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CAS No. : | 114676-69-6 | MDL No. : | MFCD00797548 |
Formula : | C11H19NO5 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | - |
M.W : | 245.27 | Pubchem ID : | - |
Synonyms : |
(2R,4R)-1-tert-Butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate
|
Num. heavy atoms : | 17 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.82 |
Num. rotatable bonds : | 5 |
Num. H-bond acceptors : | 5.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 63.85 |
TPSA : | 76.07 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) : | -7.38 cm/s |
Log Po/w (iLOGP) : | 2.41 |
Log Po/w (XLOGP3) : | 0.58 |
Log Po/w (WLOGP) : | 0.15 |
Log Po/w (MLOGP) : | 0.22 |
Log Po/w (SILICOS-IT) : | -0.11 |
Consensus Log Po/w : | 0.65 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.4 |
Solubility : | 9.85 mg/ml ; 0.0402 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.75 |
Solubility : | 4.36 mg/ml ; 0.0178 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -0.27 |
Solubility : | 131.0 mg/ml ; 0.535 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 3.36 |
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 |
---|---|---|
84% | With dipyridinium dichromate In dichloromethane at 20℃; | Preparation 6 4-chloro-6-fluoropyrrolo[l,2-b]pyridazine-3-carboxamideStep 1 : (R)- 1 -tert-butyl 2-methyl 4-oxopyrrolidine-l,2-dicarboxylate[00179] To slurry of pyridinium dichromate (9.97 g, 26.5 mmol) indichloromethane (60 mL) at rt was added (2R,4R)-1 -tert-butyl 2-methyl 4- hydroxypyrrolidine-l,2-dicarboxylate (5.00 g, 20.39 mmol) in several portions. The resulting mixture was stirred overnight at rt. Celite (5g) was added and the mixture stirred for 40 min, filtered and the filter cake was rinsed with additionaldichloromethane (50 mL x 3). The resulting filtrate was concentrated and toluene (40 mL) was added followed by concentration again under vacuum to give ~ 6.5 g of a brown syrup as the crude product. Purification by flash silica gel chromatography (120g column, EtOAc in hexane, 0 to 100percent gradiant, 85 mL/min) afforded 4.18 g (84percent>) of the title compound as a white solid. LCMS (condition A): m/z 144 (M-Boc) -ve. XH NMR (400 MHz, CDCl3) δ ppm 4.64-4.89 (1 H, m), 3.84-3.96 (2 H, m), 3.77 (3 H, s), 2.81-3.10 (1 H, m), 2.59 (1 H, dd, J=18.93, 1.76 Hz), 1.52 (9 H, s). |
84% | With dipyridinium dichromate In dichloromethane at 20℃; | To slurry of pyridinium dichromate (9.97 g, 26.5 mmol) indichloromethane (60 mL) at rt was added (2R,4R)- 1 -tert-butyl 2-methyl 4- hydroxypyrrolidine-l,2-dicarboxylate (5.00 g, 20.39 mmol) in several portions. The resulting mixture was stirred overnight at rt. Celite (5g) was added and the mixture stirred for 40 min, filtered and the filter cake was rinsed with additionaldichloromethane (50 mL x 3). The resulting filtrate was concentrated and toluene (40 mL) was added followed by concentration again under vacuum to give ~ 6.5 g of a brown syrup as the crude product. Purification by flash silica gel chromatography (120g column, EtOAc in Hexane, 0 to 100percent gradiant, 85 mL/min) afforded 4.18 g (84percent>) of the title compound as a white solid. LCMS (condition A): m/z 144 (M-Boc) -ve. XH NMR (400 MHz, CDCl3) δ ppm 4.64-4.89 (1 H, m), 3.84-3.96 (2 H, m), 3.77 (3 H, s), 2.81-3.10 (1 H, m), 2.59 (1 H, dd, J=18.93, 1.76 Hz), 1.52 (9 H, s). |
72% | With Dess-Martin periodane In dichloromethane at 20℃; for 2 h; | Scheme 4. Step A: Stir a mixture of N-te^butyl-cz's-4-hydroxy-D-proline methyl ester (2.0 g, 7.91 mmol), the Dess-Martin periodinane (4.84 g, 11.07 mmol), and CH2CI2 (10 mL) at room temperature for 2 h. Add CH2CI2 (150 mL), saturated aqueous NaHC03 (75 mL), and water (75 mL), then separate the layers and extract the aqueous layer with CH2CI2 (100 mL). Combine the organic phases, dry over MgS04, filter, and concentrate the filtrate under reduced pressure. Subject the resulting crude material to flash chromatography on silica gel, eluting with a gradient of 0percent to 50percent EtOAc in hexanes, to furnish the title compound (1.39 g, 72percent yield). Mass spectrum (m/z): 144 (M + 2H - Boc)+, 188 (M + 2H - t-Bu)+. |
59.8% | With Dess-Martin periodane In dichloromethane at 20℃; for 4 h; | At room temperature,3C (14.92 g, 60.87 mmol) was dissolved in dichloromethane (100 mL)Add to Martin in batches(51.63 mg, 121.73 mmol),The reaction was stirred at room temperature for 4 hours.After cooling to 0 ° C, the sodium bicarbonate solution was added dropwise to the reaction solution until no more bubbles were generated, and a white solid was precipitated.The reaction solution was filtered and the filter cake was washed with methyl tertiary butyl ether (50 mL x 3) and the filtrate was extracted with methyl tertiary butyl ether (30 mL x 2).The organic phase was washed with saturated sodium chloride solution (50 mL x 2), dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure to give pale yellow liquid 3D (10.3 g, yield 59.8percent). |
48% | Stage #1: With sodium hydrogencarbonate; Dess-Martin periodane In dichloromethane at 23℃; for 4 h; Stage #2: With sodium hyposulfite In dichloromethane; water |
Preparation of [1- (3, 4-DIMETHOXY-5-TRIFLUOROMETHYLTHIOBENZOYL)-4-ETHYNYL-2, 5-DIHYDRO-LH-] [PYRROLE-2R-CARBOXYLIC] acid hydroxyamide [100570]] Step 1: To a stirred solution of 4R-hydroxypyrrolidine-1,2R-dicarboxylic acid 1- [TERT-BUTYL] ester 2-methyl ester [(30.] 4 g, 0.124 mol, 1.0 eq.; product from Step 2 of Example 90) in [CH2C12] [(800] mL) at [23°C,] was added NaHCO3 (103 g, 1.23 mol, 10.0 eq. ), followed by Dess- Martin periodinane (61 g, 0.144 mol, 1. 16 eq. ). After being stirred at [23 °C] for 1 h, another batch of Dess-Martin periodinane (14 g, 0.033 mol, 0.27 eq. ) was added. After 3 h, the reaction mixture was quenched by addition of aqueous solution [OF NA2S203] and extracted with [CH2CL2] (3 x 300 mL). The combined organic layer was washed with brine, dried [(NA2S04)] and concentrated in [VACUUM.] The residue was chromatographed on silica gel (EtOAc/Hexane : [0percent-40percent)] to afford 4-oxopyrrolidine-1, 2R-dicarboxylic acid [1-TERT-BUTYL] ester 2-methyl ester (14.3 g, 48percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92.4% | In 1,4-dioxane; diethyl ether at 5℃; for 0.25h; | |
