467442-20-2

Basic information

• Product Name: (S)-2-(tert-butoxycarbonylamino)-4,4-difluorobutanoic acid
• Synonyms: (S)-2-(tert-butoxycarbonylamino)-4,4-difluorobutanoic acid
• CAS NO: 467442-20-2
• Molecular Formula: C₉H₁₅F₂NO₄
• Molecular Weight: 239.217
• Mol File: 467442-20-2.mol
• Article Data: 1

Chemical Properties

• Boiling Point: 348.1 °C at 760 mmHg
• Flash Point: 164.3 °C
• Appearance: /
• Density: 1.222
• Vapor Pressure: 8.96E-06mmHg at 25°C
• Refractive Index: 1.433
• PKA: 3.48±0.10(Predicted)
• CAS DataBase Reference: (S)-2-(tert-butoxycarbonylamino)-4,4-difluorobutanoic acid(CAS DataBase Reference)
• NIST Chemistry Reference: (S)-2-(tert-butoxycarbonylamino)-4,4-difluorobutanoic acid(467442-20-2)
• EPA Substance Registry System: (S)-2-(tert-butoxycarbonylamino)-4,4-difluorobutanoic acid(467442-20-2)

Safety Data

• Hazardous Substances Data: 467442-20-2(Hazardous Substances Data)

Usage

General Description

(S)-2-(tert-butoxycarbonylamino)-4,4-difluorobutanoic acid is a compound with the chemical formula C10H16F2N2O4. It is a specific enantiomer of a compound called tert-butoxycarbonylamino difluoro butanoic acid, which is used in the synthesis of pharmaceuticals and other organic compounds. The (S)-2-(tert-butoxycarbonylamino)-4,4-difluorobutanoic acid contains a fluorine atom and a tert-butoxycarbonylamino group, making it useful for introducing these functional groups into organic molecules during chemical synthesis. (S)-2-(tert-butoxycarbonylamino)-4,4-difluorobutanoic acid has potential applications in the pharmaceutical industry for the development of new drugs, as well as in other areas of organic chemistry research.

InChI:InChI=1/C9H15F2NO4/c1-9(2,3)16-8(15)12-5(7(13)14)4-6(10)11/h5-6H,4H2,1-3H3,(H,12,15)(H,13,14)/t5-/m0/s1

Synthetic route

di-tert-butyl dicarbonate (24424-99-5) + α-amino-γ,γ-difluorobutyrate (121960-22-3) → 2-[(tert-butoxycarbonyl)amino]-4,4-difluorobutanoic acid (467442-20-2)

Conditions	Yield
With triethylamine

2-[(tert-butoxycarbonyl)amino]-4,4-difluorobutanoic acid (467442-20-2) + diazomethyl-trimethyl-silane (18107-18-1) → methyl 2-[(tert-butoxycarbonyl)amino]-4,4-difluorobutanoate

Conditions	Yield
In methanol; toluene at 0℃; for 3h; Sealed tube; Inert atmosphere;	47%

L-alanine methyl ester hydrochloride (2491-20-5) + 2-[(tert-butoxycarbonyl)amino]-4,4-difluorobutanoic acid (467442-20-2) → (S)-2-((S)-2-tert-Butoxycarbonylamino-4,4-difluoro-butyrylamino)-propionic acid methyl ester

Conditions	Yield
With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dichloromethane

2,5-difluoro-4-t-butoxycarbonylphenethylamine (607403-53-2) + 2-[(tert-butoxycarbonyl)amino]-4,4-difluorobutanoic acid (467442-20-2) → 4-[2-(2-tert-butoxycarbonylamino-4,4-difluoro-butyrylamino)-ethyl]-3,5-difluoro-benzoic acid tert-butyl ester

Conditions	Yield
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane

2-[(tert-butoxycarbonyl)amino]-4,4-difluorobutanoic acid (467442-20-2) + (E)-3-[3-(2-Amino-ethyl)-phenyl]-acrylic acid ethyl ester → (E)-3-{3-[2-((S)-2-tert-Butoxycarbonylamino-4,4-difluoro-butyrylamino)-ethyl]-phenyl}-acrylic acid ethyl ester

