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Chemical Structure| 475085-57-5
Chemical Structure| 475085-57-5
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Product Details of [ 475085-57-5 ]

CAS No. :475085-57-5 MDL No. :
Formula : C25H29N3O3 Boiling Point : -
Linear Structure Formula :- InChI Key :OJQMKCBWYCWFPU-UHFFFAOYSA-N
M.W : 419.52 Pubchem ID :9931891
Synonyms :
Chemical Name :2-(4-((5,6-Diphenylpyrazin-2-yl)(isopropyl)amino)butoxy)acetic acid

Calculated chemistry of [ 475085-57-5 ]

Physicochemical Properties

Num. heavy atoms : 31
Num. arom. heavy atoms : 18
Fraction Csp3 : 0.32
Num. rotatable bonds : 11
Num. H-bond acceptors : 5.0
Num. H-bond donors : 1.0
Molar Refractivity : 123.62
TPSA : 75.55 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : No
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : Yes
CYP2C9 inhibitor : Yes
CYP2D6 inhibitor : Yes
CYP3A4 inhibitor : Yes
Log Kp (skin permeation) : -5.65 cm/s

Lipophilicity

Log Po/w (iLOGP) : 3.48
Log Po/w (XLOGP3) : 4.52
Log Po/w (WLOGP) : 4.91
Log Po/w (MLOGP) : 2.35
Log Po/w (SILICOS-IT) : 4.64
Consensus Log Po/w : 3.98

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 1.0
Egan : 0.0
Muegge : 0.0
Bioavailability Score : 0.56

Water Solubility

Log S (ESOL) : -4.99
Solubility : 0.00427 mg/ml ; 0.0000102 mol/l
Class : Moderately soluble
Log S (Ali) : -5.83
Solubility : 0.000623 mg/ml ; 0.00000149 mol/l
Class : Moderately soluble
Log S (SILICOS-IT) : -7.89
Solubility : 0.00000543 mg/ml ; 0.0000000129 mol/l
Class : Poorly soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 3.0
Synthetic accessibility : 3.56

Safety of [ 475085-57-5 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 475085-57-5 ]

* 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 [ 475085-57-5 ]