70% | In methanol; diethyl ether | |
In methanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With dmap; triethylamine; In water; acetone; | [0347] To a solution of <strong>[114676-59-4](2R,4R)-methyl 4-hydroxypyrrolidine-2-carboxylate hydrochloride</strong> (4.4 g, 24.67 mmol) in Acetone and water (3:2, 30 mL) were added Et3N (6.8 mL , 49.28 mmol), DMAP (150 mg, 1.2 mmol). Then (Boc)20 (8.0 mL, 34.54 mmol) was added slowly and the reaction was stirred overnight. All the acetone was removed and diluted with EtOAc and washed with 0.5 N HC1, water, brine, dried and concentrated to yield 6.0 g of (2R,4R)-1- tert-butyl 2-methyl 4-hydroxypyrrolidine-l,2-dicarboxylate (quantitative). |
93.4% | At room temperature,(13.83 g, 76.38 mmol) was dissolved in a mixed solvent of 1,4-dioxane (50 mL) and water (20 mL), cooled to 0 ° C,Triethylamine (19.32 g, 190.95 mmol) was added and stirred for 10 min.Twenty-three butyl dicarbonate (21.67g, 99.29mmol)In dichloromethane (20 mL) was added dropwise to the reaction solution and reacted at room temperature overnight.Water (50 mL) was added to the reaction solution and extracted with dichloromethane (50 mL x 3).The organic phases were combined and washed with a hydrochloric acid solution (1 mol / L, 20 mL x 2) and a saturated aqueous saline solution (40 mL x 2).Dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a pale yellow liquid 3C (17.49 g, yield 93.4percent). | |
88% | With triethylamine; In dichloromethane; | Step A-2. Preparation of a Boc compound To a suspension of <strong>[114676-59-4](2R,4R)-4-hydroxy-2-methoxycarbonylpyrrolidine hydrochloride</strong> (25.64 g: 125 mmole) in dichloromethane (125 ml), triethylamine (19.11 ml: 137.5 mmole) is added dropwise in a nitrogen atmosphere under ice cooling. The mixture is stirred for 5 minutes at room temperature. Then, a solution of di-t-butyl dicarbonate (34.11 g: 156.3 mmole) in dichloromethane (125 ml) is added dropwise, and the mixture is stirred for 40 minutes at room temperature to give (2R,4R)-1-t-butoxycarbonyl-4-hydroxy-2-methoxycarbonylpyrrolidine (26.85 g). Yield: 88percent. Colorless crystals. NMR delta(CDCl3) ppm: 1.46(d, J=8.4 Hz, 9H), 2.0 to 2.2(m, 1H), 2.2 to 2.5(m, 1H), 3.4 to 3.8(m, 2H), 3.79(d, J=3.0 Hz, 3H), 4.2 to 4.5(m, 2H). IR nu (KBr) cm-1: 3460, 1730, 1680. |
88% | Add triethylamine (265.9 g, 2.63 mol) to a solution of methyl ester hydrochloride in dry dichloromethane (2 L) at 0° C. and stir for 30 min. Then add N,N-dimethylaminopyridine (0.18 mol, 21.9 g) and di-tert-butyl dicarbonate (1.43 mol, 313.5 g) consecutively. Warm the reaction mixture to room temperature and stir for 18 h. Quench the reaction mixture with water, separate the organic layer and wash with water and NaHCO3 solution. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate under vacuum to obtain the title compound (260 g, 88percent) as a thick oil. 1H NMR (400 MHz, CDCl3) delta 1.43 (s, 9H), 1.46 (s, 9 H), 2.05-2.10 (m, 2H), 2.26-2.35 (m, 2H), 3.48-3.56 (m, 2H), 3.58-3.61 (m, 1H), 3.64-3.70 (m, 2H), 3.77 (s, 3H), 3.79 (s, 3H), 4.27-4.29 (m, 1H), 4.34-4.38 (m, 2H). | |
79% | With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 0 - 20℃; for 1h; | Add di-tert-butyl dicarbonate (10.4 g, 47.7 mmol) in 1,4-dioxane (10 mL) to a solution of 4- (R)-hydroxypyrrolidine-2-(R)-carboxylic methyl ester hydrochloride (6.66 g, 36.7 mmol) in 1,4-dioxane (80 mL). Cool in an ice bath and add N,N- diisopropylethylamine (11 mL, 62.4 mmol), then remove ice bath and stir 1 h at room temperature. Concentrate and dissolve in ethyl acetate and wash with aqueous citric acid solution (2 x 100 mL), water, saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, dry (magnesium sulfate), filter and concentrate to give the title compound as a white solid (7.1 g, 79percent). MS (ES): m/z = 246.1 [M+H]. |
77% | With silica gel; triethylamine; In dichloromethane; at 23℃; for 5h; | To a stirred suspension [OF 4R-HYDROXYPYRROLIDINE-2R-CARBOXYLIC] acid methyl ester hydrochloride salt (15.9 g, 76.3 mmol, 1 eq. ) in [CH2C12] (200 mL) at [23 °C] was added Et3N (21.3 mL, 153 mmol, 2 eq.) followed by Boc20 (21.1 mL, 91.6 mmol, 1.2 eq. ). The resulting mixture was stirred for 5 h, then treated with silica gel (20 g). The volatiles were removed in vacuo to give a free-flowing powder, which was dry-loaded onto a pre-packed silica gel column. The product was purified via flash column chromatography (100percent EtOAc as an eluent) to give [4R-HYDROXYPYRROLIDINE-1,] 2R-dicarboxylic acid [1-TERT-BUTYL] ester 2-methyl ester (14.4 g, 58.9 mmol, 77percent yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With lithium borohydride In tetrahydrofuran at 20℃; for 4h; Inert atmosphere; | |
74% | With lithium borohydride In tetrahydrofuran a) 0 deg C, 7 h, b) r.t., overnight; | |
72% | With lithium borohydride In tetrahydrofuran 4 h, 5 deg C to 10 deg C, 36 h; |
With lithium borohydride In tetrahydrofuran at 70℃; for 48h; | 2 LiBH4 (6.46 mmol as a solution in THF) was added to an ice cooled solution of (1,1-dimethylethyl) 2-methyl (2R,4R)-4-hydroxy-1,2-pyrrolidinedicarboxylate (0.36 g, 1.47 mmol) in THF. The reaction was heated at 70°C. for 48 hours. The reaction was quenched with isopropanol and then saturated NaHCO3. The mixture was diluted with water and extracted twice with ethyl acetate. The organic layers were washed with 1 N NaOH, dried over MgSO4 and concentrated to give 0.185 g of the title compound. 1NMR (400 MHz, DMSO-D6) δ ppm 1.4 (m, 9 H), 1. 8 (m, 1 H), 2.0 (m, 1 H), 3.0 (m, 1 H), 3.4 (m, 1 H), 3.5 (m, 2 H), 3.7 (m, 1 H), 4.1 (m, 1 H), 4.9 (dd, J=5.3, 5.3 Hz, 1 H), 5.1 (m, 1 H). | |
