899822-97-0

Basic information

• Product Name: 3-nitro-1-(4-octylphenyl)-preopanone
• Synonyms: 3-nitro-1-(4-octylphenyl)-preopanone;3-Nitro-1-(4-octylphenyl)-1-propanone
• CAS NO: 899822-97-0
• Molecular Formula: C₁₇H₂₅NO₃
• Molecular Weight: 291
• Mol File: 899822-97-0.mol
• Article Data: 3

Chemical Properties

• Boiling Point: 441.7±38.0 °C(Predicted)
• Appearance: /
• Density: 1.032
• PKA: 7.51±0.29(Predicted)
• CAS DataBase Reference: 3-nitro-1-(4-octylphenyl)-preopanone(CAS DataBase Reference)
• NIST Chemistry Reference: 3-nitro-1-(4-octylphenyl)-preopanone(899822-97-0)
• EPA Substance Registry System: 3-nitro-1-(4-octylphenyl)-preopanone(899822-97-0)

Safety Data

• Hazardous Substances Data: 899822-97-0(Hazardous Substances Data)

Usage

Description

3-Nitro-1-(4-octylphenyl)-propanone is an organic compound that serves as an intermediate in the synthesis of 1-Hydroxy-3-nitrodeamino Fingolimod (H948155), a derivative of Fingolimod (F805000, HCl salt), a novel immune modulator.

Uses

Used in Pharmaceutical Industry:
3-Nitro-1-(4-octylphenyl)-propanone is used as a synthetic intermediate for the production of 1-Hydroxy-3-nitrodeamino Fingolimod (H948155), which is an impurity of Fingolimod (F805000, HCl salt). Fingolimod is a novel immune modulator that has the potential to prolong allograft transplant survival in numerous models by inhibiting lymphocyte emigration from lymphoid organs.

Synthetic route

3-nitropropionic acid chloride (51834-15-2) + Octylbenzene (2189-60-8) → 3-nitro-1-(4-octylphenyl)propan-1-one (899822-97-0)

Conditions	Yield
With aluminum (III) chloride In dichloromethane at 0 - 20℃;	76%

3-chloro-1-(4-octylphenyl)propan-1-one (928165-59-7) → 3-nitro-1-(4-octylphenyl)propan-1-one (899822-97-0) + C17H24O

Conditions	Yield
With sodium nitrite In acetone Reflux;	A 50% B n/a

3-chloro-1-(4-octylphenyl)propan-1-one (928165-59-7) → 3-nitro-1-(4-octylphenyl)propan-1-one (899822-97-0)

Conditions	Yield
With sodium nitrite In N,N-dimethyl-formamide at 25 - 30℃; for 1.5h; Temperature; Solvent;	37 g
With sodium nitrite In N,N-dimethyl-formamide at 25 - 35℃; for 4 - 6h; Solvent; Temperature; Large scale;	5.06 kg

n-octanophenone (1674-37-9) → 3-nitro-1-(4-octylphenyl)propan-1-one (899822-97-0)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: triethylsilane; titanium tetrachloride / dichloromethane / 1.5 h / 0 - 30 °C 1.2: 1 h / 0 - 30 °C 2.1: sodium nitrite / N,N-dimethyl-formamide / 1.5 h / 25 - 30 °C View Scheme
Multi-step reaction with 3 steps 1: titanium tetrachloride; triethylsilane / dichloromethane / 3 - 5 h / 0 - 5 °C / Large scale 2: aluminum (III) chloride / dichloromethane / 3 - 5 h / -10 - -5 °C / Large scale 3: sodium nitrite / N,N-dimethyl-formamide / 4 - 6 h / 25 - 35 °C / Large scale View Scheme
Multi-step reaction with 3 steps 1: titanium tetrachloride; triethylsilane / dichloromethane / 3 - 5 h / 0 - 5 °C / Large scale 2: aluminum (III) chloride / dichloromethane / 3 - 5 h / -10 - -5 °C / Large scale 3: sodium nitrite / acetone / Reflux View Scheme

Octylbenzene (2189-60-8) → 3-nitro-1-(4-octylphenyl)propan-1-one (899822-97-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: aluminum (III) chloride / dichloromethane / 3 - 5 h / -10 - -5 °C / Large scale 2: sodium nitrite / N,N-dimethyl-formamide / 4 - 6 h / 25 - 35 °C / Large scale View Scheme
Multi-step reaction with 2 steps 1: aluminum (III) chloride / dichloromethane / 3 - 5 h / -10 - -5 °C / Large scale 2: sodium nitrite / acetone / Reflux View Scheme

