63095-51-2

Usage

Chemical Properties

(R)-4-Propyldihydrofuran-2(3H)-one is a yellow oily liquid, slightly soluble in chloroform, methanol and ethanol. It needs to be stored at 2-8°C.

Uses

(R)-Dihydro-4-propyl-2(3H)-furanone, is building block used in various chemical synthesis.

Synthesis

Add a solution of H5IO6 (24.429 g, 107.17 mmol) in water (43 mL) to a solution of (R)-2-benzylpentyl acetate (1.180 g) in CCl4 (27 mL) and CH3CN (27 mL) at 0 °C. Add RuCl3·nH2O (0.222 g, 1.07 mmol) slowly to the mixture at 0 °C. Stir the resultant mixture vigorously for 20 hours at room temperature. Quench the reaction with Et2O (50 mL) at 0 °C. Stir the mixture for 30 minutes. Extract the mixture with Et2O (3 × 50 mL). Wash the combined organic layers with brine (30 mL). Dry the combined organic layers over anhydrous Na2SO4. Filter the combined organic layers. Remove the solvent. Dissolve the oil in aqueous NaOH (1 mol L-1, 40 mL). Stir the resulting solution overnight at room temperature. Wash the solution with Et2O (30 mL). Acidify the solution with aqueous HCl (6 mol L-1, 15 mL) at 0 °C. Stir the mixture overnight at room temperature. Saturate the aqueous layer with NaCl. Extract the mixture with Et2O (5 × 40 mL). Wash the combined organic layers with water, saturated aqueous Na2S2O3 (30 mL) and brine (30 mL). Dry the combined organic layers over anhydrous Na2SO4. Filter the combined organic layers. Remove the solvent. Purify the residue by column chromatography on silica gel (hexane/acetone = 3/1) and distillation (162-209 °C/36 mmHg).

Synthetic route

(4R)-2-oxo-4-propyltetrahydrofuran-3-carboxylic acid → (+)-(R)-4-propyl-4,5-dihydrofuran-2(3H)-one (63095-51-2)

Conditions	Yield
In toluene at 120℃; for 2h; Time;	99%

(R)-3-(hydroxymethyl)hexanenitrile → (+)-(R)-4-propyl-4,5-dihydrofuran-2(3H)-one (63095-51-2)

Conditions	Yield
With hydrogenchloride In water at 75℃; for 1h; Reagent/catalyst; Solvent;	95.6%

(R)-dihydro-4-(prop-1-enyl)furan-2(3H)-one → (+)-(R)-4-propyl-4,5-dihydrofuran-2(3H)-one (63095-51-2)

Conditions	Yield
With palladium 10% on activated carbon; hydrogen In methanol under 750.075 - 1500.15 Torr; Autoclave;	95%

(4R)-4-allyldihydrofuran-2(3H)-one (80758-91-4) → (+)-(R)-4-propyl-4,5-dihydrofuran-2(3H)-one (63095-51-2)

Conditions	Yield
With palladium 10% on activated carbon; hydrogen In methanol at 35℃; for 6h; enantioselective reaction;	95%

(3R)-3-(hydroxymethyl)-N-[(1S)-1-phenylethyl]hexanamide → (+)-(R)-4-propyl-4,5-dihydrofuran-2(3H)-one (63095-51-2)

Conditions	Yield
With sulfuric acid In water at 100℃; for 6h;	95%

4-propyl-5H-furan-2-one (21963-27-9) → (+)-(R)-4-propyl-4,5-dihydrofuran-2(3H)-one (63095-51-2)

