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Chemical Structure| 1799328-86-1
Chemical Structure| 1799328-86-1
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Product Details of [ 1799328-86-1 ]

CAS No. :1799328-86-1 MDL No. :MFCD31619274
Formula : C30H42FN5O3 Boiling Point : -
Linear Structure Formula :- InChI Key :YCXOHEXZVKOGEV-DNRQZRRGSA-N
M.W : 539.68 Pubchem ID :118169620
Synonyms :
ASTX660

Safety of [ 1799328-86-1 ]

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 [ 1799328-86-1 ]

* 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 [ 1799328-86-1 ]

[ 1799328-86-1 ] Synthesis Path-Downstream   1~33

  • 1
  • [ 1403902-78-2 ]
  • [ 1799328-86-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: potassium carbonate; potassium iodide / acetonitrile / 2 h / 20 °C / Cooling with ice 2: hydrogenchloride / 1,4-dioxane; ethyl acetate / 18 h / 20 °C 3: sodium hydrogencarbonate / water / 0.33 h / 18.2 °C / pH 7.51 / Inert atmosphere
  • 2
  • [ 1604818-07-6 ]
  • [ 1799328-86-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 10 steps 1.1: borane-THF / tetrahydrofuran / Inert atmosphere; Cooling with ice 2.1: potassium carbonate / 1-methyl-pyrrolidin-2-one / 4 h / 150 °C 3.1: lithium bromide; [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) dichloride / tetrahydrofuran; 1-methyl-pyrrolidin-2-one / 18 h / 20 °C / Inert atmosphere 4.1: NBS / N,N-dimethyl-formamide / 1 h / 5 - 20 °C 5.1: lithium methide; lithium tert-butyl / tetrahydrofuran; diethyl ether; hexane / 1 h / -78 °C 5.2: 0.83 h / -78 °C 6.1: sodium tetrahydridoborate; methanol / 0.42 h / Cooling with ice 7.1: acetonitrile / 0.5 h / 5 - 20 °C 7.2: 0.33 h / 20 °C 8.1: potassium carbonate; potassium iodide / acetonitrile / 2 h / 20 °C / Cooling with ice 9.1: hydrogenchloride / 1,4-dioxane; ethyl acetate / 18 h / 20 °C 10.1: Sodium hydrogenocarbonate / lithium hydroxide monohydrate / 0.33 h / 18.2 °C / pH 7.51 / Inert atmosphere
Multi-step reaction with 12 steps 1.1: anhydrous potassium acetate; chloro(2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1’-biphenyl)[2-(2’-amino-1,1’-biphenyl)]palladium (II); dicyclohexyl[2’,4’,6’-tris(propan-2-yl)[1,1’-biphenyl]-2-yl]phosphane / 2-methyltetrahydrofuran / 5 h / 75 °C / Inert atmosphere 2.1: 1 h / Inert atmosphere 2.2: 5 h / 60 °C / Inert atmosphere 3.1: NiCl2·6H2O; sodium tetrahydridoborate / methanol / 0 - 20 °C 4.1: Sodium hydrogenocarbonate / dimethylsulfoxide-d6 / 52 h / 120 °C 5.1: NBS / N,N-dimethyl-formamide / 1 h / -18 - -12 °C / Large scale 6.1: toluene / 0 - 25 °C / Large scale 6.2: 22 h / 15 - 25 °C / Large scale 7.1: palladium diacetate; triethylamine; 2,2'-bis(diphenylphosphino)-1,1'-binaphthalene / acetonitrile / 33 h / 55 - 65 °C / 225.02 - 375.04 Torr / Inert atmosphere; Sealed tube; Large scale 8.1: hydrogenchloride / isopropanol / 9 h / 50 - 55 °C / Large scale 9.1: lithium tetrahydridoborate / 2-methyltetrahydrofuran; tetrahydrofuran / 9 h / -10 - 0 °C / Large scale 10.1: acetonitrile / 2 h / 5 - 13 °C / Large scale 11.1: potassium carbonate; potassium iodide / acetonitrile / 3 h / 15 - 25 °C / Large scale 12.1: hydrogenchloride / 14 h / 0 - 40 °C / Large scale
Multi-step reaction with 12 steps 1.1: anhydrous potassium acetate; XPhos Pd G2; dicyclohexyl[2’,4’,6’-tris(propan-2-yl)[1,1’-biphenyl]-2-yl]phosphane / 2-methyltetrahydrofuran / 5 h / 75 °C / Inert atmosphere 2.1: potassium carbonate / 2-methyltetrahydrofuran; lithium hydroxide monohydrate / 6 h / 60 °C / Inert atmosphere 3.1: NiCl2·6H2O; sodium tetrahydridoborate; methanol / 3.5 h / 0 - 20 °C 4.1: Sodium hydrogenocarbonate / dimethyl sulfoxide / 52 h / 120 °C 5.1: NBS / N,N-dimethyl-formamide / 1 h / -18 - -12 °C / Large scale 6.1: toluene / 0 - 25 °C / Large scale 6.2: 22 h / 15 - 25 °C / Large scale 7.1: palladium diacetate; triethylamine; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl / acetonitrile / 33 h / 55 - 65 °C / 225.02 - 375.04 Torr / Inert atmosphere; Sealed tube; Large scale 8.1: hydrogenchloride / isopropanol / 9 h / 50 - 55 °C / Large scale 9.1: lithium tetrahydridoborate / 2-methyltetrahydrofuran; tetrahydrofuran / 9 h / -10 - 0 °C / Large scale 10.1: acetonitrile / 2 h / 5 - 13 °C / Large scale 10.2: 0.5 h / 0 - 5 °C / Large scale 11.1: potassium carbonate; potassium iodide / acetonitrile; methanol / 3 h / 15 - 25 °C / Large scale 12.1: hydrogenchloride / 14 h / 0 - 40 °C / Large scale
  • 3
  • [ 1799328-50-9 ]
  • [ 1799328-86-1 ]
YieldReaction ConditionsOperation in experiment
With sodium hydrogencarbonate In water at 18.2℃; for 0.333333h; Inert atmosphere; 38 Example 38: 1 -{6-[(4-Fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1 H,2H,3H- pyrrolo[3,2-b]pyridi n-I -yl}-2-[(2R,5R)-5-methyl-2-[(3R)-3-methylmorpholi n-4- yl]methyl}piperazin-I-yl]ethan-I-one (Free Base) 1 -{6-[(4-Fluorophenyl)methyl]-5-(hydroxymethyl)-3, 3-dimethyl- 1 H ,2 H, 3H-pyrrolo[3,2-b]pyridin- 1 -yl}-2-[(2R ,5R)-5-methyl-2-[(3R)-3-methylmorpholin-4-yl]methyl}piperazin- 1- yl]ethan-1-one dihydrochioride (1.OOg, 1.0 eq., 1.OOwt.) (which may be prepared as described in Example 2) was charged to a RB flask, dissolved in water (10.0 mL, 10.0 vol, 10.00 wt.) and stirred under nitrogen at 18 to 23°C to give a straw coloured solution (pH =4.73, T = 19.3°C). To the aqueous solution was added ethyl acetate (10.0 mL, 10.0 vol) andthe biphasic mixture was stirred at 18 to 23°C for 5 minutes. The layers were separated and the aqueous layer (pH = 4.58, 19.6°C) was returned to the flask. Sodium hydrogen carbonate (388.2mg, 3 x 1.05 eq., 0.4 wt.) was added (cautiously) and effervescence was observed. The mixture was stirred for 20 minutes (pH = 7.51, 18.2°C), dichloromethane (5.0 mL, 5.0 vol) was added and the mixture was stirred under the same conditions, for a further 5minutes. The layers were separated, the dichloromethane layer was retained and the aqueous layer (pH = 7.66, T = 17.7°C) was returned to the flask. Two further extractions with dichloromethane (2 x 5.0 mL, 2 x 5.0 vol) were performed (pH = 8.25, T = 18.5°C & pH = 8.47, T = 18.3°C) and the combined organic layers were dried over sodium sulfate (1 .Og, 1 .Owt.), filtered and concentrated to dryness under reduced pressure at 40°C (400mbar).The concentrate was then dried at 40°C (<2ombar) over 2 hours to give a white foam (850.2mg, 102%th., 100% corr. for input and outputw/w assays), 94.3% w/w osfb (against TCNB), that contained ethyl acetate (3.4% w/w) and dichloromethane (0.8% wlw).
