769195-26-8

Basic information

• Product Name: 3-OXO-4-(2,4,5-TRIFLUORO-PHENYL)-BUTYRIC ACID METHYL ESTER
• Synonyms: 3-OXO-4-(2,4,5-TRIFLUORO-PHENYL)-BUTYRIC ACID METHYL ESTER;2,4,5-TRIFLUORO-BETA-OXO-BENZENEBUTANOIC ACID METHYL ESTER;Methyl 3-oxo-4-(2,4,5-trifluorophenyl)butanoate;4-(2,4,5 )triflorophenyl 3-oxobutanoic acid, Methy ester;3-oxo-4-(2,4,5-trifluorophenyl;Benzenebutanoicacid,2,4,5-trifluoro-b-oxo-,Methylester;Methyl 2,4,5-trifluoro-b-oxo-benzenebutanoate;Methyl 3-oxo-4-(2,4,5-trifluorophenyl)
• CAS NO: 769195-26-8
• Molecular Formula: C₁₁H₉F₃O₃
• Molecular Weight: 246.1825696
• EINECS: 1308068-626-2
• Mol File: 769195-26-8.mol
• Article Data: 10

Chemical Properties

• Melting Point: 40-41 °C
• Boiling Point: 273.265 °C at 760 mmHg
• Flash Point: 115.458 °C
• Appearance: /
• Density: 1.331 g/cm³
• Refractive Index: 1.469
• Storage Temp.: under inert gas (nitrogen or Argon) at 2-8°C
• Solubility: DMSO (Slightly), Methanol (Slightly)
• PKA: 9.95±0.46(Predicted)
• CAS DataBase Reference: 3-OXO-4-(2,4,5-TRIFLUORO-PHENYL)-BUTYRIC ACID METHYL ESTER(CAS DataBase Reference)
• NIST Chemistry Reference: 3-OXO-4-(2,4,5-TRIFLUORO-PHENYL)-BUTYRIC ACID METHYL ESTER(769195-26-8)
• EPA Substance Registry System: 3-OXO-4-(2,4,5-TRIFLUORO-PHENYL)-BUTYRIC ACID METHYL ESTER(769195-26-8)

Safety Data

• Hazardous Substances Data: 769195-26-8(Hazardous Substances Data)

Usage

Chemical Properties

Off-white solid

Uses

Methyl 3-Oxo-4-(2,4,5-trifluorophenyl)butanoate is a useful synthetic intermediate in the synthesis of Sitagliptin (S491000); a trizolopyrazine dipeptidyl peptidase (DPP) IV inhibitor for the treatment of type II diabetes.

Preparation

The preparation of methyl 3-Oxo-4-(2,4,5-trifluorophenyl)butanoate is as follows:Stage 1: (2,4,5-trifluorophenyl)acetic acid With 1,1'-carbonyldiimidazole In acetonitrile for 3.5h;Stage 2: monomethyl monopotassium malonate With triethylamine; magnesium chloride In acetonitrile at 50℃; for 8h;Stage 3: In acetonitrile at 30℃; for 26h.

Synthetic route

2-(2,4,5-trifluorophenyl)acetyl chloride (1176895-65-0) + bromoacetic acid methyl ester (96-32-2) → 4-(2,4,5-trifluoro-phenyl)-3-oxo-butyric acid methyl ester (769195-26-8)

Conditions	Yield
Stage #1: bromoacetic acid methyl ester With iodine; magnesium In tetrahydrofuran at 45 - 50℃; Inert atmosphere; Stage #2: 2-(2,4,5-trifluorophenyl)acetyl chloride With copper(l) iodide In tetrahydrofuran at -20 - 5℃; Grignard Reaction; Inert atmosphere;	91%

methanol (67-56-1) + 5-(1-hydroxy-2-(2,4,5-trifluorophenyl)ethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (764667-64-3) → 4-(2,4,5-trifluoro-phenyl)-3-oxo-butyric acid methyl ester (769195-26-8)

Conditions	Yield
In toluene for 3h; Heating;	88.7%
at 60 - 63℃;

5-(1-hydroxy-2-(2,4,5-trifluorophenyl)ethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (764667-64-3) → 4-(2,4,5-trifluoro-phenyl)-3-oxo-butyric acid methyl ester (769195-26-8)

Conditions	Yield
With methanol at 60 - 63℃;	85%
In methanol Reflux;

monomethyl monopotassium malonate (38330-80-2) + (2,4,5-trifluorophenyl)acetic acid (209995-38-0) → 4-(2,4,5-trifluoro-phenyl)-3-oxo-butyric acid methyl ester (769195-26-8)

