* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Stage #1: at 20 - 60℃; for 8 h; Stage #2: With ammonia In tetrahydrofuran; water at 0 - 20℃; for 8 h; Stage #3: at 60℃; for 8 h;
Preparation Example 23: Synthesis of 3-methyl-piperidine-2.6-dioneAcetic anhydride was added to commercially available 2-methylglutaric acid (1 g, 6.8 mmol) at room temperature, and the mixture was stirred at 60 °C for 8 hours under reflux. After completion of the reaction was confirmed by TLC, the remaining acetic anhydride was removed under reduced pressure. The concentrated compound was dissolved in tetrahydrofuran and an ammonia aqueous solution (1.7 <n="86"/>niL, 14.6 mmol) was slowly added thereto at 0°C, followed by stirring for 8 hours at room temperature. After the reaction was complete, the remaining ammonia aqueous solution was removed under reduced pressure and an acetic anhydride was added, followed by reflux at 60 °C for 8 hours. The residual acetic anhydride was removed under reduced pressure. The concentrate was purified by column chromatography (ethyl acetate:hexane = 1:1) to afford 682 mg (yield: 78percent) of the title compound.1H NMR (400 MHz, MeOH-(I4) δl.24-1.28 (m, 3H), 1.71-1.77 (IH), 2.04-2.08 (m, IH), 2.57-2.65 (m 3H); MS (m/e) 128 (M+l)
Reference：
[1] Patent: WO2009/82134, 2009, A2, . Location in patent: Page/Page column 84-85
[2] Journal of the American Chemical Society, 1943, vol. 65, p. 270
[3] Bulletin de l'Academie Polonaise des Sciences, Serie des Sciences Chimiques, 1981, vol. 29, # 1-2, p. 11 - 16
[4] Journal of the American Chemical Society, 1982, vol. 104, # 25, p. 7257 - 7267
4
[ 4553-62-2 ]
[ 29553-51-3 ]
Yield
Reaction Conditions
Operation in experiment
67%
Stage #1: at 20 - 130℃; for 1 h; Stage #2: With sodium carbonate In water
A solution OfH2SO4 (80ml), acetic acid (500ml) and 2-methylpentanedinitrile (128.0 g, 1184 mmol) was stirred at room temperature. An aqueous solution of acetic acid (100 ml in 32 ml water) was then added dropwise. Upon completion of the addition, the reaction was heated to 130 0C for 1 hour. The reaction was then allowed to cool to room temperature and filtered to remove solids, which were washed with acetic acid (100 ml). The filtrate was then concentrated until a residue resulted. This residue was poured into water (0.75 1), and adjusted to pH 5 with Na2CO3. The resulting solid was collected by filtration and washed with cold water to give the title compound (101 g, 67percent) which was used without further purification.
Reference：
[1] Patent: WO2006/82392, 2006, A1, . Location in patent: Page/Page column 110
[2] Bioorganic and Medicinal Chemistry, 2002, vol. 10, # 6, p. 1793 - 1804
[3] Journal of the American Chemical Society, 1982, vol. 104, # 25, p. 7257 - 7267
[4] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 10, p. 2958 - 2961
5
[ 14618-77-0 ]
[ 107-13-1 ]
[ 29553-51-3 ]
Reference：
[1] Angewandte Chemie - International Edition, 2003, vol. 42, # 28, p. 3302 - 3304
6
[ 4553-62-2 ]
[ 90-27-7 ]
[ 29553-51-3 ]
[ 769-68-6 ]
Yield
Reaction Conditions
Operation in experiment
76%
at 200℃; for 5 h;
Thermal Procedure: [0076] The dinitrile (3.0 mmol, 1.0 equiv.) is added, in a glass tube, to a mixture of acid (3.0 mmol) and catalyst (0.06 mmol, 0.02 equiv., except for example 1, where 0.12 mmol, 0.04 equiv., is employed). The tube is then hermetically closed (using a screw stopper) and left mechanically stirring at 200° C. for 5 h. After reaction, the crude reaction mixture is transferred into a 50 ml round-bottomed flask with 10 ml of ethanol. If necessary, the tube is placed in an ultrasonic bath at 60° C., in order to promote the dissolution of the reaction mixture in the ethanol. 3 g of silica are subsequently added to this mixture in order to produce a solid deposit after evaporation of the ethanol. Finally, the pure nitrile is obtained after chromatography on a silica column (gradient from M1 to M9, followed by M0). For its part, the cyclic imide is obtained after elution with ethyl acetate. The conversion to the desired nitrile is determined by 1H NMR of the crude product. The yields shown are the yields of the isolated products after purification.
