(1R,2S)-2-(3,4-Difluorophenyl)cyclopropanaminium (2R)-hydroxy(phenyl)ethanoate supplier

: 220352-36-3
trans-(1R,2R)-2-(3,4-difluorophenyl)cyclopropanecarboxylic acid

: 611-71-2
(R)-Mandelic Acid

: 376608-71-8
trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (2R)-2-hydroxy-2-phenylacetic acid salt

Conditions

Conditions	Yield
Stage #1: trans-(1R,2R)-2-(3,4-difluorophenyl)cyclopropanecarboxylic acid With pyridine; thionyl chloride In toluene at 70℃; for 4h; Stage #2: With sodium azide; tetrabutylammomium bromide; sodium carbonate In water; toluene at 0℃; for 2h; Stage #3: (R)-Mandelic Acid In ethyl acetate at 17 - 25℃; for 3h;	82%

: (1R,2S)-2-(3,4-difluorophenyl)cyclopropanamine

: 611-71-2
(R)-Mandelic Acid

: 376608-71-8
trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (2R)-2-hydroxy-2-phenylacetic acid salt

Conditions

Conditions	Yield
In Isopropyl acetate at 0 - 20℃; for 4h;	70.1%
In methanol at 20 - 25℃; for 14h;	46.4%
In methanol at 20 - 25℃; for 12h;

: 1345413-26-4
trans-(1R,2S)-2-(3,4-difluorophenyl)-1-nitrocyclopropane

: 611-71-2
(R)-Mandelic Acid

: 376608-71-8
trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (2R)-2-hydroxy-2-phenylacetic acid salt

Conditions

Conditions	Yield
Stage #1: trans-(1R,2S)-2-(3,4-difluorophenyl)-1-nitrocyclopropane With hydrogenchloride; zinc In methanol; water at -5 - 0℃; Stage #2: With ammonia In dichloromethane; water at 30℃; for 0.25h; Stage #3: (R)-Mandelic Acid In methanol at 20 - 25℃;	36.61%
Stage #1: trans-(1R,2S)-2-(3,4-difluorophenyl)-1-nitrocyclopropane With hydrogenchloride; zinc In deuteromethanol at -5 - 0℃; Stage #2: (R)-Mandelic Acid In methanol at 0 - 25℃; for 14h;	36.61%

: 367-11-3
ortho-difluorobenzene

: 376608-71-8
trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (2R)-2-hydroxy-2-phenylacetic acid salt

Conditions

Conditions	Yield
Multi-step reaction with 5 steps 1.1: aluminum (III) chloride / dichloromethane / 4 h / 20 - 25 °C / Industry scale 2.1: sodium iodide; 3,5-dihydroxyphenol; sodium nitrite / N,N-dimethyl-formamide / 5 - 30 °C / Inert atmosphere 3.1: (S)-1-methyl-3,3-diphenyl-hexahydropyrrolo[1,2-c][1,3,2]oxazaborole; borane N,N-diethylaniline complex / toluene / 25 - 40 °C / Inert atmosphere 4.1: triphenylphosphine / toluene / 2 h / 0 - 10 °C 5.1: hydrogenchloride; zinc / water; methanol / -5 - 0 °C 5.2: 0.25 h / 30 °C 5.3: 20 - 25 °C View Scheme
Multi-step reaction with 6 steps 1.1: aluminum (III) chloride / dichloromethane / 30 h / 20 - 25 °C / Industry scale 2.1: sodium iodide; sodium azide; 3,5-dihydroxyphenol / N,N-dimethyl-formamide / 5 - 30 °C / Inert atmosphere 3.1: (S)-1-methyl-3,3-diphenyl-hexahydropyrrolo[1,2-c][1,3,2]oxazaborole; borane Ν,Ν-diethylaniline complex / toluene / 1.5 h / 15 - 20 °C / Inert atmosphere 4.1: triphenylphosphine; di-isopropyl azodicarboxylate / toluene / 5 - 10 °C 5.1: hydrogenchloride; zinc / methanol / -5 - 0 °C 5.2: 0.25 h / 10 - 30 °C 6.1: methanol / 12 h / 20 - 25 °C View Scheme
Multi-step reaction with 5 steps 1.1: aluminum (III) chloride / dichloromethane / 20 - 25 °C / Large scale 2.1: sodium nitrite; 3,5-dihydroxyphenol; sodium iodide / N,N-dimethyl-formamide / 5 - 30 °C / Inert atmosphere 3.1: borane Ν,Ν-diethylaniline complex; (S)-1-methyl-3,3-diphenyl-hexahydropyrrolo[1,2-c][1,3,2]oxazaborole / toluene / 25 - 30 °C / Inert atmosphere 4.1: triphenylphosphine; di-isopropyl azodicarboxylate / toluene / 2 h / 0 - 10 °C 5.1: hydrogenchloride; zinc / deuteromethanol / -5 - 0 °C 5.2: 14 h / 0 - 25 °C View Scheme

: 1215969-79-1
3-chloro-1-(3',4'-difluorophenyl)-propan-1-one

: 376608-71-8
trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (2R)-2-hydroxy-2-phenylacetic acid salt

Conditions

Conditions	Yield
Multi-step reaction with 4 steps 1.1: sodium iodide; 3,5-dihydroxyphenol; sodium nitrite / N,N-dimethyl-formamide / 5 - 30 °C / Inert atmosphere 2.1: (S)-1-methyl-3,3-diphenyl-hexahydropyrrolo[1,2-c][1,3,2]oxazaborole; borane N,N-diethylaniline complex / toluene / 25 - 40 °C / Inert atmosphere 3.1: triphenylphosphine / toluene / 2 h / 0 - 10 °C 4.1: hydrogenchloride; zinc / water; methanol / -5 - 0 °C 4.2: 0.25 h / 30 °C 4.3: 20 - 25 °C View Scheme
Multi-step reaction with 5 steps 1.1: sodium iodide; sodium azide; 3,5-dihydroxyphenol / N,N-dimethyl-formamide / 5 - 30 °C / Inert atmosphere 2.1: (S)-1-methyl-3,3-diphenyl-hexahydropyrrolo[1,2-c][1,3,2]oxazaborole; borane Ν,Ν-diethylaniline complex / toluene / 1.5 h / 15 - 20 °C / Inert atmosphere 3.1: triphenylphosphine; di-isopropyl azodicarboxylate / toluene / 5 - 10 °C 4.1: hydrogenchloride; zinc / methanol / -5 - 0 °C 4.2: 0.25 h / 10 - 30 °C 5.1: methanol / 12 h / 20 - 25 °C View Scheme
Multi-step reaction with 4 steps 1.1: sodium nitrite; 3,5-dihydroxyphenol; sodium iodide / N,N-dimethyl-formamide / 5 - 30 °C / Inert atmosphere 2.1: borane Ν,Ν-diethylaniline complex; (S)-1-methyl-3,3-diphenyl-hexahydropyrrolo[1,2-c][1,3,2]oxazaborole / toluene / 25 - 30 °C / Inert atmosphere 3.1: triphenylphosphine; di-isopropyl azodicarboxylate / toluene / 2 h / 0 - 10 °C 4.1: hydrogenchloride; zinc / deuteromethanol / -5 - 0 °C 4.2: 14 h / 0 - 25 °C View Scheme

