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CAS No. : | 19444-84-9 | MDL No. : | MFCD00134268 |
Formula : | C4H6O3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | FWIBCWKHNZBDLS-UHFFFAOYSA-N |
M.W : | 102.09 | Pubchem ID : | 545831 |
Synonyms : |
|
Num. heavy atoms : | 7 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.75 |
Num. rotatable bonds : | 0 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 21.67 |
TPSA : | 46.53 Ų |
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) : | -7.19 cm/s |
Log Po/w (iLOGP) : | 0.67 |
Log Po/w (XLOGP3) : | -0.37 |
Log Po/w (WLOGP) : | -0.71 |
Log Po/w (MLOGP) : | -0.79 |
Log Po/w (SILICOS-IT) : | 0.48 |
Consensus Log Po/w : | -0.14 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -0.24 |
Solubility : | 58.8 mg/ml ; 0.576 mol/l |
Class : | Very soluble |
Log S (Ali) : | -0.14 |
Solubility : | 73.2 mg/ml ; 0.717 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | 0.26 |
Solubility : | 187.0 mg/ml ; 1.83 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.85 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* 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 |
---|---|---|
With barium hydroxide octahydrate In water at 100℃; for 15h; | 8 Experiment 8 (According to the Invention):9.5 g (0.035 mol) of PBr3 were slowly added to 30 g (0.348 mol) of γ-butyrolactone at 0° C. Then, over a period of 3 h, 71.9 g (0.450 mol) of Br2 were slowly added dropwise. After the solution had been heated at 99° C. for 6 h, H2O was added and the bromine residues were reduced with a little NaHSO3 solution. Thereafter 220 g (0.7 mol) of Ba(OH)2.8H2O were added and the solution was heated at 100° C. for 15 h. The barium was precipitated with conc. H2SO4, the precipitate was filtered off with suction, and the solution was evaporated to dryness. The solid was taken up in ethanol and insolubles were removed. The EtOH was removed and the remaining solid was distilled at 110° C. (6·10-3 mbar), with marked elimination of water occurring.The resulting colorless oil was distilled once again to result in 8.2 g (0.08 mol, yield: 23%) of D,L-α-hydroxy-γ-butyrolactone. | |
90.1 g | With potassium carbonate In water for 2h; Reflux; | 2 Preparation of α-hydroxy-γ-butyrolactone Dissolve 217g potassium carbonate in 1L deionized water and heat to reflux,Slowly add 172.5 g of the crude product of α-bromo-γ-butyrolactone obtained in Example 1 dropwise,After the dripping is completed, the reaction is continued with heat preservation and stirring for 2 hours, and the reaction is reduced to room temperature177 mL of concentrated hydrochloric acid was added dropwise, and then the reaction mixture was concentrated to dryness under reduced pressure.Add 500 mL of absolute ethanol to the residue and stir for 30 minutes.Then filtered to remove the insoluble matter, the filtrate was concentrated under reduced pressure to remove the solvent to obtain the crude product.After distillation under reduced pressure, 90.1 g of α-hydroxy-γ-butyrolactone was obtained as a colorless oily liquid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | In N,N-dimethyl-formamide for 8h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With 15-crown-5; sodium hydride In tetrahydrofuran at 22℃; for 15h; | |
With N-ethyl-N,N-diisopropylamine |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With TEA In tetrahydrofuran for 4h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With 1H-imidazole In N,N-dimethyl-formamide at 0 - 20℃; for 3h; Inert atmosphere; | 9.1 Step 1: 3-[tert-butyl(dimethyl)silyl]oxytetrahydrofuran-2-one te/f-Butyldimethylsilyl chloride (508 mg, 3.4 mmol) was added portionwise to a stirred mixture of 3-hydroxytetrahydrofuran-2-one (0.2 mL, 2.6 mmol) and imidazole (357 mg, 5.2 mmol) in DMF (4 mL) at 0 °C under argon. The reaction mixture was allowed to warm to rt and stirred at that temperature for 3h. Saturated aq. ammonium chloride (10 mL) was added. The aqueous mixture was extracted with DCM (3 x 10 mL). The organic extracts were combined, dried over sodium sulfate and concentrated in vacuo. Purification by flash chromatography (50 g KP-SIL, 0% to 30% EtOAc in cyclohexane afforded 3-[tert- butyl(dimethyl)silyl]oxytetrahydrofuran-2-one (527 mg, 95%) as a colourless oil. 1 H NMR (500 MHz, chloroform-d) δ 4.44 - 4.37 (m, 2H), 4.23 - 4.18 (m, 1 H), 2.50 - 2.43 (m, 1 H), 2.28 - 2.19 (m, 1 H), 0.93 (s, 9H), 0.18 (s, 3H), 0.16 (s, 3H). |
94% | With 1H-imidazole; dmap In dichloromethane at 30℃; for 16h; | 75.1 Step 1: 3-((tert-butyldimethylsilyl)oxy)dihydrofuran-2(3H)-one To a solution of 75-1 (300 mg, 2.94 mmol, 0.23 mL, 1 eq) in DCM (3 mL) were added imidazole (400.1 mg, 5.88 mmol, 2 eq ), DMAP (359.0 mg, 2.94 mmol, 1 eq) and 75-la (531.5 mg, 3.53 mmol, 0.43 mL, 1.2 eq). The mixture was stirred at 30°C for 16 h. The reaction mixture was diluted with water (20 mL) and extracted with EA (20 mL *3). The combined organic layers were washed with water (20 mL *2) and brine (20 mL*2), dried over Na2S04, filtered and concentrated under reduced pressure give 75-2 (664 mg, 2.76 mmol, 94.0% yield). 1H NMR (400 MHz, CDCl3) d 4.44 - 4.33 (m, 2H), 4.18 (dt, J= 6.4, 9.2 Hz, 1H), 2.50 - 2.42 (m, 1H), 2.21 (qd, 7= 8.8, 12.6 Hz, 1H), 0.90 (s, 9H), 0.15 (d, J= 9.3 Hz, 6H) |
84% | With 1H-imidazole In acetonitrile at 25℃; for 24h; |
84% | With 1H-imidazole In N,N-dimethyl-formamide at 25℃; for 16h; | |
70% | With 1H-imidazole; dmap In acetonitrile at 20℃; for 16h; | |
