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CAS No. : | 34368-52-0 |
Formula : | C4H7NO2 |
M.W : | 101.10 |
SMILES Code : | O=C1NCC[C@@H]1O |
MDL No. : | MFCD06796625 |
GHS Pictogram: | ![]() |
Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 7 |
Num. arom. heavy atoms | 0 |
Fraction Csp3 | 0.75 |
Num. rotatable bonds | 0 |
Num. H-bond acceptors | 2.0 |
Num. H-bond donors | 2.0 |
Molar Refractivity | 27.31 |
TPSA ? Topological Polar Surface Area: Calculated from | 49.33 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from | 0.82 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by | -0.95 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from | -1.51 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from | -1.19 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by | 0.16 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions | -0.54 |
Log S (ESOL):? ESOL: Topological method implemented from | 0.13 |
Solubility | 137.0 mg/ml ; 1.35 mol/l |
Class? Solubility class: Log S scale | Highly soluble |
Log S (Ali)? Ali: Topological method implemented from | 0.4 |
Solubility | 253.0 mg/ml ; 2.5 mol/l |
Class? Solubility class: Log S scale | Highly soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by | -0.05 |
Solubility | 90.7 mg/ml ; 0.897 mol/l |
Class? Solubility class: Log S scale | Soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg | Low |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg | No |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) | No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) | No |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) | No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) | No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) | No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) | No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from | -7.59 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from | 0.0 |
Ghose? Ghose filter: implemented from | None |
Veber? Veber (GSK) filter: implemented from | 0.0 |
Egan? Egan (Pharmacia) filter: implemented from | 0.0 |
Muegge? Muegge (Bayer) filter: implemented from | 2.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat | 0.55 |
PAINS? Pan Assay Interference Structures: implemented from | 0.0 alert |
Brenk? Structural Alert: implemented from | 0.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from | No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) | 1.41 |
* 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 |
---|---|---|
12.9% | With aluminum oxide In toluene for 19 h; Reflux; Dean-Stark | Compound 27: Compound 1 (l .Og, 8.40 mmol ) and alumina (2.57g, 25.20 mmol) were suspended in toluene (43 mL) and heated to reflux with attached Dean- Stark apparatus. The reaction was allowed to proceed at reflux for 19 hours. The reaction was filtered and the solid washed with CH2CI2. The filtrate was then collected and concentrated to yield compound 27 as colorless crystals (0.1 10 g, 12.9percent). Using FI RM S analysis, the composition of compound 27 was determined to be CiH NChNa. Measured mass was 124.0371 ; theoretical mass was 124.0369. NMR analysis results for compound 27 were NMR (600 MHz, CDC I3) δ 7.63 (bs, I H), 5.35 (d, J 5.4 Hz, 1H), 4.02-3.95 (m, I H), 3.18-3.12 (m, 1H), 3. 1 I - 3.04 (m, I H), 2.28-2.21 (m, IH), 1.79- 1.69 (m, I H). 13C NMR (151 MHz, CDCI3) δ 176.7, 68.4, 37.5, 30.5. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
12.9% | With aluminum oxide; In toluene; for 19h;Reflux; Dean-Stark; | Compound 27: Compound 1 (l .Og, 8.40 mmol ) and alumina (2.57g, 25.20 mmol) were suspended in toluene (43 mL) and heated to reflux with attached Dean- Stark apparatus. The reaction was allowed to proceed at reflux for 19 hours. The reaction was filtered and the solid washed with CH2CI2. The filtrate was then collected and concentrated to yield compound 27 as colorless crystals (0.1 10 g, 12.9%). Using FI RM S analysis, the composition of compound 27 was determined to be CiH NChNa. Measured mass was 124.0371 ; theoretical mass was 124.0369. NMR analysis results for compound 27 were NMR (600 MHz, CDC I3) delta 7.63 (bs, I H), 5.35 (d, J 5.4 Hz, 1H), 4.02-3.95 (m, I H), 3.18-3.12 (m, 1H), 3. 1 I - 3.04 (m, I H), 2.28-2.21 (m, IH), 1.79- 1.69 (m, I H). 13C NMR (151 MHz, CDCI3) delta 176.7, 68.4, 37.5, 30.5. |
Cone. H2SO4 (14.8 g, 8 mL) was added drop wise over 5 min to the stirring solution of (5)-(-)-4-Amino-2-hydroxybutyric acid (15 g) [CAS No. 40371-51-5] in MeOH (95 rnL) under dry conditions using anhydrous CaCl2 guard tube. After refluxing for 4 h, the reaction mixture was allowed to cool to room temperature and diluted with water (15 mL). Potassium carbonate (24 g) was added in portions to the reaction mixture and stirred overnight (20 h). Reaction mixture was diluted with CHCl3, filtered through celite. Celite bed was thoroughly washed with 1 % MeOHiCHCl3. The filtrates were combined and evaporated to dryness to obtain thick liquid residue. The residue was subjected to aging using 1-2 % MeOHiCHCl3 and then filtered. Organic layers were combined, dried over anhydrous sodium sulphate, filtered and concentrated to obtain the white solid. (1 1.8 g)1H NMR (CDCl3, 400 MHz) delta ppm: 2.03-2.13 (m, 1 H), 2.48-2.55 (m, 1 H), 3.30-3.35(m, IH), 3.36-3.50 (m, 1 H), 4.34 (t, J = 8.4 Hz, 1 H), 6.51 (bs, 1 H); [alpha]D25: + 98, c =1, CHCl3 | ||