[ 475085-57-5 ] Synthesis Path-Downstream   1~41

  • 1
  • [ 475085-57-5 ]
  • [ 81363-76-0 ]
  • 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(isopropylsulfonyl)acetamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
46% Stage #1: MRE-269 With 1,1'-carbonyldiimidazole In tetrahydrofuran for 0.5h; Heating; Stage #2: propane-2-sulfonamide With 1,8-diazabicyclo[5.4.0]undec-7-ene In tetrahydrofuran at 20℃; for 36h; Further stages.;
Stage #1: MRE-269 With 1,1'-carbonyldiimidazole In tetrahydrofuran for 1h; Reflux; Stage #2: propane-2-sulfonamide In tetrahydrofuran for 0.166667h; Stage #3: With 1,8-diazabicyclo[5.4.0]undec-7-ene In tetrahydrofuran for 36h;
  • 2
  • [ 475085-57-5 ]
  • [ 421-85-2 ]
  • 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(trifluoromethanesulfonyl)acetamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
54% Stage #1: MRE-269 With 1,1'-carbonyldiimidazole In tetrahydrofuran for 0.5h; Heating; Stage #2: Trifluoromethanesulfonamide With 1,8-diazabicyclo[5.4.0]undec-7-ene In tetrahydrofuran at 20℃; for 36h; Further stages.;
Stage #1: MRE-269 With 1,1'-carbonyldiimidazole In tetrahydrofuran for 1h; Reflux; Stage #2: Trifluoromethanesulfonamide In tetrahydrofuran for 0.166667h; Stage #3: With 1,8-diazabicyclo[5.4.0]undec-7-ene In tetrahydrofuran for 36h;
  • 3
  • [ 98-10-2 ]
  • [ 475085-57-5 ]
  • N-(benzenesulfonyl)-2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
43% Stage #1: MRE-269 With 1,1'-carbonyldiimidazole In tetrahydrofuran for 0.5h; Heating; Stage #2: benzenesulfonamide With 1,8-diazabicyclo[5.4.0]undec-7-ene In tetrahydrofuran at 20℃; for 36h; Further stages.;
Stage #1: MRE-269 With 1,1'-carbonyldiimidazole In tetrahydrofuran for 1h; Reflux; Stage #2: benzenesulfonamide In tetrahydrofuran for 0.166667h; Stage #3: With 1,8-diazabicyclo[5.4.0]undec-7-ene In tetrahydrofuran for 36h;
  • 4
  • [ 475085-57-5 ]
  • [ 6339-87-3 ]
  • 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(2-thiophenesulfonyl)acetamide [ No CAS ]
  • 5
  • [ 475085-57-5 ]
  • [ 25999-04-6 ]
  • 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(morpholin-4-ylsulfonyl)acetamide [ No CAS ]
  • 6
  • [ 475085-57-5 ]
  • N-(aminosulfonyl)-2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino] butyloxy}acetamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
50% Stage #1: MRE-269 With 1,1'-carbonyldiimidazole In tetrahydrofuran for 0.5h; Heating; Stage #2: With SULFAMIDE; 1,8-diazabicyclo[5.4.0]undec-7-ene In tetrahydrofuran at 20℃; for 36h; Further stages.;
  • 7
  • [ 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
[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 43
[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 43-44
[8]Current Patent Assignee: HONOUR R D - WO2017/168401, 2017, A1 Location in patent: Page/Page column 11
[9]Current Patent Assignee: NANJING NMG ADDS - CN106957269, 2017, A Location in patent: Paragraph 0023; 0024
[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 0057; 0058; 0059; 0060
[12]Current Patent Assignee: NIPPON SHINYAKU CO LTD - US2020/223804, 2020, A1 Location in patent: Paragraph 0089-0093
  • 8
  • [ 475085-57-5 ]
  • [ 3144-09-0 ]
  • Selexipag [ No CAS ]
YieldReaction ConditionsOperation in experiment
96.8% Stage #1: MRE-269 With 1,1'-carbonyldiimidazole In dichloromethane for 1h; Reflux; Stage #2: methanesulfonamide In dichloromethane at 20 - 30℃; for 0.166667h; Stage #3: With triethylamine In dichloromethane for 5h; 4 Example 4 Add in the reaction flask2- (4 - ((5,6-diphenylpyrazin-2-yl) (isopropyl) amino) butoxy) acetic acid (S-I)(21.0 g, 0.05 mol), carbonyldiimidazole (12.2 g, 0.075 mol) andDichloromethane (210 mL), heated to reflux for 1 hour,The temperature was lowered to 20-30 ° C, methanesulfonamide (9.5 g, 0.10 mol)After stirring for 10 minutes, triethylamine (10.1 g, 0.10 mol)Continue to react for 5 hours. Water (50 mL) was added,Dropping 1N hydrochloric acid to adjust the pH of the system to 5-6, liquid separation,The organic phase was washed with water (50 mL × 2), dried over anhydrous sodium sulfate,Filtration, the filtrate was concentrated under reduced pressure Sai Xip crude(Purity: 99.16%, HPLC chromatogram shown in Figure 1),The crude product was recrystallized from absolute ethanol (270 mL) to give a white solid racemic solution(24.0 g, yield: 96.8%, purity: 99.93%,HPLC chromatogram shown in Figure 2).
88% Stage #1: MRE-269 With oxalyl dichloride In dichloromethane at 5 - 20℃; for 2h; Stage #2: methanesulfonamide With triethylamine In acetonitrile at 10℃; for 5h; 4.4 (4) Preparation of NS-304 8.4 g (0.02 mol) of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino] butyloxy} acetic acid and 60 mL of dichloromethane were added into a 100 mL flask and cooled to 5° C., 3.8 g (0.03 mol) of oxalyl chloride was added dropwise, then reacted at room temperature for 2 hours, the solvent was concentrated to dryness, 50 mL of acetonitrile was added to dissolve, and the X4 solution was obtained as a stand-by. (0077) 2.85 g of methanesulfonamide, 20 mL of acetonitrile and 3 g of triethylamine were added into another flask and cooled to 10° C., the X4 solution obtained above was added dropwise, then reacted at this temperature for 5 hours, until the reaction was completed. (0078) The finished reaction solution was poured into 100 mL of ice water, the mixture was extracted with ethyl acetate, the solvent of the organic phase was concentrated to dry, the residue was recrystallized with ethanol, and 8.8 g off-white crystals of NS-304 was obtained, the molar yield was 88%, HPLC purity was 99.5%. (0079) 1H-NMR data: 1H-NMR (400 MHz, CDCl3) δ: 8.19 (s, 1H), 7.44 (m, 2H), 7.35 (m, 2H), 7.30-7.21 (m, 6H), 3.97 (s, 2H), 3.59 (t, J=6.0 Hz, 2H), 3.45 (t, J=6.8 Hz, 2H), 3.29 (s, 3H), 1.75-1.70 (m, 4H).
