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(S)-(-)-4-Hydroxy-2-pyrrolidinone is a biochemical reagent that can serve as a biological material or organic compound for life science-related research.
Synonyms: (4S)-4-Hydroxy-2-pyrrolidinone
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CAS No. : | 68108-18-9 |
Formula : | C4H7NO2 |
M.W : | 101.10 |
SMILES Code : | O[C@@H]1CNC(=O)C1 |
Synonyms : |
(4S)-4-Hydroxy-2-pyrrolidinone
|
MDL No. : | MFCD00273370 |
InChI Key : | IOGISYQVOGVIEU-VKHMYHEASA-N |
Pubchem ID : | 155084 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H319 |
Precautionary Statements: | P305+P351+P338 |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With 1H-imidazole; In N,N-dimethyl-formamide; at 20℃; for 16h; | Imidazole (93.73 g, 1 .26 mol) and tert-butyldimethylsilyl chloride (145.3 g, 0.96 mol) were added to a solution of (S)-4-hydroxy-2-pyrrolidone (92.8 g, 0.92 mol) in dimethylformaide (560 ml_). The mixture was then stirred at room temperature for 16 hours, after which time it was poured over ice and an aqueous solution of hydrochloric acid (0.2 M, 300 ml_) was added. The mixture was stirred at room temperature for 10 minutes, and then extracted with ethyl acetate (4 x 500 ml_). The combined organic extracts were washed with brine (1000 ml_), dried over sodium sulphate, filtered, and evaporated u n d er red u ced p ressu re to g ive (S )-4-(tert-butyl-dimethyl-silanyloxy)- pyrrolidin-2-one as a solid (200 g, 100%). |
97.4% | With 1H-imidazole; In N,N-dimethyl-formamide; at 20℃; for 6h; | (17 g, 100 mmol) of (S) -4-hydroxy-2-oxopyrrolidine and 17 g (250 mmol) of imidazole were dissolved in 120 ml of DMF,A DMF solution of tert-butyldimethylchlorosilane (18.1 g of t-butyldimethylchlorosilane, 120 mmol) At room temperature for 6 hours,The reaction solution was poured into ice water, extracted three times with ethyl acetate, washed three times with saturated brine,Concentrated under reduced pressure, and recrystallized from diethyl ether to give 20.98 g of the compound represented by the formula III protected by t-butyldimethylsilane in a yield of 97.4%. |
97.1% | With 1H-imidazole; In N,N-dimethyl-formamide; at 20℃; for 6.5h; | (S)-4-hydroxy-2-oxo-pyrrolidine 10.1 g (100 mmol), imidazole 13.6g (200mmol) was dissolved in 100ml DMF, followed by the dropwise addition of t-butyldimethylchlorosilane in DMF (Containing tert-butyldimethylchlorosilane 18.1 g, 120 mmol) at room temperature for 6.5 hours. The reaction solution was poured into ice water, Ethyl acetate was extracted three times, washed with saturated brine three times, concentrated under reduced pressure and recrystallized from diethyl ether to give 20.9 g of the compound represented by the formula III protected by t-butyldimethylsilane in a yield of 97.1%. |
92% | With 1H-imidazole; In N,N-dimethyl-formamide; at 0 - 20℃; for 12h; | To a solution of ()-4-hydroxypyrrolidin-2-one (cas: 68108-18-9, 5.0 g, 49.5 mmol) in DMF (20 mL) at 0- 5 C was added /cvV-butyl chi orodi m ethyl si 1 an e (8.9 g, 1.2 equiv.) and imidazole (8.4 g, 2.5 equiv.). The reaction mixture was allowed to warm to ambient temperature and stirred for 12 hours. Water (50 mL) was then added and the reaction mixture was stirred for 10 minutes. The white precipitate that was formed was filtered and washed with water (15 mL) and then dried under high vacuum to afford 1-258 (9.8 g, 92% yield). MS (ESI, pos. ion) m/z: 2l6. l(M+l). |
With 1H-imidazole; In N,N-dimethyl-formamide; at 20℃; | 1.02 g of imidazole and 1.58 g of t-butyldimethylchlorosilane were added to a dimethylformamide (5 ml) solution of 1.01 g of (S)-4-hydroxy-2-pyrrolidone, and stirred overnight at room temperature. Water was added to the reaction liquid, and stirred with cooling with ice. The precipitated crystal was taken out through filtration and dried to obtain 2.07 g of the entitled compound as a colorless crystal. | |
With 1H-imidazole; In N,N-dimethyl-formamide; at 0 - 20℃; for 21h; | (S)-4-Hydroxypyrrolidin-2-one (101 g) was dissolved in N,N-dimethylformamide (400 mL), imidazole (102 g) and t-butyldimethylchlorosilane (158 g) were added thereto at 0 C., and stirring was conducted at room temperature for 21 hours. The reaction liquid was added to water, and the precipitated white solid was collected by filtration and washed with water to give the title compound (210 g) as a white solid.1H-NMR (CDCl3) δ (ppm): 0.02 (6H, s), 0.81 (9H, s), 2.16-2.22 (1H, m), 2.42-2.50 (1H, m), 3.14-3.18 (1H, m), 3.49-3.54 (1H, m), 4.46-4.52 (1H, m), 5.76 (1H, br.s).ESI/MS (m/z): 216 (M+H)+. | |
With 1H-imidazole; In N,N-dimethyl-formamide; at 0 - 20℃; for 0.5h;Inert atmosphere; | (S)-4-hydroxy-2-pyrrolidone S20 (500 mg, 4.95 mmol) was dissolved in DMF (50 mL), and tertbutyldimethyl silyl chloride (894.5 mg, 5.93 mmol, 1.2 equiv) and imidazole (673.4 mg, 9.89 mmol,2equiv) were added under the protection of nitrogen at 0 C and stirred for 30 minutes at roomtemperature. The mixture was poured into H2O, filtered, collected, and dried to obtain 4-tert-butyldimethylsiloxane -2-pyrrolidone S21 white crystals. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80.1% | EXAMPLE 2 Synthesis of (S)-4-Hydroxy-2-pyrrolidone (One-pot Reaction) In a 200 ml autoclave were charged 40 g of the product obtained in Reference Example 1 (containing 35.9 g (0.129 mol) of ethyl 4-benzyloxycarbonylamino-3-oxobutanoate), 120 ml of ethanol, and 0.179 g (0.204 mmol) of [RuCl(benzene)((R)-BINAP)]Cl in a nitrogen stream, and asymmetric hydrogenation was conducted at 50 C. and at a hydrogen pressure of 30 atm for 17 hours (conversion: 98.2%; optical purity: 93.8% e.e.). Thereafter, 1.68 g of wet 5% palladium-on-carbon was put therein, and hydrogenolysis was carried out at 25 C. and at a hydrogen pressure of 4 to 6 atm for 4.5 hours. The reaction mixture was stirred at 60 C. for 8 hours and then at room temperature for 7 hours to carry out cyclization. To the reaction mixture was added 0.5 g of activated carbon, followed by stirring at 50 C. for 1 hour. To the mixture was added 20 ml of ethanol, and the mixture was filtered. The methanolic filtrate was crystallized by stirring at -10 C. for 1.5 hours, followed by filtration to obtain 10.4 g of the title compound in a yield of 80.1%. Melting point: 158 to 162 C. Optical purity: 100% e.e. | |
