881995-69-3

Basic information

• Product Name: Benzenebutanoicacid,b-aMino-2,4,5-trifluoro-,Methylester,(bR)-
• Synonyms: Benzenebutanoicacid,b-aMino-2,4,5-trifluoro-,Methylester,(bR)-;(R)-Sitagliptin Methyl-Ester IMpurity;(3R)-3-aMino-4-(2,4,5-trifluorophenyl)butanoate;(R)-Methyl 3-aMino-4-(2,4,5-trifluoro phenyl) butanoate;Methyl (R)-b-Amino-2,4,5-F3-benzenebutanoate HCl;Benzenebutanoic acid, β-amino-2,4,5-trifluoro-, methyl ester, (βR)-
• CAS NO: 881995-69-3
• Molecular Formula: C₁₁H₁₂F₃NO₂
• Molecular Weight: 247.2136896
• EINECS: 1312995-182-4
• Mol File: 881995-69-3.mol
• Article Data: 12

Chemical Properties

• Boiling Point: 316.0±42.0 °C(Predicted)
• Appearance: /
• Density: 1.287±0.06 g/cm3(Predicted)
• PKA: 6.90±0.10(Predicted)
• CAS DataBase Reference: Benzenebutanoicacid,b-aMino-2,4,5-trifluoro-,Methylester,(bR)-(CAS DataBase Reference)
• NIST Chemistry Reference: Benzenebutanoicacid,b-aMino-2,4,5-trifluoro-,Methylester,(bR)-(881995-69-3)
• EPA Substance Registry System: Benzenebutanoicacid,b-aMino-2,4,5-trifluoro-,Methylester,(bR)-(881995-69-3)

Safety Data

• Hazardous Substances Data: 881995-69-3(Hazardous Substances Data)

Usage

General Description

Benzenebutanoic acid, b-amino-2,4,5-trifluoro-, methylester, (bR)- is a chemical compound with a complex molecular structure. It is a methyl ester derivative of benzenebutanoic acid, containing a trifluoromethyl group and an amino group on the 2, 4, and 5 positions of the benzene ring. The compound exists as a single stereoisomer, with the (bR)- configuration. It is commonly used in the field of organic chemistry for its unique reactivity and potential applications in the synthesis of pharmaceuticals and materials. However, it is important to handle this chemical with caution due to its potential hazards and toxicity.

Synthetic route

methanol (67-56-1) + benzyl 3-oxo-4-(2,4,5-trifluorophenyl)butanoate → (R)-3-amino-4-(2,4,5-trifluorophenyl)butyric acid methyl ester (881995-69-3)

Conditions	Yield
With Ru(OAc)2((R)-dm-Segphos); ammonium acetate; hydrogen; salicylic acid at 40 - 80℃; for 20h; Catalytic behavior; Temperature; Green chemistry;	95.2%

(R)-(-)-mandelic acid salt of (R)-methyl 3-amino-4-(2,4,5-trifluorophenyl)butanoate (1253055-94-5) → (R)-3-amino-4-(2,4,5-trifluorophenyl)butyric acid methyl ester (881995-69-3)

Conditions	Yield
With sodium carbonate In water pH=8 - 9;	95%
With sodium carbonate In water pH=8 - 9;	90%

methyl 3-amino-4-(2,4,5-trifluorophenyl)but-2-enoate → (R)-3-amino-4-(2,4,5-trifluorophenyl)butyric acid methyl ester (881995-69-3)

Conditions	Yield
With hydrogen; chloro(1,5-cyclooctadiene)rhodium(I) dimer In 2,2,2-trifluoroethanol at 50℃; under 5171.62 Torr; for 40h;	68%

(2Z)-3-amino-4-(2,4,5-trifluorophenyl)but-2-enoic acid methyl ester (881995-70-6) → methyl (3S)-3-amino-4-(2,4,5-trifluorophenyl)butanoate + (R)-3-amino-4-(2,4,5-trifluorophenyl)butyric acid methyl ester (881995-69-3)

