* 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.
The 3-azidomethyl-benzonitrile (12.4 g, 0.078 mol) in ethyl acetate (40 mL) was hydrogenated at 45 psi in the presence of 5percent palladium on carbon (4.0 g) at room temperature overnight. The product was filtered through a celite pad and the solvent was evaporated to give 3-aminomethyl-benzonitrile as light brown solid (7.87 g, 76percent yield). 1H-NMR (CDCl3): δ 7.62-7.57 (m, 1H), 7.56-7.43 (m, 2H), 7.42-7.31 (m, 1H), 3.87 (s, 2H).
Reference：
[1] Journal of Medicinal Chemistry, 2015, vol. 58, # 3, p. 1067 - 1088
[2] Patent: WO2016/7966, 2016, A2, . Location in patent: Paragraph 0031
[3] Patent: US2006/94749, 2006, A1, . Location in patent: Page/Page column 11
[4] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 20, p. 3477 - 3482
3
[ 626-17-5 ]
[ 1477-55-0 ]
[ 10406-24-3 ]
Yield
Reaction Conditions
Operation in experiment
92.8%
With hydrogen In methanol; ammonia at 65℃; for 4 h;
The same type of sponge nickel catalyst as used in Comparative Example 5 was charged into a glass tube with a 10-mm inner diameter in an amount of 3 g and dried at 200° C. in a nitrogen stream. Then, a mixed gas (methanol:nitrogen=4:96 by volume) was allowed to pass through the catalyst bed to pretreat the catalyst under the conditions of atmospheric pressure, 200° C., a flow rate of 1.5 NL/h, and 3 h. After the pretreatment, the catalyst was cooled to 30° C. in a nitrogen gas flow. The pretreated catalyst was slurried in 60 g of methanol in a nitrogen atmosphere. The hydrogenation of isophthalonitrile was conducted in the same manner as in Comparative Example 5 except for using the pretreated catalyst thus prepared. After 4 h of the hydrogenation, a part of the reaction liquid was sampled and analyzed. The conversion of isophthalonitrile was 100 mol percent, the yield of m-xylylenediamine was 92.8 mol percent, the yield of 3-cyanobenzylamine was 0.2 mol percent, and the yield of high-boiling condensation products was 7 mol percent.
87.3%
With hydrogen In ammonia; 1,3,5-trimethyl-benzene at 50℃;
EXAMPLE 1 Hydrogenation of Isophthalonitrile Into a 100-ml autoclave, were charged 3.2 g of isophthalonitrile, 10.4 g of mesitylene, 10.0 g of liquid ammonia and 2.0 g of Pd-alumina pellets (manufactured by N.E. Chemcat Corporation; Pd content = 5percent by weight), and the inner pressure was raised to 4.9 MPa by hydrogen gas. Then, the autoclave was shaken at 50°C until the change of pressure was no longer appreciated. The analysis on the reaction product solution showed that the conversion of isophthalonitrile was 95.7 molpercent, the yield of 3-cyanobenzylamine was 87.3 molpercent and the yield of m-xylynenediamine was 7.7 molpercent. The reaction solution separated from the catalyst was charged into a 100-ml autoclave together with 10.0 g of liquid ammonia and 2.0 g of Ni-diatomaceous earth pellets (manufactured by Nikki Chemical Co., Ltd.; Ni supported amount = 46percent by weight). The inner pressure was raised to 4.9 MPa by hydrogen gas. Then, the autoclave was shaken at 50°C until the change of pressure was no longer appreciated. The analysis on the reaction product solution showed that the conversion of isophthalonitrile was 100 molpercent, the yield of 3-cyanobenzylamine was 0.2 molpercent and the yield of m-xylynenediamine was 89.4 molpercent EXAMPLE 4 Hydrogenation of Isophthalonitrile Into a 100-ml autoclave, were charged 3.2 g of isophthalonitrile, 10.4 g of mesitylene, 10.0 g of liquid ammonia and 2.0 g of Pd-alumina pellets (manufactured by N.E. Chemcat Corporation; Pd content = 5percent by weight), and the inner pressure was raised to 4.9 MPa by hydrogen gas. Then, the autoclave was shaken at 50°C until the change of pressure was no longer appreciated. The analysis on the reaction product solution showed that the conversion of isophthalonitrile was 95.7 molpercent, the yield of 3-cyanobenzylamine was 87.3 molpercent and the yield of m-xylynenediamine was 7.7 molpercent. The reaction solution separated from the catalyst was charged into a 100-ml autoclave together with 10.0 g of liquid ammonia and 2.0 g of the catalyst A. The inner pressure was raised to 4.9 MPa by hydrogen gas. Then, the autoclave was shaken at 50°C until the change of pressure was no longer appreciated. The analysis on the reaction product solution showed that the conversion of isophthalonitrile was 100 molpercent, the yield of 3-cyanobenzylamine was 0.0 molpercent and the yield of m-xylynenediamine was 91.1 molpercent.
84.8%
With hydrogen In methanol; ammonia at 65℃; for 4 h; autoclave
Into a 300-ml SUS autoclave equipped with a stirrer, 10 g of isophthalonitrile was charged. Then, a slurry prepared by dispersing 3 g of a leached sponge nickel catalyst ("NDHT" available from Kawaken Fine Chemicals Co., Ltd.) in 60 g of methanol was charged and the autoclave was closed. After replacing the air in the autoclave with nitrogen, 30 g of ammonia was charged. The inner pressure was raised to 5 MPaG by hydrogen, and the hydrogenation was allowed to proceed at 65° C. The pressure was maintained at 5 MPaG by introducing hydrogen to supplement the consumed hydrogen. After 4 h of the hydrogenation, a part of the reaction liquid was sampled and analyzed. The conversion of isophthalonitrile was 100 mol percent, the yield of m-xylylenediamine was 84.8 mol percent, the yield of 3-cyanobenzylamine was 0.2 mol percent, and the yield of high-boilig condensation products was 15 mol percent.
With sulfuric acid In 1,4-dioxane; methanol at 25℃; for 0.25 h;
3- (DI-TERT-BUTOXYCARBONYLAMINO) BENZONITRILE (2g, 6. Ommoles) (prepared as described in Preparative Example 246, Step A above) was dissolved in methanol (30mL) and 10percent (v/v) (10percent CONC. sulfuric acid in 1,4-dioxane) (79mL) was added. The solution was stirred at 25 C for 0.25h and worked up as described in Preparative Example 89, Step C above). The residue was chromatographed on a SILICA GEL COLUMN (15X5CM) using 3percent (10percent CONC. ammonium hydroxide in METHANOL)-DICHLOROMETHANE as the eluant to give the title compound (651.4mg, 82percent): FABMS: m/z 133.1 (MH+) ; HRFABMS: m/z 133.0762 (MH+). Calcd. for C8H9N2 : m/z 133.0766 ; 8H (CDCI3) 2.57 (2H, S,-CH2NH2), 3.92 (2H, s,- CH2NH2), 7.46 (1 H, m, Ar-H), 7.57 (2H, m, Ar-H) and 7.64 ppm (1 H, m, Ar-H); BC (CDC13) CH2: 45.2 ; CH: 129.4, 130.7, 130.7, 131.8 ; C: 112.4, 118.8, 143.8.
EXAMPLE 2 [0055] Hydrogenation Test [0056] A tubular insulated reactor having an inner diameter of 0.4 m was filled with 0.9 t of a commercially available catalyst (Ni-3266E manufactured by Harshaw Co., Ltd.; nickel content: about 50percent) to a packing height of 8 m. After activating the catalyst by reduction at 200° C. under a hydrogen flow, hydrogen gas and a hydrogenation raw material (IPN:MX:NH3=6:21:73 by weight) each pre-heated to 55° C. were fed into the reactor from the top thereof at respective feed rates of 100 Nm3/h and 1.5 t/h to allow the hydrogenation to proceed. The reaction pressure was 15 MPa. The reaction solution sampled from the outlet of the reactor was analyzed by gas chromatography. The conversion of isophthalonitrile was 100percent, the yield of m-xylylenediamine was 92 mol percent, and the yield of 3-cyanobenzyldiamine was 0.1 mol percent. The reaction was further continued by raising the pre-heating temperature only of the raw material so as to maintain the yield of 3-cyanobenzyldiamine at 0.5 mol percent or lower. After 28 days, the pressure difference between the inlet and the outlet of the catalyst layer was increased to 0.4 MPa, and the reaction was interrupted by stopping the supply of the hydrogenation raw material and hydrogen gas. [0057] Regeneration of Catalyst [0058] After cooling the catalyst layer to 45° C. and returning the inner pressure of the reactor to atmospheric pressure, nitrogen was flowed through the catalyst layer at a rate of 10 Nm3/h. The temperature of nitrogen gas being fed was raised from room temperature to 140° C. over 3 h. While maintaining the feed of nitrogen gas, hydrogen gas was fed at a rate of 0.1 Nm3/h. The temperature of the feed gas was raised to 200° C. over 2 h at a speed of 0.5° C./min. The average treating temperature during the temperature rise was 170° C. The temperature of the feed gas was successively raised to a final temperature of 340° C. over 6 h. While maintaining the feed gas at 340° C., the flow rate of hydrogen gas was increased stepwise to 3 Nm3/h and the feed amount of nitrogen gas was reduced stepwise to zero. During the course of maintaining the catalyst between 200° C. and 340° C., hydrogen gas was fed for 15 h. The feeding of hydrogen gas was carried out by monitoring the catalyst temperature. No steep temperature rise over 10° C./min was observed throughout the regeneration treatment. [0059] Hydrogenation Test after Regeneration [0060] After regenerating the catalyst, the hydrogenation was performed again by feeding the raw material of 55° C. under the same conditions as described above. The conversion of isophthalonitrile was 100percent, the yield of m-xylylenediamine was 91 mol percent, and the yield of 3-cyanobenzylamine was 0.1 mol percent, indicating that the regenerated catalyst was equivalent to the fresh catalyst in their catalytic activity. The pressure drop through the catalyst layer was 0.00 MPa, indicating that the pressure drop was completely got rid of. COMPARATIVE EXAMPLE 2 [0061] Hydrogenation Test [0062] A tubular insulated reactor having an inner diameter of 0.4 m was filled with 0.9 t of a commercially available catalyst (Ni-3266E manufactured by Harshaw Co., Ltd.; nickel content: about 50percent) to a packing height of 8 m. After activating the catalyst by reduction at 200° C. under a hydrogen flow, hydrogen gas and a hydrogenation raw material (IPN:MX:NH3=6:21:73 by weight) each pre-heated to 55° C. were fed into the reactor from the top thereof at respective feed rates of 100 Nm3/h and 1.5 t/h to allow the hydrogenation to proceed. The reaction pressure was 15 MPa. The reaction solution sampled from the outlet of the reactor was analyzed by gas chromatography. The conversion of isophthalonitrile was 100percent, the yield of m-xylylenediamine was 92 mol percent, and the yield of 3-cyanobenzyldiamine was 0.1 mol percent. The reaction was further continued by raising the pre-heating temperature only of the raw material so as to maintain the yield of 3-cyanobenzyldiamine at 0.5 mol percent or lower. After 31 days, the pressure difference between the inlet and the outlet of the catalyst layer was increased to 0.4 MPa, and the reaction was interrupted by stopping the supply of the hydrogenation raw material and hydrogen gas. [0063] Regeneration of Catalyst [0064] After reducing the inner pressure of the reactor to atmospheric pressure, hydrogen gas per-heated to 280° C. was fed to the catalyst layer at a rate of 10 Nm3/h. Immediately after beginning the feeding of hydrogen gas, a steep temperature rise occurred in the upper portion of the catalyst. The catalyst temperature was raised to 370° C. at highest to make the operation out of control. The temperature rise speed of the catalyst during the feed of hydrogen gas was 59° C. at highest. The feed of hydrogen gas was stopped and the catalyst layer was cooled to 140° C. by allowing nitrogen gas of room temperature to pass through the catalyst layer. [0065] Then, nitrogen gas and hydrogen gas were fed again at respective rates of 10 Nm3/h and 0.1 Nm3/h. The temperature of the feed gas was raised to 340° C. at a speed of 0.5° C./min, and finally the feed of the hydrogen-containing gas was continued at 340° C. for 2 h. While maintaining the feed gas at 340° C., the flow rate of hydrogen gas was increased stepwise to 3 Nm3/h and the feed amount of nitrogen gas was reduced stepwise to zero. Thereafter, the feed of gas was continued for 5 h in total. The feeding of hydrogen gas was carried out by monitoring the catalyst temperature. No steep temperature rise over 10° C./min was observed throughout the repetitive treatment. [0066] Hydrogenation Test after Regeneration [0067] After regenerating the catalyst, the hydrogenation was performed again by feeding the raw material of 55° C. under the same conditions as described above. The conversion of isophthalonitrile was 100percent, the yield of m-xylylenediamine was 82 mol percent, and the yield of 3-cyanobenzylamine was 6 mol percent, indicating the deterioration of the catalyst performance.
