764667-64-3

Basic information

• Product Name: 5-1-hydroxy-2-(2,4,5-trifluorophenyl)ethylidene-2,2-dimethyl-1,3-dioxane-4,6-dione
• Synonyms: 5-1-hydroxy-2-(2,4,5-trifluorophenyl)ethylidene-2,2-dimethyl-1,3-dioxane-4,6-dione;5-[1-hydroxy-2-92,4,5-trifluorophenyl0ethylidene]-2,2-dimethyl;5-[1-Hydroxy-2-(2,4,5-trifluorophenyl)ethylidene]-2,2-diMethyl-1,3-dioxane-4,6-dion;1,3-Dioxane-4,6-dione,5-[1-hydroxy-2-(2,4,5-trifluorophenyl)ethylidene]-2,2-diMethyl-;5-[1-Hydroxy-2-(2,4,5-trifluorophenyl)-4,6-dionethylidene]-2,2-dimethyl-1,3-dioxane-4,6-dione;5-(1-Hydroxy-2-(2,4,5-trifluorophenyl);ethylidene)
• CAS NO: 764667-64-3
• Molecular Formula: C₁₄H₁₁F₃O₅
• Molecular Weight: 316.23
• Product Categories: Aromatics;Heterocycles;Impurities;Intermediates
• Mol File: 764667-64-3.mol

Chemical Properties

• Melting Point: 117 °C (decomp)
• Boiling Point: 489.0±45.0 °C(Predicted)
• Appearance: /
• Density: 1.462±0.06 g/cm3(Predicted)
• Refractive Index: 1.523
• Storage Temp.: under inert gas (nitrogen or Argon) at 2-8°C
• Solubility: Chloroform (Slightly), Ethyl Acetate (Slightly), Methanol (Slightly)
• PKA: 4.50±1.00(Predicted)
• CAS DataBase Reference: 5-1-hydroxy-2-(2,4,5-trifluorophenyl)ethylidene-2,2-dimethyl-1,3-dioxane-4,6-dione(CAS DataBase Reference)
• NIST Chemistry Reference: 5-1-hydroxy-2-(2,4,5-trifluorophenyl)ethylidene-2,2-dimethyl-1,3-dioxane-4,6-dione(764667-64-3)
• EPA Substance Registry System: 5-1-hydroxy-2-(2,4,5-trifluorophenyl)ethylidene-2,2-dimethyl-1,3-dioxane-4,6-dione(764667-64-3)

Safety Data

• Hazardous Substances Data: 764667-64-3(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
5-1-hydroxy-2-(2,4,5-trifluorophenyl)ethylidene-2,2-dimethyl-1,3-dioxane-4,6-dione is used as an intermediate for the synthesis of sitagliptin, a DPP-IV inhibitor drug for the treatment of type II diabetes. It plays a crucial role in the development of this medication, which helps manage blood sugar levels in patients with type II diabetes.

InChI:InChI=1/C14H11F3O5/c1-14(2)21-12(19)11(13(20)22-14)10(18)4-6-3-8(16)9(17)5-7(6)15/h3,5,18H,4H2,1-2H3

Synthetic route

cycl-isopropylidene malonate (2033-24-1) + (2,4,5-trifluorophenyl)acetic acid (209995-38-0) → 5-(1-hydroxy-2-(2,4,5-trifluorophenyl)ethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (764667-64-3)

Conditions	Yield
With dmap; pivaloyl chloride; N-ethyl-N,N-diisopropylamine In acetonitrile at 45℃; for 3h;	95%
With dmap; pivaloyl chloride; N-ethyl-N,N-diisopropylamine In acetonitrile at 20 - 50℃;	94%
With dmap; pivaloyl chloride; N-ethyl-N,N-diisopropylamine In acetonitrile at 45 - 55℃;	94%

cycl-isopropylidene malonate (2033-24-1) + 2-(2,4,5-trifluorophenyl)acetyl chloride (1176895-65-0) → 5-(1-hydroxy-2-(2,4,5-trifluorophenyl)ethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (764667-64-3)