Example 11 [0084] 200 mmol of 2-methylglutaronitrile and 100 mmol of dodecanedioic acid are introduced into a 100 ml three-necked flask. 3 mmol of anhydrous AlCl3 are added to the suspension. Heating to 200° C. is then carried out with stirring. The mixture is maintained under these conditions for 5 hours. The reaction medium is subsequently analyzed and the following results are obtained: [0085] DC percent of the MGN=90percent, RY percent of the MGI=88percent, RY percent for dodecanedinitrile=81percent.
Example 12 130 g (1200 mmol) of 2-methylglutaronitrile and 20 g (120 mmol) of isophthalic acid are introduced into a 250 ml glass reactor. The white suspension is stirred and 0.32 g (2.4 mmol) of anhydrous aluminum chloride is added. The mixture is gradually heated to 270° C. and is maintained under these conditions for 4 h. During the rise in temperature, the isophthalic acid dissolves in the MGN. The reaction medium is subsequently analyzed by GC. An RY percent for MGI of 76percent and a yield of 1,3-dicyanobenzene of 69percent are obtained.
Reference：
[1] Heterocycles, 2005, vol. 65, # 1, p. 9 - 22
[2] Journal of the American Chemical Society, 1982, vol. 104, # 25, p. 7257 - 7267
[3] Journal of Organic Chemistry, 1986, vol. 51, # 11, p. 2071 - 2077
10
[ 4553-62-2 ]
[ 110-15-6 ]
[ 123-56-8 ]
[ 29553-51-3 ]
Yield
Reaction Conditions
Operation in experiment
96 %Chromat.
With phosphoric acid In water at 270℃; for 2 h;
Example 5 Preparation of a Mixture of Imides From Pure MGN and From Bio-Sourced Succinic Acid [0169] In a 100 mL reactor, are introduced 23 g of 2-methyl-glutaronitrile and then 25 g of succinic acid obtained by fermentation are added. Stirring is applied and 0.1 g of 85percent ortho-phosphoric acid are added. The reaction medium is heated up to 270° C. and these conditions are maintained for 2 hours. By GC analysis, the following results are obtained: [0170] TT percent (MGN)=98percent [0171] RR percent (MGI)=96percent [0172] RR percent (succinimide)=97percent
Reference：
[1] Journal of the American Chemical Society, 1982, vol. 104, # 25, p. 7257 - 7267
12
[ 558-37-2 ]
[ 82621-79-2 ]
[ 29553-51-3 ]
[ 82621-95-2 ]
[ 82621-94-1 ]
Reference：
[1] Journal of the American Chemical Society, 1982, vol. 104, # 25, p. 7257 - 7267
13
[ 18069-17-5 ]
[ 4553-62-2 ]
[ 29553-51-3 ]
Yield
Reaction Conditions
Operation in experiment
97 %Chromat.
at 270℃; for 2 h;
Example 1 Preparation of 3-methyl-glutarimide (MGI) Without Any Catalyst [0156] In a 100 mL stirred reactor, are introduced 29.2 g of 2-methyl-glutaric acid and 21.6 g of 2-methyl-glutaronitrile (MGN). With stirring, the reaction mixture is brought to 270° C. and these conditions are maintained for 2 hours. The brown reaction medium is then analyzed by gas chromatography (GC) and the following results are obtained: [0157] TT percent (MGN)=99percent [0158] RR percent (MGI)=97percent
2,3 ,6-Trichloro-5-methylpyridine A well powdered mixture of <strong>[29553-51-3]3-methylpiperidine-2,6-dione</strong> (Method 49, 15.0 g, 118 mmol) and PCl5 (155.0 g, 743 mmol) was slowly heated to 1500C and kept at that temperature for 2 hours. The resulting solution was then cooled to room temperature, and slowly poured onto ice. The resulting precipitate was filtered, washed with cold water, and dried. The resulting precipitate was then recrystallized from a mixture of EtOH-petroleum ether (1 : 8) to give the title compound (11.8 g, 51%).