77.3% | Thereafter, 1.68 g of wet 5% palladium-on-carbon was put therein, and hydrogenolysis was carried out at 25 C. and at a hydrogen pressure of 4 to 6 atm for 4.5 hours. The reaction mixture was stirred at 60 C. for 8 hours and then at room temperature for 7 hours to carry out cyclization. To the reaction mixture was added 0.5 g of activated carbon, followed by stirring at 50 C. for 1 hour. To the mixture was added 20 ml of ethanol, and the mixture was filtered. The methanolic filtrate was crystallized by stirring at -15 C. for 1.5 hours, followed by filtration to obtain 10.1 g of the title compound in a yield of 77.3%. Melting point: 158 to 162 C. Optical purity: 100% e.e. | |
70.6% | 18 ml of methanol was added to the primary mother liquor weighing 7.1 g to perform crystallization in the same manner as above thereby producing 2.35 g of secondary crystals. The primary and secondary crystals were added up to find that the title compound amounted to 9.2 g and the yield was 70.6%. Melting point: 158-162C Chemical purity: 100% Optical purity: 100% e.e. 1H-NMR: δppm (400 MHz, D2O) 2.26 (1H, dd, J=2Hz, 18Hz), 2.75 (1H, dd, J=6.4Hz, 17.6Hz), 3.32 (1H, dd, J=1.6Hz, 11.6Hz), 3.7 (1H, dd, J=5.2Hz, 11.6Hz), 4.59-4.62 (1H, m) |
63.0% | 6 ml of methanol was added to the primary mother liquor weighing 2.41 g to perform crystallization in the same manner as above thereby producing 0.71 g of secondary crystals. The primary and secondary crystals were added up to find that the title compound amounted to 2.95 g and the yield was 63.0%. | |
Then the crude product was dissolved in methanol (1 Lit.) and to it 5% palladium-carbon (10 g) was added. The mixture was stirred for 17 hours at room temperature under a hydrogen atmosphere. After the reaction was over, palladium-carbon was filtered off and the solvent was distilled off under vacuo. The resulting product was recrystallized from acetone-water to give (S)-4-hydroxy-2-pyrrolidone (99 g, 0.98 mol, yield:84%) as a colorless crystalline solid. Optical purity:98.3% ee, Specific rotation:[α]D22 -57.6(c=1.00, H2 O). | ||
After completion of the ring-closing reaction, methanol was distilled off under reduced pressure and the resulting crude crystals were recrystallized from ethanol (10 ml) to obtain colorless crystals. Yield: 1.40 g (83.4%). Melting point: 156.2-157.6 C. NMR (500 MHz. D2 O, δ ppm): 4.62 (1H, m), 3.72 (1H, dd, J=5.4 11.7 Hz), 3.33 (1H, dd, J=1.3 11.7 Hz), 2.77 (1H, dd, J=6.4 17.7 Hz), 2.27 (1H, dd, J=1.9 17.7 Hz). [α]D25-58.5 (c=1.01, H2 O). IR (KBr, cm-1): 3242, 3135, 1674, 1303, 968, 682. | ||
EXAMPLE 2 Production of (S)-4-hydroxy-2-pyrrolidinone A 28% methanol solution of sodium methoxide (40 mg, 0.2 mmol as NaOMe) was added to a methanol solution (25 ml) of ethyl (S)-4-amino-2-hydroxybutyrate (1.32 g, 9.0 mmol) and the mixture was stirred at room temperature for 2 hours. After completion of the ring-closing reaction, methanol was distilled off under reduced pressure and the resulting crude crystals were recrystallized from ethanol to obtain colorless crystals. The yield was 0.71 g (79%) and the melting point was 156.6-157.9 C. The NMR data, IR data, and behavior during the HPLC analysis using an optical resolution column of the thus-obtained colorless crystals were identical with those obtained in Example 1. | ||
(2) Synthesis of (S)-4-Hydroxy-2-pyrrolidone In a 200 ml autoclave were charged 33.5 g of the product obtained in (1) (containing 28.16 g (0.1 mol) of ethyl (3S)-4-benzyloxycarbonylamino-3-hydroxybutanoate), 100 ml of methanol, and 1.68 g of wet 5% palladium-on-carbon, and hydrogenolysis was conducted at 25 C. under a hydrogen pressure of 4 to 6 atm for 3.5 hours. The reaction mixture was filtered, and methanol was evaporated under reduced pressure to obtain 18.95 g (liquid) of a crude aminohydroxy-ester. A 17 g portion of the crude product was weighed out, and 85 ml of methanol was added thereto, followed by stirring at 60 C. for 8 hours and then at room temperature for 7 hours to conduct cyclization. One gram of activated carbon was added to the reaction mixture, and the mixture was stirred at 50 C. for 1 hour, followed by filtration. For the filtration, 20 ml of methanol was used. The methanolic filtrate was crystallized by stirring at -15 C. for 1.5 hours. The crystals were collected by filtration and washed with ethyl acetate/methanol (4/1) to obtain 6.03 g of first crystals. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium phosphate; copper(l) iodide; N,N`-dimethylethylenediamine; In 1,4-dioxane; at 110℃; for 140h; | Part F An amide from the table below (1.2 eq) was added to a test tube containing 8 mg (0.4 eq) of copper iodide, 42 mg of potassium phosphate, and a magnetic stir bar. A solution of 1-[4-amino-7-bromo-2-(ethoxymethyl)-1H imidazo[4,5-c][1,5]naphthyridin-1- yl] -2-methylpropan-2-ol (38 mg, 1.0 eq) in 1,4-dioxane (1.0 mL) was added to the test tube and the test tube was purged with nitrogen. A solution of N,N- dimethylethylenediamine (4.4 µL) in 1,4-dioxane (25 µL) was added to the test tube and the test tube was purged with nitrogen. The test tube was capped and the reaction mixture was stirred at 110 C for 140 hours. The reaction mixture was filtered and then concentrated by vacuum centrifugation. The compounds were purified as described in Examples 15 - 30. The table below shows the amide used for each example, the structure of the resulting compound, and the observed accurate mass for the isolated trifluoroacetate salt. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium methylate;palladium-carbon catalyst; In methanol; | EXAMPLE 3 Production of (S)-4-hydroxy-2-pyrrolidinone Ethyl (S)-4-azido-3-hydroxybutyrate (4.8 g, 27.7 mmol) was dissolved in methanol (50 ml) and 5% palladium-carbon catalyst (100 mg) and a 28% methanol solution of sodium methoxide (280 mg, 1.4 mmol as NaOMe) were added thereto. The mixture was stirred at room temperature for 2.5 hours with blowing hydrogen gas to effect reduction and subsequent ring-closing reactions. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. The resulting crude crystals were recrystallized from ethanol (17 ml) to obtain colorless crystals. The yield was 2.1 g (76%) and the melting point was 156.7-157.6 C. The NMR data, IR data, and behavior during the HPLC analysis using an optical resolution column of the thus-obtained colorless crystals were identical with those obtained in Example 1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydrogencarbonate; In pyridine; methanol; ethyl acetate; | PREPARATION 1 (4R)-4-Acetylthio-2-oxopyrrolidine 1-(1) (4S)-4-Methanesulfonyloxy-2-oxopyrrolidine 1.90 g of <strong>[68108-18-9](4S)-4-hydroxy-2-oxopyrrolidine</strong> were dissolved in 100 ml of pyridine, after which 2.26 g of methanesulfonyl chloride were added dropwise to the solution, whilst stirring and ice-cooling. The resulting mixture was then stirred at room temperature for 1.5 hours, after which the reaction mixture was concentrated by evaporation under reduced pressure. 