With 1H-imidazole In N,N-dimethyl-formamide at 20℃; for 3h; | 68; 91.A To a solution of 3-hydroxydihydrofuran-2(3H)-one (5 g, 49 mmol) in anhydrous DMF (50 niL) was added imidazole (6.7 g, 98 mmol) and TBDMS chloride (8.1 g, 54 mmol). The reaction was allowed to stir under an N2 atmosphere at room temperature overnight. The reaction was diluted with diethyl ether and washed with 1 N aqueous HCl x 2 then brine x 1. The organic phase was dried over Na2SO4 and the solvent removed in vacuo to yield 3-(tert- butyldimethylsilyloxy)dihydrofuran-2(3H)-one (11 g, 49 mmol) as a clear oil. [M+η] calc'd for Ci0H20O3Si, 217; found, 217. Example 91. (S)-4-((Z)-((λ)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4- methyl-7,8-dihydropyrido[4,3-rf]pyrimidin-5(6H)-ylidene)aminooxy)-2-hydroxybutanoic acid (Compound 86)Step A.[0656] To a solution of (S)-3-hydroxydihydrofuran-2(3H)-one (91a, 5 g, 49 mmol) in anhydrous DMF (40 niL) was added imidazole (6.7 g, 98 mmol) and TBDMS-chloride (8.1 g, 54 mmol) and the reaction is stirred for 3 h. The reaction was diluted with diethyl ether and washed with IN HCl x 3. The organic phase was dried over anhydrous sodium sulfate and the solvent was removed in vacuo to yield (S)-3-(te?t-butyldimethylsilyloxy)dihydrofuran-2(3H)-one (91b) as a clear oil (10.6 g, 49 mmol). 1H NMR (400 MHz, CHLOROFORM-d) δ 0.15 (s, 3 H), 0.18 (s, 3 H), 0.86 - 0.99 (m, 9 H), 2.23 (dq, J = 12.63, 8.67 Hz, 1 H), 2.46 (dddd, J = 12.63, 7.58, 6.57, 3.28 Hz, 1 H), 2.84 - 3.01 (m, 1 H), 4.20 (td, J = 9.16, 6.44 Hz, 1 H), 4.33 - 4.47 (m, 2 H). | |
With 1H-imidazole | 7 Preparation of hydroxyalkyl segments. 2-Hydroxy-[gamma]-butyrolactone 120 was used as a starting material. (This compound is commercially available as both R and S isomers.) Following the protection of hydroxy group with t-butyldimethylsilyl chloride (TBDMSCl), the resulting lactone 121 was treated with a THF solution of EtNH2. The resulting hydroxy amide 122 was subjected to a Mitsunobu reaction with phthalimide (PhTh), diethylazodicarboxylate (DEAD), and triphenylphosphine, followed by deprotection with hydrazine to obtain amine 123. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With diethylamino-sulfur trifluoride In dichloromethane at -78 - 20℃; for 2h; Inert atmosphere; | 429.1 Step 1. Synthesis of 3-fluorodihydrofuran-2(3H)-one To a solution of a-Hydroxy-y-butyrolactone (CAS No. 19444-84-9, 3.3 g, 32.3 mmol, 1.0 eq) in DCM (100 mL) was added DAST (13.0 mL, 96.9 mmol, 3.0 eq) at -78 °C under N2 atmosphere. The mixture was stirred at -78 °C for 1 h and stirred at rt for 1 h. The mixture was then slowly poured into saturated aqueous NaHC03 solution (200 mL) at 0 °C, and extracted with DCM (60 mL x 2). The organic layers were dried over anhydrous Na2S04 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/EA = 10/1) to give 3-fluorodihydrofuran-2(3H)-one (2.2 g, Y: 65%) as colorless oil. 1H NMR (400 MHz, CDC13) δ: 5.29-5.12 (m, 1H), 4.53-4.78 (m, 1H), 4.35-4.29 (m, 1H), 2.75-2.64 (m, 1H), 2.59-2.44 (m, 1H). |
58% | With diethylamino-sulfur trifluoride In dichloromethane at 0 - 20℃; for 3h; Inert atmosphere; | |
55% | With 4,4'-diaminostilbene-2,2'-disulfonic acid In dichloromethane at 20℃; for 12h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With dmap In N,N-dimethyl-formamide at 20℃; for 12h; | |
With 1H-imidazole In dichloromethane at 0 - 25℃; for 2h; Inert atmosphere; | 1 Intermediate 8o: 3-[(tert-butyldiphenylsilyl)oxyJoxoIan-2-one Intermediate 8o: 3-[(tert-butyldiphenylsilyl)oxyJoxoIan-2-one To a stirred suspension 3-hydroxyoxolan-2-one (CM ; 1.94 g, 19.0 mmol) and imidazole (2.98 g, 43.7 mmol) in DCM (30 mE) under nitrogen at o °C was added tertbutyl(chloro)diphenylsilane (5.86 mE, 22.80 mmol). The reaction was stirred at room temperature for 2 hours. The mixture was partitioned between DCM and water. The organics were dried (H-fit) and concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-20 % ethyl acetate/petroleum ether) to afford the title compound.‘H NMR (400 MHz, DM80-cl6) 6 ppm 1.03 (s, 9 H) 2.10 - 2.31 (m, 2 H) 3.99 - 4.11 (m,H) 4.22 - 4.3° (m, iH) 4.55 - 4.62 (m, 1 H) 7.40 - 7.50 (m, 6 H) 7.63 - 7.70 (m, 2 H) 7.70 - 7.77 (m, 2 H) | |
With 1H-imidazole In dichloromethane at 20℃; for 2h; | 175.2 [0940] Synthesis of compound (±)-175.2. To a solution of (±)-175.1 (9.5 g, 93.06 mmol, 1.0 equiv) and imidazole (14.55 g, 214.03 mmol, 2.3 equiv) in dichloromethane (150 mL) at 0 °C was added tert-butyldiphenylchlorosilane (31.04 g, 111.67 mmol, 1.2 equiv). The reaction mixture was allowed to warm to rt and stirred for 2 h. It was poured over ice-water and was extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash, 6% ethyl acetate in hexane) to afford (±>175.2. 1H NMR (DMSO-d6, 400 MHz): δ 7.74-7.65 (m, 4H), 7.51-7.39 (m, 6H), 4.61-4.56 (m, 1H), 4.28-4.24 (m, 1H), 4.10-4.04 (m, 1H), 2.29-2.14 (m, 2H), 1.03 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | Stage #1: 3-hydroxyoxolan-2-one With sodium hydride In tetrahydrofuran at 20℃; for 0.25h; Stage #2: benzyl bromide In tetrahydrofuran; N,N-dimethyl-formamide at 20℃; for 46h; | |
80% | With tetra-(n-butyl)ammonium iodide; silver(l) oxide In dichloromethane at 20℃; for 30h; Darkness; | |
61% | With tetra-(n-butyl)ammonium iodide; sodium hydride In tetrahydrofuran at 20℃; for 3h; |
60% | With silver(l) oxide In dichloromethane at 20℃; for 10h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | Stage #1: 1,3-DIOXOLANE; acrylic acid methyl ester With oxygen; toluene-4-sulfonic acid In isopropyl alcohol at 70℃; for 6h; Stage #2: With hydrogen In isopropyl alcohol at 60℃; for 6h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | Stage #1: 2-hydroxy-4-oxo-butyric acid With sodium tetrahydroborate In methanol at 20℃; for 1h; Stage #2: With hydrogenchloride In water at 20℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With sulfuric acid; acetic anhydride at 0℃; for 0.25h; | |