Conditions	Yield
With bis(η5-cyclopentadienyl)ruthenium; (R,R)-(+)-2,2'-isopropylidene bis(4-isopropyl-2-oxazoline); hydrogen In methanol at 50℃; under 15001.5 Torr; Temperature; Pressure; Solvent; Reagent/catalyst; Autoclave;	93%
With water; (S)-(1,1'-binaphthalene)-2,2'-diylbis(diphenylphosphine); copper(l) chloride; sodium t-butanolate In toluene; tert-butyl alcohol at 0 - 30℃; Inert atmosphere;	79.63%
Multi-step reaction with 2 steps 1: palladium 10% on activated carbon; hydrogen / methanol / 4 h / 20 °C / 9000.9 Torr 2: sodium hydroxide / water / 2 h / 30 °C View Scheme
Multi-step reaction with 4 steps 1: palladium 10% on activated carbon; hydrogen / ethanol / 9 h / 20 °C / 225.02 - 375.04 Torr / Large scale 2: sodium hydroxide / ethanol / 1 h / 20 °C / Large scale 3: 0.5 h / 20 °C / Large scale 4: hydrogenchloride / water / 3 h / 20 - 60 °C / Large scale View Scheme

cis-4-propyl-5-p-tolylthio-4,5-dihydrofuran-2(3H)-one (123975-96-2) → (+)-(R)-4-propyl-4,5-dihydrofuran-2(3H)-one (63095-51-2)

Conditions	Yield
With 2,2'-azobis(isobutyronitrile); tri-n-butyl-tin hydride In toluene at 90 - 100℃; for 0.5h;	92%

(S)-3-p-toluenesulfonyl-γ-butyrolactone + n-propylmagnesium bromide (927-77-5) → (+)-(R)-4-propyl-4,5-dihydrofuran-2(3H)-one (63095-51-2)

Conditions	Yield
With [2,2]bipyridinyl; copper(l) iodide; lithium methanolate In tetrahydrofuran at 0℃; for 24h; Reagent/catalyst; Solvent;	92%

C7H14O3*C14H15NO → (+)-(R)-4-propyl-4,5-dihydrofuran-2(3H)-one (63095-51-2)

Conditions	Yield
With hydrogenchloride In water at 20 - 60℃; for 3h; Large scale;	92%

(2R)-2-propyl-3-(1,3-dithian-2-ylidene)propanol (147725-41-5) → (+)-(R)-4-propyl-4,5-dihydrofuran-2(3H)-one (63095-51-2)

Conditions	Yield
With toluene-4-sulfonic acid In dichloromethane for 1h; Ambient temperature;	90%

(R)-2-(2-methoxy-2-oxoethyl)pentanoic acid → (+)-(R)-4-propyl-4,5-dihydrofuran-2(3H)-one (63095-51-2)

Conditions	Yield
With dimethylsulfide borane complex In tetrahydrofuran at -20 - 0℃; for 3h; Reagent/catalyst;	90%

3-<(R)-<2-(1,1-dimethylethoxy)-2-oxoethyl>-1-oxopentyl>-4(S)-(phenylmethyl)-2-oxazolidinone (225377-55-9) → (+)-(R)-4-propyl-4,5-dihydrofuran-2(3H)-one (63095-51-2)

Conditions	Yield
With sodium tetrahydroborate In methanol at -25 - 20℃; for 16h; Reagent/catalyst; Temperature;	89.25%
Multi-step reaction with 2 steps 1.1: dihydrogen peroxide; lithium hydroxide; water / tetrahydrofuran; water / 15 h / 5 - 25 °C / Cooling with ice 2.1: dimethyl sulfide borane / tetrahydrofuran / 16 h / 10 - 25 °C / Cooling with ice 2.2: 24 h / 0 - 25 °C View Scheme
Multi-step reaction with 3 steps 1: dihydrogen peroxide; lithium hydroxide / tetrahydrofuran / 2 h / 0 - 5 °C / Large scale 2: sodium tetrahydroborate; boron trifluoride-tetrahydrofuran complex / tetrahydrofuran / 5 h / 0 - 5 °C / Large scale 3: trifluoroacetic acid / 6 h / 60 °C / Large scale View Scheme
Multi-step reaction with 3 steps 1: lithium hydroxide / tetrahydrofuran / 6 h / 20 °C 2: sodium tetrahydroborate / tetrahydrofuran; water / 20 °C 3: trifluoroacetic acid / toluene / 20 - 30 °C View Scheme

C8H14O4 → (+)-(R)-4-propyl-4,5-dihydrofuran-2(3H)-one (63095-51-2)

Conditions	Yield
With sodium tetrahydroborate; water; calcium chloride In methanol; ethanol at 0 - 20℃;	86.9%

