486460-00-8

Basic information

• Product Name: BOC-(R)-3-AMINO-4-(2,4,5-TRIFLUORO-PHENYL)-BUTYRIC ACID
• Synonyms: Benzenebutanoicacid,b-[[(1,1-diMethylethoxy)carbonyl]aMino]-2,4,5-trifluoro-,(bR)-;(R)-Sitagliptin N-Boc-Acid IMpurity;(3R)-N-(tert-Butoxycarbonyl)-3-aMino-4-(2,4,5-trifluorophenyl)-butanoic acid- Boc-(R)-3-AMino-4-(2,4,5-trifluorophenyl) butanoic acid (BOC acid);[[(1,1-diMethylethoxy)carbonyl]aMino]-2,4,5-trifluoro-(R)-benzenebuta;Boc-(R)-3-Amino-4-(2,4,5-trifluorophenyl)butanoic acid (3R)-N-(tert-Butoxycarbonyl)-3-amino-4-(2,4,5-trifluorophenyl)butanoic acid;Boc-(R)-3-Amino-4-(2,4,5-trifluorophenyl)butanoic acid, >=99%;(3R)-N-Boc-3-amino-4-(2,4,5-trifluorophenyl)butanoic acid;BOC-(R)-3-AMINO-4-(2,4,5-TRIFLUORO-PHENYL)-BUTYRIC ACID
• CAS NO: 486460-00-8
• Molecular Formula: C₁₅H₁₈F₃NO₄
• Molecular Weight: 333.3
• EINECS: 1308068-626-2
• Product Categories: B-Amino
• Mol File: 486460-00-8.mol

Chemical Properties

• Melting Point: 136-138℃
• Boiling Point: 443.1 °C at 760 mmHg
• Flash Point: 221.8 °C
• Appearance: /
• Density: 1.292 g/cm³
• Vapor Pressure: 1.25E-08mmHg at 25°C
• Refractive Index: 1.494
• Storage Temp.: 2-8°C
• Solubility: Chloroform (Slightly), DMSO (Slightly), Ethyl Acetate (Slightly), Methanol (Slig
• PKA: 4.30±0.10(Predicted)
• CAS DataBase Reference: BOC-(R)-3-AMINO-4-(2,4,5-TRIFLUORO-PHENYL)-BUTYRIC ACID(CAS DataBase Reference)
• NIST Chemistry Reference: BOC-(R)-3-AMINO-4-(2,4,5-TRIFLUORO-PHENYL)-BUTYRIC ACID(486460-00-8)
• EPA Substance Registry System: BOC-(R)-3-AMINO-4-(2,4,5-TRIFLUORO-PHENYL)-BUTYRIC ACID(486460-00-8)

Safety Data

• HazardClass: IRRITANT
• Hazardous Substances Data: 486460-00-8(Hazardous Substances Data)

Usage

Physical Form

White to Yellow Solid

Uses

(R)-3-((tert-Butoxycarbonyl)amino)-4-(2,4,5-trifluorophenyl)butanoic Acid has been used as a reactant for the preparation of dipeptidyl peptidase-4 (DPP4) inhibitors for the treatment of type 2 diabetes, such as sitagliptin.

InChI:InChI=1/C15H18F3NO4/c1-15(2,3)23-14(22)19-9(6-13(20)21)4-8-5-11(17)12(18)7-10(8)16/h5,7,9H,4,6H2,1-3H3,(H,19,22)(H,20,21)/t9-/m1/s1

Synthetic route

3-(R)-tert-butoxycarbonylamino-4-(2,4,5-trifluorophenyl)butyric acid methyl ester (881995-73-9) → (3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (486460-00-8)

Conditions	Yield
With lithium hydroxide In tetrahydrofuran; methanol at 20℃; for 3h;	99%
With lithium hydroxide monohydrate; water In tetrahydrofuran for 16h;	95.1%
Stage #1: 3-(R)-tert-butoxycarbonylamino-4-(2,4,5-trifluorophenyl)butyric acid methyl ester With water; lithium hydroxide In methanol at 20℃; for 24h; Stage #2: With hydrogenchloride In water; ethyl acetate	95%

C15H16F3NO4 → (3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (486460-00-8)

Conditions	Yield
With palladium on carbon; hydrogen In methanol for 24h;	99%

(R)-tert-butyl (4-hydroxy-1-(2,4,5-trifluorophenyl)butan-2-yl)carbamate (1048703-14-5) → (3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (486460-00-8)

Conditions	Yield
With sodium hypochlorite; sodium chlorite; disodium hydrogenphosphate; sodium dihydrogenphosphate; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical In water; acetonitrile at 38℃; for 0.333333h; Solvent;	98%
With sodium hypochlorite; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; sodium hydrogencarbonate; sodium bromide In dichloromethane at 0℃; for 2h;	90%
Stage #1: (R)-tert-butyl (4-hydroxy-1-(2,4,5-trifluorophenyl)butan-2-yl)carbamate With sodium hypochlorite; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; sodium hydrogencarbonate; sodium bromide In dichloromethane at 0℃; for 2h; Stage #2: With hydrogenchloride In dichloromethane; water pH=2 - 3;	90%
With sodium hypochlorite; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical	90%

(R)-3-tertbutoxycarbonylamino-4-(2,4,5-trifluorophenyl)butyric acid ethyl ester (1152439-74-1) → (3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (486460-00-8)

Conditions	Yield
With lithium hydroxide monohydrate In methanol; water at 30 - 40℃;	95%
Stage #1: (R)-3-tertbutoxycarbonylamino-4-(2,4,5-trifluorophenyl)butyric acid ethyl ester With water; sodium hydroxide In methanol at 40 - 45℃; for 2h; Stage #2: In methanol; water pH=3; Acidic conditions;
Stage #1: (R)-3-tertbutoxycarbonylamino-4-(2,4,5-trifluorophenyl)butyric acid ethyl ester With sodium hydroxide In methanol; water at 40 - 45℃; for 2h; Stage #2: In methanol; water pH=3;