EXAMPLE 1 [0041] Preparation of Catalyst [0042] Into an aqueous solution prepared by dissolving 305.0 g of nickel nitrate hexahydrate (Ni(NO3)2.6H2O), 6.5 g of copper nitrate trihydrate (Cu(NO3)2.3H2O) and 7.1 g of chromium nitrate nonahydrate (Cr(NO3)3.9H2O) into 1 kg of pure water at 40° C., 29.6 g of diatomaceous earth was dispersed under stirring at 40° C. Then, an aqueous solution prepared by dissolving 128.6 g of sodium carbonate (Na2CO3) in 1 kg of pure water at 40° C. was poured into the resultant suspension under thorough stirring to prepare a precipitate slurry. After heated to 80° C. and held at that temperature for 30 min, the precipitate slurry was filtered to separate the precipitates, which were then washed with water, dried at 110° C. overnight, and then calcined in air at 380° C. for 18 h. The calcined powder was mixed with 3percent by weight of graphite and made into 3.0 mm 0.x.2.5 mm tablets by a tablet machine. The tablets were reduced at 400° C. under a hydrogen flow, and then, stabilized by an oxidation treatment overnight at a temperature from room temperature to 40° C. under a flow of diluted oxygen gas (oxygen/nitrogen={fraction (1/99)} by volume). Then, the tablets were crushed and sieved to have a particle size of 12 to 28 mesh, thereby obtaining a catalyst A. [0043] Hydrogenation Test [0044] A tube reactor having an inner diameter of 10 mm was filled with 10 g of the catalyst A (packing height: 130 mm). The catalyst A was activated by reduction at 200° C. under hydrogen flow. Then, a hydrogenation raw material consisting of a mixed solution of isophthalonitrile (IPN), m-xylene (MX) and ammonia (NH3) in a weight ratio of IPN:MX:NH3=6:54:40 was introduced into the tube reactor from the top thereof at a feed rate of 32 g/h. The hydrogenation was allowed to proceed at 55° C. under a reaction pressure of 7 MPa by supplying hydrogen gas under pressure in a rate of 20 NL/h. The reaction solution sampled from the outlet of the reactor was analyzed by gas chromatography. The conversion of isophthalonitrile was 100percent, the yield of m-xylylenediamine was 91.6 mol percent, and the yield of 3-cyanobenzyldiamine was 0.1 mol percent. The reaction was further continued by raising the temperature so as to maintain the above yields. After 24 days, the pressure difference between the inlet and the outlet of the catalyst layer was increased to 0.5 MPa, and the reaction was interrupted by stopping the supply of the hydrogenation raw material and hydrogen gas. [0045] Regeneration of Catalyst [0046] After cooling the catalyst layer to room temperature and returning the inner pressure of the reactor to atmospheric pressure, hydrogen was flowed through the catalyst layer at a rate of 5 NL/h. After heating the catalyst layer to 150° C., hydrogen was further allowed to continuously flow though the catalyst layer for 2 h (two-hour treatment at an average temperature of 150° C.). Thereafter, the temperature of the catalyst layer was raised to 260° C. at a rate of 4° C./min, and then, hydrogen was continuously flowed though the catalyst layer for 40 h. Finally, the catalyst layer was cooled to room temperature. [0047] Hydrogenation Test after Regeneration [0048] After regenerating the catalyst, the hydrogenation was performed again at 55° C. under the same conditions as described above. The conversion of isophthalonitrile was 100percent, the yield of m-xylylenediamine was 90.9 mol percent, and the yield of 3-cyanobenzylamine was 0.1 mol percent, indicating that the regenerated catalyst was equivalent to the fresh catalyst in their catalytic activity. The pressure drop through the catalyst layer was 0.00 MPa, indicating that the pressure drop was completely got rid of. COMPARATIVE EXAMPLE 1 [0049] Hydrogenation Test [0050] A tube reactor having an inner diameter of 10 mm was filled with 10 g of the catalyst A (packing height: 130 mm). The catalyst A was activated by reduction at 200° C. under hydrogen flow. Then, a hydrogenation raw material consisting of a mixed solution of isophthalonitrile (IPN), m-xylene (MX) and ammonia (NH3) in a weight ratio of IPN:MX:NH3=6:54:40 was introduced into the tube reactor from the top thereof at a feed rate of 32 g/h. The hydrogenation was allowed to proceed at 55° C. under a reaction pressure of 7 MPa by supplying hydrogen gas under pressure in a rate of 20 NL/h. The reaction solution sampled from the outlet of the reactor was analyzed by gas chromatography. The conversion of isophthalonitrile was 100percent, the yield of m-xylylenediamine was 90.9 mol percent, and the yield of 3-cyanobenzyldiamine was 0.1 mol percent. The reaction was further continued by raising the temperature so as to maintain the above yields. After 22 days, the pressure difference between the inlet and the outlet of the catalyst layer was increased to 0.5 MPa, and the reaction was interrupted by stopping the supply of the hydrogenation raw material and hydrogen gas. [0051] Regeneration of Catalyst [0052] After cooling the catalyst layer to room temperature and returning the inner pressure of the reactor to atmospheric pressure, hydrogen was flowed through the catalyst layer at a rate of 5 NL/h. After heating the catalyst layer to 150° C., hydrogen was further allowed to continuously flow though the catalyst layer for 2 h. Thereafter, the catalyst layer was cooled to room temperature. [0053] Hydrogenation Test after Regeneration [0054] After regenerating the catalyst, the hydrogenation was performed again at 55° C. under the same conditions as described above. The conversion of isophthalonitrile was 45.1percent, the yield of m-xylylenediamine was 0.1 mol percent, and the yield of 3-cyanobenzylamine was 28.6 mol percent. The pressure drop through the catalyst layer was 0.4 MPa.
Reference：
[1] Journal of the American Chemical Society, 1991, vol. 113, # 11, p. 4208 - 4218
[2] Patent: WO2006/55951, 2006, A2, . Location in patent: Page/Page column 37
8
[ 28188-41-2 ]
[ 10406-24-3 ]
Reference：
[1] Chemical Communications, 2015, vol. 51, # 39, p. 8253 - 8256
[2] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 20, p. 3477 - 3482
[3] Journal of the American Chemical Society, 1991, vol. 113, # 11, p. 4208 - 4218
[4] Journal of Medicinal Chemistry, 2015, vol. 58, # 3, p. 1067 - 1088
[5] Patent: WO2016/7966, 2016, A2,
With hydrazine; In methanol; for 1h;Heating / reflux;
A solution of the N-(3-cyanobenzyl)phthalimide (2.70 g, 10.4 mmol) and hydrazine hydrate (2.5 mL, 51 mmol) in MeOH (50 mL) was heated to reflux for 1 h. After cooling at room temperature, CH2Cl2 and aq. IN NaOH were added. The CH2Cl2 layer was separated, washed with brine, dried over Na2SO4, concentrated in vacuo to give an oil (1.10 g), which was pure enough for the next reaction. MS 133 (M+H) and 116 (M-NH2)
With hydrogen;nickel/diatomaceous earth catalyst (nickel 50wtpercent) reduced with hydrogen at 200C; at 100℃; under 30003 Torr;Product distribution / selectivity;
EXAMPLE 12; By removing ammonia by evaporation from the second hydrogenation product solution discharged from the outlet of the reaction tube B which was obtained in Example 2, a crude xylylenediamine containing 92.1% by weight of m-xylylenediamine and 520 ppm by weight of <strong>[10406-24-3]3-cyanobenzylamine</strong> was obtained. In a SUS reaction tube having an inner diameter of 35 mm, 50 mL of a nickel/diatomaceous earth catalyst with a column shape having a diameter of 5 mm and a length of 5 mm (nickel content: 50% by weight) was packed. The catalyst was reduced for activation at 200 C. under hydrogen gas flow. After cooling, hydrogen gas was introduced under pressure into the reaction tube. The pressure was kept constant at 4 MPa, and the catalyst layer temperature was kept at 100 C. under external heating. Then, hydrogen gas was supplied from the inlet of the reaction tube at a flow rate of 1.1 NL/h. While keeping the flow of hydrogen gas, the above crude xylylenediamine was supplied from the inlet of the reaction tube in a rate of 25.2 g/h, to conduct the re-hydrogenation continuously. The hydrogenation product solution and unreacted hydrogen gas were discharged from the outlet of the reaction tube. The discharged hydrogenation product solution was sampled and analyzed by a gas chromatography. The concentration of m-xylylenediamine was 91.7% by weight and the concentration of <strong>[10406-24-3]3-cyanobenzylamine</strong> was less than the detection limit of 30 ppm by weight. After evaporating off liquid ammonia from the obtained hydrogenation product solution, the crude m-xylylenediamine was distilled under reduced pressure (125 C., 6 Torr). The concentration of m-xylylenediamine was 99.99% by weight and the concentration of <strong>[10406-24-3]3-cyanobenzylamine</strong> was less than the detection limit of 30 ppm by weight. As described above, in the method of the present invention, the amount of the solvent containing liquid ammonia to be used is reduced while keeping high yields even when using a simple apparatus, to reduce the quantity of energy required for removing the solvent. Therefore, the present invention provides a cost-effective method of producing xylylenediamines by the hydrogenation of phthalonitriles. Thus, the present invention is of a great industrial value.