Conditions	Yield
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane

2-[(tert-butoxycarbonyl)amino]-4,4-difluorobutanoic acid (467442-20-2) + 2-[3-(2-amino-ethyl)-phenylamino]-butyric acid methyl ester → 2-{3-[2-(2-tert-butoxycarbonylamino-4,4-difluoro-butyrylamino)-ethyl]-phenylamino}-butyric acid methyl ester

Conditions	Yield
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane

2-[(tert-butoxycarbonyl)amino]-4,4-difluorobutanoic acid (467442-20-2) + (E)-3-[3-(2-Amino-ethyl)-4-fluoro-phenyl]-acrylic acid ethyl ester → (E)-3-{3-[2-((S)-2-tert-Butoxycarbonylamino-4,4-difluoro-butyrylamino)-ethyl]-4-fluoro-phenyl}-acrylic acid ethyl ester

Conditions	Yield
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane

2-[(tert-butoxycarbonyl)amino]-4,4-difluorobutanoic acid (467442-20-2) + [3-(2-amino-ethyl)-phenoxy]-phenyl-acetic acid methyl ester → {3-[2-(2-tert-butoxycarbonylamino-4,4-difluoro-butyrylamino)-ethyl]-phenoxy}-phenyl-acetic acid methyl ester

Conditions	Yield
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane

2-[(tert-butoxycarbonyl)amino]-4,4-difluorobutanoic acid (467442-20-2) + 2-[2,6-difluoro-4-(2H-tetrazol-5-yl)-phenyl]-ethylamine (467438-35-3) → (1-{2-[2,6-difluoro-4-(2H-tetrazol-5-yl)-phenyl]-ethylcarbamoyl}-3,3-difluoro-propyl)-carbamic acid tert-butyl ester

Conditions	Yield
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane

2-[(tert-butoxycarbonyl)amino]-4,4-difluorobutanoic acid (467442-20-2) + 2-[3-(2-amino-ethyl)-2,4-difluoro-phenoxy]-propionic acid methyl ester (467438-38-6) → 2-{3-[2-(2-tert-butoxycarbonylamino-4,4-difluoro-butyrylamino)-ethyl]-phenoxy}-propionic acid methyl ester

Conditions	Yield
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane

2-[(tert-butoxycarbonyl)amino]-4,4-difluorobutanoic acid (467442-20-2) + (E)-3-[3-(2-Amino-ethyl)-2-fluoro-phenyl]-acrylic acid ethyl ester → (E)-3-{3-[2-((S)-2-tert-Butoxycarbonylamino-4,4-difluoro-butyrylamino)-ethyl]-2-fluoro-phenyl}-acrylic acid ethyl ester

Conditions	Yield
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane

2-[(tert-butoxycarbonyl)amino]-4,4-difluorobutanoic acid (467442-20-2) + [3-(2-amino-ethyl)-2,4-difluoro-phenoxy]-acetic acid methyl ester → {3-[2-(2-tert-butoxycarbonylamino-4,4-difluoro-butyrylamino)-ethyl]-phenoxy}-acetic acid methyl ester

Conditions	Yield
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane

2-[(tert-butoxycarbonyl)amino]-4,4-difluorobutanoic acid (467442-20-2) + [3-(2-amino-ethyl)-phenylamino]-phenyl-acetic acid methyl ester → {3-[2-(2-tert-butoxycarbonylamino-4,4-difluoro-butyrylamino)-ethyl]-phenylamino}-phenyl-acetic acid methyl ester

Conditions	Yield
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane

2-[(tert-butoxycarbonyl)amino]-4,4-difluorobutanoic acid (467442-20-2) + 4-(2-amino-ethyl)-3,5-difluoro-benzoic acid methyl ester; hydrochloride → 4-[2-(2-tert-butoxycarbonylamino-4,4-difluoro-butyrylamino)-ethyl]-3,5-difluoro-benzoic acid methyl ester

Conditions	Yield
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane

2-[(tert-butoxycarbonyl)amino]-4,4-difluorobutanoic acid (467442-20-2) → (S)-2-((S)-2-tert-Butoxycarbonylamino-4,4-difluoro-butyrylamino)-propionic acid

Conditions	Yield
Multi-step reaction with 2 steps 1: PyBOP; i-Pr2NEt / CH2Cl2 2: aq. NaOH / methanol View Scheme