[3-diazo-2-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester (486460-25-7) → (3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (486460-00-8)

Conditions	Yield
With silver benzoate In 1,4-dioxane; water for 1.5h; Sonication;	94%
With silver benzoate In 1,4-dioxane at 20℃; for 2h; sonication;	401 mg
With silver benzoate In 1,4-dioxane; water for 2h; Sonographic reaction;

(R)-3-amino-4-phenyl(2,4,5-trifluorophenyl)butanoic acid (936630-57-8) + di-tert-butyl dicarbonate (24424-99-5) → (3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (486460-00-8)

Conditions	Yield
With triethylamine In 1,4-dioxane; water at 20℃;	91%
Stage #1: (R)-3-amino-4-phenyl(2,4,5-trifluorophenyl)butanoic acid With lithium hydroxide In 1,4-dioxane; water at 0 - 30℃; Stage #2: di-tert-butyl dicarbonate In 1,4-dioxane; water at 25 - 30℃;	91%
With sodium hydrogencarbonate In tetrahydrofuran; water at 20℃; for 24h;	91%

(R)-cyclohexyl 3-(tert-butoxycarbonyl amino)-4-(2,4,5-trifluorophenyl)butyrate (1276113-61-1) → (3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (486460-00-8)

Conditions	Yield
Stage #1: (R)-cyclohexyl 3-(tert-butoxycarbonyl amino)-4-(2,4,5-trifluorophenyl)butyrate With water; potassium carbonate at 60℃; for 3h; Stage #2: With hydrogenchloride; water at 20 - 30℃; for 2h;	90%
Stage #1: (R)-cyclohexyl 3-(tert-butoxycarbonyl amino)-4-(2,4,5-trifluorophenyl)butyrate With potassium carbonate In water at 60℃; for 3h; Stage #2: With hydrogenchloride In water at 20 - 30℃; for 2h;	90%

C16H20F3NO2 → (3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (486460-00-8)

Conditions	Yield
With potassium permanganate In acetone at 20℃; for 3h; Concentration;	89%
With ruthenium trichloride; sodium periodate In water; acetonitrile at -10℃; for 2h;	70%

di-tert-butyl dicarbonate (24424-99-5) + (R)-3-((R)-1-phenylethylamino)-4-(2,4,5-trifluorophenyl)-N-phenyl butanamide → (3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (486460-00-8)

Conditions	Yield
Stage #1: (R)-3-((R)-1-phenylethylamino)-4-(2,4,5-trifluorophenyl)-N-phenyl butanamide With 5%-palladium/activated carbon; hydrogen In methanol at 70℃; under 6000.6 Torr; Stage #2: With hydrogenchloride; water In methanol at 90℃; Stage #3: di-tert-butyl dicarbonate In tetrahydrofuran; water at 10 - 20℃; for 20h;	88%

di-tert-butyl dicarbonate (24424-99-5) + diethyl 2-((R)-1-((R)-1,1-dimethylethylsulfinamido)-2-(2,4,5-trifluorophenyl)ethyl)malonate → (3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (486460-00-8)

Conditions	Yield
Stage #1: diethyl 2-((R)-1-((R)-1,1-dimethylethylsulfinamido)-2-(2,4,5-trifluorophenyl)ethyl)malonate With hydrogenchloride In water for 18h; Reflux; Stage #2: di-tert-butyl dicarbonate With sodium hydroxide In water at 20℃; pH=8;	88%

(R)-3-amino-4-(2,4,5-trifluorophenyl)butyric acid methyl ester (881995-69-3) + di-tert-butyl dicarbonate (24424-99-5) → (3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (486460-00-8)

Conditions	Yield
Stage #1: (R)-3-amino-4-(2,4,5-trifluorophenyl)butyric acid methyl ester; di-tert-butyl dicarbonate With triethylamine In ethyl acetate at 20 - 30℃; for 7h; Stage #2: With water; sodium hydroxide In ethanol at 20 - 30℃; for 2h;	85.5%
Stage #1: (R)-3-amino-4-(2,4,5-trifluorophenyl)butyric acid methyl ester With water; lithium hydroxide In tetrahydrofuran at 0 - 30℃; Stage #2: di-tert-butyl dicarbonate In tetrahydrofuran; water at 25 - 30℃; for 6h; Stage #3: With sodium hydrogen sulfate In water pH=2;	80%

di-tert-butyl dicarbonate (24424-99-5) + di-tert-butyl 2-((R)-1-((R)-1,1-dimethylethylsulfinamido)-2-(2,4,5-trifluorophenyl)ethyl)malonate → (3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (486460-00-8)

Conditions	Yield
Stage #1: di-tert-butyl 2-((R)-1-((R)-1,1-dimethylethylsulfinamido)-2-(2,4,5-trifluorophenyl)ethyl)malonate With hydrogenchloride In water for 9h; Reflux; Stage #2: di-tert-butyl dicarbonate With sodium hydroxide In water at 20℃;	83%

(R)-tert-butyl (1-cyano-3-(2,4,5-trifluorophenyl)propan-2-yl)carbamate (1246960-23-5) → (3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (486460-00-8)

Conditions	Yield
With sodium hydroxide In ethanol at 75 - 85℃;	81%
With dihydrogen peroxide; sodium hydroxide In water at 100℃; for 3h;	75%
Stage #1: (R)-tert-butyl (1-cyano-3-(2,4,5-trifluorophenyl)propan-2-yl)carbamate With potassium hydroxide In ethanol; water at 80℃; for 12h; Stage #2: With oxalic acid In ethanol; water at 20℃;

di-tert-butyl dicarbonate (24424-99-5) + C19H16F3NO5 → (3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (486460-00-8)