  • 4
  • [ 1604818-08-7 ]
  • [ 1799328-86-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 9 steps 1.1: potassium carbonate / 1-methyl-pyrrolidin-2-one / 4 h / 150 °C 2.1: lithium bromide; [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(ll) dichloride / tetrahydrofuran; 1-methyl-pyrrolidin-2-one / 18 h / 20 °C / Inert atmosphere 3.1: N-Bromosuccinimide / N,N-dimethyl-formamide / 1 h / 5 - 20 °C 4.1: methyllithium; tert.-butyl lithium / tetrahydrofuran; diethyl ether; hexane / 1 h / -78 °C 4.2: 0.83 h / -78 °C 5.1: sodium tetrahydroborate; methanol / 0.42 h / Cooling with ice 6.1: acetonitrile / 0.5 h / 5 - 20 °C 6.2: 0.33 h / 20 °C 7.1: potassium carbonate; potassium iodide / acetonitrile / 2 h / 20 °C / Cooling with ice 8.1: hydrogenchloride / 1,4-dioxane; ethyl acetate / 18 h / 20 °C 9.1: sodium hydrogencarbonate / water / 0.33 h / 18.2 °C / pH 7.51 / Inert atmosphere
  • 5
  • [ 1604818-09-8 ]
  • [ 1799328-86-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 8 steps 1.1: lithium bromide; [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) dichloride / tetrahydrofuran; 1-methyl-pyrrolidin-2-one / 18 h / 20 °C / Inert atmosphere 2.1: NBS / N,N-dimethyl-formamide / 1 h / 5 - 20 °C 3.1: lithium methide; lithium tert-butyl / tetrahydrofuran; diethyl ether; hexane / 1 h / -78 °C 3.2: 0.83 h / -78 °C 4.1: sodium tetrahydridoborate; methanol / 0.42 h / Cooling with ice 5.1: acetonitrile / 0.5 h / 5 - 20 °C 5.2: 0.33 h / 20 °C 6.1: potassium carbonate; potassium iodide / acetonitrile / 2 h / 20 °C / Cooling with ice 7.1: hydrogenchloride / 1,4-dioxane; ethyl acetate / 18 h / 20 °C 8.1: Sodium hydrogenocarbonate / lithium hydroxide monohydrate / 0.33 h / 18.2 °C / pH 7.51 / Inert atmosphere
Multi-step reaction with 10 steps 1.1: anhydrous sodium carbonate / tetrahydrofuran; lithium hydroxide monohydrate 1.2: 24 h 2.1: anhydrous potassium acetate; dicyclohexyl[2’,4’,6’-tris(propan-2-yl)[1,1’-biphenyl]-2-yl]phosphane / 2-methyltetrahydrofuran / 0.5 h / 75 °C / Inert atmosphere 3.1: potassium carbonate / 4 h / 75 °C / Inert atmosphere 4.1: NBS; sodium chloride / N,N-dimethyl-formamide / 60.08 h / 0 - 20 °C 5.1: palladium diacetate; triethylamine; 2,2'-bis(diphenylphosphino)-1,1'-binaphthalene / acetonitrile / 33 h / 55 - 65 °C / 225.02 - 375.04 Torr / Inert atmosphere; Sealed tube; Large scale 6.1: hydrogenchloride / isopropanol / 9 h / 50 - 55 °C / Large scale 7.1: lithium tetrahydridoborate / 2-methyltetrahydrofuran; tetrahydrofuran / 9 h / -10 - 0 °C / Large scale 8.1: acetonitrile / 2 h / 5 - 13 °C / Large scale 9.1: potassium carbonate; potassium iodide / acetonitrile / 3 h / 15 - 25 °C / Large scale 10.1: hydrogenchloride / 14 h / 0 - 40 °C / Large scale
Multi-step reaction with 10 steps 1.1: anhydrous sodium carbonate / tetrahydrofuran; lithium hydroxide monohydrate / 40 h 1.2: 24 h 2.1: anhydrous potassium acetate; dicyclohexyl[2’,4’,6’-tris(propan-2-yl)[1,1’-biphenyl]-2-yl]phosphane; XPhosPd(crotyl)Cl / 2-methyltetrahydrofuran / 0.5 h / 75 °C / Inert atmosphere 3.1: potassium carbonate / 4 h / 75 °C / Inert atmosphere 4.1: NBS; sodium chloride / N,N-dimethyl-formamide / 60.08 h / 0 - 20 °C 5.1: palladium diacetate; triethylamine; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl / acetonitrile / 33 h / 55 - 65 °C / 225.02 - 375.04 Torr / Inert atmosphere; Sealed tube; Large scale 6.1: hydrogenchloride / isopropanol / 9 h / 50 - 55 °C / Large scale 7.1: lithium tetrahydridoborate / 2-methyltetrahydrofuran; tetrahydrofuran / 9 h / -10 - 0 °C / Large scale 8.1: acetonitrile / 2 h / 5 - 13 °C / Large scale 8.2: 0.5 h / 0 - 5 °C / Large scale 9.1: potassium carbonate; potassium iodide / acetonitrile; methanol / 3 h / 15 - 25 °C / Large scale 10.1: hydrogenchloride / 14 h / 0 - 40 °C / Large scale
Multi-step reaction with 9 steps 1.1: dicyclohexyl[2’,4’,6’-tris(propan-2-yl)[1,1’-biphenyl]-2-yl]phosphane; lithium bromide; palladium diacetate / 1-methyl-pyrrolidin-2-one; tetrahydrofuran / 12 h / 30 - 36 °C 2.1: NBS / N,N-dimethyl-formamide / 1 h / -18 - -12 °C / Large scale 3.1: toluene / 0 - 25 °C / Large scale 3.2: 22 h / 15 - 25 °C / Large scale 4.1: palladium diacetate; triethylamine; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl / acetonitrile / 33 h / 55 - 65 °C / 225.02 - 375.04 Torr / Inert atmosphere; Sealed tube; Large scale 5.1: hydrogenchloride / isopropanol / 9 h / 50 - 55 °C / Large scale 6.1: lithium tetrahydridoborate / 2-methyltetrahydrofuran; tetrahydrofuran / 9 h / -10 - 0 °C / Large scale 7.1: acetonitrile / 2 h / 5 - 13 °C / Large scale 7.2: 0.5 h / 0 - 5 °C / Large scale 8.1: potassium carbonate; potassium iodide / acetonitrile; methanol / 3 h / 15 - 25 °C / Large scale 9.1: hydrogenchloride / 14 h / 0 - 40 °C / Large scale

  • 6
  • [ 1403903-11-6 ]
  • [ 1799328-86-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 7 steps 1.1: NBS / N,N-dimethyl-formamide / 1 h / 5 - 20 °C 2.1: lithium methide; lithium tert-butyl / tetrahydrofuran; diethyl ether; hexane / 1 h / -78 °C 2.2: 0.83 h / -78 °C 3.1: sodium tetrahydridoborate; methanol / 0.42 h / Cooling with ice 4.1: acetonitrile / 0.5 h / 5 - 20 °C 4.2: 0.33 h / 20 °C 5.1: potassium carbonate; potassium iodide / acetonitrile / 2 h / 20 °C / Cooling with ice 6.1: hydrogenchloride / 1,4-dioxane; ethyl acetate / 18 h / 20 °C 7.1: Sodium hydrogenocarbonate / lithium hydroxide monohydrate / 0.33 h / 18.2 °C / pH 7.51 / Inert atmosphere
Multi-step reaction with 8 steps 1.1: NBS / N,N-dimethyl-formamide / 1 h / -18 - -12 °C / Large scale 2.1: toluene / 0 - 25 °C / Large scale 2.2: 22 h / 15 - 25 °C / Large scale 3.1: palladium diacetate; triethylamine; 2,2'-bis(diphenylphosphino)-1,1'-binaphthalene / acetonitrile / 33 h / 55 - 65 °C / 225.02 - 375.04 Torr / Inert atmosphere; Sealed tube; Large scale 4.1: hydrogenchloride / isopropanol / 9 h / 50 - 55 °C / Large scale 5.1: lithium tetrahydridoborate / 2-methyltetrahydrofuran; tetrahydrofuran / 9 h / -10 - 0 °C / Large scale 6.1: acetonitrile / 2 h / 5 - 13 °C / Large scale 7.1: potassium carbonate; potassium iodide / acetonitrile / 3 h / 15 - 25 °C / Large scale 8.1: hydrogenchloride / 14 h / 0 - 40 °C / Large scale
Multi-step reaction with 8 steps 1.1: NBS / N,N-dimethyl-formamide / 1 h / -18 - -12 °C / Large scale 2.1: toluene / 0 - 25 °C / Large scale 2.2: 22 h / 15 - 25 °C / Large scale 3.1: palladium diacetate; triethylamine; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl / acetonitrile / 33 h / 55 - 65 °C / 225.02 - 375.04 Torr / Inert atmosphere; Sealed tube; Large scale 4.1: hydrogenchloride / isopropanol / 9 h / 50 - 55 °C / Large scale 5.1: lithium tetrahydridoborate / 2-methyltetrahydrofuran; tetrahydrofuran / 9 h / -10 - 0 °C / Large scale 6.1: acetonitrile / 2 h / 5 - 13 °C / Large scale 6.2: 0.5 h / 0 - 5 °C / Large scale 7.1: potassium carbonate; potassium iodide / acetonitrile; methanol / 3 h / 15 - 25 °C / Large scale 8.1: hydrogenchloride / 14 h / 0 - 40 °C / Large scale