Preparation Example 23: Synthesis of 3-methyl-piperidine-2.6-dioneAcetic anhydride was added to commercially available 2-methylglutaric acid (1 g, 6.8 mmol) at room temperature, and the mixture was stirred at 60 C for 8 hours under reflux. After completion of the reaction was confirmed by TLC, the remaining acetic anhydride was removed under reduced pressure. The concentrated compound was dissolved in tetrahydrofuran and an ammonia aqueous solution (1.7 <n="86"/>niL, 14.6 mmol) was slowly added thereto at 0C, followed by stirring for 8 hours at room temperature. After the reaction was complete, the remaining ammonia aqueous solution was removed under reduced pressure and an acetic anhydride was added, followed by reflux at 60 C for 8 hours. The residual acetic anhydride was removed under reduced pressure. The concentrate was purified by column chromatography (ethyl acetate:hexane = 1:1) to afford 682 mg (yield: 78%) of the title compound.1H NMR (400 MHz, MeOH-(I4) deltal.24-1.28 (m, 3H), 1.71-1.77 (IH), 2.04-2.08 (m, IH), 2.57-2.65 (m 3H); MS (m/e) 128 (M+l)
A solution OfH2SO4 (80ml), acetic acid (500ml) and 2-methylpentanedinitrile (128.0 g, 1184 mmol) was stirred at room temperature. An aqueous solution of acetic acid (100 ml in 32 ml water) was then added dropwise. Upon completion of the addition, the reaction was heated to 130 0C for 1 hour. The reaction was then allowed to cool to room temperature and filtered to remove solids, which were washed with acetic acid (100 ml). The filtrate was then concentrated until a residue resulted. This residue was poured into water (0.75 1), and adjusted to pH 5 with Na2CO3. The resulting solid was collected by filtration and washed with cold water to give the title compound (101 g, 67%) which was used without further purification.
Example 1 Preparation of 3-methyl-glutarimide (MGI) Without Any Catalyst [0156] In a 100 mL stirred reactor, are introduced 29.2 g of 2-methyl-glutaric acid and 21.6 g of 2-methyl-glutaronitrile (MGN). With stirring, the reaction mixture is brought to 270 C. and these conditions are maintained for 2 hours. The brown reaction medium is then analyzed by gas chromatography (GC) and the following results are obtained: [0157] TT % (MGN)=99% [0158] RR % (MGI)=97%
Example 5 Preparation of a Mixture of Imides From Pure MGN and From Bio-Sourced Succinic Acid [0169] In a 100 mL reactor, are introduced 23 g of 2-methyl-glutaronitrile and then 25 g of succinic acid obtained by fermentation are added. Stirring is applied and 0.1 g of 85% ortho-phosphoric acid are added. The reaction medium is heated up to 270 C. and these conditions are maintained for 2 hours. By GC analysis, the following results are obtained: [0170] TT % (MGN)=98% [0171] RR % (MGI)=96% [0172] RR % (succinimide)=97%
Example 12 130 g (1200 mmol) of 2-methylglutaronitrile and 20 g (120 mmol) of isophthalic acid are introduced into a 250 ml glass reactor. The white suspension is stirred and 0.32 g (2.4 mmol) of anhydrous aluminum chloride is added. The mixture is gradually heated to 270 C. and is maintained under these conditions for 4 h. During the rise in temperature, the isophthalic acid dissolves in the MGN. The reaction medium is subsequently analyzed by GC. An RY % for MGI of 76% and a yield of 1,3-dicyanobenzene of 69% are obtained.