Conditions	Yield
Stage #1: C19H16F3NO5 With hydrogenchloride; palladium on activated charcoal; hydrogen In diethyl ether; ethanol at 20℃; for 10h; Stage #2: With hydrogenchloride In diethyl ether; ethanol for 0.5h; Reflux; Stage #3: di-tert-butyl dicarbonate With lithium hydroxide In tetrahydrofuran; diethyl ether; ethanol at 20℃; for 8h;	66%

di-tert-butyl dicarbonate (24424-99-5) + 2-hydroxyethyl 3-oxo-4-(2,4,5-trifluorophenyl)butanoate → (3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (486460-00-8)

Conditions

Yield

Stage #1: 2-hydroxyethyl 3-oxo-4-(2,4,5-trifluorophenyl)butanoate With pyridoxal 5'-phosphate; recombinant aminotransferase from Arthobacter sp.; water; isopropylamine In dimethyl sulfoxide at 45℃; for 24h; Green chemistry; Enzymatic reaction; Stage #2: With lithium hydroxide In dimethyl sulfoxide at 45℃; for 3h; Green chemistry; Stage #3: di-tert-butyl dicarbonate In tetrahydrofuran; dimethyl sulfoxide at 35℃; Green chemistry; enantioselective reaction;

60.6%

C11H10F3NO3 + tert-butyl alcohol (75-65-0) → (3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (486460-00-8)

Conditions	Yield
With bromine; 1,8-diazabicyclo[5.4.0]undec-7-ene In tetrahydrofuran at 50℃; Hofmann Rearrangement; enantioselective reaction;	55%

4-(2,4,5-trifluoro-phenyl)-3-oxo-butyric acid methyl ester (769195-26-8) → (3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (486460-00-8)

Conditions	Yield
Multi-step reaction with 4 steps 1: 95 percent / ammonium acetate / methanol / 7 h / Heating 2: 68 percent / H2; (R) chiral ferrocenyl derivative / chloro(1,5-cyclooctadiene)rhodium(I) dimer / 2,2,2-trifluoro-ethanol / 40 h / 50 °C / 5171.62 Torr 3: 93 percent / CH2Cl2 / 3 h / 20 °C 4: 99 percent / aq. LiOH / tetrahydrofuran; methanol / 3 h / 20 °C View Scheme
Multi-step reaction with 6 steps 1.1: ammonium acetate / methanol / 60 - 63 °C 2.1: sulfuric acid / methanol / -10 - 0 °C 2.2: 2 h / -10 - 0 °C 2.3: pH 8 - 9 3.1: isopropyl alcohol / 3 h / 25 - 30 °C 4.1: sodium carbonate / water / pH 8 - 9 5.1: water; lithium hydroxide / tetrahydrofuran / 0 - 30 °C 6.1: water; tetrahydrofuran / 6 h / 25 - 30 °C 6.2: pH 2 View Scheme
Multi-step reaction with 4 steps 1: acetic acid / methanol / Reflux; Large scale 2: boron trifluoride diethyl etherate; sodium tetrahydroborate / tetrahydrofuran / 1.5 h / -78 - 0 °C / Large scale 3: palladium 10% on activated carbon; hydrogen / methanol / 48 h / 25 °C 4: lithium hydroxide monohydrate / methanol; water / 30 - 40 °C View Scheme

(R)-3-amino-4-(2,4,5-trifluorophenyl)butyric acid methyl ester (881995-69-3) → (3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (486460-00-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: 93 percent / CH2Cl2 / 3 h / 20 °C 2: 99 percent / aq. LiOH / tetrahydrofuran; methanol / 3 h / 20 °C View Scheme
Multi-step reaction with 2 steps 1.1: water; lithium hydroxide / tetrahydrofuran / 0 - 30 °C 2.1: water; tetrahydrofuran / 6 h / 25 - 30 °C 2.2: pH 2 View Scheme

methyl 3-amino-4-(2,4,5-trifluorophenyl)but-2-enoate → (3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (486460-00-8)

Conditions	Yield
Multi-step reaction with 3 steps 1: 68 percent / H2; (R) chiral ferrocenyl derivative / chloro(1,5-cyclooctadiene)rhodium(I) dimer / 2,2,2-trifluoro-ethanol / 40 h / 50 °C / 5171.62 Torr 2: 93 percent / CH2Cl2 / 3 h / 20 °C 3: 99 percent / aq. LiOH / tetrahydrofuran; methanol / 3 h / 20 °C View Scheme

(2,4,5-trifluorophenyl)acetic acid (209995-38-0) → (3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (486460-00-8)

Conditions	Yield
Multi-step reaction with 6 steps 1: 95 percent / N,N-dimethylaminopyridine; N,N-diisopropylethylamine; trimethylacetylchloride / acetonitrile / 3 h / 45 °C 2: 88.7 percent / toluene / 3 h / Heating 3: 95 percent / ammonium acetate / methanol / 7 h / Heating 4: 68 percent / H2; (R) chiral ferrocenyl derivative / chloro(1,5-cyclooctadiene)rhodium(I) dimer / 2,2,2-trifluoro-ethanol / 40 h / 50 °C / 5171.62 Torr 5: 93 percent / CH2Cl2 / 3 h / 20 °C 6: 99 percent / aq. LiOH / tetrahydrofuran; methanol / 3 h / 20 °C View Scheme
Multi-step reaction with 6 steps 1.1: 1,1'-carbonyldiimidazole / tetrahydrofuran / 3 h / 50 °C 2.1: ethanol / 3 h / 70 °C 3.1: formic acid / ethanol / 3 h / Reflux 3.2: 2 h / 40 °C / Reflux 4.1: methanol / Reflux 5.1: sodium carbonate / water; methanol / 3 h / 30 °C / pH 10 6.1: sodium hydroxide; water / methanol / 2 h / 40 - 45 °C 6.2: pH 3 / Acidic conditions View Scheme
Multi-step reaction with 8 steps 1.1: 1,1'-carbonyldiimidazole 1.2: 3 h / 50 °C 2.1: 3 h / 70 °C 3.1: ethanol / 3 h / Reflux 4.1: ethanol; sodium cyanoborohydride / 2 h / 40 °C / Reflux 5.1: methanol / Reflux 6.1: Basic conditions 7.1: sodium carbonate / water; methanol / 3 h / 30 °C / pH 10 8.1: sodium hydroxide / water; methanol / 2 h / 40 - 45 °C 8.2: pH 3 View Scheme