  • 7
  • [ 1799327-37-9 ]
  • [ 1799328-86-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 6 steps 1.1: lithium methide; lithium tert-butyl / tetrahydrofuran; diethyl ether; hexane / 1 h / -78 °C 1.2: 0.83 h / -78 °C 2.1: sodium tetrahydridoborate; methanol / 0.42 h / Cooling with ice 3.1: acetonitrile / 0.5 h / 5 - 20 °C 3.2: 0.33 h / 20 °C 4.1: potassium carbonate; potassium iodide / acetonitrile / 2 h / 20 °C / Cooling with ice 5.1: hydrogenchloride / 1,4-dioxane; ethyl acetate / 18 h / 20 °C 6.1: Sodium hydrogenocarbonate / lithium hydroxide monohydrate / 0.33 h / 18.2 °C / pH 7.51 / Inert atmosphere
Multi-step reaction with 7 steps 1.1: toluene / 0 - 25 °C / Large scale 1.2: 22 h / 15 - 25 °C / Large scale 2.1: palladium diacetate; triethylamine; 2,2'-bis(diphenylphosphino)-1,1'-binaphthalene / acetonitrile / 33 h / 55 - 65 °C / 225.02 - 375.04 Torr / Inert atmosphere; Sealed tube; Large scale 3.1: hydrogenchloride / isopropanol / 9 h / 50 - 55 °C / Large scale 4.1: lithium tetrahydridoborate / 2-methyltetrahydrofuran; tetrahydrofuran / 9 h / -10 - 0 °C / Large scale 5.1: acetonitrile / 2 h / 5 - 13 °C / Large scale 6.1: potassium carbonate; potassium iodide / acetonitrile / 3 h / 15 - 25 °C / Large scale 7.1: hydrogenchloride / 14 h / 0 - 40 °C / Large scale
Multi-step reaction with 7 steps 1.1: toluene / 0 - 25 °C / Large scale 1.2: 22 h / 15 - 25 °C / Large scale 2.1: palladium diacetate; triethylamine; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl / acetonitrile / 33 h / 55 - 65 °C / 225.02 - 375.04 Torr / Inert atmosphere; Sealed tube; Large scale 3.1: hydrogenchloride / isopropanol / 9 h / 50 - 55 °C / Large scale 4.1: lithium tetrahydridoborate / 2-methyltetrahydrofuran; tetrahydrofuran / 9 h / -10 - 0 °C / Large scale 5.1: acetonitrile / 2 h / 5 - 13 °C / Large scale 5.2: 0.5 h / 0 - 5 °C / Large scale 6.1: potassium carbonate; potassium iodide / acetonitrile; methanol / 3 h / 15 - 25 °C / Large scale 7.1: hydrogenchloride / 14 h / 0 - 40 °C / Large scale
  • 8
  • [ 1799327-42-6 ]
  • [ 1799328-86-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1.1: acetonitrile / 0.5 h / 5 - 20 °C 1.2: 0.33 h / 20 °C 2.1: potassium carbonate; potassium iodide / acetonitrile / 2 h / 20 °C / Cooling with ice 3.1: hydrogenchloride / 1,4-dioxane; ethyl acetate / 18 h / 20 °C 4.1: Sodium hydrogenocarbonate / lithium hydroxide monohydrate / 0.33 h / 18.2 °C / pH 7.51 / Inert atmosphere
Multi-step reaction with 3 steps 1: acetonitrile / 2 h / 5 - 13 °C / Large scale 2: potassium carbonate; potassium iodide / acetonitrile / 3 h / 15 - 25 °C / Large scale 3: hydrogenchloride / 14 h / 0 - 40 °C / Large scale
Multi-step reaction with 3 steps 1.1: acetonitrile / 2 h / 5 - 13 °C / Large scale 1.2: 0.5 h / 0 - 5 °C / Large scale 2.1: potassium carbonate; potassium iodide / acetonitrile; methanol / 3 h / 15 - 25 °C / Large scale 3.1: hydrogenchloride / 14 h / 0 - 40 °C / Large scale
  • 9
  • [ 1799327-45-9 ]
  • [ 1799328-86-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: potassium carbonate; potassium iodide / acetonitrile / 2 h / 20 °C / Cooling with ice 2: hydrogenchloride / 1,4-dioxane; ethyl acetate / 18 h / 20 °C 3: Sodium hydrogenocarbonate / lithium hydroxide monohydrate / 0.33 h / 18.2 °C / pH 7.51 / Inert atmosphere
Multi-step reaction with 2 steps 1: potassium carbonate; potassium iodide / acetonitrile / 3 h / 15 - 25 °C / Large scale 2: hydrogenchloride / 14 h / 0 - 40 °C / Large scale
Multi-step reaction with 2 steps 1: potassium carbonate; potassium iodide / acetonitrile; methanol / 3 h / 15 - 25 °C / Large scale 2: hydrogenchloride / 14 h / 0 - 40 °C / Large scale
  • 10
  • [ 89402-43-7 ]
  • [ 1799328-86-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 11 steps 1.1: sodium hexamethyldisilazane / tetrahydrofuran; toluene / 20 °C / Inert atmosphere; Cooling with ice 2.1: borane-THF / tetrahydrofuran / Inert atmosphere; Cooling with ice 3.1: potassium carbonate / 1-methyl-pyrrolidin-2-one / 4 h / 150 °C 4.1: lithium bromide; [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(ll) dichloride / tetrahydrofuran; 1-methyl-pyrrolidin-2-one / 18 h / 20 °C / Inert atmosphere 5.1: N-Bromosuccinimide / N,N-dimethyl-formamide / 1 h / 5 - 20 °C 6.1: methyllithium; tert.-butyl lithium / tetrahydrofuran; diethyl ether; hexane / 1 h / -78 °C 6.2: 0.83 h / -78 °C 7.1: sodium tetrahydroborate; methanol / 0.42 h / Cooling with ice 8.1: acetonitrile / 0.5 h / 5 - 20 °C 8.2: 0.33 h / 20 °C 9.1: potassium carbonate; potassium iodide / acetonitrile / 2 h / 20 °C / Cooling with ice 10.1: hydrogenchloride / 1,4-dioxane; ethyl acetate / 18 h / 20 °C 11.1: sodium hydrogencarbonate / water / 0.33 h / 18.2 °C / pH 7.51 / Inert atmosphere
  • 11
  • [ 1799327-65-3 ]
  • [ 1799328-86-1 ]
YieldReaction ConditionsOperation in experiment
88.6% With hydrogenchloride at 0 - 40℃; for 14h; Large scale; 18 Example 18: Preparation and synthesis of the compound of formula (XXII) (l-(6-(4- fluorobenzyl)-5-(hydroxymethyl)-3,3-dimethyl-2,3-dihydro-lH-pyrrolo[3,2-b]pyridine-l-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-l-yl)ethenone): The solution of the compound of (XXI) in methanol (114.6 Kg, 10.5% assay, 98.7% purity, 1 eq) obtained from the previous step in Example 17 was cooled to a temperature of 0 to 10°C, and 6N hydrochloric acid in methanol (22 Kg, 7.7 eq) was added. The reaction mixture was warmed to a temperature of 15 to 25°C and stirred at this temperature for 12 hours followed by 2 hours at a temperature of 30 to 40°C until reaction completion or until the compound of formula (XXI) reached NMT 0.5%. The reaction mixture was distilled under reduced pressure at NMT a temperature of 40°C to about 5 volumes. The solvent was swapped with water (2 x 48 Kg) followed by the addition of ethyl acetate (43 Kg). The organic phase was separated, and the aqueous phase containing the product was washed with ethyl acetate (43 Kg). The pH of the aqueous phase was adjusted to 11.5 to 12.0 using aqueous sodium hydroxide (37.6 Kg) followed by extraction with ethyl acetate (3 x 54Kg). The combined organic layer was washed twice with brine (7 Kg in water 65 Kg). The organic layer was separated and azeotropically distilled to 9 volumes under reduced pressure at NMT a temperature of 40°C using ethyl acetate (3 x 108 Kg) until the water content was NMT 0.7% to obtain the compound of formula (XXII) as a solution in ethyl acetate (100.7 Kg, 88.6% yield, 8.9% assay, 98.2% purity), which is used as was in the next step in Example 19 to prepare the compound of formula (XXIII).