: 1345413-22-0
1-(3',4'-difluorophenyl)-3-nitro-propan-1-one

: 376608-71-8
trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (2R)-2-hydroxy-2-phenylacetic acid salt

Conditions

Conditions	Yield
Multi-step reaction with 3 steps 1.1: (S)-1-methyl-3,3-diphenyl-hexahydropyrrolo[1,2-c][1,3,2]oxazaborole; borane N,N-diethylaniline complex / toluene / 25 - 40 °C / Inert atmosphere 2.1: triphenylphosphine / toluene / 2 h / 0 - 10 °C 3.1: hydrogenchloride; zinc / water; methanol / -5 - 0 °C 3.2: 0.25 h / 30 °C 3.3: 20 - 25 °C View Scheme
Multi-step reaction with 4 steps 1.1: (S)-1-methyl-3,3-diphenyl-hexahydropyrrolo[1,2-c][1,3,2]oxazaborole; borane Ν,Ν-diethylaniline complex / toluene / 1.5 h / 15 - 20 °C / Inert atmosphere 2.1: triphenylphosphine; di-isopropyl azodicarboxylate / toluene / 5 - 10 °C 3.1: hydrogenchloride; zinc / methanol / -5 - 0 °C 3.2: 0.25 h / 10 - 30 °C 4.1: methanol / 12 h / 20 - 25 °C View Scheme
Multi-step reaction with 3 steps 1.1: borane Ν,Ν-diethylaniline complex; (S)-1-methyl-3,3-diphenyl-hexahydropyrrolo[1,2-c][1,3,2]oxazaborole / toluene / 25 - 30 °C / Inert atmosphere 2.1: triphenylphosphine; di-isopropyl azodicarboxylate / toluene / 2 h / 0 - 10 °C 3.1: hydrogenchloride; zinc / deuteromethanol / -5 - 0 °C 3.2: 14 h / 0 - 25 °C View Scheme

: 1345413-25-3
(1S)-1-(3,4-difluorophenyl)-3-nitropropan-1-ol

: 376608-71-8
trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (2R)-2-hydroxy-2-phenylacetic acid salt

Conditions

Conditions	Yield
Multi-step reaction with 3 steps 1.1: triphenylphosphine; di-isopropyl azodicarboxylate / toluene / 5 - 10 °C 2.1: hydrogenchloride; zinc / methanol / -5 - 0 °C 2.2: 0.25 h / 10 - 30 °C 3.1: methanol / 12 h / 20 - 25 °C View Scheme
Multi-step reaction with 2 steps 1.1: triphenylphosphine; di-isopropyl azodicarboxylate / toluene / 2 h / 0 - 10 °C 2.1: hydrogenchloride; zinc / deuteromethanol / -5 - 0 °C 2.2: 14 h / 0 - 25 °C View Scheme

: 1345413-26-4
trans-(1R,2S)-2-(3,4-difluorophenyl)-1-nitrocyclopropane

: 376608-71-8
trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (2R)-2-hydroxy-2-phenylacetic acid salt

Conditions

Conditions	Yield
Multi-step reaction with 2 steps 1.1: hydrogenchloride; zinc / methanol / -5 - 0 °C 1.2: 0.25 h / 10 - 30 °C 2.1: methanol / 12 h / 20 - 25 °C View Scheme

: 218430-47-8
(E)-methyl 3-(3,4-difluorophenyl)acrylate

: 376608-71-8
trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (2R)-2-hydroxy-2-phenylacetic acid salt

Conditions

Conditions	Yield
Multi-step reaction with 5 steps 1.1: sodium hydride / dimethyl sulfoxide / 0.5 h / 25 °C 1.2: 16 h / 0 - 25 °C 2.1: hydrazine / water; methanol / 16 h / 25 - 70 °C 3.1: sodium nitrite; acetic acid / 0.5 h / 25 °C 4.1: toluene / 1 h / 110 °C 4.2: 2 h / 100 °C 4.3: 25 °C / pH 10 5.1: methanol / 2.5 h / 18 - 45 °C View Scheme

: 112897-97-9
(E)-3-(3,4-difluorophenyl)acrylic acid

: 376608-71-8
trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (2R)-2-hydroxy-2-phenylacetic acid salt

Conditions

Conditions	Yield
Multi-step reaction with 6 steps 1.1: sulfuric acid / 72 h / 60 °C 2.1: sodium hydride / dimethyl sulfoxide / 0.5 h / 25 °C 2.2: 16 h / 0 - 25 °C 3.1: hydrazine / water; methanol / 16 h / 25 - 70 °C 4.1: sodium nitrite; acetic acid / 0.5 h / 25 °C 5.1: toluene / 1 h / 110 °C 5.2: 2 h / 100 °C 5.3: 25 °C / pH 10 6.1: methanol / 2.5 h / 18 - 45 °C View Scheme
Multi-step reaction with 7 steps 1.1: oxalyl dichloride / dichloromethane / 0 h / 25 - 30 °C 1.2: 0 h / 25 - 30 °C 2.1: pyridine / acetone / 0 h / 0 - 30 °C 2.2: 0 - 5 °C 3.1: sodium hydride / dimethyl sulfoxide / 1 h / 25 - 30 °C 3.2: 3 h / 25 - 30 °C 4.1: hydrazine hydrate / methanol / 12 h / 60 - 65 °C 5.1: sodium nitrite; acetic acid / 0.5 h / 25 °C 6.1: toluene / 1 h / 110 °C 6.2: 2 h / 100 °C 6.3: 25 °C / pH 10 7.1: methanol / 2.5 h / 18 - 45 °C View Scheme
Multi-step reaction with 9 steps 1.1: oxalyl dichloride / dichloromethane / 0 h / 25 - 30 °C 1.2: 0 h / 25 - 30 °C 2.1: pyridine / acetone / 0 h / 0 - 30 °C 2.2: 0 - 5 °C 3.1: sodium hydride / dimethyl sulfoxide / 1 h / 25 - 30 °C 3.2: 3 h / 25 - 30 °C 4.1: hydrogenchloride / 1,4-dioxane / 16 h / 25 - 30 °C 5.1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 0.5 h / 20 °C 6.1: hydrazine hydrate / 1,4-dioxane / 3 h / 65 °C 7.1: sodium nitrite; acetic acid / 0.5 h / 25 °C 8.1: toluene / 1 h / 110 °C 8.2: 2 h / 100 °C 8.3: 25 °C / pH 10 9.1: methanol / 2.5 h / 18 - 45 °C View Scheme
Multi-step reaction with 9 steps 1.1: oxalyl dichloride / dichloromethane / 0 h / 25 - 30 °C 1.2: 0 h / 25 - 30 °C 2.1: pyridine / acetone / 0 h / 0 - 30 °C 2.2: 0 - 5 °C 3.1: sodium hydride / dimethyl sulfoxide / 1 h / 25 - 30 °C 3.2: 3 h / 25 - 30 °C 4.1: hydrogenchloride / 1,4-dioxane / 16 h / 25 - 30 °C 5.1: sulfuric acid / 2 h / 60 °C 6.1: hydrazine / water; methanol / 16 h / 25 - 70 °C 7.1: sodium nitrite; acetic acid / 0.5 h / 25 °C 8.1: toluene / 1 h / 110 °C 8.2: 2 h / 100 °C 8.3: 25 °C / pH 10 9.1: methanol / 2.5 h / 18 - 45 °C View Scheme