5-(1-hydroxy-2-(2,4,5-trifluorophenyl)ethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (764667-64-3) → (3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (486460-00-8)

Conditions	Yield
Multi-step reaction with 5 steps 1: 88.7 percent / toluene / 3 h / Heating 2: 95 percent / ammonium acetate / methanol / 7 h / Heating 3: 68 percent / H2; (R) chiral ferrocenyl derivative / chloro(1,5-cyclooctadiene)rhodium(I) dimer / 2,2,2-trifluoro-ethanol / 40 h / 50 °C / 5171.62 Torr 4: 93 percent / CH2Cl2 / 3 h / 20 °C 5: 99 percent / aq. LiOH / tetrahydrofuran; methanol / 3 h / 20 °C View Scheme
Multi-step reaction with 7 steps 1.1: 60 - 63 °C 2.1: ammonium acetate / methanol / 60 - 63 °C 3.1: sulfuric acid / methanol / -10 - 0 °C 3.2: 2 h / -10 - 0 °C 3.3: pH 8 - 9 4.1: isopropyl alcohol / 3 h / 25 - 30 °C 5.1: sodium carbonate / water / pH 8 - 9 6.1: water; lithium hydroxide / tetrahydrofuran / 0 - 30 °C 7.1: water; tetrahydrofuran / 6 h / 25 - 30 °C 7.2: pH 2 View Scheme
Multi-step reaction with 3 steps 1.1: acetonitrile / 24 h / 80 - 84 °C / Inert atmosphere 2.1: salicylic acid; ammonium acetate; Ru(OAc)2((R)-dm-Segphos); hydrogen / 20 h / 40 - 80 °C / Green chemistry 3.1: triethylamine / ethyl acetate / 7 h / 20 - 30 °C 3.2: 2 h / 20 - 30 °C View Scheme
Multi-step reaction with 7 steps 1.1: toluene / Reflux 2.1: ammonium acetate / acetonitrile / Reflux 3.1: N-tert-butylaminoborane / tetrahydrofuran / 20 °C 3.2: 8 h / 0 - 20 °C 4.1: acetonitrile; water / 0.5 h / Reflux 5.1: sodium hydrogencarbonate / water; ethyl acetate / 0.5 h 6.1: palladium on activated charcoal; hydrogen / methanol / 25 - 30 °C 7.1: sodium carbonate / tetrahydrofuran; water / 25 - 30 °C View Scheme
Multi-step reaction with 4 steps 1: acetonitrile / 65 °C 2: sodium tetrahydroborate; ethanol / 65 °C / Cooling with ice 3: hydrogenchloride / methanol / 20 °C / pH 1 4: sodium hydrogencarbonate / tetrahydrofuran; water / 24 h / 20 °C View Scheme

methyl (3R)-3-amino-4-(2,4,5-trifluorophenyl)butanoate (1S)-(+)-10-camphorsulfonic acid → (3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (486460-00-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: LiOH*H2O / tetrahydrofuran; H2O / 24 h 2: 14 g / LiOH*H2O / tetrahydrofuran; H2O / 12 h / 20 °C View Scheme

di-tert-butyl dicarbonate (24424-99-5) + 1.) NaH; 2.) SOCl2 → (3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (486460-00-8)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: aq. HCl / acetonitrile / 72 h / 20 °C 1.2: 2.41 g / triethylamine / CH2Cl2 / 16 h / 20 °C 2.1: aq. LiOH / tetrahydrofuran / 20 °C 3.1: isobutyl chloroformate; triethylamine / diethyl ether / 0.25 h / -20 °C 3.2: 0.36 g / diethyl ether / 1 h 4.1: 401 mg / aq. silver benzoate / dioxane / 2 h / 20 °C / sonication View Scheme

2,4,5-trifluorobenzyl bromide (157911-56-3) → (3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (486460-00-8)

Conditions

Yield

Multi-step reaction with 5 steps 1.1: n-BuLi / tetrahydrofuran / -78 °C 1.2: tetrahydrofuran / -78 °C 2.1: aq. HCl / acetonitrile / 72 h / 20 °C 2.2: 2.41 g / triethylamine / CH2Cl2 / 16 h / 20 °C 3.1: aq. LiOH / tetrahydrofuran / 20 °C 4.1: isobutyl chloroformate; triethylamine / diethyl ether / 0.25 h / -20 °C 4.2: 0.36 g / diethyl ether / 1 h 5.1: 401 mg / aq. silver benzoate / dioxane / 2 h / 20 °C / sonication View Scheme

(R)-methyl 2-((tert-butoxycarbonyl)amino)-3-(2,4,5-trifluorophenyl)propanoate (486460-08-6) → (3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (486460-00-8)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: aq. LiOH / tetrahydrofuran / 20 °C 2.1: isobutyl chloroformate; triethylamine / diethyl ether / 0.25 h / -20 °C 2.2: 0.36 g / diethyl ether / 1 h 3.1: 401 mg / aq. silver benzoate / dioxane / 2 h / 20 °C / sonication View Scheme

(2S,5R)-2,5-dihydro-3,6-dimethoxy-2-isopropyl-5-(2',4',5'-trifluorobenzyl)-pyrazine (486460-07-5) → (3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (486460-00-8)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: aq. HCl / acetonitrile / 72 h / 20 °C 1.2: 2.41 g / triethylamine / CH2Cl2 / 16 h / 20 °C 2.1: aq. LiOH / tetrahydrofuran / 20 °C 3.1: isobutyl chloroformate; triethylamine / diethyl ether / 0.25 h / -20 °C 3.2: 0.36 g / diethyl ether / 1 h 4.1: 401 mg / aq. silver benzoate / dioxane / 2 h / 20 °C / sonication View Scheme