(S)-(-)-3-hydroxy-2-pyrrolidinone Conc. H2SO4 (14.8 g, 8 mL) was added drop wise over 5 min to the stirring solution of (S)-(-)-4-Amino-2-hydroxybutyric acid (15 g) [CAS No. 40371-51-5] in MeOH (95 mL) under dry conditions using anhydrous CaCl2 guard tube. After refluxing for 4 h, the reaction mixture was allowed to cool to room temperature and diluted with water (15 mL). Potassium carbonate (24 g) was added in portions to the reaction mixture and stirred overnight (20 h). Reaction mixture was diluted with CHCl3, filtered through celite. Celite bed was thoroughly washed with 1% MeOH:CHCl3. The filtrates were combined and evaporated to dryness to obtain thick liquid residue. The residue was subjected to aging using 1-2% MeOH:CHCl3 and then filtered. Organic layers were combined, dried over anhydrous sodium sulphate, filtered and concentrated to obtain the white solid. (11.8 g) 1H NMR (CDCl3, 400 MHz) delta ppm: 2.03-2.13 (m, 1H), 2.48-2.55 (m, 1H), 3.30=3.35 (m, 1H), 3.36-3.50 (m, 1H), 4.34 (t, J=8.4 Hz, 1H), 6.51 (bs, 1H); [alpha]D25: +98, c=1, CHCl3 |
With sulfuric acid; In methanol; water; for 18h;Reflux; | Step 1. Preparation of 018-1: (Prepared according to W0201 1013141) Toa solution of (S)-4-amino-2-hydroxybutanoic acid (15 g, 126 mmol) in methanol(95 mL) was added concentrated sulfuric acid (8 mL), and the reaction washeated to reflux. After 18 h, the resulting mixture was allowed to cool to roomtemperature and was concentrated in vacuo. The residue was slurried with ethylacetate (95 mL) and 018-1 was collected by vacuum filtration. 1H NMR (400MHz, ODd3) 6 5.69 (br s, 1 H), 4.31 (ddd, J = 9.2, 8.1, 2.2 Hz, 1 H), 3.49 (d, J = 5.6 Hz, 1 H), 3.41 (tt, J = 9.2, 1 .7 Hz, 1 H), 3.33 (td, J = 9.4, 6.5 Hz, 1 H), 2.81 (br s, 1H), 2.59-2.48 (m, 1H), 2.09 (dq, J= 12.9, 9.1 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ammonium hydroxide; copper(I) iodide; potassium carbonate; In 1-methyl-pyrrolidin-2-one; ethyl acetate; | a 2-Benzyl-3-methoxymethyloxy-6-[<strong>[34368-52-0](3S)-3-hydroxy-2-pyrrolidinone</strong>-1-yl]pyridine 14.3 g of 2-benzyl-3-methoxymethyloxy-6-iodopyridine (Production Example 12) and 4.1 g of <strong>[34368-52-0](3S)-3-hydroxy-2-pyrrolidinone</strong> synthesised according to a method well-known in a literature (Synthesis, 1978, 614), 4.6 g of cuprous iodide and 13.7 g of potassium carbonate were suspended in 30 ml of 1-methyl-2-pyrrolidinone, followed by heating under stirring at 140 C. in an oil bath for 20 minutes in a nitrogen atmosphere. After cooling as it was, ethyl acetate and aqueous ammonia were added thereto. The mixture was extracted with ethyl acetate, and the organic phase was further washed with brine, dried over anhydrous sodium sulfate and the solvent was removed. The residue was subjected to silica gel column chromatography using 50-60% ethyl acetate as an eluent for separation and purification, to give 9.7 g of the target compound. 1H-NMR (CDCl3) delta=1.95-2.08 (1H, m), 2.53-2.58 (1H, m), 3.09 (1H, br.s), 3.37 (3H, s), 3.76 (1H, td, J=10 Hz, 6.6 Hz), 4.12 (2H, s), 4.19 (1H, t, J=9.2 Hz), 4.48 (1H, t, J=10 Hz), 5.14 (2H, s), 7.17-7.30 (5H, m), 7.42 (1H, d, J=9.0 Hz), 8.14 (1H, d, J=9.0 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With acetic anhydride; In pyridine; | (1) To a solution of 1.439 g of (S)-(-)-3-hydroxy-2-pyrrolidinone [P. W. K. Woo, Tetrahedron Letters, 2617 (1971); mp. 103.5°-104.5° C., [alpha]D26 =-118.8°+-2.3° (c=0.688, CHCl3)] in 14 ml of pyridine is added 2.8 ml of acetic anhydride, and the mixture is allowed to stand at room temperature for 4 hours and concentrated under reduced pressure at a temperature below 40° C. The residue is crystallized from ether and recrystallized from methylene chloride-n-hexane to give 1.735 g of (S)-(-)-3-acetoxy-2-pyrrolidinone in 86.3percent yield. mp. 85.5°-87° C. [alpha]D26 =-40.1°+-0.8° (c=1.015, CHCl3) Elemental Analysis (for C6 H9 NO3) Calcd (percent): C, 50.35; H, 6.29; N, 9.79. Found (percent): C, 50.50; H, 6.36; N, 9.66. IR: numaxNujol 3170, 3135, 1742, 1715, 1692 cm-1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; acetone; | EXAMPLE 2 (S)-3-Methanesulfonyloxy-Pyrrolidin-2-One Suspend the product of Example 1 (8 g., 79.2 mmol.) in dry methylene chloride (30 ml.) and cool to 0 C. Treat the suspension sequentially with dry triethylamine (16 ml., 118.8 mmol.) and methane sulfonyl chloride (6.74 ml., 87.12 mmol.). Stir at 5-10 C. for 1.5 hours, and subject the mixture to flash chromatography using acetone (5-10%) in dichloromethane to yield the title compound as a white solid. Optical rotation: [alpha]D26 =-68.3 (C=0.62, CHCl3) M.P.: 122-124 C. 200 MHz NMR(CDCl3): delta2.45(m,2H), 3.20(s,3H), 3.35(m,2H), 5.10(t,J=8 Hz,1H) and 7.75(br-S,1H-NH). MS: 180(M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77.5% | With pyridine; thionyl chloride; sodium chloride; In 1,4-dioxane; water; ethyl acetate; | Example 1 [Compound (1) --> (2)] <strong>[34368-52-0](S)-3-Hydroxy-2-pyrrolidinone</strong> (100.4 mg) was dissolved in 3 ml of dioxane, 248.4 mg of thionyl chloride was added, and the mixture was stirred at room temperature