: methyl trans-2-(3,4-difluorophenyl)cyclopropanecarboxylate

: 376608-71-8
trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (2R)-2-hydroxy-2-phenylacetic acid salt

Conditions

Conditions	Yield
Multi-step reaction with 4 steps 1.1: hydrazine / water; methanol / 16 h / 25 - 70 °C 2.1: sodium nitrite; acetic acid / 0.5 h / 25 °C 3.1: toluene / 1 h / 110 °C 3.2: 2 h / 100 °C 3.3: 25 °C / pH 10 4.1: methanol / 2.5 h / 18 - 45 °C View Scheme

: trans-2-(3,4-difluorophenyl)cyclopropanecarbohydrazide

: 376608-71-8
trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (2R)-2-hydroxy-2-phenylacetic acid salt

Conditions

Conditions	Yield
Multi-step reaction with 3 steps 1.1: sodium nitrite; acetic acid / 0.5 h / 25 °C 2.1: toluene / 1 h / 110 °C 2.2: 2 h / 100 °C 2.3: 25 °C / pH 10 3.1: methanol / 2.5 h / 18 - 45 °C View Scheme

: 376608-66-1
(2E)-3-(3,4-difluorophenyl)acryloylchloride

: 376608-71-8
trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (2R)-2-hydroxy-2-phenylacetic acid salt

Conditions

Conditions	Yield
Multi-step reaction with 6 steps 1.1: pyridine / acetone / 0 h / 0 - 30 °C 1.2: 0 - 5 °C 2.1: sodium hydride / dimethyl sulfoxide / 1 h / 25 - 30 °C 2.2: 3 h / 25 - 30 °C 3.1: hydrazine hydrate / methanol / 12 h / 60 - 65 °C 4.1: sodium nitrite; acetic acid / 0.5 h / 25 °C 5.1: toluene / 1 h / 110 °C 5.2: 2 h / 100 °C 5.3: 25 °C / pH 10 6.1: methanol / 2.5 h / 18 - 45 °C View Scheme
Multi-step reaction with 8 steps 1.1: pyridine / acetone / 0 h / 0 - 30 °C 1.2: 0 - 5 °C 2.1: sodium hydride / dimethyl sulfoxide / 1 h / 25 - 30 °C 2.2: 3 h / 25 - 30 °C 3.1: hydrogenchloride / 1,4-dioxane / 16 h / 25 - 30 °C 4.1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 0.5 h / 20 °C 5.1: hydrazine hydrate / 1,4-dioxane / 3 h / 65 °C 6.1: sodium nitrite; acetic acid / 0.5 h / 25 °C 7.1: toluene / 1 h / 110 °C 7.2: 2 h / 100 °C 7.3: 25 °C / pH 10 8.1: methanol / 2.5 h / 18 - 45 °C View Scheme
Multi-step reaction with 8 steps 1.1: pyridine / acetone / 0 h / 0 - 30 °C 1.2: 0 - 5 °C 2.1: sodium hydride / dimethyl sulfoxide / 1 h / 25 - 30 °C 2.2: 3 h / 25 - 30 °C 3.1: hydrogenchloride / 1,4-dioxane / 16 h / 25 - 30 °C 4.1: sulfuric acid / 2 h / 60 °C 5.1: hydrazine / water; methanol / 16 h / 25 - 70 °C 6.1: sodium nitrite; acetic acid / 0.5 h / 25 °C 7.1: toluene / 1 h / 110 °C 7.2: 2 h / 100 °C 7.3: 25 °C / pH 10 8.1: methanol / 2.5 h / 18 - 45 °C View Scheme

: 1421708-29-3
(E)-3-(3,4-difluorophenyl)-N-methoxy-N-methyl-prop-2-enamide

: 376608-71-8
trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (2R)-2-hydroxy-2-phenylacetic acid salt

Conditions

Conditions	Yield
Multi-step reaction with 5 steps 1.1: sodium hydride / dimethyl sulfoxide / 1 h / 25 - 30 °C 1.2: 3 h / 25 - 30 °C 2.1: hydrazine hydrate / methanol / 12 h / 60 - 65 °C 3.1: sodium nitrite; acetic acid / 0.5 h / 25 °C 4.1: toluene / 1 h / 110 °C 4.2: 2 h / 100 °C 4.3: 25 °C / pH 10 5.1: methanol / 2.5 h / 18 - 45 °C View Scheme
Multi-step reaction with 7 steps 1.1: sodium hydride / dimethyl sulfoxide / 1 h / 25 - 30 °C 1.2: 3 h / 25 - 30 °C 2.1: hydrogenchloride / 1,4-dioxane / 16 h / 25 - 30 °C 3.1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 0.5 h / 20 °C 4.1: hydrazine hydrate / 1,4-dioxane / 3 h / 65 °C 5.1: sodium nitrite; acetic acid / 0.5 h / 25 °C 6.1: toluene / 1 h / 110 °C 6.2: 2 h / 100 °C 6.3: 25 °C / pH 10 7.1: methanol / 2.5 h / 18 - 45 °C View Scheme
Multi-step reaction with 7 steps 1.1: sodium hydride / dimethyl sulfoxide / 1 h / 25 - 30 °C 1.2: 3 h / 25 - 30 °C 2.1: hydrogenchloride / 1,4-dioxane / 16 h / 25 - 30 °C 3.1: sulfuric acid / 2 h / 60 °C 4.1: hydrazine / water; methanol / 16 h / 25 - 70 °C 5.1: sodium nitrite; acetic acid / 0.5 h / 25 °C 6.1: toluene / 1 h / 110 °C 6.2: 2 h / 100 °C 6.3: 25 °C / pH 10 7.1: methanol / 2.5 h / 18 - 45 °C View Scheme

