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CAS No. :1253955-19-9 MDL No. :MFCD30532784
Formula : C33H35N3O5 Boiling Point : -
Linear Structure Formula :- InChI Key :-
M.W : 553.65 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 [ 1253955-19-9 ]

[ 1253955-19-9 ] Synthesis Path-Downstream   1~9

  • 1
  • [ 23687-26-5 ]
  • (S)-3-((tert-butoxycarbonyl)amino)-2-(4-(((2,4-dimethylbenzoyl)oxy)methyl)phenyl)propanoic acid [ No CAS ]
  • [ 1253955-19-9 ]
YieldReaction ConditionsOperation in experiment
55.3% With 2,2,2-trichloro-1,1-dimethylethoxychloroformate; In N,N-dimethyl-formamide; at 0 - 10℃; for 1h; A mixture of 2 (340.41 g assay-corrected, 1.0 equiv.), collidine (1.3 equiv.) and <strong>[23687-26-5]6-aminoisoquinoline</strong> (1.3 equiv.) in DMF at 0°C in a 50 L reactor was treated rapidly with a solution of 2,2,2-trichloro-l,l-dimethylethyl chloro formate (1.3 equiv.) in DMF in a single portion. The reaction was exothermic, with a rise in temperature to about 10°C. Upon stirring for a minimum of 60 minutes, the reaction was assayed by TLC and deemed complete when two samples taken one hour apart showed no further conversion. The reaction was quenched by the addition of 10percent KHC03 (aq.), followed by diluting with ethyl acetate, washing with citric acid, a final 10percent KHC03 (aq.) wash and concentrating to near dryness to afford a crude residue. The crude residue was dissolved in dichloromethane/ethyl acetate (1 : 1) and the resulting solution returned to the 50 L reactor, where it was stirred for 4.5 h. The resulting solution was filtered through a 10 muetaiota Teflon filter to remove a colloidal solid. The selection of a 10 muiotaeta Teflon filter was based on the filter having enough surface area and being chemically compatible with the dichloromethane/ethyl acetate (1 : 1) solvent mixture. Concentration of the filtrate in vacuo yielded 666.3 g of crude material. The resulting crude product was diluted with dichloromethane to give a solution that was divided into two portions for silica gel chromatography. The splitting of the dichloromethane solution maintained a 25 : 1 ratio of silica gel to crude product found to be useful for successful purification. The two portions of dichloromethane solution represented 166.5 g and 170.2 g of the crude product respectively. The purifications were achieved through the use of two 5 kg silica gel columns eluting with ethyl acetate/heptane (60:40) until the desired product had eluted. Fractions containing a high concentration of the desired material, irrespective of the impurities content, were combined and concentrated to afford 363.3 g of an off-white solid. The off- white solid was dissolved in dichloromethane and filtered through a 10 muiotaeta Teflon filter. The bulk of the solvent was then distilled off and the remainder gradually switched to acetonitrile via chase distillation. At this point, a white solid crystallized and the mixture was cooled to 0 ± 5°C. The solid was isolated by filtration and dried to obtain 333.7 g of a white solid. A sample of the solid was subjected to TLC and HPLC purity analyses. No impurities could be detected by TLC, but the HPLC analysis showed the presence of an unspecified impurity at a level of 0.46percent while all identified impurities were below In-Process Action Levels. A first recrystallization from dichloromethane/heptane was then implemented. After dissolving the solid in