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CAS No. :475084-96-9 MDL No. :
Formula : C29H37N3O3 Boiling Point : -
Linear Structure Formula :- InChI Key :-
M.W : 475.62 Pubchem ID :-
Synonyms :

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* 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 [ 475084-96-9 ]

[ 475084-96-9 ] Synthesis Path-Downstream   1~7

  • 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
  • [ 475084-96-9 ]
  • [ 475085-57-5 ]
YieldReaction ConditionsOperation in experiment
90% With water; lithium hydroxide In ethanol at 0℃; for 2h; 3.3 (3) Preparation of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino] butyloxy} acetic Acid 23.8 g of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}tert-butyl acetate (obtained by the previous reaction) and 115 mL of anhydrous ethanol were added into a 500 mL flask and cooled to 0° C., 40 g of 30% aqueous solution of lithium hydroxide was added dropwise, then reacted at this temperature for 2 hours until the reaction was completed. (0063) The reaction solution was adjusted to pH 1-2 with 2N sulfuric acid and extracted with ethyl acetate, the organic phase was concentrated, the obtained crude product was recrystallized by 100 mL of isopropanol, and 18.9 g of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino] butyloxy} acetic acid was obtained, the molar yield was 90%, HPLC purity was 99.2%. (0064) 1H-NMR data: 1H-NMR (400 MHz, CDCl3) δ 8.03 (s, 1H), 7.35 (d, 2H, J=7.2 Hz), 7.24 (d, 2H, J=7.2 Hz), 7.17-7.15 (m, 6H), 4.80-4.77 (m, 1H), 4.0 (s, 2H), 3.56 (t, 2H, J=6.0 Hz), 3.38 (t, 2H, J=6.4 Hz), 1.71-1.66 (m, 4H), 1.20 (d, 6H, J=6.8 Hz).
72% With methanol; water; sodium hydroxide for 1.5h; Reflux; 1.; 2.1; 3.1 (1) Preparation of Intermediate 3: Add 63g of methanol to a 100mL reaction flask, start stirring, and then add 8.26g of Intermediate 2, 1N sodium hydroxide aqueous solution (. After the addition is complete, the system is heated to reflux, and the reaction is kept warm for 1.5 hours. TLC monitoring (n-hexane: ethyl acetate) =5:1), the reaction is complete. The reaction solution is concentrated under reduced pressure at 50-55°C until it is evaporated without solvent. After concentration is completed, a light yellow solid is obtained. Add 81g of drinking water to the residue and stir to dissolve. Then add 39g of n-hexane Wash, stand for phase separation, collect the water phase. Then add 1N hydrochloric acid, 79g ethyl acetate, extract the phases, and collect the organic phase. Add 10g anhydrous magnesium sulfate and dry for 1 hour. After drying, filter to remove the magnesium sulfate, and the filtrate Transfer to a 100mL flask. After the transfer is completed, the filtrate is concentrated under reduced pressure at 50-55°C until it is evaporated without solvent. After concentration is completed, a yellow solid is obtained. Add 19.93g of n-hexane to make a slurry and wash. Suction filtration, collect the solid at 50-55°C Concentrated under reduced pressure to obtain 5.23 g of intermediate 3, a pale yellow solid, with a yield of 72%. HPLC inspection: purity of 99.91%.
71.83% With sodium hydroxide In methanol for 1.5h; Reflux; 5 Example 5: Preparation of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N- isopropylamino]butyloxy}acetic acid (VII): 6.0 gm of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetic acid tert-butyl ester was dissolved in 60 ml of methanol and 30 ml of IN sodium hydroxide solution was added. After the mixture was heated at reflux for 1.5 hours, the solvent was evaporated under reduced pressure and the residue was dissolved in 60 ml water. After washing with 30 ml diethyl ether, the pH of aqueous layer was adjusted to 4.1 with 3.0 ml of cone hydrochloric acid and then extracted with 30 ml ethyl acetate. Layers are separated and aqueous layer was washed with 30 ml of ethyl acetate. The ethyl acetate layers were combined and washed with 30 ml water, dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure, and then the residue was treated with 30 ml heptane to obtain solid, which was then filtered and washed with 6 ml hexane and dried to obtain 3.8 gm of the desired compound. Yield: 71.83 %.
With sodium hydroxide In methanol for 1h; Heating;
With sodium hydroxide In methanol; water for 2h; Heating / reflux; 42 Example 42
2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetic acid
Example 42 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetic acid 21.07 g of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetic acid tert-butyl ester was dissolved in 200 ml of methanol and 60 ml of 1N sodium hydroxide solution was added.. After the mixture was heated at reflux for 2 hours, the solvent was evaporated under reduced pressure and the residue was dissolved in water.. After washing with diethyl ether, the aqueous layer was neutralized with 60 ml of 1N hydrochloric acid and then extracted with ethyl acetate.. The extract was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure, and then the residue was washed with diisopropyl ether to obtain 15.82 g of the desired compound.
With sodium hydroxide In methanol for 1h; Reflux;
