376608-71-8

Basic information

• Product Name: (1R,2S)-2-(3,4-Difluorophenyl)cyclopropanamine (2R)-Hydroxy(phenyl)ethanoate
• Synonyms: (1R,2R)-2-(3,4-difluorophenyl)cyclopropanamine(S)-(carboxylato(phenyl)methyl)holmium;trans-(1R,2S)-2-(2,3-difluorophenyl)cyclopropylaMine Mandelat;(1R,2S)-2-(3,4-Difluorophenyl)cyclopropanaminium (2R)-hydroxy(phenyl)ethanoate;(alphaR)-alpha-Hydroxybenzeneacetic acid compd. with (1R,2S)-2-(3,4-difluorophenyl)cyclopropanamine;(αR)-(1R,2S)-α-hydroxy-Benzeneacetic acid-coMpd.with 2-(3,4-difluorophenyl)cyclopropanaMine(1:1);Ticagrelor InterMediate 4;(1R,2S)-2-(3,4-Difluorophenyl)cyclopropanaMine (2R)-Hydroxy(phenyl)ethanoate;(αR)-α-Hydroxybenzeneacetic Acid coMpd. with (1R,2S)-2-(3,4-Difluorophenyl)cyclopropanaMine
• CAS NO: 376608-71-8
• Molecular Formula: C₈H₈O₃*C₉H₉F₂N
• Molecular Weight: 321.3185864
• EINECS: 1308068-626-2
• Product Categories: Intermediate of Ticagrelor
• Mol File: 376608-71-8.mol

Chemical Properties

• Appearance: /
• Storage Temp.: under inert gas (nitrogen or Argon) at 2–8 °C
• CAS DataBase Reference: (1R,2S)-2-(3,4-Difluorophenyl)cyclopropanamine (2R)-Hydroxy(phenyl)ethanoate(CAS DataBase Reference)
• NIST Chemistry Reference: (1R,2S)-2-(3,4-Difluorophenyl)cyclopropanamine (2R)-Hydroxy(phenyl)ethanoate(376608-71-8)
• EPA Substance Registry System: (1R,2S)-2-(3,4-Difluorophenyl)cyclopropanamine (2R)-Hydroxy(phenyl)ethanoate(376608-71-8)

Safety Data

• Safety Statements: 24/25
• Hazardous Substances Data: 376608-71-8(Hazardous Substances Data)

Usage

References

http://www.tradekorea.com/product/detail/P483269/Ticagrelor-intermediates---CAS-376608-71-8.html https://en.wikipedia.org/wiki/Ticagrelor

Synthetic route

trans-(1R,2R)-2-(3,4-difluorophenyl)cyclopropanecarboxylic acid (220352-36-3) + (R)-Mandelic Acid (611-71-2) → trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (2R)-2-hydroxy-2-phenylacetic acid salt (376608-71-8)

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 + (R)-Mandelic Acid (611-71-2) → trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (2R)-2-hydroxy-2-phenylacetic acid salt (376608-71-8)

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;

trans-(1R,2S)-2-(3,4-difluorophenyl)-1-nitrocyclopropane (1345413-26-4) + (R)-Mandelic Acid (611-71-2) → trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (2R)-2-hydroxy-2-phenylacetic acid salt (376608-71-8)

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%

ortho-difluorobenzene (367-11-3) → trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (2R)-2-hydroxy-2-phenylacetic acid salt (376608-71-8)

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

3-chloro-1-(3',4'-difluorophenyl)-propan-1-one (1215969-79-1) → trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (2R)-2-hydroxy-2-phenylacetic acid salt (376608-71-8)

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

1-(3',4'-difluorophenyl)-3-nitro-propan-1-one (1345413-22-0) → trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (2R)-2-hydroxy-2-phenylacetic acid salt (376608-71-8)

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

(1S)-1-(3,4-difluorophenyl)-3-nitropropan-1-ol (1345413-25-3) → trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (2R)-2-hydroxy-2-phenylacetic acid salt (376608-71-8)

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

trans-(1R,2S)-2-(3,4-difluorophenyl)-1-nitrocyclopropane (1345413-26-4) → trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (2R)-2-hydroxy-2-phenylacetic acid salt (376608-71-8)

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

(E)-methyl 3-(3,4-difluorophenyl)acrylate (218430-47-8) → trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (2R)-2-hydroxy-2-phenylacetic acid salt (376608-71-8)