dichloromethane, heptane was added and the resulting mixture stirred for 4 h at room temperature. A white solid crystallized out. The solid was filtered and dried to obtain 307.0 g of the solid. A sample of the solid was taken and subjected to TLC and HPLC purity analyses. No impurities could be detected by TLC, but the HPLC analysis showed the presence of the same unspecified impurity, but was reduced to a level of 0.28percent. [00125] A second recrystallization was employed. After dissolving the solid in dichloromethane, heptane was added and the resulting mixture stirred for 3.5 h at room temperature. A white solid crystallized out. The solid was filtered and dried to obtain 288.5 g of the solid, which was subjected to HPLC purity analysis. Again, the HPLC analysis showed the presence of the same unspecified impurity, this time reduced to a level of 0.16percent. A third recrystallization was implemented similarly to the first two. After dissolving the solid in dichloromethane, heptane was added and the resulting mixture stirred for 4 h at room temperature. A white solid crystallized out. The white solid was filtered and dried to obtain the title compound as a white solid (272.1 g; 60.5percent assay-corrected yield. A fourth recrystallization from dichloromethane/heptane was utilized. After dissolving the solid in dichloromethane, heptane was added and the resulting mixture stirred for 4 h at room temperature during which time a white solid crystallized out. The white solid was filtered, dried, and subjected to HPLC purity testing. The impurity was detected at less than 0.05percent. The fourth recrystallization from dichloromethane/heptane yielded 250.9 g (55.3percent assay corrected yield) of the title compound as a white solid. To achieve even higher purities of the desired product, it may be useful to implement additional recrystallizations. 1H NMR (500 MHz, d6-OMSO) delta 1.32 (s, 9 H), 2.29 (s, 3 H), 2.49 (s, 3 H), 3.3 (m, 1 H), 3.56 (m, 1 H), 4.11 (m, 1 H), 5.25 (s, 2 H), 7.02 (bt, J= 5.4 Hz, 1 H), 7.07 (d, J= 8.4 H, 1 H), 7.11 (s, 1 H), 7.43 (s, 4 H), 7.68 (m, 2 H), 7.75 (d, J= 7.9 Hz, 1 H), 8.02 (d, J= 8.7 Hz, 1 H), 8.38 (s, 1 H), 8.39 (d, J= 5.7 Hz, 1 H), 9....
55.3% With 2,2,2-trichloro-1,1-dimethylethoxychloroformate; In 2,4,6-trimethyl-pyridine; N,N-dimethyl-formamide; for 1h; A mixture of 2 (340.41 g assay-corrected, 1.0 equiv.), collidine (1.3 equiv.) and <strong>[23687-26-5]6-aminoisoquinoline</strong> (1.3 equiv.) in DMF at 0° C. in a 50 L reactor was treated rapidly with a solution of 2,2,2-trichloro-1 , 1 -dimethylethyl chloroformate (1.3 equiv.) in DMF in a single portion. The reaction was exothermic, with a rise in temperature to about 10° C. Upon stirring for a minimum of 60 minutes, the reaction was assayed by TLC and deemed complete when two samples taken one hour apart showed no further conversion. Thereaction was quenched by the addition of 10percent KHCO3 (aq.), followed by diluting with ethyl acetate, washing with citric acid, a final 10percent KHCO3 (aq.) wash and concentrating to near dryness to afford a crude residue.The crude residue was dissolved in dichloromethane/ethylacetate (1:1) and the resulting solution returned to the 50 Lreactor, where it was stirred for 4.5 h. The resulting solution was filtered through a 10 jim Teflon filter to remove a colloidal solid. The selection of a 10 jim Teflon filter was based on the filter having enough surface area