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CAS No. :475086-75-0 MDL No. :MFCD28411750
Formula : C23H27N3O Boiling Point : -
Linear Structure Formula :- InChI Key :PKBSUZWFQXNCSI-UHFFFAOYSA-N
M.W : 361.48 Pubchem ID :18452655
Synonyms :

Safety of [ 475086-75-0 ]

Signal Word:Warning Class:
Precautionary Statements:P261-P280-P301+P312-P302+P352-P305+P351+P338 UN#:
Hazard Statements:H302-H315-H319-H335 Packing Group:
GHS Pictogram:

Application In Synthesis of [ 475086-75-0 ]

* 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.

  • Downstream synthetic route of [ 475086-75-0 ]

[ 475086-75-0 ] Synthesis Path-Downstream   1~42

  • 1
  • [ 475086-75-0 ]
  • [ 5292-43-3 ]
  • [ 475084-96-9 ]
YieldReaction ConditionsOperation in experiment
100% With cetyltrimethylammonim bromide; sodium hydroxide In water; toluene at 5℃; for 5h; 3.2 (2) Preparation of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}tert-butyl acetate 18.5 g (0.05 mol) of 4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]-1-butanol, 200 mL of toluene, 80 g of 45% aqueous solution of sodium hydroxide and 2 g of cetyltrimethylammonium bromide were added into a 500 mL flask and cooled by ice water to 5° C., 20 g (0.10 mol) of tert-butyl bromoacetate was added dropwise, then reacted at this temperature for 5 hours until HPLC analysis showed the raw materials were reacted completely. (0061) The mixture was placed to separate into layers, the aqueous phase was extracted once with 100 mL of toluene, the combined organic phase was washed with water and dried with anhydrous sodium sulfate, concentrated, toluene was recovered, and 23.8 g of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}tert-butyl acetate was obtained, the molar yield was 100%, HPLC purity was 96%.
80% With tetrabutyl-ammonium chloride; sodium hydroxide In water; toluene at 0 - 10℃; for 1h; 4 Example 4: 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetic acid tert-butyl ester (VI) 3.0 gm of 4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]-l-butanol (V) was dissolved in 39 ml of toluene and 0.76 gm of tetra-n-butylammonium chloride was added with stirring. 40 ml of an aqueous 35% sodium hydroxide solution was then added at 0-5 °C. 1.62 gm of tert-butyl bromoacetate was added drop wise so as to control the temperature within a range from 5 to 10°C. After stirring for 60 minutes, an ice bath was removed and the mixture was stirred at room temperature for one hour. Layers are separated and aqueous layer was washed with 10 ml of toluene. The toluene layers are combined and washed with 15 ml water, dried over anhydrous magnesium sulfate and then concentrated to obtain 3.19 gm of the desired compound, as an oily substance. Yield: 80.00 %.
72% With tetra(n-butyl)ammonium hydrogensulfate; potassium hydroxide In water; toluene at 5 - 25℃; for 1.75h; 1-3 Example 1 Add 153 g of toluene into a 1 L reaction flask, add 25 g of Intermediate 1 under stirring, and then add 11.78 g of tetrabutylammonium hydrogen sulfate and about 40% potassium hydroxide aqueous solution. The temperature of the system was lowered to 5-10°C, and 12g of tert-butyl bromoacetate was added dropwise at 7°C. The temperature was controlled at 5-10°C, and after stirring for 45 minutes, the system was raised to room temperature, and the temperature was controlled at 23-25°C and stirred for 1 hour. TLC monitoring (n-hexane: ethyl acetate = 2:1), the reaction of the raw materials was complete. Add 150g of water, then add 160g of ethyl acetate to extract the phases, collect the organic phase and wash the phases with 152g of water, transfer the organic phase to a 1L flask, concentrate under reduced pressure at 50-55°C until solvent-free evaporation. After concentration, 32 g of reddish brown oil was obtained. Add 28ml of benzyl alcohol and 8ml of n-propanol to the oil, stir to dissolve, then add 160ml of n-heptane, the system becomes turbid, heat to reflux to dissolve, then stir and cool to 10-20, keep incubating and crystallize for 1-2 hours . Filter, rinse the filter cake with 20ml n-hexane, and drain it. The filter cake was collected and dried under vacuum at 50-60°C for 8-12 hours to obtain about 24 g of intermediate 2 as a yellow solid with a yield of 72%. HPLC purity: 99.58%.
With potassium hydroxide; tetra(n-butyl)ammonium hydrogensulfate In benzene for 1.75h;
With potassium hydroxide; tetra(n-butyl)ammonium hydrogensulfate In water; benzene at 0 - 20℃; for 1.75h; 1.2 Step 2
2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetic acid tert-butyl ester
22.84 g of 4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]-1-butanol was dissolved in 160 ml of benzene and 10.73 g of tetra-n-butylammonium hydrogensulfate and 160 ml of an aqueous, 40% potassium hydroxide solution were added.. While stirring vigorously under ice cooling, 10.73 g of tert-butyl bromoacetate was added dropwise so as to control the inner temperature within a range from 5 to 10°C. After stirring for 45 minutes, an ice bath was removed and the mixture was stirred at room temperature for one hour.. The reaction solution was diluted with water and then extracted with diethyl ether.. The extract was washed with water and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure.. The residue was purified by silica gel column chromatography to obtain 21.70 g of the desired compound as a pale yellow oily substance.1H-NMR(CDCl3)δ: 1.27(6H,d), 1.48(9H,s), 1.55 to 1.90(4H,m), 3.45(2H,t), 3.58(2H,t), 3.95(2H,s), 4.82(1H,qn), 7.17 to 7.50(10H,m), 8.00(1H,s)
With potassium hydroxide In water; benzene at 10 - 20℃; for 1.75h;
104 g With tetrabutylammomium bromide; sodium hydroxide In water; toluene at 5 - 30℃; 12 EXAMPLE-12: Preparation of 2-{4-[IM-(5, 6-diphenypyrazin-2-yl)-N- isopropyl amino] butyloxy} acetic acid The tetra butyl ammonium bromide (129.5 g, 0.664 mol) was added at 15- 20°C to the mixture of 4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropyl amino]-1- butanol (80 g, 0.22 mol) in toluene (704 ml) and aqueous 35% sodium hydroxide solution (704 ml). The tert-butyl bromoacetate (129.52 g, 0.664 mol) was added drop wise at 5-10°C to reaction with constant stirring. Then the reaction is stirred at 25-30 °C for 5-6 hr. After the reaction, biphasic layers were separated and concentrated toluene layer completely to obtain the {4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropyl amino] butyloxyjacetic acid tert-butyl ester (104 g). {4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropyl amino] butyloxyjacetic acid tert- butyl ester (104 g) was dissolved in methanol (1050 ml) and 1 N sodium hydroxide solution (300 ml) was added at RT after mixture was heated at reflux for 2 hours, The progress of the reaction was monitored by the HPLC. After reaction completes, add the water and wash the impurities using ethyl acetate. Then adjust the pH 2.0-2.5 of the aqueous layer using 1 N HCI solution (300 ml) to obtain the product precipitation, which was filtered and washed with water (210 ml) to obtain crude product. The crude 2-{4-[N-(5, 6- diphenylpyrazin-2-yl)-N-isopropyl amino] butyloxy} acetic acid was added Methanol (630 ml) and refluxed for 2 hr, which was cooled gradually to 25-30 °C, Then the precipitation of the product is filtered and dried to obtain pure 2- {4-[N-(5, 6-diphenylpyrazin-2-yl)-N-isopropyl amino] butyloxy} acetic acid. [Yield = 64 g; Purity (HPLC) = 99.1 %]
91 g With tetra(n-butyl)ammonium hydrogensulfate; potassium hydroxide In water; toluene at 0 - 25℃; 1 Preparation of tert-butyl 2-(4-(5,6-diphenylpyrazin-2-yl) isopropyl) (amino) butoxy) acetate To 4-(5,6-diphenylpyrazin-2-yl)isopropyl)(amino)butan-l-ol (75 gm) in toluene added tetrabutyl ammonium hydrogen sulfate (35.2 gm) at 20 - 25 °C. Further added 40% potassium hydroxide (560 ml) solution dropwise and tert-butyl bromoacetate (121.4 gm) dropwise at 0 - 5°C, stirred for 1 hour to 1 hour 30 minutes and diluted with water, extracted with methyl tert- butyl ether. The organic layer was dried and distilled off to yield tert-butyl 2-(4-(5,6- diphenylpyrazin-2-yl) isopropyl)(amino)butoxy)acetate Yield: 91 gm Chromatographic Purity (by HPLC): 98.35%
Stage #1: 4-((5,6-diphenylpyrazin-2-yl)(isopropyl)amino)butan-1-ol With tetra(n-butyl)ammonium hydrogensulfate In toluene at 0 - 5℃; for 0.166667h; Stage #2: bromoacetic acid <i>tert</i>-butyl ester With potassium hydroxide In water; toluene for 0.166667h; 3 Example 3 Preparation of Compound 3 11.5g of compound 2 was dissolved in 80mL of toluene, the temperature was controlled at 0-5 ° C, 5.4g of tetrabutyl ammonium hydrogen sulfate was added, and the mixture was stirred for 10min,Add 40% KOH aqueous solution 80mL, addition was completed, stirred 10min,At this temperature continued dropwise tert-butyl bromoacetate 35g,The reaction was monitored overnight by TLC until the starting material no longer decreased. The organic phase was washed three times with saturated brine, separated and dried over anhydrous sodium sulfate. After 3 hours, the mixture was filtered with suction and the filtrate was evaporated to dryness with toluene.The compound 3 crude reddish brown gum 25g, directly into the next reaction.
