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[ CAS No. 102767-28-2 ] {[proInfo.proName]}

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Chemical Structure| 102767-28-2
Chemical Structure| 102767-28-2
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Product Details of [ 102767-28-2 ]

CAS No. :102767-28-2 MDL No. :MFCD03265610
Formula : C8H14N2O2 Boiling Point : -
Linear Structure Formula :- InChI Key :HPHUVLMMVZITSG-LURJTMIESA-N
M.W : 170.21 Pubchem ID :5284583
Synonyms :
UCB L059;SIB-S1;Levetiracetam, Keppra, Etiracetam, UCB 6474
Chemical Name :(S)-2-(2-Oxopyrrolidin-1-yl)butanamide

Calculated chemistry of [ 102767-28-2 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 12
Num. arom. heavy atoms : 0
Fraction Csp3 : 0.75
Num. rotatable bonds : 3
Num. H-bond acceptors : 2.0
Num. H-bond donors : 1.0
Molar Refractivity : 48.37
TPSA : 63.4 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : No
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -7.58 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.32
Log Po/w (XLOGP3) : -0.34
Log Po/w (WLOGP) : -0.51
Log Po/w (MLOGP) : -0.27
Log Po/w (SILICOS-IT) : 0.27
Consensus Log Po/w : 0.1

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 1.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -0.48
Solubility : 56.0 mg/ml ; 0.329 mol/l
Class : Very soluble
Log S (Ali) : -0.53
Solubility : 50.3 mg/ml ; 0.295 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -0.64
Solubility : 39.1 mg/ml ; 0.23 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.82

Safety of [ 102767-28-2 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P305+P351+P338 UN#:N/A
Hazard Statements:H302-H319 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 102767-28-2 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

  • Downstream synthetic route of [ 102767-28-2 ]

[ 102767-28-2 ] Synthesis Path-Downstream   1~80

  • 1
  • [ 102767-28-2 ]
  • [ 664304-29-4 ]
  • 2
  • [ 103833-72-3 ]
  • levetiracetam [ No CAS ]
  • [ 102767-28-2 ]
  • 3
  • [ 102849-49-0 ]
  • levetiracetam [ No CAS ]
  • [ 102767-28-2 ]
  • 4
  • [ 102849-49-0 ]
  • [ 102767-28-2 ]
YieldReaction ConditionsOperation in experiment
78.4% Example 1 (Invention) Step 1 (-)-(S)-alpha-ethyl-2-oxo-1-pyrrolidine acetic acid (150 g, 0.87 mol) was dissolved in methanol (235 g, 300 ml) at 45C and thionyl chloride (56 g, 0.47 mol) was added dropwise over 30 min. The reaction mixture was stirred at 45C for additional 15-30 min until complete conversion of (-)-(S)-alpha-ethyl-2-oxo-1-pyrrolidine acetic acid was observed via HPLC (unreacted (-)-(S)-alpha-ethyl-2-oxo-1-pyrrolidine acetic acid ? 2%, by HPLC % area). At reaction completed, the volatiles were distilled off at moderate temperature and reduced pressure (35-40C, 150-200 mbar) until 10% of the whole volume was eliminated, then the mixture was reintegrated with fresh methanol up to initial volume. After that, the reaction mixture was neutralized by bubbling ammonia gas at 20C up to a pH value equal to about 5, and stirred at 20C for 1 h. A limited amount of salts (about 44 g) precipitated and was filtered off. The resulting methanol solution was directly transferred to the autoclave.Step 2 The reaction mixture was pressurized up to about 3 bar with ammonia gas at 20C, and stirred until complete conversion to (-)-(S)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide was observed via HPLC. Then, once the reaction mixture was taken out of the autoclave, the residual salts formed (about 20 grams) were filtered off and the methanol solution was distilled up to a minimum volume at moderate temperature and reduced pressure (35- 40C, 150 - 200 mbar). Acetone (115 ml) was added and the mixture was distilled again at moderate temperature and reduced pressure (35-40C, 150-200 mbar) to minimum volume. After that acetone (300 ml) was charged over the residue and the mixture was heated and refluxed for 30 minutes. Finally, the solution was cooled down slowly to 0C and crude levetiracetam was isolated by filtration. Crude levetiracetam (molar yield 73.1 %, (R)-enantiomer: 1.171 %) was then submitted to a final purification process in one step to give pure levetiracetam. Acetone (750 ml) was charged over crude levetiracetam and the mixture was again stirred and heated to reflux. Once refluxed for about 30 minutes the hot mixture was filtered to remove residual salts and cooled slowly to 0C. Pure levetiracetam ((R)-enantiomer: 0.01%) was obtained by filtration and drying under vacuum at 40C. Overall molar yield was 60.0 % by mole of the starting amount of (-)-(S)-alpha-ethyl-2-oxo-1-pyrrolidine acetic acid (ponderal yield 78.4 % by weight).
65% With ammonium hydroxide; chloroformic acid ethyl ester; triethylamine; In tetrahydrofuran; water; at 0 - 20℃; for 12.5h; To a cold 0 C. solution of acid 4 (0.292 mol) and Et3N (0.307 mol) in anhydrous THF (20 ml) was added ethyl chloroformate (0.304 mol) and the mixture stirred at 0 C. for 30 min. Ammonium hydroxide (25% w/v aqueous solution, 19 ml, 136.0 mol) was added and the reaction mixture was stirred at room temperature for 12 h. After the addition of K2CO3 (30.0 mol), the mixture was filtered and the volatile material (solvent and Et3N) distilled off in vacuo. The solid residue was extracted with DCM (3×50 ml) and combined extracts were dried over Na2SO4 and concentrated in vacuo, recrystallization from acetone gave compound 5 as white solid.
EXAMPLE 1Preparation of Crude Levetiracetam[0032] 75 parts by weight (pbw) of (S)-alpha-ethyl-2-oxo-l-pyrrolidineacetic acid(levo acid) is charged to a dry flask equipped with means for establishing a nitrogen atmosphere, with a mechanical stirrer and with a cooling bath. About 373 pbw of acetonitrile is added and the mixture is stirred at a temperature of 10 - 15 0C under a nitrogen atmosphere. A suspension is formed. About 105 pbw of DiBOC is added to the suspension and is stirred at a temperature of 10 - 15 0C. Thereafter, 42 pbw of ammonium bicarbonate is added to the mixture with further stirring at a temperature of 10 - 15 0C. Finally, about 21 pbw of pyridine is added to the mixture and the resulting mixture is stirred at a temperature of 10 - 20 0C. As the reaction progresses, CO2 gas is generated and the suspension gradually becomes a solution. The reaction temperature should be controlled such that it does not exceed 20 0C. Higher temperatures lead to undesired racemization.
  • 5
  • (2S)-2-(3,4-dichloro-2,5-dihydro-2-oxo-1H-pyrrol-1-yl)butanamide [ No CAS ]
  • [ 102767-28-2 ]
  • 6
  • [ 358629-51-3 ]
  • [ 102767-28-2 ]
YieldReaction ConditionsOperation in experiment
78.4% With ammonia; In methanol; at 20℃; under 2250.23 Torr;Autoclave;Product distribution / selectivity; Step 2The reaction mixture was pressurized up to about 3 bar with ammonia gas at 20 C., and stirred until complete conversion to (-)-(S)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide was observed via HPLC.Then, once the reaction mixture was taken out of the autoclave, the residual salts formed (about 20 grams) were filtered off and the methanol solution was distilled up to a minimum volume at moderate temperature and reduced pressure (35-40 C., 150-200 mbar).Acetone (115 ml) was added and the mixture was distilled again at moderate temperature and reduced pressure (35-40 C., 150-200 mbar) to minimum volume. After that acetone (300 ml) was charged over the residue and the mixture was heated and refluxed for 30 minutes. Finally, the solution was cooled down slowly to 0 C. and crude levetiracetam was isolated by filtration.Crude levetiracetam (molar yield 73.1%, (R)-enantiomer: 1.171%) was then submitted to a final purification process in one step to give pure levetiracetam.Acetone (750 ml) was charged over crude levetiracetam and the mixture was again stirred and heated to reflux. Once refluxed for about 30 minutes the hot mixture was filtered to remove residual salts and cooled slowly to 0 C.Pure levetiracetam ((R)-enantiomer: 0.01%) was obtained by filtration and drying under vacuum at 40 C. Overall molar yield was 60.0% by mole of the starting amount of (-)-(S)-alpha-ethyl-2-oxo-1-pyrrolidine acetic acid (ponderal yield 78.4% by weight).