and beingchemically compatible with the dichloromethane/ethyl acetate (1:1) solvent mixture. Concentration of the filtrate in vacuo yielded 666.3 g of crude material.The resulting crude product was diluted with dichloromethane to give a solution that was divided into two portions for silica gel chromatography. The splitting of the dichloromethane solution maintained a 25:1 ratio of silicagel to crude product found to be useful for successful 41Fractions containing a high concentration of the desired material, irrespective of the impurities content, were combined and concentrated to afford 363.3 g of an off-white solid.The off-white solid was dissolved in dichloromethane and filtered through a 10 tm Teflon filter. The bulk of the solvent was then distilled off and the remainder gradually switched to acetonitrile via chase distillation. At this point, a white solid crystallized and the mixture was cooled to 0±5° C. Thesolid was isolated by filtration and dried to obtain 333.7 g ofa white solid. A sample of the solid was subjected to TLCand HPLC purity analyses. No impurities could be detected by TLC, but the HPLC analysis showed the presence of an unspecified impurity at a level of 0.4 6percent while all identified impurities were below In-Process Action Levels.A first recrystallization from dichloromethane/heptane was then implemented. Afier dissolving the solid in dichloromethane, heptane was added and the resulting mixture stirred for 4 hat room temperature. A white solid crystallized out. The solid was filtered and dried to obtain 307.0 g of the solid. A sample of the solid was taken and subjected to TLC and HPLC purity analyses. No impurities could be detected by TLC, but the HPLC analysis showed the presence of the same unspecified impurity, but was reduced to a level of0.28percent.2025purification. The two portions of dichloromethane solution represented 166.5 g and 170.2 g of the crude product respectively. The purifications were achieved through theuse of two 5 kg silica gel colunms eluting with ethyl acetate/heptane (60:40) until the desired product had eluted.white solid was filtered and dried to obtain the title compound as a white solid (272.1 g; 60.5percent assay-correctedA fourth recrystallization from dichloromethane/heptane was utilized. After dissolving the solid in dichloromethane, heptane was added and the resulting mixture stirred for 4 h at room temperature during which time a white solid crystallized out. The white solid was filtered, dried, and sub-jected to HPLC purity testing. The impurity was detected at less than 0.05percent. The fourth recrystallization from dichloromethane/heptane yielded 250.9 g (55.3percent assay corrected yield) of the title compound as a white solid.To achieve even higher purities of the desired product, it may be useful to implement additional recrystallizations. ?H NMR (500 MHz, d5-DMSO) oe 1.32 (s, 9H), 2.29 (s, 3H), 2.49 (s, 3H), 3.3 (m, 1H), 3.56 (m, 1H), 4.11 (m, 1H), 5.25 (s, 2H), 7.02 (bt, J=5.4 Hz, 1H), 7.07 (d, J=8.4H, 1H), 7.11(s, 1H), 7.43 (s, 4H), 7.68 (m, 2H), 7.75 (d, J=7.9 Hz, 1H),8.02 (d, J=8.7 Hz, 1H), 8.38 (s, 1H), 8.39 (d, J=5.7 Hz, 1H),9.14 (s, 1H). 13C NMR (125 MHz, d5-DMSO) oe 20.8, 21.2,28.2, 42.9, 51.7, 65.6, 77.8, 113.1, 120.0, 121.0, 125.0,126.1, 126.6, 128.0, 128.1, 128.5, 130.4, 132.3, 135.2,136.1, 137.8, 139.5, 140.4, 142.4, 143.2, 151.5, 155.8,166.4, 171.0. LC-MS (ES+): mlz=554 (M+1), 576 (M+23).yield).