: 2-(3,4-difluorophenyl)-N-methoxy-N-methylcyclopropanecarboxamide

: 376608-71-8
trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (2R)-2-hydroxy-2-phenylacetic acid salt

Conditions

Conditions	Yield
Multi-step reaction with 4 steps 1.1: hydrazine hydrate / methanol / 12 h / 60 - 65 °C 2.1: sodium nitrite; acetic acid / 0.5 h / 25 °C 3.1: toluene / 1 h / 110 °C 3.2: 2 h / 100 °C 3.3: 25 °C / pH 10 4.1: methanol / 2.5 h / 18 - 45 °C View Scheme
Multi-step reaction with 6 steps 1.1: hydrogenchloride / 1,4-dioxane / 16 h / 25 - 30 °C 2.1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 0.5 h / 20 °C 3.1: hydrazine hydrate / 1,4-dioxane / 3 h / 65 °C 4.1: sodium nitrite; acetic acid / 0.5 h / 25 °C 5.1: toluene / 1 h / 110 °C 5.2: 2 h / 100 °C 5.3: 25 °C / pH 10 6.1: methanol / 2.5 h / 18 - 45 °C View Scheme
Multi-step reaction with 6 steps 1.1: hydrogenchloride / 1,4-dioxane / 16 h / 25 - 30 °C 2.1: sulfuric acid / 2 h / 60 °C 3.1: hydrazine / water; methanol / 16 h / 25 - 70 °C 4.1: sodium nitrite; acetic acid / 0.5 h / 25 °C 5.1: toluene / 1 h / 110 °C 5.2: 2 h / 100 °C 5.3: 25 °C / pH 10 6.1: methanol / 2.5 h / 18 - 45 °C View Scheme

: trans-2-(3,4-difluorophenyl)cyclopropanamine

: 611-71-2
(R)-Mandelic Acid

: 376608-71-8
trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (2R)-2-hydroxy-2-phenylacetic acid salt

Conditions

Conditions	Yield
In methanol at 18 - 45℃; for 2.5h;	7.56 g

: trans-2-(3,4-difluorophenyl)cyclopropanecarbonyl azide

: 376608-71-8
trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (2R)-2-hydroxy-2-phenylacetic acid salt

Conditions

Conditions	Yield
Multi-step reaction with 2 steps 1.1: toluene / 1 h / 110 °C 1.2: 2 h / 100 °C 1.3: 25 °C / pH 10 2.1: methanol / 2.5 h / 18 - 45 °C View Scheme

: C10H7ClF2O

: 376608-71-8
trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (2R)-2-hydroxy-2-phenylacetic acid salt

Conditions

Conditions	Yield
Multi-step reaction with 4 steps 1.1: hydrazine hydrate / 1,4-dioxane / 3 h / 65 °C 2.1: sodium nitrite; acetic acid / 0.5 h / 25 °C 3.1: toluene / 1 h / 110 °C 3.2: 2 h / 100 °C 3.3: 25 °C / pH 10 4.1: methanol / 2.5 h / 18 - 45 °C View Scheme

: trans-2-(3,4-difluorophenyl)cyclopropanecarboxylic acid

: 376608-71-8
trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (2R)-2-hydroxy-2-phenylacetic acid salt

Conditions

Conditions	Yield
Multi-step reaction with 5 steps 1.1: sulfuric acid / 2 h / 60 °C 2.1: hydrazine / water; methanol / 16 h / 25 - 70 °C 3.1: sodium nitrite; acetic acid / 0.5 h / 25 °C 4.1: toluene / 1 h / 110 °C 4.2: 2 h / 100 °C 4.3: 25 °C / pH 10 5.1: methanol / 2.5 h / 18 - 45 °C View Scheme
Multi-step reaction with 5 steps 1.1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 0.5 h / 20 °C 2.1: hydrazine hydrate / 1,4-dioxane / 3 h / 65 °C 3.1: sodium nitrite; acetic acid / 0.5 h / 25 °C 4.1: toluene / 1 h / 110 °C 4.2: 2 h / 100 °C 4.3: 25 °C / pH 10 5.1: methanol / 2.5 h / 18 - 45 °C View Scheme

: 51336-95-9
2-chloro-1-(3,4-difluorophenyl)ethan-1-one

: 376608-71-8
trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (2R)-2-hydroxy-2-phenylacetic acid salt

Conditions

Conditions	Yield
Multi-step reaction with 5 steps 1.1: N,N-diethylaniline hydrochloride; sodium tetrahydroborate; (S)-diphenylprolinol / chloroform; 1,2-dimethoxyethane / 2 h / 0 - 30 °C 2.1: potassium tert-butylate / toluene / 30 h / 30 - 50 °C 3.1: thionyl chloride / toluene / 2 h / Reflux 3.2: 15 - 30 °C 4.1: sodium hydroxide; sodium hypochlorite / 16 h / 25 - 40 °C 5.1: Isopropyl acetate / 4 h / 0 - 20 °C View Scheme
Multi-step reaction with 5 steps 1.1: (S)-1-methyl-3,3-diphenyl-hexahydropyrrolo[1,2-c][1,3,2]oxazaborole; borane-THF / toluene / 3 h / 10 °C / Inert atmosphere 2.1: sodium t-butanolate / toluene / 2 h / 20 °C 2.2: 25 h / 40 - 60 °C 3.1: ammonia; Methyl formate; sodium methylate / methanol / 10 h / 70 °C / 1500.15 Torr 4.1: sodium hydroxide; sodium hypochlorite / water / 2 h / 0 - 55 °C 5.1: methanol / 14 h / 20 - 25 °C View Scheme
Multi-step reaction with 5 steps 1.1: (S)-5,5-diphenyl-2-methoxy-3,4-propano-1,3,2-oxazaborolidine; dimethylsulfide borane complex / 1 h / 15 °C 2.1: sodium t-butanolate / toluene / 2 h / 20 °C 2.2: 25 h / 40 - 60 °C 3.1: ammonia; Methyl formate; sodium methylate / methanol / 10 h / 70 °C / 1500.15 Torr 4.1: sodium hydroxide; sodium hypochlorite / water / 2 h / 0 - 55 °C 5.1: methanol / 14 h / 20 - 25 °C View Scheme
Multi-step reaction with 5 steps 1.1: sodium tetrahydroborate; Trimethyl borate; (S)-diphenylprolinol / toluene / 0.97 h / 38 °C / Inert atmosphere 2.1: sodium t-butanolate / toluene / 13 h / 38 - 58 °C 3.1: sodium hydroxide / water / 1.5 h / 48 °C 4.1: oxalyl dichloride / dichloromethane; N,N-dimethyl-formamide / 1.5 h / 30 °C 4.2: 1.5 h 5.1: sodium hydroxide; sodium hypochlorite / water / 4.5 h / 20 - 38 °C 5.2: 1.5 h View Scheme