for 4 hours. Further, 3.0 mg of pyridine was added, and the mixture was stirred at 50°C for 3 hours. After confirmation of disappearance of the starting material by TLC, the reaction solvent was distilled off under reduced pressure and, then, water and ethyl acetate were added. The aqueous layer was extracted five times with ethyl acetate. All the organic layers were combined and washed with a saturated aqueous solution of sodium chloride. After drying over sodium sulfate, the solvent was distilled off to give 92.0 mg of (R)-3-chloro-2-pyrrolidinone (yield 77.5percent, optical purity 93.5percent ee). For the analysis of the optical purity, high performance liquid chromatography using a chiral column (Chiralcel OB-H (Daicel)) was used. 1H-NMR (D2O) delta 2.35 (m, 1H), 2.74 (m, 1H), 3.46 (m, 1H), 3.54 (m, 1H), 4.58 (t, 1H) 13C-NMR (D2O) delta 34.2, 43.2, 58.0, 179.1 IR (KBr) 1700 cm-1 |
With pyridine; thionyl chloride; In dichloromethane; at 10℃; for 3h; | To a 10 °C solution of <strong>[34368-52-0](S)-3-hydroxypyrrolidin-2-one</strong> (120 g, 1 .19 mol) in pyridine (38.4 ml, 475 mmol) and dichloromethane (3 L) at 10 °C was added thionyl chloride (173 ml, 2.37 mol) dropwise and the reaction was stirred for an additional 3 h. The reaction was concentrated in vacuo, taken up in dichloromethane and purified by filtering through a plug of silica gel, eluting with 10 L ethyl acetate. The material was concentrated in vacuo to approximately 1 L, diluted with 1 .5 L diethyl ether and heated gently for 15 min. The suspension was filtered, washed with diethyl ether (500 ml_), dried in vacuo, taken up in diethyl ether (1 L) and heated at 45 °C then filtered to afford 105 g of the title compound as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
(S)-3-Hydroxy-2-pyrrolidineon 9 (0.1 mol, 10.11 g), diglym (1.13 mol, 151.65 g) and NaBH (0.4 mol, 15.13 g) were added to a 500D round-bottom flask at 25oC°C, and sulfuric acid (20.2 g) was gently dropped thereto for 1 hour. After the dropping, the mixture was heated to 8O0C and kept for 12 hours to complete the reaction. When the reaction was completed, methanol was added thereto to inactivate the reaction, and the reaction mixture was neutralized with diluted hydrochloric acid (0.4 mol, 41.67 g). Then, pH of the reaction mixture was adjusted to 11 or more by using an aqueous sol ution of sodium hydroxide (ION 35D), and salts precipitated therefrom were removed through filtration. A resulting filtrate was concentrated under reduced pressure to obtain a (S)-3-hydroxypyrrolidine 1 residue. The residue was distilled under reduced pressure to obtain pure (S)-3-hydroxypyrrolidine 1.[122] 1H-NMR (CDCl ): delta 4.3-4.4 (m, IH), 3.05-3.15 (m, IH), 3.0 (bs, 2H), 2.75-2.9 (m,3H), 1.85-2.0 (m, IH), 1.6-1.75 (m, IH). EPO <DP n="15"/>[123] [124] | ||
EXAMPLE 9 Preparation of (S)-3-hydroxypyrrolidine 1 (S)-3-Hydroxy-2-pyrrolidineon 9 (0.1 mol, 10.11 g), diglym (1.13 mol, 151.65 g) and NaBH (0.4 mol, 15.13 g) were added to a 500.box. round-bottom flask at 25oC° C., and sulfuric acid (20.2 g) was gently dropped thereto for 1 hour. After the dropping, the mixture was heated to 80° C. and kept for 12 hours to complete the reaction. When the reaction was completed, methanol was added thereto to inactivate the reaction, and the reaction mixture was neutralized with diluted hydrochloric acid (0.4 mol, 41.67 g). Then, pH of the reaction mixture was adjusted to 11 or more by using an aqueous solution of sodium hydroxide (10N 35.box.), and salts precipitated therefrom were removed through filtration. A resulting filtrate was concentrated under reduced pressure to obtain a (S)-3-hydroxypyrrolidine 1 residue. The residue was distilled under reduced pressure to obtain pure (S)-3-hydroxypyrrolidine 1. 1H-NMR (CDCl3): delta 4.3-4.4 (m, 1H), 3.05-3.15 (m, 1H), 3.0 (bs, 2H), 2.75-2.9 (m, 3H), 1.85-2.0 (m, 1H), 1.6-1.75 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With potassium carbonate; In water; at 20℃; for 12h; | After the reaction mixture was cooled down to room temperature, water (11.91 g) and potassium carbonate were added thereto and agitated at room temperature for 12 hours to obtain (S)-3-hydroxy-2-pyrrolidineon. At this time, the formation of (S)-3-hydroxy-2-pyrrolidineon was confirmed by NMR. Inorganic substances, which were precipitated by adding methanol to a residue obtained after filtering and concentrating the reaction mixture, were removed by filtering the reaction mixture twice, and a filtrate thus obtained was concentrated under reduced pressure to obtain (S)-3-hydroxy-2-pyrrolidineon 9 (yield: 89percent).[118] 1H-NMR (DMSO-d ): delta 7.6 (bs, IH), 5.4 (bs, IH), 3.97 (t, IH, J = 8.4 Hz), 3.0-3.2(m, 2H), 2.2-2.3 (m, IH), 1.6-1.8 (m, IH). |
