Поиск физико-химических характеристик и составление план-синтеза биологически-активных веществ на примере Кветиапина

Reagents: 11 -piperazinyl dibenzo[b,f][1,4] thiazepine hydrochloride 2.75 gr (7.5 mmole) 2-(2-Chloroethoxy) ethanol 1.2 gr (9.6 mmole) Na2CO3 4.75 gr Nal 40-50 mg Toluene 15 mL TBAB 0.5 grams Procedure: The reagents were charged to a round-bottomed flask equipped with a magnetic stirrer and a condenser with a calcium chloride drying tube. The flask and contents were heated on an oil bath at 115C-120C under gentle reflux. After 17 hours the progress of the reaction was checked by HPLC analysis of the contents of the flask which were found to include 98.2percent product and 0.45percent starting material.

With sodium carbonate, sodium iodide, tetrabutylammomium bromide in toluene, Time= 17h, T= 115 - 120 °C , Heating / refluUTICALS USA, INC.;

a) ll-piperazinyl-dibenzo[b,f][l,4] thiazepine dihydrochloride (IV)Dibenzo[b,fj[l,4] thiazepin-l l-[10H]one 100 gm, phosphorus oxychloride 125 ml, N₅N- dimethyl aniline 33 ml in toluene 500 ml were refluxed for 4 hour. Toluene was distilled off under vacuum to obtain residue. The residue was dissolved in 250 ml toluene and the reaction mixture was cooled to 10⁰C. Aqueous Potassium carbonate solution (100 g in 200 ml water) was added to the reaction mixture below 15⁰C. The toluene layer was separated and refluxed with piperazine 100 g for 24 hour. The reaction mixture was cooled and filtered to remove unreacted piperazine. Toluene was distilled off under vacuum. The residue was dissolved in 390 ml of isopropyl alcohol. 100 ml of 33percent ethanolic hydrochloride was added to the reaction mixture at 25-35.deg. C. White solid obtained was filtered, washed with 100 ml ethanol and dried at 60-70⁰C. Yield : 138 g (90 percent).

Stage 1: With trichlorophosphate in toluene, Time= 4h, T= 10 °C, Heating / reflux Stage 2: With potassium carbonate in water, toluene, T= 15 °C Stage 3: With hydrogenchloride, more than 3 stages

Patent; USV LIMITED; WO2007/4234; (2007); (A1) English View in Reaxys

Example 2 shows the product mix from a reductive amination process where MEA and ammonia are fed to the reductive amination reactor. Accordingly, Example 2 is indicative of the product mix coming out of the reductive amination reactors in FIGS. 2 or 3, described above.The reductive amination reaction for Example 2 took place over a Nickel/Rhenium/Boron (8.0:2.0: 1.7 wt. percent) catalyst on an alumina/silica (80:20) support prepared as described above. The catalyst was loaded into 86.25" of 0.688" ID tubular stainless steel adiabatic reactor. MEA and ammonia were fed into a mixer to provide an ammonia/MEA molar feed ratio of approximately 10. Hydrogen was also fed to yield a feed mix that was 1-2 molpercent hydrogen. The mixture was fed to a reactor preheated to 165.deg.C at a pressure of 3000 psig and a space velocity of 10-12 g-mol MEA/kg catalyst/hour. The liquid sample was collected in a receiver at ambient temperature, to allow the ammonia and hydrogen to flash off. The product mix of reaction at 37.5percent MEA conversion was as, follows: is 88.2percent by weight EDA, 2.2percent by weight PIP, 5.4percent by weight DETA, 3.3percent by weight AEEA, and 0.9per- cent by weight Others. The product mix was determined by capillary gas chromatography on a dry product basis (i.e., on a reactant-free and water-free basis).