3-nitro-1-(4-octylphenyl)propan-1-one (899822-97-0) → 3-nitro-1-(4-octylphenyl)propan-1-ol (899822-98-1)

Conditions	Yield
Stage #1: 3-nitro-1-(4-octylphenyl)propan-1-one With lithium borohydride In tetrahydrofuran at 0℃; for 0.616667h; Inert atmosphere; Stage #2: With hydrogenchloride In tetrahydrofuran; water pH=< 6; Product distribution / selectivity;	94%
Stage #1: 3-nitro-1-(4-octylphenyl)propan-1-one With lithium borohydride In tetrahydrofuran at 0℃; for 0.616667h; Inert atmosphere; Stage #2: With hydrogenchloride In tetrahydrofuran; water pH=< 6; Product distribution / selectivity;	94%
Stage #1: 3-nitro-1-(4-octylphenyl)propan-1-one With lithium borohydride In tetrahydrofuran at 0℃; for 0.616667h; Inert atmosphere; Stage #2: With hydrogenchloride In tetrahydrofuran; water pH=< 6; Product distribution / selectivity;	94%

3-nitro-1-(4-octylphenyl)propan-1-one (899822-97-0) → fingolimod (162359-55-9)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: lithium borohydride / tetrahydrofuran / 0.62 h / 0 °C / Inert atmosphere 1.2: pH < 6 2.1: triethylamine / water; methanol / 2 h / 40 °C 3.1: toluene-4-sulfonic acid; hydrogen / palladium on activated charcoal / methanol / 3.83 h / 50 °C / 37503.8 Torr 3.2: 50 - 65 °C View Scheme
Multi-step reaction with 4 steps 1.1: lithium borohydride / tetrahydrofuran / 0.62 h / 0 °C / Inert atmosphere 1.2: pH < 6 2.1: triethylamine / water; methanol / 2 h / 40 °C 3.1: toluene-4-sulfonic acid / toluene / 0.5 h / 50 °C / Reflux 4.1: hydrogenchloride; hydrogen / palladium 10% on activated carbon / isopropyl alcohol; methanol / 2 h / 100 °C / 26252.6 Torr View Scheme
Multi-step reaction with 3 steps 1.1: lithium borohydride / tetrahydrofuran / 0.62 h / 0 °C / Inert atmosphere 1.2: pH < 6 2.1: triethylamine / water / 2 h / 40 °C 3.1: toluene-4-sulfonic acid; hydrogen / palladium on activated charcoal / methanol / 3.83 h / 50 °C / 37503.8 Torr 3.2: 50 - 65 °C View Scheme

3-nitro-1-(4-octylphenyl)propan-1-one (899822-97-0) → fingolimod hydrochloride

Conditions	Yield
Multi-step reaction with 4 steps 1.1: lithium borohydride / tetrahydrofuran / 0.62 h / 0 °C / Inert atmosphere 1.2: pH < 6 2.1: triethylamine / water; methanol / 2 h / 40 °C 3.1: toluene-4-sulfonic acid; hydrogen / palladium on activated charcoal / methanol / 3.83 h / 50 °C / 37503.8 Torr 3.2: 50 - 65 °C 4.1: hydrogenchloride / isopropyl alcohol; hexane / 1.08 h / 60 - 65 °C View Scheme
Multi-step reaction with 5 steps 1.1: lithium borohydride / tetrahydrofuran / 0.62 h / 0 °C / Inert atmosphere 1.2: pH < 6 2.1: triethylamine / water; methanol / 2 h / 40 °C 3.1: toluene-4-sulfonic acid / toluene / 0.5 h / 50 °C / Reflux 4.1: hydrogen / 5%-palladium/activated carbon / toluene / 2 h / 30 °C / 26252.6 Torr 5.1: hydrogenchloride / isopropyl alcohol; hexane / 1.08 h / 60 - 65 °C View Scheme
Multi-step reaction with 5 steps 1.1: lithium borohydride / tetrahydrofuran / 0.62 h / 0 °C / Inert atmosphere 1.2: pH < 6 2.1: triethylamine / water; methanol / 2 h / 40 °C 3.1: toluene-4-sulfonic acid / toluene / 0.5 h / 50 °C / Reflux 4.1: hydrogenchloride; hydrogen / palladium 10% on activated carbon / isopropyl alcohol; methanol / 2 h / 100 °C / 26252.6 Torr 5.1: hydrogenchloride / isopropyl alcohol; hexane / 1.08 h / 60 - 65 °C View Scheme