84.51% Stage #1: MRE-269 With 1,1'-carbonyldiimidazole In tetrahydrofuran at 65 - 70℃; for 2h; Stage #2: methanesulfonamide In tetrahydrofuran for 0.5h; Stage #3: With 1,8-diazabicyclo[5.4.0]undec-7-ene In tetrahydrofuran for 0.666667h; 5 Example 6: Preparation of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N- isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide (I): A solution of 3 gm of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N- isopropylamino]butyloxy} acetic acid in 48 ml of tetrahydrofuran, 1.28 gm of 1,1'- carbonyl diimidazole was added and, after stirring the reaction mixture at 65-70°C for 2 hrs, the reaction mixture cooled to room temperature, 0.695 gm of methanesulfonamide was added. After stirring for 30 minutes, 1.11 gm of l,8-diazabicyclo[5.4.0.]-7-undecene was added dropwise with stirring for 40 minutes. To the mixture, 30 ml of IN hydrochloric acid was added and extracted with 30 ml of ethyl acetate followed by layer separation. Aqueous layer washed with 15 ml ethyl acetate and then ethyl acetate layers combined and washed with 30 ml water and then with 30 ml of 5% brine solution. The ethyl acetate layer then concentrated under reduced pressure, and then 36 ml of heptane added to obtain solid which was then filtered and washed with 3 ml heptane and dried to obtain 3.0 gm of the desired compound. Yield: 84.51 %.
77% With 1,8-diazabicyclo[5.4.0]undec-7-ene; 1,1'-carbonyldiimidazole In tetrahydrofuran at 20℃; for 12h;
77% Stage #1: MRE-269 With 1,1'-carbonyldiimidazole In tetrahydrofuran for 1h; Reflux; Stage #2: methanesulfonamide In tetrahydrofuran for 0.166667h; Stage #3: With 1,8-diazabicyclo[5.4.0]undec-7-ene In tetrahydrofuran for 12h;
60.5% Stage #1: MRE-269 With 1,1'-carbonyldiimidazole In tetrahydrofuran at 20℃; for 1h; Reflux; Stage #2: methanesulfonamide With 1,8-diazabicyclo[5.4.0]undec-7-ene In tetrahydrofuran at 20℃; 1.2; 2.2; 3.2 (2) Preparation of selepag: Add 55 g of tetrahydrofuran to a 100 mL reaction flask, add 3.75 g of Intermediate 3 under stirring, and stir to dissolve. Then 1.63g of N,N'-carbonyldiimidazole (CDI) was added, and after stirring for 30 minutes at room temperature, it was heated to reflux and stirred for 30 minutes. After cooling to room temperature, 0.86 g of methanesulfonamide was added, and after stirring for 10 minutes, 1.39 g of 1,8-diazabicycloundec-7-ene (DBU) was added dropwise. After the dropwise addition, it was stirred overnight at room temperature. Monitoring by TLC (ethyl acetate: methanol = 5:1), the reaction was complete. Add 30 g of water, then add 30 g of ethyl acetate for extraction, separate the phases, and dry the organic phase with 7.50 g of anhydrous magnesium sulfate for 1 hour. After drying, the magnesium sulfate was removed by filtration, and the filtrate was transferred to a 100 mL 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, 2.5 g of crude product is obtained. Add 10 g of ethyl acetate to the above flask, add 15 g of anhydrous ethanol, heat to reflux to dissolve, then cool to 0-10°C to crystallize, filter,The filter cake was dried at 55-60°C for 10 hours to obtain 2.68 g of light yellow selepag product with a yield of 60.5%. HPLC inspection: the purity is 99.4%.
52% Stage #1: MRE-269 With 1,1'-carbonyldiimidazole In tetrahydrofuran for 1h; Reflux; Stage #2: methanesulfonamide With 1,8-diazabicyclo[5.4.0]undec-7-ene In tetrahydrofuran at 0 - 5℃; 5 Example 5 Preparation of Compound selexipag 7.1 g of compound 4 was dissolved in 120 mL of THF, 8.15 g of CDI was added, the temperature was raised to reflux for 1 h, the temperature was lowered to 0-5 ° C., DBU 7.65 mL was added, the temperature was kept stable, methanesulfonamide 5 g,The reaction was allowed to stand overnight until TLC no longer changed. The reaction solution was poured into 30mL 4M hydrochloric acid, then add 40mL ethyl acetate, stirred evenly and then liquid separation, the organic phase washed with water three times (30mL * 3), liquid separation, the organic phase was dried over anhydrous sodium sulfate, after 3h , Filtered out sodium sulfate, the organic phase was concentrated until no liquid drops, the crude oil 10.3g, recrystallized 5 times with ethanol,Methanol once qualified 4.33g, 99.74% purity,Yield 52%.
Stage #1: MRE-269 With 1,1'-carbonyldiimidazole In tetrahydrofuran at 20℃; for 1h; Heating / reflux; Stage #2: methanesulfonamide In tetrahydrofuran at 20℃; for 0.166667h; Stage #3: With 1,8-diazabicyclo[5.4.0]undec-7-ene In tetrahydrofuran at 20℃; 84 Example 84
2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide
Under an argon atmosphere, to a solution of 300 mg of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetic acid obtained in Example 42 in 5 ml of anhydrous tetrahydrofuran, 128 mg of 1,1'-carbonyl diimidazole was added and, after stirring at room temperature for 30 minutes, the mixture was heated at reflux for 30 minutes.. After air-cooling to room temperature, 69 mg of methanesulfonamide was added.. After stirring for 10 minutes, 0.11 ml of 1,8-diazabicyclo[5.4.0.]-7-undecene was added dropwise.. After stirring at room temperature overnight, the reaction solution was diluted with water and then extracted with diethyl ether.. The extract was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure, and then the residue was purified by silica gel column chromatography to obtain 272 mg of the desired compound.