90% | Stage #1: 3-hydroxyoxolan-2-one With sulfuric acid; acetic anhydride at 0℃; for 0.25h; Stage #2: With dmap at 100℃; for 3h; | 3-hydroxy butyrolactone (3) (10 mmol, 0.779 ml) and acetic anhydride (10 mmol, 0.95 ml) were mixed in an RB and 2 drops of conc. H2SO4 was added at 0° C. The pale yellow solution became dark yellow. The reaction mixture was stirred for 15 min. DMAP was added to neutralize H2SO4 and heated at 100° C. for 3 h in an oil bath. The reaction mixture was distilled at atm pressure to remove acetic acid and followed by vacuum distillation to yield the desired product, 4 (90% yield). 1H NMR (CDCl3): δ 4.83(m, 2H), 6.06 (m, 1H), 7.56 (m, 1H). 13C NMR (CDCl3): 72.11, 121.00, 153.22, 173.76. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With hydrogen; toluene-4-sulfonic acid In water; isopropyl alcohol at 60℃; for 6h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With 1H-imidazole In N,N-dimethyl-formamide at 25℃; for 8h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With potassium carbonate; acetyl chloride In dichloromethane at 20℃; | 1 A mixture of racemic α-hydroxy-γ-butyrolactone (25 g; 0.25 mol), DMAP (1.5 g), acetylchloride (25.5 ml ; 0.37 mol) in CH2Cl2 (325 mL) was added solid K2CO3 (50 g) in portions (slightly exothermic). The reaction mixture was stirred at room temperature overnight, filtered and evaporated to dryness. Column chromatography (Petrol ether 80-100: EtOAc=2:1) gave 26.4 g (75%) racemic α-acetoxy-γ- butyrolactone. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | In water at 70℃; for 3h; Aqueous phophate buffer; | 11 Example 11 An aqueous solution of 4-chloro-2-hydroxybutylamide (10% by mass, 100 ml, containing 20 mM phosphatebuffer) was reacted in a water bath at 70C for 3 hours. During the reaction, a pH controller was used to maintain apH of 3.5 by adjusting with 24% by mass NaOH.After the reaction mixture was extracted with ethyl acetate and evaporated under reduced pressure to removethe solvent, the residue was analyzed by IR, 1H-NMR and 13C-NMR to confirm the production of a-hydroxy-g-butyrolactone.The amount of residual 4-chloro-3-hydroxybutylamide was 1% or less of the initial amount and the yield was54%, as quantified in the same manner as used in Example 1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With caesium carbonate In DMF (N,N-dimethyl-formamide) at 70℃; for 76h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
16% | With sodium hydride; In tetrahydrofuran; at -10 - 25℃; for 0.666667h; | Sodium hydride (60% dispersion in mineral oil, 0.44 g, 18.34 mmol) was added in portions to a cold (-10 0C) stirring solution consisting of 2-hydroxy-gamma- butyrolactone (1.29 g, 12.6 mmol) in tetrahydrofuran (25 mL). The reaction mixture was stirred for about 40 minutes before direct addition of the solid 4- fluoro-(2-trifluoromethyl)-benzonitrile (2.0 g, 11.0 mmol). The reaction mixture was allowed to gradually warm to room temperature overnight. Water was added and the product was extracted into ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, was dried over anhydrous magnesium sulfate, and was filtered and concentrated. The crude product was purified by flash chromatography. Elution with a gradient of 25-50% ethyl acetate in hexanes afforded a white solid. The product was recrystallized from ethyl acetate-hexanes to obtain 0.45 g (16 % yield) of a white crystalline solid; melting point 120 0C; 1H-NMR (400 MHz; CDCl3) delta 7.79 (d, IH, J=8.5 Hz), 7.43 (d, IH, J=2.4 Hz), 7.33 (dd, IH, J=8.5, 2.4 Hz), 5.08 (t, IH, J=7.8 Hz), 4.57 (m, IH), 4.43 (m, IH), 2.78 (m, IH), 2.56 (m, IH); 19F-NMR (376 MHz; CDCl3) 6 -62.72 (s, 3F); MS (APCI) 270.0 (M-I); microanalysis for C12H8F3O3N (Theoretical/Found): C, 53.15/53.01; H, 2.97/2.81; N, 5.16/4.97; F, 21.02/21.24. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
29% | With triphenylphosphine; diethylazodicarboxylate; at 20℃; | Step C: Preparation (S)-3-(4-((tert-butyldimethylsilyloxy)methyl)phenoxy)-dihydrofuran-2(3H)-one: A solution of diethyl azodicarboxylate (40% toluene, 15 mL) was slowly added to a 0 C. solution of (R)-3-hydroxy-dihydrofuran-2(3H)-one, <strong>[126070-20-0]4-((tert-butyldimethylsilyloxy)methyl)phenol</strong>, and triphenylphosphine. The reaction was stirred at room temperature overnight. The volatiles were removed under reduced pressure and the residue was taken up in diethyl ether and filtered. The filtrate was then successively washed with H2O and brine. The organics were dried over MgSO4 and concentrated under reduced pressure. The residue was chromatographed (1:4 ethyl acetate/hexanes) to provide the desired product (2.0 g, 29%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With chloro-trimethyl-silane; triethylamine In tetrahydrofuran | C.A 3-Benzyloxy-4-hydroxy-5-(2-hydroxy)ethyl-2(5H)-furanone A. A solution of 10.0 g (98 mmol) of α-hydroxy-γ-butyrolactone in 100 mL of anhydrous THF under argon was cooled to 0-5° C. with magnetic stirring. Addition of 14 mL (110 mmol) of trimethylsilyl chloride and 16 mL (115 mmol) of triethylamine immediately produced a white precipitate. The suspension was warmed to room temperature and stirred for 4 hours. The suspension was poured into a separatory funnel containing 100 mL of H2 O and 500 mL of ether. The organic layer was washed with 50 mL of H2 O, 50 mL of brine, dried (MgSO4) and concentrated. Purification (Kugelrohr distillation) provided 14.7 g (90% yield) of α-trimethylsilyloxy-γ-butyrolactone bp 80-100° C. (8 mm Hg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With chloro-trimethyl-silane; sodium iodide In ethanol; acetonitrile | 3 Production of R-ethyl (+)-4-iodo-2-hydroxybutanoate Example 3 Production of R-ethyl (+)-4-iodo-2-hydroxybutanoate 20 ml of an acetonitrile solution of trimethylsilyl chloride was slowly added into 50 ml of an acetonitrile solution containing 1.3 g of R-(+)-α-hydroxy-γ-butyrolactone (70% ee) and 5.7 g of sodium iodide. After the solution was heated under reflux for 14 hours, 10 ml of ethanol was added dropwise and the solution was stirred at room temperature for 10 minutes. Acetonitrile was distilled away, and ether was added to the residue. The ether layer was washed with sodium bicarbonate and then with a saturated saline solution. After the ether layer was dried on anhydrous magnesium sulfate, ether was distilled away. 0.73 g of the desired R-ethyl (+)-4-iodo-2-hydroxybutanoate was obtained. Specific rotation: [α]D +4.0° (C1.15, CHCl3) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide In dichloromethane | 15.1 Preparation of 1(3-bromo-4-fluorophenyl)3(N(t-butylcarbamoyl)ethylaminopyrrolidin-2-one Step 1: Preparation of 1(3-bromo-4-fluorophenyl)3-hydroxypyrrolidin-2-one. 3-Bromo-4-fluoroaniline (20 g) and 3-hydroxy-2-ketotetrahydrofuran (8.9 g) were mixed and heated to 150° C. for 64 hours. The mixture was allowed to cool and diluted with dichloromethane (200 ml). A solution (37 ml) of sodium hydroxide (10molar) was added and the mixture left to stand for an hour. The solid was filtered off and washed with dichloromethane, and suspended in more dichloromethane (200 ml). The mixture was acidified with concentrated hydrochloric acid and stirred for an hour. The organic layer was separated, washed three times with water, dried (magnesium sulphate) and concentrated to yield a pale brown solid (25.4 g) identified as the title compound. The NMR spectrum was consistent with this structure. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
potassium carbonate; In dichloromethane; water; N,N-dimethyl-formamide; | Preparation of (+/-)-3-(4,6-dimethoxy-2-pyrimidinyloxy)-2-dihydrofuranone 1.75 g (10 mmol) of <strong>[13223-25-1]2-<strong>[13223-25-1]chloro-4,6-dimethoxypyrimidine</strong></strong>, 1.02 g (10 mmol) of alpha-hydroxy-gamma-butyrolactone and 0.26 g (2.5 mmol) of sodium methanesulfinate were heated in the presence of 2.07 g (15.0 mmol) of potassium carbonate in 10 ml of N,N-dimethylformamide to 120 C. with stirring. After 2 hours, the solvent was removed in a rotary evaporator at 70 C./20 mbar. The residue was taken up in 30 ml of water and 30 ml of dichloromethane. After the organic phase had been separated off, the aqueous phase was again extracted with 20 ml of dichloromethane. The combined organic phases was washed with water, dried over magnesium sulfate and evaporated. The title product was obtained in a yield of 0.43 g (15.5 percent of theory) in the form of a pale brown oil (GC content 94 percent). Other data concerning the title compound was: MS: 240; 210; 181; 157. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With dmap; triethylamine In water; ethyl acetate | 1.A A. A. (R)-α-(Methylsulfonyl)oxy-γ-butyrolactone Triethylamine (45ml, 323mmol) and 4-N,N-dimethylaminopyridine (3.6g, 29mmol) in anhydrous AcOEt (75ml) were added to a stirred solution of (R)-(+)-α-hydroxy-γ-butyrolactone (30g, 294mmol) in anhydrous AcOEt (300ml), under N2, at -40°. The solution was stirred for 10min. Methanesulfonyl chloride (25ml, 323mmol) was added slowly to the reaction, maintaining the temperature below -35°. The mixture was stirred for 2h at -40°. Upon completion the mixture was allowed to warm up to ambient temperature. The mixture was diluted with AcOEt (450ml) and filtered. The solid was washed with AcOEt (3x60ml). The filtrate was washed with a solution of 50% H2O and 50% brine (60ml). The organic layer was washed with 1 N HCI (45ml), a solution of 50% H2O and 50% saturated brine (45ml), a saturated aqueous NaHCO3 solution (45ml), and a solution of 50% H2O and 50% brine (2x45ml). The solvent (780ml) was removed under reduced pressure and hexanes (500 ml) was added to the mixture. The mixture was stirred at 5° for 2h. The mixture was filtered, and solid was dried under vacuum at room temperature to yield (R)-α-(methylsulfonyl)oxy-γ-butyrolactone as a white solid (45g, 85%). 1H-NMR (CDCl3): δ 5.32 (1H, t, J=8.7Hz), 4.52 (1H, m), 4.33 (1H, m), 3.27 (3H, s), 2.76 (1H, m), 2.56 (1H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 20.0℃; for 10.0h; | 4-Chloro-6-hydroxy-quinazoline (77 mg; 0.43 mmol), 131 mg (1.28 mmol) of 2-hydroxy-butyrolactone and 336 mg (1.28 mmol) of triphenyl phosphine were dissolved in 7 ml of THF and 558 mg (1.28 mmol) of diethyl azodicarboxylate was added thereto at room temperature. The reaction solution was further stirred at room temperature for 10 hours, water was added thereto and the mixture was extracted with chloroform. The organic layer was dried and concentrated and the resulting residue was purified by a silica gel column chromatography (hexane : ethyl acetate = 1:1) to give 4-chloro-6-(butyrolactone-2-yloxy)-quinazoline. The resulting chloro compound was heated to stirr at 140C for 30 minutes with 60 mg (0.147 mmol) of 1-methyl-1H-pyrazole-3-amine in 0.2 ml of phenol. Chloroform was added to the reaction solution and the mixture was washed with a saturated aqueous solution of sodium hydrogen carbonate. The organic layer was dried and concentrated and the resulting residue was purified by a reversed phase preparative HPLC (0.1% TFA-containing water : acetonitrile = 90:10 ? 10:90) to give 1 mg (yield: 1%) of the title compound as a yellow solid. 1 HNMR (CDCl3) delta: 2.39-2.44 (1H, m), 2.95-2.96 (1H, m), 3.89 (3H, s), 4.39-4.46 (1H, m), 4.51-4.53 (1H, m), 5.35-5.38 (1H, m), 6.73-6.75 (1H, m), 7.32-7.33 (1H, m), 7.52-7.53 (1H, m), 7.85 (1H, d, J=8.6Hz), 8.17 (1H, s), 8.51 (1H, s) ESI-MS(m/e):326[M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With silver(l) oxide In chloroform for 1h; Heating; | |
75% | With silver(l) oxide In acetonitrile at 75℃; for 4h; Inert atmosphere; | 1 Step 1: 3-methoxytetrahydrofuran-2-one Silver oxide (520 mg, 2.2 mmol) was added portionwise to a stirred solution of 3- hydroxytetrahydrofuran-2-one (0.15 mL, 1.9 mmol) and iodomethane (0.36 mL, 5.8 mmol) in acetonitrile (5 mL) at rt under Ar. The reaction mixture was subsequently stirred at 75 °C for 4h. The reaction mixture was allowed to cool to rt, filtered and the solid residue was washed with Et20 (3 x 15 mL). The filtrate was concentrated in vacuo and directly dry loaded onto silica gel. Purification by flash chromatography (50 g KP-SIL; 60% EtOAc in cyclohexane to 100% EtOAc) afforded 3-methoxytetrahydrofuran-2-one (168 mg, 75%) as a colourless oil. 1 H NMR (500 MHz, chloroform-d) δ 4.43 (ddd, J = 9.1 , 8.1 , 4.3 Hz, 1 H), 4.26 (ddd, J = 9.1 , 8.0, 6.9 Hz, 1 H), 4.03 (t, J = 7.6 Hz, 1 H), 3.59 (s, 3H), 2.56 - 2.48 (m, 1 H), 2.30 - 2.21 (m, 1 H). |