Conditions	Yield
With collidine In dichloromethane at -5 - 0℃; for 4h; Product distribution / selectivity; Inert atmosphere;
Stage #1: cycl-isopropylidene malonate; 2-(2,4,5-trifluorophenyl)acetyl chloride In dichloromethane at -5 - 30℃; for 4h; Inert atmosphere; Stage #2: With hydrogenchloride In dichloromethane; water at 0 - 5℃; Product distribution / selectivity;

(2,4,5-trifluorophenyl)acetic acid (209995-38-0) → 5-(1-hydroxy-2-(2,4,5-trifluorophenyl)ethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (764667-64-3)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: oxalyl dichloride / dichloromethane; N,N-dimethyl-formamide / 4 h / 20 - 25 °C 2.1: dichloromethane / 4 h / -5 - 30 °C / Inert atmosphere 2.2: 0 - 5 °C View Scheme

2-oxo-2-(2,4,5-trifluorophenyl)acetamide → 5-(1-hydroxy-2-(2,4,5-trifluorophenyl)ethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (764667-64-3)

Conditions	Yield
Multi-step reaction with 3 steps 1: hydrogenchloride / water / 5 h / 70 °C / Inert atmosphere 2: phosphonic Acid; iodine; methanesulfonic acid / 24 h / 110 °C 3: dmap; N-ethyl-N,N-diisopropylamine; pivaloyl chloride / N,N-dimethyl acetamide / 3 h / 5 - 40 °C / Inert atmosphere View Scheme

(2,4,5-trifluorophenyl)oxoacetic acid → 5-(1-hydroxy-2-(2,4,5-trifluorophenyl)ethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (764667-64-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: phosphonic Acid; iodine; methanesulfonic acid / 24 h / 110 °C 2: dmap; N-ethyl-N,N-diisopropylamine; pivaloyl chloride / N,N-dimethyl acetamide / 3 h / 5 - 40 °C / Inert atmosphere View Scheme

2,4-dichloro-5-fluorobenzoyl chloride (86393-34-2) → 5-(1-hydroxy-2-(2,4,5-trifluorophenyl)ethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (764667-64-3)

Conditions

Yield

Multi-step reaction with 7 steps 1: potassium fluoride; tetraphenylphosphonium bromide; 18-crown-6 ether / 1,2-dichloro-benzene / 15 h / 120 - 130 °C / Inert atmosphere 2: 1,2-dichloro-benzene / 140 °C 3: potassium fluoride / 1,2-dichloro-benzene / 7 h / 110 °C / Inert atmosphere 4: sulfuric acid; sodium chloride / water / 8 h / 20 °C / Inert atmosphere 5: hydrogenchloride / water / 5 h / 70 °C / Inert atmosphere 6: phosphonic Acid; iodine; methanesulfonic acid / 24 h / 110 °C 7: dmap; N-ethyl-N,N-diisopropylamine; pivaloyl chloride / N,N-dimethyl acetamide / 3 h / 5 - 40 °C / Inert atmosphere View Scheme

2-chloro-4,5-difluorobenzoyl fluoride → 5-(1-hydroxy-2-(2,4,5-trifluorophenyl)ethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (764667-64-3)

Conditions

Yield

Multi-step reaction with 6 steps 1: 1,2-dichloro-benzene / 140 °C 2: potassium fluoride / 1,2-dichloro-benzene / 7 h / 110 °C / Inert atmosphere 3: sulfuric acid; sodium chloride / water / 8 h / 20 °C / Inert atmosphere 4: hydrogenchloride / water / 5 h / 70 °C / Inert atmosphere 5: phosphonic Acid; iodine; methanesulfonic acid / 24 h / 110 °C 6: dmap; N-ethyl-N,N-diisopropylamine; pivaloyl chloride / N,N-dimethyl acetamide / 3 h / 5 - 40 °C / Inert atmosphere View Scheme

2,4,5-trifluorobenzoyl fluoride → 5-(1-hydroxy-2-(2,4,5-trifluorophenyl)ethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (764667-64-3)