: 1006376-60-8
(1S)-2-chloro-1-(3,4-difluorophenyl)-1-ethanol

: 376608-71-8
trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (2R)-2-hydroxy-2-phenylacetic acid salt

Conditions

Conditions	Yield
Multi-step reaction with 4 steps 1.1: potassium tert-butylate / toluene / 30 h / 30 - 50 °C 2.1: thionyl chloride / toluene / 2 h / Reflux 2.2: 15 - 30 °C 3.1: sodium hydroxide; sodium hypochlorite / 16 h / 25 - 40 °C 4.1: Isopropyl acetate / 4 h / 0 - 20 °C View Scheme
Multi-step reaction with 4 steps 1.1: sodium t-butanolate / toluene / 2 h / 20 °C 1.2: 25 h / 40 - 60 °C 2.1: ammonia; Methyl formate; sodium methylate / methanol / 10 h / 70 °C / 1500.15 Torr 3.1: sodium hydroxide; sodium hypochlorite / water / 2 h / 0 - 55 °C 4.1: methanol / 14 h / 20 - 25 °C View Scheme
Multi-step reaction with 4 steps 1.1: sodium t-butanolate / toluene / 13 h / 38 - 58 °C 2.1: sodium hydroxide / water / 1.5 h / 48 °C 3.1: oxalyl dichloride / dichloromethane; N,N-dimethyl-formamide / 1.5 h / 30 °C 3.2: 1.5 h 4.1: sodium hydroxide; sodium hypochlorite / water / 4.5 h / 20 - 38 °C 4.2: 1.5 h View Scheme

: 220352-36-3
trans-(1R,2R)-2-(3,4-difluorophenyl)cyclopropanecarboxylic acid

: 376608-71-8
trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (2R)-2-hydroxy-2-phenylacetic acid salt

Conditions

Conditions	Yield
Multi-step reaction with 3 steps 1.1: thionyl chloride / toluene / 2 h / Reflux 1.2: 15 - 30 °C 2.1: sodium hydroxide; sodium hypochlorite / 16 h / 25 - 40 °C 3.1: Isopropyl acetate / 4 h / 0 - 20 °C View Scheme
Multi-step reaction with 2 steps 1.1: oxalyl dichloride / dichloromethane; N,N-dimethyl-formamide / 1.5 h / 30 °C 1.2: 1.5 h 2.1: sodium hydroxide; sodium hypochlorite / water / 4.5 h / 20 - 38 °C 2.2: 1.5 h View Scheme

: 1006376-61-9
(1R,2R)-2-(3,4-difluorophenyl)-1-cyclopropanecarboxylic acid ethyl ester

: 376608-71-8
trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (2R)-2-hydroxy-2-phenylacetic acid salt

Conditions

Conditions	Yield
Multi-step reaction with 3 steps 1: ammonia; Methyl formate; sodium methylate / methanol / 10 h / 70 °C / 1500.15 Torr 2: sodium hydroxide; sodium hypochlorite / water / 2 h / 0 - 55 °C 3: methanol / 14 h / 20 - 25 °C View Scheme
Multi-step reaction with 3 steps 1.1: sodium hydroxide / water / 1.5 h / 48 °C 2.1: oxalyl dichloride / dichloromethane; N,N-dimethyl-formamide / 1.5 h / 30 °C 2.2: 1.5 h 3.1: sodium hydroxide; sodium hypochlorite / water / 4.5 h / 20 - 38 °C 3.2: 1.5 h View Scheme

: 1006376-62-0
(1R,2R)-trans-2(3,4-difluorophenyl)cyclopropyl carboxamide

: 376608-71-8
trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (2R)-2-hydroxy-2-phenylacetic acid salt

Conditions

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium hydroxide; sodium hypochlorite / water / 2 h / 0 - 55 °C 2: methanol / 14 h / 20 - 25 °C View Scheme

: 1006376-62-0
(1R,2R)-trans-2(3,4-difluorophenyl)cyclopropyl carboxamide

: 611-71-2
(R)-Mandelic Acid

: 376608-71-8
trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (2R)-2-hydroxy-2-phenylacetic acid salt

Conditions

Conditions	Yield
Stage #1: (1R,2R)-trans-2(3,4-difluorophenyl)cyclopropyl carboxamide With sodium hypochlorite; sodium hydroxide In water at 20 - 38℃; for 4.5h; Stage #2: (R)-Mandelic Acid In ethanol for 1.5h; Temperature;

: 376608-71-8
trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (2R)-2-hydroxy-2-phenylacetic acid salt

: 24424-99-5
di-tert-butyl dicarbonate

: 1350749-64-2
(tert-butyl (1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)carbamate

Conditions

Conditions	Yield
Stage #1: trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (2R)-2-hydroxy-2-phenylacetic acid salt With N-ethyl-N,N-diisopropylamine In dichloromethane at 10 - 20℃; for 1h; Stage #2: di-tert-butyl dicarbonate In dichloromethane at 10 - 20℃; for 4h; Solvent;	99%
Stage #1: trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (2R)-2-hydroxy-2-phenylacetic acid salt With N-ethyl-N,N-diisopropylamine In dichloromethane at 20 - 25℃; for 0.5h; Stage #2: di-tert-butyl dicarbonate In dichloromethane at 20 - 25℃; for 3h;	94.51%

: 376608-71-8
trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (2R)-2-hydroxy-2-phenylacetic acid salt

: 1354945-69-9
9-[(1’R,2’S,3’S,4’S)-2’,3’-dihydroxyl-4'-hydroxyethoxycyclopenta-1'-yl]-9H-2-thiopropyl-6-chloro-8-azepine

: 274693-27-5
ticagrelor

Conditions

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In 2-methyltetrahydrofuran at 20 - 30℃; for 3h; Reagent/catalyst; Solvent;	87%
With potassium carbonate In acetonitrile at 25 - 30℃;	62.19%
With N-ethyl-N,N-diisopropylamine In acetonitrile at 25 - 30℃; for 4h;	2.29 g

: 2-({(3aR,4S,6R,6aS)-6-[7-chloro-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-3-yl]-2,2-dimethyltetrahydro-3aH-cyclopentadiene[d][1,3]dioxolene-4-yl}oxy)ethanol

: 376608-71-8
trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (2R)-2-hydroxy-2-phenylacetic acid salt

: 274693-26-4
[3aR-[3aα,4α,6α,(1R,2S),6aα]]-2-[6-[[[7-(2-(3,4-difluorophenyl)cyclopropyl)]amino-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]tetrahydro-2,2-dimethyl-4H-cyclopenteno-1,3-dioxolan-4-yl]oxy]ethanol