4-propyl-2-furanone → (+)-(R)-4-propyl-4,5-dihydrofuran-2(3H)-one (63095-51-2)

Conditions	Yield
With copper(II) choride dihydrate; 1,1′-binaphthalene-2,2′-diylbis[bis(4-methylphenyl)phosphine]; sodium t-butanolate In hexane; toluene at -25℃; for 5h; Reagent/catalyst; Inert atmosphere;	86.1%

(R)-3-(hydroxymethyl)hexanoic acid tert-butyl ester → (+)-(R)-4-propyl-4,5-dihydrofuran-2(3H)-one (63095-51-2)

Conditions	Yield
With trifluoroacetic acid In dichloromethane at 20℃; Cooling with ice;	85.6%
With trifluoroacetic acid at 60℃; for 6h; Large scale;	78%
In water at 25℃; for 1h;	n/a
With toluene-4-sulfonic acid In dichloromethane Reflux;
With hydrogenchloride; water at 30℃;

(R)-3-methoxycarbonylhexanoic acid → (+)-(R)-4-propyl-4,5-dihydrofuran-2(3H)-one (63095-51-2)

Conditions	Yield
With sodium tetrahydroborate; calcium chloride In methanol; ethanol; water at 0 - 30℃; for 12h;	85%
With sodium tetrahydroborate; calcium chloride In methanol; ethanol; water at 0 - 30℃;	85%
With sodium tetrahydroborate; calcium chloride In methanol; ethanol; water at 0℃; for 12h;	85%

(4R,5R)-5-amino-4-propyldihydrofuran-2(3H)-one → (+)-(R)-4-propyl-4,5-dihydrofuran-2(3H)-one (63095-51-2)

Conditions	Yield
With N,N,N,N,N,N-hexamethylphosphoric triamide; samarium diiodide In tetrahydrofuran at 0 - 20℃; for 0.5h;	85%

(±)-dihydro-4-propyl-2(3H)-furanone (72397-60-5) → (+)-(R)-4-propyl-4,5-dihydrofuran-2(3H)-one (63095-51-2)

Conditions	Yield
Stage #1: (±)-dihydro-4-propyl-2(3H)-furanone With titanium(IV) isopropylate In tetrahydrofuran at 75℃; Stage #2: With sulfuric acid In 1,4-dioxane; water at 80℃;	80%
With sodium hydroxide In water at 30℃; for 2h; Temperature;	36%
Multi-step reaction with 3 steps 1: sodium hydroxide / ethanol / 1 h / 20 °C / Large scale 2: 0.5 h / 20 °C / Large scale 3: hydrogenchloride / water / 3 h / 20 - 60 °C / Large scale View Scheme
Multi-step reaction with 2 steps 1: triethylamine; water / 95 - 100 °C 2: sulfuric acid / water / 6 h / 100 °C View Scheme

(R)-2-((tert-butoxycarbonyl)methyl)pentanoic acid (112106-16-8) → (+)-(R)-4-propyl-4,5-dihydrofuran-2(3H)-one (63095-51-2)

Conditions	Yield
Stage #1: (R)-2-((tert-butoxycarbonyl)methyl)pentanoic acid With dimethyl sulfide borane In tetrahydrofuran at 10 - 25℃; for 16h; Cooling with ice; Stage #2: With hydrogenchloride In water at 0 - 25℃; for 24h; Temperature;	78%
Stage #1: (R)-2-((tert-butoxycarbonyl)methyl)pentanoic acid With dimethylsulfide borane complex In tetrahydrofuran at 20℃; Stage #2: With hydrogenchloride; trifluoroacetic acid In tetrahydrofuran at 50℃; for 12h;	52%
Multi-step reaction with 2 steps 1.1: triethylamine / toluene / 0.58 h / -6 - -5 °C / Inert atmosphere 1.2: 1.63 h / -6.6 - -3.4 °C 1.3: -18.7 °C / Inert atmosphere; Cooling 2.1: water / 1 h / 25 °C View Scheme

C7H14O3 → (+)-(R)-4-propyl-4,5-dihydrofuran-2(3H)-one (63095-51-2)