With potassium carbonate; In methanol; water; at 20℃; for 12h; | EXAMPLE 8Preparation of (S)-3-hydroxy-2-pyrrolidineon 9After 4-amino-(S)-2-hydroxybutylic acid 2 (0.1 mol, 11.91 g) was dissolved in a solvent of methanol (1.5 mol, 48.06 g) contained in a 500 round-bottom flask, sulfuric acid (1 to 2 equivalents) was added thereto at 25° C. When 4-amino-(S)-2-hydroxybutylic acid 2 was completely dissolved, the reaction mixture was heated to 80° C. and agitated under reflux for 4 hours to complete the reaction. Thereafter, 4-amino-(S)-2-hydroxybutylic acid methylester sulfonate 8 was confirmed by NMR.1H-NMR (D2O): delta 4.46 (dd, 1H, J=8.4 Hz, 4.2 Hz), 3.78 (s, 3H), 3.17 (t, 2H, J=7.2 Hz), 2.18-2.35 (m, 1H), 1.95-2.13 (m, 1H).After the reaction mixture was cooled down to room temperature, water (11.91 g) and potassium carbonate were added thereto and agitated at room temperature for 12 hours to obtain (S)-3-hydroxy-2-pyrrolidineon. At this time, the formation of (S)-3-hydroxy-2-pyrrolidineon was confirmed by NMR. Inorganic substances, which were precipitated by adding methanol to a residue obtained after filtering and concentrating the reaction mixture, were removed by filtering the reaction mixture twice, and a filtrate thus obtained was concentrated under reduced pressure to obtain (S)-3-hydroxy-2-pyrrolidineon 9 (yield: 89percent).1H-NMR (DMSO-d6): delta 7.6 (bs, 1H), 5.4 (bs, 1H), 3.97 (t, 1H, J=8.4 Hz), 3.0-3.2 (m, 2H), 2.2-2.3 (m, 1H), 1.6-1.8 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With 1H-imidazole; In N,N-dimethyl-formamide; at 20℃; | 1-79: to a solution of fSj-3 -hydroxypyrrol i di none (488 mg, 4.83 mmol) in DMF (10 mL), was added imidazole (493 mg, 1.5 equiv.), followed by triisopropyl silyl chloride (1.12 g, 1.2 equiv.). The reaction mixture was stirred at ambient temperature. On completion of the reaction, the reaction mixture was diluted with EtOAc (100 mL) and washed with H20 (5 x 20 mL). The aqueous washes were combined and back-extracted with EtOAc (50 mL). The combined organic extracts were washed with brine (50 mL), dried (MgS04) and concentrated to afford a colorless oil. Purification by silica gel chromatography (12 g pre-packed column, eluting with 35-60% EtOAc in Hexanes) afforded 1.23 g (99% yield) of the TIPS -protected alcohol as a colorless oil. |
With dmap; triethylamine; In dichloromethane; for 72h; | In step 3-1, triethylamine (20 ml ,139 mmol), p-N,N-dimethylaminopyridine (150 mg, 1 mmol) and then triisopropylsilyl chloride (22.6 grams, 118 mmol) were added dropwise over 4 minutes to a solution of iotaS'-3-hydroxy-2-pyrrolidinone (4.00 grams, 39.6 mmol) in 40 mL of methylene chloride. The reaction mixture was stirred for 3 days and was then quenched with 200 mL of brine. The solution was extracted with of ethyl acetate (3 x 300 mL) and the organic extracts were concentrated using a rotary evaporator. The product was then used directly without any purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | To a stirring mixture of 4-nitrobenzoic acid (9.273 g, 55.5 mmol, 1.1 equiv.) and (S)-(-)-3-3ydroxy-2-pyrrolidone (5.100 g, 50.4 mmol, 1.0 equiv.) in anhydrous tetrahydrofuran (175 mL) under a nitrogen atmosphere, triphenylphosphine (26.461 g, 100.9 mmol, 2.0 equiv.) was added. To this reaction mixture, disopropyl azodicarboxylate (14.898 mL, 75.7 mmol, 1.5 equiv.) was added dropwise (with external cooling with cold water bath). The reaction was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo to afford a crude residue. Methanol (130 mL) was added to the residue followed by potassium carbonate (0.38 g) at room temperature. The reaction mixture was stirred at room temperature for 8 h. The reaction mixture was diluted with methylene chloride and filtered through Celite. The Celite bed was washed with 1percent methanol in methylene chloride. The filtrates were combined and concentrated to dryness. The residue was partitioned between ethyl acetate: dilute aqueous hydrochloric acid (20 mL, 9:1) and stirred for 15 min. The layers were separated and the aqueous layer washed with ethyl acetate three times. The aqueous layer was concentrated to dryness and a solid residue was obtained. The crude residue was washed with 1-2percent methanol in methylene chloride (3*50 mL), dried (anhydrous sodium sulfate), filtered, and concentrated to afford a tan oil (3.3 g, 60percent). 1H NMR (300 MHz, CDCl3): delta 4.32-4.27 (t, 1H, J=8.5 Hz), 3.36-3.19 (m, 2H), 2.48-2.40 (m, 1H), 2.07-1.93 (m, 1H), 1.16-1.14 (d, 1H, J=6.3 Hz). | |
To a stirring mixture of 4-Nitrobenzoic acid (21.5 g) and (5)-(-)-3-hydroxy-2- pyrrolidinone (11.8 g) (Intermediate 17) in dry THF (360 mL) taken in a round bottomed flask fitted with anhydrous CaCl2 guard tube, triphenyl phosphine (61.2 g) was added. To this reaction mixture, diisopropyl diazodicarboxylate (DIAD) (34 mL) was added drop wise in three portions at room temperature. The reaction was stirred at room temperature. The progress of the reaction was monitored by TLC (developing agents: UV, I2, as well as aqueous acidic KMnO4). After completion, reaction mixture was concentrated under vacuum to obtain residue. Methanol (360 mL) was added to the residue followed by potassium carbonate (10 g) at room temperature. The reaction was stirred at room temperature. The progress of the reaction was monitored by TLC (developing agents: UV, I2, as well as aqueous acidic KMnO4). After completion, reaction mixture was diluted with CHCl3 and filtered through celite. Celite bed was successively washed with 1 percent MeOH:CHCl3. The filtrates were combined and concentrated to dryness to remove solvents. The residues were partitioned between EtOAc: dil. HCl (200 mL, 9:1) and stirred for 15 min. Layers were separated, aq. layer was washed