Conditions

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 20℃;	84%
With potassium carbonate In toluene at 30℃; for 24h;	81.31%
With potassium carbonate In water at 30℃; Product distribution / selectivity;

: 376608-71-8
trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (2R)-2-hydroxy-2-phenylacetic acid salt

: C15H16F3N3OS

: C24H25F5N4S*2ClH

Conditions

Conditions	Yield
Stage #1: trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (2R)-2-hydroxy-2-phenylacetic acid salt; C15H16F3N3OS With sodium tris(acetoxy)borohydride; acetic acid In 1,2-dichloro-ethane at 20℃; for 2h; Molecular sieve; Stage #2: With hydrogenchloride In diethyl ether; dichloromethane at 20℃; for 0.5h;	79%
Stage #1: trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (2R)-2-hydroxy-2-phenylacetic acid salt; C15H16F3N3OS With sodium tris(acetoxy)borohydride; acetic acid In 1,2-dichloro-ethane at 20℃; for 2h; Molecular sieve; Stage #2: With hydrogenchloride In diethyl ether; dichloromethane at 20℃; for 0.5h;	79%

: 376608-71-8
trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (2R)-2-hydroxy-2-phenylacetic acid salt

: 79099-07-3
N-tert-butyloxycarbonylpiperidin-4-one

: C19H26F2N2O2

Conditions

Conditions	Yield
With sodium tris(acetoxy)borohydride; acetic acid In 1,2-dichloro-ethane at 20℃; for 5h;	78%
With sodium tris(acetoxy)borohydride; acetic acid In 1,2-dichloro-ethane at 20℃; for 5h;	78%

: 145783-15-9
4,6-dichloro-2-(propylsulfanyl)-5-pyrimidinamine

: 376608-71-8
trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (2R)-2-hydroxy-2-phenylacetic acid salt

: 6-chloro-N4-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-2-(propylthio)pyrimidine-4,5-diamine

Conditions

Conditions	Yield
With triethylamine In 1,2-dimethoxyethane at 100℃; for 7h;	68%

: 376608-71-8
trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (2R)-2-hydroxy-2-phenylacetic acid salt

: C14H14F3N3OS

: C23H23F5N4S*2ClH

Conditions

Conditions	Yield
Stage #1: trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (2R)-2-hydroxy-2-phenylacetic acid salt; C14H14F3N3OS With sodium tris(acetoxy)borohydride; acetic acid In dichloromethane at 20℃; for 3h; Molecular sieve; Stage #2: With hydrogenchloride In diethyl ether; dichloromethane at 20℃; for 0.5h;	54%

: 376608-71-8
trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (2R)-2-hydroxy-2-phenylacetic acid salt

: C14H14F3N3OS

A: C23H23F5N4S*2ClH

B: C23H23F5N4S*2ClH

Conditions

Conditions	Yield
Stage #1: trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (2R)-2-hydroxy-2-phenylacetic acid salt; C14H14F3N3OS With sodium tris(acetoxy)borohydride; acetic acid In 1,2-dichloro-ethane at 20℃; for 3h; Stage #2: With hydrogenchloride In diethyl ether; dichloromethane at 20℃; for 0.5h;	A 54% B 34%

...Expand

: 376608-71-8
trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (2R)-2-hydroxy-2-phenylacetic acid salt

: 137076-22-3
tert butyl 4-formylpiperidine-1-carboxylate

: C20H28F2N2O2

Conditions

Conditions	Yield
With sodium cyanoborohydride; acetic acid In methanol at 0℃; for 2h;	45%
With sodium cyanoborohydride; acetic acid In methanol for 2h; Cooling with ice;	45%

: 376608-71-8
trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (2R)-2-hydroxy-2-phenylacetic acid salt

: C14H14F3N3OS

: C23H23F5N4S*2ClH

Conditions

Conditions	Yield
Stage #1: trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (2R)-2-hydroxy-2-phenylacetic acid salt; C14H14F3N3OS With sodium tris(acetoxy)borohydride; acetic acid In dichloromethane at 20℃; for 3h; Molecular sieve; Stage #2: With hydrogenchloride In diethyl ether; dichloromethane at 20℃; for 0.5h;	34%

: 376608-71-8
trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (2R)-2-hydroxy-2-phenylacetic acid salt

: 274693-26-4
[3aR-[3aα,4α,6α,(1R,2S),6aα]]-2-[6-[[[7-(2-(3,4-difluorophenyl)cyclopropyl)]amino-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]tetrahydro-2,2-dimethyl-4H-cyclopenteno-1,3-dioxolan-4-yl]oxy]ethanol

Conditions

Conditions	Yield
Multi-step reaction with 6 steps 1.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 0.5 h / 20 - 25 °C 1.2: 3 h / 20 - 25 °C 2.1: lithium hexamethyldisilazane / tetrahydrofuran / 1 h / -25 - -15 °C 2.2: 1.5 h / -25 - -15 °C 2.3: 0.08 h 3.1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 2 h / 20 - 25 °C 4.1: sodium hydrogencarbonate; sodium dithionite / water; acetone / 2 h / 20 - 25 °C 5.1: sodium azide; acetic acid / toluene; water / 1 h / 5 - 10 °C 6.1: iodine / acetone / 2 h / 25 - 60 °C View Scheme

Yield

Multi-step reaction with 6 steps
1.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 0.5 h / 20 - 25 °C
1.2: 3 h / 20 - 25 °C
2.1: lithium hexamethyldisilazane / tetrahydrofuran / 1 h / -25 - -15 °C
2.2: 1.5 h / -25 - -15 °C
2.3: 0.08 h
3.1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 2 h / 20 - 25 °C
4.1: sodium hydrogencarbonate; sodium dithionite / water; acetone / 2 h / 20 - 25 °C
5.1: sodium azide; acetic acid / toluene; water / 1 h / 5 - 10 °C
6.1: iodine / acetone / 2 h / 25 - 60 °C
View Scheme

: 376608-71-8
trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (2R)-2-hydroxy-2-phenylacetic acid salt