With ammonia, hydrogen, Nickel/Rhenium/Boron (8.0:2.0: 1.7 wt. percent) catalyst on an alumina/ silica (80:20), T= 165 °C, p= 155909Torr

Patent; DOW GLOBAL TECHNOLOGIES INC.; DO, David; DOMKE, Christopher, H.; LOPEZ- TOLEDO, Jacinto; PETRAITIS, David, M.; SRNAK, Thomas, Z.; W02010/42168; (2010); (A2) English

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HydrogenationThe hydrogenation experiments were performed in a multi-autoclave unit containing four 60 ml batch autoclaves, all equipped with common electrical heating and with individual gas entrainment impellers, manometers and temperature indication . The hydrogenation catalysts were activated in-situ (typical conditions : 230 ⁰C, 10 - 20 bar H₂ for 4 hrs ) . The substrates, dissolved in ca . 20 ml solvent , were introduced into the autoclaves by injection. Then, the autoclaves were pressurized with Hz, stirred at 800 rpm and heated to ca. 170 ⁰C. After the reaction, the liquid reactor contents were analyzed by GC-MS. Table 2 shows the reaction conditions and analytical results from the different experiments. Table 23 This specie was qualitatively observed by NMR analysis and/or GC-MS.4 GC-MS peak area percentage (A_npercent) = (peak area n) x 100 / (sum of substrate, 2- hydroxyacetamide, MEG, HOCH₂CH₂NR₂, R₂NCH₂CH₂NR₂ and all polyamine peak areas) .5 MEG peak corrected for overlaying methyl glycolate peak (10percent peak area reduction) . n.d. = not determined

With hydrogen, Cu/Al₂O₃/SiO₂ in ethanol, Time= 18h, T= 170 °C, p= 36753.7Torr , Autoclave

Patent; SHELL INTERNATIONALE RESEARCH MAATSCHAPPIJ B.V.; DE BOER, Eric Johannes Maria; VAN DER HEIJDEN, Harry; MEURS, Jan Hermen Hendrik; WIJNANS, Sanne;WO2010/130696; (2010); (A1) English View in Reaxys

Polivka, Zdenek; Holubek, Jiri; Svatek, Emil; Dlabac, Antonin; Pucek, Dusan; et al.; Collection of Czechoslovak Chemical Communications; vol. 48; nb. 5; (1983); p. 1465 - 1476 View in Reaxys

Para-Toluene sulphonic acid (41 mg, 0.2175 mmol) was added to the ethyl acetate solution obtained in Example 2, and approx. 50percent of the ethyl acetate was removed by distillation. Xylene (320 ml) was added to the reactor and the distillation was continued until a batch temperature of 125.deg. C. was reached. The reaction was then heated for 10 hours with azeotropic removal of water. The vessel contents were cooled to 55.deg. C. and the resulting suspension was filtered. The cake was washed with methanol (120 ml), isolated and dried in vacuo to give 10,11-dihydrodibenzo[b,f][1,4]thia- zepin-11-one (28.4 g, 86percent).

With toluene-4-sulfonic acid in ethyl acetate, xylene, Time= 10h, T= 125 °C

Patent; Murray, Paul Michael; Vaz, Luis-Manuel; Ainge, Debra; Harada, Katsumasa; Nishino, Shigeyoshi; Yoshii, Kiyotaka; US2007/203336; (2007); (A1) English View in Reaxys

McClelland; Peters; Journal of the Chemical Society; (1947); p. 1229,1233 View in Reaxys

Mayer,F.; Chemische Berichte; vol. 42; (1909); p. 3065 View in Reaxys

With iron(III) chloride, iron, 1.) H₂O, heating, 12 h, 2.) H₂O, ethanol, heating, 5 h

Kuti, M.; Rabai, J.; Kapovits, I.; Phosphorus, Sulfur and Silicon and the Related Elements; vol. 85; nb. 1-4; (1993); p. 119 - 128 View in Reaxys

Example Name 2

In a 2 liter capacity autoclave, 2-nitro-2'-carboxydiphenylsulphide (100 g) and methanol (1000 ml) were taken and 5percentPd/C (10 g) was added. The reaction mixture was then hydrogenated for 10-15 hours at a pressure of 100 psi at 30-35.deg.C. The resulting mixture was filtered and the filtrate was concentrated under vacuum at 45-50.deg.C to obtain the title compound.