With tetra(n-butyl)ammonium hydrogensulfate; potassium hydroxide In toluene at 0 - 25℃; 30 Example 30: Preparation of 2-{4-[N-(5,6-diphenylpyrazi n-2-yl)-N-isopropylam mo] butyloxy} acetic acid (formula IV) 4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butanol hydrate (formula VI, 100 g) was dissolved in toluene (1.000 L). Tetra-n-butylammonium hydrogen sulfate (23.5 g)and potassium hydroxide solution (820 mL) was added to the solution while stirring. The reaction mixture was cooled to 0-10 CC and tert-butyl bromoacetate (formula V, 165 g)was added drop wise maintaining the temperature between 5-10 CC. After stirring at 5-10 CC, the temperature was raised to 20-25 CC and the reaction mixture was further stirred for 1-3 hours. The aqueous and organic layers were separated with the aqueous layer at pH 8-band the aqueous layer was extracted with toluene (2*250mL). The combined toluene layers were washed with water and concentrated to get oily 2-{4-[N-(5,6-diphenyl pyrazin-2-yl)-N-isopropylamino]butyloxy}acetic acid tert-butyl ester (formula IV).
With tetra(n-butyl)ammonium hydrogensulfate; potassium hydroxide for 20h; Cooling with ice; Heating; 2 Example 2 Add in the reaction flask2-yl) -isopropylamino) -1-butanol (72.3 g, 0.20 mol), toluene (200 mL)Tetrabutylammonium hydrogen sulfate (33.9 g, 0.10 mol) and 40% potassium hydroxide solution (150 mL, w%),An ice-water bath was added dropwise tert-butyl bromoacetate (78.0 g, 0.40 mol)Bi completed, continue to heat the reaction for 20 hours. Concentrated hydrochloric acid was added dropwise to adjust the pH of the system to 5-6, the mixture was extracted with ethyl acetate (500 mL), washed with water (500 mL × 2)Concentrated under reduced pressure2- (4 - ((5,6-diphenylpyrazinyl)(Isopropyl) amino) butoxy)Acetic acidTert-butyl esterCrude, the next reaction.
80 % With tetra(n-butyl)ammonium hydrogensulfate; potassium hydroxide In 5,5-dimethyl-1,3-cyclohexadiene at 0 - 20℃; 1.3 (3) Weigh 1g of compound d-1 and 0.54g TBA (tetrabutylammonium bisulfate) obtained in step (2), add it to a 100mL round bottom flask, add 50mL xylene: 40%KOH=1:1 mixing Solution, 0.6mL of tert-butyl bromoacetate was added dropwise under ice bath, the temperature of the system was controlled between 05°C during the dropwise addition, and then stirred at room temperature for 24 hours. After the reaction was completed, the column chromatography purification method ( The volume ratio of cyclohexane/ethyl acetate is 10:1) to obtain white solid compound e-1(2-(4-(((5,6-diphenylpyrazin-2-yl)(isopropyl) Tert-butyl amino)butoxy)acetate, Tert-butyl2-(4-((5,6-diphenylpyrazin-2-yl)(isopropyl)amino)butoxy)acetate). Yield 80%.
80 % With tetra(n-butyl)ammonium hydrogensulfate; potassium hydroxide In 5,5-dimethyl-1,3-cyclohexadiene at 0 - 20℃; 1.3 (3) Weigh 1g of compound d-1 and 0.54g TBA (tetrabutylammonium bisulfate) obtained in step (2), add it to a 100mL round bottom flask, add 50mL xylene: 40%KOH=1:1 mixing Solution, 0.6mL of tert-butyl bromoacetate was added dropwise under ice bath, the temperature of the system was controlled between 05°C during the dropwise addition, and then stirred at room temperature for 24 hours. After the reaction was completed, the column chromatography purification method ( The volume ratio of cyclohexane/ethyl acetate is 10:1) to obtain white solid compound e-1(2-(4-(((5,6-diphenylpyrazin-2-yl)(isopropyl) Tert-butyl amino)butoxy)acetate, Tert-butyl2-(4-((5,6-diphenylpyrazin-2-yl)(isopropyl)amino)butoxy)acetate). Yield 80%.
With tetra(n-butyl)ammonium hydrogensulfate; sodium hydroxide In 5,5-dimethyl-1,3-cyclohexadiene; water at 20℃;

Reference: [1]Current Patent Assignee: SEASONS BIOTECHNOLOGY TAIZHOU; SHANGHAI SEASONS BIOTECHNOLOGY; SHANGHAI SHIJI BIOLOGICAL TECH - US2018/29998, 2018, A1 Location in patent: Paragraph 0060-0061
[2]Current Patent Assignee: LUPIN LIMITED - WO2017/60827, 2017, A1 Location in patent: Page/Page column 12
[3]Current Patent Assignee: JIANGSU FANGSHENG PHARMACEUTICAL - CN113480484, 2021, A Location in patent: Paragraph 0020-0025
[4]Asaki, Tetsuo; Hamamoto, Taisuke; Sugiyama, Yukiteru; Kuwano, Keiichi; Kuwabara, Kenji [Bioorganic and Medicinal Chemistry, 2007, vol. 15, # 21, p. 6692 - 6704]
[5]Current Patent Assignee: NIPPON SHINYAKU CO LTD - EP1400518, 2004, A1 Location in patent: Page 32
[6]Asaki, Tetsuo; Kuwano, Keiichi; Morrison, Keith; Gatfield, John; Hamamoto, Taisuke; Clozel, Martine [Journal of Medicinal Chemistry, 2015, vol. 58, # 18, p. 7128 - 7137]
[7]Current Patent Assignee: MEGAFINE PHARMA (P) LTD. - WO2017/42828, 2017, A2 Location in patent: Page/Page column 43
[8]Current Patent Assignee: HONOUR R D - WO2017/168401, 2017, A1 Location in patent: Page/Page column 12
[9]Current Patent Assignee: NANJING NMG ADDS - CN106957269, 2017, A Location in patent: Paragraph 0021; 0022
[10]Current Patent Assignee: VIATRIS INC - WO2018/15974, 2018, A1 Location in patent: Page/Page column 37; 38
[11]Current Patent Assignee: EAST CHINA PHARMACEUTICAL GROUP LIMITED CO LTD - CN107365275, 2017, A Location in patent: Paragraph 0055; 0056
[12]Current Patent Assignee: ZHENGZHOU UNIVERSITY - CN113968824, 2022, A Location in patent: Paragraph 0089; 0093; 0096
[13]Current Patent Assignee: ZHENGZHOU UNIVERSITY - CN113968824, 2022, A Location in patent: Paragraph 0089; 0093; 0096
[14]Zhang, Kun; Hu, Kaizhao; Li, Qian; Li, Min; Gao, Ke; Yang, Kecheng; Zhao, Bing; Shi, Xiao-Jing; Zhang, Lirong; Liu, Hong-Min [Journal of Medicinal Chemistry, 2023, vol. 66, # 11, p. 7221 - 7242]
  • 2
  • [ 41270-66-0 ]
  • [ 42042-71-7 ]
  • [ 475086-75-0 ]
YieldReaction ConditionsOperation in experiment
96% With tris-(o-tolyl)phosphine; bis(dibenzylideneacetone)-palladium(0); sodium t-butanolate; In 1,4-dioxane; at 120℃; for 1.8h; In one embodiment of the preparation method of the sirepag intermediate of the present invention, the preparation method of the siriparg intermediate according to the present embodiment is: in a reaction bottle equipped with a reflux tube, a drying tube and a thermometer, adding 5- Chloro-2,3-diphenylpyrazine (30.0 g, 0.11 mol, 1.0 eq.), 4-(isopropylamino)-1-butanol (18.5 g, 0.14 mol, 1.25 eq.), 1, 4-Dioxane 150 mL, stir and dissolve, and then add Pd (dba)2(2.4g, 4.2mmol), P(o-tolyl)3(1.69 g, 8.3 mmol), sodium tert-butoxide (13.0 g, 0.135 mol), heated to 120° C., and incubated for 1.8 hours. The reaction was complete by TLC and the reaction was stopped.The mixture was cooled to room temperature and filtered. The filtrate was adjusted to pH 6.5-7.5 with 1N hydrochloric acid, extracted with ethyl acetate (150 mL x 2), washed with 150 mL of brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure with the residue being ethanol: The mixture was recrystallized with 300 mL of n-hexane = 1:15 mixed solvent and dried in an oven to obtain 39.0 g of a white solid. The yield was 96percent, and the liquid purity was 97.1percent.