With silver(l) oxide In chloroform at 63℃; for 3h; Darkness; | B12.a a) 3-methoxvdihydrofuran-2(3H)-one A soution of apha-hydroxy-butyroactone (1.33 g, 13.03 mmoD, methy iodide (8.15 m,130 mmo) and si’ver oxide (9.7 g, 41.9 mmo) in dry CHC3 (43.4 mD was stirred at63°C for 3h in absence of ight. The reaction mixture was cooed and fitered over a ceitepad and the fitrate was concentrated to afford 3-methoxydihydrofuran-2(3H)-one. 1HNMR (400 MHz, DMSO-d6) 6 ppm: 4.31 (tdd, IH), 4.24-4.14 (m, 2H), 3.41 (d, 3H). 2.55-2.45 (m, IH), 2.12-2.01 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 20℃; for 16h; | 29 Intermediate 29: 3-[6-(Azetidine-1-carbonyl)pyridin-3-yl]oxy-N-(5-methylpyrazin-2-yl)-5-(2-oxooxolan-3-yl)oxy-benzamide 3-[6-(Azetidine-1-carbonyl)pyridin-3-yl]oxy-5-hydroxy-N-(5-methylpyrazin-2-yl)benzamide (Intermediate 1) (203 mg, 0.5 mmol), 3-hydroxyoxolan-2-one (CAS no. 19444-84-9) (0.078 mL, 1 mmol) and triphenyl phosphine (262 mg, 1 mmol) in anhydrous THF (10 mL) under argon at 0° C. was treated dropwise with DIAD (0.20 mL, 1 mmol). The mixture allowed to warm to room temperature and stirred for 16 hours. The solvent was removed by evaporation under reduced pressure and the residue was purified by chromatography on silica eluding with 0-4% methanol:DCM to give product (212 mg 86%). 1H NMR δ (400 MHz, CDCl3) 2.29 (quintet, 2H), 2.40-2.48 (m, 1H), 2.50 (s, 3H), 2.69-2.78 (m, 1H), 4.18 (t, 2H), 4.33 (q, 1H), 4.49 (t, 1H), 4.64 (t, 2H), 4.99 (t, 1H), 6.89 (s, 1H), 7.18 (s, 1H), 7.33 (d, 1H), 7.36 (s, 1H), 8.06 (d, 1H), 8.08 (s, 1H), 8.28 (s, 1H), 8.41 (s, 1H), 9.46 (s, 1H); m/z 490 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 3; (S)-methyl 4-(3-(6-chloro-3,4-dihydroquinolin-1(2H)-yl)-2-oxopyrrolidin-1-yl)phenylsulfonylcarbamate; Step 1: (S)-3-(6-chloro-3,4-dihydroquinolin-1(2H)-yl)dihydrofuran-2(3H)-one; Under an N2 atmosphere at -20 C., N,N-diisopropylethylamine (1.74 mL, 10 mmol) was added dropwise to a solution of (R)-(+)(alpha-hydroxy-gamma-butyrolactone (0.39 mL, 5 mmol) in dichloromethane (8 mL). Then trifluoromethanesulfonic anhydride (0.88 mL, 5.25 mmol) was added dropwise by maintaining internal temperature of the reaction mixture <-20 C. Upon completion of addition, the mixture was stirred at -20 C. for 1 hour. Then at -20 C., 6-Cl tetrahydroquinolin (1.26 g, 7.5 mmol) was added dropwise. The reaction was allowed to warm to RT over a period of 30 minutes and continued to stir at RT for 16 h. The reaction mixture was diluted with 200 mL of ethylacetate and washed with saturated sodium bicarbonate (3×). The organic layer was washed with a saturated aqueous NaCl solution (2×). The solution was dried over magnesium sulfate, filtered, and concentrated. Purification of the residue by silica gel chromatography using 10-30% ethyl acetate in hexane gave (S)-3-(6-chloro-3,4-dihydroquinolin-1(2H)-yl)dihydrofuran-2(3H)-one (1.14 g) as white solid. LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=252.2; tR=3.20 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | Stage #1: 3-hydroxyoxolan-2-one; sodium thiomethoxide In N,N-dimethyl-formamide at 153℃; for 3h; Stage #2: With hydrogenchloride; water | 7 A) Synthesis of D,L-2-hydroxy-4-methylthiobutyric Acid (MHA); α-Hydroxy-γ-butyrolactone and sodium methylthiolate NaSCH3 were introduced into 20 ml of solvent (see table 1) and heated at the reaction temperature indicated in table 1 for a plurality of hours (reaction time). After cooling, the solvent was removed and the residue was taken up in 1N HCl. The solution was extracted with methyl tert-butyl ether, and the combined organic phases were dried over MgSO4 and evaporated to dryness.Amounts employed, reaction times, solvents and yields are to be found in table 1.The yield was determined by final weighing. The purity of the product was analyzed by 1H-NMR. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With pyridinium p-toluenesulfonate In dichloromethane at 20℃; for 3h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With N,N,N,N,-tetramethylethylenediamine In dichloromethane at -78℃; for 0.5h; | |
35% | With pyridine In dichloromethane at 20℃; for 8h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 66% 2: 7% | With Oxone; C8H6O4(2-)*Cu(2+) In toluene at 60 - 110℃; for 11h; Molecular sieve; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With di-tert-butyl-diazodicarboxylate; triphenylphosphine; In toluene; at 0 - 20℃; for 12.0833h;Inert atmosphere; | Step A: To a suspension of (R)-3-hydroxydihydrofuran-2(3H)-one (500 mg,4.9 mmol) in toluene (15 mL) was added triphenylphosphine (1.54 g, 5.88 mmol) and 6- bromopyridin-3-ol (1.02 g, 5.88 mmol). The solution was cooled to 0 C and degassed with nitrogen bubble for 10 minutes. Di-tert-butyl diazene-l,2-dicarboxylate was dissolved in toluene (5 mL) and added over a 5 minute period. The reaction was allowed to stir for 12 hours with warming to ambient temperature. The reaction was concentrated in vacuo and the resulting material purified by silica gel chromatography eluting 1 : 1 hexanes/EtOAc to yield (S)-3-(6-bromopyridin-3-yloxy)dihydrofuran-2(3H)-one (1.0 g, 79%) as an off white solid. |
79% | [00399] Step A: To a suspension of (R)-3-hydroxydihydrofuran-2(3H)-one (500 mg,4.9 mmol) in toluene (15 mL) was added triphenylphosphine (1.54 g, 5.88 mmol) and 6- bromopyridin-3-ol (1.02 g, 5.88 mmol). The solution was cooled to 0 C and degassed with nitrogen for 10 minutes. Di-tert-butyl diazene- 1 ,2-dicarboxylate was dissolved in toluene (5 mL) and added over a 5 minute period. The reaction was allowed to stir for 12 hours with warming to ambient temperature. The reaction was concentrated in vacuo and the resulting material was purified by silica gel chromatography, eluting 1 : 1 hexanes/EtOAc, to yield (S)- 3-(6-bromopyridin-3-yloxy)dihydrofuran-2(3H)-one (1.0 g, 79%) as an off-white solid. | |