Conditions	Yield
Stage #1: (2,4,5-trifluorophenyl)acetic acid With 1,1'-carbonyldiimidazole In acetonitrile for 3.5h; Stage #2: monomethyl monopotassium malonate With triethylamine; magnesium chloride In acetonitrile at 50℃; for 8h; Stage #3: In acetonitrile at 30℃; for 26h;	84%
Stage #1: monomethyl monopotassium malonate With triethylamine In acetonitrile at 30 - 50℃; for 8.3h; Stage #2: (2,4,5-trifluorophenyl)acetic acid With 1,1'-carbonyldiimidazole In acetonitrile at 30℃; for 3.5h;	83%
Stage #1: monomethyl monopotassium malonate With triethylamine; magnesium chloride In acetonitrile at 30 - 50℃; Inert atmosphere; Stage #2: (2,4,5-trifluorophenyl)acetic acid With 1,1'-carbonyldiimidazole In acetonitrile at 30℃; for 5.5h; Inert atmosphere;	83%

magnesium monomethyl malonate + (2,4,5-trifluorophenyl)acetic acid (209995-38-0) → 4-(2,4,5-trifluoro-phenyl)-3-oxo-butyric acid methyl ester (769195-26-8)

Conditions	Yield
Stage #1: (2,4,5-trifluorophenyl)acetic acid With 1,1'-carbonyldiimidazole In tetrahydrofuran at 0 - 20℃; Stage #2: magnesium monomethyl malonate In tetrahydrofuran at 20℃; for 24h;	77.3%

monomethyl monopotassium malonate (38330-80-2) + (2,4,5-trifluorophenyl)acetic acid (209995-38-0) → 4-(2,4,5-trifluoro-phenyl)-3-oxo-butyric acid methyl ester (769195-26-8) + 1,3-bis-(2,4,5-trifluoro-phenyl)-propan-2-one

Conditions	Yield
Stage #1: (2,4,5-trifluorophenyl)acetic acid With 1,1'-carbonyldiimidazole In acetonitrile for 3.5h; Stage #2: monomethyl monopotassium malonate With triethylamine; magnesium chloride In acetonitrile at 50℃; for 8h; Stage #3: In acetonitrile at 30℃; for 26h;

(2,4,5-trifluorophenyl)acetic acid (209995-38-0) → 4-(2,4,5-trifluoro-phenyl)-3-oxo-butyric acid methyl ester (769195-26-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: 95 percent / N,N-dimethylaminopyridine; N,N-diisopropylethylamine; trimethylacetylchloride / acetonitrile / 3 h / 45 °C 2: 88.7 percent / toluene / 3 h / Heating View Scheme
Multi-step reaction with 2 steps 1.1: oxalic acid / dichloromethane; N,N-dimethyl-formamide / 25 - 30 °C 1.2: -5 °C 2.1: methanol / Reflux View Scheme
Multi-step reaction with 2 steps 1.1: 1,1'-carbonyldiimidazole / tetrahydrofuran / 25 - 30 °C 1.2: 6 h / 50 - 55 °C 2.1: 60 - 63 °C View Scheme
Multi-step reaction with 2 steps 1.1: thionyl chloride / chloroform / 2 h / 0 - 30 °C 2.1: magnesium; iodine / tetrahydrofuran / 45 - 50 °C / Inert atmosphere 2.2: -20 - 5 °C / Inert atmosphere View Scheme

methanol (67-56-1) + sodium 1-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)-2-(2,4,5-trifluorophenyl)ethanolate (1253055-91-2) → 4-(2,4,5-trifluoro-phenyl)-3-oxo-butyric acid methyl ester (769195-26-8)

Conditions	Yield
With methanesulfonic acid Reflux;

methyl 3-hydroxy-4-(2,4,5-trifluorophenyl)butanoate (1253056-13-1) → 4-(2,4,5-trifluoro-phenyl)-3-oxo-butyric acid methyl ester (769195-26-8)

Conditions	Yield
With potassium dichromate; sulfuric acid; acetic acid at 25 - 30℃; for 24h;

4-(2,4,5-trifluoro-phenyl)-3-oxo-butyric acid methyl ester (769195-26-8) + (R)-1-phenyl-ethyl-amine (3886-69-9) → (Z)-3-(((R)-1-phenylethyl)amino)-4-(2,3,5-trifluorophenyl)-2-butenoic acid methyl ester

Conditions	Yield
With acetic acid In methanol Reflux; Large scale;	98.5%

4-(2,4,5-trifluoro-phenyl)-3-oxo-butyric acid methyl ester (769195-26-8) → (R)-methyl 3-hydroxy-4-(2,4,5-trifluorophenyl)butanoate (1138326-05-2)