47% With 2,4,6-trimethyl-pyridine; 2,2,2-trichloro-1,1-dimethylethoxychloroformate; In N,N-dimethyl-formamide; at 0℃; for 2h;Inert atmosphere; To (S)-3-[(tert-butoxycarbonyl)amino)]-2-(4-[(2,4-dimethylbenzoyl) oxy]methyl}phenyl)propanoic acid (8) (2.3 g, 5.5 mmol) in DMF (33 mL) cooled to 0 °C was added <strong>[23687-26-5]6-aminoisoquinoline</strong> (1.0 g, 7.1 mmol) and 2,4,6-trimethylpyridine (947 muL, 7.1 mmol). After 10 min at 0 °C, a solution of 2,2,2-trichloro-1,1-dimethylethyl chloroformate (1.7 g, 7.1 mmol) in DMF (8.6 mL) was added and the reaction stirred at 0 °C for 2 h. The mixture was poured into NaHCO3 (sat.)/EtOAc and extracted with EtOAc. The organic layers were then washed with NaCl (sat.), dried (Na2SO4) filtered and evaporated. Column chromatography (70percent EtOAc/hexanes) gave pure (S)-4-{3-[(tert-butoxycarbonyl) amino]-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl}benzyl 2,4-dimethylbenzoate (9) (1.93 g, 63percent, 98percent ee) as a off-white solid. Recrystallization from EtOAc/hexanes gave 9 (1.43 g, 47percent, 99.7percent ee, S,SWhelk-01) as a off-white crystalline solid. Mp 155-156 °C. IR (ATR): 1713, 1644, 1527 cm-1. 1H NMR (500 MHz, DMSO-d6): delta = 9.14 (s, 1H), 8.39 (d, J = 5.7 Hz, 1H), 8.38 (s, 1H), 8.02 (d, J = 8.7 Hz, 1H), 7.75 (d, J = 7.9 Hz, 1H), 7.69- 7.66 (m, 2 H), 7.43 (s, 4 H), 7.11 (s, 1H), 7.07 (d, J = 8.4 Hz, 1H), 7.02 (br t, J = 5.4 Hz, 1H), 5.25 (s, 2 H), 4.13-4.10 (m, 1H), 3.58-3.53 (m, 1H), 3.34-3.30 (m, 1H), 2.49 (s, 3 H), 2.29 (s, 3 H), 1.32 (s, 9 H). 13C NMR (125 MHz, DMSO-d6): delta = 171.0, 166.4, 155.8, 151.5, 143.2, 142.4, 140.4, 139.5, 137.8, 136.1, 135.2, 132.3, 130.4, 128.5, 128.1, 128.0, 126.6, 126.1, 125.0, 121.0, 120.0, 113.1, 77.8, 65.6, 51.7, 42.9, 28.2, 21.2, 20.8. LC-MS (ES+): m/z = 554 [M + 1]+, 576 [M + 23]+. Anal Calcd for C33H35N3O5: C, 71.59; H, 6.37; N, 7.59. Found: C, 71.54; H, 6.51; N, 7.58.
  • 2
  • [ 75-75-2 ]
  • [ 1253955-19-9 ]
  • [ 1422144-42-0 ]
YieldReaction ConditionsOperation in experiment
93% In dichloromethane at 20℃; for 22h; Inert atmosphere; (S)-4-[3-Amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl]benzyl 2,4-Dimethylbenzoate Dimesylate (10) To (S)-4-{3-[(tert-butoxycarbonyl)amino]-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl}benzyl 2,4-dimethylbenzoate (9) (1.0 g, 1.81 mmol, 99.7 % ee) in CH2Cl2 (8.1 mL) was added methanesulfonic acid (293 μL, 4.52 mL) and the solution was stirred for 22 h at room temperature. The solvents were evaporated and the residue was recrystallized with isopropanol to give pure (S)-4-[3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl]benzyl 2,4-dimethylbenzoate dimesylate (10) (1.1 g, 93%, >99% ee, Chiralpak AS-H) as a off-white crystalline solid. Mp 122-135 °C; [α]D -175 (c 1.0, H2O). IR (ATR): 1708, 1645, 1613, 1563 cm-1. 1H NMR (500 MHz, MeOD): δ = 9.49 (s, 1H), 8.73 (s, 1H), 8.39 (d, J = 6.7 Hz, 1H), 8.34 (d, J = 9.1Hz, 1H), 8.21 (d, J = 6.7 Hz, 1H), 8.00 (dd, J = 3.0, 9.0 Hz, 1H), 7.73 (d, J = 8.1Hz, 1H), 7.53 (dd, J = 8.4, 14.9 Hz, 4 H), 7.03 (s, 1H), 6.99 (d, J = 8.1Hz, 1H), 4.89 (s, 2 H), 4.35 (dd, J = 5.5, 8.7 Hz, 1H), 3.70 (dd, J = 8.9, 12.8 Hz, 1H), 3.34 (dd, J = 5.4, 12.9 Hz, 1H), 2.79 (s, 6 H), 2.46 (s, 3 H), 2.28 (s, 3 H). 13C NMR (125 MHz, MeOD): δ = 172.2, 168.6, 147.5, 146.7, 144.2, 141.9, 141.4, 138.6, 136.5, 133.4, 132.9, 132.4, 131.8, 130.3, 129.6, 127.55, 127.53, 127.46, 125.5, 125.3, 114.9, 66.8, 51.5, 42.8, 39.6, 21.9, 21.3. LC-MS (ES+): m/z = 454 [M + 1 (- 2 CH4O3S)]+, 476 [M + 23 (- 2 CH4O3S)]+. Anal Calcd for C28H27N3O3.2CH4O3S·H2O: C, 54.29; H, 5.62; N, 6.33; S, 9.66. Found: C, 54.04; H, 5.57; N, 6.21; S, 9.77.