(R)-2-(tert-butoxycarbonylamino)-3-(2,4,5-trifluorophenyl)propanoic acid (486460-09-7) → (3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (486460-00-8)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: isobutyl chloroformate; triethylamine / diethyl ether / 0.25 h / -20 °C 1.2: 0.36 g / diethyl ether / 1 h 2.1: 401 mg / aq. silver benzoate / dioxane / 2 h / 20 °C / sonication View Scheme
Multi-step reaction with 2 steps 1.1: isobutyl chloroformate; triethylamine / diethyl ether / 0.25 h / -20 °C 1.2: 1 h / -20 °C 2.1: silver benzoate / water; 1,4-dioxane / 1.5 h / Sonication View Scheme
Multi-step reaction with 2 steps 1.1: isobutyl chloroformate; triethylamine / diethyl ether / 0.25 h / -20 °C 1.2: 1 h / -20 °C 2.1: silver benzoate / 1,4-dioxane; water / 2 h View Scheme

di-tert-butyl dicarbonate (24424-99-5) + (R)-3-amino-4-phenyl(2,4,5-trifluorophenyl)butanoic acid hydrochloride (1204818-19-8) → (3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (486460-00-8)

Conditions	Yield
With sodium carbonate In tetrahydrofuran at 0 - 20℃;

3-tert-butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyric acid ethyl ester → (3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (486460-00-8)

Conditions	Yield
Stage #1: 3-tert-butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyric acid ethyl ester With water; sodium hydroxide In methanol at 40 - 45℃; Stage #2: With hydrogenchloride In water pH=2 - 3; Cooling with ice;

(3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (486460-00-8) + 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride (762240-92-6) → (R)-tert-butyl 4-oxo-4-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-1-(2,4,5-trifluorophenyl)butan-2-ylcarbamate (486460-23-5)

Conditions	Yield
With 1,1'-carbonyldiimidazole In tetrahydrofuran at 55 - 60℃; for 12h;	99.02%
With triethylamine; 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride In methanol at 20 - 50℃; Reagent/catalyst; Solvent;	96%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In acetonitrile at 0 - 20℃; for 24h;	95%

3-trifluoromethyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine (486460-21-3) + (3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (486460-00-8) → (R)-tert-butyl 4-oxo-4-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-1-(2,4,5-trifluorophenyl)butan-2-ylcarbamate (486460-23-5)

Conditions	Yield
With (2-iodo-5-methoxyphenyl)boronic acid; 4-(dimethylamino)pyridine N-oxide In fluorobenzene for 40h; Catalytic behavior; Reagent/catalyst;	99%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In water; ethyl acetate at 20℃; for 12h;	91%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 20℃; for 12h;	88%

C11H13F5N4 + (3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (486460-00-8) → tert-butyl ((2R)-4-oxo-4-(1-(perfluoroethyl)-4,5,5a,8,9,9a-hexahydro-[1,2,4]triazolo[4,3-a][1,6]naphthyridin-7(6H)-yl)-1-(2,4,5-trifluorophenyl)butan-2-yl)carbamate

Conditions	Yield
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃;	98%

rac-(5aS,9aR)-1-(6-ethoxypyridin-2-yl)-4,5,5a,6,7,8,9,9a-octahydro[1,2,4]triazolo[4,3-a][1,6]naphthyridine + (3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (486460-00-8) → tert-butyl ((R)-4-((5aS*,9aR*)-1-(6-ethoxypyridin-2-yl)-4,5,5a,8,9,9a-hexahydro-[1,2,4]triazolo[4,3-a][1,6]naphthyridin-7(6H)-yl)-4-oxo-1-(2,4,5-trifluorophenyl)butan-2-yl)carbamate

Conditions	Yield
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 20h; Inert atmosphere;	98%

hexahydro-2-(4-cyanophenyl)-imidazo[1,5-a]pyrazin-3-one (1256815-22-1) + (3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (486460-00-8) → tert-butyl [(1R)-3-[2-(4-cyanophenyl)-hexahydro-3-oxoimidazo[1,5-a]pyrazin-7(8H)-yl]-3-oxo-1-(2,4,5-trifluorobenzyl)propyl]carbamate (1256815-41-4)

Conditions	Yield
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃; for 12h;	97%

(3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (486460-00-8) + 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride (762240-92-6) → Sitagliptin hydrochloride

Conditions	Yield
Stage #1: (3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid; 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride In N,N-dimethyl-formamide for 0.166667h; Stage #2: With 2-chloro-1,3-dimethylimidazolinium chloride In N,N-dimethyl-formamide at 20 - 25℃; for 5h; Reagent/catalyst;	97%

1-(1-methanesulfonylpiperazin-2-yl)cyclopropylcarboxylic acid methyl ester + (3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (486460-00-8) → 1-[4-[(3R)-3-(tert-butoxycarbonylamino)-4-(2,4,5-trifluorophenyl)butanoyl]-1-methanesulfonylpiperazin-2-yl]cyclopropylcarboxylic acid methyl ester

Conditions	Yield
With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In dichloromethane at 0 - 30℃; for 1h; Inert atmosphere;	97%

(3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (486460-00-8) + 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride (762240-92-6) → sitagliptin (486460-32-6)

Conditions	Yield
Stage #1: (3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid With triethylamine In dichloromethane for 0.166667h; Stage #2: With benzotriazol-1-ol; dicyclohexyl-carbodiimide In dichloromethane at 25 - 30℃; for 4h; Stage #3: 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride Further stages;	96.5%

hexahydro-2-(pyridin-2-yl)-imidazo[1,5-a]pyrazin-3(5h)-one (1256815-18-5) + (3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (486460-00-8) → tert-butyl [(1R)-3-[2-(pyridin-2-yl)-hexahydro-3-oxoimidazo[1,5-a]pyrazin-7(8H)-yl]-3-oxo-1-(2,4,5-trifluorobenzyl)propyl]carbamate (1256815-36-7)