(3-[2-(6-methyl-2-oxo-3-phenylmethanesulfonylamino-2<i>H</i>-pyridin-1-yl)-acetylamino]-methyl}-benzyl)-carbamic acid <i>tert</i>-butyl ester[ No CAS ]
With hydrogen;Ni-3266E manufactured by Harshaw Co., Ltd.; nickel content: about 50percent; at 55℃; under 112511 Torr;tube reactor; feed rate = 1.5 t/h; supplying hydrogen rate = 100 Nm3/h;Product distribution / selectivity;
EXAMPLE 2 [0055] Hydrogenation Test [0056] A tubular insulated reactor having an inner diameter of 0.4 m was filled with 0.9 t of a commercially available catalyst (Ni-3266E manufactured by Harshaw Co., Ltd.; nickel content: about 50%) to a packing height of 8 m. After activating the catalyst by reduction at 200 C. under a hydrogen flow, hydrogen gas and a hydrogenation raw material (IPN:MX:NH3=6:21:73 by weight) each pre-heated to 55 C. were fed into the reactor from the top thereof at respective feed rates of 100 Nm3/h and 1.5 t/h to allow the hydrogenation to proceed. The reaction pressure was 15 MPa. The reaction solution sampled from the outlet of the reactor was analyzed by gas chromatography. The conversion of isophthalonitrile was 100%, the yield of m-xylylenediamine was 92 mol %, and the yield of 3-cyanobenzyldiamine was 0.1 mol %. The reaction was further continued by raising the pre-heating temperature only of the raw material so as to maintain the yield of 3-cyanobenzyldiamine at 0.5 mol % or lower. After 28 days, the pressure difference between the inlet and the outlet of the catalyst layer was increased to 0.4 MPa, and the reaction was interrupted by stopping the supply of the hydrogenation raw material and hydrogen gas. [0057] Regeneration of Catalyst [0058] After cooling the catalyst layer to 45 C. and returning the inner pressure of the reactor to atmospheric pressure, nitrogen was flowed through the catalyst layer at a rate of 10 Nm3/h. The temperature of nitrogen gas being fed was raised from room temperature to 140 C. over 3 h. While maintaining the feed of nitrogen gas, hydrogen gas was fed at a rate of 0.1 Nm3/h. The temperature of the feed gas was raised to 200 C. over 2 h at a speed of 0.5 C./min. The average treating temperature during the temperature rise was 170 C. The temperature of the feed gas was successively raised to a final temperature of 340 C. over 6 h. While maintaining the feed gas at 340 C., the flow rate of hydrogen gas was increased stepwise to 3 Nm3/h and the feed amount of nitrogen gas was reduced stepwise to zero. During the course of maintaining the catalyst between 200 C. and 340 C., hydrogen gas was fed for 15 h. The feeding of hydrogen gas was carried out by monitoring the catalyst temperature. No steep temperature rise over 10 C./min was observed throughout the regeneration treatment. [0059] Hydrogenation Test after Regeneration [0060] After regenerating the catalyst, the hydrogenation was performed again by feeding the raw material of 55 C. under the same conditions as described above. The conversion of isophthalonitrile was 100%, the yield of m-xylylenediamine was 91 mol %, and the yield of 3-cyanobenzylamine was 0.1 mol %, indicating that the regenerated catalyst was equivalent to the fresh catalyst in their catalytic activity. The pressure drop through the catalyst layer was 0.00 MPa, indicating that the pressure drop was completely got rid of. COMPARATIVE EXAMPLE 2 [0061] Hydrogenation Test [0062] A tubular insulated reactor having an inner diameter of 0.4 m was filled with 0.9 t of a commercially available catalyst (Ni-3266E manufactured by Harshaw Co., Ltd.; nickel content: about 50%) to a packing height of 8 m. After activating the catalyst by reduction at 200 C. under a hydrogen flow, hydrogen gas and a hydrogenation raw material (IPN:MX:NH3=6:21:73 by weight) each pre-heated to 55 C. were fed into the reactor from the top thereof at respective feed rates of 100 Nm3/h and 1.5 t/h to allow the hydrogenation to proceed. The reaction pressure was 15 MPa. The reaction solution sampled from the outlet of the reactor was analyzed by gas chromatography. The conversion of isophthalonitrile was 100%, the yield of m-xylylenediamine was 92 mol %, and the yield of 3-cyanobenzyldiamine was 0.1 mol %. The reaction was further continued by raising the pre-heating temperature only of the raw material so as to maintain the yield of 3-cyanobenzyldiamine at 0.5 mol % or lower. After 31 days, the pressure difference between the inlet and the outlet of the catalyst layer was increased to 0.4 MPa, and the reaction was interrupted by stopping the supply of the hydrogenation raw material and hydrogen gas. [0063] Regeneration of Catalyst [0064] After reducing the inner pressure of the reactor to atmospheric pressure, hydrogen gas per-heated to 280 C. was fed to the catalyst layer at a rate of 10 Nm3/h. Immediately after beginning the feeding of hydrogen gas, a steep temperature rise occurred in the upper portion of the catalyst. The catalyst temperature was raised to 370 C. at highest to make the operation out of control. The temperature rise speed of the catalyst during the feed of hydrogen gas was 59 C. at highest. The feed of hydrogen gas was stopped and the catalyst layer was cooled to 140 C. by allowing nitrogen gas of room temperature to pass through the catalyst layer. [0065] Then, nitrogen gas and hydrogen gas were fed again at respective rates of 10 Nm3/h and 0.1 Nm...
90.9 - 91.6%; 0.1%
With hydrogen;catalyst A; at 55℃; under 52505.3 Torr;tube reactor; feed rate = 32 g/h; supplying hydrogen rate = 20 NL/h;Product distribution / selectivity;
EXAMPLE 1 [0041] Preparation of Catalyst [0042] Into an aqueous solution prepared by dissolving 305.0 g of nickel nitrate hexahydrate (Ni(NO3)2.6H2O), 6.5 g of copper nitrate trihydrate (Cu(NO3)2.3H2O) and 7.1 g of chromium nitrate nonahydrate (Cr(NO3)3.9H2O) into 1 kg of pure water at 40 C., 29.6 g of diatomaceous earth was dispersed under stirring at 40 C. Then, an aqueous solution prepared by dissolving 128.6 g of sodium carbonate (Na2CO3) in 1 kg of pure water at 40 C. was poured into the resultant suspension under thorough stirring to prepare a precipitate slurry. After heated to 80 C. and held at that temperature for 30 min, the precipitate slurry was filtered to separate the precipitates, which were then washed with water, dried at 110 C. overnight, and then calcined in air at 380 C. for 18 h. The calcined powder was mixed with 3% by weight of graphite and made into 3.0 mm 0×2.5 mm tablets by a tablet machine. The tablets were reduced at 400 C. under a hydrogen flow, and then, stabilized by an oxidation treatment overnight at a temperature from room temperature to 40 C. under a flow of diluted oxygen gas (oxygen/nitrogen={fraction (1/99)} by volume). Then, the tablets were crushed and sieved to have a particle size of 12 to 28 mesh, thereby obtaining a catalyst A. [0043] Hydrogenation Test [0044] A tube reactor having an inner diameter of 10 mm was filled with 10 g of the catalyst A (packing height: 130 mm). The catalyst A was activated by reduction at 200 C. under hydrogen flow. Then, a hydrogenation raw material consisting of a mixed solution of isophthalonitrile (IPN), m-xylene (MX) and ammonia (NH3) in a weight ratio of IPN:MX:NH3=6:54:40 was introduced into the tube reactor from the top thereof at a feed rate of 32 g/h. The hydrogenation was allowed to proceed at 55 C. under a reaction pressure of 7 MPa by supplying hydrogen gas under pressure in a rate of 20 NL/h. The reaction solution sampled from the outlet of the reactor was analyzed by gas chromatography. The conversion of isophthalonitrile was 100%, the yield of m-xylylenediamine was 91.6 mol %, and the yield of 3-cyanobenzyldiamine was 0.1 mol %. The reaction was further continued by raising the temperature so as to maintain the above yields. After 24 days, the pressure difference between the inlet and the outlet of the catalyst layer was increased to 0.5 MPa, and the reaction was interrupted by stopping the supply of the hydrogenation raw material and hydrogen gas. [0045] Regeneration of Catalyst [0046] After cooling the catalyst layer to room temperature and returning the inner pressure of the reactor to atmospheric pressure, hydrogen was flowed through the catalyst layer at a rate of 5 NL/h. After heating the catalyst layer to 150 C., hydrogen was further allowed to continuously flow though the catalyst layer for 2 h (two-hour treatment at an average temperature of 150 C.). Thereafter, the temperature of the catalyst layer was raised to 260 C. at a rate of 4 C./min, and then, hydrogen was continuously flowed though the catalyst layer for 40 h. Finally, the catalyst layer was cooled to room temperature. [0047] Hydrogenation Test after Regeneration [0048] After regenerating the catalyst, the hydrogenation was performed again at 55 C. under the same conditions as described above. The conversion of isophthalonitrile was 100%, the yield of m-xylylenediamine was 90.9 mol %, and the yield of 3-cyanobenzylamine was 0.1 mol %, indicating that the regenerated catalyst was equivalent to the fresh catalyst in their catalytic activity. The pressure drop through the catalyst layer was 0.00 MPa, indicating that the pressure drop was completely got rid of. COMPARATIVE EXAMPLE 1 [0049] Hydrogenation Test [0050] A tube reactor having an inner diameter of 10 mm was filled with 10 g of the catalyst A (packing height: 130 mm). The catalyst A was activated by reduction at 200 C. under hydrogen flow. Then, a hydrogenation raw material consisting of a mixed solution of isophthalonitrile (IPN), m-xylene (MX) and ammonia (NH3) in a weight ratio of IPN:MX:NH3=6:54:40 was introduced into the tube reactor from the top thereof at a feed rate of 32 g/h. The hydrogenation was allowed to proceed at 55 C. under a reaction pressure of 7 MPa by supplying hydrogen gas under pressure in a rate of 20 NL/h. The reaction solution sampled from the outlet of the reactor was analyzed by gas chromatography. The conversion of isophthalonitrile was 100%, the yield of m-xylylenediamine was 90.9 mol %, and the yield of 3-cyanobenzyldiamine was 0.1 mol %. The reaction was further continued by raising the temperature so as to maintain the above yields. After 22 days, the pressure difference between the inlet and the outlet of the catalyst layer was increased to 0.5 MPa, and the reaction was interrupted by stopping the supply of the hydrogenation raw material and hydrogen gas. [0051] Regeneration of Catalyst [0052] After cooling the catalyst layer to room temperature and returning the i...
With hydrogen;nickel catalyst "NDHT"; pretreatment is given in full text; In methanol; ammonia; at 65℃; for 4h;Product distribution / selectivity;
The same type of sponge nickel catalyst as used in Comparative Example 5 was charged into a glass tube with a 10-mm inner diameter in an amount of 3 g and dried at 200 C. in a nitrogen stream. Then, a mixed gas (methanol:nitrogen=4:96 by volume) was allowed to pass through the catalyst bed to pretreat the catalyst under the conditions of atmospheric pressure, 200 C., a flow rate of 1.5 NL/h, and 3 h. After the pretreatment, the catalyst was cooled to 30 C. in a nitrogen gas flow. The pretreated catalyst was slurried in 60 g of methanol in a nitrogen atmosphere. The hydrogenation of isophthalonitrile was conducted in the same manner as in Comparative Example 5 except for using the pretreated catalyst thus prepared. After 4 h of the hydrogenation, a part of the reaction liquid was sampled and analyzed. The conversion of isophthalonitrile was 100 mol %, the yield of m-xylylenediamine was 92.8 mol %, the yield of 3-cyanobenzylamine was 0.2 mol %, and the yield of high-boiling condensation products was 7 mol %.