90.3% In dichloromethane at 20℃; for 50h; Reflux; 7 (S)-4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4- dimethylbenzoate dimethanesulfonate (1): A solution of 3 (242.68 g assay-corrected, 1.0 equiv.) in dichloromethane was treated with methanesulfonic acid (2.5 equiv.) and allowed to stir for 48 h at room temperature. The reaction mixture was then heated to reflux for 2 h. Completion of the reaction was ascertained by TLC assay. A gradual solvent switch from dichloromethane to isopropanol was then carried out. The bulk of the dichloromethane solvent was removed by distillation at 45°C under low vacuum (200-400 mm Hg). Addition of isopropanol, followed by low vacuum distilling at 60°C until 10 volumes of distillate had been collected led to the removal of residual dichloromethane. A second portion of IPA was added and the volume adjusted by low vacuum distilling at 60°C to the initial volume of the reaction mixture. Upon cooling to 20 ± 5°C and stirring for 9 h at this temperature, the dimesylate salt was isolated as a solid by filtration on a 30 micron Teflon filter housed in a filtration reactor under mechanical stirring and a stream of nitrogen. After rinsing with heptane, the resulting pasty solid was transferred to a drying dish and subsequently to a vacuum oven pre-heated at 69°C. After 24.5 h of drying under vacuum, the solid was ground in a glass mortar and pestle. The resulting free flowing solid was submitted for impurity analysis, and the solid met all purity specifications. The solid was further dried under vacuum at 69°C for 96 h to remove residual isopropanol. The solid subsequently met both isopropanol and water content specifications. The title compound was obtained as a white solid (258.7 g; 90.3% assay-corrected yield). 1H NMR (500 MHz, MeOD) δ 2.28 (s, 3 H), 2.46 (s, 3 H), 2.79 (s, 6 H), 3.34 (dd, J= 5.4, 12.9 Hz, 1 H), 3.70 (dd, J= 8.9, 12.8 Hz, 1 H), 4.35 (dd, J= 5.5, 8.7 Hz, 1 H), 4.89 (s, 2 H), 6.99 (d, J= 8.1 Hz, 1 H), 7.03 (s, 1 H), 7.53 (dd, J= 8.4, 14.9 Hz, 4 H), 7.73 (d, J= 8.1 Hz, 1 H), 8.00 (dd, J= 3.0, 9.0 Hz, 1 H), 8.21 (d, J= 6.7 Hz, 1 H), 8.34 (d, J= 9.1 Hz, 1 H), 8.39 (d, J= 6.7 Hz, 1 H), 8.73 (s, 1 H), 9.49 (s, 1 H). 13C NMR (125 MHz, MeOD) δ 21.3, 21.9, 39.6, 42.8, 51.5, 66.8, 114.9, 125.3, 125.4, 125.7, 127.5, 129.6, 130.3, 131.7, 131.8, 132.4, 132.9, 133.4, 136.5, 138.6, 141.4, 141.9, 144.2, 146.7, 147.5, 168.6, 172.2. Chiral LC (>99% ee, Chiralpak AS-H). LC-MS (ES+): m/z = 454 (M+l), 476 (M+23). 