62.2% With ammonia; water; at 0 - 20℃; for 14h;Product distribution / selectivity; Example 6; (-)-(S)-alpha-ethyl-2-oxo-l-pyrrolidineacetamide (levetiracetam).; In a 25 ml flask equipped with thermometer, mechanical stirring and bubble condenser, 3.344 g of (-)-(S)-alpha-ethyl-2-oxo-l-pyrrolidineacetic acid (19.58 mmol, e.e.= 95.0%), 0.11 ml of concentrated sulfuric acid (95.6% m/m, 1.97 mmol) and 17 ml of methanol were charged under nitrogen atmosphere at room temperature. Reaction mixture was heated up to 65C temperature by oil bath and maintained at reflux temperature up to complete disappearing of starting material (about 2.5 h; checked by TLC, Rf = 0.58 CH2Cl2:Me0H:Ac0H 80:20: 1/silica gel). Reaction mixture was concentrated under vacuum up to a residue was formed then water (2.0 ml) was added. In a 25 ml flask equipped with magnetic stirring and condenser, 7.5 ml of 30% aqueous ammonia solution was charged and cooled to 00C temperature <n="21"/>and, keeping under stirring, the aqueous solution of crude (-)-(S)-alpha-ethyl-2-oxo- 1-pyrrolidineacetic acid methyl ester was charged dropwise. When addition was completed, reaction mixture was thermostabilized at 200C and said conditions were maintained overnight.At complete conversion (about 10 h) excess of ammonia was eliminated by vacuum evaporator. Reaction mixture was extracted with dichloromethane (2 x 3.5 ml), transferred into a continuous liquid-liquid extractor and then refluxed with 7 ml of dichloromethane for 6 hours. Collected organic phases were concentrated under vacuum up to a residue was formed. 2.666 g of a yellow solid was obtained which was suspended in 15.0 ml of acetone. Reaction mixture was heated up to 600C temperature so that complete dissolution of the solid was reached. Then, mixture was slowly cooled. White solid was isolated by filtration, washed with mother liquors and then with 3 ml of cold acetone and, finally, dried in oven under vacuum at 400C temperature for 4 hours to give 2.259 g of levetiracetam (13.274 mmol, 67.8% yield, e.e. 99.9%).; Example 8; (-)-(S)-alpha-ethyl-2-oxo-l-pyrrolidineacetamide (levetiracetam) (alternative 1).; 365.1 g of the solution of (-)-(S)-alpha-ethyl-2-oxo-l-pyrrolidineacetic acid methyl ester (0.462%, 1.69 g, 9.110 mmol) obtained in Example 7 was charged in a flask and concentrated up to a residue was formed. 2.482 g of a brown oil was obtained. Residue was charged in a 10 ml flask equipped with magnetic stirring and condenser. Reaction mixture was cooled to 00C temperature and, keeping under stirring, 0.8 ml of water and 3.2 ml of 30% aqueous ammonia solution were charged dropwise in about 10 minutes. When addition was completed, reaction mixture was thermostabilized at 200C and said conditions were maintained overnight.At complete conversion (about 14 h) excess of ammonia was eliminated by vacuum evaporator. Reaction mixture was then extracted with dichloromethane (10 x 5 ml). Collected organic phases were dried on Na2SO4, and concentrated under vacuum up to a residue was formed. 1.999 g of a yellow solid was obtained which was suspended in 5 ml of acetone. Reaction mixture was heated up to 600C temperature so that complete dissolution of the solid was reached. Then, mixture was slowly cooled. White solid was isolated by filtration, washed with mother liquors and then with 1 ml of cold acetone and, finally, dried in oven under vacuum at 25C temperature for 1 night to give 0.965 g of levetiracetam (5.669 mmol, 62.2% yield, e.e. 94.2%).; Example 9; (-)-(S)-alpha-ethyl-2-oxo-l-pyrrolidineacetamide (levetiracetam) (alternative 2).; In a 50 ml reactor equipped with mechanical stirring, thermometer and condenser, 0.275 g of (-)-(S)-alpha-ethyl-2-oxo-l-pyrrolidineacet-N-(+)-(R)-(l-phenylethyl)- amide (1.0 mmol, d.e.= 99.3%), 10.0 g of ethyl-thiophenyl-sulfonic acid supported on silica (0.6 mmol/g, supplied by Phosphonics ) and 15 ml of toluene were charged. To the reaction mixture was added 0.075 ml (4.0 mmol) of water under stirring and mixture was heated up to reflux temperature. Reaction is monitored by HPLC and at complete conversion of starting material (about 5 h), reaction mixture was cooled to 600C temperature and 10 ml of methanol added. Reaction mixture was maintained at that temperature for 3 h up to complete formation of (-)-(S)-alpha-ethyl-2-oxo-l- pyrrolidineacetic acid methyl ester. Reaction mixture was permitted to cool and then worked up according to the procedure described in example 7. 57.9 g of a 0.280% organic solution of (-)-(S)-alpha-ethyl-2-oxo-l-pyrrolidineacetic acid methyl ester (0.162 g, 0.875 mmol, 87.5% yield) was thus obtained. Such solution was charged in a flask and concentrated up to a residue was formed. 0.486 g of a brown oil was obtained. Residue was charged in a 5 ml flask equipped with magnetic stirring and condenser. Reaction mixture was cooled to 00C temperature and, keeping under stirring, 1.5 ml of 30% aqueous ammonia solution were charged dropwise. When addition was completed, reaction mixture was thermostabilized at 200C and said condition...
  • 9
  • [ 873786-87-9 ]
  • [ 102767-28-2 ]
  • 10
  • [ 873786-88-0 ]
  • [ 102767-28-2 ]
  • 12
  • [ 102767-28-2 ]
  • (S)-2-(2-Oxo-pyrrolidin-1-yl)-thiobutyramide [ No CAS ]
  • 13
  • [ 102767-28-2 ]
  • 2-(2-oxopyrrolidin-1-yl)butanimidamide [ No CAS ]
  • 14
  • [ 102767-28-2 ]
  • (2S)-N'-hydroxy-2-(2-oxopyrrolidin-1-yl)butanimidamide [ No CAS ]
  • 15
  • [ 53726-14-0 ]
  • [ 4635-59-0 ]
  • [ 102767-28-2 ]
YieldReaction ConditionsOperation in experiment
89% 50 g of anhydrous sodium sulfate was added to 650 g of dichloromethane of 50 g of (S)-2-aminobutanamide hydrochloride at room temperature.After cooling to 0 C, 2.5 g of tetrabutylammonium bromide was further added, and the mixture was stirred for 30 minutes, and 83 g of potassium hydroxide powder was added.56.5 g of 4-chlorobutyryl chloride was added dropwise at 0 C under vigorous stirring. After the dropwise addition, after reacting for 5 hours, 21 g of potassium hydroxide powder was further added. After 2 hours, it was directly filtered, and the filtrate was directly concentrated. The residue was refluxed with 80 g of ethyl acetate for 30 minutes, and then concentrated to obtain crude levetiracetam.
84% Anhydrous sodium sulfate 99.6 g is added with stirring into acetonitrile 700 ml under a nitrogen blanket. The temperature is set and maintained at 3-5 degrees during the reaction. L-ABA HC1 69. 25 g (0.5 M), followed by 124 g ground KOH are then introduced into THE ABOVE MIXED SUSPENSION. 4-CHLOROBUTYRYL CHLORIDE 77.6 G (0.55 M. ) IS ADDED AT A rate sufficient to keep the temperature at 3-5 degrees C. The reaction mixture is kept for 5 hrs under these conditions. The mixture is then neutralized with care to about pH 6 using concentrated HC1 (32%). The mixture is filtered and washed twice with acetonitrile (total 400 ml). The filtrate and washes are combined and concentrated to a 500 ml solution which is filtered. Upon cooling, crude levetiracetam crystallizes displaying about 99 % purity (HPLC). Recrystallization from warm ethyl acetate leads to 72 g (84 %) of pure levetiracetam, displaying >99.5% isomeric purity by chiral capillary GC.
74.1% With potassium hydroxide; tetrabutylammomium bromide; sodium sulfate;molecular sieve; In dichloromethane; ethyl acetate; toluene; EXAMPLE 4 Preparation of (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide This example illustrates a varient of the process of Example 3, in which the intermediate 4-chlorobutanamide obtained in situ is not isolated. 84 g of anhydrous sodium sulfate are added to a suspension of 69.25 g (0.5 mole) of (S)-2-amino-butanamide hydrochloride in 600 ml of dichloromethane at ambient temperature. The mixture is cooled to 0 C. and 115 g of ground potassium hydroxide are added, followed by 8.1 g (0.025 mole) of tetrabutylammonium bromide dissolved in 100 ml of dichloromethane. A solution of 77.5 g of 4-chlorobutyryl chloride in 100 ml of dichloromethane is added dropwise at 0 C., with vigorous stirring. After 5 hours' reaction, a further 29 g of ground potassium hydroxide are added. Two hours later, the reaction mixture is filtered over Hyflo-cel and the filtrate evaporated under reduced pressure. The residue (93.5 g) is dispersed in 130 ml of hot toluene for 45 minutes. The resultant mixture is filtered and the filtrate evaporated under reduced pressure. The residue (71.3 g) is dissolved hot in 380 ml of ethyl acetate to which 23 g of 0.4 nm molecular sieve in powder form are added. This mixture is heated to reflux temperature and filtered hot. After cooling the filtrate, the desired product crystallizes to give 63 g of (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide. Melting point: 117 C. [alpha]D25: -91.3 (c=1, acetone). Yield: 74.1%.
72% With potassium hydroxide; molecular sieve; In acetonitrile; at 10 - 20℃; for 3h;Product distribution / selectivity; L-ABA HC1 69. 25 g (0.5 M) and powdered KOH 101.25 g (1.8 M) are added to a vigorously stirred suspension of powdered molecular sieves in 625 ml acetonitrile under nitrogen. The temperature is kept at about 10 degrees C. A solution of 4- chlorobutyryl chloride 77.5 g (0. 5M) in acetonitrile 250 ml is added drop-wise. The temperature is kept under 20 degrees C. After 2 hrs, 1.25 liters of acetonitrile are added and the mixture is stirred for 1 hour and then filtered. The solid is washed with acetonitrile (25ML). The combined filtrate and washes are evaporated in vacuo to yield a semi-solid oil 70 g, which upon crystallization from warm ethyl-acetate (150) ml leads to 60.5. 5 g (72 %) of levetiracetam 98.2 % purity (crude product).The amount of D-isomer was determined as follows: Column: Beta Dex325 capillary column 30m x 0.25mm+0. 25micron thickness. Oven: 160 degrees C.; Carry gas: nitrogen, flow LML/MIN. ; Detector FID, 230 degrees C.; Injection: split. 150: 1, 210 degrees C.; Sample: 1 microliter of 0.05% levitiracetam solution in methanol; RT of D-isomer: 34.5 min, levitiracetam-33.4 min.
70% With potassium hydroxide; sodium sulfate; In acetonitrile; at 5℃; for 6h;Product distribution / selectivity; Anhydrous sodium sulfate 13.6 g (0.096 M) is added to dry acetonitrile (ACN) (96 ML) UNDER VIGOROUS STIRRING AT 3-5 DEGREES C. AND UNDER A NITROGEN BLANKET. (S) -2- AMINO-BUTANAMIDE hydrochloride (L-ABA HC1) 11. 08G (0.08 M) is added. The mixture is stirred at 3-5 degrees C. for 30 minutes. Powdered KOH 17.23 g (0.28 M) is added. 4-chlorobutyryl chloride 12.41g (0.088M) in 39 ml dry acetonitrile is added drop-wise over a period of about 30 minutes, while the temperature is kept under 5 degrees C. The reaction mixture is stirred while the temperature is kept under 5 degrees C for a further 5 hrs. The insoluble matter is filtered off and washed with acetonitrile (15 ML). The filtrate and washing are evaporated IN VACUO at 35-40 degrees C. The residue is recrystallized from 50 ml ethyl-acetate to give 9.6 g (Yield=70 %) of product displaying 99 % purity (crude product) by capillary GC; 99.65% L-isomer and 0.35 % D-isomer (D-Levetiracetam) by dextrine based chiral capillary GC. The amount of D-isomer was determined as follows: Column: Beta Dex325 capillary column 30m x 0.25mm+0. 25micron thickness. Oven: 160 degrees C.; Carry gas: nitrogen, flow LML/MIN. ; Detector FID, 230 degrees C.; Injection: split. 150: 1, 210 degrees C.; Sample: 1 microliter of 0.05% levitiracetam solution in methanol; RT of D-isomer: 34.5 min, levitiracetam-33.4 min.