Conditions	Yield
With hydrogenchloride In water at 20℃; pH=3;	77%
With toluene-4-sulfonic acid In toluene for 20h; Reflux;	12 g
With toluene-4-sulfonic acid In toluene Reflux;	7.8 g

ethylmagnesium bromide (925-90-6) + (1S,5R)-ethyl 2-oxo-3-oxabicycio[3.1.0]hexane-1-carboxylate (145032-58-2) → (+)-(R)-4-propyl-4,5-dihydrofuran-2(3H)-one (63095-51-2)

Conditions	Yield
Stage #1: ethylmagnesium bromide With copper(l) iodide In 2-methyltetrahydrofuran at -30 - -20℃; for 0.5h; Stage #2: ethyl (1S,5R)-2-oxo-3-oxabicyclo[3.1.0]hexane-1-carboxylate In 2-methyltetrahydrofuran at -30℃; for 0.5h;	75%

n-propylmagnesium bromide (927-77-5) + C5H5F3O5S → (+)-(R)-4-propyl-4,5-dihydrofuran-2(3H)-one (63095-51-2)

Conditions	Yield
With zinc(II) chloride In tetrahydrofuran at -5 - 5℃; for 3h; Solvent; Inert atmosphere;	73%

diethyl (R)-2-(1-(tert-butyldimethylsilyloxy)pentan-2-yl)malonate → (+)-(R)-4-propyl-4,5-dihydrofuran-2(3H)-one (63095-51-2)

Conditions	Yield
With hydrogenchloride; acetic acid In water at 20℃; for 28h; Reflux;	70.9%

n-propylmagnesium bromide (927-77-5) + C4H5IO2 → (+)-(R)-4-propyl-4,5-dihydrofuran-2(3H)-one (63095-51-2)

Conditions	Yield
With zinc(II) chloride In tetrahydrofuran at -5 - 5℃; for 3h; Inert atmosphere;	63%

C9H18O3 → (+)-(R)-4-propyl-4,5-dihydrofuran-2(3H)-one (63095-51-2)

Conditions	Yield
With toluene-4-sulfonic acid In toluene for 3h; Time; Reflux;	60%
With toluene-4-sulfonic acid In toluene for 3h; Time; Reflux;	59%
With toluene-4-sulfonic acid In toluene for 3h; Reflux;

(1S,5R)-3-oxabicyclo[3.1.0]hexan-2-one (75658-86-5) + ethylmagnesium bromide (925-90-6) → (+)-(R)-4-propyl-4,5-dihydrofuran-2(3H)-one (63095-51-2)

Conditions	Yield
Stage #1: ethylmagnesium bromide With copper(l) iodide In tetrahydrofuran at -40 - -30℃; for 1h; Stage #2: (1S,5R)-3-oxabicyclo[3.1.0]hexan-2-one With ammonium chloride In tetrahydrofuran; water at -20 - 0℃; Reagent/catalyst;	55%

C10H9NO7S + n-propylmagnesium bromide (927-77-5) → (+)-(R)-4-propyl-4,5-dihydrofuran-2(3H)-one (63095-51-2)

Conditions	Yield
With zinc(II) chloride In tetrahydrofuran at -5 - 5℃; for 3h; Inert atmosphere;	49%

(2R,3S)-3,4-Dimethyl-2-phenyl-6-propyl-3,4,6,7-tetrahydro-2H-furo[3,2-f][1,4]oxazepin-5-one → (+)-(R)-4-propyl-4,5-dihydrofuran-2(3H)-one (63095-51-2) + (-)-(S)-β-propyl-γ-butyrolactone (63095-60-3)

Conditions	Yield
In sulfuric acid; water; acetic acid Heating; Yield given. Yields of byproduct given. Title compound not separated from byproducts;

(4R,5S)-3-<1-oxo-3-(1,3-dithian-2-ylidene)-2-propylpropyl>-4-methyl-5-phenyl-2-oxazolidinone (147725-30-2) → (+)-(R)-4-propyl-4,5-dihydrofuran-2(3H)-one (63095-51-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: 95 percent / LiAlH4 / tetrahydrofuran / 0.5 h / 0 °C 2: 90 percent / TsOH / CH2Cl2 / 1 h / Ambient temperature View Scheme