9 ml of a saturated aqueous solution of sodium hydrogencarbonate were then added to the mixture, and the mixture was again concentrated to dryness by evaporation under reduced pressure. A 1:1 by volume mixture of ethyl acetate and methanol was then added to the resulting residue, after which the insoluble portion was removed by filtration and the soluble portion was concentrated by evaporation under reduced pressure. The residue obtained from the soluble portion was subjected to column chromatography (Merck 9385, 150 ml) through silica gel using a gradient elution method, with mixtures of ethyl acetate and methanol ranging from 9:1 to 4:1 by volume as the eluent. The fractions containing the compound of the invention were combined and concentrated by evaporation under reduced pressure, and the desired compound was recrystallized from a mixture of ethyl acetate and methanol to produce 2.44 g of the title compound as crystals, melting between 137.5 and 139 C. Optical rotation [α]D24 -35.5 (C=1.09, MeOH); Infrared Absorption Spectrum, (KBr) νmax cm-1: 1719, 1697, 1659, 1305, 1177, 1171, 1159, 963. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triphenylphosphine; In tetrahydrofuran; | PREPARATION 2 (4R)-4-Acetylthio-2-oxopyrrolidine 380 mg of <strong>[68108-18-9](4S)-4-hydroxy-2-oxopyrrolidine</strong> were suspended in 21 ml of anhydrous tetrahydrofuran, and 1.18 g of triphenylphosphine were added to the suspension at room temperature. 783 mg of diethyl azodicarboxylate were then added dropwise to the solution, whilst maintaining a temperature of -30 C. The mixture was then gradually heated to 4 C., after which the mixture was stirred at the same temperature for 30 minutes to produce a homogeneous mixture. At the end of this time, the reaction mixture was cooled to -20 C., and then 320 μl of thioacetic acid were added dropwise to the cooled mixture. The resulting mixture was gradually heated to a temperature equivalent to ice-cooling; and the mixture was stirred for 1.5 hours at that temperature. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and then subjected to column chromatography (Merck 9385, 60 ml) through silica gel using a gradient elution method, with mixtures of benzene and acetonitrile ranging from 2:1 and 1:1 by volume as the eluent. The desired fraction was concentrated by evaporation under reduced pressure to give 69 mg of a crystalline residue. This residue was recrystallized from a mixture of ethyl acetate and cyclohexane to give 54 mg of the title compound as crystals. The melting point, optical rotation, Infrared Absorption Spectrum and Nuclear Magnetic Resonance Spectrum of the compound obtained in this manner were identical with the corresponding values of the compound obtained in Step (2) of Preparation 1, above. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
(1) (4S)-4-Hydroxy-2-pyrrolidone (1.7 g) is treated in the same manner as described in Reference Example 1-(1) to give (4R)-4-acetylthio-2-pyrrolidone (2 g) as an oil. NMR (CDCl3) δppm: 2.29 (1H, dd), 2.35 (3H, s), 2.80 (1H, dd), 3.31 (1H, dd), 3.89 (1H, dd), 4.10-4.23 (1H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83.4% | In methanol; | EXAMPLE 4 Synthesis of (S)-4-hydroxy-2-pyrrolidone A 200 ml autoclave was charged with 5 g (0.033 mol) of the ammonium salt of 4-amino-3-oxobutanoic acid prepared in Reference Example 3, 15 ml of methanol and 0.056 g (0.066 mmol) of Ru2Cl4((R)-BINAP)2·NEt3in flowing nitrogen gas. The mixture was hydrogenated asymmetrically at a reaction temperature of 50C under a hydrogen pressure of 30 atoms for 17 hours (conversion rate: 100%). After the solvent was distilled under reduced pressure, the same procedures as in Example 2 were conducted to obtain 2.78 g of the title compound (yield: 83.4%). This compound was coincident with that obtained in Example 2 in melting point and nuclear magnetic resonance spectrum. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In methanol; | EXAMPLE 6 Synthesis of (S)-4-hydroxy-2-pyrrolidone A 200 ml autoclave was charged with 36.2 g of the crude product (containing 30.3 g (0.1 ml) of the ammonium salt of methyl 4-amino-3-oxobutanoate) prepared in Reference Example 4, 108 ml of methanol and 0.169 g (0.2 mmol) of Ru2Cl4((R)-BINAP)2·NEt3in flowing nitrogen gas. The mixture was hydrogenated asymmetrically at a reaction temperature of 50C under hydrogen of 30 atmospheric pressures for 17 hours (conversion rate: 100%). After the solvent was distilled under reduced pressure, the same procedures as in Example 2 in the formation of a free amine and the cyclization reaction were conducted to obtain a crude product of (S)-4-hydroxy-2-pyrrolidone. The crude product was subjected to column chromatography using silica gel to obtain 7.3 g of the title compound in a yield of 72.2% from the fraction eluted by an eluent consisting of chloroform and methanol (5:1 by volume). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; N,N`-dimethylethylenediamine;copper(l) iodide; In 1,4-dioxane; at 140℃; for 14h;Microwave synthesizer; | Example 12 (4S)-l-(8-[(2,6-dimethylphenyl)methyl]amino}-2,3-dimethylimidazo[l,2- -2-pyrrolidinone hydrochlorideA mixture of 6-bromo-7V-[(2,6-dimethylphenyl)methyl]-2,3-dimethylimidazo[ 1 ,2- α]pyridin-8-amine (200 mg, 0.558 mmol; WO 98/37080), (45)-4-hydroxy-2- EPO <DP n="27"/>pyrrolidinone (112 mg, 1.12 mmol), copper(I) iodide (32 mg, 0.167 mmol), potassium carbonate (276 mg, 2.0 mmol) and N.N'-dimethylethylenediamine (15 mg, 0.167 mmol) in dioxane (2 mL) was heated in an Initiator Microwave Synthesizer at 140C for 14 hours. The cooled mixture was applied to an Isolute SCX cartridge. Elution with methanol, followed by water, then methanol then IM NH3 in methanol gave, after evaporation, the product which was further purified by chromatography on silica gel. Elution with dichloromethane/methanol (0 to 10%) gave a pale yellow solid which was dissolved in methanol (2 mL), Ethereal HCl (IM; 0.5ml) was added and the solvent evaporated to give the title compound as a brick-red coloured solid. MS (ES+ve): [M+H]+ at m/z 379 (C22H26N4O2 requires [M+H]+ at m/z 379). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; trans-N,N'-dimethylcyclohexane-1,2-diamine;copper(l) iodide; In N,N-dimethyl-formamide; at 120℃; for 4h;Microwave synthesizer; | Description 10. (4S)-l-[2,3-Dimethyl-8-([4-(methyloxy)phenyl]methyl}oxy)imidazo[l,2- 2-pyrrolidinoneA mixture of 6-bromo-2,3-dimethyl-8-( [4-(methyloxy)phenyl]methyl} oxy)imidazo[l,2-α]pyridine (500 mg, 1.38 mmol;. Description 5), (S) 4-hydroxy- pyrrolidin-2-one (279 mg, 2.76 mmol), potassium carbonate (666 mg, 4.83 mmol) and copper(I) iodide (76 mg, 0.4 mmol) along with racemic-trans-N,N'- dimethylcyclohexane-l,2-diamine (56 mg, 0.4 mmol) in dry dimethylformamide (10 mL) was heated in an Initiator Microwave Synthesizer in 2 equal vessels at 120C for 4 hours. The cooled mixture was applied to an Isolute SCX cartridge and washed with methanol followed by elution with 2M NH3 in methanol. The basic fractions were combined and evaporated under reduced pressure. This residue was purified by column chromatography on silica eluting with a 0-10% methanol in ethyl acetate gradient to afford the title compound MS (ES+ve): [M+H]+ at m/z 382 (C2)H23N3O4 requires [M+H]+ at m/z 382) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium phosphate; copper(l) iodide; In 1,4-dioxane; at 110℃; for 18h;Inert atmosphere; Sonographic reaction; | To a vessel containing Λ/-(4-bromo-2-(trifluoromethoxy)benzyl)-l-(2- morpholinoethyl)-2,6-dioxo-l,2,3,6-tetrahydropyrimidine-4-carboxamide (65 mg, 0.125 mmol), (iS)-4-hydroxypyrrolidin-2-one (25.2 mg, 0.249 mmol), potassium phosphate tribasic (52.9 mg, 0.249 mmol) and copper(I) iodide (4.75 mg, 0.025 mmol) was added dioxane (2.5 mL). Nitrogen was blown over the top of the reaction mixture and the vessel was covered with a PTFE cap. The mixture was sonicated and then heated to 1100C for 18 hours. The reaction was cooled to room temperature. The mixture was filtered and the filtrate was purified by mass-triggered HPLC (gradient: 20 to 25% ACN in water containing 0.05% TFA) to give the title compound as a TFA salt. MS [M+H] found 542. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium phosphate; copper(l) iodide; N,N`-dimethylethylenediamine; In 1,4-dioxane; at 110℃; for 18h;Inert atmosphere; Sonographic reaction; | To a vessel containing 3-(benzyloxymethyl)-JV-(4-bromo-2- (trifluoromethoxy)benzyl)-2,6-dioxo- 1 -(pyridin-2-ylmethyl)- 1 ,2,3 ,6-tetrahydropyrimidine- 4-carboxamide (100 mg, 0.161 mmol), (5)-4-hydroxypyrrolidin-2-one (32.6 mg, 0.323 mmol), potassium phosphate tribasic (68.5 mg, 0.323 mmol), copper(I) iodide (6.15 mg, 0.032 mmol) and N,Λ^-dimethylethane-l,2-diamine (6.95 μL, 0.065 mmol) was added dioxane (3.2 mL). Nitrogen was blown over the top of the reaction mixture and the vessel was covered with a PTFE cap. The mixture was sonicated and then heated to 1100C for 18 hours. The reaction was cooled to room temperature. The mixture was filtered and the filtrate was purified by mass-triggered HPLC (gradient: 30 to 40% ACN in water containing 0.05% TFA) to give the title compound. MS [M+H] found 640 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79.3% | With dmap; ammonia; In methanol; at 20℃; for 10h;Industrial scale; | A solution of 15.82 g (100 mmol) of isobutyl 2-oxiranylacetate and 1.22 g (10 mmol) of 4-dimethylaminopyridine was added to a saturated solution of methanol in 200 ml of ammonia, and the mixture was stirred at room temperature for 10 hours. The organic phase was concentrated under reduced pressure and the petroleum ether was recrystallized to give 8.02 g of (S) -4-hydroxy-2-oxopyrrolidine in a yield of 79.3%, and the mixture was concentrated in 10 ml of water and extracted with ethyl acetate. , HPLC purity 99.47% (area normalization), ee value of 99.52%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89.3% | With copper(l) iodide; ammonia; caesium carbonate; In methanol; at 50℃; for 10h; | 2-oxiranylacetamide (10 mmol), CuI, 1.5 g (8 mmol) and 2 g (200 mmol) of cesium carbonate were added to a saturated solution of 13 ml of ammonia in methanol, 50 C for 10 h, the reaction solution was concentrated under reduced pressure, 10 ml of water, extracted twice with methylene chloride, Saturated brine washing three times, ethyl acetate reduced under reduced pressure, petroleum ether recrystallization obtained, (S)-3-hydroxy-butyrolactam 0.9g, yield 89.3%, HPLC purity 99.54% (area normalization), ee value 99.71%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With acetic acid; In toluene; at 110℃; for 12h;Dean-Stark; | General procedure: From a modified procedure2, 2-pyrrolidinone (2 equiv) and an aldehyde (1 equiv) were added to a solution of 3:1 toluene:AcOH (0.25 M). A Dean-Stark trap was affixed to the flask and the reaction was stirred at 110 C to remove water via azeotropic distillation for 12 hours or until complete by TLC. After allowing the flask to cool toroom temperature, the reaction was quenched with a saturated solution of NaHCO3 and extracted twice with EtOAc. The organic layer was rinsed with a saturated NaCl solution and dried over MgSO4. The organic layer was then concentrated under vacuum and purified using flash chromatography on silica (EtOAc:Hexanes). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27.3 mg | With palladium diacetate; caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; In 1,4-dioxane;Inert atmosphere; Heating; | General procedure: Potassium carbonate or caesium carbonate (1.5-2.5 eq.) was baked in a reaction vessel under reduced pressure. It was cooled to RT and flooded with argon. Palladium acetate (0.1-0.36 eq.), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (Xantphos, 0.18-0.36 eq.) and dioxane (0.04-0.12M) were added, and the suspension was degassed in an argon stream at room temperature for 10 min. Subsequently, the appropriate amide (1.0-1.2 eq.) and the appropriate 7-chloro-4-oxo-1,4-dihydro-1,8-naphthyridine (1.0 eq.) were added. The mixture was stirred at 80-110 C. for 1 h (or until conversion was complete by analytical HPLC or thin-layer chromatography with appropriate eluent mixtures). The mixture was cooled to RT and all volatile components were removed under reduced pressure, or alternatively the reaction mixture was poured into water, the pH was adjusted to pH 1 with 1M aqueous hydrochloric acid, the mixture was extracted with ethyl acetate, the combined organic phases were washed with