56% at 190℃; for 10.0h; 30 g of 2-chloro-5,6-diphenylpyrazin and 131.22 g (0.3 mol) of 4-isopropylamino-1-butanol were added into a 500 mL flask, the mixture was heated to 190° C. and reacted at this temperature for 10 hours, cooled, samples were taken for testing, HPLC purity of the product was 63.5percent. The reaction solution was poured into 1 L of ice water, the mixture was extracted with ether 200 mL×3, the organic phases were combined and the solvent was concentrated to dryness, then the residue was purified by column chromatography, and 22.96 g of 4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]-1-butanol was obtained, HPLC purity was 97.2percent, the molar yield was 56percent. (0083) 1H-NMR data: 1H-NMR (400 MHz, CDCl3) delta 8.02 (s, 1H), 7.46 (d, 2H, J=7.6 Hz), 7.36 (d, 2H, J=7.2 Hz), 7.28-7.22 (m, 6H), 4.80-4.78 (m, 1H), 3.71 (t, 2H, J=6.4 Hz), 3.45 (t, 2H, J=7.6 Hz), 1.77-1.74 (m, 2H), 1.66-1.64 (m, 2H), 1.29 (d, 6H, J=6.8 Hz).
49.41% With potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 150 - 155℃; 5 gm of <strong>[41270-66-0]2-chloro-5,6-diphenylpyrazine</strong> (IV) in 25 ml N-Methyl-2-pyrrolidone (NMP) and 5.18 gm of K2CO3 were mixed with 9.92 gm of 4-(isopropylamino)-l-butanol (III), the reaction mixture was then heated with stirring at 150-155 °C for 20-21 hrs. The reaction solution was air-cooled, poured into 25 ml water, extracted with 20 ml ethyl acetate. Aqueous layer washed with 10 ml ethyl acetate. Ethyl acetate layers are combined and washed with 15 ml of water, dried over anhydrous magnesium sulfate and then concentrated to obtain 6.3 gm of residue. 6 gm of the residue was purified by silica gel column chromatography by eluting with 2000 ml hexane and 550 ml ethyl acetate to obtain solid 3.2 gm of the desired compound. Yield: 49.41 percent
at 190℃; for 10.0h; 30 g of <strong>[41270-66-0]2-chloro-5,6-diphenylpyrazine</strong> and 131.22 g of 4-(isopropylamino)-1-butanol were mixed and then heated with stirring at 190°C for 10 hours.. The reaction solution was air-cooled, poured into water, extracted with diethyl ether, dried over anhydrous magnesium sulfate and then concentrated.. The residue was purified by silica gel column chromatography to obtain 22.96 g of the desired compound as a colorless crystal having a melting point of 102 to 103°C.
9 g at 190℃; for 10.0h; <strong>[41270-66-0]2-chloro-5,6-diphenylpyrazine</strong> (10 gm), 4-(isopropylamino)-1 -butanol (44 gm) and N-methylpyrrolidine (50 mL) were charged into a 250 mL round bottom flask at 30°C. The reaction mass was heated to 190°C and stirred for 10 hours. The reaction mass was cooled to 30°C and poured into cold water, extracted with ethylacetate, dried over anhydrous magnesium sulphate and then concentrated to get 9 gm of the title compound.
at 180 - 185℃; for 24.0h; To the stirred mixture of 5-chloro 2-3 diphenyl pyrazine (100 g, 0.375 mol) & 4-isopropyl amino butane-1-ol (172.17 g, 1.31 mol) was added at room temperature. The resultant reaction mixture was heated at 180-185°C and maintain at same temperature for 24 hrs. After completion of reaction by HPLC analysis, cool the reaction mass and diluted it with ethyl acetate (1000 ml), purified water (1500 ml) and product was extracted : in ethyl acetate further aqueous layer was rewashed with ethyl acetate (500 ml). After combining the both ethyl acetate layers, wash it with 5percent sodium bicarbonate (1000 ml) to remove the hydroxyl impurity formed during the reaction followed by washing of 10percent sodium chloride solution (1000 ml). Ethyl acetate layer was concentrated under reduced pressure to obtain thick syrup of compound (4). Obtained thick syrup was diluted with ethyl acetate (20 ml) and n-heptane (500 ml) was added to the diluted mass and stirred for 60-90 min. the resultant isolated solid was filtered and washed with n-heptane (100 ml), suck dried and dried the solid under vacuum at 35-40 °C for 3-4 hrs. [Yield = 95.0 g; Purity (HPLC) = 91.5percent]
252 g at 170 - 195℃; 5-Chloro-2,3-diphenylpyrazine (300 gm), 4-isopropylaminobutanol (443 gm) were taken and then heated to 170 - 195 °C, stirred for 10 hours to 12 hours and further cooled to 25- 30°C. Then added water, extracted with methyl tert-butyl ether, dried the organic layer and concentrated to obtain the desired compound. Yield: 252 gm Chromatographic Purity (by HPLC): 99.01percent
In 1-methyl-pyrrolidin-2-one; at 170 - 190℃; <strong>[41270-66-0]2-Chloro-5,6-diphenylpyrazine</strong>(formula VIII, 100 g)in N-methyl-2-pyrrolidone(200 mL)was mixed with 4-(isopropylamino)-1 -butanol (formula VII, 200 g) and the reaction mixture was then heated with stirring at 170-190 CC for 12-14 hours. The reaction mixture was cooled, poured into toluene (1.000 L), washed with water (1.000 L), and then further extracted with toluene (2*250 mL). The toluene layers are combined and washed with water (500 mL), 5percent Sodium hydroxide solution (300 mL), and brine solution (500 mL). After washing, the reaction mixture was concentrated under vacuum to obtain crude solids (125 g) isolated as a residue. Toluene (300 mL) and n-heptane (1 .000 L) were added. The precipitated product was cooled to 25-30 CC and stirred for 4-5 hours. The solution was filtered and the product was washed with nheptane. The crude product was then purified from mixture of acetonitrile (1 .000 L) and water (850 mL). The precipitated product was cooled to 5-10 CC, stirred for 4-5 hours, filtered, and the solid was washed with water. The wet product was dried under vacuum at 40CC for 6-8 hours to give 4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butanol hydrate (formula VI).

  • 3
  • [ 475086-75-0 ]
  • [ 590-17-0 ]
  • [ 952091-66-6 ]
YieldReaction ConditionsOperation in experiment
28% With potassium hydroxide; tetra(n-butyl)ammonium hydrogensulfate In benzene for 1.75h;
  • 4
  • [ 475086-75-0 ]
  • [ 475086-01-2 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: potassium hydroxide / water; benzene / 1.75 h / 10 - 20 °C 2.1: sodium hydroxide / methanol / 1 h / Reflux 3.1: 1,1'-carbonyldiimidazole / tetrahydrofuran / 1 h / Reflux 3.2: 0.17 h 3.3: 12 h
Multi-step reaction with 3 steps 1.1: sodium hydroxide; tetrabutylammomium bromide / water; toluene / 5 - 30 °C 2.1: sodium hydroxide; methanol / 2 h / Reflux 3.1: 1,1'-carbonyldiimidazole / tetrahydrofuran / 0.75 h / 65 - 70 °C 3.2: 3 h / 25 - 30 °C
Multi-step reaction with 4 steps 1.1: sodium hydroxide; tetrabutylammomium bromide / water; toluene / 5 - 30 °C 2.1: sodium hydroxide; methanol / 2 h / Reflux 3.1: thionyl chloride / 5 h / 25 - 30 °C 3.2: ammonia solution / 10 - 25 °C 4.1: sodium hydride / tetrahydrofuran / 0.33 h 4.2: 3 h / 0 - 25 °C
Multi-step reaction with 3 steps 1.1: tetrabutyl-ammonium chloride; sodium hydroxide / water; toluene / 1 h / 0 - 10 °C 2.1: sodium hydroxide / methanol / 1.5 h / Reflux 3.1: 1,1'-carbonyldiimidazole / tetrahydrofuran / 2 h / 65 - 70 °C 3.2: 0.5 h 3.3: 0.67 h
Multi-step reaction with 3 steps 1.1: tetra(n-butyl)ammonium hydrogensulfate; potassium hydroxide / toluene; water / 0 - 25 °C 2.1: sodium hydroxide; water / methanol / 2 h / Reflux 3.1: 1,1'-carbonyldiimidazole / tetrahydrofuran / 1 h / 20 °C / Inert atmosphere; Reflux 3.2: 0.17 h / 20 °C 3.3: 20 °C
Multi-step reaction with 3 steps 1.1: tetra(n-butyl)ammonium hydrogensulfate / toluene / 0.17 h / 0 - 5 °C 1.2: 0.17 h 2.1: sodium hydroxide / methanol / 40 °C / Reflux 3.1: 1,1'-carbonyldiimidazole / tetrahydrofuran / 1 h / Reflux 3.2: 0 - 5 °C
Multi-step reaction with 3 steps 1.1: tetra(n-butyl)ammonium hydrogensulfate; potassium hydroxide / toluene / 0 - 25 °C 2.1: methanol; sodium hydroxide / 60 - 65 °C 3.1: dmap / dichloromethane / 0.25 h / 20 - 30 °C 3.2: 24 h / 20 - 30 °C
Multi-step reaction with 3 steps 1.1: tetra(n-butyl)ammonium hydrogensulfate; potassium hydroxide / 20 h / Cooling with ice; Heating 2.1: sodium hydroxide / tetrahydrofuran / Reflux 3.1: 1,1'-carbonyldiimidazole / dichloromethane / 1 h / Reflux 3.2: 0.17 h / 20 - 30 °C 3.3: 5 h