with EtOAc thrice until all organic impurities were washed out. The aq. Layer was concentrated to dryness to remove the water and solid residues were obtained. The residues obtained were washed with 1-2 percent MeOH: CHCl3 (3 x 100 mL), dried over sodium sulfate, filtered trough cotton, concentrated to get brown thick liquid product.1U NMR (CDCl3, 400 MHz) delta ppm: 2.03-2.13 (m, 1 H), 2.46-2.54 (m, 1 H), 3.28-3.35 (m, IH), 3.38-3.48 (m, 1 H), 4.50 (t, J = 8.4 Hz, 1 H), 4.55 (bs, 1 H), 7.02 (bs, 1 H); [alpha]D25: + 68, c = l, CHCl3 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃; | To a stirring mixture of Methyl 3-hydroxy-5-[4-(5-methyl-l,3,4-oxadiazol-2- yl)phenoxy] benzoate (2.5 g) (Intermediate 7) and (5)-(-)-3-hydroxy-2-pyrrolidinone (Intermediate 17) (0.8 g) in dry THF (70 mL) taken in round bottomed flask fitted with anhydrous CaCl2 guard tube, triphenyl phosphine (3.77 g) was added. Diisopropyl azodicarboxylate (DIAD) (2.1 mL) in dry THF (2 mL) was added drop wise to the above reaction mixture. The reaction was stirred at room temperature. Reaction was monitored by TLC for completion. After completion, reaction mixture was concentrated under vacuum to remove the solvents. Diluted with DCM and coated over silica gel and chromatographed to furnish the product as white solid (2 g).1H NMR (CDCl3, 400 MHz) delta ppm: 2.23-2.30 (m, 1 H); 2.62 (s, 3 H), 2.64-2.71 (m, 1 H), 3.40-3.46 (m, 1 H), 3.50-3.55 (m, 1 H), 3.89 (s, 3 H), 4.89 (t, J= 7.6 Hz, 1 H), 6.99 (t, J= 2.4 Hz, 1 H), 7.11 (d, J= 8.8 Hz, 2 H), 7.36 (s, 1 H), 7.51 (s, 1 H), 8.03 (d, J = 8.8 Hz, 2 H); ESI MS m/z (relative intensities): 410.1 (M+H)+ (45 percent); UPLC Purity: 96.40 percent, Ret. time: 3.48 min. Chiral Purity by HPLC: 90.92 percent, Ret. Time: 48.36 min | |
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃; | (R)-(+)-Methyl 3-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenoxy)-5-((2-oxopyrrolidin-3-yl)oxy)benzoateTo a stirring mixture of Methyl 3-hydroxy-5-[4-(5-methyl-1,3,4-oxadiazol-2-yl)phenoxy]benzoate (2.5 g) (Intermediate 7) and (S)-(-)-3-hydroxy-2-pyrrolidinone (Intermediate 17) (0.8 g) in dry THF (70 mL) taken in round bottomed flask fitted with anhydrous CaCl2 guard tube, triphenyl phosphine (3.77 g) was added.Diisopropyl azodicarboxylate (DIAD) (2.1 mL) in dry THF (2 mL) was added drop wise to the above reaction mixture.The reaction was stirred at room temperature.Reaction was monitored by TLC for completion.After completion, reaction mixture was concentrated under vacuum to remove the solvents.Diluted with DCM and coated over silica gel and chromatographed to furnish the product as white solid (2 g).1H NMR (CDCl3, 400 MHz) delta ppm: 2.23-2.30 (m, 1H); 2.62 (s, 3H), 2.64-2.71 (m, 1H), 3.40-3.46 (m, 1H), 3.50-3.55 (m, 1H), 3.89 (s, 3H), 4.89 (t, J=7.6 Hz, 1H), 6.99 (t, J=2.4 Hz, 1H), 7.11 (d, J=8.8 Hz, 2H), 7.36 (s, 1H), 7.51 (s, 1H), 8.03 (d, J=8.8 Hz, 2H); ESI MS m/z (relative intensities): 410.1 (M+H)+ (45percent); UPLC Purity: 96.40percent, Ret. time: 3.48 min.Chiral Purity by HPLC: 90.92percent, Ret. Time: 48.36 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate;palladium diacetate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 20 - 80℃; for 16h; | EXAMPLE 62; (^-{(3ffy2-oxo-l-[4-ftrifluorommethylamino diazen- 1 -ium- 1 ,2-diolate; Step A: (3^-3-hydroxy- 1 -[4-(trifluoromethyl phenyl pyrrolidin-2-one; To a 1,4-dioxane (20 mL) solution of (3S -3-hydroxypyrrolidin-2-one (372 mg, 3.68 mmol) and l-bromo-4-(trifluoromethyl)benzene (508 , 3.68 mmol) at room temperature was added 4s5-bis(diphenylphosphino)-9,9-dirnethylxanthene (64 mg, 0.1 1 mmol), palladium(H) acetate (17 mg, 0.070 mmol) and cesium carbonate (1.80 g, 5.52 mmol), After stirring at 80 °C for 16 hours, the reaction mixture was allowed to cool down to room temperature and partitioned between diethyl ether (100 mL) and brine (100 mL). The organic layer was washed with brine (2 x 100 mL), dried (magnesium sulfate) and concentrated in vacuo to afford the crude product. Chromatography over silica gel, eluting with hexanes/ethyl acetate, afforded the title compound. 1H NMR (500 MHz, CDC ) delta 7.81 (d, J= 8.6 Hz, 2H), 7.64 (d, J= 8.7 Hz, 2H), 4.52-4.48 (m, 1H), 3.89-3.77 (m, 2H), 3.05 (br s, 1H), 2.68-2.62 (m, 1H), 2.18-2.09 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃; | (R)-(+)-3-Hydroxy-2-pyrrolidinoneTo a stirring mixture of 4-Nitrobenzoic acid (21.5 g) and (S)-(-)-3-hydroxy-2-pyrrolidinone (11.8 g) (Intermediate 17) in dry THF (360 mL) taken in a round bottomed flask fitted with anhydrous CaCl2 guard tube, triphenyl phosphine (61.2 g) was added.To this reaction mixture, diisopropyl diazodicarboxylate (DIAD) (34 mL) was added drop wise in three portions at room temperature.The reaction was stirred at room temperature.The progress of the reaction was monitored by TLC (developing agents: UV, I2, as well as aqueous acidic KMnO4).After completion, reaction mixture was concentrated under vacuum to obtain residue.Methanol (360 mL) was added to the residue followed by potassium carbonate (10 g) at room temperature.The reaction was stirred at room temperature.The progress of the reaction was monitored by TLC (developing agents: UV, I2, as well as aqueous acidic KMnO4).After completion, reaction