saturated aqueous sodium chloride solution, dried over magnesium sulphate and filtered, and the solvent was removed under reduced pressure. The crude product was then purified either by normal phase chromatography (eluent: cyclohexane/ethyl acetate mixtures or dichloromethane/methanol mixtures) or preparative RP-HPLC (water/acetonitrile gradient). According to GP2, 100 mg (153 μmol, 73.6% purity) of the compound from Example 81A were reacted with 15.5 mg (153 μmol) of <strong>[68108-18-9](4S)-4-hydroxypyrrolidin-2-one</strong> in the presence of 74.8 mg (230 μmol) of caesium carbonate, 6.2 mg (28 μmol) of palladium(II) acetate and 16 mg (28 μmol) of Xantphos in 2 ml of dioxane. The residue was purified by means of flash chromatography (cyclohexane/ethyl acetate gradient) and finally by preparative thin-layer chromatography (dichloromethane/methanol=95/5, 20*20 cm plates, 1 mm of silica). The product fraction was visualized by UV detection and scratched off, and eluted from the silica gel with ethyl acetate. The mixture was filtered through Celite and the solvent was removed under reduced pressure. The residue was lyophilized from water/acetonitrile, and 27.3 mg (33% of theory; 100% purity) of the title compound were obtained. 1H-NMR (400 MHz, DMSO-d6): δ [ppm]=11.7 (s, 1H), 8.92 (s, 1H), 8.77 (d, 1H), 8.57-8.52 (m, 1H), 7.96-7.86 (m, 1H), 7.67-7.57 (m, 3H), 7.42-7.33 (m, 2H), 5.33 (dd, 1H), 4.32-4.25 (m, 1H), 3.74-3.63 (m, 1H), 3.54-3.43 (m, 1H), 3.01-2.89 (m, 1H), 2.43-2.31 (m, 1H). LC-MS (Method 1): Rt=1.03 min; 545 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | With palladium diacetate; caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; In 1,4-dioxane;Inert atmosphere; Heating; | General procedure: Potassium carbonate or caesium carbonate (1.5-2.5 eq.) was baked in a reaction vessel under reduced pressure. It was cooled to RT and flooded with argon. Palladium acetate (0.1-0.36 eq.), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (Xantphos, 0.18-0.36 eq.) and dioxane (0.04-0.12M) were added, and the suspension was degassed in an argon stream at room temperature for 10 min. Subsequently, the appropriate amide (1.0-1.2 eq.) and the appropriate 7-chloro-4-oxo-1,4-dihydro-1,8-naphthyridine (1.0 eq.) were added. The mixture was stirred at 80-110 C. for 1 h (or until conversion was complete by analytical HPLC or thin-layer chromatography with appropriate eluent mixtures). The mixture was cooled to RT and all volatile components were removed under reduced pressure, or alternatively the reaction mixture was poured into water, the pH was adjusted to pH 1 with 1M aqueous hydrochloric acid, the mixture was extracted with ethyl acetate, the combined organic phases were washed with saturated aqueous sodium chloride solution, dried over magnesium sulphate and filtered, and the solvent was removed under reduced pressure. The crude product was then purified either by normal phase chromatography (eluent: cyclohexane/ethyl acetate mixtures or dichloromethane/methanol mixtures) or preparative RP-HPLC (water/acetonitrile gradient). According to GP2, 55.0 mg (115 μmol) of the compound from Example 92A were reacted with 11.6 mg (115 μmol) of <strong>[68108-18-9](4S)-4-hydroxypyrrolidin-2-one</strong> in the presence of 56.3 mg (173 μmol) of caesium carbonate, 4.7 mg (21 μmol) of palladium(II) acetate and 24 mg (41 μmol) of Xantphos in 2.3 ml of 1,4-dioxane. Subsequently, the mixture was diluted with 3 ml of acetonitrile and 0.5 ml of water, filtered and purified by means of preparative HPLC (column: Chromatorex C18, 10 μm, 125*30 mm, solvent: acetonitrile/0.05% formic acid gradient; 0 to 3 min 10% acetonitrile, to 35 min 90% acetonitrile and for a further 3 min 90% acetonitrile). 22 mg (35% of theory, 99% purity) of the title compound were obtained as a mixture of the atropisomers. In analogy to the experimental procedure described in A, 56 mg (117 μmol) of the compound from Example 93A were reacted with 11.9 mg (117 μmol) of <strong>[68108-18-9](4S)-4-hydroxypyrrolidin-2-one</strong> in the presence of 57.3 mg (176 μmol) of caesium carbonate, 4.7 mg (21 μmol) of palladium(II) acetate and 24 mg (41 μmol) of Xantphos in 2.3 ml of 1,4-dioxane. Subsequently, the mixture was diluted with 3 ml of acetonitrile and 0.5 ml of water, filtered and purified by means of preparative HPLC (column: Chromatorex C18, 10 μm, 125*30 mm, solvent: acetonitrile/0.05% formic acid gradient; 0 to 3 min 10% acetonitrile, to 35 min 90% acetonitrile and for a further 3 min 90% acetonitrile). 27 mg (42% of theory, 99% purity) of the title compound were obtained as a mixture of the atropisomers. The mixture of the atropisomers A and B was combined and the combined batch was then separated into the atropisomers by chiral HPLC (preparative HPLC: column: Daicel Chiralcel OZ-H 5 μm 250*20 mm; eluent: 30% ethanol, 70% isohexane; temperature: 25 C.; flow rate: 15 ml/min; UV detection: 220 nm). This gave (in the sequence of elution from the column) 22 mg of atropisomer 1 (90% de) Rt=3.99 min and 18 mg (83% de) of atropisomer 2 Rt=4.79 min. [Analytical HPLC: column: Daicel Chiralpak AZ-H 5 μm 250×4.6 mm; eluent: 30% ethanol, 70% isohexane with 0.2% diethylamine; temperature: 50 C.; flow rate: 1.0 ml/min; UV detection: 270 nm] Atropisomer 1 was additionally purified by means of preparative HPLC (column: Chromatorex C18, 10 μm, 125×30 mm, solvent: acetonitrile/0.05% formic acid gradient; (0 to 3 min. 10% acetonitrile to 35 min. 90% acetonitrile and a further 3 min. 90% acetonitrile)), and 16.8 mg (26.6% of theory, 99% purity) of the title compound from Example 269 were obtained. Atropisomer 2 was additionally purified by means of preparative HPLC (column: Chromatorex C18, 10 μm, 125×30 mm, solvent: acetonitrile/0.05% formic acid gradient; (0 to 3 min. 10% acetonitrile to 35 min. 90% acetonitrile and a further 3 min. 90% acetonitrile)), and 20.1 mg (32% of theory, 99% purity) of the title compound from Example 270 were obtained. Example 269 7-[(4S)-4-Hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-N-[(2R)-1,1,1-trifluorobutan-2-yl]-1-[2-(trifluoromethyl)phenyl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide (atropisomer 1) 1H-NMR (400 MHz, DMSO-d6): δ [ppm]=0.97 (t, 3H), 1.59-1.73 (m, 1H), 1.83-1.95 (m, 1H), 2.32 (d, 1H), 2.93 (dd, 1H), 3.47 (dd, 1H), 4.17-4.23 (m, 1H), 4.70-4.82 (m, 1H), 5.27 (d, 1H), 7.91-7.84 (m, 2H), 7.95-8.00 (m, 1H), 8.02-8.07 (m, 1H), 8.51 (d, 1H), 8.71 (d, 1H), 