79% | With di-tert-butyl-diazodicarboxylate; triphenylphosphine; In toluene; at 0 - 20℃; for 12.08h;Inert atmosphere; | Step A: To a suspension of (R)-3-hydroxydihydrofuran-2(3H)-one (500 mg, 4.9 mmol) in toluene (15 mL) was added triphenylphosphine (1.54 g, 5.88 mmol) and 6- bromopyridin-3-ol (1.02 g, 5.88 mmol). The solution was cooled to 0 C and degassed with nitrogen bubble for 10 minutes. Di-tert-butyl diazene-l,2-dicarboxylate was dissolved in toluene (5 mL) and added over a 5 minute period. The reaction was allowed to stir for 12 hours with warming to ambient temperature. The reaction was concentrated in vacuo and the resulting material purified by silica gel chromatography eluting 1 : 1 hexanes/EtOAc to yield (S)-3-(6-bromopyridin-3-yloxy)dihydrofuran-2(3H)-one (1.0 g, 79%) as an off white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 3-hydroxyoxolan-2-one With water; sodium hydroxide In methanol at 20℃; for 1h; Stage #2: benzyl bromide In N,N-dimethyl-formamide at 20℃; | Synthesis of benzyl 2.4-dihydroxybutanoate To a solution of oc-hydroxylactone (10 g, 0.098 moles) in methanol (50 mL) was added sodium hydroxide (5.88 g, 0.147 moles) in water (10 mL) and allowed to stir at room temperature for about one hour. The reaction mixture was concentrated and taken in N, N'-dimethylformamide (40 mL) and benzyl bromide (14 mL, 0. 1 17 moles) was added drop wise. The reaction mixture was again allowed to stir for overnight at room temperature. After completion of reaction, solvent was evaporated under vacuum and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water, brine and dried over anhydrous sodium sulphate and evaporated under vacuum to obtain a crude product. The crude product was purified on silica gel column using 80% ethyl acetate: hexane as eluent to afford the title compound. Yield: 10.4 g LCMS: 21 1.47 (M+l), 233.5 (M+Na) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0℃; for 0.5h; | 5.a Example 5: Synthesis of 2- {r4-(6-methoxypyridin-3-yl)phenyl1(methylsulfonyl)amino} - 4-(4-oxo- l ,2,3-benzotriazin-3(4H)-yl)butanoic acid (Compound no. 19) (when Ry is halogen) (Scheme III, Path E) Step a: Preparation of A'-(4-bromophenyl)-A'-(2-oxotetrahydrofuran-3- yl)methanesulfonamide To a solution of oc-hydroxy lactone (673 mg, 0.0072 moles) at 0°C were added N- (4-bromophenyl)methanesulfonamide (1.5 g, 0.006 moles) and triphenylphosphine (2.35 g, 0.009 moles). The reaction mixture was allowed to stir for aboutl 5 minutes at 0°C and diisopropylazodicarboxylate (1.8 g, 0.0009 moles) was added. The reaction mixture was again stirred for about 30 minutes at 0°C. After completion, the reaction mixture was concentrated to get a crude product which was purified on silica gel column using 40% ethyl acetate: hexane as eluent to get the desired compound.Yield: 920 mg LCMS: 351.18 and 353.12 (Μ+ΝΗ4+) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 20℃; for 2h; | b Step b: Preparation of A'-(4,-chlorobiphenyl-4-yl)-A'-(2-oxotetrahydrofuran-3- yl)methane sulfonamide To a compound obtained from step a (10 g, 0.035 moles) in tetrahydrofuran (70 mL) were added oc-hydroxy lactone (8.8 g, 0.05 moles) and triphenylphosphine (13.9 g, 0.05 moles) at 0°C. The reaction mixture was allowed to stir for about 10 minutes and diisopropylazodicarboxylate DIAD (10.7 mL, 0.05 moles) was added to it at 0°C. The reaction mixture was again stirred for about 2 hours at room temperature. After completion, solvent was evaporated to obtain a crude product which was purified on silica gel column using 20% ethyl acetate: hexane as eluent to get the desired product.Yield: 10 g LCMS: 365.71 (M+l) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 20℃; for 2h; | d Step d: Preparation of tert-but 4-[(methylsulfonyl)(2-oxotetrahydrofuran-3- yl)amino] benzoate To an ice cooled solution alpha-hydroxy lactone (1 g, 9.80 mmoles) in tetrahydrofuran (30 mL) were added compound obtained from Step c (2.6 g, 9.80 mmoles) and triphenylphosphine (13.6 g, 14.70 mmoles). The reaction mixture was stirred for about 15 minutes and diisopropylazodicarboxylate (DIAD) (2.9 g, 14.70 mmoles) was added at same temperature. The reaction mixture was allowed to stir for about 2 hours at room temperature. After complete conversion of starting material, solvent was evaporated under vacuum to obtain a crude compound. The crude compound was purified on silica gel column using 30% ethyl acetate: hexane as elutent to get the desired product.Yield: 6 g LCMS: 354.82 (M). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 3-hydroxyoxolan-2-one With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.25h; Stage #2: 1-bromomethyl-4-bromobenzene In N,N-dimethyl-formamide; mineral oil at 20℃; | D Example D: Synthesis of 3-[(4-bromobenzvDoxy1dihydrofuran-2nH)-oneSodium hydride (1.4g, 0.058 g) was added to a solution of 2-hydroxy- butyrolactone (5 g, 0.049 mol) in dimethylformamide (50 mL) at about 0°C. The reaction mixture was stirred at same temperature for about 15 minutes and 4-bromobenzylbromide (12.2 g, 0.049 mol) was added to it. The reaction mixture was stirred at room temperature overnight and quenched with water (50 mL), extracted with ethyl acetate. Combined organic extract was washed with water and brine, dried (Na2S04) and concentrated to get crude compound, which was purified on column using 20% ethyl acetate :hexane to obtain the title compound.Yield: 6.7 g | |