: 274693-27-5
ticagrelor

Conditions

Conditions	Yield
Multi-step reaction with 6 steps 1.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 0.5 h / 20 - 25 °C 1.2: 3 h / 20 - 25 °C 2.1: lithium hexamethyldisilazane / tetrahydrofuran / 1 h / -25 - -15 °C 2.2: 1.5 h / -25 - -15 °C 2.3: 0.08 h 3.1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 2 h / 20 - 25 °C 4.1: sodium hydrogencarbonate; sodium dithionite / water; acetone / 2 h / 20 - 25 °C 5.1: sodium azide; acetic acid / toluene; water / 1 h / 5 - 10 °C 6.1: hydrogenchloride; water / toluene; methanol / 2 h / 25 - 30 °C 6.2: pH > 8 View Scheme
Multi-step reaction with 7 steps 1.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 0.5 h / 20 - 25 °C 1.2: 3 h / 20 - 25 °C 2.1: lithium hexamethyldisilazane / tetrahydrofuran / 1 h / -25 - -15 °C 2.2: 1.5 h / -25 - -15 °C 2.3: 0.08 h 3.1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 2 h / 20 - 25 °C 4.1: sodium hydrogencarbonate; sodium dithionite / water; acetone / 2 h / 20 - 25 °C 5.1: sodium azide; acetic acid / toluene; water / 1 h / 5 - 10 °C 6.1: potassium carbonate / acetone / 24 h / 25 - 60 °C 7.1: hydrogenchloride; water / methanol / 5.5 h / 20 - 55 °C 7.2: 25 - 30 °C / pH 10 View Scheme
Multi-step reaction with 9 steps 1.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 0.5 h / 20 - 25 °C 1.2: 3 h / 20 - 25 °C 2.1: lithium hexamethyldisilazane / tetrahydrofuran / 1 h / -25 - -15 °C 2.2: 1.5 h / -25 - -15 °C 2.3: 0.08 h 3.1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 2 h / 20 - 25 °C 4.1: sodium hydrogencarbonate; sodium dithionite / water; acetone / 2 h / 20 - 25 °C 5.1: sodium azide; acetic acid / toluene; water / 1 h / 5 - 10 °C 6.1: iodine / acetone / 2 h / 25 - 60 °C 7.1: potassium carbonate / acetone / 20 h / 55 - 60 °C 8.1: hydrogenchloride; water / methanol / 5 h / 20 - 25 °C 8.2: 25 - 30 °C / pH 10 9.1: formic acid / palladium 10% on activated carbon / 50 °C View Scheme
Multi-step reaction with 4 steps 1.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 1 h / 10 - 20 °C 1.2: 4 h / 10 - 20 °C 2.1: lithium hexamethyldisilazane / tetrahydrofuran / 2 h / -80 - -75 °C / Inert atmosphere 3.1: potassium carbonate / tetrahydrofuran / 3 h / 10 - 20 °C / pH 9 4.1: zinc; acetic acid / dichloromethane / 2 h / 5 - 10 °C 4.2: 2 h / 0 - 3 °C 4.3: 4 h View Scheme

: 376608-71-8
trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (2R)-2-hydroxy-2-phenylacetic acid salt

: 1383715-58-9
tert-butyl (6-chloro-5-nitro-2-(propylthio)pyrimidin-4-yl)((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)carbamate

Conditions

Conditions	Yield
Multi-step reaction with 2 steps 1.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 0.5 h / 20 - 25 °C 1.2: 3 h / 20 - 25 °C 2.1: lithium hexamethyldisilazane / tetrahydrofuran / 1 h / -25 - -15 °C 2.2: 1.5 h / -25 - -15 °C 2.3: 0.08 h View Scheme
Multi-step reaction with 2 steps 1.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 1 h / 10 - 20 °C 1.2: 4 h / 10 - 20 °C 2.1: lithium hexamethyldisilazane / tetrahydrofuran / 2 h / -80 - -75 °C / Inert atmosphere View Scheme

: 376608-71-8
trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (2R)-2-hydroxy-2-phenylacetic acid salt

: 1383715-59-0
2-[[(3aR,4S,6R,6aS)-6-[[4-[N-[(1R,2S)-2-(3,4-difluorophenyl)cyclopropan-1-yl]-N-tert-butoxycarbonyl]amino]-2-(propylthio)-5-nitropyrimidin-6-yl]-2,2-dimethyl-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]oxy] ethanol

Conditions

Conditions	Yield
Multi-step reaction with 3 steps 1.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 0.5 h / 20 - 25 °C 1.2: 3 h / 20 - 25 °C 2.1: lithium hexamethyldisilazane / tetrahydrofuran / 1 h / -25 - -15 °C 2.2: 1.5 h / -25 - -15 °C 2.3: 0.08 h 3.1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 2 h / 20 - 25 °C View Scheme
Multi-step reaction with 3 steps 1.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 1 h / 10 - 20 °C 1.2: 4 h / 10 - 20 °C 2.1: lithium hexamethyldisilazane / tetrahydrofuran / 2 h / -80 - -75 °C / Inert atmosphere 3.1: potassium carbonate / tetrahydrofuran / 3 h / 10 - 20 °C / pH 9 View Scheme

: 376608-71-8
trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (2R)-2-hydroxy-2-phenylacetic acid salt

: 1383715-60-3
2-[[(3aR,4S,6R,6aS)-6-[[4-[N-[(1R,2S)-2-(3,4-difluorophenyl)cyclopropan-1-yl]-N-tert-butoxycarbonyl]amino]-2-(propylthio)-5-aminopyrimidin-6-yl]-2,2-dimethyl-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]oxy]ethanol

Conditions

Conditions	Yield
Multi-step reaction with 4 steps 1.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 0.5 h / 20 - 25 °C 1.2: 3 h / 20 - 25 °C 2.1: lithium hexamethyldisilazane / tetrahydrofuran / 1 h / -25 - -15 °C 2.2: 1.5 h / -25 - -15 °C 2.3: 0.08 h 3.1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 2 h / 20 - 25 °C 4.1: sodium hydrogencarbonate; sodium dithionite / water; acetone / 2 h / 20 - 25 °C View Scheme

Yield

Multi-step reaction with 4 steps
1.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 0.5 h / 20 - 25 °C
1.2: 3 h / 20 - 25 °C
2.1: lithium hexamethyldisilazane / tetrahydrofuran / 1 h / -25 - -15 °C
2.2: 1.5 h / -25 - -15 °C
2.3: 0.08 h
3.1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 2 h / 20 - 25 °C
4.1: sodium hydrogencarbonate; sodium dithionite / water; acetone / 2 h / 20 - 25 °C
View Scheme

: 376608-71-8
trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (2R)-2-hydroxy-2-phenylacetic acid salt

: 1383715-61-4
tert-butyl N-[3-[(3aS,4R,6S,6aR)-6-(2-hydroxyethoxy)-2,2-dimethyl-hexahydrocyclopenta[d][1,3]dioxol-4-yl]-5-(propylsulfanyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl]-N-[(1R,2S)-2-(3,4-difluorophenyl)cyclopropyl]carbamate

Conditions

Conditions	Yield
Multi-step reaction with 5 steps 1.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 0.5 h / 20 - 25 °C 1.2: 3 h / 20 - 25 °C 2.1: lithium hexamethyldisilazane / tetrahydrofuran / 1 h / -25 - -15 °C 2.2: 1.5 h / -25 - -15 °C 2.3: 0.08 h 3.1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 2 h / 20 - 25 °C 4.1: sodium hydrogencarbonate; sodium dithionite / water; acetone / 2 h / 20 - 25 °C 5.1: sodium azide; acetic acid / toluene; water / 1 h / 5 - 10 °C View Scheme