Multi-step reaction with 3 steps 1.1: sodium hydroxide; cetyltrimethylammonim bromide / toluene; water / 5 h / 5 °C 2.1: lithium hydroxide; water / ethanol / 2 h / 0 °C 3.1: oxalyl dichloride / dichloromethane / 2 h / 5 - 20 °C 3.2: 5 h / 10 °C
Multi-step reaction with 3 steps 1.1: tetra(n-butyl)ammonium hydrogensulfate; potassium hydroxide / toluene; water / 1.75 h / 5 - 25 °C 2.1: methanol; water; sodium hydroxide / 1.5 h / Reflux 3.1: 1,1'-carbonyldiimidazole / tetrahydrofuran / 1 h / 20 °C / Reflux 3.2: 20 °C
Multi-step reaction with 3 steps 1.1: sodium hydroxide; tetra(n-butyl)ammonium hydrogensulfate / 5,5-dimethyl-1,3-cyclohexadiene; water / 24 h / 20 °C 2.1: sodium hydroxide / methanol; water / 4 h / 80 °C 2.2: 30 min / 20 °C 3.1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 5 min / 20 °C 3.2: 20 °C

  • 5
  • [ 475086-75-0 ]
  • [ 475086-03-4 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: potassium hydroxide / water; benzene / 1.75 h / 10 - 20 °C 2.1: sodium hydroxide / methanol / 1 h / Reflux 3.1: 1,1'-carbonyldiimidazole / tetrahydrofuran / 1 h / Reflux 3.2: 0.17 h 3.3: 36 h
  • 6
  • [ 475086-75-0 ]
  • [ 475086-05-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: potassium hydroxide / water; benzene / 1.75 h / 10 - 20 °C 2.1: sodium hydroxide / methanol / 1 h / Reflux 3.1: 1,1'-carbonyldiimidazole / tetrahydrofuran / 1 h / Reflux 3.2: 0.17 h 3.3: 36 h
  • 7
  • [ 475086-75-0 ]
  • [ 475086-10-3 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: potassium hydroxide / water; benzene / 1.75 h / 10 - 20 °C 2.1: sodium hydroxide / methanol / 1 h / Reflux 3.1: 1,1'-carbonyldiimidazole / tetrahydrofuran / 1 h / Reflux 3.2: 0.17 h 3.3: 36 h
  • 8
  • [ 475086-75-0 ]
  • [ 475086-18-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: potassium hydroxide / water; benzene / 1.75 h / 10 - 20 °C 2.1: sodium hydroxide / methanol / 1 h / Reflux 3.1: 1,1'-carbonyldiimidazole / tetrahydrofuran / 1 h / Reflux 3.2: 0.17 h 3.3: 36 h
  • 9
  • [ 475086-75-0 ]
  • [ 475086-20-5 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: potassium hydroxide / water; benzene / 1.75 h / 10 - 20 °C 2.1: sodium hydroxide / methanol / 1 h / Reflux 3.1: 1,1'-carbonyldiimidazole / tetrahydrofuran / 1 h / Reflux 3.2: 0.17 h 3.3: 36 h
  • 10
  • [ 475086-75-0 ]
  • [ 475086-23-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: potassium hydroxide / water; benzene / 1.75 h / 10 - 20 °C 2.1: sodium hydroxide / methanol / 1 h / Reflux 3.1: 1,1'-carbonyldiimidazole / tetrahydrofuran / 1 h / Reflux 3.2: 0.17 h 3.3: 36 h
  • 11
  • [ 475086-75-0 ]
  • [ 475085-57-5 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: potassium hydroxide / water; benzene / 1.75 h / 10 - 20 °C 2: sodium hydroxide / methanol / 1 h / Reflux
Multi-step reaction with 2 steps 1: sodium hydroxide; tetrabutylammomium bromide / water; toluene / 5 - 30 °C 2: sodium hydroxide; methanol / 2 h / Reflux
Multi-step reaction with 2 steps 1: tetrabutyl-ammonium chloride; sodium hydroxide / water; toluene / 1 h / 0 - 10 °C 2: sodium hydroxide / methanol / 1.5 h / Reflux
Multi-step reaction with 2 steps 1: tetra(n-butyl)ammonium hydrogensulfate; potassium hydroxide / toluene; water / 0 - 25 °C 2: sodium hydroxide; water / methanol / 2 h / Reflux
Multi-step reaction with 2 steps 1.1: tetra(n-butyl)ammonium hydrogensulfate / toluene / 0.17 h / 0 - 5 °C 1.2: 0.17 h 2.1: sodium hydroxide / methanol / 40 °C / Reflux
Multi-step reaction with 2 steps 1: tetra(n-butyl)ammonium hydrogensulfate; potassium hydroxide / 20 h / Cooling with ice; Heating 2: sodium hydroxide / tetrahydrofuran / Reflux
Multi-step reaction with 2 steps 1: sodium hydroxide; cetyltrimethylammonim bromide / toluene; water / 5 h / 5 °C 2: lithium hydroxide; water / ethanol / 2 h / 0 °C
Multi-step reaction with 2 steps 1: tetra(n-butyl)ammonium hydrogensulfate; potassium hydroxide / toluene; water / 1.75 h / 5 - 25 °C 2: methanol; water; sodium hydroxide / 1.5 h / Reflux

  • 12
  • [ 475086-75-0 ]
  • [ 59504-75-5 ]
  • [ 475086-01-2 ]
YieldReaction ConditionsOperation in experiment
83.8% With potassium <i>tert</i>-butylate In 1,4-dioxane at 25 - 30℃; for 3h; 2 Example 1 A process for the preparation of selexipag comprising the steps of sequentially adding 1,4-dioxane (700 mL), a compound of formula I (60 g, 0.166 mol), a compound of formula II (85.44 G, 0.498 mol) and potassium t-butoxide (111 g, 0.996 mol) were added and the mixture was stirred at 30-35 ° C for 3 h, and the reaction was complete by TLC.The residue was diluted with water (300 mL). The pH was adjusted to 6-7 with 1 N aqueous hydrochloric acid, extracted with dichloromethane (3 x 50 mL), and the organic layer was separated with water (300 mL) ), Dried over anhydrous magnesium sulfate and decolored with activated charcoal (15 g). The solvent was evaporated under reduced pressure and the residual solution was recrystallized from a mixed solution (THF: n-hexane volume ratio = 1: 1.1) (700 mL), and dried under reduced pressure to give 68.4 g of a light yellow powdery solid; mp: 138-141 ° C, 83% molar yield.
Stage #1: 4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]-1-butanol With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide at -10 - 40℃; for 1h; Inert atmosphere; Stage #2: N-(bromoacetyl)methanesulfonamide In N,N-dimethyl-formamide 1.c-d Step c: Preparation of (2-[4-[(5,6-diphenyl-2-pyrazinyl)(1-methylethyl)amino]butoxy]-N- (methylsulfonyl)-acetamide) - Selexipag To 10 g (0.028 mol) of 4-((5,6-diphenyl-pyrazin-2-yl)(isopropyl)amino)butan-1-ol was added a strong base (t-BuOK) (6.0 eq/mol), previously suspended in N-N- dimethylformamide solvent, within a range of from -10°C to 40°C under a nitrogen atmosphere and stirred for 60 min. Then, a solution of 17.9 g (3.0 eq/mol) of 2-bromo-N-(methylsulfonyl)- acetamide, previously dissolved in N,N-dimethylformamide, was added dropwise within a range of from 120 tol80 min, controlling the exothermic temperature. The reaction was monitored by TLC up to completion. Subsequently, the mixture reaction was cooled down around 5°C and water is added by controlling the exotherm (NMT 15°C). Finally, an acetic acid solution was added, the suspension was stirred for about 60 min at 0°C -5°C. The product (crude) was filtered off and washed with water. An amorphous solid was obtained. The crude product was purified by crystallization from ethanol:THF. Crude Selexipag can be purified by crystallization in an organic solvent for example alcohols such as ethanol, iso-amyl alcohol, iso-propyl alcohol, butanol; ethers such as tetrahydrofuran, hydrocarbons such as heptane and mixed solvents thereof.
Stage #1: 4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]-1-butanol With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide at 20 - 25℃; for 1h; Inert atmosphere; Stage #2: N-(bromoacetyl)methanesulfonamide In N,N-dimethyl-formamide for 2h; Inert atmosphere; 1 [00142] C. Route 3 [00143] 33.3 g (0.297 mol, 6.0 eq/mol) of potassium tert-butoxide were dissolved in DMF (2.8 vol) in a flask (500 mL) under nitrogen atmosphere and stirred for 15 min. Then, a solution of 17.9 g (0.049 mol, 1.0 eq/mol) of 4-((5,6-diphenyl-pyrazin-2-yl)(isopropyl) amino) butan-l-ol (SLX-4) dissolved in DMF (1.2 vol) was added in one portion. The reaction mixture was stirred for 60 min within a temperature range from 20°C to 25°C at 150 rpm Then, a solution of 32.1 g (0.15 mol, 3.0 Eq/mol) of 2-bromo-N-(methylsulfonyl)- acetamide (SLX-9), previously dissolved in DMF (1.3 vol), was added dropwise for 120 minutes by controlling the temperature (exothermic process). (0221) [00144] The reaction mixture was quenched with cool water (0.33 vol), transferred into a flask of more capacity (1000 mL) and placed in an ice bath. Cool water (38.32 vol) was added to the reaction mixture and the pH was adjusted to 5.0 with AcOH (0.33 vol). The mixture was stirred at 300 rpm for 40 min. Then, the flask with the reaction mixture was stored in the refrigerator at 8°C. After 8h, the solid was filtered and washed with cool water (5 vol, 2 times). The crude product (yellow solid) was drained (i.e. dried) for 30 min and was stored at 8°C.