60 - 65% With potassium hydroxide; tetrabutylammomium bromide; In dichloromethane; at -5 - 20℃; The compound (-)-(S)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide is prepared by suspending 50 grams of (S)-2-aminobutyramide hydrochloride in 500 mL of dichloromethane at room temperature, then cooling to temperatures between -5 and 0 C. and adding 81.2 grams of potassium hydroxide and 23.3 grams of tetrabutylammonium bromide at those temperatures. A 66.4 gram amount of 4-chlorobutyryl chloride is added at the same temperatures. After completion of the reaction, solids are removed by filtration, the solution is adjusted to pH 7-7.5 with acetic acid, and dichloromethane is partially evaporated by the application of a vacuum. 150 mL of ethyl acetate are added to precipitate the product, which is isolated by filtration and washed with ethyl acetate and then with acetone; the product has a chiral purity of 99.8 percent by high performance liquid chromatography. The final product is purified by recrystallization from ethyl acetate, giving a yield of 60-65 percent.
60.5% With tetrabutylammomium bromide; potassium hydroxide; In dichloromethane; at -15 - -10℃; for 6.91667h; (S)-2-aminobutanamide hydrochloride (30.0 g) was mixed with dichloromethane(300 mL), and tetra-butyl ammonium bromide (3.5 g)was added. Then, the reactionmixturewas cooled to -15 C. The furtheraddition of potassium hydroxide and 4-chlorobutyryl chloride was dividedinto three batches. For each round, potassium hydroxide (20.2 g) was added first with vigorous stirring for 10 min. After that,the solution of 4-chlorobutyryl chloride (12.2 g) in dichloromethane(45 mL) was slowly added to maintain the temperature under -10 C.The reaction was stirred vigorously at -10 C for further 45 min beforeadding another batch of potassiumhydroxide and 4-chlorobutyryl chloride.After adding total three batches, the reactionmixturewas stirred at-10 C for over 2 h. Additional potassium hydroxide (6.6 g) was addedinto the reactionmixture followed by stirring for 4 h. Then, the insolublesubstance was filtered and washed by dichloromethane (10 × 3 mL).The organic layerwas combined and neutralized by acetic acid. The unwantedsalt was filtered and washed by dichloromethane (10 × 3 mL).The combined organic layer was dried by anhydrous sodium sulfateand then filtered. Dichloromethane was evaporated under reducedpressure followed by the addition of ethyl acetate (150 mL). The solutionwas concentrated to over 75 mL to afford slurry. The slurry wasstirred at -5 C for an hour. The precipitate was filtered and washedby cold ethyl acetate (10 × 3 mL), and then dried under a vacuum at30 C to give 27.5 g of crude product. The crude product was recrystallizedin isopropanol (40 mL) to afford refined product of levetiracetamas white solid (22.3 g, yield 60.5%). purity: 99.67%; ee: 99.94%; m.p.:116.0 C-118.0 C; [alpha]D25: -90.0 (c = 1, EtOH); HRESIMS m/z:193.0948 [M Na] (calcd. for C8H14O2N2Na, 193.0947); 1H NMR(600 MHz, CDCl3): delta 6.98 (s, 1H), 6.61 (s, 1H), 4.52 (t, J = 5 Hz, 1H),3.51-3.55 (m, 1H), 3.37-3.41 (m, 1H), 2.43 (t, J = 8.5 Hz, 2H),2.02-2.07 (m, 2H), 1.93-1.98 (m, 1H), 1.65-1.70 (m, 1H), 0.89 (t, J =7.5 Hz, 3H); 13C NMR (CDCl3, 150 MHz): delta 175.7, 172.6, 55.5, 43.4,30.7, 21.0, 17.8, 10.2; ECD revealed a negative cotton effect at around223 nm, which was consisted with reported ECD behavior oflevetiracetam.
34.61% With potassium hydroxide; sodium sulfate;tetrabutylammomium bromide; In dichloromethane; at 0 - 35℃; for 8.5h;Product distribution / selectivity; EXAMPLE-7: PREPARATION OF (-)-(S)-alpha-ETHYL-2-OXO-1 -PYRROLIDINE ACETAMIDE AS PER US 4,943,639Sodium sulfate (25 g) was added to a suspension of (S)-2-amino- butanamide hydrochloride (20 g) in dichloromethane (175 ml) at a temperature of <n="18"/>about 25 to about 35C. The reaction mixture was cooled to about O0C to about - 1O0C followed by the addition of potassium hydroxide (33.1 g) and tetra butylammonium bromide (2.3 g). A solution of 4-chlorobutyrylchloride (22.3 g) in dichloromethane (30 ml) was added to the reaction mixture over a period of 1 hour and stirred for about 2 hours. Potassium hydroxide (8.3 g) was added to the reaction mixture and stirred for about 5 hours 30 minutes. The reaction mixture was filtered and washed with dichloromethane (50 ml). The filtrate was concentrated completely followed by the addition of toluene and then distilled off the solvent completely. Ethylacetate (110 ml) was added to the reaction crude and heating given to a temperature of about 75 to about 800C and stirred for about 20 minutes. Filtered the suspension and washed the solid with ethylacetate (10 ml). The obtained filtrate was distilled completely followed by ethylacetate (80 ml) was added and then stirred for about 15 minutes. The reaction suspension was cooled to about 0C to about 5C and stirred for about 1 hour 45 minutes. Acetone (10 ml) was added to the reaction mixture and stirred for about 1 hour 40 minutes. The sususpension was filtered and dried the solid at a temperature of about 600C for about 3 hours 30 minutes to afford 8.5 g of title compound. Purity: 96.7% by HPLC; Yield: 34.61% 16.1% of (S)-2-amino-butanamide hydrochloride, 65% of 4-chlorobutyrylchloride and 7.2% of intermediate of Formula A were not converted to title compound.
EXAMPLE1 : PREPARATION OF (-)-(S)-alpha-ETHYL-2-OXO-1-PYRROLIDINE ACETAMIDE (FORMULA I) S-aminobutyramide hydrochloride (25 g) and dichloromethane (300 ml) were^harged into a clean dry4 neck round bottom flask and stirred at about100C for about 10 minutes. Tetra-n-butyl ammonium bromide (1 1.6 g) was added and stirred at a temperature of about -1O0C for about 10 minutes. Potassium hydroxide (20.2 g) was added at a temperature of about -100C and stirred for 15 minutes followed by addition of mixture of 4-chloro butyrlchloride (12.7 g) and dichloromethane (25 ml) was added slowly at a temperature of about -6C over a period of about 45 minutes. The resultant reaction mixture was stirred for about 45 minutes. Potassium hydroxide (20.2 g) was added at a temperature of about - 1O0C and stirred for about 15 minutes followed by addition of 4-chlorobutyrl chloride (7.6 g) and dichloromethane (25 ml) slowly over a period of about 30 minutes and stirred for about 45 minutes. A lot of potassium hydroxide (10.1 g) was added at a temperature of about -100C and stirred for about 15 minutes followed by addition of 4-chlorobutyrl chloride (7.6 g of) dissolved in dichloromethane (25 ml) slowly over about 30 minutes. The resultant reaction mixture was stirred at a temperature of about -2C for about 5 hours. Potassium hydroxide (5.05 g) was added followed by stirring for about 2 hours. The separated unwanted solid was filtered and the solid was washed with dichloromethane (50 ml). pH of the filtrate was adjusted to about 7 by addition of acetic acid (0.8 ml). The organic layer was dried over anhydrous sodium sulphate. The obtained clear organic layer was distilled off completely at about 35C under vacuum. Ethyl acetate (25 X 2 ml) was added to the residue and distilled completely under vacuum to remove the traces dichloromethane, yielding the title compound as a solid residue.To the obtained residue ethyl acetate (10 ml) was added at a temperature of about 25C to about 300C and cooled to about 0C followed by stirring for about 30 minutes. The separated solid was filtered and the solid was washed with precooled ethyl acetate (10 ml). The obtained solid was dried at about 400C under vacuum for about 3 hours to afford 27 g of pure title compound. <n="15"/>Purity by HPLC: 99.94%. Purity by chiral HPLC: 99.7%.; EXAMPLE-8: PREPARATION OF (-)-(S)-alpha-ETHYL-2-OXO-1 -PYRROLIDINE ACETAMIDE (FORMULA I) S-aminobutyramide hydrochloride (60 g) and dichloromethane (720 ml) were charged into a clean dry round bottom flask and stirred at a temperature of about -10C for about 10 minutes. Tetra-butyl ammonium bromide (27.8 g) was added and stirred at -10C for about 10 minutes. Potassium hydroxide (48.5 g) was added at about -10C and stirred for about 15 minutes followed by addition of mixture of 4-chloro butyrlchloride (30.5 g) and dichloromethane (60 ml) was added slowly at a temperature of about -60C over a period of about 45 minutes. The resultant reaction mixture was stirred for about 45 minutes. Potassium hydroxide (48.5 g) was added at about -10C and stirred for about 15 minutes followed by <n="19"/>addition of 4-chlorobutyrl chloride (18.4 g) and dichloromethane (60 ml) slowly over about 30 minutes and stirred for about 45 minutes. A lot of potassium hydroxide (24.2 g) was added at a temperature of about -1O0C and stirred for about 15 minutes followed by the addition of 4-chlorobutyrl chloride (18.4 g of) dissolved in dichloromethane (60 ml) over a period of about 30 minutes. The restiotaltantHr?aepsilontionHmxture^/vas stirred at a temperature of about -2C for about 5 hours. Potassium hydroxide (12.1 g) was added followed by stirring for about 2 hours. pH of the reaction mixture was adjusted to about 7 to about 7.5 by addition of acetic acid (45 ml). The unwanted solid was filtered and the solid was washed with dichloromethane (120 ml). The organic layer was dried over anhydrous sodium sulphate (60 g). The obtained clear organic layer was distilled off completely at about 35C under vacuum. Ethyl acetate (60 X 2 ml) was added to the residue and distilled completely under vacuum to remove the traces dichloromethane, yielding the title compound as a solid residue. To the obtained residue ethyl acetate (120 ml) was added at a temperature of about 250C to about 300C and stirred for about 30 minutes. The reaction mixture was cooled to a temperature of about O0C followed by stirring for about 30 minutes. The separated solid was filtered and the solid was washed with precooled ethyl acetate (24 ml). The obtained solid was dried at about 40C under vacuum for about 3 hours to afford 70.5 g of pure title compound. Yield: 95.68% Purity by HPLC: 99.15%. Purity by chiral HPLC: 99.8%.; EXAMPLE-8: PREPARATION OF (-)-(S)-alpha-ETHYL-2-OXO-1 -PYRROLIDINE ACETAMIDE (FORMULA I) S-aminobutyramide hydrochloride (60 g) and dichloromethane (720 ml) were charged into a clean dry round bottom flask and stirred at a temperature of about -10C for about 10 minutes...
With potassium hydroxide; sodium sulfate; In tert-butyl methyl ether; at 5 - 20℃; for 4h;Product distribution / selectivity; 6.92 g (0.05 M) L-ABA HCL and 10.12 g (0.18 M) ground KOH and 7.53 g (0.053M) of NaS04 are mixed vigorously in 62 ml methyl tert butyl ether (MTBE). The temperature is kept at 5 degrees C. A solution of 7.75 g (0.05 M) of 4- chlorobutyryl chloride (CBC) is added drop-wise. After 3 hours, the mixture is allowed to return to room temperature during 1 hour. The reaction mix is filtered and the solid is washed with a total of 87 ml MTBE to give a crude solid 6.5 g containing levetiracetam having a purity of 76% as per HPLC.