Conditions

Yield

Multi-step reaction with 5 steps 1: potassium fluoride / 1,2-dichloro-benzene / 7 h / 110 °C / Inert atmosphere 2: sulfuric acid; sodium chloride / water / 8 h / 20 °C / Inert atmosphere 3: hydrogenchloride / water / 5 h / 70 °C / Inert atmosphere 4: phosphonic Acid; iodine; methanesulfonic acid / 24 h / 110 °C 5: dmap; N-ethyl-N,N-diisopropylamine; pivaloyl chloride / N,N-dimethyl acetamide / 3 h / 5 - 40 °C / Inert atmosphere View Scheme

2,4,5-trifluorobenzene-1-carbonyl cyanide → 5-(1-hydroxy-2-(2,4,5-trifluorophenyl)ethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (764667-64-3)

Conditions	Yield
Multi-step reaction with 4 steps 1: sulfuric acid; sodium chloride / water / 8 h / 20 °C / Inert atmosphere 2: hydrogenchloride / water / 5 h / 70 °C / Inert atmosphere 3: phosphonic Acid; iodine; methanesulfonic acid / 24 h / 110 °C 4: dmap; N-ethyl-N,N-diisopropylamine; pivaloyl chloride / N,N-dimethyl acetamide / 3 h / 5 - 40 °C / Inert atmosphere View Scheme

5-(1-hydroxy-2-(2,4,5-trifluorophenyl)ethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (764667-64-3) + 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride (762240-92-6) → 1-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-4-(2,4,5-trifluorophenyl)butane-1,3-dione (764667-65-4)

Conditions	Yield
With 4-methyl-morpholine In ethyl acetate for 6h; Reflux;	98.1%
With N-ethyl-N,N-diisopropylamine In Isopropyl acetate at 85℃; for 4h;	93.3%
With N-ethyl-N,N-diisopropylamine In Isopropyl acetate at 85℃; for 3.5h;	92%

propan-1-ol (71-23-8) + 5-(1-hydroxy-2-(2,4,5-trifluorophenyl)ethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (764667-64-3) → 3-oxo-4-(2,4,5-trifluorophenyl)butyric acid propyl ester

Conditions	Yield
In N,N-dimethyl acetamide at 51℃; Kinetics;	97%
In N,N-dimethyl acetamide at 51℃;	97%

aniline (62-53-3) + 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-trifluorophenyl)-3-oxo-N-phenylbutanamide

Conditions	Yield
In N,N-dimethyl acetamide at 50.8℃; Kinetics;	92%
In N,N-dimethyl acetamide at 50.8℃;	92%

3-trifluoromethyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine (486460-21-3) + 5-(1-hydroxy-2-(2,4,5-trifluorophenyl)ethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (764667-64-3) → 1-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-4-(2,4,5-trifluorophenyl)butane-1,3-dione (764667-65-4)

Conditions	Yield
In N,N-dimethyl acetamide at 41.1℃; Kinetics; Further Variations:; Temperatures;	91%

benzyl alcohol (100-51-6) + 5-(1-hydroxy-2-(2,4,5-trifluorophenyl)ethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (764667-64-3) → benzyl 3-oxo-4-(2,4,5-trifluorophenyl)butanoate

Conditions	Yield
In toluene Reflux;	90%
In acetonitrile at 80 - 84℃; for 24h; Inert atmosphere;	81.6%
In acetonitrile for 2h; Reflux;

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;

(R)-1-phenyl-ethyl-amine (3886-69-9) + 5-(1-hydroxy-2-(2,4,5-trifluorophenyl)ethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (764667-64-3) → tert-butyl 3-[[(1R)-1-phenylethyl]amino]-4-(2,4,5-trifluorophenyl)-but-2-enoate (1345822-93-6)

Conditions	Yield
With acetic acid In tert-butyl alcohol at 30 - 82℃; for 8h;	83%

C6H3(2)H4F3N4*ClH + 5-(1-hydroxy-2-(2,4,5-trifluorophenyl)ethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (764667-64-3) → C16H8(2)H4F6N4O2