(+)-(R)-4-propyl-4,5-dihydrofuran-2(3H)-one (63095-51-2) → (R)-γ-bromo-3-propylbutyric acid

Conditions	Yield
With hydrogen bromide; acetic acid In dichloromethane at 0 - 30℃; for 16h; Temperature;	100%
With hydrogen bromide In acetic acid at 40 - 50℃; for 4h; Large scale;	93%
With hydrogen bromide; acetic acid at 5 - 80℃; for 2.83h; Inert atmosphere;	91.95%
With hydrogen bromide In acetic acid at 5 - 80℃; for 3.16667h; Inert atmosphere; Large scale;	81%
With hydrogen bromide; acetic acid at 20 - 55℃;

(+)-(R)-4-propyl-4,5-dihydrofuran-2(3H)-one (63095-51-2) → C7H13IO2

Conditions	Yield
With trimethylsilyl iodide In dichloromethane at 0 - 30℃; for 2h; Inert atmosphere;	99.5%
With trimethylsilyl iodide In dichloromethane at 0 - 30℃; for 2h; Inert atmosphere;	99.5%
With trimethylsilyl iodide In dichloromethane at 0 - 30℃; for 2h; Inert atmosphere;	99.5%
With trimethylsilyl iodide In dichloromethane at 0 - 25℃; for 2h; Inert atmosphere;	97%

(+)-(R)-4-propyl-4,5-dihydrofuran-2(3H)-one (63095-51-2) → 3-(hydroxymethyl)hexanoyloxy sodium

Conditions	Yield
With sodium hydroxide for 2h;	95%

(+)-(R)-4-propyl-4,5-dihydrofuran-2(3H)-one (63095-51-2) → C6H11IO2

Conditions	Yield
With trimethylsilyl iodide In dichloromethane at 20℃; for 3h;	94%
With trimethylsilyl iodide In dichloromethane at 20℃; for 3h;	94%

(+)-(R)-4-propyl-4,5-dihydrofuran-2(3H)-one (63095-51-2) + ethanol (64-17-5) → ethyl (R)-γ-bromo-3-propylbutyrate

Conditions	Yield
With trimethylsilyl bromide In dichloromethane at 30℃; for 8h; Temperature; Solvent; Cooling with ice;	93%
With trimethylsilyl bromide In dichloromethane at 0 - 20℃;	87%
With trimethylsilyl bromide In dichloromethane at 20℃; for 6h; Inert atmosphere;

(+)-(R)-4-propyl-4,5-dihydrofuran-2(3H)-one (63095-51-2) + L-2-aminobutyric acid (1492-24-6) → C11H21NO4

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 50℃; for 15h; Reagent/catalyst; Temperature;	90%

(+)-(R)-4-propyl-4,5-dihydrofuran-2(3H)-one (63095-51-2) → C7H12Br2O

Conditions	Yield
With thionyl chloride; hydrogen bromide In toluene at 20℃; for 8h; Reagent/catalyst;	90%

(+)-(R)-4-propyl-4,5-dihydrofuran-2(3H)-one (63095-51-2) → C6H11BrO2

Conditions	Yield
With trimethylsilyl bromide; zinc(II) chloride In dichloromethane at 20℃; for 28h;	89%
With trimethylsilyl bromide; zinc(II) chloride In dichloromethane at 20℃; for 28h;	89%

(+)-(R)-4-propyl-4,5-dihydrofuran-2(3H)-one (63095-51-2) + (S)-2-amino-butanamide (7324-11-0, 53726-14-0, 104652-77-9, 143164-46-9) → (R)-3-hydroxymethylhexanoic acid [(S)-1-carbamoylpropyl]amide

Conditions	Yield
With titanium(IV) isopropylate In tetrahydrofuran at 10 - 35℃; for 5h; Temperature; Solvent; Reagent/catalyst; Green chemistry;	84.15%
In ethanol for 24h; Solvent; Reflux;

(+)-(R)-4-propyl-4,5-dihydrofuran-2(3H)-one (63095-51-2) → (R)-3-(chloromethyl)hexanoyl chloride