  • 13
  • [ 243472-70-0 ]
  • [ 42042-71-7 ]
  • [ 475086-75-0 ]
YieldReaction ConditionsOperation in experiment
71% With potassium iodide; at 140℃; for 48.0h; To a mixture of 5- bromo-2,3-diphenylpyrazine (1 g, 3.21 mmol) and 4-(isopropylamino)butan-1 -ol (2.32 g, 17.7 mmol) was added potassium iodide (266 mg, 1 .6 mmol). The mixture was stirred in a pressure vessel at 140C for 2 days. The reaction mixture was cooled to room temp and diluted with water. The mixture was extracted with EtOAc (x4) and the combined organic layers washed with brine, dried over Na2S04, filtered and concentrated. The crude residue was purified with column chromatography eluting with 0-2% MeOH in DCM. The fractions of the desired product were combined, concentrated, and dried under reduced pressure to obtain a brown oil (0.82 g, 71 %). 1 H NMR (400 MHz, Chloroform-d) d 8.02 (s, 1 H), 7.49 - 7.42 (m, 2H), 7.39 - 7.33 (m, 2H), 7.29 - 7.21 (m, 6H), 4.78 (p, J = 6.7 Hz, 1 H), 3.68 (t, J = 6.4 Hz, 2H), 3.43 (dd, J = 9.2, 6.7 Hz, 2H), 1.76 (qd, J = 7.8, 7.1 , 3.9 Hz, 2H), 1.65 (q, J = (0159) 6.8 Hz, 2H), 1.28 (d, J = 6.7 Hz, 6H).
66.5% With potassium iodide; at 140℃; To 50 g (0.161 mol) of <strong>[243472-70-0]5-bromo-2,3-diphenylpyrazine</strong>, 116 g (0.884 mol, 5.5 eq/mol) of 4-(isopropylamino)-butan-1-ol and 13.33 g of KI (0.080 mol, 0.5 Eq/mol) were added. The reaction mixture was stirred, warmed and then heated up to 140C for about 18-20 hrs. The reaction was monitored by TLC up to completion (starting material about 1% by TLC). The reaction mixture was cooled down to room temperature. After the reaction was completed, the following work up step was performed: Option 1 : Ethyl acetate was added (500 mL, 10 vol) and the organic phase was washed with water (150 mL, 3 vol). The organic phase was separated and aqueous phase was extracted with ethyl acetate (150 mL, 3 vol). The organic phases were joined and washed with water (200 mL, 2 vol) three times. The solvent was distilled off under vacuum at not more than ("NMT") 40C until 1 vol (oil appearance). Option 2: The material (reaction mixture obtained in step a) was dissolved in acetone (250 mL, 5vol), the solution obtained was cooled down to 0C to 5C and anti-solvent / water was added (1000 mL, 20 vol) for 40 minutes, then the suspension was stirred for about 30 minutes at about 0C-5C. The solid material was filtered and washed with water (200 mL, 4 vol). Crude wet product was obtained as yellow solid yielding 101.8 % Weight Yield (WY) (87 % Molar Yield (MY)), HPLC purity 90.8% on area at this stage. The crude material, obtained in either of the above described options, was purified through crystallization from acetone: heptane as follows: to a solution of 4-((5,6- diphenyl-pyrazin-2-yl)(isopropyl)amino)butan-1-ol crude in acetone (175 mL, 3.5 vol) at 0C - 5C, hexane (600 mL, 12 vol) dropwise in about 120 min was added, then the precipitated mixture was cooled down to about -10C and stirred for about 60 min. The product was filtered off and washed with hexane (250 mL, 5 vol) and dried under vacuum at 25C. Pure product was obtained as yellowish solid yielding overall 77.2%, (66.5% MY), HPLC purity 98.2% on area.
With potassium iodide; at 140℃; [00130] To 50 g (0.161 mol) of <strong>[243472-70-0]5-bromo-2,3-diphenylpyrazine</strong>, 116 g (0.884 mol, 5.5 eq/mol) of 4-(isopropylamino)-butan-l-ol and 13.33 g of KI (0.080 mol, 0.5 Eq/mol) were added. The reaction mixture was stirred, warmed and then heated up to 140C for about 18- 20 hrs. The reaction was monitored by TLC up to completion (starting material about 1% by TLC). The reaction mixture was cooled down to room temperature. After the reaction was completed, the following work up step was performed: (0208) [00131] Option 1 : Ethyl acetate was added (500 mL, 10 vol) and the organic phase was washed with water (150 mL, 3 vol). The organic phase was separated and aqueous phase was extracted with ethyl acetate (150 mL, 3 vol). The organic phases were joined and washed with water (200 mL, 2 vol) three times. (0209) [00132] The solvent was distilled off under vacuum at not more than ("NMT") 40C until 1 vol (oil appearance). (0210) [00133] Option 2: The material (mixture) was dissolved in acetone (250 mL, 5 vol), the solution obtained was cooled down to 0C to 5C and anti-solvent / water was added (1000 mL, 20 vol) for 40 minutes, then the suspension was stirred for about 30 minutes at about 0C-5C. The solid material was filtered and washed with water (200 mL, 4 vol). Crude wet product was obtained as yellow solid yielding 101.8 % WY (87 % MY), HPLC purity 90.8% on area at this stage. (0211) [00134] The crude material, obtained in either of the above described options, was purified through crystallization from acetone :-heptane as follows: to a solution of 4-((5,6-diphenyl- pyrazin-2-yl)(isopropyl)amino)butan-l-ol crude in acetone (175 mL, 3.5 vol) at 0C - 5C, hexane (600 mL, 12 vol) dropwise in about 120 min was added, then the precipitated mixture was cooled down to about -10C and stirred for about 60 min. The product was filtered off and washed with hexane (250 mL, 5 vol) and dried under vacuum at 25C. Pure product was obtained as yellowish solid yielding overall 77.2%, (66.5% MY), HPLC purity 98.2% on area.
  • 14
  • [ 42042-71-7 ]
  • toluene-4-sulfonic acid 5,6-diphenyl-pyrazin-2-yl ester [ No CAS ]
  • [ 475086-75-0 ]
YieldReaction ConditionsOperation in experiment
at 185 - 190℃; for 2.0h; To the stirred mixture of Toluene-4-sulfonic acid 5,6-diphenyl-pyrazin-2-yl ester (15) (100 g, 0.248 mol) & 4-isopropyl amino butane-1-ol (130.44 g, 0.99 mol) was added at room temperature. Reaction mixture was stirred at 185- 190°C temperature for 2 hr. Reaction was monitored by HPLC analysis. After completion of reaction, charged purified Water and product extracted in Ethyl acetate, which was washed using 5percent sodium bicarbonate to remove the hydroxyl impuritiy produced during the reaction. Then the ethyl acetate layer was concentrated to obtain the 4-[(5,6-diphenyl-pyrazin-2-yl)-isopropyl - amino]-butan-1-ol. [Yield = 90 g; Purity (HPLC) = 89.71 percent]
  • 15
  • [ 1182787-74-1 ]
  • [ 475086-75-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: 24 h / 185 - 190 °C 2: sodium hydroxide; water / ethanol / 4.17 h / 20 - 50 °C 3: lithium aluminium tetrahydride / tetrahydrofuran / 10 h / 0 - 20 °C / Inert atmosphere
Multi-step reaction with 2 steps 1: lithium aluminium tetrahydride / tetrahydrofuran / -10 - 0 °C / Inert atmosphere 2: 2 h / 185 - 190 °C
Multi-step reaction with 2 steps 1: lithium aluminium tetrahydride / tetrahydrofuran / -10 - 0 °C / Inert atmosphere 2: 24 h / 180 - 185 °C
  • 16
  • [ 2088835-59-8 ]
  • [ 475086-75-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: sodium hydroxide; water / ethanol / 4.17 h / 20 - 50 °C 2: lithium aluminium tetrahydride / tetrahydrofuran / 10 h / 0 - 20 °C / Inert atmosphere
  • 17
  • [ 2088835-60-1 ]
  • [ 475086-75-0 ]
YieldReaction ConditionsOperation in experiment
1.54 g With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 20℃; for 10h; Inert atmosphere; 8 EXAMPLE-8: Preparation of 4-[(5,6-diphenyl-pyrazin-2^yl)-isopropyl - amino]-butan-1 -ol. To a mixture of UAIH4 (760 mg) in anhydrous THF (45 ml) was added a solution of 4-[(5,6-diphenyl-pyrazin-2-yl)-isopropyl-amino]-butyric acid (1.75 g) in anhydrous THF (5 ml) at 0 °C under a nitrogen atmosphere. The mixture was allowed to warm to room temperature. After stirring for 10 hr, the reaction was quenched with 6 mL of 20% aqueous NaOH solution at 0 °C and then filtered. The filter cake was washed with ethyl acetate (10 mL χ 4). Combined organic layers were concentrated under reduced pressure and residue was isolated from 9:1 heptane and ethyl acetate to obtain 4-[(5,6- Diphenyl-pyrazin-2-yl)-isopropyl -amino]-butan-1-ol. [Yield=1.54g;Purity (HPLC)=96%]
  • 19
  • [ 928-51-8 ]
  • [ 2068134-98-3 ]
  • [ 475086-75-0 ]