Thermal Procedure: [0076] The dinitrile (3.0 mmol, 1.0 equiv.) is added, in a glass tube, to a mixture of acid (3.0 mmol) and catalyst (0.06 mmol, 0.02 equiv., except for example 1, where 0.12 mmol, 0.04 equiv., is employed). The tube is then hermetically closed (using a screw stopper) and left mechanically stirring at 200 C. for 5 h. After reaction, the crude reaction mixture is transferred into a 50 ml round-bottomed flask with 10 ml of ethanol. If necessary, the tube is placed in an ultrasonic bath at 60 C., in order to promote the dissolution of the reaction mixture in the ethanol. 3 g of silica are subsequently added to this mixture in order to produce a solid deposit after evaporation of the ethanol. Finally, the pure nitrile is obtained after chromatography on a silica column (gradient from M1 to M9, followed by M0). For its part, the cyclic imide is obtained after elution with ethyl acetate. The conversion to the desired nitrile is determined by 1H NMR of the crude product. The yields shown are the yields of the isolated products after purification.
Example 11 [0084] 200 mmol of 2-methylglutaronitrile and 100 mmol of dodecanedioic acid are introduced into a 100 ml three-necked flask. 3 mmol of anhydrous AlCl3 are added to the suspension. Heating to 200 C. is then carried out with stirring. The mixture is maintained under these conditions for 5 hours. The reaction medium is subsequently analyzed and the following results are obtained: [0085] DC % of the MGN=90%, RY % of the MGI=88%, RY % for dodecanedinitrile=81%.
With hydrogen; at 200℃; under 11251.1 - 15001.5 Torr; for 12.0h;
Hydrogenation of 3-methylglutarimide (MGI) with a Mixed Catalyst 20 g of MGI are placed in a stainless steel stirred autoclave, and 1.0 g of (5% by weight Ru +1% by weight Pd)/C catalyst is added. The autoclave is flushed twice with 20 bar of nitrogen and then with 3 times 20 bar of hydrogen. The autoclave is then placed at 15 bar and heating is carried out at 200 C. while stirring. A constant pressure of 20 bar is maintained in the autoclave throughout the duration of the reduction. After 12 hours of reaction the autoclave is brought back to ambient temperature and flushed with twice 20 bar of nitrogen. The reaction medium is then analyzed by gas chromatography. The MGI conversion is 100% and the yield of mixture of the two lactams is 92%; the presence of 3-methylpiperidine is not detected.
N<SUP>1</SUP>-hexyl-4-methylpentanediamide[ No CAS ]
N<SUP>1</SUP>-hexyl-2-methylpentanediamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With 2-ethyl succinimide; sodium t-butanolate; at 130℃; for 2h;
In a round bottom flask equipped with a magnetic stirrer and a condenser, are added 50.0 g of a mixture composed of 2-methylgiutarimide (MGI) (86.4 wt%, 0.34 mol) and 2-ethylsuccinimide (10.7 wt%, 0.04 mol), 40.1 g of hexylamine (0.40 mol) and 0.9 g of tBuONa.The mixture is then allowed to stir at 130C during 2 hours. Over thecourse of the reaction the mixture becomes monophasic (yellow solution). Thereaction progress is followed thanks to GC analysis and at the end of the reaction, the product is recovered thanks to recrystallization in 150 mL of methyl ethyl ketone (MEK) followed by washing two times with 100 mL of ethyl acetate.After drying under vacuum, 71.5 g (92% yield based on MGI) of the product is obtained as a white powder (melting point (mp): 111.8 - 115.4 C).NMR analysis shows that the product is obtained as a mixture of 2 isomers:- N1 -hexyl-4-methylpentanediamide (57 wt%),- N1 -hexyl-2-methylpentanediamide (43 wt%).