7.7%; 87.3%
With hydrogen;Pd-alumina; In ammonia; 1,3,5-trimethyl-benzene; at 50℃; under 36753.7 Torr;
EXAMPLE 1 Hydrogenation of Isophthalonitrile Into a 100-ml autoclave, were charged 3.2 g of isophthalonitrile, 10.4 g of mesitylene, 10.0 g of liquid ammonia and 2.0 g of Pd-alumina pellets (manufactured by N.E. Chemcat Corporation; Pd content = 5% by weight), and the inner pressure was raised to 4.9 MPa by hydrogen gas. Then, the autoclave was shaken at 50C until the change of pressure was no longer appreciated. The analysis on the reaction product solution showed that the conversion of isophthalonitrile was 95.7 mol%, the yield of 3-cyanobenzylamine was 87.3 mol% and the yield of m-xylynenediamine was 7.7 mol%. The reaction solution separated from the catalyst was charged into a 100-ml autoclave together with 10.0 g of liquid ammonia and 2.0 g of Ni-diatomaceous earth pellets (manufactured by Nikki Chemical Co., Ltd.; Ni supported amount = 46% by weight). The inner pressure was raised to 4.9 MPa by hydrogen gas. Then, the autoclave was shaken at 50C until the change of pressure was no longer appreciated. The analysis on the reaction product solution showed that the conversion of isophthalonitrile was 100 mol%, the yield of 3-cyanobenzylamine was 0.2 mol% and the yield of m-xylynenediamine was 89.4 mol% EXAMPLE 4 Hydrogenation of Isophthalonitrile Into a 100-ml autoclave, were charged 3.2 g of isophthalonitrile, 10.4 g of mesitylene, 10.0 g of liquid ammonia and 2.0 g of Pd-alumina pellets (manufactured by N.E. Chemcat Corporation; Pd content = 5% by weight), and the inner pressure was raised to 4.9 MPa by hydrogen gas. Then, the autoclave was shaken at 50C until the change of pressure was no longer appreciated. The analysis on the reaction product solution showed that the conversion of isophthalonitrile was 95.7 mol%, the yield of 3-cyanobenzylamine was 87.3 mol% and the yield of m-xylynenediamine was 7.7 mol%. The reaction solution separated from the catalyst was charged into a 100-ml autoclave together with 10.0 g of liquid ammonia and 2.0 g of the catalyst A. The inner pressure was raised to 4.9 MPa by hydrogen gas. Then, the autoclave was shaken at 50C until the change of pressure was no longer appreciated. The analysis on the reaction product solution showed that the conversion of isophthalonitrile was 100 mol%, the yield of 3-cyanobenzylamine was 0.0 mol% and the yield of m-xylynenediamine was 91.1 mol%.
84.8%; 0.2%
With hydrogen;nickel catalyst "NDHT"; In methanol; ammonia; at 65℃; for 4h;autoclave;Product distribution / selectivity;
Into a 300-ml SUS autoclave equipped with a stirrer, 10 g of isophthalonitrile was charged. Then, a slurry prepared by dispersing 3 g of a leached sponge nickel catalyst (?NDHT? available from Kawaken Fine Chemicals Co., Ltd.) in 60 g of methanol was charged and the autoclave was closed. After replacing the air in the autoclave with nitrogen, 30 g of ammonia was charged. The inner pressure was raised to 5 MPaG by hydrogen, and the hydrogenation was allowed to proceed at 65 C. The pressure was maintained at 5 MPaG by introducing hydrogen to supplement the consumed hydrogen. After 4 h of the hydrogenation, a part of the reaction liquid was sampled and analyzed. The conversion of isophthalonitrile was 100 mol %, the yield of m-xylylenediamine was 84.8 mol %, the yield of 3-cyanobenzylamine was 0.2 mol %, and the yield of high-boilig condensation products was 15 mol %.
With ammonia; hydrogen;G-67; In methanol; m-xylylene; at 95 - 130℃; under 90009 Torr; for 4.5 - 6h;Conversion of starting material;
EXAMPLE 4; Into a 1-L autoclave equipped with an electromagnetic stirrer, 8 g of a 380C hydrogen-reduced cobalt catalyst supported on diatomaceous earth ("G-67" manufactured by Nissan Girdler Catalyst Co., Ltd.; cobalt content = 56% by weight) was charged. Then, 60 g of IPN, 60 g of MX and 120 g of methanol were charged into the autoclave and the inner atmosphere thereof was replaced with nitrogen. After introducing 120 g of NH3, the autoclave was heated to 95C. Then, hydrogen gas was introduced into the autoclave to perform the hydrogenation under 12 MPaG at 95C. After initiating the hydrogenation, the reaction liquids were sampled at regular time intervals and analyzed by gas chromatography. After three hours from the initiation, the nitrile conversion reached 95.6 mol%. At this time, the residue of isophthalonitrile was 0.0 mol%, the yield of m-xylylenediamine was 77.5 mol%, and the yield of 3-cyanobenzylamine was 8.9 mol%. After three hours from the initiation, the reaction temperature was raised to 130C to continue the hydrogenation for 1.5 h (overall reaction time = 4.5 h). The results of gas chromatographic analysis showed that the nitrile conversion was 99.99 mol%, the residue of isophthalonitrile was 0.0 mol%, the yield of m-xylylenediamine was 86.7 mol%, and the yield of 3-cyanobenzylamine was 0.01 mol%. COMPARATIVE EXAMPLE 5; The procedure of Example 4 was repeated except for performing the hydrogenation for 6 h at a constant reaction temperature of 95C. After 6 h of the initiation of hydrogenation, the reaction liquid was analyzed by gas chromatography. The residue of isophthalonitrile was 0.0 mol%, the yield of m-xylylenediamine was 84.4 mol%, and the yield of 3-cyanobenzylamine was 1.1 mol%. Although the hydrogenation was continued longer than in Example 4, a larger amount of the intermediate 3-cyanobenzylamine remained. COMPARATIVE EXAMPLE 6; The procedure of Example 4 was repeated except for performing the hydrogenation for 4.5 h at a constant reaction temperature of 130C. The results of gas chromatographic analysis showed that the residue of isophthalonitrile was 0.0 mol%, the yield of m-xylylenediamine was 81.2 mol%, and the yield of 3-cyanobenzylamine was 0.01 mol%.
With ammonia; hydrogen;catalyst A; In m-xylylene; at 70 - 110℃; under 90009 Torr;Conversion of starting material;
EXAMPLE 1; Preparation of Catalyst Into 1 kg of pure water, were dissolved 305.0 g of nickel nitrate hexahydrate (Ni(NO3)2·6H2O), 6.5 g of copper nitrate trihydrate (Cu(NO3)2·3H2O) and 7.1 g of chromium nitrate nonahydrate (Cr(NO3)3·9H2O) at 40C. To the resultant aqueous solution, 29.6 g of diatomaceous earth was dispersed at 40C under stirring, and then an aqueous solution prepared by dissolving 128.6 g of sodium carbonate (Na2CO3) in 1 kg of pure water at 40C was added under vigorous stirring, thereby preparing a precipitation slurry. The precipitation slurry was heated to 80C, kept at there for 30 min and filtered. The collected precipitation was washed, dried at 110C for 15 h, and calcined at 380C for 18 h in air. After blended with 3% by weight of graphite, the calcined powder was made into 3.0 mmphi× 2.5 mm tablets. The tablets were reduced at 400C in hydrogen gas stream, and then, stabilized by oxidizing treatment at room temperature to 40C for 15 h in a stream of dilute oxygen gas (oxygen/nitrogen = 1/99 by volume). Thereafter, the tablets were crushed and classified into a particle size of 12 to 28 mesh to obtain a crushed catalyst (Catalyst A).Hydrogenation Two reaction tubes of 10 mm inner diameter were connected lengthwise to form a vertical fixed-bed reactor having an upper reaction tube for the step (a) and a lower reaction tube for the step (b). The upper and lower reaction tubes were equipped with respective heaters so as to independently control the reaction temperatures. After packing 5 g of Catalyst A in a packing height of 65 mm in each of the upper and lower reaction tubes, the packed catalysts were reduced and activated at 200C under hydrogen gas flow. The hydrogenation was performed under a reaction pressure of 12 MPa at a reaction temperature of 70C in the upper reaction tube and 110C in the lower reaction tube, while supplying a liquid raw material of isophthalonitrile (IPN), m-xylylene (MX) and ammonia (NH3) in a proportion of IPN:MX:NH3 = 10:10:80 by weight and hydrogen gas from the top of the reactor. The liquid raw material and hydrogen gas were supplied at a rate of 60 g/h and 20 NL/h (N: normal condition) so that a nitrile conversion of 90 mol% or more and less than 99.9 mol% was attained at the outlet of the upper reaction tube, and a nitrile conversion of 99.5 mol% or more and higher than that attained at the outlet of the upper reaction tube was attained at the outlet of the lower reaction tube. The reaction liquids sampled from the outlets of the upper and lower reaction tubes were analyzed by gas chromatography. At the outlet of the upper reaction tube, the nitrile conversion was 91.6 mol%, the residue of isophthalonitrile was 0.3 mol%, the yield of m-xylylenediamine was 76.0 mol%, and the yield of 3-cyanobenzylamine was 16.3 mol%. At the outlet of the lower reaction tube, the nitrile conversion was 99.995 mol%, the residue of isophthalonitrile was 0.0 mol%, the yield of m-xylylenediamine was 91.3 mol%, and the yield of 3-cyanobenzylamine was 0.01 mol%.Purification of Xylylenediamine After removing gaseous components from the reaction mixture taken out of the outlet of the reactor, ammonia was removed by gradual evacuation to obtain a crude xylylenediamine liquid, which was then subject to batch distillation in a glass flask under reduced pressure. After removing m-xylylene at 10 kPa, the distillation was continued at 1 kPa to obtain m-xylylenediamine as the major distillate. The purity of m-xylylenediamine thus obtained was 99.9% by weight or more and the concentration of 3-cyanobenzylamine was 0.01% by weight or less. EXAMPLE 2 ; The hydrogenation was performed in the same manner as in Example 1 except for setting the reaction temperatures in the upper and lower reaction tubes to 80C and 110C. The reaction liquids sampled from the outlets of the upper and lower reaction tubes were analyzed by gas chromatography. At the outlet of the upper reaction tube, the nitrile conversion was 99.55 mol%, the residue of isophthalonitrile was 0.0 mol%, the yield of m-xylylenediamine was 91.5 mol%, and the yield of 3-cyanobenzylamine was 0.9 mol%. At the outlet of the lower reaction tube, the nitrile conversion was 99.99 mol% or more, the residue of isophthalonitrile was 0.0 mol%, the yield of m-xylylenediamine was 92.4 mol%, and the yield of 3-cyanobenzylamine was 0.004 mol%. COMPARATIVE EXAMPLE 1; Hydrogenation The hydrogenation was performed in the same manner as in Example 1 except for setting both the reaction temperatures in the upper and lower reaction tubes to 70C. The reaction liquids sampled from the outlets of the upper and lower reaction tubes were analyzed by gas chromatography. At the outlet of the upper reaction tube, the nitrile conversion was 90.5 mol%, the residue of isophthalonitrile was 0.3 mol%, the yield of m-xylylenediamine was 73.2 mol%, and the yield of 3-cyanobenzylamine was 18.4 mol%. At the outlet of the lower reaction tube, the nitrile conversion was only 9...