6.7 g | Stage #1: 3-hydroxyoxolan-2-one With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.25h; Stage #2: 1-bromomethyl-4-bromobenzene In N,N-dimethyl-formamide at 20℃; | D Synthesis of 3-[(4-bromobenzyl)oxy]dihydrofuran-2(3H)-one Sodium hydride (1.4 g, 0.058 g) was added to a solution of 2-hydroxy-butyrolactone (5 g, 0.049 mol) in dimethylformamide (50 mL) at about 0° C. The reaction mixture was stirred at same temperature for about 15 minutes and 4-bromobenzylbromide (12.2 g, 0.049 mol) was added to it. The reaction mixture was stirred at room temperature overnight and quenched with water (50 mL), extracted with ethyl acetate. Combined organic extract was washed with water and brine, dried (Na2SO4) and concentrated to get crude compound, which was purified on column using 20% ethyl acetate:hexane to obtain the title compound. Yield: 6.7 g |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With hydrogen In water at 300℃; for 5h; | 12 Example 12 Preparation of 2-Hydroxy-γ-Butyrolactone [0253] 10 ml of catalyst 4 reduced beforehand at 450° C. and 5 ml of glass powder used as static mixer vaporizer are placed in a vertical glass reactor 22 mm in diameter. [0254] The catalytic bed is heated under a stream of 5 l/h of hydrogen to 300° C. [0255] After stabilizing the catalytic bed under these conditions for 30 minutes, injection onto the catalytic bed of an aqueous malic acid solution at 30% w/w at a flow rate of 8 ml/h is commenced. [0256] The reaction gas stream is then condensed in a receiver immersed in an ice-water bath. [0257] After injection for 5 hours under these conditions, the condensate is analyzed by GC and HPLC. [0258] For a degree of conversion of 85%, a 55% yield of 2-hydroxy-γ-butyrolactone is obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tin (IV) chloride pentahydrate In water; acetonitrile at 59.84℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With bromoacetic acid; sodium bromide In water-d2 at 135℃; for 3h; | 4 “1 Pot” Preparation of 2HBL and Effect of Adding aSalt (NaBr) The conditions used for test B were reproduced with the following performances (‘H NMR assay, after 3 hours at 135° C.): complete TTSAATh8, RR2HBL=33-39%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
24% | With Sn-Beta zeolite In 1,4-dioxane at 20 - 160℃; for 3h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 10% 2: 60% 3: 8% | With Sn-MCM-41 In methanol at 139.84℃; for 5h; Inert atmosphere; | |
1: 50% 2: 18% 3: 8% | With tin In methanol at 159.84℃; for 5h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 61% 2: 7% | With Sn-MCM-41 In methanol at 89.84℃; for 5h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 70℃; for 20h; | (ii) 1-Benzhydryl-5-nitro-3-(2-oxotetrahydrofuran-3-yl)pyrimidine-2,4(1H,3H)-dione (6) METHOD B: Diisopropylazodicarboxylate (91.1 µl, 0.46mmol, 1.50 eq) was added dropwise to a stirred solution of 1-benzhydryl-5-nitropyrimidine-2,4(1H,3H)-dione(100 mg, 0.31 mmol, 1.00 eq), 3-hydroxydihydrofuran-2(3H)-one (26.5µl, 0.34 mmol, 1.10 eq) and triphenylphosphine (121 mg, 0.46 mmol, 1.50 eq) inTHF (4.00 ml). The reaction mixture was heated at 70°C for 20h, concentrated to dryness and the residue was purified by flash chromatography (silica gel, eluting with a gradient heptane/EtOAc from 0to 30%) to afford the title compound (50.0 mg, 40%) as a white solid: MS ES+m/z 408.31 (M+H)+; 1HNMR (400MHz, DMSO-d6) δ2.40-2.50 (m, 2H), 4.30-4.60 (m, 2H), 5.55 (t, J = 9.5Hz, 0.5H), 5.82 (t, J= 9.5Hz, 0.5H), 6.98 (s, 0.5H), 7.01 (s, 0.5H), 7.25-7.50 (m, 10H), 8.48(s, 1H) mixture of rotamers. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | at 150℃; for 24h; | 49 Reference Synthesis Example 49 (0627) 1-(4-Fluorophenyl)-3-hydroxypyrrolidin-2-one Reference Synthesis Example 49 (0627) 1-(4-Fluorophenyl)-3-hydroxypyrrolidin-2-one (0628) A mixture of 3-hydroxydihydrofuran-2(3H)-one (5.00 g, 49.0 mmol) and 4-fluoroaniline (6.53 g, 59.0 mmol) was stirred at 150° C. for 1 day. After completion of the reaction, dichloromethane and 10 M sodium hydroxide aqueous solution were added to the reaction solution and the resultant mixture was filtered. To the filtrate, dichloromethane and concentrated hydrochloric acid were added to adjust pH to 1. The obtained solid was collected by filtration, washed with water, and dried under reduced pressure to obtain the title compound (6.78 g, yield 71%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
26% | Stage #1: 3-hydroxyoxolan-2-one With sodium hydride In N,N-dimethyl-formamide at 20℃; for 0.25h; Cooling with ice; Stage #2: 2-(2-bromoethoxy)tetrahydropyran In N,N-dimethyl-formamide at 100℃; for 15h; | 21a (21a) 3-[2-(tetrahydropyran-2-yloxy)ethoxy]dihydrofuran-2-one Example 21 4-acetyl-3-{4-[2-(2-oxotetrahydrofuran-3-yloxy)ethoxy]phenylamino}benzamide (21a) 3-[2-(tetrahydropyran-2-yloxy)ethoxy]dihydrofuran-2-one 3-Hydroxydihydrofuran-2-one (5.00 g, 49.0 mmol) was dissolved in dimethylformamide (100 mL) and, under ice-cooling, sodium hydride (P=60%) (1.96 g, 49 mmol) was separately added, and the mixture was stirred at room temperature for 15 min. 2-(2-Bromoethoxy)tetrahydropyran (8.59 g, 57.9 mmol) was added and the mixture was stirred at 100° C. for 15 hr. The mixture was allowed to cool, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate 1:1, V/V). The solvent of the object fraction was evaporated under reduced pressure to give the title object compound as a slightly yellow oil (2.88 g, yield 26%). 