With hydrogen, palladium on activated carbon, Time= 10 - 15h, T= 30 - 35 °C, p= 5171.62Torr Patent; JUBILANT ORGANOSYS LIMITED; WO2006/27789; (2006); (A1) English View in Reaxys

Thiosalicylic (20 g, 0.126 mol, 96.9percent) and 2-chloronitrobenzene (24.6 g, 0.156 mol, 99.7per- cent) were added to an appropriate vessel, followed by IPA (50 ml) and water (10 ml) at 20-25.deg. C. The reactor was inerted (nitrogen), the suspension was heated to 30-35.deg. C. and a solution of KOH aq (30.9 g, 0.273 mol, 49.51percent w/w) was added, followed by a water wash (24.4 ml). The reaction mixture was heated to reflux and was maintained at this temperature for 6 hours. On completion of the reaction, the solution was cooled to 65.deg. C. and water (50 ml) was added. The solution was held at 65.deg. C. and c.HCl (20 g) was added, leading to precipitation of crude Nitro Acid. The suspension was re-heated to reflux and stirred at this temperature for 1 hour. The solution was then cooled to 25-30.deg. C. After stirring for 30 min at 25-30.deg. C., the suspension was filtered and the cake was washed with water (2.x.40 ml) and toluene (2.x.40 ml) and was left on the filter under vacuum for 1 hour to give 2-(2-nitrophenylsulfuryl)benzoic acid (31.1 g at 100percent w/w, 90percent).

Stage 1: With potassium hydroxide in water, isopropyl alcohol, Time= 6h, T= 20 - 35 °C, Heating / reflux

Stage 2: With hydrogenchloride in water, isopropyl alcohol, T= 65 °C

Patent; Murray, Paul Michael; Vaz, Luis-Manuel; Ainge, Debra; Harada, Katsumasa; Nishino, Shigeyoshi; Yoshii, Kiyotaka; US2007/203336; (2007); (A1) English View in Reaxys

Truce; Simms; Journal of Organic Chemistry; vol. 22; (1957); p. 617,620 View in Reaxys

To the suspension of potassium carbonate (134.3 g) in dimethylformamide (250 ml), thiosalicylic acid (50 g) was added and heated to 80.deg. C. To the reaction mixture 2-chloro nitrobenzene (51.1 g) was added at 80-85.deg. C. Reaction mixture was stirred at 100-110.deg. C. till completion of reaction. After completion of reaction, the reaction mixture was cooled and filtered the residue. Filtrate was concentrated to get residue. To the residue, water (100 ml) was added and pH of the solution was adjusted to 11 using sodium hydroxide solution. The aqueous layer was washed with toluene (100 ml). The pH of aqueous layer again adjusted to 2 using conc. hydrochloric acid at 25-30.deg. C. The product obtained was filtered, washed with water (200 ml) and dried under vacuum at 60.deg. C. to get 82-86 gm of titled product. (HPLC purity: 99-100percent). With potassium carbonate in DMF (N,N-dimethyl-formamide), T= 80 - 110 °C

Patent; ORCHID CHEMICALS and PHARMACEUTICALS LTD.; US2005/80072; (2005); (A1) English

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Yield Conditions & References

13.7 g (0.1 mole) of anthranilic acid, 41.1 g of water, and 20.86 g (0.2 mole) of 35percent hydrochloric acid were charged into a 100-ml glass flask equipped with agitator and thermometer. The charged materials were cooled to a temperature of 5.deg. C. while agitation was employed. Next, an aqueous solution prepared by dissolving 7.25 g (0.105 mole) of sodium nitrite in 13.5 g of water was dropped into the thus obtained reactant liquid using a dropping funnel over 30 min. with the temperature maintained at 5.deg. C. or below and the same temperature level was maintained for another 30 min. [0023] Charged into a 200-ml glass flask equipped with agitator, thermometer, and reflux condenser, separate from the aforesaid glass flask, were 21.6 g (0.09 mole) of sodium sulfide 9 hydrate, 0.64 g (0.02 mole) of sulfur, 24 g of water, and 12.5 g (0.15 mole) of 48percent aqueous solution of sodium hydroxide, which were thereupon cooled to a temperature of 5.deg. C. while agitation was employed throughout. Next, the aforesaid diazotized aqueous solution was dropped into the thus obtained reactant liquid using a dropping funnel over 1 hr with the temperature maintained at 5.deg. C. or below and the reaction was allowed to progress for further 1 hr at room temperature and for further 2 hr at a temperature of 60.deg. C., respectively, whereupon the reaction was terminated. [0024] Upon termination of the reaction the reaction mixture was cooled down and added to 84 g of 10percent hydrochloric acid for crystallizing thiosalicylic acid. The precipitated crystalline matters were filtered out and dried into 15.5 g of crystalline matters. Liquid chromatography analysis of the obtained crystalline matters revealed that the components comprised 83.2percent of thiosalicylic acid and 2.6percent of dithiosalicylic acid. The yield of thiosalicylic acid was 83.7percent. Pertinent test results are summarized in Table 1