88.6% With hydrogenchloride at 0 - 40℃; for 14h; Large scale; 18 Example 18: Preparation and synthesis of the compound of formula (XXII) (l-(6-(4- fluorobenzyl)-5-(hydroxymethyl)-3,3-dimethyl-2,3-dihydro-lH-pyrrolo[3,2-b]pyridine-l-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-l-yl)ethenone): The solution of the compound of (XXI) in methanol (114.6 Kg, 10.5% assay, 98.7% purity, 1 eq) obtained from the previous step in Example 17 was cooled to a temperature of 0 to 10°C, and 6N hydrochloric acid in methanol (22 Kg, 7.7 eq) was added. The reaction mixture was warmed to a temperature of 15 to 25°C and stirred at this temperature for 12 hours followed by 2 hours at a temperature of 30 to 40°C until reaction completion or until the compound of formula (XXI) reached NMT 0.5%. The reaction mixture was distilled under reduced pressure at NMT a temperature of 40°C to about 5 volumes. The solvent was swapped with water (2 x 48 Kg) followed by the addition of ethyl acetate (43 Kg). The organic phase was separated, and the aqueous phase containing the product was washed with ethyl acetate (43 Kg). The pH of the aqueous phase was adjusted to 11.5 to 12.0 using aqueous sodium hydroxide (37.6 Kg) followed by extraction with ethyl acetate (3 x 54Kg). The combined organic layer was washed twice with brine (7 Kg in water 65 Kg). The organic layer was separated and azeotropically distilled to 9 volumes under reduced pressure at NMT a temperature of 40°C using ethyl acetate (3 x 108 Kg) until the water content was NMT 0.7% to obtain the compound of formula (XXII) as a solution in ethyl acetate (100.7 Kg, 88.6% yield, 8.9% assay, 98.2% purity), which is used as was in the next step in Example 19 to prepare the compound of formula (XXIII).
Multi-step reaction with 2 steps 1: hydrogenchloride / 1,4-dioxane; ethyl acetate / 18 h / 20 °C 2: Sodium hydrogenocarbonate / lithium hydroxide monohydrate / 0.33 h / 18.2 °C / pH 7.51 / Inert atmosphere
  • 12
  • [ 1799327-43-7 ]
  • [ 1799328-86-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1.1: sodium tetrahydroborate; methanol / 0.42 h / Cooling with ice 2.1: acetonitrile / 0.5 h / 5 - 20 °C 2.2: 0.33 h / 20 °C 3.1: potassium carbonate; potassium iodide / acetonitrile / 2 h / 20 °C / Cooling with ice 4.1: hydrogenchloride / 1,4-dioxane; ethyl acetate / 18 h / 20 °C 5.1: sodium hydrogencarbonate / water / 0.33 h / 18.2 °C / pH 7.51 / Inert atmosphere
  • 13
  • [ 1799328-86-1 ]
  • [ 1799328-88-3 ]
YieldReaction ConditionsOperation in experiment
79% With sulfuric acid In ethanol at 18 - 23℃; for 0.166667h; 41 Example 41: 1 -{6-[(4-Fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1 H,2H,3H- pyrrolo[3,2-b]pyridi n-I -yl}-2-[(2R,5R)-5-methyl-2-[(3R)-3-methylmorpholi n-4-yl]methyl}piperazin-1-yl]ethan-1-one sulfate (Form F) The free base of 1 -{6-[(4-fluorophenyl) methyl]-5-(hydroxymethyl)-3, 3-dimethyl- 1 H ,2 H, 3H- pyrrolo[3,2-b]pyridin- 1 -yl}-2-[(2R ,SR)-5-methyl-2-[(3R)-3-methylmorpholin-4- yl]methyl}piperazin-1-yl]ethan-1-one (500.0mg, 1.0 wt) (which may be prepared as described in Example 38) was charged to a 10 mL vessel and dissolved in ethanol (1.0 mL, 2.0 vol).Sulfuric acid (103.2mg, 1.0 eq.) solution in ethanol (4.0 mL, 8.0 vol) was added over 10 minutes with stirring at 18 to 23°C to give a clear gel. The contents of the vessel were stirred for 1 hour at the same temperature, during which time the gel dissolved to give a yellow solution. Stirring was continued for 16 hours and a white suspension was generated. The progress of the salt crystallisation was monitored by XRPD. Ethanol (2.0 mL, 4.0 vol) wasthen added to properly mobilise the suspension and the product was isolated by filtration and dried under a stream of nitrogen to give a white solid (465.2mg, 79%th.), 94.9% w/w oasfb (against TCNB) that contained ethanol (2.9% w/w) and water (3.6% w/w) and was indicated as Form F by XRPD. Detailed characterising data (1H NMR, XRPD and DSC) for Example 41 is shown in Figures 7-9.
  • 14
  • [ 26811-96-1 ]
  • [ 1799328-86-1 ]
  • [ 2734874-76-9 ]
YieldReaction ConditionsOperation in experiment
91% In Isopropyl acetate at 18 - 23℃; 43 Example 43: 1 -{6-[(4-Fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1 H,2H,3H- pyrrolo[3,2-b]pyridi n-I -yl}-2-[(2R,5R)-5-methyl-2-[(3R)-3-methylmorpholi n-4- yl]methyl}pi perazi n-I -yl]ethan-I -one L-(+)-lactate (Form C) The free base of 1 -{6-[(4-fluorophenyl) methyl]-5-(hydroxymethyl)-3, 3-dimethyl- 1 H ,2 H ,3H- pyrrolo[3,2-b]pyridin- 1 -yl}-2-[(2R ,5R)-5-methyl-2-[(3R)-3-methylmorpholin-4- yl]methyl}piperazin-1-yl]ethan-1-one (bOg, corr.) (which may be prepared as described in Example 38) was dissolved in isopropyl acetate (60.OmL, 6.Ovol) to give a pale yellowsolution. To which was added anhydrous L-(+)-lactic acid (1 .67g, 1 .Oeq.) dissolved in isopropyl acetate (10.OmL, 1.Ovol). A line rinse of isopropyl acetate (10.OmL, 1.Ovol) was applied and the mixture was stirred at 18-23°C to give a pale yellow solution. n-Heptane (l2OmL, 12.Ovol) was added drop wise over 40mm and gum was formed on the bottom of the flask. After stirring for 1 h 40mm the appearance of the mixture had improvedbut the gum was still present on the base of the flask.The mixture was stirred for 16h at 18-23°C during which time the gum had mobilised and a granular, finely divided suspension had formed. The suspension was filtered under nitrogen (filtration was rapid) and the cake was sampled and analysed by XRPD (Form C). The cake was washed with isopropyl acetate/n-heptane (2.0/3.0, v/v, 5.Ovol), sampled and analysed byXRPD (Form C) and left to pull dry on the filter under a stream of nitrogen over 16h. The product consisted of a slightly off-white powdery solid (11 .36g, 91% corr.) Form C, 94.3%w/w (oasfb), Form C, m.p. 172°C and contained isopropyl acetate (1.0%ww).