Conditions	Yield
With chloro(1,5-cyclooctadiene)rhodium(I) dimer; chiral ferrocenyl ligand; hydrogen In 2,2,2-trifluoroethanol at 40℃; under 10343 Torr; for 24h;

4-(2,4,5-trifluoro-phenyl)-3-oxo-butyric acid methyl ester (769195-26-8) → (R)-3-amino-4-(2,4,5-trifluorophenyl)butyric acid methyl ester (881995-69-3)

Conditions	Yield
Multi-step reaction with 2 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 View Scheme
Multi-step reaction with 2 steps 1: 91 percent / ammonium acetate / methanol / 2 h / Heating 2: [Rh(COD)Cl]2; chiral ferrocenyl ligand; H2 / 2,2,2-trifluoro-ethanol / 24 h / 40 °C / 10343 Torr View Scheme
Multi-step reaction with 4 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 View Scheme
With transaminase; pyridoxal 5'-phosphate; isopropylamine In water; dimethyl sulfoxide at 45℃; for 8h; Enzymatic reaction;

(2,4,5-trifluorophenyl)acetic acid (209995-38-0) → (R)-3-amino-4-(2,4,5-trifluorophenyl)butyric acid methyl ester (881995-69-3)

Conditions	Yield
Multi-step reaction with 4 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 View Scheme
Multi-step reaction with 3 steps 1.1: 1,1'-carbonyldiimidazole / acetonitrile / 3.5 h 1.2: Et3N; MgCl2 / acetonitrile / 8 h / 50 °C 1.3: 84 percent / acetonitrile / 26 h / 30 °C 2.1: 91 percent / ammonium acetate / methanol / 2 h / Heating 3.1: [Rh(COD)Cl]2; chiral ferrocenyl ligand; H2 / 2,2,2-trifluoro-ethanol / 24 h / 40 °C / 10343 Torr View Scheme
Multi-step reaction with 3 steps 1.1: 1,1'-carbonyldiimidazole / acetonitrile / 3.5 h 1.2: Et3N; MgCl2 / acetonitrile / 8 h / 50 °C 1.3: acetonitrile / 26 h / 30 °C 2.1: 91 percent / ammonium acetate / methanol / 2 h / Heating 3.1: [Rh(COD)Cl]2; chiral ferrocenyl ligand; H2 / 2,2,2-trifluoro-ethanol / 24 h / 40 °C / 10343 Torr View Scheme

5-(1-hydroxy-2-(2,4,5-trifluorophenyl)ethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (764667-64-3) → (R)-3-amino-4-(2,4,5-trifluorophenyl)butyric acid methyl ester (881995-69-3)

Conditions	Yield
Multi-step reaction with 3 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 View Scheme
Multi-step reaction with 5 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 View Scheme
Multi-step reaction with 2 steps 1: acetonitrile / 24 h / 80 - 84 °C / Inert atmosphere 2: salicylic acid; ammonium acetate; Ru(OAc)2((R)-dm-Segphos); hydrogen / 20 h / 40 - 80 °C / Green chemistry View Scheme

3-(R)-[(R)-(α-methylbenzyl)benzylamino]-4-(2,4,5-trifluoro-phenyl)butyric acid methyl ester (1260029-46-6) → (R)-3-amino-4-(2,4,5-trifluorophenyl)butyric acid methyl ester (881995-69-3)

Conditions	Yield
With 20 % Pd(OH)2/C; hydrogen In methanol at 20℃; under 3800.26 Torr;

(R)-methyl 3-hydroxy-4-(2,4,5-trifluorophenyl)butanoate (1138326-05-2) → (R)-3-amino-4-(2,4,5-trifluorophenyl)butyric acid methyl ester (881995-69-3)

Conditions	Yield
With sodium azide; triphenylphosphine In tetrachloromethane; N,N-dimethyl-formamide at 90℃; for 8h;