Conditions	Yield
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃; for 12h;	96%

3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-α]pyrazine hydrochloride + (3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (486460-00-8) → sitagliptin (486460-32-6)

Conditions	Yield
Stage #1: (3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid With thionyl chloride In ethyl acetate at 26℃; for 2h; Stage #2: 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-α]pyrazine hydrochloride With triethylamine In ethyl acetate at 25℃; Solvent; Temperature;	96%
Stage #1: 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-α]pyrazine hydrochloride; (3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid With 1-methyl-1H-imidazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride at 0 - 20℃; for 16h; Stage #2: With hydrogenchloride In ethanol at 20℃; for 18h; Stage #3: With sodium hydroxide In ethanol; water pH=10 - 12; Time; Solvent;	90%
Stage #1: (3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid With pivaloyl chloride; sodium carbonate In toluene Cooling; Stage #2: 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-α]pyrazine hydrochloride In toluene Stage #3: With hydrogenchloride In water; toluene Reagent/catalyst;	4.4 g

(3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (486460-00-8) → (R)-3-(amino-d2)-4-(2,4,5-trifluorophenyl)-2,2-d2-butanoic acid deuterochloride (1078568-89-4)

Conditions	Yield
With water-d2; hydrogen chloride at 70 - 160℃; for 15h;	95%

hexahydro-2-(3-cyanobenzyl)-imidazo[1,5-a]pyrazin-3-one (1256815-17-4) + (3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (486460-00-8) → tert-butyl [(1R)-3-[2-(3-cyanobenzyl)-hexahydro-3-oxoimidazo[1,5-a]pyrazin-7(8H)-yl]-3-oxo-1-(2,4,5-trifluorobenzyl)propyl]carbamate

Conditions	Yield
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃; for 12h;	95%

3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-α]pyrazine hydrochloride + (3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (486460-00-8) → (R)-tert-butyl 4-oxo-4-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-1-(2,4,5-trifluorophenyl)butan-2-ylcarbamate (486460-23-5)

Conditions	Yield
With pyridine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride at 0 - 20℃; for 16h;	95%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In acetonitrile at 0 - 20℃; for 24h;	95%
Stage #1: (3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid With Triisopropyl borate; sulfuric acid In toluene at 20℃; for 2h; Reflux; Stage #2: 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-α]pyrazine hydrochloride With triethylamine In toluene at 80℃; Reagent/catalyst; Temperature; Solvent; Concentration; Reflux; Dean-Stark;	92.1%

3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-α]pyrazine hydrochloride + (3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (486460-00-8) → N-Boc-sitagliptin

Conditions	Yield
With 4-(dimethylamino)pyridine N-oxide; sodium hydroxide; 2,6-difluorophenylboronic acid In fluorobenzene; water at 100℃; for 23h; Reagent/catalyst; Molecular sieve;	95%

C14H19N3O2 (1256815-14-1) + (3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (486460-00-8) → tert-butyl [(1R)-3-[2-(2-methoxybenzyl)-hexahydro-3-oxoimidazo[1,5-a]pyrazin-7(8H)-yl]-3-oxo-1-(2,4,5-trifluorobenzyl)propyl]carbamate (1256815-32-3)

Conditions	Yield
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃; for 12h;	94%

4-[3-methyl-5-(trifluoromethyl)-4H-1,2,4-triazol-4-yl]piperidine (868669-70-9) + (3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (486460-00-8) → tert-butyl (R)-(4-(4-(3-methyl-5-(trifluoromethyl)-4H-1,2,4-triazol-4-yl)piperidin-1-yl)-4-oxo-1-(2,4,5-trifluorophenyl)butan-2-yl)carbamate

Conditions	Yield
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃;	93%

bis(pentafluorophenyl)carbonate (59483-84-0) + (3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (486460-00-8) → (R)-pentafluorophenyl 3-(t-butoxycarbonylamino)-4-(2,4,5-trifluorophenyl)butanoate

Conditions	Yield
Stage #1: (3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid With triethylamine In N,N-dimethyl-formamide at 25℃; for 0.333333h; Stage #2: bis(pentafluorophenyl)carbonate In N,N-dimethyl-formamide at 25℃; for 2h;	92.3%

hexahydro-2-(4-chlorobenzyl)-imidazo[1,5-a]pyrazin-3-one (1256815-12-9) + (3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (486460-00-8) → tert-butyl [(1R)-3-[2-(4-chlorobenzyl)-hexahydro-3-oxoimidazo[1,5-a]pyrazin-7(8H)-yl]-3-oxo-1-(2,4,5-trifluorobenzyl)propyl]carbamate (1256815-30-1)

Conditions	Yield
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃; for 12h;	92%

7-methoxy-1,3,4,5-tetrahydrobenzo[e][1,4]diazepin-2-one hydrochloride (1364122-94-0) + (3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (486460-00-8) → (R)-[3-(7-methoxy-2-oxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepine-4-yl)-3-oxo-1-(2,4,5-trifluorophenyl)propyl]carbamic acid tert-butyl ester

Conditions	Yield
Stage #1: (3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid With N-ethyl-N,N-diisopropylamine; 1,1'-carbonyldiimidazole In acetonitrile at 20℃; for 0.5h; Stage #2: 7-methoxy-1,3,4,5-tetrahydrobenzo[e][1,4]diazepin-2-one hydrochloride In acetonitrile at 65 - 70℃; for 22h;	92%

bis-(p-nitrophenyl) carbonate (5070-13-3) + (3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (486460-00-8) → (R)-4-nitrophenyl 3-(t-butoxycarbonylamino)-4-(2,4,5-trifluorophenyl)butanoate

Conditions	Yield
Stage #1: (3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid With triethylamine In N,N-dimethyl-formamide at 25℃; for 0.333333h; Stage #2: bis-(p-nitrophenyl) carbonate In N,N-dimethyl-formamide at 25 - 70℃; for 4h;	91.9%