64 g With methanol; sodium hydroxide for 2h; Reflux; 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 %]
15.82 g With water; sodium hydroxide In methanol for 2h; Reflux; Reference example
Preparation of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N- (methylsulfonyl)acetamide 21.07 g of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetic acid tert- butyl ester was dissolved in 200 ml of methanol and 60 ml of IN sodium hydroxide solution was added. After the mixture was heated at reflux for 2 hours, the solvent was evaporated under reduced pressure and the residue was dissolved in water. After washing with diethyl ether, the aqueous layer was neutralized with 60 ml of IN hydrochloric acid and then extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure, and then the residue was washed with diisopropyl ether to obtain 15.82 g of the desired compound.
With sodium hydroxide In methanol at 40℃; Reflux; 4 Example 4 Preparation of Compound 4 25g crude compound 3 was dissolved in 225mL methanol, warmed to 40 °C,Start dropping 1M NaOH, a total of 125mL dropwise, warmed to reflux, TLC trace hydrolysis is completed,Concentrated to no liquid dripping, to give a jelly 14.2g, the jelly was dissolved in 2.8L water, dropping dilute hydrochloric acid to pale yellow solid all precipitation, when pH is about 5-6 .Filtration, drying, Recrystallization from ethanol to give a yellow powdery solid (in the fourth) 7.1g,The purity of liquid was 91.5%.
With methanol; sodium hydroxide at 60 - 65℃; 30 Example 30: Preparation of 2-{4-[N-(5,6-diphenylpyrazi n-2-yl)-N-isopropylam mo] butyloxy} acetic acid (formula IV) 8% sodium hydroxide solution (800 mL) was charged to a stirred solution of crude 2-{4-[N-(5,6- diphenyl pyrazin-2-yl)-N-isopropylamino]butyloxy}acetic acid tert-butyl ester taken in methanol (1.300 L). The reaction mixture was heated to 60-65 CC for 2-3 hours. The solvent was evaporated under reduced pressure to get a residue. This residue was dissolved in water (2.500 L)and washed with mixture of ethyl acetate and methyl tert-butyl ether. This reaction mixture was adjusted to pH 2.5-3.Swith concentrated hydrochloric acid (60 mL) and then extracted with dichloromethane (1 .500 L). The organic layers were combined and washed with water (2*600 mL), the solvent was evaporated under reduced pressure, and a residue was formed. This residue was stirred with methyl tert-butyl ether (500 mL) for 2hours and filtered to obtain a solid, which was washed with methyl tert-butyl ether (100 mL) to form a crude product. The crude product was dissolved in isopropyl alcohol (800 mL) at 70-75 CC and the solution was cooled to 0-5CC to precipitate asolid, which was washed with chilled isopropyl alcohol (100 mL). The solid was then dried to get 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy} acetic acid (formula III).
55.8 g With sodium hydroxide In tetrahydrofuran Reflux; 3 Example 3 To the crude product from Example 2 above was added tetrahydrofuran (300 mL) and10% sodium hydroxide solution (300 mL, w%), heated to reflux,TLC detection until the reaction is complete. Concentrated under reduced pressure to remove tetrahydrofuran,The aqueous phase was extracted with methyl tert-butyl ether (300 mL × 2)The pH was then adjusted to 2-3 with 1 N hydrochloric acid and extracted with ethyl acetate (800 mL)Concentration under reduced pressure and the residue was recrystallized from ethyl acetate (500 mL)2- (4 - ((5,6-diphenylpyrazin-2-yl) (isopropyl) amino) butoxy) acetic acid(S-I) (55.8 g, two steps yield: 66.5%).
9.88 g With water; sodium hydroxide In methanol for 1h; Reflux; 1 Reference Example 1: Production of Form-III Crystal After tert-butyl 2-{(4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetate (see, for example, PTL 1) (13.15 g) was dissolved in methanol (179.7 mL), a 1 N aqueous sodium hydroxide solution (41.47 mL) was added thereto. After the resulting mixture was heated under reflux for 1 hour, the solvent was distilled off under reduced pressure, and water was added to the residue to dissolve the residue. After washing was performed with diethyl ether, the obtained aqueous layer was neutralized with 1 N hydrochloric acid (44 mL), and extraction was performed with ethyl acetate. The obtained ethyl acetate layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure, and then, diisopropyl ether was added to the residue to effect crystallization. The resulting crystal was filtered and washed with an appropriate amount of diisopropyl ether. The crystal was dried at 40° C. under reduced pressure, whereby a form-III crystal (9.88 g) was obtained. (0090) The results of powder X-ray diffraction measurement, IR measurement, and DSC measurement of the form-III crystal are shown in FIG. 1, FIG. 2, and FIG. 3, respectively. (0091) diffraction angles (2θ): 8.4°, 12.6°, 13.4°, 14.3°, 14.6°, 15.9°, 16.9°, 18.0°, 18.8°, 19.4°, 20.3°, 20.6°, 21.6°, 21.7°, 22.3°, 22.5°, 23.3°, 23.7°, 23.9°, 27.0°, 29.6°, and 30.8°. (0092) IR absorption peaks: 2867 cm-1, 1747 cm-1, 1558 cm-1, 1380 cm-1, 1131 cm-1, and 701 cm-1 (0093) DSC endothermic peak: 118° C.