3-nitro-1-(4-octylphenyl)propan-1-one (899822-97-0) → C19H29NO4

Conditions	Yield
Multi-step reaction with 3 steps 1.1: lithium borohydride / tetrahydrofuran / 0.62 h / 0 °C / Inert atmosphere 1.2: pH < 6 2.1: triethylamine / water; methanol / 2 h / 40 °C 3.1: toluene-4-sulfonic acid / toluene / 0.5 h / 50 °C / Reflux View Scheme

3-nitro-1-(4-octylphenyl)propan-1-one (899822-97-0) → 3-(hydroxymethyl)-3-nitro-1-(4-octylphenyl)butane-1,4-diol (899822-99-2)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: lithium borohydride / tetrahydrofuran / 0.62 h / 0 °C / Inert atmosphere 1.2: pH < 6 2.1: triethylamine / water; methanol / 2 h / 40 °C View Scheme
Multi-step reaction with 2 steps 1.1: lithium borohydride / tetrahydrofuran / 0.62 h / 0 °C / Inert atmosphere 1.2: pH < 6 2.1: triethylamine / water / 2 h / 40 °C View Scheme
Multi-step reaction with 4 steps 1: sodium tetrahydroborate; methanol / 4.5 h / 0 - 20 °C 2: pyridine / dichloromethane / 20 °C 3: triethylamine / 1,4-dioxane / 24 h / 70 °C 4: water / 1,4-dioxane / 16 h / 40 °C / pH ~ 9 - 10 View Scheme
Multi-step reaction with 2 steps 1: sodium tetrahydroborate / methanol 2: triethylamine View Scheme

3-nitro-1-(4-octylphenyl)propan-1-one (899822-97-0) → (3-amino-5-(4-octylphenyl)tetrahydrofuran-3-yl)methanol + fingolimod (162359-55-9)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: lithium borohydride / tetrahydrofuran / 0.62 h / 0 °C / Inert atmosphere 1.2: pH < 6 2.1: triethylamine / water; methanol / 2 h / 40 °C 3.1: toluene-4-sulfonic acid / toluene / 0.5 h / 50 °C / Reflux 4.1: hydrogen / 5%-palladium/activated carbon / toluene / 2 h / 30 °C / 26252.6 Torr View Scheme
Multi-step reaction with 4 steps 1.1: lithium borohydride / tetrahydrofuran / 0.62 h / 0 °C / Inert atmosphere 1.2: pH < 6 2.1: triethylamine / water / 2 h / 40 °C 3.1: toluene-4-sulfonic acid / toluene / 0.5 h / 50 °C / Reflux 4.1: hydrogen / 5%-palladium/activated carbon / toluene / 2 h / 30 °C / 26252.6 Torr View Scheme

3-nitro-1-(4-octylphenyl)propan-1-one (899822-97-0) → (3-nitro-5-(4-octylphenyl)tetrahydrofuran-3-yl)-methanol (1369968-69-3)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: lithium borohydride / tetrahydrofuran / 0.62 h / 0 °C / Inert atmosphere 1.2: pH < 6 2.1: triethylamine / water; methanol / 2 h / 40 °C 3.1: toluene-4-sulfonic acid / toluene / 0.5 h / 50 °C / Reflux View Scheme
Multi-step reaction with 3 steps 1.1: lithium borohydride / tetrahydrofuran / 0.62 h / 0 °C / Inert atmosphere 1.2: pH < 6 2.1: triethylamine / water / 2 h / 40 °C 3.1: toluene-4-sulfonic acid / toluene / 0.5 h / 50 °C / Reflux View Scheme

3-nitro-1-(4-octylphenyl)propan-1-one (899822-97-0) → 2-nitro-2-[2-(4-octyl-phenyl)ethyl]propane-1,3-diol (374077-88-0)