Conditions	Yield
With [Ir(H)2((R)-N-((1,3-dithian-2-yl)methyl)-7'-(bis(3,5-di-tert-butylphenyl)phosphanyl)-1,1'-spirobiindanyl-7-amine)Cl]; hydrogen; sodium hydroxide In methanol at 25 - 30℃; under 7600.51 Torr; for 2h; Reagent/catalyst; Autoclave; enantioselective reaction;	98%
Stage #1: 4-(2,4,5-trifluoro-phenyl)-3-oxo-butyric acid methyl ester With dimethylsulfide borane complex; (3aR)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2-c][1,3,2]oxazaborole In toluene at 0 - 5℃; Inert atmosphere; Stage #2: With methanol In toluene
With hydrogen; dichloro[(S)-(-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl]ruthenium(II) In methanol; acetic acid at 70℃; under 3620.13 Torr; for 6h; Inert atmosphere;

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

Conditions	Yield
With ammonium acetate In methanol for 7h; Heating;	95%

4-(2,4,5-trifluoro-phenyl)-3-oxo-butyric acid methyl ester (769195-26-8) + benzamide (55-21-0) → methyl 3-benzoylamino-4-(2,4,5-trifluorophenyl)-2-butenoate

Conditions	Yield
With toluene-4-sulfonic acid In toluene at 110℃;	95%

4-(2,4,5-trifluoro-phenyl)-3-oxo-butyric acid methyl ester (769195-26-8) → methyl 3-hydroxy-4-(2,4,5-trifluorophenyl)butanoate (1253056-13-1)

Conditions	Yield
With sodium tetrahydroborate In methanol at 0℃;	92%

4-(2,4,5-trifluoro-phenyl)-3-oxo-butyric acid methyl ester (769195-26-8) → 3(S)-4-(2,4,5-trifluorophenyl)-3-hydroxybenzenebutanoic acid methyl ester (868071-16-3)

Conditions	Yield
With formic acid In methanol at 65℃; for 2h; Reagent/catalyst; Temperature; Inert atmosphere;	91.1%
With hydrogen; (S)-BINAP RuCl2-triethylamine In methanol at 80 - 85℃; under 4413.43 - 4781.22 Torr;

4-(2,4,5-trifluoro-phenyl)-3-oxo-butyric acid methyl ester (769195-26-8) → (2Z)-3-amino-4-(2,4,5-trifluorophenyl)but-2-enoic acid methyl ester (881995-70-6)

Conditions	Yield
With ammonium acetate In methanol for 2h; Heating;	91%
With ammonium acetate In methanol for 4h; Reflux;	89.6%
With ammonium acetate In methanol at 60 - 63℃;	85%
With ammonium acetate In methanol at 60 - 63℃;

4-(2,4,5-trifluoro-phenyl)-3-oxo-butyric acid methyl ester (769195-26-8) + (R)-1-phenyl-ethyl-amine (3886-69-9) → methyl 4-(2,4,5-trifluorophenyl)-3-[(R)-1-phenylethylamino]-2-butenoate

Conditions	Yield
With acetic acid In toluene for 3h; Reflux;	87%

4-(2,4,5-trifluoro-phenyl)-3-oxo-butyric acid methyl ester (769195-26-8) → 3(S)-4-(2,4,5-trifluorophenyl)-3-hydroxybutanoic acid (868071-17-4)

Conditions	Yield
With dichloro[(S)-(-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl]ruthenium(II); hydrogen In methanol; acetic acid at 70℃; under 3620.13 Torr; Inert atmosphere; Autoclave;	86%
Multi-step reaction with 2 steps 1.1: hydrogen / dichloro[(S)-(-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl]ruthenium(II) / acetic acid; methanol / 6 h / 70 °C / 3620.13 Torr / Inert atmosphere 2.1: sodium hydroxide; methanol / water / 1.5 h / 20 - 25 °C 2.2: 2 h / 10 - 15 °C View Scheme
Multi-step reaction with 2 steps 1: hydrogen / (S)-BINAP RuCl2-triethylamine / methanol / 80 - 85 °C / 4413.43 - 4781.22 Torr 2: sodium hydroxide; water / 65 - 70 °C / Reflux View Scheme

4-(2,4,5-trifluoro-phenyl)-3-oxo-butyric acid methyl ester (769195-26-8) + benzamide (55-21-0) → (Z)-methyl 3-benzamido-4-(2,4,5-trifluorophenyl) but-2-enoate

Conditions	Yield
With diphenylammonium trifluoromethanesulfonate In toluene for 8h; Reflux; Green chemistry; stereoselective reaction;	83%