(R)-methyl 3-(1,3-dioxoisoindolin-2-yl)-4-(2,4,5-trifluorophenyl)butanoate (1253056-07-3) → (R)-3-amino-4-(2,4,5-trifluorophenyl)butyric acid methyl ester (881995-69-3)

Conditions	Yield
With methylamine In water; toluene at 25 - 40℃;

(R)-methyl 3-(p-toluenesulfonyloxy)-4-(2,4,5-trifluorophenyl)butanoate (1253056-08-4) → (R)-3-amino-4-(2,4,5-trifluorophenyl)butyric acid methyl ester (881995-69-3)

Conditions	Yield
With ammonia In methanol for 3h; Reflux;

(2Z)-3-amino-4-(2,4,5-trifluorophenyl)but-2-enoic acid methyl ester (881995-70-6) → (R)-3-amino-4-(2,4,5-trifluorophenyl)butyric acid methyl ester (881995-69-3)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: sulfuric acid / methanol / -10 - 0 °C 1.2: 2 h / -10 - 0 °C 1.3: pH 8 - 9 2.1: isopropyl alcohol / 3 h / 25 - 30 °C 3.1: sodium carbonate / water / pH 8 - 9 View Scheme

methyl 3-amino-4-(2,4,5-trifluorophenyl)butanoate (1253055-92-3) → (R)-3-amino-4-(2,4,5-trifluorophenyl)butyric acid methyl ester (881995-69-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: isopropyl alcohol / 3 h / 25 - 30 °C 2: sodium carbonate / water / pH 8 - 9 View Scheme
Multi-step reaction with 2 steps 1: ethyl acetate / 1 h / 65 - 70 °C 2: sodium hydrogencarbonate / water View Scheme

C11H12F3NO2*C14H19NO3 (1449289-64-8) → (R)-3-amino-4-(2,4,5-trifluorophenyl)butyric acid methyl ester (881995-69-3)

Conditions	Yield
With sodium hydrogencarbonate In water	3 g

4-(2,4,5-trifluoro-phenyl)-3-oxo-butyric acid methyl ester (769195-26-8) → (R)-3-amino-4-(2,4,5-trifluorophenyl)butyric acid methyl ester (881995-69-3) + (R)-3-amino-4-phenyl(2,4,5-trifluorophenyl)butanoic acid (936630-57-8)

Conditions	Yield
With pyridoxal 5'-phosphate; recombinant aminotransferase from Arthobacter sp.; water; isopropylamine In dimethyl sulfoxide at 45℃; for 8h; pH=8.5; Catalytic behavior; Concentration; Time; Enzymatic reaction; enantioselective reaction;

C17H22F3NO5S → (R)-3-amino-4-(2,4,5-trifluorophenyl)butyric acid methyl ester (881995-69-3)

Conditions	Yield
With hydrogenchloride In water at 50 - 115℃;	3.1 g

C16H25NOS → (R)-3-amino-4-(2,4,5-trifluorophenyl)butyric acid methyl ester (881995-69-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium hydrogencarbonate / 120 h / -30 - 20 °C 2: hydrogenchloride / water / 50 - 115 °C View Scheme

2-(2,4,5-trifluorophenyl)ethanol (883267-70-7) → (R)-3-amino-4-(2,4,5-trifluorophenyl)butyric acid methyl ester (881995-69-3)

Conditions	Yield
Multi-step reaction with 3 steps 1: 1-hydroxy-3H-benz[d][1,2]iodoxole-1,3-dione; magnesium sulfate / dichloromethane / 24 h / -20 - 20 °C 2: sodium hydrogencarbonate / 120 h / -30 - 20 °C 3: hydrogenchloride / water / 50 - 115 °C View Scheme

(R)-3-amino-4-(2,4,5-trifluorophenyl)butyric acid methyl ester (881995-69-3) + di-tert-butyl dicarbonate (24424-99-5) → 3-(R)-tert-butoxycarbonylamino-4-(2,4,5-trifluorophenyl)butyric acid methyl ester (881995-73-9)