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

(E)-3-(3,4-difluorophenyl)acrylic acid (112897-97-9) → trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (2R)-2-hydroxy-2-phenylacetic acid salt (376608-71-8)

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

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

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

(2E)-3-(3,4-difluorophenyl)acryloylchloride (376608-66-1) → trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (2R)-2-hydroxy-2-phenylacetic acid salt (376608-71-8)

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

(E)-3-(3,4-difluorophenyl)-N-methoxy-N-methyl-prop-2-enamide (1421708-29-3) → trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (2R)-2-hydroxy-2-phenylacetic acid salt (376608-71-8)

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

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 + (R)-Mandelic Acid (611-71-2) → trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (2R)-2-hydroxy-2-phenylacetic acid salt (376608-71-8)

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

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

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

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

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

2-chloro-1-(3,4-difluorophenyl)ethan-1-one (51336-95-9) → trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (2R)-2-hydroxy-2-phenylacetic acid salt (376608-71-8)

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

(1S)-2-chloro-1-(3,4-difluorophenyl)-1-ethanol (1006376-60-8) → trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (2R)-2-hydroxy-2-phenylacetic acid salt (376608-71-8)

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

trans-(1R,2R)-2-(3,4-difluorophenyl)cyclopropanecarboxylic acid (220352-36-3) → trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (2R)-2-hydroxy-2-phenylacetic acid salt (376608-71-8)

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

(1R,2R)-2-(3,4-difluorophenyl)-1-cyclopropanecarboxylic acid ethyl ester (1006376-61-9) → trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (2R)-2-hydroxy-2-phenylacetic acid salt (376608-71-8)

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

(1R,2R)-trans-2(3,4-difluorophenyl)cyclopropyl carboxamide (1006376-62-0) → trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (2R)-2-hydroxy-2-phenylacetic acid salt (376608-71-8)

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

(1R,2R)-trans-2(3,4-difluorophenyl)cyclopropyl carboxamide (1006376-62-0) + (R)-Mandelic Acid (611-71-2) → trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (2R)-2-hydroxy-2-phenylacetic acid salt (376608-71-8)

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;

trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (2R)-2-hydroxy-2-phenylacetic acid salt (376608-71-8) + di-tert-butyl dicarbonate (24424-99-5) → (tert-butyl (1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)carbamate (1350749-64-2)

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%

trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (2R)-2-hydroxy-2-phenylacetic acid salt (376608-71-8) + 9-[(1’R,2’S,3’S,4’S)-2’,3’-dihydroxyl-4'-hydroxyethoxycyclopenta-1'-yl]-9H-2-thiopropyl-6-chloro-8-azepine (1354945-69-9) → ticagrelor (274693-27-5)

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 + trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (2R)-2-hydroxy-2-phenylacetic acid salt (376608-71-8) → [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 (274693-26-4)

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;

trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (2R)-2-hydroxy-2-phenylacetic acid salt (376608-71-8) + C15H16F3N3OS → C24H25F5N4S*2ClH

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%

trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (2R)-2-hydroxy-2-phenylacetic acid salt (376608-71-8) + N-tert-butyloxycarbonylpiperidin-4-one (79099-07-3) → C19H26F2N2O2

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%

4,6-dichloro-2-(propylsulfanyl)-5-pyrimidinamine (145783-15-9) + trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (2R)-2-hydroxy-2-phenylacetic acid salt (376608-71-8) → 6-chloro-N4-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-2-(propylthio)pyrimidine-4,5-diamine

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

trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (2R)-2-hydroxy-2-phenylacetic acid salt (376608-71-8) + C14H14F3N3OS → C23H23F5N4S*2ClH

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%

trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (2R)-2-hydroxy-2-phenylacetic acid salt (376608-71-8) + C14H14F3N3OS → C23H23F5N4S*2ClH + C23H23F5N4S*2ClH

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%

trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (2R)-2-hydroxy-2-phenylacetic acid salt (376608-71-8) + tert butyl 4-formylpiperidine-1-carboxylate (137076-22-3) → C20H28F2N2O2

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%

trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (2R)-2-hydroxy-2-phenylacetic acid salt (376608-71-8) + C14H14F3N3OS → C23H23F5N4S*2ClH

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%

trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (2R)-2-hydroxy-2-phenylacetic acid salt (376608-71-8) → [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 (274693-26-4)