With hydrogen;nickel/diatomaceous earth catalyst (nickel 50wtpercent) reduced with hydrogen at 200C; In ammonia; at 75 - 90℃; under 60006 Torr;Product distribution / selectivity;
EXAMPLE 1 An experimental apparatus shown in FIG. 1, which was composed of a reaction tube A for the first reaction zone and a reaction tube B for the second reaction zone, was used. Each reaction tube was made of SUS and had an inner diameter of 25 mm. A nickel/diatomaceous earth catalyst with a column shape having a diameter of 3 mm and a length of 3 mm (nickel content: 50% by weight) was packed in each reaction tube in an amount of 120 mL for the reaction tube A and 60 mL for the reaction tube B. The catalyst was reduced for activation at 200 C. under hydrogen gas flow. After cooling, hydrogen gas was introduced under pressure into the reaction tubes A and B and a pipe connecting the reaction tubes. The pressure was kept constant at 8 MPa, and the catalyst layer temperature was kept at 75 C. in the reaction tube A and 80 C. in the reaction tube B under external heating. Then, hydrogen gas was supplied from the inlet of the reaction tube A at a flow rate of 13 NL/h (NL: normal litter) and allowed to discharge from the reaction tube B. While keeping the flow of hydrogen gas, a starting solution containing 1 part by weight of the starting isophthalonitrile and 9 parts by weight of liquid ammonia was supplied from the inlet of the reaction tube A in a rate of 139 g/h. The hydrogenation was conducted continuously in the circulation manner while returning a part of the first hydrogenation product solution discharged from the reaction tube A to the inlet of the reaction tube A in a rate of 417 g/h (circulation rate: 75% by weight) by using a circulation pump. The first hydrogenation product solution discharged from the reaction tube A was sampled just before entering into the reaction tube B and analyzed by a gas chromatography. The conversion of the starting isophthalonitrile was 95.2 mol %, the selectivity of m-xylylenediamine was 85.4 mol %, and the selectivity of 3-cyanobenzylamine was 6.5 mol %. In addition, 84.4% of the total nitrile groups in the starting isophthalonitrile were hydrogenated to aminomethyl groups. The rest of the first hydrogenation product solution from the outlet of the reaction tube A was introduced into the inlet of the reaction tube B in a rate of 139 g/h together with unreacted hydrogen gas from the outlet of the reaction tube A, to continuously conduct the hydrogenation. Then, the second hydrogenation product solution and unreacted hydrogen gas were discharged from the outlet of the reaction tube B. The discharged second hydrogenation product solution was sampled and analyzed by a gas chromatography. The amount of 3-cyanobenzylamine was 0.046% by weight on the basis of the weight of m-xylylenediamine. The conversion of isophthalonitrile was 99.9 mol % or more, the selectivity of m-xylylenediamine was 91.9 mol % and the selectivity of 3-cyanobenzylamine was 0.0438 mol %, each being the overall value throughout the hydrogenation step 1 and the hydrogenation step 2. After evaporating off ammonia from the second hydrogenation product solution, the crude m-xylylenediamine was distilled under reduced pressure (125 C., 6 Torr). The purified product contained 99.95% by weight of m-xylylenediamine and 480 ppm by weight of 3-cyanobenzylamine when determined by a gas chromatography. COMPARATIVE EXAMPLE 1 The hydrogenation of phthalonitrile was conducted by using an experimental apparatus composed of a single reaction tube (SUS, 25-mm inner diameter) in place of the apparatus shown in FIG. 1. A nickel/diatomaceous earth catalyst with a column shape having a diameter of 3 mm and a length of 3 mm (nickel content: 50% by weight) was packed in the reaction tube in an amount of 180 mL. The catalyst was reduced for activation at 200 C. under hydrogen gas flow. After cooling, hydrogen gas was introduced under pressure into the reaction tube. The pressure was kept constant at 8 MPa, and the catalyst layer temperature was kept at 80 C. under external heating. Then, hydrogen gas was supplied from the inlet of the reaction tube at a flow rate of 13 NL/h. While keeping the flow of hydrogen gas, a starting solution containing 1 part by weight of the starting isophthalonitrile and 9 parts by weight of liquid ammonia was supplied from the inlet of the reaction tube in a rate of 139 g/h, to conduct the hydrogenation continuously. Apart of the hydrogenation product solution discharged from the reaction tube was returned to the inlet of the reaction tube in a rate of 417 g/h (circulation rate: 75% by weight) by using a circulation pump. After hydrogenation, the hydrogenation product solution and unreacted hydrogen gas were discharged from the outlet of the reaction tube. The discharged hydrogenation product solution was sampled and analyzed by a gas chromatography. The degree of hydrogenation of nitrile groups to aminomethyl groups was 90.6% on the basis of the total nitrile groups in the starting isophthalonitrile. The conversion of isophthalonitrile was 99.9 mol % or more, the selectivity of m-xylylenediamine...
With hydrogen;nickel/diatomaceous earth catalyst (nickel 50wtpercent) reduced with hydrogen at 200C; In ammonia; m-xylene; at 75 - 80℃; under 60006 Torr;Product distribution / selectivity;
EXAMPLE 11; The hydrogenation was conducted in the same manner as in Example 2 except for changing the starting solution to a mixture of 1 part by weight of the starting isophthalonitrile, 8 parts by weight of liquid ammonia and 1 part by weight of m-xylene. The first hydrogenation product solution discharged from the reaction tube A was sampled just before entering into the reaction tube B and analyzed by a gas chromatography. The conversion of the starting isophthalonitrile was 95.4 mol %, the selectivity of m-xylylenediamine was 84.5 mol %, and the selectivity of 3-cyanobenzylamine was 6.20 mol %. In addition, 83.6% of the total nitrile groups in the starting isophthalonitrile were hydrogenated to aminomethyl groups in the hydrogenation step 1. The second hydrogenation product solution and unreacted hydrogen gas were discharged from the outlet of the reaction tube B. The discharged second hydrogenation product solution was sampled and analyzed by a gas chromatography. The amount of 3-cyanobenzylamine was 0.057% by weight on the basis of the weight of m-xylylenediamine. The conversion of isophthalonitrile was 99.9 mol % or more, the selectivity of m-xylylenediamine was 90.6 mol % and the selectivity of 3-cyanobenzylamine was 0.0530 mol %, each being the overall value throughout the hydrogenation step 1 and the hydrogenation step 2. After evaporating off ammonia from the second hydrogenation product solution, the crude m-xylylenediamine was distilled under reduced pressure (125 C., 6 Torr). The purified product contained 99.94% by weight of m-xylylenediamine and 580 ppm by weight of 3-cyanobenzylamine when determined by a gas chromatography.
With hydrogen;nickel/diatomaceous earth; In ammonia; at 70℃; under 60006 Torr;Product distribution / selectivity;
<Comparative Example 1> The procedure of Example 1 was repeated, except that no hydrogenation stopping (operation (1)) or (operation (2)) was performed and hydrogenation was continued, to thereby perform continuous hydrogenation. After start of reaction, the hydrogenation reaction mixture was sampled through the outlet of the reactor at appropriate timings, and the obtained liquid samples were analyzed through gas chromatography. Six hundred hours after the start of reaction, the conversion of raw-material isophthalomitrile was 100 mass%, the selectivity to the target reaction product, MXDA, of 78.1 mass%, and the selectivity to reaction intermediate CUBA was 18.1 mass%, indicating a drop in hydrogenation catalytic activity. The differential pressure of the catalyst layer increased to 0.14 MPa. Table 1 shows changes over time in selectivity to MXDA and to reaction intermediate CBA and differential pressure of the catalyst layer in the reactor.
With hydrogen;catalyst A; In ammonia; 1,3,5-trimethyl-benzene; at 50℃; under 36753.7 Torr;
EXAMPLE 4 Hydrogenation of Isophthalonitrile Into a 100-ml autoclave, were charged 3.2 g of isophthalonitrile, 10.4 g of mesitylene, 10.0 g of liquid ammonia and 2.0 g of Pd-alumina pellets (manufactured by N.E. Chemcat Corporation; Pd content = 5% by weight), and the inner pressure was raised to 4.9 MPa by hydrogen gas. Then, the autoclave was shaken at 50C until the change of pressure was no longer appreciated. The analysis on the reaction product solution showed that the conversion of isophthalonitrile was 95.7 mol%, the yield of <strong>[10406-24-3]3-cyanobenzylamine</strong> was 87.3 mol% and the yield of m-xylynenediamine was 7.7 mol%. The reaction solution separated from the catalyst was charged into a 100-ml autoclave together with 10.0 g of liquid ammonia and 2.0 g of the catalyst A. The inner pressure was raised to 4.9 MPa by hydrogen gas. Then, the autoclave was shaken at 50C until the change of pressure was no longer appreciated. The analysis on the reaction product solution showed that the conversion of isophthalonitrile was 100 mol%, the yield of <strong>[10406-24-3]3-cyanobenzylamine</strong> was 0.0 mol% and the yield of m-xylynenediamine was 91.1 mol%.
89.4%
With hydrogen;Ni-diatomaceous earth; In ammonia; 1,3,5-trimethyl-benzene; at 50℃; under 36753.7 Torr;
EXAMPLE 1 Hydrogenation of Isophthalonitrile Into a 100-ml autoclave, were charged 3.2 g of isophthalonitrile, 10.4 g of mesitylene, 10.0 g of liquid ammonia and 2.0 g of Pd-alumina pellets (manufactured by N.E. Chemcat Corporation; Pd content = 5% by weight), and the inner pressure was raised to 4.9 MPa by hydrogen gas. Then, the autoclave was shaken at 50C until the change of pressure was no longer appreciated. The analysis on the reaction product solution showed that the conversion of isophthalonitrile was 95.7 mol%, the yield of <strong>[10406-24-3]3-cyanobenzylamine</strong> was 87.3 mol% and the yield of m-xylynenediamine was 7.7 mol%. The reaction solution separated from the catalyst was charged into a 100-ml autoclave together with 10.0 g of liquid ammonia and 2.0 g of Ni-diatomaceous earth pellets (manufactured by Nikki Chemical Co., Ltd.; Ni supported amount = 46% by weight). The inner pressure was raised to 4.9 MPa by hydrogen gas. Then, the autoclave was shaken at 50C until the change of pressure was no longer appreciated. The analysis on the reaction product solution showed that the conversion of isophthalonitrile was 100 mol%, the yield of <strong>[10406-24-3]3-cyanobenzylamine</strong> was 0.2 mol% and the yield of m-xylynenediamine was 89.4 mol%
With hydrogen;catalyst A; In methanol; ammonia; at 80℃; under 150015 Torr;batch-wise method ; concentration benzamide-0.043w.%, benzoic acid-0.004w.%;Conversion of starting material;
[0030] A 100-ml autoclave was charged with 4.0 g of the catalyst A previously reduced and activated under a hydrogen flow at 200° C and 12.8 g of isophthalonitrile containing as impurities 0.12% by weight of 3-cyanobenzamide and 0.01% by weight of 3-cyanobenzoic acid.After further charging 16 g of methanol and 7 g of liquid ammonia, the inner pressure was increased to 20 MPa (gauge) by introducing hydrogen.The concentration in the reaction solution was 0.043% by weight for the benzamide compound and 0.004% by weight for the benzoic acid compound.The autoclave was shaken at 80° C until the inner pressure was no longer changed.The gas chromatographic analysis showed that the conversion of isophthalonitrile was 99.6 mol % and the yield of m-xylylenediamine was 75.7 mol %.The by-products were substantially high-boiling substances and the yield of 3-cyanobenzylamine was 0.3 mol %.