20 g Stage #1: MRE-269 With 1,1'-carbonyldiimidazole In tetrahydrofuran at 65 - 70℃; for 0.75h; Stage #2: methanesulfonamide With 1,8-diazabicyclo[5.4.0]undec-7-ene In tetrahydrofuran at 25 - 30℃; for 3h; 14 EXAMPLE-14: Preparation of 2-{4-[N-(5, 6-diphenylpyrazin-2-yl)-N- isopropyl amino] butyloxy}-N-(methylsulfonyl) acetamide The reaction mixtures of 2-{4-[N-(5, 6-diphenynylpyrazin-2-yl)-N-isopropyl amino] butyloxy} acetic acid (25 g, 59 mmol) anhydrous tetrahydrofuran (375 ml) and 1 ,1carbonyl diimidazole (12.5 g, 77 mmol) were heated to 65-70 °C and stirred for 45 min. The addition of methanesulfonamide (7.36 g, 77 mmol) and 1 ,8-diazabicyclo{5,4,0}-7-undecane (12.5 ml) were done at 25-30 °C with vigorous stirring. The reaction is maintained for 3 hr and monitor using the HPLC analysis. Then after the completion of the reaction removed THF completely, followed by the addition of water, aqueous layer was washed with MTBE then adjust the pH of the solution to 5-6 using 1 N Hydrochloric acid. The product obtained was extracted from ethyl acetate, distillation of ethyl acetate completely at below 50 °C to obtain crude 2-{4-[N- (5, 6-diphenylpyrazin-2-yl)-N-isopropyl amino] butyloxy}-N-(methylsulfonyl) acetamide. Purification of Selexipa Selexipag crude (100 g) wet solid was dissolved in Ethanol (1000.0 ml) at 25- 30 °C. heat the solution to 80 -85 °C and stir for 2 hr. The resulting solution was gradually cooled to room temperature then cooled to 0-5°C and maintained for 45-60 min. Obtained solid was filtered, washed with ethanol (100.0 ml), suck dried and dried under vacuum at 55-60°C to afford pure Selexipag.[Yield = 20 g; Purity (HPLC) = 99.7%]
272 mg Stage #1: MRE-269 With 1,1'-carbonyldiimidazole In tetrahydrofuran at 20℃; for 1h; Inert atmosphere; Reflux; Stage #2: methanesulfonamide In tetrahydrofuran at 20℃; for 0.166667h; Stage #3: With 1,8-diazabicyclo[5.4.0]undec-7-ene In tetrahydrofuran at 20℃; Reference example
Preparation of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N- (methylsulfonyl)acetamide Under an argon atmosphere, to a solution of 300 mg of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N- isopropylamino]butyloxy} acetic acid in 5 ml of anhydrous tetrahydrofuran, 128 mg of 1,1'- carbonyl diimidazole was added and, after stirring at room temperature for 30 minutes, the mixture was heated at reflux for 30 minutes. After air-cooling to room temperature, 69 mg of methanesulfonamide was added. After stirring for 10 minutes, 0.11 ml of 1,8- diazabicyclo[5.4.0.]-7-undecene was added dropwise. After stirring at room temperature overnight, the reaction solution was diluted with water and then extracted with diethyl ether. The extract was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure, and then the residue was purified by silica gel column chromatography to obtain 272 mg of the desired compound.
Stage #1: MRE-269; methanesulfonamide With dmap In dichloromethane at 20 - 30℃; for 0.25h; Stage #2: With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20 - 30℃; for 24h; 32 Example 32: Preparation of crystalline selexipag 2-{4-[N-(5,6-diphenyl pyrazin-2-yl)-N-isopropylamino]butyloxy} acetic acid (140 g) was taken in dichloromethane (2800 mL). Methane sulfonamide (71 .4g) and N, N-dimethylaminopyridine (285.6g) were added to the reaction mixture at 20-30CC for 15 minutes. To this reaction mixture 1- carbodrnde hydrochorde(31 9.2g) was added and stirred the resulting mixture at 20-30CC for 24 hours. The resu Iting mixture was cooled to 0-10CC and water (84 mL) added followed by drop wise addition of 1:1 aqueous hydrochloride (490 mL). Separated the organic layer and washed with 30% aqueous sodium chloride solution (980 mL). Distilled out the organic layer to obtain the residue and this residue was dissolved in ethyl acetate (1400 mL) and cooled to 12-18CC and washed with 4% aqueous hydrochloride solution (980 mL) followed by 20% aqueous sodium chloride solution for two times (2 x 700 mL). Extracted the product with 4% aqueous sodium carbonate solution (1750 mL) from the ethyl acetate layer. The basic aqueous layer washed twice with ethyl acetate (1260 mL). The pH of aqueous layer adjusted to 2 to 3 by using 1:1 aqueous hydrochloride (336 mL) followed by extracted with ethyl acetate (1960 mL). The ethyl acetate layer was washed twice with water (2 x 840 mL). The ethyl acetate layer was treated with activated carbon (END-PC) at 30-35CC a nd filtered through celite bed, washed the bed with ethyl acetate (140 mL). Charged the filtrates into a clean and dry round bottom flask. To the ethyl acetate layer was added n-hexane (2100 mL) at 20-30CC. Stirred the mixture at 20- 30CC for 4 hours. The obtained solid material was filtered and washed with 1:1 mixture of ethyl acetate and n-hexane (140 mL) at 20-30CC. Dried the solid compound at 50-550 under vacuum for 4 hours to get the crude selexipag (103 g).
Stage #1: MRE-269 With 1,1'-carbonyldiimidazole In tetrahydrofuran at 60 - 65℃; for 1h; Stage #2: methanesulfonamide With 1,8-diazabicyclo[5.4.0]undec-7-ene In tetrahydrofuran at 0 - 65℃; for 12h; 5; 6; 8 Reaction steps Dissolve NS-303 (10.00g) in THF (200mL), add CDI (5.71g, 1.5eq), heat up to 60-65 and react for 1h,Begin to drop to 0-5°C, add DBU (4.82mL, 1.2eq), keep the temperature stable,Methanesulfonamide (3.44g, 1.5eq) was added and reacted at 60°C-65°C for 12h. TLC tracked until the product point no longer changed. Add water (50mL) to dilute the reaction solution, then add methyl tert-butyl ether (50mL), stir well and then stand for liquid separation.The organic phase was extracted and washed with saturated brine, separated, the organic phase was dried with anhydrous sodium sulfate, sodium sulfate was filtered out, and the organic phase was concentrated until no liquid dripped out to obtain 13.51 g of crude oil.