8.82 (s, 1H), 10.24 (d, 1H). LC-MS (Method 3): Rt=1.88 min; 543 [M+H]+. Example 270 7-[(4S)-4-Hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-N-[(2R)-1,1,1-trifluorobutan-2-yl]-1-[2-(trifluoromethyl)phenyl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide (atropisomer 2) 1H-NMR (400 MHz, DMSO-d6): δ [ppm]=0.99 (t, 3H), 1.61-1.75 (m, 1H), 1.84-1.96 (m,... |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With palladium diacetate; potassium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; In 1,4-dioxane; at 80℃; for 1.5h;Inert atmosphere; | General procedure: Potassium carbonate or caesium carbonate (1.5-2.5 eq.) was baked in a reaction vessel under reduced pressure. It was cooled to RT and flooded with argon. Palladium acetate (0.1-0.36 eq.), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (Xantphos, 0.18-0.36 eq.) and dioxane (0.04-0.12M) were added, and the suspension was degassed in an argon stream at room temperature for 10 min. Subsequently, the appropriate amide (1.0-1.2 eq.) and the appropriate 7-chloro-4-oxo-1,4-dihydro-1,8-naphthyridine (1.0 eq.) were added. The mixture was stirred at 80-110 C. for 1 h (or until conversion was complete by analytical HPLC or thin-layer chromatography with appropriate eluent mixtures). The mixture was cooled to RT and all volatile components were removed under reduced pressure, or alternatively the reaction mixture was poured into water, the pH was adjusted to pH 1 with 1M aqueous hydrochloric acid, the mixture was extracted with ethyl acetate, the combined organic phases were washed with saturated aqueous sodium chloride solution, dried over magnesium sulphate and filtered, and the solvent was removed under reduced pressure. The crude product was then purified either by normal phase chromatography (eluent: cyclohexane/ethyl acetate mixtures or dichloromethane/methanol mixtures) or preparative RP-HPLC (water/acetonitrile gradient). According to GP2, 50.0 g (141 mmol) of the compound from Example 100B were reacted with 17.1 g (169 mmol) of <strong>[68108-18-9](4S)-4-hydroxypyrrolidin-2-one</strong> in the presence of 29.2 g (211 mmol) of potassium carbonate, 6.33 g (28.2 mmol) of palladium(II) acetate and 16.3 g (28.2 mmol) of Xantphos in 1000 ml of 1,4-dioxane at 80 C. for 1.5 h. The mixture was cooled down and extracted by stirring in a mixture of ice-water, hydrochloric acid and ethyl acetate. The mixture was filtered with suction through kieselguhr, and the organic phase was washed with water and saturated aqueous sodium chloride solution, dried and finally concentrated. The residue was admixed with acetonitrile, cooled and filtered off with suction, and the precipitate was washed with cold acetonitrile. 48 g (81% of theory, 97% purity) of the title compound were obtained. LC-MS (Method 3): Rt=1.33 min; MS (ESIpos) m/z 420 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With palladium diacetate; potassium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; In 1,4-dioxane;Inert atmosphere; Heating; | General procedure: Potassium carbonate or caesium carbonate (1.5-2.5 eq.) was baked in a reaction vessel under reduced pressure. It was cooled to RT and flooded with argon. Palladium acetate (0.1-0.36 eq.), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (Xantphos, 0.18-0.36 eq.) and dioxane (0.04-0.12M) were added, and the suspension was degassed in an argon stream at room temperature for 10 min. Subsequently, the appropriate amide (1.0-1.2 eq.) and the appropriate 7-chloro-4-oxo-1,4-dihydro-1,8-naphthyridine (1.0 eq.) were added. The mixture was stirred at 80-110 C. for 1 h (or until conversion was complete by analytical HPLC or thin-layer chromatography with appropriate eluent mixtures). The mixture was cooled to RT and all volatile components were removed under reduced pressure, or alternatively the reaction mixture was poured into water, the pH was adjusted to pH 1 with 1M aqueous hydrochloric acid, the mixture was extracted with ethyl acetate, the combined organic phases were washed with saturated aqueous sodium chloride solution, dried over magnesium sulphate and filtered, and the solvent was removed under reduced pressure. The crude product was then purified either by normal phase chromatography (eluent: cyclohexane/ethyl acetate mixtures or dichloromethane/methanol mixtures) or preparative RP-HPLC (water/acetonitrile gradient). According to GP2, 750 mg (1.36 mmol, 96% purity) of the compound from Example 73A were reacted with 138 mg (1.36 mmol) of <strong>[68108-18-9](4S)-4-hydroxypyrrolidin-2-one</strong> in the presence of 283 mg (2.04 mmol) of potassium carbonate, 30.6 mg (136 μmol) of palladium(II) acetate and 158 mg (273 μmol) of Xantphos in 14 ml of dioxane. The mixture was filtered, washed through with acetonitrile and concentrated, and the crude product was purified by means of flash chromatography (cyclohexane/ethyl acetate gradient). 555 mg (65% of theory, 95% purity) of the title compound were obtained. 1H-NMR (400 MHz, DMSO-d6): δ [ppm]=11.33 (d, 1H), 8.86 (s, 1H), 8.75 (d, 1H), 8.57-8.51 (m, 1H), 7.93-7.76 (m, 1H), 7.67-7.48 (m, 5H), 7.41-7.32 (m, 1H), 6.53-6.42 (m, 1H), 5.37-5.27 (m, 1H), 4.31-4.25 (m, 1H), 3.72-3.61 (m, 1H), 3.51-3.42 (m, 1H), 3.00-2.88 (m, 1H), 2.42-2.31 (m, 1H). LC-MS (Method 3): Rt=2.13 min; 593 [M+H]+. 550 mg of the title compound (diastereomer mixture) were separated into the diastereomers by chiral HPLC (preparative HPLC: column: Chiralpak AZ-H 5 μm 250×20 mm; eluent: 50% isopropanol, 50% isohexane; temperature: 25 C.; flow rate: 15 ml/min; UV detection: 210 nm). This gave (in the sequence of elution from the column) 229 mg of diastereomer 1 (99% de) Rt=0.96 min and 235 mg (99% de) of diastereomer 2 Rt=1.44 min. [Analytical HPLC: column: Chiralcel AZ-3 3 μm 50×4.6 mm; eluent: 50% isopropanol, 50% isohexane; flow rate: 1 ml/min; UV detection: 220 nm] Diastereomer 1 was additionally purified by means of preparative HPLC (column: Chromatorex C18, 10 μm, 125×30 mm, solvent: acetonitrile/0.05% formic acid gradient; (0 to 3 min. 10% acetonitrile to 35 min. 90% acetonitrile and a further 3 min. 90% acetonitrile)), and 151.6 mg (19% of theory, 100% purity) of the title compound from Example 212 were obtained. Diastereomer 2 was additionally purified by means of preparative HPLC (column: Chromatorex C18, 10 μm, 125×30 mm, solvent: acetonitrile/0.05% formic acid gradient; (0 to 3 min. 10% acetonitrile to 35 min. 90% acetonitrile and a further 3 min. 