With sodium sulfide, sodium hydroxide, sulfur in water, Time= 4h, T= 5 - 60 °C Patent; Yokota, Keiichi; US2004/116734; (2004); (A1) English View in Reaxys

Carcer, Inigo Aguirre de; Heinekey, D. Michael; Journal of Organometallic Chemistry; vol. 694; nb. 6; (2009); p. 840 - 844 View in Reaxys

South, Michael S.; Liebeskind, Lanny S.; Journal of Organic Chemistry; vol. 47; nb. 20; (1982); p.

3815 - 3821

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Pomerantz,M. et al.; Journal of Organic Chemistry; vol. 36; (1971); p. 2080 - 2082 View in Reaxys

Example Title Example 1; Example 2; Comparative Example 1

Example 1 A rotary evaporator having a capacity of 500 ml, equipped with an oil bath at a temperature of 450 C. and containing therein glass balls with a diameter of 1 cm, was charged with 50 g of dimethyl oxalate and 5.6 g of methyl alcohol to provide a starting material having a melting point of 430 C. The starting material was melted at a temperature of 450 C. While the rotary evaporator was rotated at speed of 100 rpm, an ammonia gas was fed in an average feed rate of 0.45 liter/min calculated under a standard temperature (00 C.) and pressure (1 atm.), to start the ammonia-addition and decomposition reaction of the dimethyl oxalate. The feed of the ammonia gas was continued for 180 minutes. The resultant solid reaction product was removed from the evaporator and dried in a vacuum dryer under a reduced pressure of 3 mmHg at a temperature of 400 C. for 12 hours, to evaporate and remove methyl alcohol from the solid reaction product. The resultant powdery product was 37.0 g of high purity oxamide. In the above-mentioned reaction procedure, the content of methyl alcohol in the reaction mixture was 24.9percent by weight at 60 minutes after the start of the reaction, 21.7percent of weight at 120 minutes after the start of the reaction and 18.8percent by weight at 180 minutes after the start of the reaction. Also, in the reaction, the powdery product was obtained in an yield of 98.6percent based on the molar amount of the dimethyl oxalate. Example 2 The same procedures as in Example 1 were carried out, with the following exceptions. The average feed rate of the ammonia gas was 0.34 liter/minute when determined under the standard temperature and pressure. The temperature of the oil bath was 600 C. After 60 minutes from the start of the reaction, the temperature of the oil bath was gradually elevated to 1700 C., to evaporate and remove the generated by-product consisting of methyl alcohol from the reaction product. A powdery solid product comprising oxamide with a high purity was obtained in an amount of 36.7 g, without the drying procedure. Comparative Example 1 A flat-bottomed separable flask was charged with a mixture of 300 g of methyl alcohol with 35.4 g of dimethyl oxalate. Then, while the mixture was stirred at a constant temperature of 200 C., an ammonia gas was fed at an average feed rate of 300 ml/minute under the standard temperature and pressure into the mixture for 45 minutes. The reaction procedure was further continued at a temperature of 200 C. for 60 minutes. When the reaction procedure was completed, it was found that the reaction mixture was in the state of a slurry in which oxamide particles were dispersed in methyl alcohol. The slurry was subjected to filtration through a filter paper sheet, to collect the oxamide particles. The filtered oxamide particles contained methyl alcohol in an amount of about 50percent of weight. Thus, the filtered oxamide particles were heated at a temperature of 1100 C., to evaporate and remove methyl alcohol wherefrom. The resultant oxamide powder was in an amount of 25.9 g. Stage 1: With ammonia, Time= 3h, T= 45 °C, p= 760.051Torr Stage 2: With ammonia, Time= 0.75 - 3h, T= 20 - 170 °C, p= 760.051Torr