With lithium borohydride In tetrahydrofuran; ethyl acetate | 30 (2R,4R)-1-(tert-Butyloxycarbonyl)-2-hydroxymethyl-4-hydroxypyrrolidine (37) (2R,4R)-1-(tert-Butyloxycarbonyl)-2-hydroxymethyl-4-hydroxypyrrolidine (37) (2R,4R)-1-(tert-Butyloxycarbonyl)-2-carbomethoxy-4-hydroxypyrrolidine 36 (7.0 g, 28.6 mmol) was dissolved in dry THF (100 ml) and cooled in ice salt bath under argon atmosphere. To this cold solution was added lithium borohydride (1.88 g, 85.8 mmol) in small portions during 15 min period. After the addition of lithium borohydride, the reaction mixture was allowed to stir at 0° C. for 1 h followed by 15 h at room temperature under argon. The solution was cooled to 0° C. and diluted with water (50 ml) and the pH was adjusted with AcOH to 6. The reaction was evaporated to dryness and dissolved in EtOAc (200 ml), washed with water (100 ml) and brine (100 ml). The EtOAc extract was dried and evaporated to dryness. The residue was purified by flash column chromatography over silica gel using CH2 Cl2 →EtOAc as the eluent. The pure fractions were collected and evaporated to dryness to afford 5.00 g (81%) of clear oil. The oil on standing gave colorless solid. mp: 95-97C. 1 H-NMR (CDCl3): 1.45 (s, 9H, Boc), 1.90 (dd, 1H), 2.34 (m, 1H), 3.40 -3.62 (m, 3H), 4.00 (m, 2H), 4.28 (bs, 1H), 4.44 (m, 1H). | |
With lithium borohydride In tetrahydrofuran |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | In N,N-dimethyl-formamide at 0 - 20℃; for 4h; | 1 (2R,4R)-1-tert-butyl 2-methyl 4-((tert-butyldimethylsilyl)oxy)pyrrolidine-1,2-dicarboxylate 3C (49.05 g, 0.2 mol) was dissolved in N, N-dimethylformamide (300 mL) at room temperature, cooled to 0 ° C,(21.8 g, 0.22 mol) and tri-butyldimethylchlorosilane (62.7 g, 0.42 mmol) were added to the reaction mixture, and the reaction was stirred at room temperature for 4 hours.The reaction solution was poured into ice water (400 mL) and extracted with methyl tertiary butyl ether (200 mL x 3).The organic phase was washed successively with hydrochloric acid (1 mol / L, 300 mL x 1), sodium bicarbonate solution (300 mL x 1), saturated brine solution (300 mL x 2).Dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a pale yellow liquid 5A (72 g, yield 100%). |
99% | With 1H-imidazole In N,N-dimethyl-formamide for 1.5h; Ambient temperature; | |
94% | With 1H-imidazole In N,N-dimethyl-formamide |
With 1H-imidazole |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93.9% | With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran for 42h; Ambient temperature; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With dmap; triethylamine In dichloromethane at 20℃; for 15h; Inert atmosphere; | 159.1 Step 1) : (2R, 4R) -1-tert-butyl 2-methyl 4- (tosyloxy) pyrrolidine-1, 2-dicarboxylate To a solution of (2R, 4R) -1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1, 2-dicarboxylate (1.0 g, 4.08 mmol) , 4-dimethylaminopyridine (50 mg, 0.408 mmol) and triethylamine (1.42 mL, 10.2 mmol) in DCM (20 mL) was added a solution of 4-methylbenzene-1-sulfonyl chloride (1.17 g, 6.12 mmol) in DCM (10 mL) . The mixture was stirred at rt for 15 h and diluted with saturated aqueous NaCl (20 mL × 3) . The resulting mixture was extracted with DCM (20 mL × 3) . The combined organic layers were dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel chromatography eluted with Petroleum ether/EtOAc (v/v) 3/1 to give the title compound as yellow oil (1.39 g, 85) .1H NMR (600 MHz, CDCl3) : δ ppm 7.76-7.79 (m, 2H) , 7.35-7.37 (m, 2H) , 5.03-5.08 (m, 1H) , 4.33-4.45 (m, 1H) , 3.69-3.70 (m, 3H) , 3.57-3.67 (m, 2H) , 2.46 (s, 3H) , 2.36-2.43 (m, 2H) , 1.41-1.45 (m, 9H) and MS-ESI: m/z 300.00 [M+H-100] +. |
With pyridine |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran | |
With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran for 5h; Ambient temperature; Yield given; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With sodium carbonate In 1,4-dioxane; water | |
86% | With sodium hydrogencarbonate In methanol at 20℃; Inert atmosphere; | |
With sodium carbonate In 1,4-dioxane; water Ambient temperature; |
With triethylamine In dichloromethane at 20℃; for 3h; | ||
With triethanolamine In tetrahydrofuran; water; ethyl acetate | 30 (2R,4R)-1-(tert-Butyloxycarbonyl)-2-carbomethoxy-4-hydroxypyrrolidine (36) (2R,4R)-1-(tert-Butyloxycarbonyl)-2-carbomethoxy-4-hydroxypyrrolidine (36) To a stirred solution of (2R,4R)-2-Carbomethoxy-4-hydroxypyrrolidine 35 (6.9 g, 38.12 mmol) in THF/water (8:2, 150 ml) was added TEA (10.1 g, 100 mmol) followed by di-tert-butyldicarbonate (10.9 g, 50 mmol) at room temperature. The reaction was stirred at room temperature for 6 h and evaporated to dryness. The residue was dissolved in EtOAc (200 ml) and washed with 0.5N potassium hydrogen sulfate (50 ml), water (100 ml) and brine (50 ml). The organic extract was dried over Na2 SO4 and evaporated to dryness to give 7.8 g (84%) of an oily product. The oily product on drying gave colorless solid: mp: 75-77° C. 1 H-NMR (CDCl3): 1.45 (s, 9H, Boc), 2.09 (2 dd, 1H), 2.34 (m, 1H), 3.49-3.73 (m, 3H), 3.79 (s, 3H, CH3), 4.34 (m, 2H). | |
With dmap; triethylamine | ||
With dmap; triethylamine In dichloromethane at 20℃; for 12h; | 7.7.2 7.2 50 g of methyl (2R,4R)-4-hydroxypyrrolidine-2-carboxylate, 64.2 ml of di-tert-butyl dicarbonate, 116.4 ml of triethylamine and 2.4 g of 4-(dimethylamino)pyridine are dissolved in 500 ml of dichloromethane and stirred at RT for 12 h. The reaction mixture is washed with water, and the organic phase is dried over magnesium sulfate and evaporated. The residue is chromatographed over a silica-gel column, giving 37 g of colourless crystals 1-tert-butyl 2-methyl (2R,4R)-4-hydroxypyrrolidine-1,2-carboxylate. | |
With potassium hydrogencarbonate In 1,4-dioxane; water at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran 1.) 0 deg C, 1 h, 2.) RT, 1 h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran Ambient temperature; | |
95% | With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran Ambient temperature; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With silver(l) oxide In N,N-dimethyl-formamide at 0℃; for 36h; | 1.4.2 [0348] To a solution of (2R,4R)-l-tert-butyl 2-methyl 4-hydroxypyrrolidine-l,2- dicarboxylate (3.1 g, 12.64 mmol) in DMF (20 mL) at 0°C, were added BnBr (3.3 mL, 27.81 mmol) followed by Ag20 (3.22 g, 13.90 mmol) and stirred for 36h. Then 50 mL of ether was added to the reaction mixture and filtered. The filtrate was further diluted with ether and washed with water, brine, dried and concentrated. Purification with 30% EtOAc/ 70%Hexanes yielded 3.59 g (85%) of (2S,4R)-l-tert-butyl 2-methyl 4-(benzyloxy)pyrrolidine- 1 ,2-dicarboxylate. |