Conditions	Yield
Multi-step reaction with 5 steps 1: sodium tetrahydroborate; methanol / 4.5 h / 0 - 20 °C 2: pyridine / dichloromethane / 20 °C 3: triethylamine / 1,4-dioxane / 24 h / 70 °C 4: water / 1,4-dioxane / 16 h / 40 °C / pH ~ 9 - 10 5: hydrogenchloride; hydrogen / palladium 10% on activated carbon / water; methanol / 20 h / 20 °C / 4137.29 Torr View Scheme
Multi-step reaction with 2 steps 1: triethylsilane; titanium tetrachloride / dichloromethane / 1.5 h / 0 - 30 °C 2: triethylamine / methanol / 2 h / 68 °C View Scheme
Multi-step reaction with 3 steps 1: sodium tetrahydroborate / methanol / 3.5 h / 6 - 20 °C 2: triethylsilane; trifluoroacetic acid / 0 - 20 °C 3: triethylamine / methanol / 2 h / 68 °C View Scheme
Multi-step reaction with 2 steps 1: titanium tetrachloride; triethylsilane / dichloromethane / 4 - 5 h / -10 - -5 °C / Large scale 2: potassium carbonate / toluene / 4 - 6 h / 23 - 27 °C / Large scale View Scheme
Multi-step reaction with 3 steps 1: sodium tetrahydroborate / methanol 2: trifluoroacetic acid; triethylsilane 3: potassium carbonate / toluene / 4 - 6 h / 23 - 27 °C / Large scale View Scheme

3-nitro-1-(4-octylphenyl)propan-1-one (899822-97-0) → C21H33NO6

Conditions	Yield
Multi-step reaction with 3 steps 1: sodium tetrahydroborate; methanol / 4.5 h / 0 - 20 °C 2: pyridine / dichloromethane / 20 °C 3: triethylamine / 1,4-dioxane / 24 h / 70 °C View Scheme

3-nitro-1-(4-octylphenyl)propan-1-one (899822-97-0) → 3-nitro-1-(4-octylphenyl)propyl acetate (1373549-72-4)

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium tetrahydroborate; methanol / 4.5 h / 0 - 20 °C 2: pyridine / dichloromethane / 20 °C View Scheme

3-nitro-1-(4-octylphenyl)propan-1-one (899822-97-0) → 1-(3-nitropropyl)-4-octylbenzene (374077-87-9)

Conditions	Yield
With triethylsilane; titanium tetrachloride In dichloromethane at 0 - 30℃; for 1.5h; Temperature;	64 g
Multi-step reaction with 2 steps 1: sodium tetrahydroborate / methanol / 3.5 h / 6 - 20 °C 2: triethylsilane; trifluoroacetic acid / 0 - 20 °C View Scheme
With triethylsilane; titanium tetrachloride In dichloromethane at -10 - -5℃; for 4 - 5h; Large scale;
Multi-step reaction with 2 steps 1: sodium tetrahydroborate / methanol 2: trifluoroacetic acid; triethylsilane View Scheme

Upstream product

• 928165-59-7 3-chloro-1-(4-octylphenyl)propan-1-one 
• 2189-60-8 Octylbenzene 
• 1674-37-9 n-octanophenone 
• 51834-15-2 3-nitropropionic acid chloride 

Downstream Products

• 374077-87-9 1-(3-nitropropyl)-4-octylbenzene 
• 1373549-72-4 3-nitro-1-(4-octylphenyl)propyl acetate 
• 374077-88-0 2-nitro-2-[2-(4-octyl-phenyl)ethyl]propane-1,3-diol 
• 1369968-69-3 (3-nitro-5-(4-octylphenyl)tetrahydrofuran-3-yl)-methanol 
• 162359-55-9 fingolimod 
• 899822-99-2 3-(hydroxymethyl)-3-nitro-1-(4-octylphenyl)butane-1,4-diol 
• 899822-98-1 3-nitro-1-(4-octylphenyl)propan-1-ol 

Relevant articles and documents

An alternative efficient approach for the synthesis of Fingolimod hydrochloride

An efficient process for the synthesis of API Fingolimod Hydrochloride is presented. This proposed synthesis involves simple commercially available octanophenone as a starting material. The route is effective involving seven steps to achieve the target, thus reducing the cycle time, and is cost efficient by 50%. It is an immune modulating drug for the treatment of heart failure and arrhythmias.

INTERMEDIATE COMPOUNDS AND PROCESS FOR THE PREPARATION OF FINGOLIMOD

The present invention relates to processes for the preparation of (2-Amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol hydrochloride (Fingolimod) and pharmaceutically acceptable salts thereof, and intermediates formed in such processes.