Patent; Ube Industries, Ltd.; US6348626; (2002); (B1) English View in Reaxys

Example Title (2) Oxidative Esterification Reaction (Production of a-Hydroxycarboxylic Acid Ester) Synthesis of an a-hydroxycarboxylic acid ester was carried out using the Pb-Au alloy/Ti02-Si02 catalyst obtained in (1) above. [0314] 62 g (1.0 mol) of ethylene glycol, 320 g (10 mol) of methanol, and 20 g of the above-mentioned catalyst were put into a rotating stirring type 1 L autoclave having a condenser tube, and the autoclave was hermetically sealed. Next, a mixed gas of oxygen and nitrogen (volume ratio 10/90) was blown into the liquid at a flow rate of 1 L/min while adjusting using a back pressure valve such that the pressure inside the system was maintained at 0.5 Mpa, and reaction was carried out for 5 hours at 90.deg. C. while carrying out this bubbling. [0315] After that, cooling was carried out, and the autoclave was opened; upon analyzing the contents using gas chromatography, it was found that 0.180 mol of the ethylene glycol starting material was contained, and the contents of the products methyl glycolate, 2-hydroxyethyl glycolate, glycolide, dimethyl oxalate, and other oxalic acid compounds were 0.656 mol, 0.068 mol, 0.012 mol, 0.008 mol and 0.001 mol respectively. Moreover, the molar production ratios for methyl formate and 2-hydroxyethyl formate relative to methyl glycolate were 0.12 and 0.03 respectively. [0316] (3) Removal of Oxalic Acid Esters, Followed by Purification of Glycolic Acid Ester [0317] The reaction filtrate (404.9 g) obtained by separating away the catalyst from the reaction liquid obtained through the oxidative esterification reaction of (2) above contained ethylene glycol and methanol as residual starting materials, the reaction products, and water produced in the reaction. Out of the contents there was a total of 0.011 mol of oxalic acid esters, that is 0.008 mol (0.92 g) of dimethyl oxalate and 0.001 mol of other oxalic acid compounds (oxalic acid etc.). [0318] 3 mL of a methanol solution containing 0.013 mol of the magnesium salt of glycolic acid was added to the reaction solution, and then all of the solution was put into a 1 L autoclave, and after purging with nitrogen, the temperature was raised to 80.deg. C. and stirring was carried out for 2 hours. After that, cooling was carried out, and the autoclave was opened, whereupon it was found that a white precipitate of magnesium oxalate had been produced. Then, after filtering, the reaction liquid was analyzed using gas chromatography, whereupon it was found that the signals corresponding to dimethyl oxalate and other oxalic acid compounds had virtually disappeared. [0319] After filtering off the magnesium oxalate, methanol and water were distilled off from the obtained filtrate under reduced pressure using a thin-layer distillation apparatus. After that, the methyl glycolate was distilled off using a 3-stage glass distillation column with a bottom temperature of 70 to 80.deg. C. at a pressure of 5 to 10 torr. The purity of the methyl glycolate in the distillate was greater than 98 wt percent; a total of approximately 1.5 wt percent of methanol and water was contained, but the content of other impurities was less than 0.1 wt percent. The total content of dimethyl oxalate and other oxalic acid compounds (oxalic acid etc.) was less than 100 ppm by weight. [0320]

Stage 1: With oxygen, Time= 5h, T= 90 °C, p= 3750.38Torr , Autoclave Stage 2: in methanol, Time= 2h, T= 80 °C, Autoclave

Patent; Hayashi, Toshio; Baba, Hideyuki; US2004/138409; (2004); (A1) English View in Reaxys