Reference: [1]Current Patent Assignee: EAST CHINA PHARMACEUTICAL GROUP LIMITED CO LTD - CN107365275, 2017, A Location in patent: Paragraph 0061; 0062; 0063; 0064; 0065; 0066-0070
[2]Current Patent Assignee: SHANGHAI SHIJI BIOLOGICAL TECH; SEASONS BIOTECHNOLOGY TAIZHOU; SHANGHAI SEASONS BIOTECHNOLOGY - US2018/29998, 2018, A1 Location in patent: Paragraph 0076-079
[3]Current Patent Assignee: LUPIN LIMITED - WO2017/60827, 2017, A1 Location in patent: Page/Page column 12; 13
[4]Asaki, Tetsuo; Hamamoto, Taisuke; Sugiyama, Yukiteru; Kuwano, Keiichi; Kuwabara, Kenji [Bioorganic and Medicinal Chemistry, 2007, vol. 15, # 21, p. 6692 - 6704]
[5]Asaki, Tetsuo; Kuwano, Keiichi; Morrison, Keith; Gatfield, John; Hamamoto, Taisuke; Clozel, Martine [Journal of Medicinal Chemistry, 2015, vol. 58, # 18, p. 7128 - 7137]
[6]Current Patent Assignee: JIANGSU FANGSHENG PHARMACEUTICAL - CN113480484, 2021, A Location in patent: Paragraph 0027; 0029; 0030; 0032; 0033; 0035
[7]Current Patent Assignee: NANJING NMG ADDS - CN106957269, 2017, A Location in patent: Paragraph 0025; 0026
[8]Current Patent Assignee: NIPPON SHINYAKU CO LTD - EP1400518, 2004, A1 Location in patent: Page 53-54
[9]Current Patent Assignee: MEGAFINE PHARMA (P) LTD. - WO2017/42828, 2017, A2 Location in patent: Page/Page column 45-46
[10]Current Patent Assignee: HONOUR R D - WO2017/168401, 2017, A1 Location in patent: Page/Page column 11
[11]Current Patent Assignee: VIATRIS INC - WO2018/15974, 2018, A1 Location in patent: Page/Page column 39; 40
[12]Current Patent Assignee: NANJING UNIVERSITY OF SCIENCE AND TECHNOLOGY - CN112939877, 2021, A Location in patent: Paragraph 0059-0063; 0064-0066; 0069-0070
  • 9
  • [ 475085-57-5 ]
  • 2-{4-[N-{5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Stage #1: MRE-269 With chloroformic acid ethyl ester; triethylamine In tetrahydrofuran at 0℃; for 0.75h; Stage #2: With ammonia In tetrahydrofuran at 0 - 20℃; for 19h; 99 Example 99
2-{4-[N-{5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetamide
1.50 g of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetic acid was dissolved in 20 ml of anhydrous tetrahydrofuran and 0.500 ml of triethylamine was added and then 0.376 ml of ethyl chlorocarbonate was added while stirring under ice cooling. After stirring under ice cooling for 45 minutes, a solution of saturated ammonia in 20 ml of tetrahydrofuran was added, followed by stirring for one hour.. After removing an ice bath and stirring at room temperature for 18 hours, almost all of the solvent was evaporated.. The residue was combined with water and then extracted with ethyl acetate.. The extract was washed in turn with an aqueous saturated sodium hydrogen carbonate solution, 1N sodium hydroxide solution and water and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure.. The residue was washed with diethyl ether and then dried under reduced pressure to obtain 1.19 g of the desired product.
30 g Stage #1: MRE-269 With thionyl chloride at 25 - 30℃; for 5h; Stage #2: at 10 - 25℃; 17 EXAMPLE-17: Preparation of 2-{4-[(5,6-diphenyl-pyrazin-2-yl)-isopropyl- amino]-butoxy}-acetamide The thionylchloride (124.8 g, 1.048 mol) is added to {4-[(5,6-diphenyl- pyrazin-2-yl)-isopropyl-amino]-butoxy}-acetic acid (50 g, 0.1191 mol) drop wise at 25-30 °C. Stir the reaction mass for 5 hr at 25-30 °C and pour the reaction mass to ammonia solution at 10-25 °C, then extracted with toluene. Distilled out toluene completely and isolation of the product from 10-20 % ethyl acetate in heptane to obtain 2-{4-[(5,6-diphenyl-pyrazin-2-yl)-isopropyl- amino]-butoxy}-acetamide. [Yield = 30 g; Purity (HPLC) = 96%]
  • 10
  • [ 475085-57-5 ]
  • [ 70-55-3 ]
  • [ 475086-02-3 ]
YieldReaction ConditionsOperation in experiment
Stage #1: MRE-269 With 1,1'-carbonyldiimidazole In tetrahydrofuran at 20℃; for 1h; Heating / reflux; Stage #2: toluene-4-sulfonamide In tetrahydrofuran at 20℃; for 0.166667h; Stage #3: With 1,8-diazabicyclo[5.4.0]undec-7-ene In tetrahydrofuran at 20℃; 85 Example 85
2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(p-toluenesulfonyl)acetamide
To a solution of 500 mg of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetic acid obtained in Example 42 in 5 ml of anhydrous tetrahydrofuran, 214 mg of 1,1'-carbonyldiimidazole was added and, after stirring at room temperature for 30 minutes, the mixture was heated at reflux for 30 minutes.. After air-cooling to room temperature, 206 mg of p-toluenesulfonamide was added.. After stirring for 10 minutes, 0.18 ml of 1,8-diazabicyclo[5.4.0.]undec-7-ene was added dropwise.. After stirring at room temperature overnight, almost all of the solvent was evaporated under reduced pressure.. The residue was combined with water and then neutralized with 1N hydrochloric acid.. The reaction solution was extracted with ethyl acetate and dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure.. The residue was purified by silica gel column chromatography to obtain 460 mg of the desired compound.
  • 11
  • [ 475085-57-5 ]
  • [ 7803-58-9 ]
  • N-(aminosulfonyl)-2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino] butyloxy}acetamide [ No CAS ]
  • 13
  • [ 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