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

trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (2R)-2-hydroxy-2-phenylacetic acid salt (376608-71-8) → ticagrelor (274693-27-5)

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

trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (2R)-2-hydroxy-2-phenylacetic acid salt (376608-71-8) → tert-butyl (6-chloro-5-nitro-2-(propylthio)pyrimidin-4-yl)((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)carbamate (1383715-58-9)

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

trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (2R)-2-hydroxy-2-phenylacetic acid salt (376608-71-8) → 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 (1383715-59-0)

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

trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (2R)-2-hydroxy-2-phenylacetic acid salt (376608-71-8) → 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 (1383715-60-3)

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

trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (2R)-2-hydroxy-2-phenylacetic acid salt (376608-71-8) → 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 (1383715-61-4)

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

trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (2R)-2-hydroxy-2-phenylacetic acid salt (376608-71-8) → 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 (1383715-62-5)

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

trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (2R)-2-hydroxy-2-phenylacetic acid salt (376608-71-8) → C30H34F2N6O4S (1383715-63-6)

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

trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (2R)-2-hydroxy-2-phenylacetic acid salt (376608-71-8) → 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 (1383715-64-7)

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

Upstream product

• 367-11-3 ortho-difluorobenzene 
• 1345413-26-4 trans-(1R,2S)-2-(3,4-difluorophenyl)-1-nitrocyclopropane 
• 611-71-2 (R)-Mandelic Acid 
• 1215969-79-1 3-chloro-1-(3',4'-difluorophenyl)-propan-1-one 
• 1345413-22-0 1-(3',4'-difluorophenyl)-3-nitro-propan-1-one 
• 1006614-49-8 (1R,2S)-2-(3,4-difluorophenyl)cyclopropanamine 
• 1345413-25-3 (1S)-1-(3,4-difluorophenyl)-3-nitropropan-1-ol 
• 218430-47-8 (E)-methyl 3-(3,4-difluorophenyl)acrylate 
• 112897-97-9 (E)-3-(3,4-difluorophenyl)acrylic acid 
• 376608-66-1 (E)-3-(3,4-difluorophenyl)acryloyl chloride 
• 1421708-29-3 (E)-3-(3,4-difluorophenyl)-N-methoxy-N-methyl-prop-2-enamide 
• 1006614-49-8 trans-2-(3,4-difluorophenyl)cyclopropanamine 
• 1006614-50-1 trans-2-(3,4-difluorophenyl)cyclopropanecarboxylic acid 
• 51336-95-9 2-chloro-1-(3,4-difluorophenyl)ethan-1-one 

Downstream Products

• 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 
• 1350749-64-2 tert-butyl ((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)carbamate 
• 274693-27-5 ticagrelor 
• 1383715-58-9 tert-butyl (6-chloro-5-nitro-2-(propylthio)pyrimidin-4-yl)((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)carbamate 
• 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 
• 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 
• 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 

Relevant articles and documents

SUBSTITUTED ARYLUREA COMPOUNDS FOR INDUCING APOPTOSIS AND COMPOSITION FOR ANTICANCER COMPRISING THE SAME

The present invention relates to a substituted arylurea compound inducing apoptosis and an anticancer composition comprising the same. The present invention relates to a novel compound capable of preventing, treating and alleviating cancer diseases such as prostate cancer, breast cancer, lung cancer, colorectal cancer, and skin cancer by inhibiting apoptosis of cancer cells and inhibiting proliferation of cancer cells.

Preparation method of ticagrelor key intermediate

The invention belongs to the technical field of medicines, and particularly relates to a preparation method of a ticagrelor key intermediate, and the method is used for preparing the ticagrelor intermediate, has the advantages of short reaction steps, mild reaction conditions and higher yield than the existing preparation method, is economical and effective, and is suitable for large-scale industrial production.

Preparation method of ticagrelor

The invention discloses a preparation method of ticagrelor. The preparation method comprises the following steps: (1) preparation of ticagrelor intermediate product 1-TK acid; (2) preparation of ticagrelor intermediate product 2-TK-amide; (3) preparation of ticagrelor intermediate product 3-TK-amino compound hydrochloride; (4) preparation of ticagrelor intermediate product 4-TK-amino compound R-tartrate; ( 5) preparation of ticagrelor intermediate product 5-TK-amino compound L-mandelate; and (6) preparation of ticagrelor-TK. The preparation method has the advantages of cost advantage, mature and stable process, stable product quality, and safe and reliable production process.