60% | With silver(l) oxide In diethyl ether at 40℃; | 20 Add silver oxide (2.8 g, 12.3 mmol) to a mixture of 4-(R)-hydroxypyrrolidine-N- 1,2- (R)-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (3 g, 12.3 mmol) and benzyl bromide (4.7 g, 27,6 mmol) in diethyl ether (20 mL). Stir the mixture overnight in a sealed tube at 40 °C. Filter the silver oxide, concentrate and purify (silica gel chromatography, eluting with ethyl acetate/hexanes mixtures) to give the title compound as a colorless oil (2.5 g, 60%). MS (ES) : m/z = 236.1 [M+H, Product -Boc], MS (ES) : m/z = 358.1 [M+Na]. |
With sodium hydride In N,N-dimethyl-formamide at 5℃; for 4h; |
With sodium hydride In N,N-dimethyl-formamide at 20℃; for 16h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | Stage #1: (3R,5R)-1-(tert-butoxycarbonyl)-3-(tert-butyldimethylsiloxy)-5-(methoxycarbonyl)pyrrolidin-2-one With dimethylsulfide borane complex In tetrahydrofuran at 20℃; for 8h; Stage #2: With tetrabutyl ammonium fluoride In tetrahydrofuran at 20℃; for 2h; Further stages.; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With dipyridinium dichromate; In dichloromethane; at 20℃; | Preparation 6 4-chloro-6-fluoropyrrolo[l,2-b]pyridazine-3-carboxamideStep 1 : (R)- 1 -tert-butyl 2-methyl 4-oxopyrrolidine-l,2-dicarboxylate[00179] To slurry of pyridinium dichromate (9.97 g, 26.5 mmol) indichloromethane (60 mL) at rt was added (2R,4R)-1 -tert-butyl 2-methyl 4- hydroxypyrrolidine-l,2-dicarboxylate (5.00 g, 20.39 mmol) in several portions. The resulting mixture was stirred overnight at rt. Celite (5g) was added and the mixture stirred for 40 min, filtered and the filter cake was rinsed with additionaldichloromethane (50 mL x 3). The resulting filtrate was concentrated and toluene (40 mL) was added followed by concentration again under vacuum to give ~ 6.5 g of a brown syrup as the crude product. Purification by flash silica gel chromatography (120g column, EtOAc in hexane, 0 to 100% gradiant, 85 mL/min) afforded 4.18 g (84%>) of the title compound as a white solid. LCMS (condition A): m/z 144 (M-Boc) -ve. XH NMR (400 MHz, CDCl3) delta ppm 4.64-4.89 (1 H, m), 3.84-3.96 (2 H, m), 3.77 (3 H, s), 2.81-3.10 (1 H, m), 2.59 (1 H, dd, J=18.93, 1.76 Hz), 1.52 (9 H, s). |
84% | With dipyridinium dichromate; In dichloromethane; at 20℃; | To slurry of pyridinium dichromate (9.97 g, 26.5 mmol) indichloromethane (60 mL) at rt was added (2R,4R)- 1 -tert-butyl 2-methyl 4- hydroxypyrrolidine-l,2-dicarboxylate (5.00 g, 20.39 mmol) in several portions. The resulting mixture was stirred overnight at rt. Celite (5g) was added and the mixture stirred for 40 min, filtered and the filter cake was rinsed with additionaldichloromethane (50 mL x 3). The resulting filtrate was concentrated and toluene (40 mL) was added followed by concentration again under vacuum to give ~ 6.5 g of a brown syrup as the crude product. Purification by flash silica gel chromatography (120g column, EtOAc in Hexane, 0 to 100% gradiant, 85 mL/min) afforded 4.18 g (84%>) of the title compound as a white solid. LCMS (condition A): m/z 144 (M-Boc) -ve. XH NMR (400 MHz, CDCl3) delta ppm 4.64-4.89 (1 H, m), 3.84-3.96 (2 H, m), 3.77 (3 H, s), 2.81-3.10 (1 H, m), 2.59 (1 H, dd, J=18.93, 1.76 Hz), 1.52 (9 H, s). |
72% | With Dess-Martin periodane; In dichloromethane; at 20℃; for 2h; | Scheme 4. Step A: Stir a mixture of N-te^butyl-cz's-4-hydroxy-D-proline methyl ester (2.0 g, 7.91 mmol), the Dess-Martin periodinane (4.84 g, 11.07 mmol), and CH2CI2 (10 mL) at room temperature for 2 h. Add CH2CI2 (150 mL), saturated aqueous NaHC03 (75 mL), and water (75 mL), then separate the layers and extract the aqueous layer with CH2CI2 (100 mL). Combine the organic phases, dry over MgS04, filter, and concentrate the filtrate under reduced pressure. Subject the resulting crude material to flash chromatography on silica gel, eluting with a gradient of 0% to 50% EtOAc in hexanes, to furnish the title compound (1.39 g, 72% yield). Mass spectrum (m/z): 144 (M + 2H - Boc)+, 188 (M + 2H - t-Bu)+. |
59.8% | With Dess-Martin periodane; In dichloromethane; at 20℃; for 4h; | At room temperature,3C (14.92 g, 60.87 mmol) was dissolved in dichloromethane (100 mL)Add to Martin in batches(51.63 mg, 121.73 mmol),The reaction was stirred at room temperature for 4 hours.After cooling to 0 C, the sodium bicarbonate solution was added dropwise to the reaction solution until no more bubbles were generated, and a white solid was precipitated.The reaction solution was filtered and the filter cake was washed with methyl tertiary butyl ether (50 mL x 3) and the filtrate was extracted with methyl tertiary butyl ether (30 mL x 2).The organic phase was washed with saturated sodium chloride solution (50 mL x 2), dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure to give pale yellow liquid 3D (10.3 g, yield 59.8%). |
48% | Preparation of [1- (3, 4-DIMETHOXY-5-TRIFLUOROMETHYLTHIOBENZOYL)-4-ETHYNYL-2, 5-DIHYDRO-LH-] [PYRROLE-2R-CARBOXYLIC] acid hydroxyamide [100570]] Step 1: To a stirred solution of 4R-hydroxypyrrolidine-1,2R-dicarboxylic acid 1- [TERT-BUTYL] ester 2-methyl ester [(30.] 4 g, 0.124 mol, 1.0 eq.; product from Step 2 of Example 90) in [CH2C12] [(800] mL) at [23C,] was added NaHCO3 (103 g, 1.23 mol, 10.0 eq. ), followed by Dess- Martin periodinane (61 g, 0.144 mol, 1. 16 eq. ). After being stirred at [23 C] for 1 h, another batch of Dess-Martin periodinane (14 g, 0.033 mol, 0.27 eq. ) was added. After 3 h, the reaction mixture was quenched by addition of aqueous solution [OF NA2S203] and extracted with [CH2CL2] (3 x 300 mL). The combined organic layer was washed with brine, dried [(NA2S04)] and concentrated in [VACUUM.] The residue was chromatographed on silica gel (EtOAc/Hexane : [0%-40%)] to afford 4-oxopyrrolidine-1, 2R-dicarboxylic acid [1-TERT-BUTYL] ester 2-methyl ester (14.3 g, 48%). | |