  • 15
  • [ 75-75-2 ]
  • [ 1799328-86-1 ]
  • [ 1799328-90-7 ]
YieldReaction ConditionsOperation in experiment
63% In isopropyl alcohol at 18 - 23℃; for 1h; 42 Example 42: 1 -{6-[(4-Fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1 H,2H,3H- pyrrolo[3,2-b]pyridi n-I -yl}-2-[(2R,5R)-5-methyl-2-[(3R)-3-methylmorpholi n-4-yl]methyl}piperazin-I-yl]ethan-I-one mesylate (Form B) The free base of 1 -{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3, 3-dimethyl- 1 H ,2 H, 3H-pyrrolo[3,2-b]pyridin- 1 -yl}-2-[(2R ,5R)-5-methyl-2-[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one (500.0mg, 1.0 wt) (which may be prepared as described in Example 38) was charged to a 25 mL vessel and dissolved in 2-propanol (2.5 mL, 5.0 vol). Methanesulfonic acid (276.0mg, 3.0 eq.) was added (small exotherm was observed) and the resulting oily-gummy mixture was stirred for 1 hour at 18 to 23°C. n-Heptane (10.0 mL, 20.0vol) was added slowly over 10 minutes to give a white suspension and a small quantity of gummy solid. The progress of the salt crystallisation was monitored by XRPD. The salt did not crystallise under mild conditions (stirring at 18 to 23°C for 3 days), therefore the temperature was increased to 40 to 45°C to give a sticky gummy solid and clear supernatant. This mixture was cooled to 18 to 23°C, mobilised with a spatula and sonicated for 20 minutesto provide a white suspension that contained some gummy solids. The suspension was stirred for 20 hours at the same temperature, filtered and dried under a stream of nitrogen to give a beige solid (402.9mg, 63%th.), 99.0% w/w oasfb (against TCNB), that contained 2- propanol (2.3% wlw), n-heptane (0.2% wlw), water (1.9% w/w) and was indicated as Form B by XRPD. Detailed characterising data (1H NMR, XRPD and DSC) for Example 42 is shownin Figures 10-12.
  • 16
  • [ 1403898-64-5 ]
  • 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one [ No CAS ]
  • 17
  • [ 1403901-32-5 ]
  • [ 1799328-86-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 6 steps 1: triethylamine; methanesulfonyl chloride / dichloromethane / 18 h / 0 - 20 °C 2: potassium carbonate; potassium iodide / acetonitrile / 18 h / 70 °C 3: palladium 10% on activated carbon; glacial acetic acid; hydrogen / ethanol / 18 h / 20 °C / 760.05 Torr 4: potassium carbonate; potassium iodide / acetonitrile / 2 h / 20 °C / Cooling with ice 5: hydrogenchloride / 1,4-dioxane; ethyl acetate / 18 h / 20 °C 6: Sodium hydrogenocarbonate / lithium hydroxide monohydrate / 0.33 h / 18.2 °C / pH 7.51 / Inert atmosphere
Multi-step reaction with 5 steps 1.1: triethylamine / dichloromethane / 9.5 h / 0 - 10 °C / Large scale 2.1: potassium carbonate; potassium iodide / acetonitrile / 6 h / 15 - 62 °C / Large scale 3.1: palladium 10% on activated carbon; hydrogen / ethanol / 3 h / 65 - 75 °C / 1500.15 Torr / Large scale 3.2: 1 h / 15 - 25 °C / Large scale 4.1: potassium carbonate; potassium iodide / acetonitrile / 3 h / 15 - 25 °C / Large scale 5.1: hydrogenchloride / 14 h / 0 - 40 °C / Large scale
Multi-step reaction with 5 steps 1.1: triethylamine; methanesulfonyl chloride / dichloromethane / 15 h / 0 - 30 °C / Large scale 2.1: potassium carbonate; potassium iodide / acetonitrile / 0.9 h / 15 - 62 °C / Large scale 3.1: palladium 10% on activated carbon; hydrogen / ethanol / 3 h / 65 - 75 °C / 1500.15 Torr / Large scale 3.2: 1 h / 15 - 25 °C / Large scale 4.1: potassium carbonate; potassium iodide / acetonitrile; methanol / 3 h / 15 - 25 °C / Large scale 5.1: hydrogenchloride / 14 h / 0 - 40 °C / Large scale
  • 18
  • [ 1403902-55-5 ]
  • [ 1799328-86-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1: potassium carbonate; potassium iodide / acetonitrile / 18 h / 70 °C 2: palladium 10% on activated carbon; glacial acetic acid; hydrogen / ethanol / 18 h / 20 °C / 760.05 Torr 3: potassium carbonate; potassium iodide / acetonitrile / 2 h / 20 °C / Cooling with ice 4: hydrogenchloride / 1,4-dioxane; ethyl acetate / 18 h / 20 °C 5: Sodium hydrogenocarbonate / lithium hydroxide monohydrate / 0.33 h / 18.2 °C / pH 7.51 / Inert atmosphere
Multi-step reaction with 4 steps 1.1: potassium carbonate; potassium iodide / acetonitrile / 6 h / 15 - 62 °C / Large scale 2.1: palladium 10% on activated carbon; hydrogen / ethanol / 3 h / 65 - 75 °C / 1500.15 Torr / Large scale 2.2: 1 h / 15 - 25 °C / Large scale 3.1: potassium carbonate; potassium iodide / acetonitrile / 3 h / 15 - 25 °C / Large scale 4.1: hydrogenchloride / 14 h / 0 - 40 °C / Large scale
Multi-step reaction with 4 steps 1.1: potassium carbonate; potassium iodide / acetonitrile / 0.9 h / 15 - 62 °C / Large scale 2.1: palladium 10% on activated carbon; hydrogen / ethanol / 3 h / 65 - 75 °C / 1500.15 Torr / Large scale 2.2: 1 h / 15 - 25 °C / Large scale 3.1: potassium carbonate; potassium iodide / acetonitrile; methanol / 3 h / 15 - 25 °C / Large scale 4.1: hydrogenchloride / 14 h / 0 - 40 °C / Large scale
  • 19
  • [ 1403902-77-1 ]
  • [ 1799328-86-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: palladium 10% on activated carbon; glacial acetic acid; hydrogen / ethanol / 18 h / 20 °C / 760.05 Torr 2: potassium carbonate; potassium iodide / acetonitrile / 2 h / 20 °C / Cooling with ice 3: hydrogenchloride / 1,4-dioxane; ethyl acetate / 18 h / 20 °C 4: Sodium hydrogenocarbonate / lithium hydroxide monohydrate / 0.33 h / 18.2 °C / pH 7.51 / Inert atmosphere
Multi-step reaction with 3 steps 1.1: palladium 10% on activated carbon; hydrogen / ethanol / 3 h / 65 - 75 °C / 1500.15 Torr / Large scale 1.2: 1 h / 15 - 25 °C / Large scale 2.1: potassium carbonate; potassium iodide / acetonitrile / 3 h / 15 - 25 °C / Large scale 3.1: hydrogenchloride / 14 h / 0 - 40 °C / Large scale
Multi-step reaction with 3 steps 1.1: palladium 10% on activated carbon; hydrogen / ethanol / 3 h / 65 - 75 °C / 1500.15 Torr / Large scale 1.2: 1 h / 15 - 25 °C / Large scale 2.1: potassium carbonate; potassium iodide / acetonitrile; methanol / 3 h / 15 - 25 °C / Large scale 3.1: hydrogenchloride / 14 h / 0 - 40 °C / Large scale
  • 20
  • [ 2739002-53-8 ]
  • [ 1799328-86-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 6 steps 1: palladium diacetate; triethylamine; 2,2'-bis(diphenylphosphino)-1,1'-binaphthalene / acetonitrile / 33 h / 55 - 65 °C / 225.02 - 375.04 Torr / Inert atmosphere; Sealed tube; Large scale 2: hydrogenchloride / isopropanol / 9 h / 50 - 55 °C / Large scale 3: lithium tetrahydridoborate / 2-methyltetrahydrofuran; tetrahydrofuran / 9 h / -10 - 0 °C / Large scale 4: acetonitrile / 2 h / 5 - 13 °C / Large scale 5: potassium carbonate; potassium iodide / acetonitrile / 3 h / 15 - 25 °C / Large scale 6: hydrogenchloride / 14 h / 0 - 40 °C / Large scale