1H NMR (500 MHz, d6-DMSO) δ 2.28 (s, 3 H), 2.38 (s, 6 H), 2.46 (s, 3 H), 3.13 (0293) (m, 1 H), 3.59 (m, 1 H), 4.24 (dd, J= 5.2, 8.9 Hz, 1 H), 5.28 (s, 2 H), 7.08 (d, J= 8.07 Hz, 1 H), 7.11 (s, 1 H), 7.48 (s, 4 H), 7.74 (d, J= 7.9 Hz, 1 H), 7.99 (m, 4 H), 8.35 (d, J= 6.5 Hz, 1 H), 8.45 (d, J= 9.1 Hz, 1 H), 8.55 (d, J= 6.6 Hz, 1 H), 8.69 (s, 1 H), 9.68 (s, 1 H). 13C NMR (125 MHz, d6-DMSO) δ 20.9, 21.2, 40.7, 49.8, 65.4, 113.3, 123.5, 123.8, 123.9, 126.1, 126.6, 126.7, 128.1, 128.6, 130.4, 131.8, 132.2, 132.4, 135.8, 136.2, 139.6, 142.5, 145.2, 146.1, 166.4, 170.5. Chiral LC (>99% ee, Chiralpak AS-H). LC-MS (ES+): m/z = 454 (M+l), 476 (M+23).
90.3% In dichloromethane at 20℃; for 50h; Reflux; 7 : (S)-4-(3-Amino-1 -(isoquinolin-6-ylamino)-1 -oxopropan-2-yl)benzyl 2,4-dimethylben- zoate dimethanesulfonate (1) A solution of 3 (242.68 g assay-corrected, 1.0 equiv.) indichloromethane was treated with methanesulfonic acid (2.5 equiv.) and allowed to stir for 48 h at room temperature. The reaction mixture was then heated to reflux for 2 h. Completion of the reaction was ascertained by TLC assay. A gradual solvent switch from dichloromethane to isopropanol wasthen carried out. The bulk of the dichloromethane solvent was removed by distillation at 45° C. under low vacuum (200-400mm Hg). Addition of isopropanol, followed by low (s, 3H), 2.46 (s, 3H), 2.79 (s, 6H), 3.34 (dd, J=5.4, 12.9 Hz, 1H), 3.70 (dd, J=8.9, 12.8 Hz, 1H), 4.35 (dd, J=5.5, 8.7 Hz, 1H), 4.89 (s, 2H), 6.99 (d, J=8.1 Hz, 1H), 7.03 (s, 1H), 7.53 (dd, J=8.4, 14.9 Hz, 4H), 7.73 (d, J=8.1 Hz, 1H), 8.00 (dd, J=3.0, 9.0 Hz, 1H), 8.21 (d, J=6.7 Hz, 1H), 8.34 (d, J=9.1 Hz, 1H), 8.39 (d, J=6.7 Hz, 1H), 8.73 (s, 1H), 9.49 (s, 1H). 13CNMR (125 MHz, MeOD) ö 21.3, 21.9, 39.6, 42.8, 51.5,66.8, 114.9, 125.3, 125.4, 125.7, 127.5, 129.6, 130.3, 131.7,131.8, 132.4, 132.9, 133.4, 136.5, 138.6, 141.4, 141.9,144.2, 146.7, 147.5, 168.6, 172.2. Chiral LC (>99% cc, Chiralpak AS-H). LC-MS (ES+): mlz=454 (M+i), 476 (M+23).‘H NMR (500 MHz, d5-DMSO) ö 2.28 (s, 3H), 2.38 (s,6H), 2.46 (s, 3H), 3.13 (m, 1H), 3.59 (m, 1H), 4.24 (dd,J=5.2, 8.9 Hz, 1H), 5.28 (s, 2H), 7.08 (d, J=8.07 Hz, 1H),7.11 (s, 1H), 7.48 (s, 4H), 7.74 (d, J=7.9 Hz, 1H), 7.99 (m,4H), 8.35 (d, J=6.5 Hz, 1H), 8.45 (d, J=9.i Hz, 1H), 8.55 (d,J=6.6 Hz, 1H), 8.69 (s, 1H), 9.68 (s, 1H). 