YieldReaction ConditionsOperation in experiment
Stage #1: (5,6-diphenyl-pyrazin-2-yl)-isopropyl-amine With sodium hydride In N,N-dimethyl-formamide; mineral oil at 80℃; for 0.583333h; Stage #2: 4-Chloro-1-butanol In N,N-dimethyl-formamide; mineral oil at 15 - 20℃; 2 EXAMPLE-2: Preparation of 4-[(5,6-diphenyl-pyrazin-2-yl)-isoprdpyl- amino]-butan-1-ol To a suspension of NaH (60% dispersion in oil, 1.2 g, 50 mmol) in DMF (100 ml) was added the (5,6-diphenyl-pyrazin-2-yl)-isopropyl-amine (10 g, 34 mmol) at room temperature, and the mixture was stirred at 80 °C for 35 min. The mixture was ice cooled to 15-20 °C and a solution of 1-chloro-4-butanol (11.25 g, 100 mmol) in DMF (21 ml) was added dropwise. The mixture was stirred at room temperature for 2-3 hrs, diluted with ice water, and extracted with EtOAc. The extract was washed with brine and dried over MgSC . After the solvent was evaporated, the crude product of 4-[(5,6-diphenyl-pyrazin-2- yl)-isopropyl -amino]-butan-1-ol (8 gm, 64%) as pale yellow solid. [Yield= 8g]
  • 21
  • [ 475086-75-0 ]
  • [ 202658-88-6 ]
  • Selexipag [ No CAS ]
YieldReaction ConditionsOperation in experiment
89.7% With potassium tert-butylate; In tetrahydrofuran; at 0 - 5℃; for 1h; To the reaction flask was added 4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]-1-butanol (100 g, 1 eq), THF (1 L), Stir and dissolve;Cooling to 0-5 C; potassium tert-butoxide (155.21 g, 5 eq) was added in portions, temperature control 0-5 C;N-(Chloroacetyl)methylsulfonamide (142 g, 3 eq) was dissolved in tetrahydrofuran (500 mL).Dropped into the above reaction bottle, the temperature is controlled at 0-5 C,The addition is completed in about 1 hour; after the reaction is completed, the reaction is stopped;The reaction solution was concentrated to dryness and dichloromethane (1L) was added.Water (1L); adjust the pH to 5-6 with 1M hydrochloric acid, dispense,The aqueous phase was extracted with dichloromethane (500 mL).The organic phase was washed with water (1 L). The organic phase was concentrated to dryness, anhydrous ethanol (1 L) was added, and the crystals were stirred to give 93.69 g.89.7%, purity 98.5%.
890 mg Potassium tertiary butoxide (700 mg) and dimethylsulfoxide (50 mL) were charged into a 100 mL round bottom flask at 30C. 4-[N-(5,6-diphenylpyrazin-2-yl)-N- isopropylamino]-1 -butanol (1 gm) at 28 C and the resulted mixture was stirred for 15 minutes. <strong>[202658-88-6]2-chloro-N-(methylsulfonyl)acetamide</strong> (1 .2 gm) was added at the resulted was added at the resulted mixture was stirred at 30C for 16 hours. Progress of the reaction was monitored by TLC and after completion of the reaction the reaction mass was poured into cold water and pH was adjusted to 6.5 with 1 N hydrochloric acid (-15 mL). The aqueous layer was extracted with ethylacetate, dried over anhydrous magnesium sulphate and then concentrated. The residue was purified by silica gel column chromatography using 2% Methanol in DCM as eluent to obtain 890 mg of Selexipag.
  • 22
  • [ 475086-75-0 ]
  • [ 475086-28-3 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: sodium hydroxide; tetrabutylammomium bromide / water; toluene / 5 - 30 °C 2.1: sodium hydroxide; methanol / 2 h / Reflux 3.1: thionyl chloride / 5 h / 25 - 30 °C 3.2: ammonia solution / 10 - 25 °C
  • 23
  • [ 42042-71-7 ]
  • C19H20N3(1+)*I(1-) [ No CAS ]
  • [ 475086-75-0 ]
YieldReaction ConditionsOperation in experiment
92% With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; General procedure: A mixture of 2,3-diphenylpiperazine trimethylammonium chloride (163.0 g, 0.5 mol)4- (isopropylamino) butanol (65.6 g, 0.5 mol)Anhydrous potassium carbonate (345.5 g, 2.5 mol) was added to DMF (3.0 L)And the mixture was stirred overnight at 80 ° C in an oil bath.TLC monitors the response completely.Cooled to room temperature,Was added to water (10 L)There is a lot of solid,filter,The solid was washed with water,50 ° C air bath dry.And recrystallized from a mixed solution of methanol (600 mL) and water (300 mL)A white solid was obtained 157.2 g,The yield was 87percent.:_The procedure of Example 8 was the same as Example 7 except that 2,3-diphenylpiperazine trimethylammonium iodide was used instead of the 2,3-diphenylpiperazine trimethylammonium chloride. The yield was 92percent.
  • 24
  • [ 42042-71-7 ]
  • C19H20N3(1+)*Cl(1-) [ No CAS ]
  • [ 475086-75-0 ]
YieldReaction ConditionsOperation in experiment
87% With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; A mixture of 2,3-diphenylpiperazine trimethylammonium chloride (163.0 g, 0.5 mol)4- (isopropylamino) butanol (65.6 g, 0.5 mol)Anhydrous potassium carbonate (345.5 g, 2.5 mol) was added to DMF (3.0 L)And the mixture was stirred overnight at 80 ° C in an oil bath.TLC monitors the response completely.Cooled to room temperature,Was added to water (10 L)There is a lot of solid,filter,The solid was washed with water,50 ° C air bath dry.And recrystallized from a mixed solution of methanol (600 mL) and water (300 mL)A white solid was obtained 157.2 g,The yield was 87percent.
  • 25
  • [ 42042-71-7 ]
  • C19H20N3(1+)*Br(1-) [ No CAS ]
  • [ 475086-75-0 ]
YieldReaction ConditionsOperation in experiment
81% With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; General procedure: A mixture of 2,3-diphenylpiperazine trimethylammonium chloride (163.0 g, 0.5 mol)4- (isopropylamino) butanol (65.6 g, 0.5 mol)Anhydrous potassium carbonate (345.5 g, 2.5 mol) was added to DMF (3.0 L)And the mixture was stirred overnight at 80 ° C in an oil bath.TLC monitors the response completely.Cooled to room temperature,Was added to water (10 L)There is a lot of solid,filter,The solid was washed with water,50 ° C air bath dry.And recrystallized from a mixed solution of methanol (600 mL) and water (300 mL)A white solid was obtained 157.2 g,The yield was 87percent.:_The procedure of Example 8 was the same as in Example 7 except that the 2,3-diphenylpiperazine trimethylammonium bromide was used instead of the 2,3-diphenylpiperazine trimethylammonium chloride.The yield was 81percent.
  • 26
  • [ 243472-70-0 ]
  • [ 475086-75-0 ]
  • 27
  • [ 42042-71-7 ]
  • [ 101727-15-5 ]
  • [ 475086-75-0 ]
YieldReaction ConditionsOperation in experiment
88% at 170℃; for 4.0h;Inert atmosphere; 35.8 g (0.1 mol) of 2-iodo-5,6-diphenylpyrazin and 105 g (0.8 mol) of <strong>[42042-71-7]4-isopropylamino-1-butanol</strong> was added into a 500 mL flask. Under the protection of nitrogen, the mixture was heated to 170° C. and reacted at this temperature for 4 hours, then cooled to 120° C. 80 g of <strong>[42042-71-7]4-isopropylamino-1-butanol</strong> was recovered by vacuum distillation, the residue was cooled and samples were taken for testing, HPLC purity of the product was 96.2percent, acetonitrile was added to recrystallize, and 31.8 g white solids of 4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]-1-butanol was obtained, the molar yield was 88percent, HPLC purity was 99.3percent, free of impurity S. (0070) 1H-NMR data: 1H-NMR (400 MHz, CDCl3) delta 8.02 (s, 1H), 7.46 (d, 2H, J=7.6 Hz), 7.36 (d, 2H, J=7.2 Hz), 7.28-7.22 (m, 6H), 4.80-4.78 (m, 1H), 3.71 (t, 2H, J=6.4 Hz), 3.45 (t, 2H, J=7.6 Hz), 1.77-1.74 (m, 2H), 1.66-1.64 (m, 2H), 1.29 (d, 6H, J=6.8 Hz)
79.5% In butan-1-ol; at 180℃; for 6.0h;Inert atmosphere; To the reaction flask was added 2-iodo-5,6,-diphenylpyrazine (83 g, 1 eq), 4-isopropylamino n-butanol (91.22 g,3 eq), nitrogen protection. The mixture was heated to 180 ° C for 6 h, and after the reaction was completed, the temperature was lowered to room temperature. Adding dichloride to the reaction solutionMethane (830 ml) was dissolved, washed with 1 mol/L hydrochloric acid (415 ml), and washed once. The organic phase was washed with water (415 ml) and weighedWash once more. The organic phase was dried over anhydrous magnesium sulfate for 2h, filtered, and then evaporated.56.0percent, purity 79.5percent.