With sodium t-butanolate; at 130℃; for 2.5h;
In a 500 ml glass reactor equipped with a cooling system, 100.0 g of<strong>[29553-51-3]methyl glutarimide</strong> (MGI) and 76.6 g of hexylamine then 1.0 g of tBuONa was added. The reactor was then heated to 130C and maintained at the reaction temperature for 2.5h. Then the reaction mixture was cooled down. The solid was added into 400 ml of methylethylketone (MEK) and heated to 100C. The solution was then cooled down and the obtained solid was collected by filtration and washed with ethyl acetate (EA, 2*300ml). The obtained solid was dried in vacuo to give 137.0 g of white solid, the yield was 76%, the purity was >98%. NMR analysis showed that the product was obtained as a mixture of 2 isomers: - N1 -hexyl-4-methylpentanediamide (65 wt%),- N1 -hexyl-2-methylpentanediamide (35 wt%).
With sodium t-butanolate; at 130℃; for 2.5h;
In a 500 ml glass reactor equipped with a cooling system, 100.0 g of <strong>[29553-51-3]methyl glutarimide</strong> (MGI) and 76.6 g of hexylamine and then 1.0 g of tBuONa was added. The reactor was then heated to 130C and maintained at the reaction temperature for 2.5h. Then the reaction mixture was cooled down. The solid was added into 400 ml of methylethylketone (MEK) and heated to 100C. The solution was then cooled down and the obtained solid was collected by filtration and washed with ethyl acetate (EA , 2*300ml). The obtained solid was dried in vacuo to give 137.0 g of white solid, the yield was 76%, the purity was >98%. NMR analysis showed that the product was a mixture of 2 isomers: (0288) - N -hexyl-4-methylpentanediamide (65 wt%), - N1-hexyl-2-methylpentanediamide (35 wt%).
With sodium t-butanolate; at 130℃; for 2.5h;
In a 500 ml glass reactor equipped with a cooling system, 100.0 g of <strong>[29553-51-3]methyl glutarimide</strong> (MGI) and 76.6 g of hexylamine and then 1.0 g of tBuONa was added. The reactor was then heated to 130C and maintained at the reaction temperature for 2.5h. Then the reaction mixture was cooled down. The solid was added into 400 ml of methylethylketone (MEK) and heated to 100C. The solution was then cooled down and the obtained solid was collected by filtration and washed with ethyl acetate (EA , 2*300ml). The obtained solid was dried in vacuo to give 137.0 g of white solid, the yield was 76%, the purity was >98%. NMR analysis showed that the product was a mixture of 2 isomers: - N -hexyl-4-methylpentanediamide (65 wt%), - N1-hexyl-2-methylpentanediamide (35 wt%).
With 2-ethyl succinimide; sodium t-butanolate; at 150℃; for 2h;
In a round bottom flask equipped with a magnetic stirrer and a condenser, are added 17.0 g of a mixture composed of <strong>[29553-51-3]2-methylglutarimide</strong> (86.4 wt%,0.12 mol) and 2-ethylsuccinimide (10.7 wt%, 0.01 mol), 25.0 g of dodecylamine (0.13 mol) and 0.4 g of tBuONa.The mixture is then allowed to stir at 150C during 2 hours. Over the course of the reaction the mixture turns yellow and reaction progress can be followed thanks to GC analysis. After reaction completion, the desired productis recovered thanks to recrystallization in 200 mL of methyl ethyl ketone (MEK) followed by washing two times with 100 mL of ethyl acetate.After drying under vacuum, 29.1 g (78 % yield based on MGI) of the product is obtained as a white powder (mp: 112.9 - 117.8 C).NMR analysis shows that the product is obtained as a mixtureof 2 isomers:- Ni -lauryl-4-methylpentanediamide (58 wt%),- Ni -lauryl-2-methylpentanediamide (42 wt%).
With sodium t-butanolate; at 150℃; for 3h;
In a 500 ml glass reactor equipped with a cooling system, 68.6 g (0.54 Mol 1 eq) of <strong>[29553-51-3]methyl glutarimide</strong> (MGI) and 100.0 g (0.54 mol 1 eq) oflaurylamine then 1.0 g of tBuONa was added. The reactor was then heated to 150C and maintained at the reaction temperature for 3h. Then the reaction mixture was cooled down. The solid was added into 400 ml of nnethylethylketone (MEK) and heated to 100C. The solution was then cooled down and the obtained solid was collected by filtration and washed by ethyl acetate (2*300ml). The Obtained solid was dried in vacuo to give 135.0 g of white solid, the yield was 80%, the purity was >98%. NMR analysis showed that the product was obtained as a mixture of 2 isomers:- N1 -hexyl-4-methylpentanediamide (55 wt%),- N1 -hexyl-2-methylpentanediamide (45 wt%).