With sulfur trioxide pyridine complex; triethylamine; In dimethyl sulfoxide; at 20℃; for 1h;Cooling with ice; | [0302] To an ice-cold solution of 4-(R)-hydroxyl-2-(R)-hydroxymethylpyrrolidine- lcarboxylic acid tert-butyl ester (9.81 g, 40.93 mmol) in DMSO (50 mL) was addedtriethylamine (16.2 mL, 163.73 mmol) and sulfurtrioxide-pyridine complex (12.73 g, 81.87 mmol). The resulting mixture was stirred 30 min, warmed to room temperature and stirred 30 min, diluted with diethyl ether and washed with 5% aqueous citric acid, saturated aqueous sodium chloride, dried (sodium sulfate) and concentrated to give the title compound as an oil which was purified with flash chromatography to produce the ketone (7.5 g). 1H NMR (300 MHz, CDC13), delta: 4.818-4.673 (m, 1 H), 3.903 (s, 1 H), 3.871(s, 1 H), 3.749 (s, 3 H), 3.003- 2.862 (m, 1 H), 2.605-2.542 (m, 1 H), 1.468, 1.445 (s, 9 H). | |
With pyridine-SO3 complex; triethylamine; In dimethyl sulfoxide; for 0.5h;Cooling with ice; | To an ice-cold solution of 4-(R)-hydroxyl-2-(R)-hydroxymethylpyrrolidine- lcarboxylic acid tert-butyl ester (9.81 g, 40.93 mmol) in DMSO (50 mL) was addedtriethylamine (16.2 mL, 163.73 mmol) and sulfurtrioxide-pyridine complex (12.73 g, 81.87 mmol). The resulting mixture was stirred 30 min, warmed to room temperature and stirred 30 min, diluted with diethyl ether and washed with 5% aqueous citric acid, saturated aqueous sodium chloride, dried (sodium sulfate) and concentrated to give the title compound as an oil which was purified with flash chromatography to produce the ketone (7.5 g). 1H NMR (300 MHz, CDCI3), delta: 4.818-4.673 (m, 1 H), 3.903 (s, 1 H), 3.871(s, 1 H), 3.749 (s, 3 H), 3.003- 2.862 (m, 1 H), 2.605-2.542 (m, 1 H), 1.468, 1.445 (s, 9 H). | |
Example 17.21b. Synthesis of (R)-l -ferz-butyl 2-methyl 4-oxopyrrolidine-l,2- dicarboxylate A stirred solution of oxalyl chloride (1.9 g, 15.0 mmol) in dichloromethane (20 mL) under N2 at -78 C was treated with DMSO (13.3 mL, 18.8 mmol) in dichloromethane (20 mL) dropwise over 15 min. The mixture was stirred at -78 C for 20 min, then (2R,4R)-l-ieri-butyl-2-methyl 4-hydroxypyrrolidine-l,2-dicarboxylate (3.0 g, 12.5 mmol) dissolved in dichloromethane (15 mL) was added over 20 min. The reaction mixture was stirred at -60 C for 40 min, then triethylamine (5 mL, 35.0 mmol) diluted with dichloromethane (10 mL) was added dropwise over 10 min. The mixture was gradually warmed to room temperature over 30 min. Then the reaction was quenched with aqueous ammonium chloride and extracted with dichloromethane (3 x 200 mL). The combined organic layers were washed with brine, dried over Na2S04, concentrated and purified by column chromatography to give 2.1 g of the desired product. MS (ESI): 244 (MH+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With caesium carbonate In N,N-dimethyl-formamide | |
99% | With potassium carbonate In acetonitrile Reflux; | 50.1 Synthesis of (2R,4R)-l-tert-butyl 2-methyl 4-hydroxypyrrolidine-l,2-dicarboxylate (50a) To a solution of N-Boc-c/s-4-hydroxy- -proline (15.00g, 64.88 mmol) in 325 mL of MeCN, K2CO3 (17.93 g, 129.76 mmol) was added, followed by Mel (8.1 mL, 129.76 mmol) and reaction was stirred overnight after which time LCMS control indicated presence of substrate. Another portion of Mel (4.0 mL, 64.88 mmol) was added and reaction was refluxed overnight. When another LCMS control indicated completion of the reaction the mixture was filtered, and solid residue was washed with EtOAc. After evaporation of solvent 16.06 g (99% yield) of product 50a was obtained as a yellowish oil.ESI-MS m/z for C11H19NO5 found 146.2 (M-Boc+l)+, 268.2 (M+Na)+ |
With caesium carbonate In DMF (N,N-dimethyl-formamide) |
With potassium carbonate In N,N-dimethyl-formamide at 20℃; | 17.21a Example 17.21a. Synthesis of (2RAR)-l-tert-b tyl-2- e yl-4- hydroxypyrrolidine- 1 ,2-dicarboxylateA solution of (2/?,4/?)-l-(ieri-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (10.0 g, 43.3 mmol), methyl iodide (9.2 g, 65.0 mmol), and potassium carbonate (12.0 g, 86.6 mmol) in DMF (120 mL) was stirred at room temperature overnight. The mixture was then diluted with H20 (500 mL) and extracted with EtOAc (4 x 500 mL), the combined organic layers were washed with brine and dried over Na2S04. After filtration, the solution was concentrated to give the desired product, which was directly used for the next step without further purification. MS (ESI): 246 (MH+). | |
With potassium carbonate In N,N-dimethyl-formamide |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine In dichloromethane at 20℃; | ||
101% | With triethylamine In dichloromethane | P.7.A.3 Step A-3. Step A-3. Preparation of a mesyl compound To a solution of (2R,4R)-1-t-butoxycarbonyl-4-hydroxy-2-methoxycarbonylpyrrolidine (9.81 g: 40 mmole) in dichloromethane (49 ml) in a nitrogen atmosphere under ice cooling, triethylamine (6.67 ml: 48 mmole) and methanesulfonyl chloride (3.70 ml: 48 mmole) are added. The mixture is stirred for 20 minutes to give (2R,4R)-1-t-butoxycarbonyl-4-methanesulfonyloxy-2-methoxycarbonylpyrrolidine as a crude oil (13.05 g). Yield: 101%. NMR δ(CDCl3) ppm: 1.46(d, J=9.6 Hz, 9H), 2.5(m, 2H), 3.02(s, 3H), 3.76(s, 3H), 3.8(m, 2H), 4.3 to 4.6(m, 1H), 5.2 to 5.3(m, 1H). |
With triethylamine In dichloromethane at 0℃; for 3h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With diphenyl-phosphinic acid; triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran | |
44% | Stage #1: (2R,4R)-1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0℃; for 0.5h; Inert atmosphere; Stage #2: With diphenyl phosphoryl azide In tetrahydrofuran at 20℃; for 2h; Inert atmosphere; | 304 (2S,4S)-1-tert-Butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate (2S,4S)-1-tert-Butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate At 0° C., to a solution of 1-tert-butyl 2-methyl (2R,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate (500 mg, 2.04 mmol) in tetrahydrofuran (10 mL) was added PPh3 (642 mg, 2.45 mmol). Then DIAD (536 mg, 2.65 mmol) was added in portions at 0° C. The resulting solution was stirred for 30 min at 0° C., and then was added by DPPA (673 mg, 2.45 mmol) slowly. The reaction mixture was stirred for additional 2 h at room temperature. When the reaction was done, it was quenched by the addition of water (20 mL). The mixture was extracted with ethyl acetate (30 mL*3). The organic phases were combined, washed with brine and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc in hexane (0% to 9% gradient) to yield 1-tert-butyl 2-methyl (2R,4S)-4-azidopyrrolidine-1,2-dicarboxylate as colorless oil (240 mg, 44%). MS: m/z=271.1 [M+H]+. |