Conditions	Yield
In dichloromethane at 20℃; for 3h;	93%
Stage #1: (R)-3-amino-4-(2,4,5-trifluorophenyl)butyric acid methyl ester With sodium hydroxide In tetrahydrofuran; water at 0℃; for 1h; Stage #2: di-tert-butyl dicarbonate In tetrahydrofuran; water-d2 at 20℃;	91.3%
With triethylamine In dichloromethane at 20℃; for 8h; optical yield given as %ee;	54.6 g
With lithium hydroxide In tetrahydrofuran; water at 0 - 5℃; for 1.5h;

(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%

(R)-3-amino-4-(2,4,5-trifluorophenyl)butyric acid methyl ester (881995-69-3) → (R)-[3-oxo-3-pyrazolidin-1-yl-1-(2,4,5-trifluorobenzyl)propyl]carbamic acid tert-butyl ester (939964-16-6)

Conditions	Yield
Multi-step reaction with 3 steps 1: 93 percent / CH2Cl2 / 3 h / 20 °C 2: 99 percent / aq. LiOH / tetrahydrofuran; methanol / 3 h / 20 °C 3: 47 percent / EDCI; triethylamine / CH2Cl2 / 1 h / 20 °C View Scheme

(R)-3-amino-4-(2,4,5-trifluorophenyl)butyric acid methyl ester (881995-69-3) → (R)-[3-oxo-3-(tetrahydropyridazin-1-yl)-1-(2,4,5-trifluorobenzyl)propyl]carbamic acid tert-butyl ester (939964-17-7)

Conditions	Yield
Multi-step reaction with 3 steps 1: 93 percent / CH2Cl2 / 3 h / 20 °C 2: 99 percent / aq. LiOH / tetrahydrofuran; methanol / 3 h / 20 °C 3: 66 percent / EDCI; triethylamine / CH2Cl2 / 12 h / 20 °C View Scheme

(R)-3-amino-4-(2,4,5-trifluorophenyl)butyric acid methyl ester (881995-69-3) → (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
Multi-step reaction with 3 steps 1: 93 percent / CH2Cl2 / 3 h / 20 °C 2: 99 percent / aq. LiOH / tetrahydrofuran; methanol / 3 h / 20 °C 3: 90 percent / EDCI; triethylamine / CH2Cl2 / 12 h / 20 °C View Scheme

(R)-3-amino-4-(2,4,5-trifluorophenyl)butyric acid methyl ester (881995-69-3) → C13H16F3N3O*HCl

Conditions	Yield
Multi-step reaction with 4 steps 1: 93 percent / CH2Cl2 / 3 h / 20 °C 2: 99 percent / aq. LiOH / tetrahydrofuran; methanol / 3 h / 20 °C 3: 47 percent / EDCI; triethylamine / CH2Cl2 / 1 h / 20 °C 4: 99 percent / HCl / ethyl acetate; dioxane / 16 h / 20 °C View Scheme

(R)-3-amino-4-(2,4,5-trifluorophenyl)butyric acid methyl ester (881995-69-3) → (R)-[3-(2-benzoylcarbamoylpyrazolidin-1-yl)-3-oxo-1-(2,4,5-trifluorobenzyl)propyl]carbamic acid tert-butyl ester (939964-27-9)

Conditions	Yield
Multi-step reaction with 4 steps 1: 93 percent / CH2Cl2 / 3 h / 20 °C 2: 99 percent / aq. LiOH / tetrahydrofuran; methanol / 3 h / 20 °C 3: 47 percent / EDCI; triethylamine / CH2Cl2 / 1 h / 20 °C 4: 85 percent / CH2Cl2 / 2 h / 20 °C View Scheme