Conditions	Yield
With thionyl chloride; zinc(II) chloride at 85℃; Concentration; Temperature;	79.7%
With thionyl chloride; zinc(II) chloride at 85℃;	66.5%

Upstream product

• 147725-41-5 (2R)-2-propyl-3-(1,3-dithian-2-ylidene)propanol 
• 123975-95-1 cis-3,3-dichloro-4-propyl-5-p-tolylthio-4,5-dihydrofuran-2(3H)-one 
• 2163-48-6 diethyl propylmalonate 
• 112106-16-8 (R)-2-((tert-butoxycarbonyl)methyl)pentanoic acid 
• 14035-96-2 dimethyl 2-propylmalonate 
• 117039-57-3 (4S)-3-pentanoyl-4-(propan-2-yl)-1,3-oxazolidin-2-one 
• 109-52-4 valeric acid 
• 143868-89-7 3-(1-oxopentyl)-4(S)-(phenylmethyl)-2-oxazolidinone 
• 225377-55-9 3-<(R)-<2-(1,1-dimethylethoxy)-2-oxoethyl>-1-oxopentyl>-4(S)-(phenylmethyl)-2-oxazolidinone 
• 155851-20-0 (4R)-3-(1-oxopentyl)-4-phenylmethyloxazolidin-2-one 
• 80758-91-4 (4R)-4-allyldihydrofuran-2(3H)-one 

Downstream Products

• 357336-20-0 brivaracetam 
• 357336-99-3 ((2S)-2-[(4S)-2-oxo-4-propyltetrahydro-1H-pyrrol-1-yl]butanamide) 
• 357337-00-9 ((2R)-2-[(4R)-2-oxo-4-propyltetrahydro-1H-pyrrol-1-yl]butanamide) 
• 910134-80-4 3-(3-methoxy-benzyl)-4-propyl-dihydro-furan-2-one 

Relevant academic research and scientific papers

COMPOUND AND USE THEREOF IN SYNTHESIS OF BRIVARACETAM INTERMEDIATE AND CRUDE DRUG

The present application provides a compound in formula III, and further provides a use of the compound in the synthesis of a Brivaracetam intermediate and a crude drug, and a synthesis method. A raw material involved in the method of the present application is low in costs and easily available; (R)-4-propyl-dihydrofuran-2-ketone having high optical purity can be prepared; complicated separation and purification steps are avoided; costs are reduced, and the method is more applicable to industrial production.

Preparation method of brivaracetam intermediate

The invention relates to a preparation method of a brivaracetam intermediate, and belongs to the field of medicinal chemistry. The preparation method comprises the following steps: reacting a compound II with urea to generate dilactam, and hydrolyzing under an alkaline condition to obtain a compound III; performing chiral resolution on the compound III to obtain a compound IV; reacting the compound IV with sodium hypochlorite to obtain a compound V; and reacting the compound V with nitrite to obtain a compound I. The raw materials used in the method are low in cost and easy to obtain, the intermediate compound is easy to purify, the process reaction steps are few, the operation is simple, the stereoselectivity is good, and the yield is high; and the method is suitable for industrial production.

Preparation method of brivaracetam intermediate

The invention provides a preparation method of a brivaracetam intermediate (R)-3-propyl-gamma-butyrolactone, which comprises the following steps: by taking 4-chloro-4-oxobutyric acid methyl ester as a starting raw material, connecting a chiral auxiliary group, introducing R configuration propyl, removing a ligand, reducing carboxyl, and finally esterifying to form a ring, thereby obtaining the (R)-3-propyl-gamma-butyrolactone. The synthesis route ingeniously utilizes the chiral adjuvant (R)-4-benzyl-2-oxazolidinone, optimizes the reaction conditions, has the advantages of few reaction steps, high yield, good reaction stereoselectivity and the like, meanwhile, the raw materials are cheap and easy to obtain, the operation is simple, convenient and safe, and the method has a better industrial application prospect;.