Reference: [1]Current Patent Assignee: SHANGHAI SHIJI BIOLOGICAL TECH; SHANGHAI SEASONS BIOTECHNOLOGY; SEASONS BIOTECHNOLOGY TAIZHOU - US2018/29998, 2018, A1 Location in patent: Paragraph 0062-0064
[2]Current Patent Assignee: JIANGSU FANGSHENG PHARMACEUTICAL - CN113480484, 2021, A Location in patent: Paragraph 0027; 0028; 0030; 0031; 0033; 0034
[3]Current Patent Assignee: LUPIN LIMITED - WO2017/60827, 2017, A1 Location in patent: Page/Page column 12
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  • [ 475084-96-9 ]
  • [ 475086-01-2 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: sodium hydroxide / methanol / 1 h / Reflux 2.1: 1,1'-carbonyldiimidazole / tetrahydrofuran / 1 h / Reflux 2.2: 0.17 h 2.3: 12 h
Multi-step reaction with 2 steps 1.1: sodium hydroxide; methanol / 2 h / Reflux 2.1: 1,1'-carbonyldiimidazole / tetrahydrofuran / 0.75 h / 65 - 70 °C 2.2: 3 h / 25 - 30 °C
Multi-step reaction with 3 steps 1.1: sodium hydroxide; methanol / 2 h / Reflux 2.1: thionyl chloride / 5 h / 25 - 30 °C 2.2: ammonia solution / 10 - 25 °C 3.1: sodium hydride / tetrahydrofuran / 0.33 h 3.2: 3 h / 0 - 25 °C
Multi-step reaction with 2 steps 1.1: sodium hydroxide; water / methanol / 2 h / Reflux 2.1: 1,1'-carbonyldiimidazole / tetrahydrofuran / 1 h / 20 °C / Inert atmosphere; Reflux 2.2: 0.17 h / 20 °C 2.3: 20 °C
Multi-step reaction with 2 steps 1.1: methanol; sodium hydroxide / 60 - 65 °C 2.1: dmap / dichloromethane / 0.25 h / 20 - 30 °C 2.2: 24 h / 20 - 30 °C
Multi-step reaction with 2 steps 1.1: lithium hydroxide; water / ethanol / 2 h / 0 °C 2.1: oxalyl dichloride / dichloromethane / 2 h / 5 - 20 °C 2.2: 5 h / 10 °C
Multi-step reaction with 2 steps 1.1: sodium hydroxide / methanol; water / 4 h / 80 °C 1.2: 30 min / 20 °C 2.1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 5 min / 20 °C 2.2: 20 °C

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  • [ 18591-57-6 ]
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  • [ 243472-70-0 ]
  • [ 475084-96-9 ]
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