(R)-3-amino-4-(2,4,5-trifluorophenyl)butyric acid methyl ester (881995-69-3) → (R)-[3-oxo-3-(2-(toluene-4-sulfonyl)pyrazolidin-1-yl)-1-(2,4,5-trifluorbenzyl)propyl]carbamic acid tert-butyl ester (939964-28-0)

Conditions	Yield
Multi-step reaction with 4 steps 1: 93 percent / CH2Cl2 / 3 h / 20 °C 2: 99 percent / aq. LiOH / tetrahydrofuran; methanol / 3 h / 20 °C 3: 47 percent / EDCI; triethylamine / CH2Cl2 / 1 h / 20 °C 4: 76 percent / Et3N / CH2Cl2 / 2 h / 20 °C View Scheme

(R)-3-amino-4-(2,4,5-trifluorophenyl)butyric acid methyl ester (881995-69-3) → (R)-[3-(2-benzoylpyrazolidin-1-yl)-3-oxo-1-(2,4,5-trifluorobenzyl)propyl]carbamic acid tert-butyl ester (939964-29-1)

Conditions	Yield
Multi-step reaction with 4 steps 1: 93 percent / CH2Cl2 / 3 h / 20 °C 2: 99 percent / aq. LiOH / tetrahydrofuran; methanol / 3 h / 20 °C 3: 47 percent / EDCI; triethylamine / CH2Cl2 / 1 h / 20 °C 4: 86 percent / Et3N / CH2Cl2 / 2 h / 20 °C View Scheme

(R)-3-amino-4-(2,4,5-trifluorophenyl)butyric acid methyl ester (881995-69-3) → (R)-[3-(2-benzoyltetrahydropyridazin-1-yl)-3-oxo-1-(2,4,5-trifluorobenzyl)propyl]carbamic acid tert-butyl ester (939964-30-4)

Conditions	Yield
Multi-step reaction with 4 steps 1: 93 percent / CH2Cl2 / 3 h / 20 °C 2: 99 percent / aq. LiOH / tetrahydrofuran; methanol / 3 h / 20 °C 3: 66 percent / EDCI; triethylamine / CH2Cl2 / 12 h / 20 °C 4: 99 percent / Et3N / CH2Cl2 / 2 h / 20 °C View Scheme

(R)-3-amino-4-(2,4,5-trifluorophenyl)butyric acid methyl ester (881995-69-3) → tert-butyl (R)-4-(2-benzoyl-1,2-diazepan-1-yl)-4-oxo-1-(2,4,5-trifluorophenyl)butan-2-ylcarbamate (939964-31-5)

Conditions	Yield
Multi-step reaction with 4 steps 1: 93 percent / CH2Cl2 / 3 h / 20 °C 2: 99 percent / aq. LiOH / tetrahydrofuran; methanol / 3 h / 20 °C 3: 90 percent / EDCI; triethylamine / CH2Cl2 / 12 h / 20 °C 4: 84 percent / Et3N / CH2Cl2 / 3 h / 20 °C View Scheme

(R)-3-amino-4-(2,4,5-trifluorophenyl)butyric acid methyl ester (881995-69-3) → C20H21F3N4O2*HCl

Conditions	Yield
Multi-step reaction with 5 steps 1: 93 percent / CH2Cl2 / 3 h / 20 °C 2: 99 percent / aq. LiOH / tetrahydrofuran; methanol / 3 h / 20 °C 3: 47 percent / EDCI; triethylamine / CH2Cl2 / 1 h / 20 °C 4: 85 percent / CH2Cl2 / 2 h / 20 °C 5: 38 percent / HCl / ethyl acetate; dioxane / 12 h / 20 °C View Scheme

(R)-3-amino-4-(2,4,5-trifluorophenyl)butyric acid methyl ester (881995-69-3) → C20H22F3N3O3S*HCl