(1 R, 2 S) - 2 - (3, 4 - difluorophenyl) amine ·D - mandelic acid salt preparation method

The invention discloses a preparation method of (1R,2S)-2-(3,4-difluorophenyl) rolicyprine.D-mandelate. The preparation method comprises the following steps: carrying out cyclopropanation on a compound shown in a formula V to obtain a compound shown in a formula IV; carrying out amide generation and Hofmann degradation to obtain a compound shown in a formula II; and performing salification with D-mandelic acid to obtain a compound shown in a formula I. The compound shown in the formula V is prepared in a way that a compound shown in a structure formula VI is subjected to CBS asymmetric reduction reaction, wherein a catalyst for the CBS asymmetric reduction reaction is a compound shown in a structural formula VII, and a reduction agent for the CBS asymmetric reduction reaction can be borane-tetrahydrofuran or borane-N,N-diethyl phenylamine.

for standard auspicious Luo river intermediate preparation method

The inventiondiscloses a preparation method of ticagrelor. The method comprises the following steps: (1) reducing a compound shown in a formula III in the presence of a proton source provided by sodium borohydride or potassium borohydride and diethyl aniline hydrochloride to obtain a compound shown in a formula IV; (2) reacting the compound IV in the presence of alkali to generate a compound VI; (3) hydrolyzing the compound VI without purification to generate a compound VII; (4) reacting the compound VII to generate acyl chloride, reacting the acyl chloride to generate formamide, thus obtaining a compound shown in a formula IX; and (5) carrying out Hofmann rearrangement on the compound IX to obtain a compound shown in a formula II. Regents used in the method are nontoxic, harmless, environmentally friendly and low in price; the used key reagents can be recycled. Therefore, the method is applicable to industrial production.

NOVEL PROCESS FOR PREPARING PHENYLCYCLOPROPYLAMINE DERIVATIVES USING NOVEL INTERMEDIATES

Provided herein is a novel process for the preparation of phenylcyclopropylamine derivatives, which are useful intermediates in the preparation of triazolo[4,5-d]pyrimidine compounds. Provided particularly herein is a novel, commercially viable and industrially advantageous process for the preparation of a substantially pure ticagrelor intermediate, trans-(1R,2S)-2-(3,4-difluorophenyl)-cyclopropylamine. The intermediate is useful for preparing ticagrelor, or a pharmaceutically acceptable salt thereof, in high yield and purity.

SYNTHESIS OF 2-(3,4-DIFLUOROPHENYL)CYCLOPROPANAMINE DERIVATIVES AND SALTS

The present invention relates to the field of organic synthesis and describes the synthesis of specific intermediates suitable for the preparation of triazolopyrimidine compounds such as ticagrelor.

NOVEL PROCESSES FOR PREPARING TRIAZOLO[4,5-D]PYRIMIDINE DERIVATIVES AND INTERMEDIATES THEREOF

Provided herein is a novel process for the preparation of triazolo[4,5-d]pyrimidine derivatives. Provided particularly herein is a novel, commercially viable and industrially advantageous process for the preparation of highly pure ticagrelor or a pharmaceutically acceptable salt thereof. Provided further herein is a novel process for the preparation of substituted cyclopentanamine derivatives, which are useful intermediates in the preparation of triazolo[4,5-d]pyrimidine compounds. Provided particularly herein is a novel, commercially viable and industrially advantageous process for the preparation of a ticagrelor intermediate, 2-[[(3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d] [1,3]- dioxol-4-yl]oxy]- 1 -ethanol.

NOVEL PROCESS FOR PREPARING PHENYLCYCLOPROPYLAMINE DERIVATIVES USING NOVEL INTERMEDIATES

Provided herein is a novel process for the preparation of phenylcyclopropylamine derivatives, which are useful intermediates in the preparation of triazolo[4,5-d]pyrimidine compounds. Provided particularly herein is a novel, commercially viable and industrially advantageous process for the preparation of a substantially pure ticagrelor intermediate, trans-(1R,2S)-2-(3,4-difluorophenyl)-cyclopropylamine. The intermediate is useful for preparing ticagrelor, or a pharmaceutically acceptable salt thereof, in high yield and purity.

Novel triazolo pyrimidine compounds

The present invention relates to a pyrimidine compound (I) useful as a pharmaceutical intermediate, to a process for preparing said pyrimidine compound, to intermediates used in said process, and to the use of said pyrimidine compound in the preparation of pharmaceuticals.