Multi-step reaction with 2 steps 1: Et3N / CH2Cl2 / 20 °C 2: 59 percent / NaN3 / dimethylformamide / 26 h / 55 °C |
Multi-step reaction with 2 steps 1: triethylamine; dmap / dichloromethane / 15 h / 20 °C / Inert atmosphere 2: sodium azide / N,N-dimethyl-formamide / 5 h / 80 °C / Inert atmosphere | ||
Multi-step reaction with 2 steps 1: triethylamine / dichloromethane / 3 h / 0 °C 2: sodium azide / N,N-dimethyl-formamide / 22 h / 65 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran at 0 - 20℃; | 14 4.14 N-tert-Butoxycarbonyl-trans-4-(4-nitrobenzoyloxy)-d-proline methyl ester (15) To a solution of compound 14 (6.83 g, 27.84 mmol) in anhydrous THF (137 mL) were added Ph3P (11 g, 41.94 mmol), 4-nitrobenzoic acid (5.6 g, 33.51 mmol), and DEAD (6.6 mL, 41.92 mmol) at 0 °C. The reaction mixture was stirred overnight at room temperature, at the end of which time TLC indicated it was finished. The white precipitate was filtered and the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (8:1, petroleum ether-EtOAc) to afford compound 15 (9.74 g, 92%) as a colorless oil. 15: Rf=0.65 (2:1, petroleum ether-EtOAc); 1H NMR (400 MHz, CDCl3): δ 8.31 (d, 2H, J=8.8 Hz), 8.20 (d, 2H, J=8.4 Hz), 5.58 (d, 1H, J=2.4 Hz), 4.46 (4.53)* (t, 1H, J=8.0 Hz), 3.95-3.70 (m, 2H), 3.79 (s, 3H), 2.65-2.52 (m, 1H), 2.42-2.23 (m, 1H), 1.44 (1.47) (s, 9H); 13C NMR (100 MHz, CDCl3): δ 172.8 (172.6)*, 164.0 (163.9), 153.5 (150.6), 134.9, 130.7, 123.5, 80.72 (80.68), 73.6 (74.2), 57.8 (57.4), 52.4 (52.2), 52.1 (51.9), 36.5 (35.5), 28.2 (28.1). |
66% | With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 20℃; for 7h; | |
With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 23℃; for 24h; | 91.1 Preparation of 1-(3,4-dimethoxy-5-trifluoromethylthiobenzoyl)-4R-fluoropyrrolidine-2R-carboxylic acid hydroxyamide; Step 1 To a stirred solution of 4R-hydroxypyrrolidine-1, 2R-dicarboxylic acid [1-] [TERT-BUTYL] ester 2-methyl ester (2.23 g, 9.11 mmol, [1] [EQ. ;] Product from Step 2 of Example 90), 4- nitrobenzoic acid (3.05 g, 18.2 mmol, 2 eq. ) and PPh3 (4.78 g, 18.2 mmol, 2 eq. ) in THF (100 mL) at 0 [°C] was added DIAD (3.59 mL, 18.2 mmol, 2 eq. ). The reaction bath was slowly allowed to warm to [23 °C.] After 24 h the reaction mixture was partitioned between [H20] (100 mL) and EtOAc (200 mL). The layers were separated, the organic layer was washed with saturated aqueous [NAHC03] (200 mL), brine (200 mL), dried [MGS04] and concentrated in vacuo. The product was purified via flash column chromatography on silica gel (33% EtOAc/hexanes as an eluent) to give 4S- (4-nitrobenzoyloxy) pyrrolidine-1, 2R-dicarboxylic acid [L-TERT-BUTYL] ester 2- methyl ester (6.46 g) which was contaminated with hydrazine biscarbamate. This was used without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With 1H-imidazole; dmap | |
90% | With 1H-imidazole In N,N-dimethyl-formamide at 0 - 20℃; for 16.5h; | 78.1 Step 1: 1-(Tert-butyl) 2-methyl (2R,4R)-4-((tert-butyldiphenylsilyl)oxy)pyrrolidine-1,2- dicarboxylate To a stirred solution of 1-(tert-butyl) 2-methyl (2R,4R)-4-hydroxypyrrolidine-1,2- dicarboxylate (8.00 g, 32.62 mmol) and imidazole (4.44 g, 65.23 mmol) in DMF (80.00 mL) was added tert-butyl(chloro)diphenylsilane (13.45 g, 48.93 mmol) at 0oC over 30 min. The reaction mixture was stirred for 16 h at room temperature. The resulting mixture was diluted with water (400 mL) and extracted with EA (3 x 300 mL). The combined organic layers was washed with brine (5 x 500 mL), dried over anhydrous Na2SO4and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (6/1). The fractions contained desired product were combined and concentrated to afford 1-(tert-butyl) 2-methyl (2R,4R)-4-((tert- butyldiphenylsilyl)oxy)pyrrolidine-1,2-dicarboxylate (14.20 g, 90%) as a colorless oil. MS ESI calculated for C27H37NO5Si [M + H]+, 484.24, found 484.25 |
90% | With 1H-imidazole In N,N-dimethyl-formamide at 0 - 20℃; for 16.5h; | 78.1 Step 1: 1-(Tert-butyl) 2-methyl (2R,4R)-4-((tert-butyldiphenylsilyl)oxy)pyrrolidine-1,2- dicarboxylate To a stirred solution of 1-(tert-butyl) 2-methyl (2R,4R)-4-hydroxypyrrolidine-1,2- dicarboxylate (8.00 g, 32.62 mmol) and imidazole (4.44 g, 65.23 mmol) in DMF (80.00 mL) was added tert-butyl(chloro)diphenylsilane (13.45 g, 48.93 mmol) at 0oC over 30 min. The reaction mixture was stirred for 16 h at room temperature. The resulting mixture was diluted with water (400 mL) and extracted with EA (3 x 300 mL). The combined organic layers was washed with brine (5 x 500 mL), dried over anhydrous Na2SO4and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (6/1). The fractions contained desired product were combined and concentrated to afford 1-(tert-butyl) 2-methyl (2R,4R)-4-((tert- butyldiphenylsilyl)oxy)pyrrolidine-1,2-dicarboxylate (14.20 g, 90%) as a colorless oil. MS ESI calculated for C27H37NO5Si [M + H]+, 484.24, found 484.25 |
85% | With 1H-imidazole; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide | |
60% | With 1H-imidazole In dichloromethane at 0 - 20℃; | Step 1: (2R,4R)-1-tert-butyl 2-methyl 4-((tert-butyldiphenylsilyl)oxy)pyrrolidine-1,2- dicarboxylate To a mixture of (2R,4R)-1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate (100.0 g, 408.2 mmol) and imidazole (39.0 g, 573.5 mmol) in DCM (1.5 L) was added TBDPSCl (123.0 g, 448.9 mmol) at 0 oC. The reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with water (1.5 L) and extracted with DCM (1.0 L) twice. The combined organic layers were washed with brine (1.5 L), dried over Na2SO4, filtered and concentrated. The residue was triturated with PE (1.5 L) to afford (2R,4R)-1-tert-butyl 2-methyl 4-((tert-butyldiphenylsilyl)oxy)pyrrolidine-1,2-dicarboxylate (120.0 g, 60%) as a white solid. [M+H] Calcd.: 484.2; Found, 484.2. |