With hydrogen;catalyst A; In methanol; ammonia; at 80℃; under 150015 Torr;The butch-wize method.The concentration of bezamide-0.30%, benoic acid-0.004%;Conversion of starting material;
[0031] The same procedure as in Example 1 was repeated except that 12.8 g of isophthalonitrile containing as impurities 0.84% by weight of 3-cyanobenzamide and 0.01% by weight of 3-cyanobenzoic acid were used as the starting phthalonitrile compound for the hydrogenation.The concentration in the reaction solution was 0.30% by weight for the benzamide compound and 0.004% by weight for the benzoic acid compound.The gas chromatographic analysis showed that the conversion of isophthalonitrile was 99.2 mol % and the yield of m-xylylenediamine was 74.8 mol %.The by-products were substantially high-boiling substances and the yield of 3-cyanobenzylamine was 0.3 mol %.
With hydrogen;catalyst A; In methanol; ammonia; at 80℃; under 150015 Torr;The batch-wize method;Conversion of starting material;
[0034] The same procedure as in Example 1 was repeated except that 12.8 g of isophthalonitrile containing as impurities 2.11% by weight of 3-cyanobenzamide and 0.01% by weight of 3-cyanobenzoic acid were used as the starting phthalonitrile compound for the hydrogenation. The concentration in the reaction solution was 0.75% by weight for the benzamide compound and 0.004% by weight for the benzoic acid compound. The gas chromatographic analysis showed that the conversion of isophthalonitrile was 99.3 mol % and the yield of m-xylylenediamine was 70.2 mol %. The by-products were substantially high-boiling substances and the yield of 3-cyanobenzylamine was 0.5 mol %.
With hydrogen;catalyst A; In methanol; ammonia; at 80℃; under 150015 Torr;The batch-wise method;Conversion of starting material;
[0035] The same procedure as in Example 1 was repeated except that 12.8 g of isophthalonitrile containing as impurities 5.36% by weight of 3-cyanobenzamide and 0.01% by weight of 3-cyanobenzoic acid were used as the starting phthalonitrile compound for the hydrogenation. The concentration in the reaction solution was 1.92% by weight for the benzamide compound and 0.004% by weight for the benzoic acid compound. The gas chromatographic analysis showed that the conversion of isophthalonitrile was 99.1 mol % and the yield of m-xylylenediamine was 69.9 mol %. The by-products were substantially high-boiling substances and the yield of 3-cyanobenzylamine was 0.9 mol %.
With hydrogen;catalyst A; In methanol; ammonia; at 80℃; under 150015 Torr;The batch-wise method .The concentration of benzamide0.043%, benzoic acid-0.043%;Conversion of starting material;
[0032] The same procedure as in Example 1 was repeated except that 12.8 g of isophthalonitrile containing as impurities 0.12% by weight of 3-cyanobenzamide and 0.12% by weight of 3-cyanobenzoic acid were used as the starting phthalonitrile compound for the hydrogenation. The concentration in the reaction solution was 0.043% by weight for the benzamide compound and 0.043% by weight for the benzoic acid compound. The gas chromatographic analysis showed that the conversion of isophthalonitrile was 99.4 mol % and the yield of m-xylylenediamine was 74.1 mol %. The by-products were substantially high-boiling substances and the yield of 3-cyanobenzylamine was 0.2 mol %.
8.4%Chromat.; 76%Chromat.
With hydrogen;sodium hydroxide; PDC-3000; In ammonia; at 50℃; under 150015 Torr; for 0.5h;The batch-wise method . The concentration of benzamide compound-0.043%, benzoic acid compound-0.043%;Product distribution / selectivity;
[0047] A commercially available activated carbon-supported palladium catalyst PDC-3000 available from Toyo C. C. I. Co., Ltd. (supported palladium: 3% by weight) was activated by reduction with hydrogen. A 100-ml autoclave was successively charged with 3.0 g of the activated catalyst, 12.8 g of isophthalonitrile containing as impurities 0.12% by weight of 3-cyanobenzamide and 0.12% by weight of 3-cyanobenzoic acid, 37 g of liquid ammonia, and 0.1 g of sodium hydroxide. Then, hydrogen was introduced into the autoclave to increase the inner pressure to 20 MPa (gauge). The concentration in the reaction solution was 0.043% by weight for the benzamide compound and 0.043% by weight for the benzoic acid compound. The autoclave was shaken at 50 C. for 30 min. The gas chromatographic analysis on the reaction product solution showed that the conversion of isophthalonitrile was 99.0 mol %, the yields of 3-cyanobenzylamine was 76.0 mol %, and the yield of m-xylylenediamine was 8.4 mol %. The by-products were substantially high-boiling substances.
With hydrogen;catalyst A; In methanol; ammonia; at 80℃; under 150015 Torr;The batch-wise method;Conversion of starting material;
[0036] The same procedure as in Example 1 was repeated except that 12.8 g of isophthalonitrile containing as impurities 3.42% by weight of 3-cyanobenzamide and 0.24% by weight of 3-cyanobenzoic acid were used as the starting phthalonitrile compound for the hydrogenation. The concentration in the reaction solution was 1.22% by weight for the benzamide compound and 0.086% by weight for the benzoic acid compound. The gas chromatographic analysis showed that the conversion of isophthalonitrile was 99.2 mol % and the yield of m-xylylenediamine was 64.3 mol %. The by-products were substantially high-boiling substances and the yield of 3-cyanobenzylamine was 0.7 mol % or lower.
4.2%Chromat.; 54.3%Chromat.
With hydrogen;sodium hydroxide; PDC-3000; In ammonia; at 50℃; under 150015 Torr; for 0.5h;The batch-wise method;Conversion of starting material;
[0048] A commercially available activated carbon-supported palladium catalyst PDC-3000 available from Toyo C. C. I. Co., Ltd. (supported palladium: 3% by weight) was activated by reduction with hydrogen. A 100-ml autoclave was successively charged with 3.0 g of the activated catalyst, 12.8 g of isophthalonitrile containing as impurities 3.42% by weight of 3-cyanobenzamide and 0.24% by weight of 3-cyanobenzoic acid, 37 g of liquid ammonia, and 0.1 g of sodium hydroxide. Then, hydrogen was introduced into the autoclave to increase the inner pressure to 20 MPa (gauge). The concentration in the reaction solution was 0.877% by weight for the benzamide compound and 0.062% by weight for the benzoic acid compound. The autoclave was shaken at 50 C. for 30 min. The gas chromatographic analysis on the reaction product solution showed that the conversion of isophthalonitrile was 92.0 mol %, the yields of 3-cyanobenzylamine was 54.3 mol %, and the yield of m-xylylenediamine was 4.2 mol %. The by-products were substantially high-boiling substances.
With sulfuric acid; In 1,4-dioxane; methanol; at 25℃; for 0.25h;
3- (DI-TERT-BUTOXYCARBONYLAMINO) BENZONITRILE (2g, 6. Ommoles) (prepared as described in Preparative Example 246, Step A above) was dissolved in methanol (30mL) and 10% (v/v) (10% CONC. sulfuric acid in 1,4-dioxane) (79mL) was added. The solution was stirred at 25 C for 0.25h and worked up as described in Preparative Example 89, Step C above). The residue was chromatographed on a SILICA GEL COLUMN (15X5CM) using 3% (10% CONC. ammonium hydroxide in METHANOL)-DICHLOROMETHANE as the eluant to give the title compound (651.4mg, 82%): FABMS: m/z 133.1 (MH+) ; HRFABMS: m/z 133.0762 (MH+). Calcd. for C8H9N2 : m/z 133.0766 ; 8H (CDCI3) 2.57 (2H, S,-CH2NH2), 3.92 (2H, s,- CH2NH2), 7.46 (1 H, m, Ar-H), 7.57 (2H, m, Ar-H) and 7.64 ppm (1 H, m, Ar-H); BC (CDC13) CH2: 45.2 ; CH: 129.4, 130.7, 130.7, 131.8 ; C: 112.4, 118.8, 143.8.
The precipitated crystals were collected through filtration, washed with water, and dried, to thereby obtain 8.2 g of m-cyanobenzoic acid (yield 56%, based on <strong>[10406-24-3]m-cyanobenzylamine</strong>). The m-cyanobenzoic acid obtained had a purity of 94%.
48%
The precipitated crystals were collected through filtration, washed with water, dried, to thereby obtain 7.1 g of m-cyanobenzoic acid (yield 48%, based on m-cyano-benzylamine). The m-cyanobenzoic acid obtained had a purity of 94%.
N-(3-cyanobenzyl)-2N-(4-chlorophenylaminocarbonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃;
To a solution of 2N-(4-chlorophenylaminocarbonyl)-l,2,3,4-tetraliydroisoquinoline- 3-carboxylic acid (291 mg, 0.880 mmol) and <strong>[10406-24-3]3-cyanobenzylamine</strong> (140 mg, 1.06 mmol) in DMF (7 mL), EDC (254 mg, 1.32 mmol) was added. The mixture was then stirred at room temperature overnight. H2O and EtOAc were added. The organic layer was separated, washed with IN HCl, dried over Na2SO4, concentrated in vacuo to give a solid. After being trituated with EtOAc / MeOH / CH2Cl2, the white solid was collected, dried on vacuum (148 mg), which was pure enough for the next reaction.
Example 8 m-Cyanobenzylamine (13.2 g), water (18 g), and 1,2-dichloroethane (22 g) were mixed, and the mixture was stirred with cooling with ice. Acetic acid (18 g) was added to the mixture. Subsequently, a 20 wt % aqueous solution (51.8 g) of sodium nitrite was added dropwise to the mixture over a one hour period. The mixture was stirred at the same temperature for four hours. The reaction mixture was subjected to extraction with 1,2-dichloroethane, and the organic solvent was concentrated. Water was added to the concentrated solution, and the residual organic solvent was removed through distillation, to thereby obtain 13.7 g of m-cyanobenzyl acetate (yield 78%). The purity of the product was 97%.
With potassium bromide; sulfuric acid; sodium thiosulfate; sodium nitrite; In dichloromethane; water;
Example 5 m-Cyanobenzylamine (13.2 g), potassium bromide (23.8 g), water (18 g), and methylene chloride (18 g) were mixed, and the mixture was stirred with cooling with ice. Concentrated sulfuric acid (98% by weight) (29.4 g) was added to the mixture. Subsequently, a 20 wt % aqueous solution (51.8 g) of sodium nitrite was added dropwise to the mixture over one hour. The mixture was stirred at the same temperature for four hours. Further, sodium thiosulfate was added to the mixture, and the resultant mixture was stirred at room temperature for one hour. Gas chromatographic analysis revealed that the yield of m-cyanobenzyl bromide was 57%.