13C NMR (125MHz, d6-DMSO) ö 20.9, 21.2, 40.7, 49.8, 65.4, 113.3,123.5, 123.8, 123.9, 126.1, 126.6, 126.7, 128.1, 128.6,130.4, 131.8, 132.2, 132.4, 135.8, 136.2, 139.6, 142.5,145.2, 146.1, 166.4, 170.5. Chiral LC (>99% cc, ChiralpakAS-H). LC-MS (ES+): m/z=454 (M+i), 476 (M+23).**diHCl salt: ‘H NMR (300 MHz, MeOD) ö 2.25 (s,3H), 2.43 (s, 3H), 3.05 (m, 1H), 3.4 (m, 1H), 3.98 (dd, J=5.7,8.4 Hz, 1H), 5.23 (s, 2H), 6.94 (d, J=7.9 Hz, 1H), 6.98 (s,1H), 7.42 (d, J=8.4 Hz, 2H), 7.48 (d, J=8.4 Hz, 2H), 7.58 (d,J=6.0 Hz, 1H), 7.64 (dd, J=2.i, 9.0 Hz, 1H), 7.70 (d, J=8.iHz, 1H), 7.88 (d, J=9.0 Hz, 1H), 8.25 (d, J=6.0 Hz, 1H), 8.31(s, 1H), 8.98 (s, 1H). 13C NMR (75 MHz, MeOD) ö 21.3,21.9, 45.3, 55.7, 66.9, 115.3, 122.1, 122.7, 127.0, 127.5,129.4, 129.8, 129.9, 129.9, 131.8, 133.4, 137.6, 138.4,138.7, 141.4, 142.2, 143.0, 144.1, 152.3, 168.6, 173.1.Chiral LC (>95% cc, Chiralpak AS-H); LC-MS (ES+):mlz=454 (M+i).**free base: ‘H NMR (500 MHz, MeOD) ö 2.25 (s, 3H),2.44 (s, 3H), 2.98 (dd, J=5.7, 12.9 Hz, 1H), 3.35 (dd, J=8.7,12.8 Hz, 1H), 3.87 (dd, J=5.7, 8.6 Hz, 1H), 5.23 (s, 2H), 6.94(d, J=7.9 Hz, 1H), 6.98 (s, 1H), 7.42 (d, J=8.2 Hz, 2H), 7.45(d, J=8.2 Hz, 2H), 7.59 (d, J=5.9 Hz, 1H), 7.63 (d, 8.9 Hz,1H), 7.71 (d, J=7.9 Hz, 1H), 7.89 (d, J=9.i Hz, 1H), 8.25 (d,J=5.9 Hz, 1H), 8.3 (s, 1H), 8.9 (s, 1H). 13C NMR (125 MHz,MeOD) ö 21.3, 21.9, 45.9, 56.8, 66.9, 115.2, 122.0, 122.7,126.9, 127.5, 127.6, 129.3, 129.8, 129.8, 131.8, 133.4,137.3, 138.4, 139.2, 141.4, 142.2, 143.0, 144.1, 152.3,168.6, 173.5.
85% In dichloromethane at 20 - 35℃; for 27h; Inert atmosphere; 1 Synthesis of compound netadil dimethanesulfonate Dissolve compound 10 (2.5g, 4.52mmol) in 25ml of dichloromethane, add methanesulfonic acid (1.1g, 110.3mmol) under nitrogen protection, stir at room temperature for 24 hours, and then warm to 35 °C for 3 hours. TLC monitors the completion of the raw material reaction. Rotate the dichloromethane to obtain a light yellow oil, and then use isopropanol to dry the residual dichloromethane to obtain a white solid. Under the protection of nitrogen, the white solid was recrystallized with 30 ml of isopropanol, and filtered under the protection of nitrogen. The filter cake was slurried with n-heptane and dried under vacuum, then slurried with isopropanol, and dried under vacuum. The filter cake was dried in vacuum at 65°C±5°C for 24 hours to obtain the pure compound netadil dimethanesulfonate (2.3g) with a yield of 85%, a purity of 99%, and an optical purity of 99%.