In a 500 ml glass reactor equipped with a cooling system, 60.0 g (0.472 Mol 1 eq) of methyl Glutarimide (MGI) and 126.0 g (0.472 mol 1 eq) of oleylamine then 1.2 g of tBuONa was added. The reactor was then heated till 150C and maintained at the reaction temperature for 3h. Then the reaction mixture was cooled down. The solid was added into 400 ml of methylethylketone (MEK) and heated to 100C. The solution was then cooled down and the obtained solid was collected by filtration and washed by ethyl acetate (2*300ml). The obtained solid was dried in vacuo to give 145.0 g of white solid, the yield was 78%, the purity was >98%. NMR analysis showed that the product was obtained as a mixture of 2 isomers:- N1 -hexyl-4-methylpentanediamide (65 wt%),- N1 -hexyl-2-methylpentanediamide (35 wt%).
In a 1000 ml round bottom flask equipped with a mechanical stirrer and a condenser 63.57 g (0.5 mol 1 eq) of methylglutarimide and 185.35 g of oleylamine (0.475 mol, 0.95 eq.) was added. The suspension was heated to 130C during 4 hours. This mixture was then cooled down to 80C, then 350 ml_ of methylethylketone were added. The mixture was then heated to 80C, then cooled down to room temperature, leading to acrystallization. The mixture was filtered and the solid was washed twice with 100 ml_ of ethyl acetate. The solid was suspended in 1.0 Lof methylethylketone, the mixture was heated to 80C, then cooled to 30C and filtered. This solid was suspended in 450 ml ofmethylethylketone and heated to 80C then cooled down to30C and filtered. The obtained solid (12.0 g, 6% yield) contained an isomer 4/ isomer 2 ratio of 96/4.
N<SUP>1</SUP>-hexyl-4-methylpentanediamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
12%
at 130℃; for 4h;
In a 500 ml round bottom flask equipped with a mechanical stirrer and a condenser 63,57 g of methylglutarimide (0,5 mol) and 50,60 g of n- hexylamine (0,5 mol, 1 eq.) was added. The suspension was heated to 130C during 4 hours. The mixture was then cooled down to 80C, then 320 ml_ of methylethylketone are added. The mixture was heated to 80C, then cooled down to room temperature, leading to a crystallization. The mixture was filtered and the solid is washed twice with 100 ml_ of ethyl acetate. The obtained solid contained an isomer 4/isomer 2 ratio of de 54/46. The solid is suspended in 1 I of methylethylketone, the mixture was heated to 80C, then cooled to 30C and filtered. The obtained solid contained an isomer 4/ isomer 2 ratio of 75/25. This solid was suspended in 500 ml of methylethylketone heated to 80C then cooled down to 30C and filtered. The obtained solid (13,3 g, 12% yield) contained an isomer 4/ isomer 2 ratio of 97/3.
In a 1000 ml round bottom flask equipped with a mechanical stirrer and a condenser 127.13 g of methylglutarimide (0.7 mol) and 185.35 g of melted dodecylamine (0.7 mol, 1 eq.) was added. The suspension was heated to 130C during 4 hours. The obtained product mixture contained an isomer4/isomer2 ratio of 52/48. This mixture was then cooled down to 100C, then 400 ml_ of methylethylketone were added. The mixture was then heated to 80C, then cooled down to room temperature, leading to a crystallization. The mixture was filtered and the solid was washed twice with 100 ml_ of ethyl acetate. The solid was suspended in 1.5 Iof methylethylketone, the mixture was heated to 80C, then cooled to 30C and filtered. This solid was suspended in 450 ml ofmethylethylketone and heated to 80C then cooled down to 30C and filtered. The obtained solid (17.1 g, 8% yield) contained an isomer 4/ isomer 2 ratio of 97/3.
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