65.1% at 100 - 190℃; for 8.0h; 17.8 g of Compound 1 and 16.4 g (2.5 d) of 4- (isopropylamino) -1-butanol were mixed and heated to 100 ° C in a solid state,At this point the solid has been fluid, the mixture was warmed to 190 ,Here TLC tracking monitoring, 8h after the reaction is basically completed and fewer by-products,The reaction mixture was cooled to 100 ° C and 70 mL of water was added. The solution was yellowish brown and stirred well. 90 mL of ethyl acetate was added and the mixture was separated. The aqueous phase was washed with 10 mL of ethyl acetate (5 mL * 2), separated and the organic phase combined. , Dried over anhydrous sodium sulfate, filtered to remove sodium sulfate, 5mL ethyl acetate washed to white, began to concentrate, concentrated to about 10mL left, cooled crystallization, filtration, drying,A total of compound 2 11.5g, yield 65.1percent, purity greater than 90percent.
  • 28
  • [ 475086-75-0 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: tetra(n-butyl)ammonium hydrogensulfate; potassium hydroxide / toluene / 0 - 25 °C 2.1: methanol; sodium hydroxide / 60 - 65 °C 3.1: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 20 - 25 °C 3.2: 60 °C
Multi-step reaction with 4 steps 1.1: tetra(n-butyl)ammonium hydrogensulfate; potassium hydroxide / toluene / 0 - 25 °C 2.1: methanol; sodium hydroxide / 60 - 65 °C 3.1: dmap / dichloromethane / 0.25 h / 20 - 30 °C 3.2: 24 h / 20 - 30 °C 4.1: 70 °C
  • 29
  • [ 39099-23-5 ]
  • [ 243472-70-0 ]
  • [ 475086-75-0 ]
YieldReaction ConditionsOperation in experiment
65.3% With potassium iodide; at 150.0℃; for 16h; The reaction flask was charged with <strong>[243472-70-0]5-bromo-2,3-diphenylpyrazine</strong> (100 g, 0.32 mol)4-Isopropylamino-1-butanol (127 g, 0.96 mol) andPotassium iodide (15.9 g, 0.096 mol) was added and the mixture was heated to 150 C for 16 hours.After the system was cooled to room temperature, ethyl acetate (800 mL)Washed with water (800 mL × 2), dried over anhydrous sodium sulfate, filtered,The filtrate was concentrated under reduced pressure and the residue treated with dichloromethane / heptane (1.2 L, v / v = 1: 5)Recrystallization, get4 - ((5,6-diphenylpyrazin-2-yl) - (isopropyl) amino) -1-butanol(75.5 g, yield: 65.3%).
  • 30
  • [ 2068134-99-4 ]
  • [ 475086-75-0 ]
YieldReaction ConditionsOperation in experiment
95% With toluene-4-sulfonic acid In ethyl acetate at 20℃; for 12h; Large scale; 9 Example 9: Preparation of SLP-9: In a 10-liter reactor, 252 g of SLP-8, 50 g of p-toluenesulfonic acid and 5 liters of ethyl acetate were added and the reaction was stirred at room temperature for 12 hours until the reaction was completed.Add 2 liters of water and stir and let stand.The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product; the crude product was recrystallized from ethyl acetate/petroleum ether to give 192 g of a pale yellow solid SLP-9.Yield: 95%.H NMR (400MHz, CDCl3): δ8.05 (s, 1H), 7.42-7.20 (m, 10H), 4.72 (m, 1H), 3.72 (t, 2H), 3.42 (t, 2H), 1.73-1.50 (m, 4H), 1.26(d,6H)ESI/MS+(m/z):361
87.52% With hydrogenchloride In methanol at 20℃; 1.4 Add N-isopropyl-5,6-diphenyl-(4-(tetrahydro-2H-pyran-2-oxy)-n-butyl)pyrazine-2-amine (50 g, 1 eq) to the reaction flask ), 2 mol / L hydrochloric acid methanol solution (500 ml);After stirring at room temperature overnight, the starting material disappeared and the reaction was stopped.The reaction solution was concentrated to remove methanol, and water (250 ml) was added.Dichloromethane (100 ml) was stirred for 15 min and then allowed to stand for liquid separation. The aqueous phase was extracted with dichloromethane (100 mL).The yield was 87.52% and the purity was 96.5%.
  • 31
  • [ 475086-75-0 ]
  • [ 59504-75-5 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
81% With potassium <i>tert</i>-butylate In 1-methyl-pyrrolidin-2-one at 20℃; for 12h; Large scale; 12 Example 12: Preparation of SLP-11 (cilipec): In a 10-liter reactor, 192 g of SLP-9 was dissolved in 2 liters of N-methylpyrrolidone; 67 g of potassium tert-butoxide was slowly added, and then 138 g of SLP-10a (0.69 mol) was added in portions; stirring at room temperature 12 Hours to the end of the reaction.Slowly cool to 0° C., add 2 kg of ice water and add 3 liters of ethyl acetate, stir and stand for phase separation; the organic phase is dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product; the crude product is ethyl acetate/ Petroleum ether crystallized and concentrated to give 212 g of pale yellow solid SLP-11 (Siliparg).Yield: 81%, purity 99.5%.H NMR (400MHz, CDCl3): δ 8.04 (s, 1H), 7.42-7.20 (m, 10H), 4.73 (m, 1H), 3.62 (t, 2H), 3.47 (t, 2H), 3.29 (s, 3H), 1.73- 1.50 (m, 4H), 1.24 (d, 6H)ESI/MS+(m/z):496
  • 32
  • [ 475086-75-0 ]
  • [ 202658-88-6 ]
  • C25H30N4O4S [ No CAS ]
YieldReaction ConditionsOperation in experiment
83% With potassium tert-butylate; In 1-methyl-pyrrolidin-2-one; at 20℃; for 12h;Large scale; In a 10-liter reaction kettle, 192 g of SLP-9 was dissolved in 2 liters of N-methylpyrrolidone; 67 g of potassium tert-butoxide was slowly added, and then 112 g of SLP-10b (0.7 mol) was added in portions; stirring at room temperature 12 Hours to the end of the reaction.Slowly cool to 0 C., add 2 kg of ice water and add 3 liters of ethyl acetate, stir and stand for phase separation; the organic phase is dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product; the crude product is ethyl acetate/ The petroleum ether crystallized and concentrated to give 219 g of a pale yellow solid SLP-11 (Siripag).Yield: 83%, purity 99.2%.
  • 33
  • [ 2068134-98-3 ]
  • [ 475086-75-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 °C / Large scale 1.2: 24 h / 5 - 25 °C / Large scale 2.1: toluene-4-sulfonic acid / ethyl acetate / 12 h / 20 °C / Large scale
Multi-step reaction with 2 steps 1.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 °C / Large scale 1.2: 24 h / 5 - 25 °C / Large scale 2.1: toluene-4-sulfonic acid / ethyl acetate / 12 h / 20 °C / Large scale
Multi-step reaction with 2 steps 1.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 °C / Large scale 1.2: 24 h / 5 - 25 °C / Large scale 2.1: toluene-4-sulfonic acid / ethyl acetate / 12 h / 20 °C / Large scale
  • 34
  • [ 475086-75-0 ]
  • [ 683-57-8 ]
  • [ 475086-28-3 ]
YieldReaction ConditionsOperation in experiment
89% With potassium carbonate In toluene for 6h; Reflux; 1.1 Step 1) Preparation of Compound I: Compound II (3.61 g, 10 mmol) was added to toluene (50 ml) and then potassium carbonate (1.38 g, 10 mmol)And 2-bromoacetamide (1.5 g, 10.9 mmol), stirring was started, and the reaction was heated under reflux for 6 hours, and the reaction was completely monitored by TLC plate.The solution was cooled to room temperature, water was added, stirred for half an hour, and the layers were allowed to stand. The upper organic phase was collected and dried over anhydrous sodium sulfate.Concentrated, the residue was crystallized from ethyl acetate: petroleum ether (volume ratio) = 1.5.The white solid compound I (3.72 g, yield 89%) was obtained.
  • 35
  • [ 2350331-43-8 ]
  • [ 475086-75-0 ]
YieldReaction ConditionsOperation in experiment
86% With hydrogenchloride In methanol at 20℃; 2.3 Add N-(4-(tert-butyldiphenylsilyloxy)n-butyl)-N-isopropyl-5,6-diphenylpyrazin-2-amine (50 g, 1 eq) to the reaction flask 2mol / L hydrochloric acid methanol solution (500ml); stirred at room temperature overnight, the disappearance of the starting materials to stop the reaction. reactionThe liquid was concentrated to remove methanol, and water (250 ml), dichloromethane (100 ml) was added, and the mixture was stirred for 15 min. ChlorineThe alkane (100 ml) was extracted, the organic phase was combined, and the organic phase was concentrated to dryness to dryness to yield 25.93 g.