60% | With 1H-imidazole In dichloromethane at 0 - 20℃; | Step 1: (2R,4R)-1-tert-butyl 2-methyl 4-((tert-butyldiphenylsilyl)oxy)pyrrolidine-1,2- dicarboxylate To a mixture of (2R,4R)-1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate (100.0 g, 408.2 mmol) and imidazole (39.0 g, 573.5 mmol) in DCM (1.5 L) was added TBDPSCl (123.0 g, 448.9 mmol) at 0 oC. The reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with water (1.5 L) and extracted with DCM (1.0 L) twice. The combined organic layers were washed with brine (1.5 L), dried over Na2SO4, filtered and concentrated. The residue was triturated with PE (1.5 L) to afford (2R,4R)-1-tert-butyl 2-methyl 4-((tert-butyldiphenylsilyl)oxy)pyrrolidine-1,2-dicarboxylate (120.0 g, 60%) as a white solid. [M+H] Calcd.: 484.2; Found, 484.2. |
With 1H-imidazole In dichloromethane at 20℃; for 18h; | 1 To a solution of (2R,4R)-4-hydroxy-pyrrolidine- 1 ,2-dicarboxylic acid 1 -tert- butyl ester 2-methyl ester (5.0 g, 20.22 mmol) in dichloromethane (35 mL) was added imidazole (2.34 g, 34.4 mmol) and tert-butylchlorodiphenylsilane (5.71 mL, 22.24 mmol). The reaction mixture was stirred at room temperature for 18 hrs and filtered through a thin layer of celite. The filtrate was washed with water and brine, dried over sodium sulfate, filtered off and concentrated under reduced pressure providing crude (2R,4R)-4-(tert-butyl-diphenyl-silanyloxy)-pyrrolidine-l ,2-dicarboxylic acid 1 -tert-butyl ester 2-methyl ester (10.9 g), which was directly used in the next step without further purification. LCMS (m/z): 486.2 [M+H]+; Rt = 1.36 min. | |
With 1H-imidazole In dichloromethane at 20℃; for 18h; | To a solution of (2R,4R)-4-hydroxy-pyrrolidine-l,2-dicarboxylic acid 1-tert- butyl ester 2-methyl ester (5.0 g, 20.22 mmol) in dichloromethane (35 mL) was added imidazole (2.34 g, 34.4 mmol) and tert-butylchlorodiphenylsilane (5.71 mL, 22.24 mmol). The reaction mixture was stirred at room temperature for 18 hrs and filtered through a thin layer of celite. The filtrate was washed with water and brine, dried over sodium sulfate, filtered off and concentrated under reduced pressure providing crude (2R,4R)-4-(tert-butyl-diphenyl-silanyloxy)-pyrrolidine-l,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (10.9 g), which was directly used in the next step without further purification. LCMS (m/z): 486.2 [M+H]+; Rt = 1.36 min. | |
With 1H-imidazole In dichloromethane at 20℃; for 18h; | 1 To a solution of (2R,4R)-4-hydroxy-pyrrolidine-1 ,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (5.0 g, 20.22 mmol) in dichloromethane (35 mL) was added imidazole (2.34 g, 34.4 mmol) and tert-butylchlorodiphenylsilane (5.71 mL, 22.24 mmol). The reaction mixture was stirred at room temperature for 18 hrs and filtered through a thin layer of celite. The filtrate was washed with water and brine, dried over sodium sulfate, filtered off and concentrated under reduced pressure providing crude (2R,4R)-4- (tert-butyl-diphenyl-silanyloxy)-pyrrolidine-1 ,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (10.9 g), which was directly used in the next step without further purification. LCMS (m/z): 486.2 [M+H]+; Rt = 1.36 min. | |
With 1H-imidazole In dichloromethane at 20℃; for 18h; | 1 To a solution of (2R,4R)-4-hydroxy-pyrrolidine-1 ,2-dicarboxylic acid 1 -tert-butyl ester 2-methyl ester (5.0 g, 20.22 mmol) in dichloromethane (35 mL) was added imidazole (2.34 g, 34.4 mmol) and tert-butylchlorodiphenylsilane (5.71 mL, 22.24 mmol). The reaction mixture was stirred at room temperature for 18 hrs and filtered through a thin layer of celite. The filtrate was washed with water and brine, dried over sodium sulfate, filtered off and concentrated under reduced pressure providing crude (2R,4R)-4-(tert-butyl-diphenyl- silanyloxy)-pyrrolidine-1 ,2-dicarboxylic acid 1 -tert-butyl ester 2-methyl ester (10.9 g), which was directly used in the next step without further purification. LCMS (m/z): 486.2 [M+H]+; Rt = 1 .36 min. | |
With 1H-imidazole In N,N-dimethyl-formamide at 0 - 20℃; for 16.5h; | 1.1; 2.1 Preparation 1 : 1 -( 7 f /7-butyl) 2-methyl (2f?,4f?)-4-((teit-butyldiphenylsilyl)oxy)pyrrolidine-l,2- di carboxyl ate To a stirred solution of l-(/er/-butyl) 2-methyl (2f?,4f?)-4-hydroxypyrrolidine-l,2-dicarboxylate (8.00 g, 32.62 mmol) and imidazole (4.44 g, 65.23 mmol) in DMF (80 mL) was added tert- butyl(chloro)diphenylsilane (13.45 g, 48.93 mmol) at 0 °C over 0.5 hours. The reaction mixture was stirred for 16 h at room temperature. The resulting mixture was diluted with water (400 mL) and extracted with EA (3 x 300 ml). The combined organic layers was washed with brine (5 x 500 ml), dried over anhydrous NaiSCL and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (6: 1). The fractions contained desired product were combined and concentrated to afford 1 -{tert- butyl) 2-methyl (2/^,4/^)-4-((tert-butyl di phenyl si 1 yl )oxy)pyrrol i di ne- 1 ,2-di carboxyl ate (14.2 g, 90%) as a colorless crude oil. MS ESI calculated for C27H37N05Si [M + H]+, 484.24, found 484.25. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 95 percent / DEAD; PPh3 / tetrahydrofuran 2: 100 percent / sodium azide / methanol / 40 °C | ||
Multi-step reaction with 2 steps 1: DEAD, Ph3P / tetrahydrofuran / 5 h / Ambient temperature 2: conc. aq. NH3 / 2 h / Ambient temperature | ||
Multi-step reaction with 2 steps 1: 76 percent / diisopropyl azodicarboxylate, triphenylphosphine / tetrahydrofuran 2: 0.64 g / 1 N NaOH / methanol |
Multi-step reaction with 2 steps 1: 93.9 percent / Ph3P, DEAD / tetrahydrofuran / 42 h / Ambient temperature 2: 93.9 percent / NaOMe / methanol / 1 h / Ambient temperature | ||
Multi-step reaction with 2 steps 1: diethylazodicarboxylate; triphenylphosphine / tetrahydrofuran / 0 - 20 °C 2: sodium methylate / methanol / 0.5 h / 0 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: 95 percent / DEAD; PPh3 / tetrahydrofuran 2: 100 percent / sodium azide / methanol / 40 °C 3: 98 percent / DPPA; DEAD; PPh3 / tetrahydrofuran | ||
Multi-step reaction with 2 steps 1: triphenylphosphine; di-isopropyl azodicarboxylate; triethylamine / toluene / 0 - 70 °C 2: sodium azide / N,N-dimethyl-formamide / 80 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: 95 percent / DEAD; PPh3 / tetrahydrofuran 2: 100 percent / sodium azide / methanol / 40 °C 3: 98 percent / DPPA; DEAD; PPh3 / tetrahydrofuran 4: LiOH / tetrahydrofuran; H2O | ||