90% acetonitrile)), and 151.7 mg (19% of theory, 100% purity) of the title compound from Example 213 were obtained. Example 212 N-[1-(2-Chlorophenyl)-2,2,2-trifluoroethyl]-1-(2,4-difluorophenyl)-7-[(4S)-4-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide (diastereomer A) 1H-NMR (400 MHz, DMSO-d6): δ [ppm]=11.33 (d, 1H), 8.86 (s, 1H), 8.75 (d, 1H), 8.57-8.51 (m, 1H), 7.91-7.78 (m, 1H), 7.67-7.48 (m, 5H), 7.41-7.33 (m, 1H), 6.52-6.42 (m, 1H), 5.32 (dd, 1H), 4.31-4.25 (m, 1H), 3.72-3.61 (m, 1H), 3.51-3.41 (m, 1H), 3.00-2.88 (m, 1H), 2.41-2.31 (m, 1H). LC-MS (Method 3): Rt=2.07 min; 593 [M+H]+. Example 213 N-[1-(2-Chlorophenyl)-2,2,2-trifluoroethyl]-1-(2,4-difluorophenyl)-7-[(4S)-4-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide (diastereomer B) 1H-NMR (400 MHz, DMSO-d6): δ [ppm]=11.33 (d, 1H), 8.86 (s, 1H), 8.75 (d, 1H), 8.57-8.51 (m, 1H), 7.93-7.76 (m, 1H), 7.67-7.48 (m, 5H), 7.42-7.32 (m, 1H), 6.52-6.42 (m, 1H), 5.32 (dd, 1H), 4.31-4.25 (m, 1H), 3.71-3.61 (m, 1H), 3.52-3.42 (m, 1H), 3.00-2.88 (m, 1H), 2.42-2.32 (m, 1H). LC-MS (Method 3): Rt=2.07 min; 593 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With palladium diacetate; potassium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; In 1,4-dioxane;Inert atmosphere; Heating; | General procedure: Potassium carbonate or caesium carbonate (1.5-2.5 eq.) was baked in a reaction vessel under reduced pressure. It was cooled to RT and flooded with argon. Palladium acetate (0.1-0.36 eq.), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (Xantphos, 0.18-0.36 eq.) and dioxane (0.04-0.12M) were added, and the suspension was degassed in an argon stream at room temperature for 10 min. Subsequently, the appropriate amide (1.0-1.2 eq.) and the appropriate 7-chloro-4-oxo-1,4-dihydro-1,8-naphthyridine (1.0 eq.) were added. The mixture was stirred at 80-110 C. for 1 h (or until conversion was complete by analytical HPLC or thin-layer chromatography with appropriate eluent mixtures). The mixture was cooled to RT and all volatile components were removed under reduced pressure, or alternatively the reaction mixture was poured into water, the pH was adjusted to pH 1 with 1M aqueous hydrochloric acid, the mixture was extracted with ethyl acetate, the combined organic phases were washed with saturated aqueous sodium chloride solution, dried over magnesium sulphate and filtered, and the solvent was removed under reduced pressure. The crude product was then purified either by normal phase chromatography (eluent: cyclohexane/ethyl acetate mixtures or dichloromethane/methanol mixtures) or preparative RP-HPLC (water/acetonitrile gradient). According to GP2, 200 mg (377 μmol) of the compound from Example 80A were reacted with 45.8 mg (453 μmol) of <strong>[68108-18-9](4S)-4-hydroxypyrrolidin-2-one</strong> in the presence of 78.3 mg (566 μmol) of potassium carbonate, 17 mg (75 μmol) of palladium(II) acetate and 44 mg (75 μmol) of Xantphos in 3.4 ml of dioxane. The crude product was purified by means of preparative HPLC (column: Chromatorex C18, 10 μm, 125*40 mm, solvent: acetonitrile/0.1% formic acid gradient; (0 to 3 min. 10% acetonitrile to 40 min. 90% acetonitrile and a further 3 min. 90% acetonitrile), and 168 mg (75% of theory, 100% purity) of the title compound were obtained. 1H NMR (400 MHz, DMSO-d6) δ [ppm]=11.37 (d, 1H), 8.87 (s, 1H), 8.75 (d, 1H), 8.52 (dd, 1H), 7.94-7.75 (m, 1H), 7.68-7.57 (m, 2H), 7.42-7.26 (m, 3H), 6.50-6.39 (m, 1H), 5.37-5.26 (m, 1H), 4.28 (br. d, 1H), 3.73-3.60 (m, 1H), 3.53-3.40 (m, 1H), 3.01-2.87 (m, 1H), 2.42-2.31 (m, 1H). LC-MS (Method 3): Rt=2.01 min; 595 [M+H]+. 133 mg of the title compound (diastereomer mixture) were separated into the diastereomers by chiral HPLC (preparative HPLC: column: Daicel Chiralpak ID 5 μm 250×20 mm; eluent: 80% isohexane, 20% ethanol; temperature: 23 C.; flow rate: 30 ml/min; UV detection: 220 nm). This gave (in the sequence of elution from the column) 53.9 mg of diastereomer 1 (99% de) Rt=2.12 min and 52.2 mg (99% de) of diastereomer 2 Rt=3.03 min. [Analytical HPLC: column: Daicel Chiralpak ID-3 3 μm 50×4.6 mm; eluent: 80% isohexane, 20% ethanol; temperature: 30 C.; flow rate: 1 ml/min; UV detection: 220 nm] Example 245 1-(2,4-Difluorophenyl)-N-[1-(2,6-difluorophenyl)-2,2,2-trifluoroethyl]-7-[(4S)-4-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide (diastereomer 1) 1H NMR (400 MHz, DMSO-d6) δ [ppm]=11.37 (d, 1H), 8.88 (s, 1H), 8.75 (d, 1H), 8.52 (dd, 1H), 7.92-7.76 (m, 1H), 7.68-7.57 (m, 2H), 7.41-7.25 (m, 3H), 6.50-6.39 (m, 1H), 5.32 (dd, 1H), 4.28 (br. d, 1H), 3.72-3.60 (m, 1H), 3.46 (t, 1H), 3.00-2.87 (m, 1H), 2.37 (dd, 1H). LC-MS (Method 3): Rt=2.01 min; 595 [M+H]+. Example 246 1-(2,4-Difluorophenyl)-N-[1-(2,6-difluorophenyl)-2,2,2-trifluoroethyl]-7-[(4S)-4-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide (diastereomer 2) 1H NMR (400 MHz, DMSO-d6) δ [ppm]=11.37 (dd, 1H), 8.87 (s, 1H), 8.75 (d, 1H), 8.52 (dd, 1H), 7.95-7.75 (m, 1H), 7.68-7.57 (m, 2H), 7.41-7.26 (m, 3H), 6.50-6.38 (m, 1H), 5.32 (dd, 1H), 4.31-4.25 (br. d, 1H), 3.71-3.60 (m, 1H), 3.52-3.41 (m, 1H), 3.00-2.88 (m, 1H), 2.37 (dd, 1H). LC-MS (Method 3): Rt=2.00 min; 595 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | With palladium diacetate; caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; In 1,4-dioxane; at 110℃; for 6h;Inert atmosphere; | General procedure: 412 mg (1.3 mmol) of caesium carbonate, 34 mg (0.15 mmol) of palladium(II) acetate and 88 mg (0.15 mmol) of Xantphos were stirred in dioxane (under an argon atmosphere) at 20 C. for 10 minutes. Then 400 mg (0.84 mmol) of the compound from Example 68A and 85 mg (0.84 mmol) of <strong>[68108-18-9](4S)-4-hydroxypyrrolidin-2-one</strong> were added and the mixture was stirred at 80 C. for 40 min. Subsequently, the mixture was added to water and brought to pH 1 with 1 M aqueous hydrochloric acid. The precipitated solid was filtered off with suction, washed with water and petroleum ether, and then purified by column chromatography (silica gel cartridge; cyclohexane/ethyl acetate gradient (5:1-2:1-1:1). This gave 169 mg (38% of theory) of the title compound. In analogy to Example 174, the example compounds shown in Table 20 were prepared by reacting the respective compounds from Examples 66A-70A with the appropriate amines (or salts thereof) under the reaction conditions described. Differences are specified in the respective examples. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | With palladium diacetate; caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; In 1,4-dioxane; at 80℃; for 0.666667h;Inert atmosphere; | 412 mg (1.3 mmol) of caesium carbonate, 34 mg (0.15 mmol) of palladium(II) acetate and 88 mg (0.15 mmol) of Xantphos were stirred in dioxane (under an argon atmosphere) at 20 C. for 10 minutes. Then 400 mg (0.84 mmol) of the compound from Example 68A and 85 mg (0.84 mmol) of <strong>[68108-18-9](4S)-4-hydroxypyrrolidin-2-one</strong> were added and the mixture was stirred at 80 C. for 40 min. Subsequently, the mixture was added to water and brought to pH 1 with 1 M aqueous hydrochloric acid. The precipitated solid was filtered off with suction, washed with water and petroleum ether, and then purified by column chromatography (silica gel cartridge; cyclohexane/ethyl acetate gradient (5:1-2:1-1:1). This gave 169 mg (38% of theory) of the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2% | With palladium diacetate; caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; In 1,4-dioxane; at 110℃; for 17h;Inert atmosphere; | General procedure: 412 mg (1.3 mmol) of caesium carbonate, 34 mg (0.15 mmol) of palladium(II) acetate and 88 mg (0.15 mmol) of Xantphos were stirred in dioxane (under an argon atmosphere) at 20 C. for 10 minutes. Then 400 mg (0.84 mmol) of the compound from Example 68A and 85 mg (0.84 mmol) of <strong>[68108-18-9](4S)-4-hydroxypyrrolidin-2-one</strong> were added and the mixture was stirred at 80 C. for 40 min. Subsequently, the mixture was added to water and brought to pH 1 with 1 M aqueous hydrochloric acid. The precipitated solid was filtered off with suction, washed with water and petroleum ether, and then purified by column chromatography (silica gel cartridge; cyclohexane/ethyl acetate gradient (5:1-2:1-1:1). This gave 169 mg (38% of theory) of the title compound. In analogy to Example 174, the example compounds shown in Table 20 were prepared by reacting the respective compounds from Examples 66A-70A with the appropriate amines (or salts thereof) under the reaction conditions described. Differences are specified in the respective examples. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
128 mg; 145 mg | With palladium diacetate; potassium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; In 1,4-dioxane;Inert atmosphere; Heating; | General procedure: Potassium carbonate or caesium carbonate (1.5-2.5 eq.) was baked in a reaction vessel under reduced pressure. It was cooled to RT and flooded with argon. Palladium acetate (0.1-0.36 eq.), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (Xantphos, 0.18-0.36 eq.) and dioxane (0.04-0.12M) were added, and the suspension was degassed in an argon stream at room temperature for 10 min. Subsequently, the appropriate amide (1.0-1.2 eq.) and the appropriate 7-chloro-4-oxo-1,4-dihydro-1,8-naphthyridine (1.0 eq.) were added. The mixture was stirred at 80-110 C. for 1 h (or until conversion was complete by analytical HPLC or thin-layer chromatography with appropriate eluent mixtures). The mixture was cooled to RT and all volatile components were removed under reduced pressure, or alternatively the reaction mixture was poured into water, the pH was adjusted to pH 1 with 1M aqueous hydrochloric acid, the mixture was extracted with ethyl acetate, the combined organic phases were washed with saturated aqueous sodium chloride solution, dried over magnesium sulphate and filtered, and the solvent was removed under reduced pressure. The crude product was then purified either by normal phase chromatography (eluent: cyclohexane/ethyl acetate mixtures or dichloromethane/methanol mixtures) or preparative RP-HPLC (water/acetonitrile gradient). According to GP2, 560 mg (1.22 mmol) of the compound from Example 101A were reacted with 124 mg (1.22 mmol) of <strong>[68108-18-9](4S)-4-hydroxypyrrolidin-2-one</strong> (CAS: 68108-18-9) in the presence of 254 mg (1.84 mmol) of potassium carbonate, 49.4 mg (220 μmol) of palladium(II) acetate and 255 mg (440 μmol) of Xantphos in 11.2 ml of 1,4-dioxane. Subsequently, the volume of the mixture was reduced under reduced pressure, and the residue was acidified with 1N aqueous hydrochloric acid and dichloromethane. The crude product was purified by means of normal phase chromatography (cyclohexane-ethyl acetate gradient), and 316 mg (49% of theory; 99% purity) of the title compound were obtained. 1H-NMR (400 MHz, DMSO-d6): δ [ppm]=10.36 (d, 1H), 8.84 (s, 1H), 8.71 (d, 1H), 8.52 (dd, 1H), 7.92-7.82 (m, 1H), 7.66-7.59 (m, 1H), 7.41-7.33 (m, 1H), 5.32 (dd, 1H), 4.48-4.35 (m, 1H), 4.31-4.26 (m, 1H), 3.72-3.61 (m, 1H), 3.52-3.42 (m, 1H), 3.00-2.87 (m, 1H), 2.42-2.32 (m, 1H), 1.29-1.19 (m, 1H), 0.71-0.50 (m, 3H), 0.39-0.30 (m, 1H). LC-MS (Method 1): Rt=1.06 min; 523 [M+H]+. 310 mg of the title compound (diastereomer mixture) were separated into the diastereomers by chiral HPLC (preparative HPLC: column: Daicel Chiralpak IE 5 μm 250×20 mm; eluent: 50% ethanol, 50% isohexane; temperature: 25 C.; flow rate: 15 ml/min; UV detection: 210 nm). This gave (in the sequence of elution from the column) 145 mg of diastereomer 136 1 (100% de) Rt=2.95 min and 128 mg (100% de) of diastereomer 2 Rt=5.61 min. [Analytical HPLC: column: Chiraltek IE-3 3 μm; eluent: 50% ethanol, 50% isohexane; UV detection: 220 nm]. Diastereomer 1 was additionally purified by means of preparative HPLC (column: Chromatorex C18, 10 μm, 125×30 mm, solvent: acetonitrile/0.05% 78 formic acid gradient; (0 to 3 min. 10% 34 acetonitrile to 35 min. 90% acetonitrile and a further 3 min. 90% acetonitrile)), and 129.7 mg (20% of theory, 99% purity) of the title compound from Example 284 were obtained. Diastereomer 2 was additionally purified by means of preparative HPLC (column: Chromatorex C18, 10 μm, 125×30 mm, solvent: acetonitrile/0.05% formic acid gradient; (0 to 3 min. 10% acetonitrile to 35 min. 90% acetonitrile and a further 3 min. 90% acetonitrile)), and 112 mg (17% of theory, 99% purity) of the title compound from Example 271 were obtained. Example 284 N-[(15S)-1-cyclopropyl-2,2,2-trifluoroethyl]-1-(2,4-difluorophenyl)-7-[(4S)-4-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide (diastereomer 1) 1H-NMR (400 MHz, DMSO-d6): δ [ppm]=10.11 (d, 1H), 9.08 (s, 1H), 8.74 (d, 1H), 8.55 (d, 1H), 7.64-7.56 (m, 2H), 5.91 (d, 1H), 4.84-4.70 (m, 1H), 4.43-4.35 (m, 1H), 3.62-3.53 (m, 1H), 3.38-3.32 (m, 1H), 2.36-2.26 (m, 1H), 1.96-1.60 (m, 3H), 0.98 (t, 3H). LC-MS (Method 3): Rt=1.89 min; 529 [M+H]+. |