4-(2,4,5-trifluoro-phenyl)-3-oxo-butyric acid methyl ester (769195-26-8) + L-phenylglycine amide (6485-52-5) → (S,Z)-methyl 3-(2-amino-2-oxo-1-phenylethylamino)-4-(2,4,5-trifluorophenyl)but-2-enoate

Conditions	Yield
With acetic acid In ethanol at 40℃; for 16h; Solvent; Schiff Reaction; Inert atmosphere;	80%

4-(2,4,5-trifluoro-phenyl)-3-oxo-butyric acid methyl ester (769195-26-8) + N-benzyloxyamine (622-33-3) → methyl (R)-3-(benzyloxyamino)-4-(2,4,5-trifluorophenyl)butanoate (868125-58-0)

Conditions

Yield

Stage #1: 4-(2,4,5-trifluoro-phenyl)-3-oxo-butyric acid methyl ester; N-benzyloxyamine In tetrahydrofuran at 20℃; for 1h; Inert atmosphere; Stage #2: With (2S)-1-[(1S)-1-[bis(1,1-dimethylethyl)phosphino]ethyl]-2-(diphenylphosphino)ferrocene; [(p-cymene)RuCl2]2 In tetrahydrofuran for 0.5h; Inert atmosphere; Stage #3: With sodium cyanoborohydride; zinc(II) chloride In tetrahydrofuran for 0.333333h; Inert atmosphere;

74%

4-(2,4,5-trifluoro-phenyl)-3-oxo-butyric acid methyl ester (769195-26-8) + Benzeneacetamide (103-81-1) → (Z)-methyl-3-(2-phenylacetamido)-4-(2,4,5-trifluorophenyl) but-2-enoate

Conditions	Yield
With diphenylammonium trifluoromethanesulfonate In toluene for 8h; Reflux; Green chemistry; stereoselective reaction;	73%

4-(2,4,5-trifluoro-phenyl)-3-oxo-butyric acid methyl ester (769195-26-8) + acetamide (60-35-5) → (Z)-methyl 3-acetamido-4-(2,4,5-trifluorophenyl) but-2-enoate (1234321-81-3)

Conditions	Yield
With diphenylammonium trifluoromethanesulfonate In toluene for 8h; Reflux; Green chemistry; stereoselective reaction;	61%

4-(2,4,5-trifluoro-phenyl)-3-oxo-butyric acid methyl ester (769195-26-8) + tert-butyl carbamate (4248-19-5) → 3-tert-butoxycarbonylamino-4-(2,4,5-trifluorophenyl)but-2-enoic acid methyl ester (1151240-93-5)

Conditions	Yield
With toluene-4-sulfonic acid In dichloromethane at 25℃; Molecular sieve;	54.1%

4-(2,4,5-trifluoro-phenyl)-3-oxo-butyric acid methyl ester (769195-26-8) → methyl 3-amino-4-(2,4,5-trifluorophenyl)butanoate (1253055-92-3)

Conditions	Yield
With ammonium acetate; sodium cyanoborohydride In methanol at 20℃;	52%
Multi-step reaction with 2 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 View Scheme

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;

4-(2,4,5-trifluoro-phenyl)-3-oxo-butyric acid methyl ester (769195-26-8) → 3-(R)-tert-butoxycarbonylamino-4-(2,4,5-trifluorophenyl)butyric acid methyl ester (881995-73-9)

Conditions	Yield
Multi-step reaction with 3 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 View Scheme
Multi-step reaction with 2 steps 1: 91 percent / ammonium acetate / methanol / 2 h / Heating 2: 75 percent / [Rh(COD)Cl]2; chiral ferrocenyl ligand; H2 / methanol / 24 h / 30 °C / 4654.33 Torr View Scheme
Multi-step reaction with 3 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 View Scheme

4-(2,4,5-trifluoro-phenyl)-3-oxo-butyric acid methyl ester (769195-26-8) → (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 5 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 5: 47 percent / EDCI; triethylamine / CH2Cl2 / 1 h / 20 °C View Scheme

4-(2,4,5-trifluoro-phenyl)-3-oxo-butyric acid methyl ester (769195-26-8) → (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 5 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 5: 66 percent / EDCI; triethylamine / CH2Cl2 / 12 h / 20 °C View Scheme

4-(2,4,5-trifluoro-phenyl)-3-oxo-butyric acid methyl ester (769195-26-8) → (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

Multi-step reaction with 5 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 5: 90 percent / EDCI; triethylamine / CH2Cl2 / 12 h / 20 °C View Scheme

