| 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. |
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