27.7 g (0.2 M) ABA HC1 is added to 80 g (0.56 M) powdered K2CO3 IN 500 ML ACN and the mixture is stirred at room temperature for 30 minutes and then cooled to about 0 degrees Celcius. A solution of 4-chlorobutyryl chloride, 31 g (0.22 M) in 100 ml of ACN is added to the mixture over a period of about 1 hour while the temperature is kept at between about 0-3 degrees Celcius. The reaction mixture is brought to room temperature and stirred for 2 hours. The temperature of the reaction mixture is raised to 30 degrees Celcius and 8.4 g (0.21 M) sodium hydroxide is added. After 90 minutes, another charge of 8.4 g sodium hydroxide is introduced and the mixture is stirred at 30 degrees Celcius for another 150 minutes. The suspension is filtered and the solid is washed with 0.25 liters of ACN. The filtrate and washes are combined and evaporated in vacuo to a solid which is crystallized from about 80 ml of hot ACN leading to a crude 26 g Levetiracetam (77 % purity). Recrystallization of the crude levetiracetam from 170 ml hot ethylacetate gives 23.5 g of the final product.
115.3 g With potassium hydroxide; In dichloromethane; at 0 - 20℃; for 5h;Inert atmosphere; Under nitrogen, 100 g of (S) -2-amino-butyramide hydrochloride was added to 860 ml of dichloromethane at room temperature,Stirring and cooling to 0 C, adding powdered potassium hydroxide 162.3g, followed by adding 10g of polyethylene glycol 400 dissolved in 145ml of methylene chloride solution, with vigorous stirring,A solution of 111.4 g of 4-chlorobutyryl chloride in 145 ml of methylene chloride was added dropwise at 0 C,After 5 hours of reaction, 42.8 g of powdered potassium hydroxide was further added,After two hours filtration, the filtrate was evaporated under reduced pressure, the residue 135.7g dissolved in 185ml of toluene,And hold for 45 minutes, filter the resulting mixture, evaporate the filtrate under reduced pressure,getLevetiracetamCrude 115.3 g, yield 94%.

  • 16
  • [ 102767-31-7 ]
  • [ 102767-28-2 ]
YieldReaction ConditionsOperation in experiment
78.9% With potassium tert-butylate; In tetrahydrofuran; at 0 - 5℃; In a 1 L reaction flask, 600 mL of tetrahydrofuran was added.(S)-2-(4-Chlorobutyramide) butanamide (50.0 g, 241.9 mmol) was added with stirring.After stirring and dissolving, the system is cooled to 0 to 5 C;Potassium tert-butoxide (67.9 g, 605.1 mmol) was added in portions, and stirring was continued for 3 to 4 hours at 0 to 5 C; the reaction of the starting material was detected by TLC dot plate (developing solvent: ethyl acetate: glacial acetic acid = 100:1).The pH of the system was adjusted to 6-7 with 4N hydrochloric acid; after concentration and removal of tetrahydrofuran under reduced pressure,Add 500 mL of dichloromethane and 150 mL of purified water, and extract by liquid separation.The aqueous phase was extracted with more than 200 mL of dichloromethane;Concentration by filtration; the obtained crude product was recrystallized from a mixed solvent (ethyl acetate / methyl tert-butyl ether) to afford 32.5 g of pure Levetiracetam.The yield is 78.9%.The optical purity was 99.9%.
76.4% With potassium hydroxide; at 20 - 25℃; for 2.5h; Add potassium hydroxide 60 g (1.07 mol), the reaction 2 hours, warmed to 20 ~ 25 , the reaction was stirred for 30min,Filtration, the filtrate was concentrated to dryness under reduced pressure, 45L ethyl acetate was added, stirred for 4 hours, filtered, washed with ethyl acetate, dried under vacuumDry, levetiracetam about 130 grams, the reaction yield of about 76.4%, purity of 99.8%, unknown less than 0.05% less than a single hybrid
With potassium hydroxide; potassium iodide; In tert-butyl methyl ether; at 20℃; for 4h;Product distribution / selectivity; 6.2 g (0.03 M) of CBA 2.5 g of ground KOH and 0.33 g (0.002 M) KI catalyst are stirred in MTBE vigorously at room temperature. After 4 hours, the mixture is filtered and the solid is washed twice with hot ethyl acetate. HPLC of the crude mixture indicates a purity of 95.9 % of levetiracetam.
With potassium hydroxide; In tert-butyl methyl ether; at 20℃; for 4h;Product distribution / selectivity; 6.2 g (0.03 M) of CBA 2.5 g of ground KOH are stirred vigorously at room temperature in MTBE. After 4 hours, the reaction mixture is filtered and the solid is washed twice with hot ethyl acetate. HPLC of the crude mix indicates 88.6 % levetiracetam.

  • 17
  • [ 332-77-4 ]
  • [ 7324-11-0 ]
  • [ 102767-28-2 ]
YieldReaction ConditionsOperation in experiment
13% (2S)-2-AMINOBUTYRAMIDE free base (2G) is dissolved in water (80 ml) and 2,5- DIMETHOXY-2,5-DIHYDRO FURAN IS ADDED (2. 4ML, 1 EQ. ). AQUEOUS HC1 (2.4 ML, 1.5 EQ. ) IS added at room temperature and the reaction mixture is stirred for 1.5 hours. Sodium carbonate is then added until the pH of the mixture reaches 8-9. Then, a Pd/C (5%) catalyst in a mixture of water and ethanol (20 ml) is added together with Ha and maintained during 35 minutes. The solution is cooled between 15 C and 25 C and filtered to remove the catalyst. Ethanol is removed under vacuum and the desired compound extracted with ethyl acetate; the organic solution is then washed with brine, dried over magnesium sulfate and evaporated to give (S)-(-)-A-ETHYL-2-OXO-1-PYRROLIDINE ACETAMIDE (Yield: 13%).
  • 18
  • (S)-N-[(1,1-diethylamino)methyl]-α-ethyl-2-oxo-1-pyrrolidineacetamide L-(+)-tartrate [ No CAS ]
  • [ 102767-28-2 ]
YieldReaction ConditionsOperation in experiment
With N-butylamine; In methanol; water; at 25℃; for 6 - 7h;Product distribution / selectivity; Preparation of levetiracetam by deaminomethylation of a free amine. 0.1 g of (S)-N-[(1,1-diethylamino)methyl]-alpha-ethyl-2-oxo-1-pyrrolidineacetamide L-(+)-tartrate (1:1) were suspended in 2.5 ml of a MeOH/H2O (1:4) mixture. Then 116 muL of butylamine were added and the resulting solution was maintained under agitation at room temperature for 6 hours. Then the reaction mixture was concentrated to dryness and subsequently recrystallized from methanol, obtaining similar results as those in Example 8. 5.0 g of (S)-N-[(1,1-diethylamino)methyl]-alpha-ethyl-2-oxo-1-pyrrolidineacetamide L-(+)-tartrate (1:1) were suspended in 21 ml of a MeOH/H2O (1:1) mixture. 3.6 ml of butylamine were added and the resulting mixture was maintained under stirring at room temperature for 7 hours. Then it was concentrated to dryness. The resulting crude product (8.6 g) was dissolved in 34 ml of dichloromethane, 8.6 ml of saturated sodium chloride solution and 8.6 ml of water. The phases were separated and the aqueous phase was extracted with dichloromethane (6 time26 ml). The pooled organic phases were dried over Na2SO4 and finally concentrated to dryness. 2.68 g of a crude product were obtained which was recrystallised twice from methanol, the first time with 2 ml of methanol and the second time with 1 ml of methanol, obtaining 0.76 g of the compound indicated in the example title, characterised by the following analytical data: chemical purity: >99% area/area and (e.e.) >99.8%, both determined by means of HPLC analysis with a chiral column (Chiralcel OD, hexane/isopropanol, 220 nm); [?]23D= -89.8 (c= 1.00 in acetone).
With hydrogenchloride; water; In methanol; for 12h;Heating / reflux;Product distribution / selectivity; 5.0 g of (S)-N-[(1,1-diethylamino)methyl]-?-ethyl-2-oxo-1-pyrrolidineacetamide L-(+)-tartrate (1:1) were suspended in 6.2 ml of methanol and 57 ml of a 1% hydrochloric acid aqueous solution. The resulting mixture was maintained under reflux for 12 hours. Then it was concentrated to dryness. The resulting crude product (9.86 g) was dissolved in 25 ml of dichloromethane and 10 ml of saturated sodium chloride solution. The phases were separated and the aqueous phase was extracted with dichloromethane (6 time15 ml). The pooled organic phases were dried over Na2SO4 and finally concentrated to dryness. 1.91 g of a solid were obtained which, after successively recrystallising it from methanol, gave similar results as in the previous example.
YieldReaction ConditionsOperation in experiment
85.5% In ethyl acetate; at 20 - 75℃; for 3 - 4h;Purification / work up; Example: lOOg of Levetiracetam was added to 2.2L of ethyl acetate at ambient temperature. The mixture was heated to about 75C, stirred and cooled gradually over a period of 3 - 4 hours.Levetiracetam was allowed to crystallize and the crystals were filtered and washed with chilled (0 - 5C) ethyl acetate. The crystals were dried under vacuum at 40 - 50C. (Yield =85.5%)
80% In water; ethyl acetate; at 50 - 55℃;Purification / work up; Example 1: Preparation of Pure LevetiracetamCrude Levetiracetam (15 g), ethyl acetate (150 mL) and water (2.5 mL) were taken in a reaction vessel and heated the reaction mass to 50 0C to 550C to get a clear solution.The clear solution was filtered through hi-flow bed and collected the clear filtrate into reaction vessel and concentrated the reaction mass till reaction mass attained 4 to 5 volumes. The concentrated mass was cooled 200C to 250C, filtered the product, washed with ethyl acetate (15 ml) and dried the material under vaccum to get the highly pure Levetiracetam. The yield of the Levetiracetam was found 12 g (w/w 80%) and the chromatographic purity was 99.98 %.
41% (b) Preparation of (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide 54 g of the crude product obtained in (a) above are dissolved in 125 ml of toluene in the presence of 2 g of 2-hydroxypyridine. The mixture is heated at 110 C. for 12 hours. The insoluble matter is filtered off hot and the filtrate is then evaporated under reduced pressure. The residue is purified by chromatography on a column of 1.1 kg of silica (column diameter: 5 cm; eluent: a mixture of ethyl acetate, methanol and concentrated ammonia solution in a proportion by volume of 85:12:3). The product isolated is recrystallized from 50 ml of ethyl acetate to obtain 17.5 g of (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide. Melting point: 117 C. [alpha]D25: -90.0 (c=1, acetone). Yield: 41%.