With hydrogen;0.5% Pd/Al2O3; In 1-methyl-pyrrolidin-2-one; at 70℃; under 15001.5 Torr; for 10h;Product distribution / selectivity;
A commercially available 3-mm cylindrical alumina carrier (BET specific surface area: 167 m2/g, pore volume: 0.47 ml/g) was crushed to alumina particles having a size of 1.5 to 2.0 mm. The alumina particles were impregnated with a palladium chloride/sodium chloride aqueous solution (palladium: 0.14% by weight, sodium: 0.063% by weight) at 35 C for 0.5 h, to allow palladium chloride to be adsorbed on the alumina particles. Then, a formaldehyde/sodium hydroxide aqueous solution was poured onto the alumina particles to quickly reduce palladium chloride to palladium metal. The alumina particles were washed with ion-exchanged water and dried to prepare an alumina-supported 0.5 wt % palladium catalyst. The thickness of the palladium-supporting layer was 80 mum. A tubular reactor (inner diameter: 10 mm, length: 300 mm) was packed with 6 g of the catalyst. From the top of tubular reactor, a 3 wt % isophthalonitrile solution in N-methylpyrrolidone was continuously fed at a flow rate of 15.5 g/h while feeding hydrogen gas in parallel manner under 2.0 MPa, to perform the hydrogenation at 70 C. After 10 h from the initiation of reaction, the product solution sampled from the outlet of reactor was gas-chromatographically analyzed. The results are shown in Table 1.EXAMPLE 2 In the same manner as in Example 1 except for changing the concentration of the palladium chloride/sodium chloride aqueous solution (palladium: 0.87% by weight, sodium: 0.38% by weight), an alumina-supported 0.5 wt % palladium catalyst was prepared. The thickness of the palladium-supporting layer was 180 mum. The results of the hydrogenation conducted under the same conditions as in Example 1 are shown in Table 1.COMPARATIVE EXAMPLE 1 In the same manner as in Example 2 except for changing the concentration of the palladium chloride/sodium chloride aqueous solution (palladium: 0.87% by weight, sodium: 0.19% by weight) and additionally using ammonia water, an alumina-supported 0.5 wt % palladium catalyst was prepared. The thickness of the palladium-supporting layer was 530 mum. The results of the hydrogenation conducted under the same conditions as in Example 1 are shown in Table 1.
With piperidine; hydrogen; In 1-methyl-pyrrolidin-2-one; at 55 - 59℃; under 37503.8 Torr; for 280h;Product distribution / selectivity;
The hydrogenation was conducted in the same manner as in Example 7 except for using the catalyst prepared in Example 7 and a 9 wt % isophthalonitrile/3.6 wt % piperidine solution in N-methylpyrrolidone. The results are shown in Table 4.
With hydrogen; In 1-methyl-pyrrolidin-2-one; at 55 - 59℃; under 37503.8 Torr; for 280h;Product distribution / selectivity;
A commercially available spherical alumina carrier (BET specific surface area: 194 m2/g, pore volume: 0.49 ml/g) was crushed to alumina particles having a size of 1.0 to 1.4 mm. The alumina particles were immersed in a palladium chloride/nitrosylruthenium trichloride/sodium chloride aqueous solution (palladium: 0.15% by weight, ruthenium: 0.014% by weight, sodium: 0.063% by weight) at 35 C for 0.25 h, to allow palladium chloride and nitrosylruthenium trichloride to be adsorbed on the alumina particles. Then, a formaldehyde/sodium hydroxide aqueous solution was poured onto the alumina particles to quickly reduce palladium chloride and nitrosylruthenium trichloride to palladium metal and ruthenium metal. The alumina particles were washed with ion-exchanged water and dried to prepare an alumina-supported 0.4 wt % palladium/0.04 wt % ruthenium catalyst. The thickness of the palladium-supporting layer was 85 mum. A tubular reactor (inner diameter: 10 mm, length: 300 mm) was packed with 4.5 g of the catalyst. From the top of tubular reactor, a 9 wt % isophthalonitrile solution in N-methylpyrrolidone was continuously fed at a flow rate of 5.0 g/h while feeding hydrogen gas in parallel manner under 5.0 MPa, to perform the hydrogenation. The hydrogenation was continued for 280 h while gradually raising the temperature from 55 C. After 280 h, the temperature reached 59 C. After 15 h and 280 h from the initiation of reaction, the product solution was analyzed. The results are shown in Table 4.
With hydrogen; In 1-methyl-pyrrolidin-2-one; at 62℃; under 15001.5 Torr; for 2h;Product distribution / selectivity;
The alumina particles obtained in Example 3 were impregnated with magnesium acetate. The alumina particles were then calcined in air at 400 C, to prepare an alumina carrier supporting 2.0 wt % magnesia. In the same manner as in Example 2, palladium was supported on the alumina carrier, to prepare an alumina-supported 0.4 wt % palladium/2.0 wt % magnesia catalyst. The thickness of the palladium-supporting layer was 180 mum. Using the obtained catalyst, the hydrogenation was conducted in the same manner as in Example 4. The results are shown in Table 2.
With hydrogen; In 1-methyl-pyrrolidin-2-one; at 62 - 70℃; under 15001.5 - 37503.8 Torr; for 2 - 140h;Product distribution / selectivity;
A commercially available spherical alumina carrier (BET specific surface area: 194 m2/g, pore volume: 0.49 ml/g) was crushed to alumina particles having a size of 1.0 to 1.4 mm. The alumina particles were impregnated with a palladium chloride/sodium chloride aqueous solution (palladium: 0.87% by weight, sodium: 0.38% by weight) at 35 C for 0.25 h, to allow palladium chloride to be adsorbed on the alumina particles. Then, a formaldehyde/sodium hydroxide aqueous solution was poured onto the alumina particles to quickly reduce palladium chloride to palladium metal. The alumina particles were washed with ion-exchanged water and dried to prepare an alumina-supported 0.4 wt % palladium catalyst. The thickness of the palladium-supporting layer was 180 mum. A tubular reactor (inner diameter: 10 mm, length: 300 mm) was packed with 5 g of the catalyst. From the top of tubular reactor, a 6 wt % isophthalonitrile solution in N-methylpyrrolidone was continuously fed at a flow rate of 7.2 g/h while feeding hydrogen gas in parallel manner under 2.0 MPa, to perform the hydrogenation at 62 C. After 2 h from the initiation of reaction, the product solution was analyzed. The results are shown in Table 2.EXAMPLE 4 The hydrogenation was performed in the same manner as in Example 3 except for changing the reaction temperature to 70 C. After 10 h from the initiation of reaction, the product solution was analyzed. The results are shown in Table 2.
With hydrogen; In tetrahydrofuran; at 65℃; under 37503.8 Torr; for 10 - 140h;Product distribution / selectivity;
In the same manner as in Example 6 except for using a 6 wt % isophthalonitrile solution in tetrahydrofuran in place of the 6 wt % isophthalonitrile solution in N-methylpyrrolidone, the hydrogenation was conducted. The results are shown in Table 3.
With ammonia; hydrogen;nickel catalyst; hydrogen reducted; at 70℃; under 52505.3 Torr; for 240h;Product distribution / selectivity;
Into a tubular vertical hydrogenation reactor having a volume of 400 ml, was packed 150 g of a commercially available supported nickel catalyst (Ni content of 60%), and this catalyst was subjected to hydrogen reduction. Then, a liquid mixture of isophthalonitrile and liquid ammonia (isophthalonitrile:liquid ammonia =1:3 (weight ratio)) was supplied from the top of the reactor at a rate of 57.8 g/h, and the first catalytic hydrogenation treatment was conducted continuously at 70C for 10 days while 30 NL/h of a hydrogen gas was introduced at a reaction pressure of 7.0 MPa, to thereby produce a reaction product (a). The reaction product (a) was passed through a gas-liquid separator, and a liquid phase part was extracted into a receiver intermittently. Ammonia was subjected to pressure reduction to a normal temperature and a normal pressure and was removed from a gas phase part of the receiver. Then, a nitrogen gas was passed therethrough for an operation of removing residual ammonia, to thereby extract intermittently the reaction product (b). The extracted reaction product (b) was mixed completely, and then was analyzed by gas chromatography. The reaction product (b) had metaxylylenediamine of 85.3 wt%, 3-cyanobenzylamine of 0.03 wt%, and 3-methylbenzylamine of 0.7 wt%. No isophthalonitrile was detected. Remaining components were oligomers of metaxylylenediamine and polymers each having a high boiling point and not detected by gas chromatography. Note that the residual ammonia amount was about 500 ppm. In this way, in the case where the amount of the solvent containing liquid ammonia was excessively small in the first catalytic hydrogenation treatment, the amount of cyanobenzylamine was small. However, large amounts of polymers were produced through a side reaction, and the yield of xylylenediamine was reduced significantly.
To tert-butyl 3-cyanobenzylcarbamate in CH2Cl2 (10 ml), TFA (3 ml) was added. After Ih, volatiles were removed on a rotavap under reduced pressure. Crude residue 3- (aminomethyl)benzonitrile was dissolved in water, basified with 2N NaOH and extracted with CHCl3 (100 ml) and used without further purification.
General Porcedure: A solution of (1.80 mmol) of 3-benzyl amine and 260 mg (1.50 mmol) 5-methyl-3-sulfonyl[1,2,4]triazine in anhydrous THF was heated to reflux. After 3 h, the reaction was cooled to rt and concentrated to obtain a yellow oil. The residue was purified using column chromatography with hexane-ethyl acetate (50:50) to obtain the desired product.
With palladium diacetate; caesium carbonate; (R)-2,2'-bis(diphenylphosphanyl)-1,1'-binaphthyl; In 1,4-dioxane; at 150℃; for 2h;Inert atmosphere;
Step 2: 3-[(5-[(2, 6-difluoro-3 , 5-dimethoxyphenyl)aminoJmethyl}-1-[2- (trimethylsilyl)ethoxyJmethyl}-JH-pyrrolo[2, 3-bJpyridin-4-yl)aminoJmethyl}benzonitrile A mixture of N-[(4-chloro- 1- { [2-(trimethylsilyl)ethoxy]methyl} -1 H-pyrrolo [2,3 -b]pyridin-5 -yl)methyl]-2,6-difluoro-3 ,5 -dimethoxyaniline (110 mg, 0.23 mmol), 3- (aminomethyl)benzonitrile (45.0 mg, 0.34 immol), palladium acetate (5.1 mg, 0.023 mmol), (R)-(+)-2,2?-bis(diphenylphosphino)- 1,1 ?-binaphthyl (14 mg, 0.023 mmol), and cesiumcarbonate (220 mg, 0.68 mmol) in 1,4-dioxane (3 mL, 40 mmol) was evacuated then filled with nitrogen. The resulting mixture was stirred at 150 C for 2 h then cooled to room temperature and diluted with water and extracted with EtOAc. The organic layer was washed with water, brine then dried over Na2SO4 and concentrated. The residue was used in the next step without further purification. LC-MS calculated for C30H36F2N5O3Si (M+H) mlz: 580.3; found: 580.2.
General procedure: 2-(2-oxo-2,3-dihydrobenzo[d]oxazole-6-sulfonamido)acetic acid 3 (0.27 g, 1 mmol) was dissolved in 3 ml of dimethylformamide and EDC (0.21g, 1.1 mol), HOBT (0.17g, 1.1 mmol) and 0.5 ml of NMM was added to the solution. The reaction mixture was stirred for 30 minutes at room temperature and then a solution of 2,5-dimethylaniline 4 (0.24g 2 mmol) in 1 ml of dimethylformamide was added. The reaction was stirred overnight at room temperature and then the solvent was removed under reduced pressure. The residue was dissolved in 30 ml of ethyl acetate and the organic layer was poured into 100 ml of water, washed successively 50 ml of saturated sodium bicarbonate, 50 ml of 1 N HCl, 50 ml of brine and the resultant organic phase was then dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting solid was chromatographed on silica gel and eluted with methylene chloride: ethyl acetate using a gradient of 100:1 to 90:10, to yield N-(2,5-dimethylphenyl)-2-(2-oxo-2,3-dihydrobenzo[d]oxazole-6-sulfonamido)acetamide ML260 (0.20 g, 55 % yield).