Conditions	Yield
Multi-step reaction with 5 steps 1: 93 percent / CH2Cl2 / 3 h / 20 °C 2: 99 percent / aq. LiOH / tetrahydrofuran; methanol / 3 h / 20 °C 3: 47 percent / EDCI; triethylamine / CH2Cl2 / 1 h / 20 °C 4: 76 percent / Et3N / CH2Cl2 / 2 h / 20 °C 5: 51 percent / HCl / ethyl acetate; dioxane / 12 h / 20 °C View Scheme

(R)-3-amino-4-(2,4,5-trifluorophenyl)butyric acid methyl ester (881995-69-3) → C20H20F3N3O2*HCl

Conditions	Yield
Multi-step reaction with 5 steps 1: 93 percent / CH2Cl2 / 3 h / 20 °C 2: 99 percent / aq. LiOH / tetrahydrofuran; methanol / 3 h / 20 °C 3: 47 percent / EDCI; triethylamine / CH2Cl2 / 1 h / 20 °C 4: 86 percent / Et3N / CH2Cl2 / 2 h / 20 °C 5: 38 percent / HCl / ethyl acetate; dioxane / 12 h / 20 °C View Scheme

(R)-3-amino-4-(2,4,5-trifluorophenyl)butyric acid methyl ester (881995-69-3) → KR 64300

Conditions	Yield
Multi-step reaction with 5 steps 1: 93 percent / CH2Cl2 / 3 h / 20 °C 2: 99 percent / aq. LiOH / tetrahydrofuran; methanol / 3 h / 20 °C 3: 66 percent / EDCI; triethylamine / CH2Cl2 / 12 h / 20 °C 4: 99 percent / Et3N / CH2Cl2 / 2 h / 20 °C 5: 92 percent / HCl / ethyl acetate; dioxane / 12 h / 20 °C View Scheme

(R)-3-amino-4-(2,4,5-trifluorophenyl)butyric acid methyl ester (881995-69-3) → KR 64301

Conditions	Yield
Multi-step reaction with 5 steps 1: 93 percent / CH2Cl2 / 3 h / 20 °C 2: 99 percent / aq. LiOH / tetrahydrofuran; methanol / 3 h / 20 °C 3: 90 percent / EDCI; triethylamine / CH2Cl2 / 12 h / 20 °C 4: 84 percent / Et3N / CH2Cl2 / 3 h / 20 °C 5: 75 percent / HCl / ethyl acetate; dioxane / 16 h / 20 °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

(R)-3-amino-4-(2,4,5-trifluorophenyl)butyric acid methyl ester (881995-69-3) → sitagliptin (486460-32-6)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: water; lithium hydroxide / tetrahydrofuran / 0 - 30 °C 2.1: water; tetrahydrofuran / 6 h / 25 - 30 °C 2.2: pH 2 3.1: N-ethyl-N,N-diisopropylamine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / N,N-dimethyl-formamide / 13 h / 0 - 30 °C 4.1: hydrogenchloride / methanol / 12 h / 25 - 45 °C View Scheme
Multi-step reaction with 3 steps 1.1: sodium hydroxide / tetrahydrofuran; water / 1 h / 0 °C 1.2: 20 °C 2.1: benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; 1,2-dichloro-ethane / N,N-dimethyl-formamide / -15 - 20 °C 3.1: hydrogenchloride / water; methanol / 20 °C View Scheme