2,2'-dipyridyl carbonate (1659-31-0) + (3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (486460-00-8) → (R)-pyridin-2-yl 3-(t-butoxycarbonylamino)-4-(2,4,5-trifluorophenyl)butanoate

Conditions	Yield
Stage #1: (3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid With triethylamine In N,N-dimethyl-formamide at 25℃; for 0.333333h; Stage #2: 2,2'-dipyridyl carbonate In N,N-dimethyl-formamide at 25 - 70℃; for 2h;	91.4%

C10H13F3N4 + (3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (486460-00-8) → tert-butyl ((2R)-4-oxo-4-(1-(trifluoromethyl)-4,5,5a,8,9,9a-hexahydro-[1,2,4]triazolo[4,3-a][1,6]naphthyridin-7(6H)-yl)-1-(2,4,5-trifluorophenyl)butan-2-yl)carbamate

Conditions	Yield
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃;	91%

1,2-diazepane dihydrochloride + (3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (486460-00-8) → (R)-[3-[1,2]diazepan-1-yl-3-oxo-1-(2,4,5-trifluorobenzyl)propyl]carbamic acid tert-butyl ester (939964-18-8)

Conditions	Yield
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃; for 12h;	90%

Upstream product

• 24424-99-5 di-tert-butyl dicarbonate 
• 1204818-19-8 (R)-3-amino-4-phenyl(2,4,5-trifluorophenyl)butanoic acid hydrochloride 
• 881995-69-3 (R)-3-amino-4-(2,4,5-trifluorophenyl)butyric acid methyl ester 
• 130622-08-1 (2R)-2-tert-butoxycarbonylamino-succinic acid dimethyl ester 
• 397246-14-9 (1-(hydroxymethyl)-3-hydroxypropyl)carbamic acid tert-butyl ester 
• 322691-00-9 2-(tert-butoxycarbonylamino)-butane-1,4-diyl dimethanesulfonate 
• 1246960-16-6 (S)-1-azido-3-(2,4,5-trifluorophenyl)propane-2-ol 
• 502462-00-2 (2,4,5-trifluorophenyl)-magnesium bromide 
• 1246960-23-5 (R)-tert-butyl (1-cyano-3-(2,4,5-trifluorophenyl)propan-2-yl)carbamate 
• 1246960-17-7 (R)-t-butyl 2-(2,4,5-trifluorobenzyl)aziridine-1-carboxylate 
• 1246960-15-5 (S)-1-chloro-3-(2,4,5-trifluorophenyl)propan-2-ol 
• 327-52-6 1-bromo-2,4,5-trifluorobenzene 
• 1361050-70-5 (R)-4-methoxy-4-oxo-2-(2,4,5-trifluorobenzyl)butanoic acid 
• 1361050-69-2 4-methoxy-4-oxo-2-(2,4,5-trifluorobenzyl)butanoic acid 

Downstream Products

• 939964-17-7 (R)-[3-oxo-3-(tetrahydropyridazin-1-yl)-1-(2,4,5-trifluorobenzyl)propyl]carbamic acid tert-butyl ester 
• 939964-18-8 (R)-[3-[1,2]diazepan-1-yl-3-oxo-1-(2,4,5-trifluorobenzyl)propyl]carbamic acid tert-butyl ester 
• 939964-16-6 (R)-[3-oxo-3-pyrazolidin-1-yl-1-(2,4,5-trifluorobenzyl)propyl]carbamic acid tert-butyl ester 
• 939964-27-9 (R)-[3-(2-benzoylcarbamoylpyrazolidin-1-yl)-3-oxo-1-(2,4,5-trifluorobenzyl)propyl]carbamic acid tert-butyl ester 
• 939964-28-0 (R)-[3-oxo-3-(2-(toluene-4-sulfonyl)pyrazolidin-1-yl)-1-(2,4,5-trifluorbenzyl)propyl]carbamic acid tert-butyl ester 
• 939964-29-1 (R)-[3-(2-benzoylpyrazolidin-1-yl)-3-oxo-1-(2,4,5-trifluorobenzyl)propyl]carbamic acid tert-butyl ester 
• 939964-30-4 (R)-[3-(2-benzoyltetrahydropyridazin-1-yl)-3-oxo-1-(2,4,5-trifluorobenzyl)propyl]carbamic acid tert-butyl ester 
• 939964-31-5 tert-butyl (R)-4-(2-benzoyl-1,2-diazepan-1-yl)-4-oxo-1-(2,4,5-trifluorophenyl)butan-2-ylcarbamate 
• 872323-68-7 C₂₃H₂₅F₃N₄O₄ 
• 866782-08-3 [(R)-1-{[(S)-1-(3-cyclopropyl[1,2,4]oxadiazol-5-yl)-2-methyl-propylcarbamoyl]-methyl}-2-(2,4,5-trifluoro-phenyl)-ethyl]-carbamic acid tert-butyl ester 
• 1256815-37-8 tert-butyl [(1R)-3-[2-(4-(trifluoromethyl)phenyl)-hexahydro-3-oxoimidazo[1,5-a]pyrazin-7(8H)-yl]-3-oxo-1-(2,4,5-trifluorobenzyl)propyl]carbamate 
• 1256815-29-8 tert-butyl [(1R)-3-[2-(4-methylbenzyl)-hexahydro-3-oxoimidazo[1,5-a]pyrazin-7(8H)-yl]-3-oxo-1-(2,4,5-trifluorobenzyl)propyl]carbamate 
• 1256815-30-1 tert-butyl [(1R)-3-[2-(4-chlorobenzyl)-hexahydro-3-oxoimidazo[1,5-a]pyrazin-7(8H)-yl]-3-oxo-1-(2,4,5-trifluorobenzyl)propyl]carbamate 

Relevant articles and documents

Application of the asymmetric hydrogenation of enamines to the preparation of a beta-amino acid pharmacophore

(3R)-3-[N-(tert-Butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid 7a has been synthesized by an asymmetric hydrogenation of enamine ester 3 using chiral ferrocenyl ligands I and II in conjunction with [Rh(COD)Cl] 2. The direct reduction of 3 provides amino ester 1b in 93% ee, which was isolated as an (S)-camphorsulfonic acid salt to upgrade the enantiomeric excess to >99%. A more concise approach was developed involving the in situ protection of 1b using di-tert-butyldicarbonate. This approach provided the desired N-Boc amino ester 7b directly from the hydrogenation with 97% ee, which was upgraded to >99% ee upon crystallization.