Purification of (S)-alpha-ethyl-2-oxo-1-pyrrolidine acetamide (Levetiracetam): Levetiracetam obtained by asymmetric hydrogenation as described above (5 g, 98% e.e.) was recrystallized from acetone (30 ml, 6 vol) as above to yield a white crystalline solid (3.94 g, 81%, >99.8% e.e., 52 ppm Rh). This material (3 g) was recrystalilsed again as above to afford a white crystalline solid (2.31 g, 77%, >99.8%e.e., 23 ppm Rh). m.p. 118.4-119.9 C.

YieldReaction ConditionsOperation in experiment
Hydrogenation at Atmospheric Pressure of H2 A dry 100 ml Schlenk tube fitted with a magnetic stirrer bar was charged with the substrate (500 mg, 3 mmol) and purged with argon gas. Degassed solvent was added via a syringe followed by addition of a catalyst solution (0.5 to 2.5 mol %). The reaction mixture was degassed (3* vacuum/argon) and then purged with hydrogen (5* vacuum/hydrogen) using hydrogen balloon. The reaction was stirred for 16-65 hrs at ambient temperature. The hydrogen atmosphere was exchanged with nitrogen and the solvent was evaporated in vacuo to afford a crude product, which was analyzed by NMR spectroscopic analysis and chiral HPLC analysis. Hydrogenation occurred at a pressure of 4 atm. All manipulations were carried out in an AtmosBagrm (Aldrich Chemical Co.) under an argon atmosphere. The substrate (500-10000 mg,) was placed in stainless steel high pressure vessel (Vinci Technologies Ltd, France) fitted with a teflon beaker (or glass dish) and a teflon coated magnetic stirrer bar. Degassed solvent and a catalyst or a catalyst solution (0.25 to 2.5 mol %) was added. The vessel was sealed and purged with hydrogen by pressurising the vessel to 4.5-5.5 atm and then releasing the pressure (5 times). Finally, the pressure was adjusted to the desired level and the reaction mixture was stirred at ambient temperature for 16-65 hrs. Upon completion the hydrogen atmosphere was exchanged with nitrogen and the solvent was evaporated in vacuo to afford a crude product, which was analyzed by NMR spectroscopic analysis and chiral HPLC analysis. Purification of final material: Purification of (S)-alpha-ethyl-2-oxo-1-pyrrolidine acetamide (Levetiracetam). Levetiracetam obtained by asymmetric hydrogenation as described above (5 g, 98% e.e.) was dissolved in water (20 ml, 4 vol) and extracted with ethyl acetate (3*10 ml, 3*2 vol). The organic phase was then back extracted with water (10 ml, 2 vol) and the aqueous phase evaporated to afford a pale yellow solid (4.83 g, 80%).
  • 21
  • C9H15NO5S [ No CAS ]
  • [ 102767-28-2 ]
YieldReaction ConditionsOperation in experiment
With ammonia; In dichloromethane; for 2h; EXAMPLE 1; Preparation of (
  • 22
  • [ 541-41-3 ]
  • [ 102849-49-0 ]
  • [ 102767-28-2 ]
YieldReaction ConditionsOperation in experiment
72.3% With ammonia; triethylamine; In molecular sieve; dichloromethane; ethyl acetate; toluene; (c) Preparation of (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide 34.2 g (0.2 mole) of (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetic acid are suspended in 225 ml of dichloromethane cooled to -30 C. 24.3 g (0.24 mole) of triethylamine are added dropwise over 15 minutes. The reaction mixture is then cooled to -40 C. and 24.3 g (0.224 mole) of ethyl chloroformate are added over 12 minutes. Thereafter, a stream of ammonia is passed through the mixture for 41/2 hours. The reaction mixture is then allowed to return to ambient temperature and the ammonium salts formed are removed by filtration and washed with dichloromethane. The solvent is distilled off under reduced pressure. The solid residue thus obtained is dispersed in 55 ml toluene and the dispersion is stirred for 30 minutes and then filtered. The product is recrystallized from 280 ml of ethyl acetate in the presence of 9 g of 0,4 nm molecular sieve in powder form. 24.6 g of (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide are obtained. Melting point: 115-118 C. [alpha]D25 =-89.7 (c=1, acetone). Yield: 72.3%. Analysis for C8 H14 N2 O2 in %: calculated: C, 56.45; H, 8.29; N, 16.46; found: C, 56.71; H, 8.22; N, 16.48.
  • 23
  • ethyl (S)-4-[[1-(aminocarbonyl)propyl]amino]butyrate [ No CAS ]
  • levetiracetam [ No CAS ]
  • [ 102767-28-2 ]
YieldReaction ConditionsOperation in experiment
With 2-hydroxypyridin; In toluene; at 92℃; for 17h;Product distribution / selectivity; 10.2. Synthesis of (S)-2-(2-oxopyrrolidin-1-yl)butyramide [Show Image] To the crude methyl-(S)-4-(1-carbamoylpropylamino)butyrate (VIg) in toluene (25 ml) is added hydroxypyrridine (0.7 g, 30 mol%). The mixture is heated to 92C until complete conversion. After 17 hours the mixture is concentrated to dryness to yield (S)-2-(2-oxopyrrolidin-1-yl)butyramide. GC: 100% conversion Chiral HPLC: 79.0%(S)/21.0% (R)
  • 24
  • [ 944582-09-6 ]
  • levetiracetam [ No CAS ]
  • [ 102767-28-2 ]
YieldReaction ConditionsOperation in experiment
With 2-hydroxypyridin; In toluene; at 80℃; for 24h;Product distribution / selectivity; 8.2. Synthesis of (R)-2-(2-oxopyrrolidin-1-yl) [Show Image] Crude methyl-(R)-4-(1-carbamoylpropylamino)butyrate (VIe) is dissolved in 10 ml of toluene and 2-hydroxypyrridine (14 mg, 10 mol%) is added. The mixture is stirred for 24 hours at 80C and then concentrated to dryness to result in 0.621 g of an oil. GC assay showed 40.2 %, which corresponds to 0.248 g of (R)-2-(2-oxopyrrolidin-1-yl)butyramide (1.45 mmol, 97%). Chiral HPLC: 12.7% (S)/87.3% (R)
  • 25
  • [ 941289-97-0 ]
  • [ 102767-28-2 ]
YieldReaction ConditionsOperation in experiment
100% With water; sodium chloride; In N,N-dimethyl-formamide; at 130 - 140℃; for 18h;Product distribution / selectivity; Example 4-Decarbalkoxylation of 1-((SVl -Carbamoyl-propyl V2-oxo-pyrrolidine-3- carboxylic acid methyl ester (compound of formula (Ic) wherein R^ is methyl); A mixture of compound of formula (Ic) wherein R^ is methyl (100 mg, 0.44 mmol), dimethylformamide (3 mL), H2O (15 drops) and NaCl (10 mg) is heated at 130-140C for 18 hours. The resulting mixture is diluted with saturated ammonium chloride (5 mL) and <n="18"/>extracted with isopropyl acetate (2x10 mL). The combined organic extracts are dried over anhydrous MgSO4, filtered and concentrated to give 75 mg (0.44 mmol, 100 %) of levetiracetam.1H NMR (400 MHz, CDCl3): delta = 6.28 (s, broad, IH); 5.50 (s, broad, IH); 4.46 (dd,J = 8.8, J = 7.1, IH); 3.43 (m, 2H); 2.44 (m, 2H); 2.10-1.92 (m, 3H); 1.71 (m, IH); 0.92 (t, J = 7.5, 3H).HPLC (method 90/10) : Retention time = 3.03 min (100%). Chiral HPLC : Retention time = 6.24 min (100%) MS (APCI) : 171 MH+
52% In 4-methyl-2-pentanone; at 115 - 120℃; for 12h;Product distribution / selectivity; Example 3 -Decarboxylation of l-((S)-l-Carbamoyl-propyl)-2-oxo-pyrrolidine-3- carboxylic acid (Ih); A suspension of compound of formula (Ih) (1.40 g, 6.5 mmol) in MIBK (10 mL) is heated at 115-12O0C for 12 hours. The resulting solution is concentrated and the crude product is recrystallised in 4 volumes of toluene: acetone (1: 1) to give 0.42 g of levetiracetam (2.5 mmol, 52 %).1H NMR (400 MHz, CDCl3): delta = 6.28 (s, broad, IH); 5.50 (s, broad, IH); 4.46 (dd, J = 8.8, J = 7.1, IH); 3.43 (m, 2H); 2.44 (m, 2H); 2.10-1.92 (m, 3H); 1.71 (m, IH); 0.92 (t, J = 7.5, 3H).HPLC (method 90/10) : Retention time = 3.03 min (100%). Chiral HPLC : Retention time = 6.24 min (100%) MS (APCI) : 171 MH+
  • 26
  • [ 429673-91-6 ]
  • [ 102767-28-2 ]
YieldReaction ConditionsOperation in experiment
7.2. Synthesis of levetiracetam [Show Image] Hydrochloride salt of methyl-4-(1-carbamoylpropylamino)butyrate (VId) (0.7 g, 2.9 mmol) is dissolved in a mixture of tetrahydrofuran (10 ml) and triethylamine (0.6 g, 2 equiv.). The suspension is filtered and filtrates are concentrated to dryness to afford an oil. The resulting residue is dissolved in toluene (15 ml) and 2-hydroxypyridine (53 mg, 0.56 mmol, 20 mol%) is added. The mixture is heated to 80C until complete conversion. After 3 days (GC: 100% conversion) the mixture is concentrated to dryness under reduced pressure. GC: retention time = 9.40 min (100%) Chiral HPLC: 98.6%(S)/1.4% (R)
  • 27
  • [ 1034332-19-8 ]
  • [ 102767-28-2 ]
YieldReaction ConditionsOperation in experiment
With ammonia; In dichloromethane; at -10℃; for 3h;Product distribution / selectivity; EXAMPLE 3: PREPARATION OF (S)-alpha-ETHYL-2-OXO PYRROLIDINE ACETIC ACID (FORMULA II)Potassium hydroxide (10 g) was dissolved into water (180 ml) and cooled to a temperature of about 1 O0C. Tetra-n-butyl ammonium bromide (2 g) and (S)- alpha-ethyl-2-oxo pyrrolidine ethanol (10 g) in methylene chloride (18 ml) were charged followed by stirring for about 10 minutes. Potassium permanganate (15 g) was charged followed by stirring at a temperature of about 300C for about 8 hours. The resultant reaction mixture was filtered through a celite bed and the celite was washed with water (100 ml) followed by separation of organic and aqueous layers. The separated aqueous layer was charged into a clean and dry round bottom flask followed by cooling to about 0C. pH of the reaction solution was adjusted to about 3 by the addition of hydrochloric acid (2 ml) followed by stirring for about 5 minutes. To the resultant reaction mixture sodium phosphate (25 g) was added followed by stirring for about 10 minutes. Toluene (150 ml) was added into the reaction solution and about 50% of the solvent was distilled off. The resultant reaction solution was extracted with dichloromethane (5*50 ml) followed by separation of organic and aqueous layers. The organic layer was dried over anhydrous sodium sulphate (10 g). Organic layer was distilled completely at a <n="16"/>temperature of about 300C under vacuum to obtain the title compound as a residue.To the residue toluene (10 ml) was added and stirred at 0C for about 30 minutes. The separated solid was filtered and the solid was washed with toluene (5 ml). The obtained solid was dried at a temperature of about 600C under vacuum for about 1 hour to afford the pure 5 3 fj ?f title compound.Purity by HPLC: 97%.