Multi-step reaction with 6 steps 1.1: palladium diacetate; triethylamine; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl / acetonitrile / 33 h / 55 - 65 °C / 225.02 - 375.04 Torr / Inert atmosphere; Sealed tube; Large scale 2.1: hydrogenchloride / isopropanol / 9 h / 50 - 55 °C / Large scale 3.1: lithium tetrahydridoborate / 2-methyltetrahydrofuran; tetrahydrofuran / 9 h / -10 - 0 °C / Large scale 4.1: acetonitrile / 2 h / 5 - 13 °C / Large scale 4.2: 0.5 h / 0 - 5 °C / Large scale 5.1: potassium carbonate; potassium iodide / acetonitrile; methanol / 3 h / 15 - 25 °C / Large scale 6.1: hydrogenchloride / 14 h / 0 - 40 °C / Large scale
  • 21
  • [ 2739002-54-9 ]
  • [ 1799328-86-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1: hydrogenchloride / isopropanol / 9 h / 50 - 55 °C / Large scale 2: lithium tetrahydridoborate / 2-methyltetrahydrofuran; tetrahydrofuran / 9 h / -10 - 0 °C / Large scale 3: acetonitrile / 2 h / 5 - 13 °C / Large scale 4: potassium carbonate; potassium iodide / acetonitrile / 3 h / 15 - 25 °C / Large scale 5: hydrogenchloride / 14 h / 0 - 40 °C / Large scale
Multi-step reaction with 5 steps 1.1: hydrogenchloride / isopropanol / 9 h / 50 - 55 °C / Large scale 2.1: lithium tetrahydridoborate / 2-methyltetrahydrofuran; tetrahydrofuran / 9 h / -10 - 0 °C / Large scale 3.1: acetonitrile / 2 h / 5 - 13 °C / Large scale 3.2: 0.5 h / 0 - 5 °C / Large scale 4.1: potassium carbonate; potassium iodide / acetonitrile; methanol / 3 h / 15 - 25 °C / Large scale 5.1: hydrogenchloride / 14 h / 0 - 40 °C / Large scale
  • 22
  • [ 2739002-55-0 ]
  • [ 1799328-86-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: lithium tetrahydridoborate / 2-methyltetrahydrofuran; tetrahydrofuran / 9 h / -10 - 0 °C / Large scale 2: acetonitrile / 2 h / 5 - 13 °C / Large scale 3: potassium carbonate; potassium iodide / acetonitrile / 3 h / 15 - 25 °C / Large scale 4: hydrogenchloride / 14 h / 0 - 40 °C / Large scale
Multi-step reaction with 4 steps 1.1: lithium tetrahydridoborate / 2-methyltetrahydrofuran; tetrahydrofuran / 9 h / -10 - 0 °C / Large scale 2.1: acetonitrile / 2 h / 5 - 13 °C / Large scale 2.2: 0.5 h / 0 - 5 °C / Large scale 3.1: potassium carbonate; potassium iodide / acetonitrile; methanol / 3 h / 15 - 25 °C / Large scale 4.1: hydrogenchloride / 14 h / 0 - 40 °C / Large scale
  • 23
  • [ 2739002-58-3 ]
  • [ 1799328-86-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 11 steps 1.1: 1 h / Inert atmosphere 1.2: 5 h / 60 °C / Inert atmosphere 2.1: NiCl2·6H2O; sodium tetrahydridoborate / methanol / 0 - 20 °C 3.1: Sodium hydrogenocarbonate / dimethylsulfoxide-d6 / 52 h / 120 °C 4.1: NBS / N,N-dimethyl-formamide / 1 h / -18 - -12 °C / Large scale 5.1: toluene / 0 - 25 °C / Large scale 5.2: 22 h / 15 - 25 °C / Large scale 6.1: palladium diacetate; triethylamine; 2,2'-bis(diphenylphosphino)-1,1'-binaphthalene / acetonitrile / 33 h / 55 - 65 °C / 225.02 - 375.04 Torr / Inert atmosphere; Sealed tube; Large scale 7.1: hydrogenchloride / isopropanol / 9 h / 50 - 55 °C / Large scale 8.1: lithium tetrahydridoborate / 2-methyltetrahydrofuran; tetrahydrofuran / 9 h / -10 - 0 °C / Large scale 9.1: acetonitrile / 2 h / 5 - 13 °C / Large scale 10.1: potassium carbonate; potassium iodide / acetonitrile / 3 h / 15 - 25 °C / Large scale 11.1: hydrogenchloride / 14 h / 0 - 40 °C / Large scale
Multi-step reaction with 11 steps 1.1: potassium carbonate / 2-methyltetrahydrofuran; lithium hydroxide monohydrate / 6 h / 60 °C / Inert atmosphere 2.1: NiCl2·6H2O; sodium tetrahydridoborate; methanol / 3.5 h / 0 - 20 °C 3.1: Sodium hydrogenocarbonate / dimethyl sulfoxide / 52 h / 120 °C 4.1: NBS / N,N-dimethyl-formamide / 1 h / -18 - -12 °C / Large scale 5.1: toluene / 0 - 25 °C / Large scale 5.2: 22 h / 15 - 25 °C / Large scale 6.1: palladium diacetate; triethylamine; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl / acetonitrile / 33 h / 55 - 65 °C / 225.02 - 375.04 Torr / Inert atmosphere; Sealed tube; Large scale 7.1: hydrogenchloride / isopropanol / 9 h / 50 - 55 °C / Large scale 8.1: lithium tetrahydridoborate / 2-methyltetrahydrofuran; tetrahydrofuran / 9 h / -10 - 0 °C / Large scale 9.1: acetonitrile / 2 h / 5 - 13 °C / Large scale 9.2: 0.5 h / 0 - 5 °C / Large scale 10.1: potassium carbonate; potassium iodide / acetonitrile; methanol / 3 h / 15 - 25 °C / Large scale 11.1: hydrogenchloride / 14 h / 0 - 40 °C / Large scale
  • 24
  • [ 2739002-56-1 ]
  • [ 1799328-86-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: potassium carbonate; potassium iodide / acetonitrile / 3 h / 15 - 25 °C / Large scale 2: hydrogenchloride / 14 h / 0 - 40 °C / Large scale
  • 25
  • [ 26811-96-1 ]
  • [ 1799328-86-1 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
100% In lithium hydroxide monohydrate; ethyl acetate at 40 - 50℃; Large scale; 19; 6; 7 Example 19: Preparation and synthesis of the compound of formula (XXIII) (l-{6-[4- fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-lH-2H,3H-pyrrolo[3,2-b]pyridine-l-yl}- 2-[(2R,5R)-5-methyl-2-[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-l-yl)ethen-l-one, L- (+)4actic acid salt): A solution of the compound of formula (XXII) (from the previous step in Example 18) in ethyl acetate (98.7 Kg, 8.9% assay, 98.2% purity) was distilled to 7.5 volumes under reduced pressure at NMT a temperature of 40°C until the water content was NMT 0.7%. A solution of anhydrous L-(+)-lactic acid (1.62 Kg, 1.10 eq) in ethyl acetate (20 Kg) with a water content of NMT 0.7%, was clarified and rinsed with ethyl acetate (4.0 Kg). The solution of the compound of formula (XXII) in ethyl acetate was heated to a temperature of 40 to 50°C, and a 1/3 portion of the anhydrous lactic acid solution in ethyl acetate was added at this temperature. The mixture was seeded with the seed compounds of formula (XXIII) (44 g) at this temperature, and the remaining 2/3 portion of lactic acid solution in ethyl acetate was added slowly over 2 hours at a temperature of 40 to 50°C. n-Heptane (66 Kg) was added at this temperature and subjected to agitation for approximately 5.5 hours followed by cooling to a temperature of 5 to 15°C with a cooling rate of 1°C in 5 min. The resulting slurry was stirred at this temperature for at least 10 hours, filtered and washed with a mixture of n-heptane (12 Kg) and ethyl acetate (16 Kg). The filter cake was dried under reduced pressure at NMT a temperature of 45°C until residual ethyl acetate was NMT 4500 ppm and residual n-heptane was NMT 4500 ppm to obtain the compound of formula (XXIII) as a lactic acid salt in crystalline white solid form (10.6 Kg, 100% yield, 99.58% purity; palladium content < 1 ppm, Form C).