4-(2,4,5-trifluoro-phenyl)-3-oxo-butyric acid methyl ester (769195-26-8) → C13H16F3N3O*HCl

Conditions

Yield

Multi-step reaction with 6 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 5: 47 percent / EDCI; triethylamine / CH2Cl2 / 1 h / 20 °C 6: 99 percent / HCl / ethyl acetate; dioxane / 16 h / 20 °C View Scheme

4-(2,4,5-trifluoro-phenyl)-3-oxo-butyric acid methyl ester (769195-26-8) → (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 6 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 5: 47 percent / EDCI; triethylamine / CH2Cl2 / 1 h / 20 °C 6: 85 percent / CH2Cl2 / 2 h / 20 °C View Scheme

4-(2,4,5-trifluoro-phenyl)-3-oxo-butyric acid methyl ester (769195-26-8) → (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 6 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 5: 47 percent / EDCI; triethylamine / CH2Cl2 / 1 h / 20 °C 6: 76 percent / Et3N / CH2Cl2 / 2 h / 20 °C View Scheme

Upstream product

• 67-56-1 methanol 
• 1253055-91-2 sodium 1-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)-2-(2,4,5-trifluorophenyl)ethanolate 
• 1253056-13-1 methyl 3-hydroxy-4-(2,4,5-trifluorophenyl)butanoate 
• 1176895-65-0 2-(2,4,5-trifluorophenyl)acetyl chloride 
• 96-32-2 bromoacetic acid methyl ester 
• 764667-64-3 5-(1-hydroxy-2-(2,4,5-trifluorophenyl)ethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione 
• 209995-38-0 (2,4,5-trifluorophenyl)acetic acid 
• 38330-80-2 monomethyl monopotassium malonate 

Downstream Products

• 1151240-93-5 3-tert-butoxycarbonylamino-4-(2,4,5-trifluorophenyl)but-2-enoic acid methyl ester 
• 1138326-05-2 (R)-methyl 3-hydroxy-4-(2,4,5-trifluorophenyl)butanoate 
• 1234321-77-7 (Z)-3-tert-butoxycarbonylamino-4-(2,4,5-trifluorophenyl)-2-butenoic acid methyl ester 
• 922178-94-7 (S)-3-((tert-butoxycarbonyl)amino)-4-(2,4,5-trifluorophenyl)butanoic acid 
• 486460-00-8 (3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid 
• 1345822-99-2 (3R)-3-[(1R)-1-phenylethylamino]-4-(2,4,5-trifluorophenyl)butanoic acid 
• 881995-69-3 (R)-3-amino-4-(2,4,5-trifluorophenyl)butyric acid methyl ester 
• 936630-57-8 (R)-3-amino-4-phenyl(2,4,5-trifluorophenyl)butanoic acid 
• 486459-71-6 (2R)-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-amine hydrochloride 
• 654671-77-9 sitagliptin phosphate monohydrate 
• 654671-78-0 sitagliptin phosphate 
• 1361389-75-4 3(R)-3-[(benzyloxy)amino]-1-[3-(trifluoromethyl)-5H,6H,7H,8H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-1-one 
• 1253055-94-5 (R)-(-)-mandelic acid salt of (R)-methyl 3-amino-4-(2,4,5-trifluorophenyl)butanoate 
• 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 

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Preparation method of sitagliptin intermediate

The invention belongs to the field of pharmaceutical synthesis, and particularly relates to a preparation method of a sitagliptin intermediate. The preparation method includes the steps of 1) acylating chlorination reaction: enabling 2,4,5-trifluorophenylacetic acid to directly react with sulfoxide chloride to generate a compound II; 2) Grignard reagent preparation: adding a compound III and magnesium chips, and triggering with iodine to obtain a Grignard reagent compound IV; 3) Grignard reaction: taking cuprous iodide as a catalyst, subjecting the compound II and the Grignard reagent compound IV to Grignard reaction to generate the sitagliptin intermediate-a compound V. The preparation method of the sitagliptin intermediate is simple in synthetic route, capable of producing highly-pure product, high in yield, low in cost, mild in reaction conditions, and applicable to industrialized production.

SITAGLIPTIN, SALTS AND POLYMORPHS THEREOF

The present invention relates to an improved process for preparation of Sitagliptin or pharmaceutically acceptable salts thereof. The present invention further relates to novel polymorphs of Sitagliptin salts and process for preparation thereof.

SITAGLIPTIN SYNTHESIS

The present invention relates to novel processes for the preparation of enantiomerically enriched β-amino acid derivatives such as β-amino esters useful for the synthesis of enantiomerically enriched biologically active molecules such as sitagliptin. The key step involves the resolution of the racemate with mandelic acid.