Conditions	Yield
In N,N-dimethyl acetamide at 80℃; for 2h; Temperature;	82.72%

(R)-2-methylpropane-2-sulfinamide (196929-78-9) + 5-(1-hydroxy-2-(2,4,5-trifluorophenyl)ethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (764667-64-3) → C18H20F3NO5S

Conditions	Yield
In acetonitrile at 65℃;	81%

(R)-2-Ethyl-4,5-dihydro-thiazole-4-carboxylic acid ethyl ester + 5-(1-hydroxy-2-(2,4,5-trifluorophenyl)ethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (764667-64-3) → 8-methyl-5-oxo-7-(2,4,5-trifluoro-benzyl)-2,3-dihydro-5H-thiazolo[3,2-a]pyridine-3-carboxylic acid ethyl ester

Conditions	Yield
With hydrogenchloride In 1,2-dichloro-ethane at 65℃; for 3h;	80%

piperidine (110-89-4) + 5-(1-hydroxy-2-(2,4,5-trifluorophenyl)ethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (764667-64-3) → 1-(1-piperidinyl)-4-(2,4,5-trifluorophenyl)-1,3-butanedione

Conditions	Yield
In N,N-dimethyl acetamide at 50.9℃; Kinetics;	78%
In N,N-dimethyl acetamide at 50.9℃;	78%

N,N-di(tert-butoxycarbonyl)hydroxylamine (85006-25-3) + 5-(1-hydroxy-2-(2,4,5-trifluorophenyl)ethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (764667-64-3) → C20H24F3NO7

Conditions	Yield
In N,N-dimethyl acetamide at 50.8℃; Kinetics; Further Variations:; Temperatures;	78%
In N,N-dimethyl acetamide at 50.8℃;	78%

ethyl (R)-4,5-dihydrothiazole-4-carboxylate (206876-90-6) + 5-(1-hydroxy-2-(2,4,5-trifluorophenyl)ethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (764667-64-3) → (2R,5S,6R)-7-Oxo-6-[2-(2,4,5-trifluoro-phenyl)-acetyl]-4-thia-1-aza-bicyclo[3.2.0]heptane-2-carboxylic acid ethyl ester

Conditions	Yield
With hydrogenchloride In benzene Heating;	41%

aniline hydrochloride (142-04-1) + 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-trifluorophenyl)-3-oxo-N-phenylbutanamide

Conditions	Yield
With trifluoroacetic acid In acetonitrile at 48.5℃; Kinetics;	92 % Chromat.

N-benzylidenemethylamine (25521-74-8) + 5-(1-hydroxy-2-(2,4,5-trifluorophenyl)ethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (764667-64-3) → 3-methyl-2-phenyl-6-(2,4,5-trifluoro-benzyl)-2,3-dihydro-[1,3]oxazin-4-one

Conditions	Yield
In acetonitrile at 55℃; for 5h;

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

5-(1-hydroxy-2-(2,4,5-trifluorophenyl)ethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (764667-64-3) → 3-(R)-tert-butoxycarbonylamino-4-(2,4,5-trifluorophenyl)butyric acid methyl ester (881995-73-9)

Conditions	Yield
Multi-step reaction with 4 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 View Scheme

5-(1-hydroxy-2-(2,4,5-trifluorophenyl)ethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (764667-64-3) → methyl 3-amino-4-(2,4,5-trifluorophenyl)but-2-enoate

Conditions	Yield
Multi-step reaction with 2 steps 1: 88.7 percent / toluene / 3 h / Heating 2: 95 percent / ammonium acetate / methanol / 7 h / Heating 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-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 6 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 6: 47 percent / EDCI; triethylamine / CH2Cl2 / 1 h / 20 °C 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-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 6 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 6: 66 percent / EDCI; triethylamine / CH2Cl2 / 12 h / 20 °C 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-[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 6 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 6: 90 percent / EDCI; triethylamine / CH2Cl2 / 12 h / 20 °C View Scheme