  • 14
  • toluene-4-sulfonic acid 5,6-diphenyl-pyrazin-2-yl ester [ No CAS ]
  • [ 475085-57-5 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: 2 h / 185 - 190 °C 2: sodium hydroxide; tetrabutylammomium bromide / water; toluene / 5 - 30 °C 3: sodium hydroxide; methanol / 2 h / Reflux
  • 15
  • 4-isopropylamino-butyric acid ethyl ester [ No CAS ]
  • [ 475085-57-5 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: lithium aluminium tetrahydride / tetrahydrofuran / -10 - 0 °C / Inert atmosphere 2: 2 h / 185 - 190 °C 3: sodium hydroxide; tetrabutylammomium bromide / water; toluene / 5 - 30 °C 4: sodium hydroxide; methanol / 2 h / Reflux
Multi-step reaction with 4 steps 1: lithium aluminium tetrahydride / tetrahydrofuran / -10 - 0 °C / Inert atmosphere 2: 24 h / 180 - 185 °C 3: sodium hydroxide; tetrabutylammomium bromide / water; toluene / 5 - 30 °C 4: sodium hydroxide; methanol / 2 h / Reflux
Multi-step reaction with 5 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 4: sodium hydroxide; tetrabutylammomium bromide / water; toluene / 5 - 30 °C 5: sodium hydroxide; methanol / 2 h / Reflux
  • 16
  • 4-[(5,6-diphenyl-pyrazin-2-yl)-isopropyl-amino]-butyric acid ethyl ester [ No CAS ]
  • [ 475085-57-5 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: sodium hydroxide; water / ethanol / 4.17 h / 20 - 50 °C 2: lithium aluminium tetrahydride / tetrahydrofuran / 10 h / 0 - 20 °C / Inert atmosphere 3: sodium hydroxide; tetrabutylammomium bromide / water; toluene / 5 - 30 °C 4: sodium hydroxide; methanol / 2 h / Reflux
  • 17
  • 4-[(5,6-diphenyl-pyrazin-2-yl)-isopropyl-amino]-butyric acid [ No CAS ]
  • [ 475085-57-5 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: lithium aluminium tetrahydride / tetrahydrofuran / 10 h / 0 - 20 °C / Inert atmosphere 2: sodium hydroxide; tetrabutylammomium bromide / water; toluene / 5 - 30 °C 3: sodium hydroxide; methanol / 2 h / Reflux
  • 19
  • (5,6-diphenyl-pyrazin-2-yl)-isopropyl-amine [ No CAS ]
  • [ 475085-57-5 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 0.58 h / 80 °C 1.2: 15 - 20 °C 2.1: sodium hydroxide; tetrabutylammomium bromide / water; toluene / 5 - 30 °C 3.1: sodium hydroxide; methanol / 2 h / Reflux
  • 20
  • [ 18591-57-6 ]
  • [ 475085-57-5 ]
  • 21
  • [ 475085-57-5 ]
  • Selexipag [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: thionyl chloride / 5 h / 25 - 30 °C 1.2: ammonia solution / 10 - 25 °C 2.1: sodium hydride / tetrahydrofuran / 0.33 h 2.2: 3 h / 0 - 25 °C
  • 22
  • [ 103-29-7 ]
  • [ 475085-57-5 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1: sodium hydroxide / methanol / 10 - 15 °C 2: trichlorophosphate / 20 °C / Reflux 3: 170 - 195 °C 4: tetra(n-butyl)ammonium hydrogensulfate; potassium hydroxide / toluene; water / 0 - 25 °C 5: sodium hydroxide; water / methanol / 2 h / Reflux
  • 23
  • [ 18591-57-6 ]
  • [ 475085-57-5 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: trichlorophosphate / 20 °C / Reflux 2: 170 - 195 °C 3: tetra(n-butyl)ammonium hydrogensulfate; potassium hydroxide / toluene; water / 0 - 25 °C 4: sodium hydroxide; water / methanol / 2 h / Reflux
Multi-step reaction with 3 steps 1: phosphorus(V) oxybromide / acetonitrile / 30 h / 70 °C 2: potassium iodide; potassium carbonate / 1,4-dioxane / 12 h / 40 - 45 °C 3: potassium <i>tert</i>-butylate / acetonitrile / 14 h / 10 °C
  • 24
  • [ 475085-57-5 ]
  • 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide isopropylamine [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: 1,1'-carbonyldiimidazole / tetrahydrofuran / 1 h / 20 °C / Inert atmosphere; Reflux 1.2: 0.17 h / 20 °C 1.3: 20 °C 2.1: Isopropyl acetate / 1 h / 90 - 95 °C
  • 25
  • [ 475085-57-5 ]
  • 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide N-methylmorpholine [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: 1,1'-carbonyldiimidazole / tetrahydrofuran / 1 h / 20 °C / Inert atmosphere; Reflux 1.2: 0.17 h / 20 °C 1.3: 20 °C 2.1: Isopropyl acetate / 1 h / 90 - 95 °C
  • 26
  • [ 475085-57-5 ]