Yield

Multi-step reaction with 5 steps
1.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 0.5 h / 20 - 25 °C
1.2: 3 h / 20 - 25 °C
2.1: lithium hexamethyldisilazane / tetrahydrofuran / 1 h / -25 - -15 °C
2.2: 1.5 h / -25 - -15 °C
2.3: 0.08 h
3.1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 2 h / 20 - 25 °C
4.1: sodium hydrogencarbonate; sodium dithionite / water; acetone / 2 h / 20 - 25 °C
5.1: sodium azide; acetic acid / toluene; water / 1 h / 5 - 10 °C
View Scheme

: 376608-71-8
trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (2R)-2-hydroxy-2-phenylacetic acid salt

: 1383715-62-5
2-({(3aR,4S,6R,6aS)-6-[7-{[[N-(IR,2S)-2-(3,4-difluorophenyl)-cyclopropan-1-yl]-N-benzyl]amino}-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]-2,2-dimethyl-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl}oxy)ethanol

Conditions

Conditions	Yield
Multi-step reaction with 7 steps 1.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 0.5 h / 20 - 25 °C 1.2: 3 h / 20 - 25 °C 2.1: lithium hexamethyldisilazane / tetrahydrofuran / 1 h / -25 - -15 °C 2.2: 1.5 h / -25 - -15 °C 2.3: 0.08 h 3.1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 2 h / 20 - 25 °C 4.1: sodium hydrogencarbonate; sodium dithionite / water; acetone / 2 h / 20 - 25 °C 5.1: sodium azide; acetic acid / toluene; water / 1 h / 5 - 10 °C 6.1: iodine / acetone / 2 h / 25 - 60 °C 7.1: potassium carbonate / acetone / 20 h / 55 - 60 °C View Scheme

Yield

Multi-step reaction with 7 steps
1.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 0.5 h / 20 - 25 °C
1.2: 3 h / 20 - 25 °C
2.1: lithium hexamethyldisilazane / tetrahydrofuran / 1 h / -25 - -15 °C
2.2: 1.5 h / -25 - -15 °C
2.3: 0.08 h
3.1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 2 h / 20 - 25 °C
4.1: sodium hydrogencarbonate; sodium dithionite / water; acetone / 2 h / 20 - 25 °C
5.1: sodium azide; acetic acid / toluene; water / 1 h / 5 - 10 °C
6.1: iodine / acetone / 2 h / 25 - 60 °C
7.1: potassium carbonate / acetone / 20 h / 55 - 60 °C
View Scheme

: 376608-71-8
trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (2R)-2-hydroxy-2-phenylacetic acid salt

: 1383715-63-6
C30H34F2N6O4S

Conditions

Conditions	Yield
Multi-step reaction with 8 steps 1.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 0.5 h / 20 - 25 °C 1.2: 3 h / 20 - 25 °C 2.1: lithium hexamethyldisilazane / tetrahydrofuran / 1 h / -25 - -15 °C 2.2: 1.5 h / -25 - -15 °C 2.3: 0.08 h 3.1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 2 h / 20 - 25 °C 4.1: sodium hydrogencarbonate; sodium dithionite / water; acetone / 2 h / 20 - 25 °C 5.1: sodium azide; acetic acid / toluene; water / 1 h / 5 - 10 °C 6.1: iodine / acetone / 2 h / 25 - 60 °C 7.1: potassium carbonate / acetone / 20 h / 55 - 60 °C 8.1: hydrogenchloride; water / methanol / 5 h / 20 - 25 °C 8.2: 25 - 30 °C / pH 10 View Scheme

Yield

Multi-step reaction with 8 steps
1.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 0.5 h / 20 - 25 °C
1.2: 3 h / 20 - 25 °C
2.1: lithium hexamethyldisilazane / tetrahydrofuran / 1 h / -25 - -15 °C
2.2: 1.5 h / -25 - -15 °C
2.3: 0.08 h
3.1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 2 h / 20 - 25 °C
4.1: sodium hydrogencarbonate; sodium dithionite / water; acetone / 2 h / 20 - 25 °C
5.1: sodium azide; acetic acid / toluene; water / 1 h / 5 - 10 °C
6.1: iodine / acetone / 2 h / 25 - 60 °C
7.1: potassium carbonate / acetone / 20 h / 55 - 60 °C
8.1: hydrogenchloride; water / methanol / 5 h / 20 - 25 °C
8.2: 25 - 30 °C / pH 10
View Scheme

: 376608-71-8
trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (2R)-2-hydroxy-2-phenylacetic acid salt

: 1383715-64-7
2-({(3aR,45,6R,6aS)-6-[7-{[[N-(1R,2S)-2-(3,4-difluorophenyl)-cyclopropan-1-yl]-N-tert-butoxycarbonyl]amino}-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]-2,2-dimethyl-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl}oxy)-O-tertbutoxycarbonylethanol

Conditions

Conditions	Yield
Multi-step reaction with 6 steps 1.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 0.5 h / 20 - 25 °C 1.2: 3 h / 20 - 25 °C 2.1: lithium hexamethyldisilazane / tetrahydrofuran / 1 h / -25 - -15 °C 2.2: 1.5 h / -25 - -15 °C 2.3: 0.08 h 3.1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 2 h / 20 - 25 °C 4.1: sodium hydrogencarbonate; sodium dithionite / water; acetone / 2 h / 20 - 25 °C 5.1: sodium azide; acetic acid / toluene; water / 1 h / 5 - 10 °C 6.1: potassium carbonate / acetone / 24 h / 25 - 60 °C View Scheme

Yield

Multi-step reaction with 6 steps
1.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 0.5 h / 20 - 25 °C
1.2: 3 h / 20 - 25 °C
2.1: lithium hexamethyldisilazane / tetrahydrofuran / 1 h / -25 - -15 °C
2.2: 1.5 h / -25 - -15 °C
2.3: 0.08 h
3.1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 2 h / 20 - 25 °C
4.1: sodium hydrogencarbonate; sodium dithionite / water; acetone / 2 h / 20 - 25 °C
5.1: sodium azide; acetic acid / toluene; water / 1 h / 5 - 10 °C
6.1: potassium carbonate / acetone / 24 h / 25 - 60 °C
View Scheme

Product Name

(1R,2S)-2-(3,4-Difluorophenyl)cyclopropanamine (2R)-Hydroxy(phenyl)ethanoate

Synthetic route

(1R,2S)-2-(3,4-Difluorophenyl)cyclopropanaminium (2R)-hydroxy(phenyl)ethanoate Specification

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