General procedure: To geldanamycin (34 mg, 0.06 mmol, 1.0 equiv.) in dichloromethane (8 mL) was added substitutional arylmethylamine (0.12 mmol, 20.0 equiv.). The reaction mixture was stirred for 24 h at room temperature, and the color changed from yellow to purple. TLC was used to monitor the progress of the reaction. After the reaction complete, the mixture was diluted with 20 mL of dichloromethane and washed with 1.5 N HCl (2 x 20 mL) followed by brine (3 x 25 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was purified by flash column chromatography (silica gel, ethyl acetate/petroleum ether 1:1) to afford a purple solid.
8-(benzyloxy)-4-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-5-yl trifluoromethanesulfonate[ No CAS ]
3-(((8-(benzyloxy)-4-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-5-yl)amino)methyl)benzonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
11 mg
In 1,4-dioxane; at 60 - 70℃; for 6h;
To a solution of 8-(benzyloxy)-5-hydroxy-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one (150 mg) and triethylamine (147 muL) in methylene chloride (5 mL), trifluoromethanesulfonic anhydride (174 muL) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 1 hour. The solvent in the reaction mixture was distilled off under reduced pressure. To the obtained residue, <strong>[10406-24-3]3-(aminomethyl)benzonitrile</strong> (190 mg) and dioxane (10 mL) were added, and the mixture was heated with stirring at 60 to 70C for 6 hours. After cooling of the reaction mixture, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 98-90% chloroform/methanol] and then suspended in a mixed solvent of methanol, 2-propanol and diisopropyl ether, and the deposit was collected by filtration to obtain a pale yellow solid of 3-(((8-(benzyloxy)-4-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-5-yl)amino)methyl)benzonitrile (11 mg). 1H-NMR (CDCl3) delta value: 3.01 (s, 3H), 4.50 (d, J=4.9 Hz, 2H), 5.25 (s, 2H), 5.42-5.50 (m, 1H), 5.63 (s, 1H), 7.24-7.45 (m, 3H), 7.50-7.58 (m, 1H), 7.59-7.74 (m, 5H), 8.93 (s, 1H).
3-((4-chloro-7-nitro-1,3-dioxoisoindolin-2-yl)methyl)benzonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With acetic acid; at 100℃; for 18h;
Synthesis of LVII:To a stirred solution of compound XXV (3.5 g, 15 mmol) in acetic acid (70 mL) was added <strong>[10406-24-3]3-(aminomethyl)benzonitrile</strong> (XXVII, 6.07 g, 46 mmol) and the reaction mixture heated at100C for 18 h. The reaction mixture was cooled to room temperature and the acetic acid removed under reduced pressure to obtain the crude product 3-((4-chloro-7-nitro- 1,3- dioxoisoindolin-2-yl)methyl)benzonitrile as a brown solid (LVII; 4.8 g,). ?H NMR (400MHz,DMSO-d6): oe 8.28-8.26 (d, J= 8.4 Hz, 1H), 8.12-8.10 (d, J 8.4 Hz, 1H), 7.85 (s, 1H), 7.76-7.72 (m, 2H), 7.58-7.54 (t, J 7.6 Hz, 1H), 4.83(s, 2H). MS (M+1): 342.02.
3-((4-nitro-1,3-dioxoisoindolin-2-yl)methyl)benzonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
55%
With acetic acid; at 100℃; for 18h;Reflux;
Synthesis of XXIX:To a stirred solution of compound I (0.5 g, 2.59 mmol) in acetic acid (10 mL) was addedcompound XXVIII (0.51 g, 3.88 mmol) and the reaction heated at 100C for 18 h. Thereaction mixture was cooled to room temperature and acetic acid was removed under reducedpressure to obtain a crude product. This was suspended in ethanol, cooled and filtered to afford3 -((4-nitro- 1,3 -dioxoisoindolin-2-yl)methyl)benzonitrile as an off white solid (XXIX; 0.4 g;55% yield). ?H NMR (400MHz, DMSO-d6): oe 8.3 1-8.29 (d, J= 8 Hz, 1H), 8.20-8.18 (d, J=7.2 Hz, 1H), 8.08-8.05 (t, J= 7.6 Hz, 1H), 7.85 (s, 1H), 7.76-7.70 (m, 2H), 7.57-7.53 (t, J 7.6 Hz, 1H), 4.84 (s, 2H). MS (M+1): 308.00.
(R)-1-[5-difluoromethyl-6-ethyl-7-oxo-6,7-dihydro[1,3]thiazolo[5,4-d]pyrimidin-2-yl]pyrrolidine-2-carboxylic acid[ No CAS ]
(R)-N-(3-cyanobenzyl)-1-(5-difluoromethyl-methyl-6-ethyl-7-oxo-6,7-dihydro[1,3]thiazolo [5,4-d]pyrimidine-2-yl)pyrrolidine-2-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
21 mg
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In water; N,N-dimethyl-formamide; at 20℃; for 3h;
DMF solution (0.5mL) 3- cyanobenzylamine of the compound obtained in Reference Example 124 (48mg) (16mg), EDChydrochloride (35mg), HOBt monohydrate (24mg) and N, N- diisopropylethylamine the (23 mg) was added, and the reaction mixture was stirred for 3 hours at room temperature.After confirmation of completion of the reaction, water was added to the reaction mixture, and the mixture was extracted twice with chloroform.After the solvent was distilled off under reduced pressure, the residue Waters XTerra (R) column; purified by (solvent 10 mmol / L aqueous ammonium carbonate solution / methanol) to give the title compound (21 mg).MS (ESI) M / Z; 459 [M TasuH]Tasu
With potassium hydroxide; In butan-1-ol; at 120℃; for 5h;
10099] A 200 mE three-neck flask equipped with a thermometer sheath tube and a reflux condenser was charged with 2.0 g of<strong>[10406-24-3]3-cyanobenzylamine</strong>, 1.0 g of dicyandiamide, 0.1 g of potassium hydroxide, 12.0 g of m-xylenediamine and 25 g of 1 -butanol. The mixture was heated to reflux at 120 C. for 5 hours under agitation at normal pressure. Subsequently, crystals precipitated afier cooling were filtered off and washed with a small amount of methanol, and then vacuum-dried to obtain white crystals. It was confirmed that the white crystals were m-aminomethylbenzoguanamine based on the retention time in gas chromatography. The yield of m-aminomethylbenzoguanamine was 74%.
7‐chloro‐5‐(1‐methyl‐1H‐indol‐6‐yl)quinoxaline[ No CAS ]
3-([8-(1-methyl-1H-indol-6-yl)quinoxalin-6-yl]amino}methyl)benzonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86%
With palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 1,4-dioxane; at 150℃; for 1h;Inert atmosphere; Sealed tube;
A sealed tube is charged with 7-chloro-5-(1-methyl-1H-indol-6-yl)-quinoxaline (175.00 mg; 0.57 mmol; 1 .00 eq.) (Intermediate 4), 3-aminomethylbenzo- nitrile (0.1 1 mL; 0.85 mmol; 1 .50 eq.), Cs2C03 (558.79 mg; 1 .70 mmol; 3.00 eq.) and 1 ,4-dioxane (10.00 mL). RM is purged with argon and then BINAP (17.98 mg; 0.03 mmol; 0.05 eq.) and Pd(OAc)2 (6.69 mg; 0.03 mmol; 0.05 eq.) are added. RM is sealed and stirred at 150 C for 1 h. After this time, the mixture is filtered through a Celite pad and the filtrate is diluted with EtOAc and extracted with water. Combined organic phases are washed with brine, dried over Na2S04. Solvent is evaporated and the residue is purified by FCC (hexane/EtOAc; gradient). 3-([8-(1 -Methyl-1 H-indol-6-yl)quinoxalin-6- yl]amino}methyl)benzonitrile (193.00 mg; yield 86 %; 98 % by HPLC) is obtained as a yellow powder.
(R)-2-(2,4-bis(benzyloxy)-5-chlorobenzoyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid[ No CAS ]
C39H32ClN3O4[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃;
General procedure: The chiral monomer (R)-2-(2,4-bis(benzyloxy)-5-chlorobenzoyl)-1, 2,3,4-tetrahydroisoquinoline-3-carboxylic acid 9 (100 mg, 0.19 mmol), EDCI (43.7 mg, 0.228 mmol), HOBt (30.8 mg, 0.228 mmol) and 2-chloro benzylamine (0.15 mL, 1.2 mmol) in DMF (3 mL) was stirred overnight at room temperature. The organic layer was washed successively with 2 M HCl and 2 M NaOH, then dried over anhydrous/Na2SO4, filtered and evaporated under vacuum to afford a yellowish powder that was used for the next step reaction without further purification. To the anhydrous CH2Cl2 (3 mL) solution of this product cooled to 0 C under N2 was added BCl3 (1.0 M in CH2Cl2, 0.57 mL, 0.56 mmol). The reaction mixture was allowed to warm to RT and stirred for 1.5 h. Sat. NaHCO3 solution (5 mL) was added and CH2Cl2 was removed under vacuum. The aqueous residue was extracted with EtOAc (4 x 10 mL) and evaporated under vacuum to produce a brown powder. The powder was purified by column chromatography over silica gel eluted with CH2Cl2-MeOH (30: 1, v/v) to give compound 10 (82.8 mg) as a white powder, yield: 91%.
With N-ethyl-N,N-diisopropylamine; HATU; In water; N,N-dimethyl-formamide; at 0 - 20℃;
In a 40 ml vial equipped with a stir bar, compound 19 (70 mg, 0.20 mmol) and HATU (95 mg, 0,25 mmol) were dissolved in 3 ml of a mixture of DMF: water (2: 1). A solution of 3- cyanobenzylamine (33 mg, 0.25 mmol) and diisopropylethylamine (0.17 ml, 1.00 mmol) was then added to compound 19 solution at 0-5 C. The mixture was then stirred at room temperature overnight. Upon the completion of the reaction, the mixture was diluted with EtOAc (50 ml), and then washed with water and brine (50 ml of each). The organic layer was then dried over anhydrous sodium sulfate, and the EtOAc was evaporated under vacuum. The residue was then purified by flash chromatography to give 49 mg of the product (yield: 56%); Compound 24 was characterized by LCMS (441 [ M i l l ; and purity was estimated to be 90%),
With triethylamine; In dichloromethane; at 0 - 20℃; for 12h;
General procedure: To a solution of alkylamine (2.96 mmol) and triethylamine (4 eq.) in dichloromethane (15 mL)was added a solution of thiophosgene (1.1 eq.) in dichloromethane (5 mL) slowly at 0 C. Afterthe addition, the reaction mixture was allowed to warm up to room temperature and stirredovernight. After the completion of the reaction, solvent was removed and the crude was filteredthrough a short silica plug using ethyl acetate/hexane (1:4) as eluent to get the desiredalkylisothiocyanate 1-1 which was immediately taken to the next step. To the solution ofalkylthiocyanate 1-1 (2.72 mmol) in diethyl ether (2 mL) was added hydrazine monohydrate (2eq.). The reaction mixture was stirred overnight at room temperature. The product precipitated outof the solution which was filtered, washed with diethyl ether and vacuum dried to afford the desiredthiosemicarbazide 1-2 as white solid.
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