  • 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide diisopropylethylamine [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: 1,1'-carbonyldiimidazole / tetrahydrofuran / 1 h / 20 °C / Inert atmosphere; Reflux 1.2: 0.17 h / 20 °C 1.3: 20 °C 2.1: Isopropyl acetate / 1 h / 90 - 95 °C
  • 27
  • [ 475085-57-5 ]
  • 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide tri-n-butylamine [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: 1,1'-carbonyldiimidazole / tetrahydrofuran / 1 h / 20 °C / Inert atmosphere; Reflux 1.2: 0.17 h / 20 °C 1.3: 20 °C 2.1: Isopropyl acetate / 1 h / 90 - 95 °C
  • 28
  • [ 101727-15-5 ]
  • [ 475085-57-5 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: 8 h / 100 - 190 °C 2.1: tetra(n-butyl)ammonium hydrogensulfate / toluene / 0.17 h / 0 - 5 °C 2.2: 0.17 h 3.1: sodium hydroxide / methanol / 40 °C / Reflux
Multi-step reaction with 3 steps 1: 4 h / 170 °C / Inert atmosphere 2: sodium hydroxide; cetyltrimethylammonim bromide / toluene; water / 5 h / 5 °C 3: lithium hydroxide; water / ethanol / 2 h / 0 °C
  • 29
  • [ 475085-57-5 ]
  • 2-[4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy]-N-(methylsulfonyl)acetamide o-xylene [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: dmap / dichloromethane / 0.25 h / 20 - 30 °C 1.2: 24 h / 20 - 30 °C 2.1: 16 h / -20 - 70 °C
  • 30
  • [ 475085-57-5 ]
  • selexipag anisole [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: dmap / dichloromethane / 0.25 h / 20 - 30 °C 1.2: 24 h / 20 - 30 °C 2.1: 70 °C
  • 31
  • [ 475085-57-5 ]
  • 2-[4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy]-N-(methylsulfonyl)acetamide chlorobenzene [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: dmap / dichloromethane / 0.25 h / 20 - 30 °C 1.2: 24 h / 20 - 30 °C 2.1: 70 °C
  • 32
  • [ 475085-57-5 ]
  • 2-[4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy]-N-(methylsulfonyl)acetamide toluene [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: dmap / dichloromethane / 0.25 h / 20 - 30 °C 1.2: 24 h / 20 - 30 °C 2.1: 70 °C
  • 33
  • [ 475085-57-5 ]
  • C26H32N4O4S*C6H5NO2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: dmap / dichloromethane / 0.25 h / 20 - 30 °C 1.2: 24 h / 20 - 30 °C 2.1: 70 °C
  • 34
  • [ 475085-57-5 ]
  • C26H32N4O4S*C6H4Cl2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: dmap / dichloromethane / 0.25 h / 20 - 30 °C 1.2: 24 h / 20 - 30 °C 2.1: 75 - 80 °C
  • 35
  • [ 475085-57-5 ]
  • [ 3144-09-0 ]
  • [ 100-66-3 ]
  • selexipag anisole [ No CAS ]
YieldReaction ConditionsOperation in experiment
Stage #1: MRE-269; methanesulfonamide With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20 - 25℃; Stage #2: methoxybenzene at 60℃; 31 Example 31: Preparation of Form V of selexipag 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino] butyloxy} acetic acid (formula III, 100 g)was dissolved in dichloromethane (2000 mL). Methane sulfonamide (51 g), 4-dimethylamino pyridine (204g), and carbodHmde (228 g) were added and the reaction rnxture was stirred at 20-25 C for 15-2Ohours. After cornpeUori of the reacUon, 15% aqueous hydrochohc acd (300 mL) was added to the reaction mxture and the organic and aqueous ayers were separated. The orgaric ayer was concentrated under reduced pressure to get an oHy residue which was then dssoved n ethy acetate (1 000 L), The product was then extracted wth water. The pH of the aqueous extracUon souUon was then adjusted to 10-11 usrig 75 g sodurn carbonate, then extracted with ethy acetate. The aqueous ayer was then acdfied usng aqueous hydrochore acd and the product was extracted with ethy’ acetate. The eombned ethy’ acetate ayers were washed with water and 10% brine souton. The organic ayer was concentrated under reduced pressure to get an ofly residue, which was dssoved n ansoe (500 rnL) at 60 0, cooed and seeded (2%)wth the anso e sovate of selexipag.The reaction rnxture was stirred at 20-25 C for lOhours, after wheh methyl tert-butylether (700 mL) was added, the reaction mixture was cooled to 0-5CC, and stirred for 5hours. The solution was filtered and the obtained solid was washed with methyl tert-butyl ether. The wet cake was dried at reduced pressure at 20-25 CC to obtain the title compound.