100% In lithium hydroxide monohydrate; ethyl acetate at 40 - 50℃; Large scale; 19; 6; 7 Example 19: Preparation and synthesis of the compound of formula (XXIII) (l-{6-[4- fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-lH-2H,3H-pyrrolo[3,2-b]pyridine-l-yl}- 2-[(2R,5R)-5-methyl-2-[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-l-yl)ethen-l-one, L- (+)4actic acid salt): A solution of the compound of formula (XXII) (from the previous step in Example 18) in ethyl acetate (98.7 Kg, 8.9% assay, 98.2% purity) was distilled to 7.5 volumes under reduced pressure at NMT a temperature of 40°C until the water content was NMT 0.7%. A solution of anhydrous L-(+)-lactic acid (1.62 Kg, 1.10 eq) in ethyl acetate (20 Kg) with a water content of NMT 0.7%, was clarified and rinsed with ethyl acetate (4.0 Kg). The solution of the compound of formula (XXII) in ethyl acetate was heated to a temperature of 40 to 50°C, and a 1/3 portion of the anhydrous lactic acid solution in ethyl acetate was added at this temperature. The mixture was seeded with the seed compounds of formula (XXIII) (44 g) at this temperature, and the remaining 2/3 portion of lactic acid solution in ethyl acetate was added slowly over 2 hours at a temperature of 40 to 50°C. n-Heptane (66 Kg) was added at this temperature and subjected to agitation for approximately 5.5 hours followed by cooling to a temperature of 5 to 15°C with a cooling rate of 1°C in 5 min. The resulting slurry was stirred at this temperature for at least 10 hours, filtered and washed with a mixture of n-heptane (12 Kg) and ethyl acetate (16 Kg). The filter cake was dried under reduced pressure at NMT a temperature of 45°C until residual ethyl acetate was NMT 4500 ppm and residual n-heptane was NMT 4500 ppm to obtain the compound of formula (XXIII) as a lactic acid salt in crystalline white solid form (10.6 Kg, 100% yield, 99.58% purity; palladium content < 1 ppm, Form C).
  • 26
  • [ 2739002-59-4 ]
  • [ 1799328-86-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 10 steps 1.1: NiCl2·6H2O; sodium tetrahydridoborate / methanol / 0 - 20 °C 2.1: Sodium hydrogenocarbonate / dimethylsulfoxide-d6 / 52 h / 120 °C 3.1: NBS / N,N-dimethyl-formamide / 1 h / -18 - -12 °C / Large scale 4.1: toluene / 0 - 25 °C / Large scale 4.2: 22 h / 15 - 25 °C / Large scale 5.1: palladium diacetate; triethylamine; 2,2'-bis(diphenylphosphino)-1,1'-binaphthalene / acetonitrile / 33 h / 55 - 65 °C / 225.02 - 375.04 Torr / Inert atmosphere; Sealed tube; Large scale 6.1: hydrogenchloride / isopropanol / 9 h / 50 - 55 °C / Large scale 7.1: lithium tetrahydridoborate / 2-methyltetrahydrofuran; tetrahydrofuran / 9 h / -10 - 0 °C / Large scale 8.1: acetonitrile / 2 h / 5 - 13 °C / Large scale 9.1: potassium carbonate; potassium iodide / acetonitrile / 3 h / 15 - 25 °C / Large scale 10.1: hydrogenchloride / 14 h / 0 - 40 °C / Large scale
Multi-step reaction with 10 steps 1.1: NiCl2·6H2O; sodium tetrahydridoborate; methanol / 3.5 h / 0 - 20 °C 2.1: Sodium hydrogenocarbonate / dimethyl sulfoxide / 52 h / 120 °C 3.1: NBS / N,N-dimethyl-formamide / 1 h / -18 - -12 °C / Large scale 4.1: toluene / 0 - 25 °C / Large scale 4.2: 22 h / 15 - 25 °C / Large scale 5.1: palladium diacetate; triethylamine; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl / acetonitrile / 33 h / 55 - 65 °C / 225.02 - 375.04 Torr / Inert atmosphere; Sealed tube; Large scale 6.1: hydrogenchloride / isopropanol / 9 h / 50 - 55 °C / Large scale 7.1: lithium tetrahydridoborate / 2-methyltetrahydrofuran; tetrahydrofuran / 9 h / -10 - 0 °C / Large scale 8.1: acetonitrile / 2 h / 5 - 13 °C / Large scale 8.2: 0.5 h / 0 - 5 °C / Large scale 9.1: potassium carbonate; potassium iodide / acetonitrile; methanol / 3 h / 15 - 25 °C / Large scale 10.1: hydrogenchloride / 14 h / 0 - 40 °C / Large scale
  • 27
  • [ 2739002-60-7 ]
  • [ 1799328-86-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 9 steps 1.1: Sodium hydrogenocarbonate / dimethylsulfoxide-d6 / 52 h / 120 °C 2.1: NBS / N,N-dimethyl-formamide / 1 h / -18 - -12 °C / Large scale 3.1: toluene / 0 - 25 °C / Large scale 3.2: 22 h / 15 - 25 °C / Large scale 4.1: palladium diacetate; triethylamine; 2,2'-bis(diphenylphosphino)-1,1'-binaphthalene / acetonitrile / 33 h / 55 - 65 °C / 225.02 - 375.04 Torr / Inert atmosphere; Sealed tube; Large scale 5.1: hydrogenchloride / isopropanol / 9 h / 50 - 55 °C / Large scale 6.1: lithium tetrahydridoborate / 2-methyltetrahydrofuran; tetrahydrofuran / 9 h / -10 - 0 °C / Large scale 7.1: acetonitrile / 2 h / 5 - 13 °C / Large scale 8.1: potassium carbonate; potassium iodide / acetonitrile / 3 h / 15 - 25 °C / Large scale 9.1: hydrogenchloride / 14 h / 0 - 40 °C / Large scale
Multi-step reaction with 9 steps 1.1: Sodium hydrogenocarbonate / dimethyl sulfoxide / 52 h / 120 °C 2.1: NBS / N,N-dimethyl-formamide / 1 h / -18 - -12 °C / Large scale 3.1: toluene / 0 - 25 °C / Large scale 3.2: 22 h / 15 - 25 °C / Large scale 4.1: palladium diacetate; triethylamine; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl / acetonitrile / 33 h / 55 - 65 °C / 225.02 - 375.04 Torr / Inert atmosphere; Sealed tube; Large scale 5.1: hydrogenchloride / isopropanol / 9 h / 50 - 55 °C / Large scale 6.1: lithium tetrahydridoborate / 2-methyltetrahydrofuran; tetrahydrofuran / 9 h / -10 - 0 °C / Large scale 7.1: acetonitrile / 2 h / 5 - 13 °C / Large scale 7.2: 0.5 h / 0 - 5 °C / Large scale 8.1: potassium carbonate; potassium iodide / acetonitrile; methanol / 3 h / 15 - 25 °C / Large scale 9.1: hydrogenchloride / 14 h / 0 - 40 °C / Large scale
  • 28
  • [ 1403898-63-4 ]
  • [ 1799328-86-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 7 steps 1.1: triethylamine / ethanol / 12 h / 15 - 30 °C / Large scale 1.2: 1.5 h / 40 - 75 °C / Large scale 2.1: sodium tris(acetoxy)borohydride / dichloromethane / 9.5 h / 0 - 30 °C / Large scale 3.1: triethylamine / dichloromethane / 9.5 h / 0 - 10 °C / Large scale 4.1: potassium carbonate; potassium iodide / acetonitrile / 6 h / 15 - 62 °C / Large scale 5.1: palladium 10% on activated carbon; hydrogen / ethanol / 3 h / 65 - 75 °C / 1500.15 Torr / Large scale 5.2: 1 h / 15 - 25 °C / Large scale 6.1: potassium carbonate; potassium iodide / acetonitrile / 3 h / 15 - 25 °C / Large scale 7.1: hydrogenchloride / 14 h / 0 - 40 °C / Large scale