Upstream product

• 486460-00-8 (3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid 
• 67-56-1 methanol 
• 486460-23-5 (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 
• 883267-70-7 2-(2,4,5-trifluorophenyl)ethanol 
• 769195-26-8 4-(2,4,5-trifluoro-phenyl)-3-oxo-butyric acid methyl ester 
• 1449289-64-8 C₁₁H₁₂F₃NO₂*C₁₄H₁₉NO₃ 
• 1253055-92-3 methyl 3-amino-4-(2,4,5-trifluorophenyl)butanoate 
• 881995-70-6 (2Z)-3-amino-4-(2,4,5-trifluorophenyl)but-2-enoic acid methyl ester 
• 1253055-94-5 (R)-(-)-mandelic acid salt of (R)-methyl 3-amino-4-(2,4,5-trifluorophenyl)butanoate 
• 1253056-08-4 (R)-methyl 3-(p-toluenesulfonyloxy)-4-(2,4,5-trifluorophenyl)butanoate 
• 1253056-07-3 (R)-methyl 3-(1,3-dioxoisoindolin-2-yl)-4-(2,4,5-trifluorophenyl)butanoate 
• 1138326-05-2 (R)-methyl 3-hydroxy-4-(2,4,5-trifluorophenyl)butanoate 
• 1260029-46-6 3-(R)-[(R)-(α-methylbenzyl)benzylamino]-4-(2,4,5-trifluoro-phenyl)butyric acid methyl ester 
• 764667-64-3 5-(1-hydroxy-2-(2,4,5-trifluorophenyl)ethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione 

Downstream Products

• 881995-73-9 3-(R)-tert-butoxycarbonylamino-4-(2,4,5-trifluorophenyl)butyric acid methyl ester 
• 939964-16-6 (R)-[3-oxo-3-pyrazolidin-1-yl-1-(2,4,5-trifluorobenzyl)propyl]carbamic acid tert-butyl ester 
• 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 
• 939964-27-9 (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 
• 486460-00-8 (3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid 
• 486460-32-6 sitagliptin 
• 486460-23-5 (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 

Relevant articles and documents

Synthesis method of sitagliptin free alkali and sitagliptin phosphate monohydrate

The invention relates to a synthesis method of sitagliptin free alkali and sitagliptin phosphate monohydrate. According to the method, dry HOBt is removed or changed into HOBt hydrate, a solvent DMF is removed in the process, and a simple solvent easy to recover is used in the production process, so that the production cost is reduced, and the reaction safety is improved. According to the invention, with the in-situ process from a compound represented by a formula 2 to a compound represented by a formula 6, the yield can be improved, the operation steps can be reduced, and the methanol or isopropanol IPA is replaced with other solvents so as to avoid the generation of impurities represented by a formula 7, a formula 8 and a formula 9, such that the product purity and the yield can be substantially improved, and the HPLC purity of the sitagliptin free alkali is more than 99%.

Purpose of compound for preparing Sitagliptin and Sitagliptin preparation method

The invention provides a compound shown by a formula I, a purpose of a stereoisomer, a geometrical isomer, a tautomer, an oxynitride, a hydrate, a solvate, a metabolite, a pharmacologically acceptable salt or prodrug of the compound in Sitagliptin preparation, and a Sitagliptin preparation method. The formula I is shown in the description, wherein R1 is a substitutional group containing the hydroxyl group. The compound shown by the formula I or the stereoisomer, the geometrical isomer, the tautomer, the oxynitride, the hydrate, the solvate, the metabolite, the pharmacologically acceptable salt or the prodrug of the compound shown by the formula I has high water solubility, and is used for obtaining a chiral amino intermediate to further obtain the Sitagliptin. Compared with the prior art, the compound has the advantages that the amino group conversion rate is greatly improved; the yield of the Sitagliptin is also greatly improved.

Substrate screening of amino transaminase for the synthesis of a sitagliptin intermediate

We reported herein a new enzymatic route to synthesize a sitagliptin intermediate using an aminotransferase. Substrate profile indicated that hydroxyethyl-3-oxo-4-(2,4,5-trifluorophenyl)butanoate, among 11 analogs, showed the best biocatalytic performance, partially due to its best solubility in the enzymatic system. The corresponding amino esters showing strong product inhibition on the reaction, were inclined to autohydrolyze, thus driving the reaction forward, which indicated the contribution of the rapid hydrolysis of hydroxyethyl ester to the biocatalytic performance. The reaction was performed at 100?mM with 82% conversion in 24?h. The amino ester product was further transformed to Boc-(R)-3-amino-4-(2,4,5-trifluorophenyl)butyric acid, the key intermediate of sitagliptin.