5-(1-hydroxy-2-(2,4,5-trifluorophenyl)ethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (764667-64-3) → C13H16F3N3O*HCl

Conditions

Yield

Multi-step reaction with 7 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 6: 47 percent / EDCI; triethylamine / CH2Cl2 / 1 h / 20 °C 7: 99 percent / HCl / ethyl acetate; dioxane / 16 h / 20 °C 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-(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 7 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 6: 47 percent / EDCI; triethylamine / CH2Cl2 / 1 h / 20 °C 7: 85 percent / CH2Cl2 / 2 h / 20 °C 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-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 7 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 6: 47 percent / EDCI; triethylamine / CH2Cl2 / 1 h / 20 °C 7: 76 percent / Et3N / CH2Cl2 / 2 h / 20 °C 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-(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 7 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 6: 47 percent / EDCI; triethylamine / CH2Cl2 / 1 h / 20 °C 7: 86 percent / Et3N / CH2Cl2 / 2 h / 20 °C 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-(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 7 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 6: 66 percent / EDCI; triethylamine / CH2Cl2 / 12 h / 20 °C 7: 99 percent / Et3N / CH2Cl2 / 2 h / 20 °C View Scheme

5-(1-hydroxy-2-(2,4,5-trifluorophenyl)ethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (764667-64-3) → 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 7 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 6: 90 percent / EDCI; triethylamine / CH2Cl2 / 12 h / 20 °C 7: 84 percent / Et3N / CH2Cl2 / 3 h / 20 °C View Scheme

Upstream product

• 2033-24-1 cycl-isopropylidene malonate 
• 209995-38-0 (2,4,5-trifluorophenyl)acetic acid 
• 1176895-65-0 2-(2,4,5-trifluorophenyl)acetyl chloride 
• 86393-34-2 2,4-dichloro-5-fluorobenzoyl chloride 
• 101513-67-1 2,4,5-trifluorobenzoyl fluoride 

Downstream Products

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

Relevant articles and documents

Preparation method of sitagliptin phosphate intermediate

The invention discloses a preparation method of a sitagliptin phosphate intermediate. In the existing synthesis method of the sitagliptin phosphate intermediate, a corresponding post-treatment method is not reported or the reported post-treatment method is tedious in operation, low in solvent recovery rate, capable of generating a large amount of three wastes, and not beneficial to environmental protection. The method comprises the following steps: directly evaporating to remove a solvent after the synthesis reaction of the sitagliptin phosphate intermediate is completed, adding a crystallization solvent, cooling, stirring for crystallization, washing and drying to obtain the corresponding sitagliptin phosphate intermediate. According to the invention, the yield and the purity of the sitagliptin phosphate intermediate are improved; the method is simple in process, high in solvent recovery rate and suitable for large-scale industrial production, and wastewater is not generated in the production process.

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.

Two methods for the preparation of sitagliptin phosphate: Via chemical resolution and asymmetric hydrogenation

Two effective processes have been developed for the preparation of sitagliptin phosphate. The approach of chemical resolution obtained R-sitagliptin in five steps from commercially available starting materials using the inexpensive NaBH4 to reduce the enamine and then using (-)-di-p-toluoyl-l-tartaric acid to resolve racemates in 11% yield overall. The route successfully avoids the use of expensive noble metal as catalysts compared with traditional synthesis methods, resulting in greatly reduced costs and simplified synthetic routes. Other alternative asymmetric hydrogenation of β-ketomide routes for the synthesis of sitagliptin were found, two of the intermediates were synthesized for the first time. This journal is

NEW EFFICIENT PROCESS FOR THE PREPARATION OF SITAGLIPTIN.