Multi-step reaction with 7 steps 1.1: triethylamine / ethanol / 31 h / 15 - 30 °C / Large scale 1.2: 1.5 h / 40 - 75 °C / Large scale 2.1: sodium tris(acetoxy)borohydride / dichloromethane / 0 - 30 °C / Large scale 3.1: triethylamine; methanesulfonyl chloride / dichloromethane / 15 h / 0 - 30 °C / Large scale 4.1: potassium carbonate; potassium iodide / acetonitrile / 0.9 h / 15 - 62 °C / Large scale 5.1: palladium 10% on activated carbon; hydrogen / ethanol / 3 h / 65 - 75 °C / 1500.15 Torr / Large scale 5.2: 1 h / 15 - 25 °C / Large scale 6.1: potassium carbonate; potassium iodide / acetonitrile; methanol / 3 h / 15 - 25 °C / Large scale 7.1: hydrogenchloride / 14 h / 0 - 40 °C / Large scale
  • 29
  • [ 1604818-10-1 ]
  • [ 1799328-86-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 9 steps 1: anhydrous potassium acetate; dicyclohexyl[2’,4’,6’-tris(propan-2-yl)[1,1’-biphenyl]-2-yl]phosphane / 2-methyltetrahydrofuran / 0.5 h / 75 °C / Inert atmosphere 2: potassium carbonate / 4 h / 75 °C / Inert atmosphere 3: NBS; sodium chloride / N,N-dimethyl-formamide / 60.08 h / 0 - 20 °C 4: palladium diacetate; triethylamine; 2,2'-bis(diphenylphosphino)-1,1'-binaphthalene / acetonitrile / 33 h / 55 - 65 °C / 225.02 - 375.04 Torr / Inert atmosphere; Sealed tube; Large scale 5: hydrogenchloride / isopropanol / 9 h / 50 - 55 °C / Large scale 6: lithium tetrahydridoborate / 2-methyltetrahydrofuran; tetrahydrofuran / 9 h / -10 - 0 °C / Large scale 7: acetonitrile / 2 h / 5 - 13 °C / Large scale 8: potassium carbonate; potassium iodide / acetonitrile / 3 h / 15 - 25 °C / Large scale 9: hydrogenchloride / 14 h / 0 - 40 °C / Large scale
Multi-step reaction with 9 steps 1.1: anhydrous potassium acetate; dicyclohexyl[2’,4’,6’-tris(propan-2-yl)[1,1’-biphenyl]-2-yl]phosphane; XPhosPd(crotyl)Cl / 2-methyltetrahydrofuran / 0.5 h / 75 °C / Inert atmosphere 2.1: potassium carbonate / 4 h / 75 °C / Inert atmosphere 3.1: NBS; sodium chloride / N,N-dimethyl-formamide / 60.08 h / 0 - 20 °C 4.1: palladium diacetate; triethylamine; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl / acetonitrile / 33 h / 55 - 65 °C / 225.02 - 375.04 Torr / Inert atmosphere; Sealed tube; Large scale 5.1: hydrogenchloride / isopropanol / 9 h / 50 - 55 °C / Large scale 6.1: lithium tetrahydridoborate / 2-methyltetrahydrofuran; tetrahydrofuran / 9 h / -10 - 0 °C / Large scale 7.1: acetonitrile / 2 h / 5 - 13 °C / Large scale 7.2: 0.5 h / 0 - 5 °C / Large scale 8.1: potassium carbonate; potassium iodide / acetonitrile; methanol / 3 h / 15 - 25 °C / Large scale 9.1: hydrogenchloride / 14 h / 0 - 40 °C / Large scale
  • 30
  • [ 2739002-61-8 ]
  • [ 1799328-86-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 8 steps 1: potassium carbonate / 4 h / 75 °C / Inert atmosphere 2: NBS; sodium chloride / N,N-dimethyl-formamide / 60.08 h / 0 - 20 °C 3: palladium diacetate; triethylamine; 2,2'-bis(diphenylphosphino)-1,1'-binaphthalene / acetonitrile / 33 h / 55 - 65 °C / 225.02 - 375.04 Torr / Inert atmosphere; Sealed tube; Large scale 4: hydrogenchloride / isopropanol / 9 h / 50 - 55 °C / Large scale 5: lithium tetrahydridoborate / 2-methyltetrahydrofuran; tetrahydrofuran / 9 h / -10 - 0 °C / Large scale 6: acetonitrile / 2 h / 5 - 13 °C / Large scale 7: potassium carbonate; potassium iodide / acetonitrile / 3 h / 15 - 25 °C / Large scale 8: hydrogenchloride / 14 h / 0 - 40 °C / Large scale
Multi-step reaction with 8 steps 1.1: potassium carbonate / 4 h / 75 °C / Inert atmosphere 2.1: NBS; sodium chloride / N,N-dimethyl-formamide / 60.08 h / 0 - 20 °C 3.1: palladium diacetate; triethylamine; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl / acetonitrile / 33 h / 55 - 65 °C / 225.02 - 375.04 Torr / Inert atmosphere; Sealed tube; Large scale 4.1: hydrogenchloride / isopropanol / 9 h / 50 - 55 °C / Large scale 5.1: lithium tetrahydridoborate / 2-methyltetrahydrofuran; tetrahydrofuran / 9 h / -10 - 0 °C / Large scale 6.1: acetonitrile / 2 h / 5 - 13 °C / Large scale 6.2: 0.5 h / 0 - 5 °C / Large scale 7.1: potassium carbonate; potassium iodide / acetonitrile; methanol / 3 h / 15 - 25 °C / Large scale 8.1: hydrogenchloride / 14 h / 0 - 40 °C / Large scale
  • 31
  • [ 1403903-10-5 ]
  • [ 1799328-86-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 7 steps 1: NBS; sodium chloride / N,N-dimethyl-formamide / 60.08 h / 0 - 20 °C 2: palladium diacetate; triethylamine; 2,2'-bis(diphenylphosphino)-1,1'-binaphthalene / acetonitrile / 33 h / 55 - 65 °C / 225.02 - 375.04 Torr / Inert atmosphere; Sealed tube; Large scale 3: hydrogenchloride / isopropanol / 9 h / 50 - 55 °C / Large scale 4: lithium tetrahydridoborate / 2-methyltetrahydrofuran; tetrahydrofuran / 9 h / -10 - 0 °C / Large scale 5: acetonitrile / 2 h / 5 - 13 °C / Large scale 6: potassium carbonate; potassium iodide / acetonitrile / 3 h / 15 - 25 °C / Large scale 7: hydrogenchloride / 14 h / 0 - 40 °C / Large scale
Multi-step reaction with 7 steps 1.1: NBS; sodium chloride / N,N-dimethyl-formamide / 60.08 h / 0 - 20 °C 2.1: palladium diacetate; triethylamine; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl / acetonitrile / 33 h / 55 - 65 °C / 225.02 - 375.04 Torr / Inert atmosphere; Sealed tube; Large scale 3.1: hydrogenchloride / isopropanol / 9 h / 50 - 55 °C / Large scale 4.1: lithium tetrahydridoborate / 2-methyltetrahydrofuran; tetrahydrofuran / 9 h / -10 - 0 °C / Large scale 5.1: acetonitrile / 2 h / 5 - 13 °C / Large scale 5.2: 0.5 h / 0 - 5 °C / Large scale 6.1: potassium carbonate; potassium iodide / acetonitrile; methanol / 3 h / 15 - 25 °C / Large scale 7.1: hydrogenchloride / 14 h / 0 - 40 °C / Large scale
  • 32
  • [ CAS Unavailable ]
  • [ 1799328-86-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: potassium carbonate; potassium iodide / acetonitrile; methanol / 3 h / 15 - 25 °C / Large scale 2: hydrogenchloride / 14 h / 0 - 40 °C / Large scale
  • 33
  • [ 312693-07-5 ]
  • [ 1799328-86-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 9 steps 1.1: dicyclohexyl[2’,4’,6’-tris(propan-2-yl)[1,1’-biphenyl]-2-yl]phosphane; lithium bromide; palladium diacetate / 1-methyl-pyrrolidin-2-one; tetrahydrofuran / 12 h / 30 - 36 °C 2.1: NBS / N,N-dimethyl-formamide / 1 h / -18 - -12 °C / Large scale 3.1: toluene / 0 - 25 °C / Large scale 3.2: 22 h / 15 - 25 °C / Large scale 4.1: palladium diacetate; triethylamine; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl / acetonitrile / 33 h / 55 - 65 °C / 225.02 - 375.04 Torr / Inert atmosphere; Sealed tube; Large scale 5.1: hydrogenchloride / isopropanol / 9 h / 50 - 55 °C / Large scale 6.1: lithium tetrahydridoborate / 2-methyltetrahydrofuran; tetrahydrofuran / 9 h / -10 - 0 °C / Large scale 7.1: acetonitrile / 2 h / 5 - 13 °C / Large scale 7.2: 0.5 h / 0 - 5 °C / Large scale 8.1: potassium carbonate; potassium iodide / acetonitrile; methanol / 3 h / 15 - 25 °C / Large scale 9.1: hydrogenchloride / 14 h / 0 - 40 °C / Large scale
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