mixture was diluted with CHCl3 and filtered through celite.Celite bed was successively washed with 1percent MeOH:CHCl3.The filtrates were combined and concentrated to dryness to remove solvents.The residues were partitioned between EtOAc: dil. HCl (200 mL, 9:1) and stirred for 15 min.Layers were separated, aq.layer was washed with EtOAc thrice until all organic impurities were washed out.The aq.Layer was concentrated to dryness to remove the water and solid residues were obtained.The residues obtained were washed with 1-2percent MeOH: CHCl3 (3*100 mL), dried over sodium sulfate, filtered trough cotton, concentrated to get brown thick liquid product.1H NMR (CDCl3, 400 MHz) delta ppm: 2.03-2.13 (m, 1H), 2.46-2.54 (m, 1H), 3.28-3.35 (m, 1H), 3.38-3.48 (m, 1H), 4.50 (t, J=8.4 Hz, 1H), 4.55 (bs, 1H), 7.02 (bs, 1H); [alpha]D25: +68, c=1, CHCl3 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate;palladium diacetate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 80℃; | Step A:(3S)-3-hydroxy-1-(3-methylphenyl)pyrrolidin-2-one(S)-3-Hydroxypyrrolidin-2-one (1.52 g, 15.0 mmol), 3-bromotoluene (2.57 g, 15.0 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.26 g, 0.45 mmol), palladium(II) acetate (0.067 g, 0.30 mmol) and cesium carbonate (7.33 g, 22.5 mmol) were mixed together in dioxane (50 mL) and stirred overnight at 80° C. overnight.The reaction mixture was washed with water (150 mL), and the aqueous layer was extracted with dichloromethane (3*150 mL).The combined organic layers were dried (sodium sulfate) and concentrated in vacuo.Chromatography over silica gel, eluting with hexanes/ethyl acetate, afforded the title compound as a white solid. 1H NMR (500 MHz, CDCl3) delta 7.47 (s, 1H), 7.42 (d, J=8.3 Hz, 1H), 7.26 (t, J=7.9 Hz, 1H), 7.00 (d, J=7.6 Hz, 1H), 4.81 (d, J=3.1 Hz, 1H), 4.56-4.49 (m, 1H), 3.80-3.70 (m, 2H), 2.60-2.53 (m, 1H), 2.37 (s, 3H), 2.16-2.06 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 0 - 20℃; for 12h;Inert atmosphere; | (R)-Methyl 2-(5-(2-oxopyrrolidin-3-yloxy)pyridin-2-yl)thiazole-5-carboxylate To a round-bottomed flask was added methyl 2-(5-hydroxypyridin-2-yl)thiazole-5-carboxylate (400 mg), (S)-3-hydroxy-pyrrolidin-2-one (188 mg), PPh3 (443 mg), and THF (10 mL). DEAD (299 mg) was added dropwise at 0° C. under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 12 hours. After being diluted with ethyl acetate (50 mL), the organic layer was washed with water (20 mL*2) and brine (10 mL) and dried over anhydrous Na2SO4. After filtration and evaporation of the solvent, the residue obtained was purified by silica gel column chromatography eluting with petroleum ether/ethyl acetate (4:1 to 1:3) to afford the subtitle compound. MS ESI+: m/z=320 [M-FH]+. | |
With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 0 - 20℃;Inert atmosphere; | To a round-bottomed flask was added methyl 2-(5-hydroxypyridin-2-yl)thiazole-5- carboxylate (400 mg), (S)-3-hydroxy-pyrrolidin-2-one (188 mg), PPh3 (443 mg), and THF (10 mL). DEAD (299 mg) was added dropwise at 0°C under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 12 hours. After being diluted with ethyl acetate (50 mL), the organic layer was washed with water (20 mL x 2) and brine (10 mL) and dried over anhydrous Na2SO4. After filtration and evaporation of the solvent, the residue obtained was purified by silica gel column chromatography eluting with petroleum ether/ethyl acetate (4:1 to 1 :3) to afford the subtitle compound. MS EST: m/z = 320 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; for 2h;Inert atmosphere; | (R)-3((6-Ethoxypyridin-3-yl)oxy)pyrrolidin-2-one A mixture of (S)-3-hydroxy-pyrrolidin-2-one (8.07 g), 6-ethoxypyridin-3-ol (11.0 g) and THF (100 mL) was purged with argon. Triphenylphosphine (20.7 g) was added followed by slow addition of DIAD (16.0 g). After 2 hours the mixture was concentrated and the residue purified by SGC (eluent: EA) to provide the subtitle compound. MS ESI+: m/z=223 [M+H]+. | |
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; for 2h;Inert atmosphere; | A mixture of (S)-3-hydroxy-pyrrolidin-2-one (8.07 g), 6-ethoxypyridin-3-ol (1 1 .0 g) and THF (100 mL) was purged with argon. Triphenylphosphine (20.7 g) was added followed by slow addition of DIAD (16.0 g). After 2 hours the mixture was concentrated and the residue purified by SGC (eluent: EA) to provide the subtitle compound. MS EST: m/z = 223 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; dichloromethane; for 0.5h;Inert atmosphere; | General procedure: (R)-3-[6-(4-Fluoro-phenoxy)-pyridin-3-yloxy]-pyrrolidin-2-one (Typical Procedure 3) A mixture of THF (200 mL) and DCM (100 mL) under argon was added triphenylphosphine (polymer, 1.8 mmol/g, 20 g). Diisopropylazodicarboxylate (8.87 g) was added. After 5 minutes (S)-3-hydroxy-pyrrolidin-2-one (3.1 g) and 6-(4-fluoro-phenoxy)-pyridin-3-ol (6.0 g) were added. After 30 minutes the mixture was filtered and the filtrate concentrated. The residue was purified by chromatography (SiO2; DCM/MeOH 15:1) to provide the title compound. MS ESI+: m/z=289 [M+H]+. | |