  • 28
  • (S)-(+)-amino butynamide tartarate [ No CAS ]
  • [ 4635-59-0 ]
  • [ 102767-28-2 ]
YieldReaction ConditionsOperation in experiment
67% 33.8 g of anhydrous Na2SO4 is added to suspension of 50 g of (S)-amino butynamide tartarate salt in 1 liter of Acetonitrile. The mixture is cooled to 0-5 C, 82 g of potassium carbonate is added to it. A solution of (30.7 g) of 4-chloro butyryl chloride in 90 ml acetonitrle is added dropwise at 00C with vigorous stirring. After the addition, the reaction mixture is allowed to return to 25 C. After 5 hours' cool the reaction mixture, 38.8 g powdered potassium hydroxide is added at 0-50C. The reaction mixture was stirred for further 10 lirs, filtered and filtrate evaporated under reduce pressure. The residue (28 g, 90% pure) is dissolved in 130 ml of Acetone and heated to reflux temperature and filtered hot. After cooling the filtrate, the desired product crystallizes to give 22.6 g of (S)-alpha-ethyl-2-oxo- 1 -pyrrolidineacetamide. Melting point : 115-117C ; [alpha]25D -88 (C=I, acetone), Yield : 67%
  • 29
  • [ 616-45-5 ]
  • (R)-2-bromobutyramide [ No CAS ]
  • levetiracetam [ No CAS ]
  • [ 102767-28-2 ]
YieldReaction ConditionsOperation in experiment
Example 2-Synthesis of levetiracetam [Show Image] To a solution of pyrrolidine-2-one (85 mg, 1 mmol) in 6 ml of toluene is added sodium methoxide (0.19 ml of a 30% solution in MeOH, 1 mmol, 1 equiv.). The mixture is heated to 40C and concentrated to dryness under reduced pressure. The solid residue is taken up in 3 ml of tetrahydrofuran, cooled to 0C and (R)-2-bromobutyramide (IId) (optical purity >98%) (166 mg, 1 mmol, 1 equiv.) is added. The mixture is stirred for 1h at 0C and further 16h at room temperature. The mixture is then concentrated to dryness under reduce pressure. GC: 40.3% conversion Chiral HPLC: 51.0%(S)/49.0% (R)
  • 30
  • [ 79-37-8 ]
  • [ 1345092-28-5 ]
  • [ 102767-28-2 ]
  • [ 1345092-06-9 ]
YieldReaction ConditionsOperation in experiment
30.6% Example 30 (Z)-4-((1-(nitrooxy)ethoxy)carbonyloxy)but-2-enyl (S)-2-(2-oxopyrrolidin-1-yl)butanoylcarbamate [NO-<strong>[102767-28-2]Levetiracetam</strong> (I-AD3-L2-R1)] This compound was synthesized as shown in Scheme 8 and the experimental procedure is described below: Oxalyl chloride (1.2 mL, 14.0 mmol) was added to a solution of <strong>[102767-28-2](S)-2-(2-oxopyrrolidin-1-yl)butanamide</strong> (AD3, <strong>[102767-28-2]levetiracetam</strong>, 2.0 g, 11.7 mmol) in 10 mL of 3:1 mixture of DCE/DCM and the mixture was refluxed for 8 h to yield the corresponding isocyanate AD3-IM1. To this cooled and stirred mixture was added drop-wise a solution of (Z)-4-hydroxybut-2-enyl 1-(nitrooxy)ethyl carbonate (HO-L2-R1, 2.5 g, 11.7 mmol, freshly prepared as described in Example 4) in 10 mL of DCM over 5 minutes and the mixture was stirred at RT for 12 h when TLC analysis of the mixture showed completion of the reaction. The mixture was concentrated to give a residue which was purified by column chromatography (silica gel 150-300 mesh, eluted with 40% EtOAc in petroleum ether) to afford the title compound (I-AD3-L2-R1) as yellow oil. Yield: 1.5 g (30.6%); 1H NMR (CDCl3, 300 MHz): delta 0.90 (t, J=7.2 Hz, 2.25H), 0.94 (t, J=7.2 Hz, 0.75H), 1.61 (d, J=5.4 Hz, 3H), 1.80-2.15 (m, 4H), 2.38-2.50 (m, 2H), 3.03-3.15 (m, 0.75H), 3.31-3.41 (m, 0.25H), 3.48-3.58 (m, 0.25H), 3.64-3.77 (m, 0.75H), 4.09 (m, 1H), 4.68-4.76 (m, 2H), 4.78-4.86 (m, 2H), 5.73-5.92 (m, 2H), 6.94 (q, J=5.4 Hz, 5.7 Hz, 1H), 8.04 (br s, 1H); MS m/z: 440.1 [M+Na]+.
  • 31
  • [ 118-92-3 ]
  • [ 102767-28-2 ]
  • C15H19N3O3 [ No CAS ]
  • 32
  • [ 10449-07-7 ]
  • [ 102767-28-2 ]
  • C14H19ClN4O [ No CAS ]
  • 34
  • C11H17NO5 [ No CAS ]
  • [ 102767-28-2 ]
YieldReaction ConditionsOperation in experiment
0.56 g With ammonium hydroxide; In tetrahydrofuran; water; at 0 - 20℃; for 16h;Inert atmosphere; To a solution of acid (S)-8 (0.70 g, 4.1 mmol) and triethylamine (0.7 mL, 4.9 mmol) in dry THF (10 mL) was added ethyl chloroformate (0.4 mL, 4.5 mmol) at 0 C under an argon atmosphere. After 1 h, ammonium hydroxide (25% w/v aqueous solution, 2.8 mL, 20.4 mmol) was added and the mixture was stirred at ambient temperature for another 16 h. After completion of the reaction, potassium carbonate (0.8 g, 6 mmol) was added and the reaction mixture was filtered, and washed with ethyl acetate. The solvent was removed under reduced pressure and the crude product was subjected to column chromatography (silica gel, dichloromethane/methanol, 95:5) to yield 1 as a pale yellow solid (0.56 g, 80%); ee >99% [The ee was determined by chiral HPLC analysis: DAICEL CHIRALCEL OD-H (250 × 4.6 mm) column; eluent: hexane/isopropanol = 90/10; flow rate: 0.5 mL/min; detector 210 nm [(R) isomer tR = 33.30 min; (S) isomer tR = 46.71 min]; mp = 116-17 C {lit.6f mp = 115-117 C}; [alpha]D25=-91.5 (c 1, acetone) {lit.6f [alpha]D25=-90.5 (c 0.99, acetone)}; IR (CHCl3): 3409, 3019, 1670, 1523, 1422, 1215, 1045, 757 cm-1; 1H NMR (200 MHz, CDCl3): deltaH = 0.90 (t, J = 7.4 Hz, 3H), 1.60-1.79 (m, 1H), 1.85-2.14 (m, 3H), 2.38-2.47 (m, 2H), 3.33-3.52 (m, 2H), 4.42-4.50 (dd, J = 8.9, 6.7 Hz, 1H), 5.77 (br s, 1H), 6.47 (br s, 1H); 13C NMR (50 MHz, CDCl3): deltaC = 176.0 (CO), 172.5 (CO), 55.9 (CH), 43.7 (CH2), 30.9 (CH2), 21.1 (CH2), 18.0 (CH2), 10.4 (CH3); MS: m/z 171 [M+1]+, 193 [M+Na]+.
  • 35
  • [ 102767-28-2 ]
  • (S)-2-((2-hydroxyethyl)disulfanyl)ethyl(2-(2-oxopyrrolidin-1-yl)butanoyl)carbamate [ No CAS ]
  • 36
  • [ 102767-28-2 ]
  • (S)-2-((2-((nicotinoylcarbamoyl)oxy)ethyl)disulfanyl)ethyl(2-(2-oxopyrrolidin-1-yl)butanoyl)carbamate [ No CAS ]
  • 37
  • [ 102767-28-2 ]
  • C25H41N3O8S2 [ No CAS ]
  • 38
  • [ 102767-28-2 ]
  • 2-((2-((((S)-2-(2-oxopyrrolidin-1-yl)butanoyl)carbamoyl)oxy)ethyl)disulfanyl)ethyl 2-(4-isobutylphenyl)propanoate [ No CAS ]
  • 39
  • [ 79-37-8 ]
  • [ 102767-28-2 ]
  • C9H12N2O3 [ No CAS ]
YieldReaction ConditionsOperation in experiment
In 1,2-dichloro-ethane; at 5℃; for 16h;Reflux; General procedure: To a solution of Drug-2 (1.00mmol) in 1,2-dichloroethane (DCE) (5 mL) at 5 oC was added oxalylchloride (1.20 mmol) and the reaction mixture was refluxed for 16 h. The reaction mixture was cooled to roomtemperature and a solution of 15a or 15d (1.00 mmol) in THF (5mL) was added drop-wise. After stirring for 24 h, the reaction mixturewas concentrated and the residue partitioned between EtOAc (30 mL) and water(10 mL). The organic layer was washed with brine (10 mL), dried (Na2SO4),concentrated and purified by silica gel column chromatography to afford thetitle compounds.