Synthesis and olfactory evaluation of optically active β-alkyl substituted γ-lactones and whiskey lactone analogues

Optically active β-alkyl substituted γ-lactones and whiskey lactone analogues were synthesized, and the odor properties were evaluated. During the preparation of the chiral intermediates, we found good reaction conditions for the highly enantioselective esterification of 3-arylmethyl-2-methyl-1-propanols to kinetically resolve them. The results of the olfactory evaluations of the synthesized lactones revealed that the alkyl groups on the γ-lactone rings played an important role for the odor profiles.

Preparation method of (R)-4-propyl-dihydrofuran-2-one and preparation intermediate of (R)-4-propyl-dihydrofuran-2-one

The invention discloses a preparation method of (R)-4-propyl-dihydrofuran-2-one and a preparation intermediate of (R)-4-propyl-dihydrofuran-2-one. The preparation method of the intermediate comprisesthe following steps: (1) in the presence of an acid or an alkali, carrying out hydrolysis reaction on a compound I to obtain a compound II or a salt thereof; and (2) carrying out reduction reaction onthe compound II or the salt thereof and a reducing agent to obtain a compound III. According to the preparation route disclosed by the invention, the use of flammable and explosive reaction reagentsin the existing route is avoided; reagents which are low in cost and easy to obtain in industry are used; compared with the prior art, the method has the advantages of low cost, safety in production,realization of the purification and the separation of the intermediate by using the acid-base property of the compound and adopting the mode of adjusting the pH value of the system in the reaction process and the post-treatment operation, avoiding of recrystallization, filtration and other tedious operation modes, simplification of the operation, and suitableness for industrial large-scale production.

ENANTIOSELECTIVE SYNTHESIS OF BRIVARACETAM AND INTERMEDIATES THEREOF

The present invention relates to an improved and economical process for enantioselective synthesis and purification of a novel key intermediate of Brivaracetam. Further, the present invention also relates to a process for the preparation of a chirally pure Brivaracetam of formula I utilizing the said intermediate.

Identification, characterization, synthesis and strategy for minimization of potential impurities observed in the synthesis of brivaracetam

A first systematic impurity profile research concerning nine observed and potential process related impurities of antiepileptic drug brivaracetam is reported. Among which three (impurity G/H/I) have not been discovered or reported before, these nine impurities were monitored by HPLC, and their structures were identified on the basis of MS and NMR spectroscopy. In addition to the formation, synthesis, and characterization, strategies for minimizing these impurities to the levels accepted by ICH are also described in this report.

Preparation method of 4 substituted-gamma butyrolactone

The invention belongs to the field of medicinal chemistry, and relates to preparation of (R)-4-propyl-dihydrofuran-2-one represented by a formula I.

Synthesis method of (R)-4-propyldihydrofuran-2-ketone

The invention discloses a synthesis method of (R)-4-propyldihydrofuran-2-ketone, and belongs to the field of organic chemical synthesis. A new process route is developed to overcome the defects that (R)-4-propyldihydrofuran-2-ketone is relatively high in material price, low in product purity, difficult to produce and amplify and the like. Meldrum's acid and R-epichlorohydrin are used as initial raw materials, and the compound is obtained by taking (1S, 5R)-3-oxabicyclo [3.1. 0]-2-hexanone as an intermediate through a two-step reaction of closing a three-membered ring and opening a ring by using a Grignard reagent. The (R)-4-propyldihydrofuran-2-ketone is synthesized by adopting the synthesis method, a novel process route is adopted in the process, the total molar yield is greater than 50%,and the method has the characteristics of novel and short route, high optical purity, low cost and the like.

Synthesis method of R-3-propyl-gamma-butyrolactone

The invention discloses a synthetic method of R-3-propyl-gamma-butyrolactone, and belongs to the technical field of organic synthesis. The method comprises the following steps: by taking D-malic acidas a raw material, performing monomethyl esterification, reduction, halogenation or sulfonic acid esterification, and finally coupling with a Grignard reagent under the catalysis of zinc chloride to obtain a brivaracetam intermediate that is the R-3-propyl-gamma-butyrolactone. The method has the advantages of cheap and easily available starting raw materials, good stereoselectivity, no need of chiral resolution, mild condition, short route and the like, and provides a feasible scheme for brivaracetam process research.