Object of the present invention is an efficient process for the preparation of the active pharmaceutical ingredient Sitagliptine and the 2,4,5-trifluorophenylacetic acid (TFAA) and salt thereof, which is a key intermediate for the synthesis of Sitagliptine. (I)

(S)-2-amino-3-(2,4,5-trifluorophenyl)propionic acid menthyl ester hydrochloride and preparation method and application thereof

The invention provides (S)-2-amino-3-(2,4,5-trifluorophenyl)propionic acid menthyl ester hydrochloride and a preparation method and application thereof and belongs to the technical field of medicinalchemistry. According to the technical problem of low synthesis efficiency of sitagliptin is solved. The technical scheme is that the structural formula of the (S)-2-amino-3-(2,4,5-trifluorophenyl)propionic acid menthyl ester hydrochloride is in the description below. The (S)-2-amino-3-(2,4,5-trifluorophenyl)propionic acid menthyl ester hydrochloride has the advantages that the (S)-2-amino-3-(2,4,5-trifluorophenyl)propionic acid menthyl ester hydrochloride is a novel compound, raw materials used for preparation are cheap and easy to obtain, the process is simple, and the yield is as high as 83.3%.

Chiral synthesis method for chiral beta-amino acid and synthesis method for medicinal intermediate

The invention relates to a chiral synthesis method for chiral beta-amino acid. The chiral synthesis method comprises the following steps: reacting a compound shown in formula (II) with an acylation reagent to prepare anhydride intermediate reaction liquid under the action of alkali; adding Meldrum's acid into the anhydride intermediate reaction liquid, and performing reaction to generate a compound shown in formula (III); reacting the compound shown in formula (III) with a compound shown in formula (IV) to generate a compound shown in formula (V); reducing the compound shown in formula (V) to generate a compound shown in formula (VI); performing acidic hydrolysis on the compound shown in formula (VI) to generate a compound shown in formula (I), i.e., the chiral beta-amino acid. The chiral synthesis method has the advantages of convenience for synthesis, low cost and simple process, and compared with a disclosed preparation method, is more suitable for industrial production.

Method for synthesizing sitagliptin intermediate

The invention relates to a method for synthesizing a sitagliptin intermediate. The method is characterized in that asymmetric reduction ammonification of a compound of formula II and ammonia or ammonium salt in the presence of a chiral phosphorus coordinated transition metal catalyst in an appropriate organic solvent containing an acidic additive to obtain a compound of formula I. The R- or S- configuration of a stereocenter is represented by *, and the formula I with the R configuration can be used to prepare sitagliptin. A reaction equation is shown in the description; and R and R in the reaction equation are respectively independently selected from hydrogen, C1-C12 linear or branched alkyl groups, C3-C12 cycloalkyl groups, C2-C12 alkene groups, C2-C12 alkynyl groups and C7-C12 arylalkyl groups. The method has the advantages of high yield and ee% value, mild reaction conditions, simple operation, convenient purification, low production cost, environmental protection, and suitableness for industrial production.

A west he row sandbank intermediate chiral separation method

The invention relates to a preparation method of a sitagliptin intermediate compound (R)-3-amino-4-(2,4,5-trifluorobenzene)benzyl butyrate (compound (1)). According to the method, a racemate of the compound (1) form a salt with a resolving agent in a solvent; the salt is precipitated, and the mixture is filtered; the resolved salt is dissociated, such that the compound (1) is obtained. With the method provided by the invention, the compound (1) with high purity and high chirality can be obtained. The method has advantages of stable process and simple operation. The solvent can be recycled and applied. Therefore, the method is suitable for industrialized productions.

plants the deuterium mark sitagliptin a process for the preparation of

The present invention discloses a method for preparing deuterium-labeled sitagliptin. The deuterium-labeled sitagliptin-D4 is synthesized by an eight-step reaction with hydrazine hydrate as a starting material and ethylene-D4 as a deuterium-labeled initiator. The optimal preparation steps and reaction conditions are screened through a plurality of experiments in the invention and the entire process is reasonable in design and high in operability. The deuterium-labeled sitagliptin prepared by the invention has purity of over 98% and the yield up to 70% or more, and isotopic abundance is greater than 99%. The deuterium-labeled sitagliptin prepared by the invention can provide test samples for a research on the metabolic mechanism of sitagliptin and has important application value.

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.