1H-NMR (CDCl3, 400 MHz) δ: 1.48-1.88 (6H, m), 2.25-2.36 (1H, m), 2.48-2.57 (1H, m), 3.46-3.54 (1H, m), 3.60-3.68 (1H, m), 3.78-3.94 (3H, m), 4.02-4.11 (1H, m), 4.18-4.27 (2H, m), 4.37-4.45 (1H, m), 4.60-4.66 (1H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34.2 mg | Stage #1: C19H22N5O4S(1-)*Na(1+) With trifluoroacetic acid; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 0℃; for 0.25h; Inert atmosphere; Stage #2: 3-hydroxyoxolan-2-one In N,N-dimethyl-formamide at 25℃; for 16h; Inert atmosphere; | To a solution of compound 1-33 (300 mg, 681.09 umol, 1 eq, Na salt) in dimethylformamide (4 mL) was added trifluoroacetic acid (87 mg, 762.41 umol, 56.45 uL, 1.12 eq), diisopropylethylamine (279 mg, 2.16 mmol, 375.49 uL, 3.17 eq) and HATU (546 mg, 1.44 mmol, 2.11 eq) at 0°C under nitrogen atmosphere, the mixture was stirred at 0°C for 15 minutes, then compound 1-35 (220 mg, 2.16 mmol, 168.00 uL, 3.17 eq) was added. The mixture was stirred at 25°C for 16 hours. LCMS showed the starting material was consumed completely and desired mass was detected. The mixture was concentrated to give crude product. The crude product was purified by prep-HPLC (column: Phenomenex Synergi C18 150*25*10um; mobile phase: [water (0.1%TFA)-ACN]; B%: 5%-35%, 10min). The fraction was adjusted to pH = 8 with sodium bicarbonate solid. The mixture was extracted with dichloromethane (20 mLx3). The combined organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford Compound (1) (34.2 mg, 68.19 umol, 10.01% yield, 100.00% purity) as a white solid. LCMS: RT = 0.821 min, purity 100.00%, m/z 502.1 [M+H]+.1H NMR (CD3OD, 400 MHz): d 8.48 (d, J = 5.2 Hz, 1H), 7.46 (s, 1H), 7.34 (dd, J1 = 4.8 Hz, J2 = 1.2 Hz, 1H), 5.52 (t, J = 9.2 Hz, 1H), 4.48 - 4.44 (m, 1H), 4.43 - 4.40 (m, 1H), 4.34 - 4.30 (m, 1H), 3.75 - 3.68 (m, 1H), 3.62 - 3.58 (m, 1H), 2.66 - 2.64 (m, 1H), 2.43 (s, 3H), 2.32 - 2.21 (m, 2H), 2.12 - 2.04 (m, 3H), 1.67 - 1.65 (m, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride In water at 100℃; | 2.1 Step 1: Preparation of l-(4-(benzyloxy)phenyl)-3-hydroxypyrrolidin-2-one : A solution of g- butirolactone (1.5 eq.) and 11 ml of 37% hydrochloric acid is added to (1 eq.) of 4- (benzyloxy)aniline. The mixture is heated at 100°C. overnight. After cooling to about 50°C. 200 ml of 2N hydrochloric acid were added dropwise under vigorous stirring and the product is collected by filtration and desiccated under vacuum at 50°C to provide l-(4-(benzyloxy)phenyl)- 3-hydroxypyrrolidin-2-one. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With toluene-4-sulfonic acid In toluene at 20℃; | 1 Dissolve 10.9 g of Intermediate II in 50 ml of dry toluene, then add 130 mg of p-toluenesulfonic acid monohydrate, and stir at room temperature for about 3 to 5 hours. TLC dot plate tracks until the reaction is complete. Then it was washed with saturated sodium carbonate solution and saturated brine successively, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 6.8 g of crude α-hydroxy-γ-butyrolactone, which was then purified by distillation under reduced pressure to obtain pure product as a colorless oily liquid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With triethylamine In dichloromethane at 25℃; for 1h; | 21 Compound 21: l-methylpiperidin-4-yl 2-(3,5-dichlorophenyl)benzo[d] oxazole-6- carboxylate A mixture of 3-hydroxytetrahydrofuran-2-one (120 mg, 1.18 mmol, 1.1 eq) and TEA (163 mg, 1.61 mmol, 1.5 eq) in DCM (6 mL) were added 2-(3,5-dichloropheny) benzo[d]oxazole-6-carbonyl chloride (350 mg, 1.07 mmol, 1 eq). The mixture was stirred at 25 °C for 1 h. The mixture was concentrated to 2 mL, then EtOH (15 mL) was added and the resulting mixture was stirred at 25 °C for 2 hrs. White solid was formed. The solid was collected by filtration and dried in vacuo to give the title compound (326 mg, 817 pmol, 76% yield, 98.2% purity) as an off-white solid. LC-MS: m/z [M]+; calcd Mass for {Ci8HiiCl2N05}+ 392.01 observed 392.1. NMR (400 MHz, DMSO-rie) d = 8.39 (d, J = 1.0 Hz, 1H), 8.19 (d, J = 2.0 Hz, 2H), 8.12 - 8.08 (m, 1H), 8.03 - 7.97 (m, 2H), 5.86 (t, J = 9.2 Hz, 1H), 4.52 (dt, J = 2.0, 8.8 Hz, 1H), 4.41 - 4.35 (m, 1H), 2.79 - 2.71 (m, 1H), 2.48 - 2.41 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93.72% | With p-benzoquinone In hexane at -18℃; for 7h; Green chemistry; | 8 Example 8: Synthesis of 2-carbonyl-tetrahydrofuran-3-hydroxy-methacrylate Add 4073ml of n-hexane in the 5L four-necked flask equipped with stirring paddle, condenser and thermometer, turn on stirring, add 78.10g of 2-carbonyl-tetrahydrofuran-3-ol to the system, slowly add 0.03g of polymerization inhibitor p-benzoquinone to the reaction system, add 107.2g basic ion exchange resin, adjust pH=7-8, cool down to -18°C, slowly add 107.2g vinyl methacrylate dropwise to the reaction system, keep the reaction for 7h, monitor the reaction progress, and take samples for detection After the reaction was completed, 1000 ml of water was added to the reaction system, and the mixture was stirred for extraction and phase separation. The organic phase was dried, concentrated under reduced pressure and evaporated to dryness to obtain 122 g of 2-carbonyl-tetrahydrofuran-3-hydroxy-methacrylate product with a yield of 93.72%. Figure 8 shows the gas chromatogram of the 2-carbonyl-tetrahydrofuran-3-hydroxy-methacrylate synthesized in this example. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93.52% | With p-benzoquinone In hexane at -17℃; for 7h; Green chemistry; | 7 Example 7: Synthesis of 2-carbonyl-tetrahydrofuran-3-hydroxy-acrylate Add 3845ml of n-hexane in the 5L four-necked flask equipped with stirring paddle, condenser tube and thermometer, turn on stirring, add 2-carbonyl-tetrahydrofuran-3-ol 83.20g to the system, slowly add 0.02g polymerization inhibitor p-benzoquinone to the reaction system, add 103.9g basic ion exchange resin, adjust pH=7-8, cool down to -17°C, slowly add 103.92g vinyl acrylate dropwise to the reaction system, keep the reaction for 7h, monitor the reaction progress, take a sample to detect the reaction is complete After adding 1000 ml of water to the reaction system, stirring and extracting the phases, the organic phase was dried, concentrated under reduced pressure and evaporated to dryness to obtain 119 g of 2-carbonyl-tetrahydrofuran-3-hydroxy-acrylate product with a yield of 93.52%.Figure 7 shows the gas chromatogram of the 2-carbonyl-tetrahydrofuran-3-hydroxy-acrylate synthesized in this example. |
Tags: 19444-84-9 synthesis path| 19444-84-9 SDS| 19444-84-9 COA| 19444-84-9 purity| 19444-84-9 application| 19444-84-9 NMR| 19444-84-9 COA| 19444-84-9 structure
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H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
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