), 7.58-7.57 (m, 2H), 6.40-6.38 (m, 2H), 6.24-6.23 (m, 2H), 5.35 (d, J=48.5Hz, 1H), 4.35-4.28 (m, 4H).
Embodiment 8
In the reactor, add 820 milligrams of (14mmol) Isopropylamines and 1.07 grams of (6mmol) diethyl fluoromalonate, stir 16 hours under room temperature condition.Reaction mixture is directly separated by column chromatography, obtains N, N '-di-isopropyl fluoro Malonamide 1.2 grams, yield 98%.Product through NMR analysis confirmation,
1h NMR (CDCl
3, 500MHz, δ/ppm): 6.62 (br, 2H), 5.11 (d, J=48Hz, 1H), 4.10-4.86 (m, 2H), 1.19 (d, J=6Hz, 12H).
Claims (4)
1. a synthesis N, the method of N '-bis-replacement fluoro malonamide compounds, N, the structural formula of N '-bis-replacement fluoro malonamide compounds is as shown in (I), its synthesis step is as follows: with primary amine, structural formula is as shown in formula II, with fluoromalonic acid ester, structural formula is as shown in formula III, for raw material, the mol ratio of primary amine and fluoromalonic acid ester is 1.0 ~ 10.0:1, temperature controls between 0 DEG C ~ 50 DEG C, reaction 8 ~ 16h, prepare N, N '-bis-replacement fluoro malonamide compounds, or with primary amine acid-salt compound, structural formula is as shown in formula IV, be raw material with fluoromalonic acid ester, the mol ratio of primary amine acid-salt compound and fluoromalonic acid ester is 1.0 ~ 10.0:1, temperature controls between 0 DEG C ~ 50 DEG C, 8 ~ 16h is reacted in organic solvent and acid binding agent, prepare N, N '-bis-replacement fluoro malonamide compounds,
In described structural formula: R
1, R
2, R
3, R
4, R
5and R
6be selected from hydrogen atom, alkyl, aromatic base, ester group, acyl group, amide group respectively, furyl, A
-be selected from the inorganic or organic acids such as chlorion, bromide anion, bisulfate ion, sulfonate radical or perchlorate.
2., according to the method for synthesis N, N according to claim 1 '-bis-replacement fluoro malonamide compounds, it is characterized in that: the mol ratio of described primary amine or primary amine acid-salt compound and fluoromalonic acid ester is: 5.0 ~ 10.0:1.
3. according to the synthesis N described in claim 1 or 2, the method of N '-bis-replacement fluoro malonamide compounds, is characterized in that: described organic solvent is methyl alcohol, ethanol, acetonitrile, DMF or 1,4-dioxane, consumption of organic solvent is 0 ~ 100 liter of/mole of ammonium salt.
4. according to synthesis N according to claim 1, the method of N '-bis-replacement fluoro malonamide compounds, it is characterized in that: described acid binding agent is sodium carbonate, triethylamine, sodium hydroxide, salt of wormwood, potassium hydroxide or calcium hydroxide, the add-on of acid binding agent is 1.0 ~ 3.0 moles of acid binding agents/mole ammonium salt.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106916043A (en) * | 2016-12-07 | 2017-07-04 | 绍兴瑞康生物科技有限公司 | Solvent-free acid amides synthetic method and its macromolecule antioxidative stabilizer synthesis in apply |
| CN111548275A (en) * | 2020-05-27 | 2020-08-18 | 龙曦宁（上海）医药科技有限公司 | Synthetic method of 2- (aminomethyl) -N1, N1-dimethylpropane-1, 3-diamine trihydrochloride |
| WO2022189190A1 (en) | 2021-03-09 | 2022-09-15 | Basf Se | Malonamides and their use as herbicides |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101506186A (en) * | 2006-05-22 | 2009-08-12 | 英国国防部 | Substituted n-acyl homoserine lactones |
| CN103717589A (en) * | 2011-08-11 | 2014-04-09 | 弗·哈夫曼-拉罗切有限公司 | Compounds for the treatment and prophylaxis of respiratory syncytial virus disease |
-
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- 2014-12-13 CN CN201410767377.XA patent/CN104529802A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101506186A (en) * | 2006-05-22 | 2009-08-12 | 英国国防部 | Substituted n-acyl homoserine lactones |
| CN103717589A (en) * | 2011-08-11 | 2014-04-09 | 弗·哈夫曼-拉罗切有限公司 | Compounds for the treatment and prophylaxis of respiratory syncytial virus disease |
Non-Patent Citations (1)
| Title |
|---|
| PALANLAPPA NANJAPPAN ET AL.: "An Efficient Synthesis of Some 6-Substituted 4,8-Diaza-3,3,9,9-tetramethylundeca-2,lO-dione Dioximes(Propylene Amine Oximes,PnAOs): Ligands for 99mTc Complexes Used in Structure Distribution Relationship(SDR) Studies", 《TETRAHEDRON》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106916043A (en) * | 2016-12-07 | 2017-07-04 | 绍兴瑞康生物科技有限公司 | Solvent-free acid amides synthetic method and its macromolecule antioxidative stabilizer synthesis in apply |
| CN111548275A (en) * | 2020-05-27 | 2020-08-18 | 龙曦宁（上海）医药科技有限公司 | Synthetic method of 2- (aminomethyl) -N1, N1-dimethylpropane-1, 3-diamine trihydrochloride |
| WO2022189190A1 (en) | 2021-03-09 | 2022-09-15 | Basf Se | Malonamides and their use as herbicides |
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