2-[(tert-butoxycarbonyl)amino]-4,4-difluorobutanoic acid (467442-20-2) → {(S)-1-[(S)-1-((1S,2S,4R)-1-Benzyl-2-hydroxy-4-{(S)-2-methyl-1-[(pyridin-4-ylmethyl)-carbamoyl]-propylcarbamoyl}-pentylcarbamoyl)-ethylcarbamoyl]-3,3-difluoro-propyl}-carbamic acid tert-butyl ester

Conditions	Yield
Multi-step reaction with 3 steps 1: PyBOP; i-Pr2NEt / CH2Cl2 2: aq. NaOH / methanol 3: HOAt; EDCI; i-Pr2NEt / tetrahydrofuran View Scheme

2-[(tert-butoxycarbonyl)amino]-4,4-difluorobutanoic acid (467442-20-2) → tert-butyl (4,4-difluoro-1-hydroxybutan-2-yl)carbamate

Conditions	Yield
Multi-step reaction with 2 steps 1: methanol; toluene / 3 h / 0 °C / Sealed tube; Inert atmosphere 2: lithium borohydride / tetrahydrofuran / 2 h / 0 - 20 °C / Sealed tube; Inert atmosphere View Scheme

2-[(tert-butoxycarbonyl)amino]-4,4-difluorobutanoic acid (467442-20-2) → 2-[(tertbutoxycarbonyl)amino]-4,4-difluorobutyl methanesulfonate

Conditions	Yield
Multi-step reaction with 3 steps 1: methanol; toluene / 3 h / 0 °C / Sealed tube; Inert atmosphere 2: lithium borohydride / tetrahydrofuran / 2 h / 0 - 20 °C / Sealed tube; Inert atmosphere 3: triethylamine / dichloromethane / 5 h / 0 - 20 °C / Sealed tube; Inert atmosphere View Scheme

2-[(tert-butoxycarbonyl)amino]-4,4-difluorobutanoic acid (467442-20-2) → tert-butyl (1-azido-4,4-difluorobutan-2-yl)carbamate

Conditions	Yield
Multi-step reaction with 4 steps 1: methanol; toluene / 3 h / 0 °C / Sealed tube; Inert atmosphere 2: lithium borohydride / tetrahydrofuran / 2 h / 0 - 20 °C / Sealed tube; Inert atmosphere 3: triethylamine / dichloromethane / 5 h / 0 - 20 °C / Sealed tube; Inert atmosphere 4: sodium azide / N,N-dimethyl-formamide / 24 h / 60 °C / Sealed tube; Inert atmosphere View Scheme

2-[(tert-butoxycarbonyl)amino]-4,4-difluorobutanoic acid (467442-20-2) → tert-butyl (1-amino-4,4-difluorobutan-2-yl)carbamate

Conditions

Yield

Multi-step reaction with 5 steps 1: methanol; toluene / 3 h / 0 °C / Sealed tube; Inert atmosphere 2: lithium borohydride / tetrahydrofuran / 2 h / 0 - 20 °C / Sealed tube; Inert atmosphere 3: triethylamine / dichloromethane / 5 h / 0 - 20 °C / Sealed tube; Inert atmosphere 4: sodium azide / N,N-dimethyl-formamide / 24 h / 60 °C / Sealed tube; Inert atmosphere 5: palladium 10% on activated carbon; hydrogen / methanol / 14 h / 20 °C / Sealed tube; Inert atmosphere View Scheme

Upstream product

• 24424-99-5 di-tert-butyl dicarbonate 
• 121960-22-3 α-amino-γ,γ-difluorobutyrate 

Downstream Products

• 669083-19-6 methyl 2-[(tert-butoxycarbonyl)amino]-4,4-difluorobutanoate 

Relevant articles and documents

Phe*-Ala-based pentapeptide mimetics are BACE inhibitors: P2 and P3 SAR.

We describe herein the syntheses and evaluation of a series of C-termini pyridyl containing Phe*-Ala-based BACE inhibitors (5-19). In conjunction with four fixed residues at the P1 (Phe), P1' (Ala), P2' (Val), and P2' cap (Pyr.), rather detailed SAR modifications at P2 and P3 positions were pursued. The promising inhibitors emerging from this SAR investigation, 12 and 17 demonstrated very good enzyme potency (IC(50)=45 nM) and cellular activity (IC(50)=0.4 microM).