  • 36
  • [ 42042-71-7 ]
  • [ 475086-75-0 ]
  • 37
  • [ 1781262-21-2 ]
  • [ 475086-75-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: triethylamine / tetrahydrofuran / 18 h / 60 °C / Inert atmosphere 2: hydrogenchloride / methanol / 20 °C
Multi-step reaction with 2 steps 1: triethylamine / tetrahydrofuran / 24 h / 60 °C / Inert atmosphere 2: hydrogenchloride / methanol / 20 °C
  • 38
  • [ 2348491-77-8 ]
  • [ 447-31-4 ]
  • [ 475086-75-0 ]
YieldReaction ConditionsOperation in experiment
30.2 g Stage #1: C9H20N2O2; Desyl chloride With sodium carbonate In chloroform at 30 - 35℃; for 5h; Stage #2: With ammonium hydroxide; dihydrogen peroxide; ammonium chloride In chloroform at 30 - 35℃; for 5h; 2 Example 2: Preparation of 2-(N-isopropyl-N-4-(hydroxy)butyl)amino-5,6-diphenylpyrazine (II) To a 500 ml four-necked flask equipped with a stirring, a thermometer and a condenser, 120 g of chloroform, 21.0 g (0.1mol) of benzoin, 15.6 g (0.15 mol) of 35% hydrochloric acid, and stirring at 37 to 35 ° C for 3.5 hours were added. Asolution of1,2-diphenyl-2-chloroethyl ketone is obtained. After completion of the reaction, the layers are separated, and the aqueous layer is extracted twice with chloroform (10 g each time), and the organic phase is combined, and theobtained organic phase is transferred to constant. In the dropping funnel, set aside.To another with stirring, condenser and thermometer 500 mlfour-necked flask, 30 g of chloroform, 20 g (0.11 mol) N- -N- isopropyl-amino-acetyl-butanol, carbonate, 12.0 gof sodiumcarbonate, Between 30 and 35 ° C, the solution in the constant pressure dropping funnel was added dropwise, and the solution was dropped in about 1 hour, and then reacted at 30 to 35 ° C for 4 hours.After slightlycooling, add 5 g of 25% ammonia water, 5.0 g of ammonium chloride, 13.0 g of 40% hydrogen peroxide, stir the reaction at 30-35 ° C for 5 hours, separate the layers, andextract the aqueous layer twice with chloroform, 20 g each time, and combine the organic phases. The chloroform was distilled off, 50 g of methyl tert-butyl etherwas added to the residue, 0.3 g of activated carbon was added, and the mixture was decolorized by stirring at 80 to 82 ° C for 1 hour, filtered while hot, and the filtrate was cooled to 0 to 5 ° C, filtered, and dried to obtain 30.2 g. white solid 2-(N-isopropyl-N-4-(hydroxy)butyl)amino-5,6-diphenylpyrazine, melting point 102-103 ° C, yield 83.8%, liquid purity 99.7%.
  • 39
  • [ 24242-77-1 ]
  • [ 2348491-77-8 ]
  • [ 475086-75-0 ]
YieldReaction ConditionsOperation in experiment
32.5 g Stage #1: α-iodo-α-phenylacetophenone; C9H20N2O2 With potassium carbonate In dichloromethane at 30 - 35℃; for 5h; Stage #2: With ammonium hydroxide; dihydrogen peroxide; ammonium chloride In dichloromethane at 20 - 25℃; for 5h; 3 Example 3: Preparation of 2-(N-isopropyl-N-4-(hydroxy)butyl)amino-5,6-diphenylpyrazine (II) Stirring, thermometer and condenser tube in a 500 ml four-necked flask, add 120 grams of dichloromethane, 21.0 g (0.1 mol) of benzoin, 38.5 g (0.12 mol) of 40% hydroiodic acid, The reaction was stirred at 20 to 25 ° C for 3 hours. a solution of 1,2-diphenyl-2-iodoethyl ketone,After the reaction is completed, layering,The aqueous layer was extracted twice with dichloromethane (10 g each time).The organic phases were combined and the resulting organic phase was transferred to a constant pressure dropping funnel for use. To another 500 with agitation, thermometer and condenserIn a milliliter four-necked flask, add 30 grams of dichloromethane.20 g (0.11 mol) of N-aminoacetyl-N-isopropyl n-butanol,15.0 g of potassium carbonate, between 30 and 35 ° C,The solution in the constant pressure dropping funnel was added dropwise, and the solution was dropped in about 1 hour.Thereafter, the reaction was carried out at 30 to 35 ° C for 4 hours. Slightly cool, add 5 grams of 25% ammonia,5.0 g of ammonium chloride, 13.0 g of 40% hydrogen peroxide,The reaction was stirred at 20 to 25 ° C for 5 hours, and the layers were separated.The aqueous layer was extracted twice with dichloromethane.20 grams each time,Combine the organic phase,Distilling off dichloromethane,50 grams of methyl tert-butyl ether was added to the residue.0.3 g of activated carbon, stirring and decoloring at 80-82 ° C for 1 hour,Filtered, the filtrate was cooled to 0-5 ° C, filtered.dry,32.5 g of a white solid -(N-isopropyl-N-4-(hydroxy)butyl)amino-5,6-diphenylpyrazine having a melting point of 102-103 ° C.The yield is 90.2%.The liquid phase purity was 99.5%.
  • 40
  • [ 119-53-9 ]
  • [ 475086-75-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: hydrogen bromide / dichloromethane / 4 h / 20 - 25 °C 2.1: potassium carbonate / dichloromethane / 5 h / 30 - 35 °C 2.2: 5 h / 20 - 25 °C
Multi-step reaction with 2 steps 1.1: hydrogenchloride / chloroform; water / 3.5 h / 30 - 35 °C 2.1: sodium carbonate / chloroform / 5 h / 30 - 35 °C 2.2: 5 h / 30 - 35 °C
  • 41
  • [ 2348491-77-8 ]
  • [ 1484-50-0 ]
  • [ 475086-75-0 ]
YieldReaction ConditionsOperation in experiment
31.6 g Stage #1: C9H20N2O2; desyl bromide With potassium carbonate In dichloromethane at 30 - 35℃; for 5h; Stage #2: With ammonium hydroxide; dihydrogen peroxide; ammonium chloride In dichloromethane at 20 - 25℃; for 5h; 1; 4 Stirring,Thermometer and condenser tube in a 500 ml four-necked flask,Add 120 grams of dichloromethane,21.0 g (0.1 mol) of benzoin,25.0 g (0.12 mol) of 40% hydrobromic acid,The reaction was stirred at 20 to 25 ° C for 4 hours.a solution of 1,2-diphenyl-2-bromoethyl ketone,After the reaction is completed, layering,The aqueous layer was extracted twice with dichloromethane (10 g each time).Combine the organic phase,Transfer the resulting organic phase to a constant pressure dropping funnel,stand-by.To the other with agitation,Thermometer and condenser tube in a 500 ml four-necked flask,Add 30 grams of dichloromethane,20 g (0.11 mol) of N-aminoacetyl-N-isopropyl n-butanol,15.0 g of potassium carbonate,Between 30 and 35 ° C, add the solution in the constant pressure dropping funnel,The mixture was dropped in about 1 hour, and thereafter reacted at 30 to 35 ° C for 4 hours.Slightly cooled,Add 5 grams of 25% ammonia water,5.0 g of ammonium chloride, 13.0 g of 40% hydrogen peroxide,Stir the reaction at 20 to 25 ° C for 5 hours.Layered, the aqueous layer was extracted twice with dichloromethane.20 grams each time, combining organic phases,Dichloromethane was distilled off, and 50 g of methyl tert-butyl ether and 0.3 g of activated carbon were added to the residue, and the mixture was decolorized by stirring at 80 to 82 ° C for 1 hour, filtered while hot, and the filtrate was cooled to 0-5 ° C.Filtered and dried to give 31.6 g of a white solid2-(N-Isopropyl-N-4-(hydroxy)butyl)amino-5,6-diphenylpyrazine. The obtained product had a melting point of 102-103 ° C, a yield of 87.7%, and a liquid phase purity of 99.6%.
  • 42
  • [ 475086-75-0 ]
  • [ 66074-86-0 ]
  • [ 2375113-56-5 ]
YieldReaction ConditionsOperation in experiment
58% In toluene at 20℃; for 20h; 3 The third step reaction: 2-(methylsulfonylamino)acetyl chloride (10.00 g, 0.06 mol) in the second step reaction was added to 130 ml of toluene.4-[(5,6-Diphenylpyrazin-2-yl)(isopropyl)amino]-1-butanol (6.90 g, 0.02 mol) was added in 7 portions, and reacted at room temperature for 20 hours. The toluene was distilled off under reduced pressure, and the temperature of the toluene was distilled off under reduced pressure to 65 ° C. The end point of the toluene removed under reduced pressure was that the toluene was not distilled off, 150 ml of dichloromethane was added, and the organic layer was extracted with water (150 ml × 3), and the organic phase was separated. Dry over anhydrous sodium sulfate, filter, concentrate the filtrate, and beat 3 times with methyl tert-butyl ether to give 5.50 g.4-[(5,6-Diphenylpyrazin-2-yl)(isopropyl)amino]butyl-2-(methylsulfonylamino)acetate, yield 58.00%.
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