Nickel-Catalyzed Asymmetric Hydrogenation for the Synthesis of a Key Intermediate of Sitagliptin

Nickel-catalyzed enantioselective hydrogenation of enamines leading to the efficient synthesis of 3-R-Boc-amino-4-(2,4,5-trifluorophenyl)butyric esters, the key intermediate of the blockbuster antidiabetic drug (R)-SITAGLIPTIN, is described. The sitagliptin motifs were isolated in more than 99% yield and with 75–92% ee using the earth-abundant nickel catalyst. Upon chiral resolution with (R)- and (S)-1-phenylethylamines, the partially enantioenriched (R)- and (S)-Boc-3-amino-4-(2,4,5-trifluorophenyl)butanoic acids provided >99.5% ee of the crucial sitagliptin intermediate. The asymmetric hydrogenation protocol was scaled up to 10 g with consistency in yield and ee, and has been reproduced in multiple batches.

Preparation method of chiral 4 - aryl - β β-amino acid derivative

Provided is a method for preparing a chiral 4-aryl-β-amino acid derivative. The preparation method comprises hydrogenating an enamine compound having a structure as shown in Formula III in an organic solvent in the presence of a catalyst containing a transition metal and BIBOPs. The preparation method of the present invention uses a small amount of a selected asymmetric catalyst, and has a simple operation, mild reaction conditions, a high yield, a high stereoselectivity, and better industrial application and economic values.

Synthesis of (?)-(R)-Sitagliptin by RhI-Catalyzed Asymmetric Hydroamination

We report of a concise synthesis of (R)-sitagliptin monophosphate – a drug predominantly applied in the treatment of type 2 diabetes. Utilizing our recently developed RhI-catalyzed hydroamination of allenes for the stereoselective construction of the inherent chiral amino function, a new approach to (R)-sitagliptin monophosphate on a 3.5 mmol scale was established.

Preparation method of 1-morpholinyl-4-(2,4,5-trifluorophenyl)butane-1,3-dione

The invention discloses a preparation method of 1-morpholinyl-4-(2,4,5-trifluorophenyl)butane-1,3-dione, and belongs to the technical field of organic synthesis. The preparation method comprises the following step: under the action of a metal chelating agent and an alkali, carrying out a reaction of the following formula on a compound 2 and a compound 3 in an organic solvent to obtain a compound 1. The preparation method disclosed by the invention is high in yield, simple in post-treatment, simple, feasible, mild in reaction condition and suitable for industrial production.

Preparation method of 1,3-dicarbonyl compound and intermediate of the 1,3-dicarbonyl compound

The invention discloses a preparation method of a 1,3-dicarbonyl compound and an intermediate of the 1,3-dicarbonyl compound, and particularly discloses a preparation method of a compound as shown ina formula I. The preparation method comprises the following step: in a solvent, performing an elimination reaction as shown in the specification on a compound as shown in a formula II to obtain the compound as shown in the formula I, wherein R is a tert-butoxy group, a methoxy group, an ethoxy group or a methyl group. The preparation method disclosed by the invention is relatively low in cost andbeneficial to industrial production.

Synthesis of (R)-3-(tert-Butoxycarbonylamino)-4-(2,4,5-trifluorophenyl)butanoic Acid, a Key Intermediate, and the Formal Synthesis of Sitagliptin Phosphate

An alternate formal synthesis of Sitagliptin phosphate is disclosed from 2,4,5-trifluorobenzadehyde in 8 linear steps with an overall yield of 31%. The chiral β-amino acid moiety present in sitaglitpin is installed via an asymmetric hydrogenation followed by a stereoselective Hofmann rearrangement as the key steps. The key chiral intermediate Boc-amino acid 1 prepared by this novel route was further converted to Sitagliptin phosphate following the known literature protocol.

AN IMPROVED PROCESS FOR THE PREPARATION OF SITAGLIPTIN AND ITS INTERMEDIATES

The present invention relates to a process for the preparation of novel intermediates useful for the preparation of Sitagliptin or its pharmaceutically acceptable salts. The present invention relates to an efficient process for the preparation of Sitagliptin intermediates. The present invention relates to an improved process for the preparation of Sitagliptin or its pharmaceutically acceptable salts.

BOC-(R)-3-amino-4-(2,4,5-trifluorophenyl)butyric acid condensation impurity and preparation method thereof

The invention provides a sitagliptin phosphate important intermediate BOC-(R)-3-amino-4-(2,4,5-trifluorophenyl)butyric acid condensation impurity and a preparation method and preparation thereof. TheBOC-(R)-3-amino-4-(2,4,5-trifluorophenyl)butyric acid condensation impurity and the preparation method thereof have important significance for the following industrial production of bulk drugs.

Method for synthesizing sitagliptin and intermediate thereof through biological catalysis

The invention provides a method for synthesizing sitagliptin and an intermediate thereof through biological catalysis, and particularly provides compounds as shown in formula I and a formula II, or pharmaceutically acceptable salt thereof, polypeptide capable of synthesizing a compound as shown in the formula I to produce a compound as shown in the formula II, nucleic acid coding the polypeptide,and a vector and a cell containing the nucleic acid. In addition, the invention further provides a method for producing the compound as shown in the formula II and sitagliptin through the polypeptideand the compound as shown in the formula I, and a preparation method for preparing the polypeptide.