  • 36
  • [ 243472-70-0 ]
  • [ 475085-57-5 ]
  • 37
  • [ 39099-23-5 ]
  • [ 475085-57-5 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: potassium iodide / 16 h / 150 °C 2: tetra(n-butyl)ammonium hydrogensulfate; potassium hydroxide / 20 h / Cooling with ice; Heating 3: sodium hydroxide / tetrahydrofuran / Reflux
  • 38
  • [ 475085-57-5 ]
  • [ 3984-14-3 ]
  • [ 475086-22-7 ]
YieldReaction ConditionsOperation in experiment
42% Stage #1: MRE-269 With 1,1'-carbonyldiimidazole In tetrahydrofuran for 1h; Inert atmosphere; Reflux; Stage #2: N,N-dimethylsulfamide With 1,8-diazabicyclo[5.4.0]undec-7-ene In tetrahydrofuran for 1h; Inert atmosphere; 3 Preparation Example 3 preparation of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butoxy}-N-(dimethylaminosulfonyl)acetamid Under the protection of nitrogen, 2-{4-[N-(5,6-Diphenylpyrazin-2-yl)-N-isopropylamino]butoxy}acetic acid (419 mg, 1.00 mmol) and N,N'-carbonyldiimidazole (CDI) (178 mg, 1.10 mmol) was dissolved in 5mL Anhydrous tetrahydrofuran, heated to reflux for 1 h, After cooling, dimethylaminosulfonamide (124 mg, 1.00 mmol) was added, and after stirring for 1 h, (DBU) (0.15 mL, 1.00 mmol) was added dropwise and allowed to react at room temperature overnight. The reaction mixture was poured into 1N HCl and extracted with EtOAc. EtOAc EtOAc. Drying 220 mg of yellow solid 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butoxy}-N-(dimethylamino)sulfonyl acetamide, yield: 42.0%
  • 39
  • Selexipag [ No CAS ]
  • [ 475085-57-5 ]
YieldReaction ConditionsOperation in experiment
208.3 g With water; sodium hydroxide In isopropyl alcohol 2 Reference Example 2: Production of Compound B To a suspension of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide (see, for example, PTL 1) (300 g) in isopropyl alcohol (1425 mL), an aqueous sodium hydroxide solution (a solution obtained by dissolving sodium hydroxide (120.8 g) in water (570 mL)) was added. After stirring was performed at 100° C. for 11 hours, the resulting mixture was cooled to 10° C. or lower. After concentrated hydrochloric acid was added dropwise thereto, stirring was performed at 10° C. or lower for 1 hour, the resulting precipitate was filtered and washed with an appropriate amount of a 50% aqueous isopropyl alcohol solution, water, and acetonitrile. The precipitate was dried at 65° C. under reduced pressure, whereby a target compound (208.3 g) was obtained.
  • 40
  • (5,6-diphenyl-pyrazin-2-yl)-isopropyl-amine [ No CAS ]
  • 2-(4-chlorobutoxy)ethanoic acid [ No CAS ]
  • [ 475085-57-5 ]
YieldReaction ConditionsOperation in experiment
62% With potassium <i>tert</i>-butylate In acetonitrile at 10℃; for 14h; 4; 7 Add acetonitrile (60mL, 4V), NS-302 (15.00g) and potassium tert-butoxide (16.32g) into a 250mL three-necked flask, stir and mix well, and water bath at 10°C.Control the temperature to be lower than 10°C, and slowly drop the acetonitrile solution of 2-(4-chlorobutoxy)acetic acid into the reaction system.The reaction was heated and stirred at the same temperature for 14 h, and the end of the reaction was monitored by TLC.The insoluble matter was filtered out, half of the acetonitrile was removed and the reaction mixture was cooled to room temperature, and the liquid was diluted with water to dissolve.Slowly add dilute hydrochloric acid dropwise until all the light yellow solids are precipitated, adjust the pH of the system to 2, and filter to obtain the solid and directly recrystallize with ethanol to obtain 14.09 g of a yellow powder solid.The yield is about 62%.
  • 41
  • [ 134-81-6 ]
  • [ 475085-57-5 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: sodium hydroxide / methanol / 12 h / 10 - 70 °C 2: phosphorus(V) oxybromide / acetonitrile / 30 h / 70 °C 3: potassium iodide; potassium carbonate / 1,4-dioxane / 12 h / 40 - 45 °C 4: potassium <i>tert</i>-butylate / acetonitrile / 14 h / 10 °C
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