2.52 g In dichloromethane at 20℃; for 15h; 10 Example 10
Preparation of Netarsudil Mesylate Form N3
To a stirred solution of (S)-4-(3-((tert-butoxycarbonyl)amino)-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate (5.0 g 1 eq.) in DCM (dichloromethane) (10 vol), methanesulfonic acid (2.5 eq) was added dropwise. The reaction mixture was stirred at room temperature over 15 h and completion of the reaction was ascertained by HPLC. A gradual solvent switch from DCM to 2-BuOH was then carried out. The solution of the DCM solvent was removed by distillation under vacuum. Next, two substantial portions of 2-BuOH were added to the residue follows by vacuum distillation. Eventually, 2-BuOH (10 vol) was added to the residue and the reaction mixture was stirred at room temperature over a period of 15 h. The dimesylate salt was isolated as a solid by filtration under nitrogen. After washing with 2-BuOH (2*1 vol) and heptane (2*1 vol), the solid was dried upon vacuum oven at 40° C. over 15 h. The compound was obtained as a white solid (2.52 g). Netarsudil mesylate form N3 has been confirmed by XRPD.

  • 6
  • tert-butyl (S)-(2-(4-(hydroxymethyl)phenyl)-3-(isoquinolin-6-ylamino)-3-oxopropyl)carbamate [ No CAS ]
  • [ 21900-42-5 ]
  • [ 1253955-19-9 ]
YieldReaction ConditionsOperation in experiment
3.9 g With triethylamine In dichloromethane at 0 - 5℃; Inert atmosphere; 1 Compound 11 (3.2 g, 7.7 mmol) and triethylamine (2 ml) were added to 20 ml of dichloromethane,Nitrogen protection,The above-prepared dichloromethane chloride solution was dropped at 0-5°C.Stir after adding,React overnight;The reaction was monitored by TLC (dichloromethane:methanol=20:1). The reaction was completed, evaporated to dryness under reduced pressure, and then stirred with a saturated sodium carbonate solution and filtered. The filter cake was washed with water 3 times and dried to give 3.9 g of a white solid. Compound 12; purity: 99.1%,
3 g With triethylamine In dichloromethane at 0 - 5℃; Inert atmosphere; 1 Add compound 9 (4.5g, 10.68mmol) and triethylamine (2ml) into 50ml of dichloromethane, under nitrogen protection, and drop the acid chloride solution of dichloromethane prepared above at 0 - 5 °C. After the addition, , Stir the reaction overnight. The reaction was monitored by TLC (dichloromethane: methanol = 10:1), and the reaction was completed. The reaction solution was quenched with 10% potassium bicarbonate and washed with 50 ml of 10% citric acid aqueous solution. Then it was washed with 50 ml of 10% potassium bicarbonate, the organic phase was dried with anhydrous sodium sulfate and spin-dried to obtain a brown oil, which was purified by column chromatography to obtain the crude compound 10. The crude compound was beaten with acetonitrile at 5-10 °C to obtain pure compound 10 (3g).
  • 7
  • [ 23687-26-5 ]
  • (S)-3-((tert-butoxycarbonyl)amino)-2-(4-(((2,4-dimethylbenzoyl)oxy)methyl)phenyl)propanoic acid [ No CAS ]
  • [ 1253955-20-2 ]
  • [ 1253955-19-9 ]
  • 8
  • [ 73401-74-8 ]
  • [ 1253955-20-2 ]
  • [ 1253955-19-9 ]
  • 9
  • [ 155380-11-3 ]
  • [ 1253955-20-2 ]
  • [ 1253955-19-9 ]
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