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; dichloromethane; for 0.5h;Inert atmosphere; | A mixture of THF (200 mL) and DCM (100 mL) under argon was added triphenylphosphine (polymer, 1 .8 mmol/g, 20 g). Diisopropylazodicarboxylate (8.87 g) was added. After 5 minutes (S)-3-hydroxy-pyrrolidin-2-one (3.1 g) and 6-(4-fluoro- phenoxy)-pyridin-3-ol (6.0 g) were added. After 30 minutes the mixture was filtered andthe filtrate concentrated. The residue was purified by chromatography (S1O2; DCM/MeOH 15:1 ) to provide the title compound. MS ESI+: m/z = 289 [M+H]+. | |
With triphenylphosphine on polystyrene; di-isopropyl azodicarboxylate; In tetrahydrofuran; dichloromethane; for 0.5h;Inert atmosphere; | A mixture of THE (200 mL) and DCM (100 mL) under argon was added triphenylphosphine (polymer, 1.8 mmol/g, 20 g). DIAD (8.87 g) was added. After 5 minutes (S)-3-hydroxy-pyrrolidin-2-one (3.1 g) and 6-(4-fluoro-phenoxy)-pyridin-3-ol (6.0 g) were added. After 30 minutes the mixture was filtered and the filtrate concentrated. The residue was purified by chromatography (Si02 DCM/MeOH 15:1) to provide the title compound. MS ESI: mlz = 289 [M+H]. |
With di-isopropyl azodicarboxylate; In tetrahydrofuran; dichloromethane; for 0.5h;Inert atmosphere; | A mixture of THE (200 mL) and DCM (100 mL) under argon was added triphenyiphosphine (polymer, 1 .8 mmol/g, 20 g). Diisopropyl azodicarboxylate (8.87 g) was added. After 5 minutes (S)-3-hydroxy-pyrrolidin-2-one (3.1 g) and 6-(4-fluoro- phenoxy)-pyridin-3-ol (6.0 g) were added. After 30 minutes the mixture was filtered andthe filtrate concentrated. The residue was purified by chromatography (Si02 DCM/MeOH 15:1) to provide the title compound. MS ESI: mlz = 289 [M+H]. | |
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; dichloromethane; for 0.5h;Inert atmosphere; | (R)-3-[6-(4-Fluoro-phenoxy)-pyridin-3-yloxy]-pyrrolidin-2-one (Typical Procedure 3) A mixture of THF (200 mL) and DCM (100 mL) under argon was added triphenylphosphine (polymer, 1 .8 mmol/g, 20 g). Diisopropyl azodicarboxylate (8.87 g) was added. After 5 minutes (S)-3-hydroxy-pyrrolidin-2-one (3.1 g) and 6-(4-fluoro- phenoxy)-pyridin-3-ol (6.0 g) were added. After 30 minutes the mixture was filtered and the filtrate concentrated. The residue was purified by chromatography (S1O2; DCM/MeOH 15:1 ) to provide the title compound. MS ESI+: m/z = 289 [M+H]+. | |
With di-isopropyl azodicarboxylate; In tetrahydrofuran; dichloromethane; for 0.5h;Inert atmosphere; | A mixture of THF (200 mL) and DCM (100 mL) under argon was added triphenylphosphine (polymer bound, 1.8 mmol/g, 20 g). Diisopropyl azodicarboxylate (8.87 g) was added. After 5 minutes, (S)-3-hydroxy-pyrrolidin-2-one (3.1 g) and 6-(4-fluoro-phenoxy)-pyridin-3-ol (6.0 g) were added. After 30 minutes, the mixture was filtered and the filtrate concentrated. The residue was purified by chromatography (SiO2; DCM/MeOH 15:1) to provide (R)-3-[6-(4-fluoro-phenoxy)-pyridin-3-yloxy]-pyrrolidin-2-one. MS ESI+: m/z=289 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; dichloromethane; for 48h; | General procedure: (R)-3-[6-(2-Cyclopropyl-ethoxy)-pyridin-3-yloxy]-pyrrolidin-2-one A mixture of (S)-3-hydroxy-pyrrolidin-2-one (0.79 g), 6-(2-cyclopropyl-ethoxy)-pyridin-3-ol (1.4 g), triphenylphosphine (2.25 g), DCM (30 mL) and THF (20 mL) was added DIAD (1.74 g). After 2 days the mixture was filtered and the filtrate was evaporated. The residue was purified by SGC (eluent: EA/MeOH 9:1) to provide the title compound. MS ESI+: m/z=263 [M+H]+. | |
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; dichloromethane; for 48h; | A mixture of (S)-3-hydroxy-pyrrolidin-2-one (0.79 g), 6-(2-cyclopropyl-ethoxy)-pyridin-3- ol (1 .4 g), triphenylphosphine (2.25 g), DCM (30 mL) and THF (20 mL) was added DIAD (1 .74 g). After 2 days the mixture was filtered and the filtrate was evaporated. The residue was purified by SGC (eluent: EA/MeOH 9:1 ) to provide the title compound. MS ESI+: m/z = 263 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; dichloromethane; at 30℃; for 12h; | (R)-3-[6-(2-Cyclopropyl-methoxy)-pyridin-3-yloxy]-pyrrolidin-2-one A mixture of (S)-3-hydroxy-pyrrolidin-2-one (3.00 g), 6-(2-cyclopropyl-methoxy)-pyridin-3-ol (4.90 g), triphenylphosphine (polymer, 8.56 g), DCM (30 mL) and THF (50 mL) was added DIAD (6.60 g) keeping the reaction temperature below 30° C. After 12 hours the mixture was filtered and the filtrate was evaporated. The residue was purified by SGC (eluent: EA/MeOH 9:1) to provide the title compound. MS ESI+: m/z=249 [M+H]+. | |
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; dichloromethane; at 30℃; for 12h; | A mixture of (S)-3-hydroxy-pyrrolidin-2-one (3.00 g), 6-(2-cyclopropyl-methoxy)-pyridin- 3-ol (4.90 g), triphenylphosphine (polymer, 8.56 g), DCM (30 mL) and THF (50 mL) was added DIAD (6.60 g) keeping the reaction temperature below 30°C. After 12 hours the mixture was filtered and the filtrate was evaporated. The residue was purified by SGC (eluent: EA MeOH 9:1 ) to provide the title compound. MS ESI+: m/z = 249 [M+H]+. | |
With triphenylphosphine on polystyrene; di-isopropyl azodicarboxylate; In tetrahydrofuran; dichloromethane; at 30℃; for 12h; | To a mixture of (S)-3-hydroxy-pyrrolidin-2-one (3.00 g), 6-(2-cyclopropyl-methoxy)- pyridin-3-ol (4.90 g), triphenylphosphine (polymer, 8.56 g), DCM (30 mL) and THE (50 mL) was added DIAD (6.60 g) keeping the reaction temperature below 30°C. After 12hours the mixture was filtered and the filtrate was evaporated. The residue was purified by SGC (eluent: EAIMeOH 9:1) to provide the title compound. MS ESI: mlz = 249 [M+H]. |