  • 41
  • [ 51146-57-7 ]
  • [ 102767-28-2 ]
  • (S-2-(2-oxopyrrolidin-1-yl)butanamide)*(S-ibuprofen) [ No CAS ]
  • 42
  • [ 2174-58-5 ]
  • [ 102767-28-2 ]
  • (S-2-(2-oxopyrrolidin-1-yl)butanamide)*(S-methylsuccinic acid) [ No CAS ]
  • 43
  • [ 3641-51-8 ]
  • [ 102767-28-2 ]
  • (S-2-(2-oxopyrrolidin-1-yl)butanamide)*(R-methylsuccinic acid) [ No CAS ]
  • 44
  • 2-(2-oxo-1-pyrrolidinyl)butanenitrile [ No CAS ]
  • [ 102767-28-2 ]
  • 46
  • [ 142-61-0 ]
  • [ 102767-28-2 ]
  • (S)-N-(2-(2-oxopyrrolidin-1-yl)butanoyl)hexanamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
21% A suspension of <strong>[102767-28-2](S)-2-(2-oxopyrrolidin-1-yl)butanamide</strong> (2 g, 11.7 mmol) in THF (30 mL) was treated with NaH (1.41 g, 35.2 mmol, 60% in mineral oil) portion-wise at 0 C. The reaction was allowed to warm to room temperature and stirred for a further 30 min. The reaction was treated with hexanoyl chloride (1.94 mL, 14.1 mmol) in THF (10 mL) drop-wise over a period of 5 min. at 0 C. The reaction was allowed to warm to room temperature and stirred overnight (16 h). The reaction was then quenched with H2O (200 mL) and the product was extracted into EtOAc (2*150 mL). The combined organic layer was washed with brine (3*50 mL), dried (Na2SO4) and evaporated under reduced pressure to obtain the crude product. The crude was then purified by column chromatography (EtOAc: Hexanes, 1:1) on silica gel to obtain the title compound 18 (0.65 g, 21%) as a pale yellow oil. 1H NMR (600 MHz, CDCl3) delta 8.85 (s, 1H), 4.55 (dd, J=3, 9 Hz, 1H), 3.42-3.38 (m, 2H), 2.63 (t, J=7.2 Hz, 2H), 2.46-2.42 (m, 2H), 2.07-2.03 (m, 2H), 1.97-1.93 (m, 1H), 1.71-1.59 (m, 3H), 1.30-1.28 (m, 4H), 0.91-0.85 (m, 6H). ESI-MS (m/z, %): 269 (MH+, 100).
  • 47
  • [ 102767-28-2 ]
  • C19H30N2O6S2 [ No CAS ]
  • 48
  • [ 102767-28-2 ]
  • [(5Z,8Z,11Z,14Z,17Z)-2-oxo-2-((S)-2-(2-oxopyrrolidin-1-yl)butanamido)ethyl-icosa-5,8,11,14,17-pentaenoate] [ No CAS ]
  • 49
  • [ 102767-28-2 ]
  • [(4Z,7Z,10Z,13Z,16Z,19Z)-2-oxo-2-((S)-2-(2-oxopyrrolidin-1-yl)butanamido)ethyl-docosa-4,7,10,13,16,19-hexanoate] [ No CAS ]
  • 50
  • [ 50893-53-3 ]
  • [ 102767-28-2 ]
  • C11H17ClN2O4 [ No CAS ]
YieldReaction ConditionsOperation in experiment
With lithium tert-butoxide; In hexane; dichloromethane; acetonitrile; at 0 - 20℃; for 0.666667h; Compound 5 (1 mmol) in 2.5 ml of DCM and 2.5 ml of CH3CN is cooled to 0 C. Lithium t-butoxide (1.0M in hexanes, 1.1 mmol) was added and the mixture was stirred at 0 C. for 15 min and then at room temperature for 10 min. The reaction mixture is re cooled to 0 C. and added 1-chloroethyl chloro formate 6 (1.2 mmol) dropwise. The reaction mixture is stirred at 0 C. for 15 min and then allowed to stir at room temperature overnight. After completion of reaction, the mixture is diluted with DCM and added water and the layers were separated. The organic layer is washed with water and brine, dried over Na2SO4 and concentrated in vacuo. Purification by silica gel chromatography afforded the compound 7.
  • 51
  • [ 79-04-9 ]
  • [ 102767-28-2 ]
  • (S)-N-(2-chloroacetyl)-2-(2-oxopyrrolidin-1-yl)butanamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
In toluene; at 20 - 80℃; for 3.5h;Inert atmosphere; To a stirred solution of <strong>[102767-28-2](S)-2-(2-oxopyrrolidin-1-yl)butanamide</strong> 1 (50 g, 0.293 mol) in toluene (500 mL) was added chloro acetylchloride (35.1 mL, 0.444 mol, 1.5 eq.) drop wise slowly at RT under N2 atmosphere for 30 min. Then heated to 80 C. and maintained for 3 h at the same temperature. After the reaction it was cooled to room temperature, concentrated under reduced pressure to get 30 g (41% yield) of Compound-3 as a gummy material [failed to get pure material via silica-gel column chromatography) (crude compound confirmed by mass analysis). Used in the next step without any further purification; Mass: 247.4 (M++H). TLC system: MeOH: DCM (10:90); Rf value: 0.5
  • 52
  • [ 10199-89-0 ]
  • [ 102767-28-2 ]
  • C14H15N5O5 [ No CAS ]
YieldReaction ConditionsOperation in experiment
In methanol; at 70℃; for 0.333333h;pH 8; General procedure: Appropriate volumes of the final working solutions were transferred into two sets of 10 mL volumetric flasks so that the final concentrations will be within the linearity ranges of 0.15-1.2 mug/mL for TOP and 0.2-1.5 mug/mL for LEV. Volume of 1.5 mL of 0.2 M borate buffer ofpH 8 was added followed by 1 mL of 0.2 % methanolic solution of NBD-Cl. The solutions were heated in a water bath at 70C for 20 min and cooled in ice water bath, after which 1 mL of 0.2 M HCl was added then completed to the mark with acetone.
  • 53
  • (2S,3R)-3-methylsulfonyloxy-2-(2-oxopyrrolidin-1-yl)butanamide [ No CAS ]
  • [ 102767-28-2 ]
YieldReaction ConditionsOperation in experiment
81% With sodium tetrahydroborate; ethanol; for 3h;Reflux; (0.076 mol) of compound (V) was dissolved in 100 ml of ethanol, 3.8 g (0.1 mol) of sodium borohydride solid was added slowly at room temperature, and the mixture was refluxed for 3 h. After completion of the reaction, the solvent was removed under reduced pressure, The organic layer was collected, the combined organic layers were evaporated and the solvent was evaporated to give a yellow solid. Recrystallization from ethyl acetate gave 10.5 g of levetiracetam as a white solid. The yield was 81%. Purity greater than 99.5%.
  • 54
  • (2S,3R)-3-(4-tolyl)sulfonyloxy-2-(2-oxopyrrolidin-1-yl)butanamide [ No CAS ]
  • [ 102767-28-2 ]
YieldReaction ConditionsOperation in experiment
78% With methanol; potassium borohydride; In dichloromethane; for 8h;Reflux; Take compound (V) 30g (0.088mol) (2S,3R)-3-(4-tolyl)sulfonyloxy-2-(2-oxopyrrolidin-1-yl)butanamide was dissolved in a mixed solvent of 100ml of dichloromethane and 100ml of methanol at room temperature potassium borohydride was added slowly with solid 8.1g (0.15mol), heated at reflux for 8h, after completion of the reaction, the solvent recovered under reduced pressure, and extracted twice with dichloromethane, organic layer was collected, combined and evaporated under reduced pressure to give a yellow solid, then Recrystallization from ethyl acetate gave a white solid, 11.7 g of levetiracetam, in 78% yield, with an optical purity of greater than 99.5% by HPLC.
  • 55
  • (2S,3R)-3-hydroxy-2-(4-chlorobutyrylamino)butanamide [ No CAS ]
  • [ 102767-28-2 ]
  • 56
  • (2S,3R)-3-hydroxy-2-(2-oxopyrrolidin-1-yl)butanamide [ No CAS ]
  • [ 102767-28-2 ]
  • 57
  • [ 102767-28-2 ]
  • C8H14N2O2*C8H8O3 [ No CAS ]
  • 58
  • [ 102767-28-2 ]
  • levetiracetam [ No CAS ]
  • 59
  • [ 102767-28-2 ]
  • C5H6O5*C8H14N2O2 [ No CAS ]
  • 60
  • [ 102767-28-2 ]
  • C8H14N2O2*C5H6O5 [ No CAS ]
  • 61
  • [ 328-50-7 ]
  • [ 102767-28-2 ]
  • C5H6O5*C8H14N2O2 [ No CAS ]
  • 62
  • C10H17NO [ No CAS ]
  • [ 102767-28-2 ]
  • 63
  • (S)-N-[1(aminocarbonyl)propyl]-4-bromobutyramide [ No CAS ]
  • [ 102767-28-2 ]
YieldReaction ConditionsOperation in experiment
82% With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; To a 3L three-neck flask was added 390.0 g (1.55 mol) of (S)-N-[1(aminocarbonyl)propyl]-4-bromobutyramide (II).The reaction was stirred at room temperature with N,N-dimethylformamide (400 mL) and potassium carbonate 320.9 g (2.33 mol).TLC test (developer: ethyl acetate/acetone = 3/1), reaction completed,1000 mL of water was added to the reaction solution with stirring.Precipitation of white solids,filter,The filter cake is rinsed with water.The solid was dried to give 236.1 g of crude product and 236.1 g of crude levetiracetam was added to a 1 L reactor.Water/acetone (1/25) 700mL,Heated to dissolve,filter,The filtrate is hot-melted,Stir down to room temperature and crystallize overnight.filter,The solid is washed with acetone,Dry at 45C overnight.It was left with 215.1 g of letrapracetam,Yield 82.0%.
