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
• Article Data: 30

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

Chemical Properties

White to Off-white Solid.

Uses

5-[1-Hydroxy-2-(2,4,5-trifluorophenyl)ethylidene]-2,2-dimethyl-1,3-dioxane-4,6-dione is an impurity of the DPP-IV inhibitor Sitagliptin (S491000).

Application

5-[1-Hydroxy-2-(2,4,5-trifluorophenyl)ethylidene] is an intermediate for the synthesis of sitagliptin. Sitagliptin is a new type of anti-type II diabetes drug approved by the FDA and the first dipeptidyl peptidase-IV inhibitor drug for the treatment of 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 
• 101513-67-1 2,4,5-trifluorobenzoyl fluoride 
• 86393-34-2 2,4-dichloro-5-fluorobenzoyl chloride 
• 1176895-65-0 2-(2,4,5-trifluorophenyl)acetyl chloride 

Downstream Products

• 764667-65-4 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 
• 1234321-81-3 (Z)-3-acetylamino-4-(2,4,5-trifluorophenyl)-2-butenoic acid methyl ester 
• 1352613-31-0 (S)-3-(methanesulfonyloxy)-1-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-4-(2,4,5-trifluorophenyl)butan-1-one 
• 1352613-30-9 (S)-3-hydroxy-1-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-4-(2,4,5-trifluorophenyl)butan-1-one 
• 823817-56-7 (R/S)-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 
• 1253055-99-0 (R)-3-hydroxy-1-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-4-(2,4,5-trifluorophenyl)butan-1-one 
• 823817-55-6 (S)-Sitagliptin 
• 486460-32-6 sitagliptin 
• 922178-94-7 (S)-3-((tert-butoxycarbonyl)amino)-4-(2,4,5-trifluorophenyl)butanoic acid 

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.

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(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%.