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; dichloromethane; at 30℃; for 12h; | (R)-3-[6-(2-Cyclopropyl-methoxy)-pyridin-3-yloxy]-pyrrolidin-2-one A mixture of (S)-3-hydroxy-pyrrolidin-2-one (3.00 g), 6-(2-cyclopropyl-methoxy)-pyridin- 3-ol (4.90 g), triphenylphosphine (polymer, 8.56 g), DCM (30 mL) and THF (50 mL) was added DIAD (6.60 g) keeping the reaction temperature below 30°C. After 12 hours the mixture was filtered and the filtrate was evaporated. The residue was purified by SGC (eluent: EA MeOH 9:1 ) to provide the title compound. MS ESI+: m/z = 249 [M+H]+. | |
With di-isopropyl azodicarboxylate; In tetrahydrofuran; dichloromethane; at 30℃; for 12h; | A mixture of (S)-3-hydroxy-pyrrolidin-2-one (3.00 g), 6-(2-cyclopropyl-methoxy)-pyridin-3-01 (4.90 g), triphenylphosphine (polymer, 8.56 g), DCM (30 mL) and THF (50 mL) was added DIAD (6.60 g) keeping the reaction temperature below 30° C. After 12 hours, the mixture was filtered and the filtrate was evaporated. The residue was purified by SGC (eluent: EA/MeOH 9:1) to provide (R)-3-[6-(2-cyclopropyl-methoxy)-pyridin-3-yloxy]-pyrrolidin-2-one. MS ESI+: m/z=249 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With trans-N,N'-dimethyl-1,2-cyclohexyldiamine; copper(l) iodide; potassium carbonate; In 1,4-dioxane; at 140℃; for 2h;Microwave irradiation; | Alternative Preparation (Method P) 1-[(2-Difluoromethoxy)benzyl]-2-({3-[(3S)-3-hydroxy-2-oxopyrrolidin-1-yl]phenoxy}-methyl)-1H-benzimidazole-6-carbonitrile A mixture of Example 165 (100 mg, 0.21 mmol), CuI (8 mg, 0.042 mmol), trans-N,N'-dimethylcyclohexane-1,2-diamine (6 mg, 0.042 mmol), K2CO3 (55 mg, 0.42 mmol) and <strong>[34368-52-0](3S)-3-hydroxy-2-pyrrolidinone</strong> (35 mg, 0.35 mmol) in 1,4-dioxane (2 mL) was heated in under microwave irradiation, with stirring, for 2 h at 140° C. After this time, the reaction mixture was partitioned between EtOAc and H2O. The organic phase was dried by passing through a phase separator cartridge, and evaporated in vacuo. The residue was purified by column chromatography (SiO2, 20-100percent EtOAc in hexane) to give the title compound (42 mg, 40percent) as a white powder. deltaH (300 MHz, DMSO) 8.14 (d, 1H, J 0.9 Hz), 7.89 (m, 1H), 7.65 (dd, 1H, J 8.4, 1.5 Hz), 7.25 (m, 7H), 6.71 (m, 2H), 5.77 (d, 1H, J 5.8 Hz), 5.69 (s, 2H), 5.43 (s, 2H), 4.28 (m, 1H), 3.64 (m, 2H), 1.81 (dd, 1H, J 12.5, 9.2 Hz). LCMS (ES+) 505 (M+H)+, RT 2.10 minutes. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 4℃; for 15h; | A solution of 2-cyclopropyl-1-(4-hydroxyphenyl)ethanone (1.1 g), <strong>[34368-52-0](S)-3-hydroxypyrrolidin-2-one</strong> (947 mg), PPh3 (2.78 g) and DIAD (2.15 g) in THE (5 mL) wasstirred at 4°C for 15 hours. The reaction mixture was diluted with EA (200 mL), and washed with water (100 mL x 2) and brine (100 mL). The organic layer was dried over anhydrous Na2504, filtered and concentrated. The residue was purified by column chromatography on silica gel eluting with DCM/MeOH = 50:1 to provide the titlecompound. MS ESI: mlz = 260 [M+H]. | |
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 4℃; for 15h; | A solution of 2-cyclopropyl-1-(4-hydroxyphenyl)ethanone (1.1 g), (S)-3- hydroxypyrrolidin-2-one (947 mg), PPh3 (2.78 g) and DIAD (2.15 g) in THE (5 mL) was stirred at 4°C for 15 hours. The reaction mixture was diluted with EA (200 mL), andwashed with water (100 mL x 2) and brine (100 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel eluting with DCM/MeOH = 50:1 to provide the title compound. MS ESI: mlz = 260 [M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With di-isopropyl azodicarboxylate; In tetrahydrofuran; dichloromethane; at 30℃; for 12h; | A mixture of (S)-3-hydroxy-pyrrolidin-2-one (3.00 g), 6-(2-cyclopropyl-methoxy)-pyridin-3-01 (4.90 g), triphenylphosphine (polymer, 8.56 g), DCM (30 mL) and THE (50 mL) wasadded DIAD (6.60 g) keeping the reaction temperature below 30°C. After 12 hours themixture was filtered and the filtrate was evaporated. The residue was purified by SGC(eluent: EAIMeOH 9:1) to provide the title compound. MS ESI: mlz = 249 [M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; dichloromethane; for 48h; | A mixture of (S)-3-hyd roxy-pyrrol id in-2-one (0.79 g), 6-(2-cyclopropyl -ethoxy)-pyrid in-3- ol (1 .4 g), triphenylphosphine (2.25 g), DCM (30 mL) and THE (20 mL) was added DIAD (1 .74 g). After 2 days the mixture was filtered and the filtrate was evaporated. The residue was purified by SGC (eluent: EAIMeOH 9:1)to provide the title compound. MS ESI: mlz = 263 [M+H]. |
Tags: 34368-52-0 synthesis path| 34368-52-0 SDS| 34368-52-0 COA| 34368-52-0 purity| 34368-52-0 application| 34368-52-0 NMR| 34368-52-0 COA| 34368-52-0 structure
A181193 [68108-18-9]
(S)-4-Hydroxypyrrolidine-2-one
Similarity: 0.89
A181193 [68108-18-9]
(S)-4-Hydroxypyrrolidine-2-one
Similarity: 0.89
A181193 [68108-18-9]
(S)-4-Hydroxypyrrolidine-2-one
Similarity: 0.89
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P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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