  • 64
  • dehydro levetiracetam [ No CAS ]
  • levetiracetam [ No CAS ]
  • [ 102767-28-2 ]
  • 65
  • dehydro levetiracetam [ No CAS ]
  • [ 102767-28-2 ]
  • 66
  • [ 4897-91-0 ]
  • [ 53726-14-0 ]
  • [ 102767-28-2 ]
YieldReaction ConditionsOperation in experiment
80% With potassium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 50℃; for 36h;Inert atmosphere; To a 1 L three-necked flask, 50 g of L-2-aminobutanamide hydrochloride, 80 g of allyl 4-chlorobutyrate, 150 g of potassium carbonate, 500 mL of DMF, and 5.5 g of potassium iodide were added, and the mixture was heated to 50 C under argon atmosphere. After 36h, TLC monitored the reaction of L-2-aminobutyramide hydrochloride completely, stopped the reaction, filtered, and evaporated the solvent under reduced pressure. The acetone was added to 300 ml, activated carbon 5 g, heated under reflux for 2 h, hot filtered, cooled, at 0- The mixture was incubated at 5 C for 3 h, and filtered to obtain 49 g of levetiracetam. The yield was 80%. The purity of HPLC was 99.9%, the ee value was 99.9%, and the optical rotation []20=-90 (C=1.0, acetone). The content of the impurity 4-(1-carbamoyl-propylamino)-butyric acid allyl ester was
  • 67
  • [ 3153-34-2 ]
  • [ 53726-14-0 ]
  • [ 102767-28-2 ]
YieldReaction ConditionsOperation in experiment
83% With sodium carbonate; sodium iodide; In N,N-dimethyl-formamide; at 110℃; for 12h;Inert atmosphere; To a 1 L three-necked flask, 50 g of L-2-aminobutanamide hydrochloride, 70 g of isopropyl 4-chlorobutyrate, 95 g of sodium carbonate, 600 mL of DMF, and 5.5 g of sodium iodide were heated to 90 C under argon atmosphere. After 24 h of reaction, the temperature was raised to 110 C, and the reaction was carried out for 12 h. The reaction of L-2-aminobutanamide hydrochloride was completely monitored by TLC, the reaction was stopped, filtered, and the solvent was evaporated to dryness under reduced pressure. Heated under reflux for 2 h, filtered hot, cooled, incubated at 0-5 C for 3 h, filtered to obtain 51 g of levetiracetam, yield 83%, HPLC purity 99.8%, ee value 99.9%, optical rotation [] 20 = -90 (C = 1.0, acetone). The impurity 4-(1-carbamoyl-propylamino)-butyric acid isopropyl ester content was
  • 68
  • [ 3153-33-1 ]
  • [ 53726-14-0 ]
  • [ 102767-28-2 ]
YieldReaction ConditionsOperation in experiment
85% With triethylamine; sodium iodide; In isopropyl alcohol; at 90℃; for 36h;Inert atmosphere; To a 1 L three-necked flask, 50 g of L-2-aminobutanamide hydrochloride, 85 g of 4-chlorobutyrate, 109.8 g of triethylamine, 500 mL of isopropyl alcohol, and 5.5 g of sodium iodide were added, and heated under argon atmosphere. After reacting at 90 C for 36 h, the reaction of L-2-aminobutanamide hydrochloride was completely monitored by TLC, the reaction was stopped, filtered, and the solvent was evaporated to dryness under reduced pressure, ethyl acetate (300 ml), activated carbon (5 g), and heated to reflux for 2 h. Filtration, cooling, incubation at 0-5 C for 2 h, filtration to obtain 52 grams of levetiracetam, yield 85%, HPLC purity 99.8%, ee value 99.9%, optical rotation [] 20 = -90 (C = 1.0, acetone). The impurity 4-(1-carbamoyl-propylamino)-butyric acid butyl ester content was
  • 69
  • [ 3153-37-5 ]
  • [ 53726-14-0 ]
  • [ 102767-28-2 ]
YieldReaction ConditionsOperation in experiment
80% With potassium carbonate; potassium iodide; In dimethyl sulfoxide; at 100℃; for 24h;Inert atmosphere; To a 1 L three-necked flask, 50 g of L-2-aminobutanamide hydrochloride, 60 g of methyl 4-chlorobutyrate, 180 g of potassium carbonate, 500 mL of DMSO, and 6 g of potassium iodide were added, and heated to 100 C under argon atmosphere for 24 hours. TLC monitors the reaction of L-2-aminobutanamide hydrochloride completely, stops the reaction, filters, and evaporates the solvent under reduced pressure. The acetone is added with 300 ml, activated carbon 5 g, heated under reflux for 2 h, hot filtered, cooled, at 0-5 Insulation for 2 h under C, filtration to obtain 49 g of levetiracetam, yield 80%, HPLC purity 99.8%, ee value 99.9%, optical rotation [] 20 = -90 (C = 1.0, acetone) . The impurity 4-(1-carbamoyl-propylamino)-butyric acid methyl ester content was
  • 70
  • [ 3153-36-4 ]
  • [ 53726-14-0 ]
  • [ 102767-28-2 ]
YieldReaction ConditionsOperation in experiment
84% With sodium carbonate; sodium iodide; In dimethyl sulfoxide; at 90℃; for 24h;Inert atmosphere; To a 1 L three-necked flask, 50 g of L-2-aminobutanamide hydrochloride, 55 g of ethyl 4-chlorobutyrate, 100 g of sodium carbonate, 600 mL of DMSO, and 5.5 g of sodium iodide were heated, and heated to 90 C under argon atmosphere. After reacting for 24 hours, TLC monitored the reaction of L-2-aminobutanamide hydrochloride completely, stopped the reaction, filtered, and evaporated the solvent under reduced pressure. The solvent was added with acetone 300 ml, activated carbon 5 g, heated under reflux for 2 h, hot filtered, cooled, at 0 Incubate at -5 C for 2 h, filter to obtain 51 g of levetiracetam, yield 84%, HPLC purity 99.8%, ee value 99.9%, optical rotation [] 20 = -90 (C = 1.0, acetone). The content of the ethyl 4-(1-carbamoyl-propylamino)-butyrate impurity was
  • 71
  • C8H15ClN2O2*ClH [ No CAS ]
  • [ 102767-28-2 ]
YieldReaction ConditionsOperation in experiment
80.6% With potassium hydroxide; In dichloromethane; at -5 - 0℃; for 3h;Large scale; To the above reaction system, 17.99 kg (320.7 mol) of KOH (95%) powder (control temperature is about 0 C) was added to the above reaction system for about 1 h. Control the temperature -5 ~ 0 C reaction for 2h,Sampling 1 mL of dichloromethane diluted TLC monitoring (spotting once, developing solvent: ethyl acetate / acetone = 3 / 1, RfI = 0.5, RfII = 0.7), After the reaction,11.28kg of glacial acetic acid was added in three portions (temperature control was around 0 C).22.2 kg of silica gel,Stir for 1h, filter, The filtrate was added with 1.04 kg of glacial acetic acid to adjust the pH to a weak acidity.The filtrate was concentrated under reduced pressure at 35 C.To the residual solid, 14.84 L of ethyl acetate was added and concentrated to dryness, and the solid was added to 7.42 L of ethyl acetate at 25 C for 1 h. filter,3L of ethyl acetate was washed and dried at 45 C to constant weight. levetiracetamcrude 12.7kg, The crude product yield was 70%. Step 5: RefineTo a 100 L reactor, 12500 g of crude levetiracetam and 62.5 L (5 v/w) of acetone were added, and the mixture was heated to reflux until completely dissolved. The filtrate was filtered while hot, and the filtrate was spun at 35 C, and 50 L of acetone/water was added to the solid (20: 1,4v / w) 45 C heating all dissolved, add 625g activated carbon for 1h, hot 0.45mum filter (solvent will volatilize, pressure filtration may lead to a decrease in yieldLow), the filtrate was decanted at -20 C for 16 h, filtered, and placed under reduced pressure at 35 C to dryness to obtain a white crystal of 10 kg.80.6%.
  • 72
  • [ 102767-28-2 ]
  • (levetiracetam)2*magnesium chloride [ No CAS ]
  • 73
  • [ 102767-28-2 ]
  • (levetiracetam)2*calcium chloride [ No CAS ]
  • 74
  • (S,E)-4-chloro-N-(hept-4-en-3-yl)butanamide [ No CAS ]
  • [ 102767-28-2 ]
  • 75
  • (S,E)-1-(hept-4-en-3-yl)pyrrolidin-2-one [ No CAS ]
  • [ 102767-28-2 ]
  • 76
  • [ 86815-10-3 ]
  • [ 102767-28-2 ]
  • 77
  • [ 102916-46-1 ]
  • [ 102767-28-2 ]
  • 78
  • (S)-2-(2-Oxo-pyrrolidin-1-yl)-butyric acid ethyl ester [ No CAS ]
  • [ 102767-28-2 ]
YieldReaction ConditionsOperation in experiment
12.4 g With ammonia; at 0 - 10℃; for 24h; Step 6: Add concentrated ammonia (10mL / g) to the oil in the previous step, reduced to 0-10 for 24h, TLC reaction was complete, after passing nitrogen to remove ammonia, it was concentrated to dryness under vacuum at 50 C.Add acetone (6mL) and ethyl acetate (18mL) and stir at 0-10 C. Precipitate solid, suction filter, wash with a little EA, the product was dried under vacuum at 40 for 8h to obtain the product Levetiracetam. White solid (12.4g, 59%), total yield was 22.2%, ee was 99.98%.
  • 79
  • [ 616-45-5 ]
  • [ 5398-24-3 ]
  • [ 102767-28-2 ]
YieldReaction ConditionsOperation in experiment
91.2% Stage #1: 2-pyrrolidinon With sodium hydroxide In toluene at 20℃; for 1.5h; Stage #2: 2-bromobutyramide With C38H33O8P In toluene for 16h; Reflux; 6 Add 20.0g (0.235mol) of 2-pyrrolidone, 120g of toluene and 10.4g (0.26mol) of sodium hydroxide into a clean reactor. After stirring for 1.5h at room temperature, add 51.5g (0.31 mol) of 2-bromobutanamide and 0.5g of the chiral BINOL-derived phosphoric acid ligand catalyst shown in formula IV, slowly warm up to reflux state, control the temperature under reflux state for holding reaction for 16h, after the reaction, cool down to 40°C , add 50g water, and stir for 5m in, stand for layering, collect the organic layer, wash the organic layer with 50g water to pH=78, extract the aqueous layer with 10g toluene once and collect the organic layer, combine the organic layers, and distill the organic layer under reduced pressure to remove the solvent to dryness Then, add 60g of methanol, heat up to a clear state and slowly cool down to 510°C for 2h to charge the crystals for analysis, filter with suction, and dry to obtain the final product, Levetiracetam, with a dry weight of 36.5g, and a yield of 91.2 %, the chiral purity is 99.0%.
  • 80
  • [ 1571-08-0 ]
  • [ 102767-28-2 ]
  • methyl 4-((2-(2-oxopyrrolidin-1-yl)butanamido)methyl)benzoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
81% With L-Tartaric acid; hydrogen In toluene at 135℃; for 24h; Autoclave; 4.3. General procedure for reductive N-alkylation of amides General procedure: The magnetic stirring bar, 0.5 mmol of amide and 0.5 mmol ofaldehyde were transferred to 8 mL glass vial and then 3 mL solvent(Toluene) was added. Then, 60 mg of catalyst (Ni-TA-MISiO2-800;11 mol% Ni) was added and the vial was fitted with septum, cap andneedle. The reaction vials (8 vials with different substrates at atime) were placed into a 300 mL autoclave. The autoclave wasflushed with hydrogen twice at 20 bar pressure and then it waspressurized with 50 bar hydrogen. The autoclavewas placed into analuminum block preheated at 145 C (placed 30 min beforecounting the reaction time in ordered to attain reaction temperature)and the reactions were stirred for required time. During thereaction the inside temperature of the autoclave was measured to be 135 C and this temperature was used as the reaction temperature.After the completion of the reactions, the autoclave wascooled to room temperature. The remaining hydrogen was dischargedand the vials containing reaction products were removedfrom the autoclave. The solid catalyst was filtered off and washedthoroughly with ethyl acetate. The reaction products were analyzedby GC-MS. The corresponding crude product was purified by flashcolumn chromatography and characterized by NMR and GC-MSanalysis. The yields were determined by GC for the selected compounds:After completion of the reaction, n-hexadecane (100 mL) asstandard was added to the reaction vials and the reaction productswere diluted with ethyl acetate followed by filtration using plug ofsilica and then analyzed by GC.
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