Multi-step reaction with 3 steps 1: triphenylphosphine; di-isopropyl azodicarboxylate; triethylamine / toluene / 0 - 70 °C 2: sodium azide / N,N-dimethyl-formamide / 80 °C 3: sodium hydroxide; water / tetrahydrofuran; methanol / 4 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: TEA / dioxane; H2O; methanol / 3 h 2: methanol | ||
Multi-step reaction with 2 steps 1: 81 percent 2: 99 percent / Cs2CO3 / dimethylformamide | ||
Multi-step reaction with 2 steps 1: HCl 2: Et3N; 4-(dimethylamino)pyridine / acetone; H2O / 18 h / 20 °C |
Multi-step reaction with 2 steps 1.1: SOCl2 / 6 h / 20 °C 2.1: Et3N / CH2Cl2 / 0.5 h / 0 °C 2.2: 1.76 g / DMAP / CH2Cl2 / 18 h / 20 °C | ||
Multi-step reaction with 2 steps 1: SOCl2 / 19 h / -20 - 20 °C 2: Et3N / CH2Cl2 / 3 h / 20 °C | ||
Multi-step reaction with 3 steps 1: SOCl2 2: -5 °C 3: Na2CO3 / dioxane; H2O / Ambient temperature | ||
Multi-step reaction with 2 steps 1: acetyl chloride / 8 h / Heating 2: 90 percent / triethylamine / CH2Cl2 / 12 h | ||
Multi-step reaction with 2 steps 1: 85 percent / Et3N / methanol; H2O; dioxane / 3 h / Ambient temperature 2: 70 percent / methanol; diethyl ether | ||
Multi-step reaction with 2 steps 1: 82.5 percent / aq. NaOH / tetrahydrofuran / Ambient temperature 2: 92.4 percent / dioxane; diethyl ether / 0.25 h / 5 °C | ||
Multi-step reaction with 2 steps 1: thionyl chloride / 13 h / 0 - 20 °C 2: dmap; triethylamine / dichloromethane / 12 h / 20 °C | ||
Multi-step reaction with 2 steps 1: acetyl chloride / 8 h / Inert atmosphere; Reflux 2: dmap; triethylamine / water monomer; acetone | ||
Multi-step reaction with 2 steps 1: thionyl chloride / 0 °C / Reflux 2: Potassium bicarbonate / water monomer; 1,4-dioxane / 20 °C | ||
Multi-step reaction with 2 steps 1: hydrogenchloride 2: triethylamine / dichloromethane | ||
With thionyl chloride; Sodium sulfate [anhydrous] | 52 1-(tert-Butyl) 2-methyl (2R,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate (99) 1-(tert-Butyl) 2-methyl (2R,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate (99) To an ice-cooled solution of 1.97 g (2R,4R)-4-hydroxypyrrolidine-2-carboxylic acid (15 mmol) in 30 ml MeOH were added dropwise 1.63 ml thionyl chloride (22.5 mmol) in a rate that held the exothermic reaction under control. After complete addition, the cooling bath was removed and the reaction was heated to reflux for three hours. After cooling back to ambient temperature, the mixture was concentrated under reduced pressure. Due to undefined inpurities in the starting material, the crude hydrochloride salt of the ester could only be obtained as brown to black colored, amorphous residue, which was carried on directly to the following Boc protection. The crude material was taken up in THF/water (20 ml each) and subsequently 1.89 g NaHCO3 (22.5 mmol) and 3.27 g Boc2O (15 mmol) were added. The dark mixture was stirred overnight at ambient temperature and was then diluted with EtOAc and transferred to a separatory funnel. The organic phase was successively washed with water, 2N HCl and brine, which removed majority of the dark inpurities. The organic phase was then stirred with Na2SO4, silica and activated carbon for 90 min at ambient temperature, before it was filtered over a bed of celite and evaporated under reduced pressure. The title compound was obtained as 3.36 g (91%) of a colorless oil. 1H NMR (400 MHz, CDCl3) δ 4.40 - 4.22 (m, 2H), 3.84 - 3.70 (m, 3H), 3.69 - 3.56 (m, 1H), 3.56 - 3.46 (m, 1H), 2.39 - 2.22 (m, 1H), 2.12 - 2.01 (m, 1H), 1.47 - 1.34 (m, 9H). 13C NMR (101 MHz, CDCl3) δ 175.7, 175.4, 154.6, 153.8, 80.5, 71.4, 70.3, 58.0, 57.8, 56.1, 55.5, 52.8, 52.5, 38.7, 37.9, 28.5, 28.4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: Et3N / CH2Cl2 / 20 °C 2: 59 percent / NaN3 / dimethylformamide / 26 h / 55 °C 3: 61 percent / H2; HCOOH / 10percent Pd/C / ethanol; tetrahydrofuran / 16 h / 2792.67 Torr 4: 75 percent / Et3N / dimethylformamide / 3 h / 60 °C 5: TFA / CH2Cl2 / 2 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1: Et3N / CH2Cl2 / 20 °C 2: 59 percent / NaN3 / dimethylformamide / 26 h / 55 °C 3: 61 percent / H2; HCOOH / 10percent Pd/C / ethanol; tetrahydrofuran / 16 h / 2792.67 Torr 4: 98 percent / Et3N / CH2Cl2 / 18 h 5: 76 percent / DBU / dimethylformamide / 18 h 6: TFA / CH2Cl2 / 2 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: Et3N / CH2Cl2 / 20 °C 2: 59 percent / NaN3 / dimethylformamide / 26 h / 55 °C 3: 61 percent / H2; HCOOH / 10percent Pd/C / ethanol; tetrahydrofuran / 16 h / 2792.67 Torr 4: 75 percent / Et3N / dimethylformamide / 3 h / 60 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: Et3N / CH2Cl2 / 20 °C 2: 59 percent / NaN3 / dimethylformamide / 26 h / 55 °C 3: 61 percent / H2; HCOOH / 10percent Pd/C / ethanol; tetrahydrofuran / 16 h / 2792.67 Torr 4: 98 percent / Et3N / CH2Cl2 / 18 h 5: 76 percent / DBU / dimethylformamide / 18 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: Et3N / CH2Cl2 / 20 °C 2: 59 percent / NaN3 / dimethylformamide / 26 h / 55 °C 3: 61 percent / H2; HCOOH / 10percent Pd/C / ethanol; tetrahydrofuran / 16 h / 2792.67 Torr 4: 98 percent / Et3N / CH2Cl2 / 18 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1: Et3N / CH2Cl2 / 20 °C 2: 59 percent / NaN3 / dimethylformamide / 26 h / 55 °C 3: 61 percent / H2; HCOOH / 10percent Pd/C / ethanol; tetrahydrofuran / 16 h / 2792.67 Torr 4: 75 percent / Et3N / dimethylformamide / 3 h / 60 °C 5: TFA / CH2Cl2 / 2 h 6: Et3N / dioxane; H2O / 16 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1: Et3N / CH2Cl2 / 20 °C 2: 59 percent / NaN3 / dimethylformamide / 26 h / 55 °C 3: 61 percent / H2; HCOOH / 10percent Pd/C / ethanol; tetrahydrofuran / 16 h / 2792.67 Torr 4: 75 percent / Et3N / dimethylformamide / 3 h / 60 °C 5: TFA / CH2Cl2 / 2 h 6: Et3N / dioxane; H2O / 16 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 7 steps 1: Et3N / CH2Cl2 / 20 °C 2: 59 percent / NaN3 / dimethylformamide / 26 h / 55 °C 3: 61 percent / H2; HCOOH / 10percent Pd/C / ethanol; tetrahydrofuran / 16 h / 2792.67 Torr 4: 98 percent / Et3N / CH2Cl2 / 18 h 5: 76 percent / DBU / dimethylformamide / 18 h 6: TFA / CH2Cl2 / 2 h 7: Et3N / dioxane; H2O / 16 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 7 steps 1: Et3N / CH2Cl2 / 20 °C 2: 59 percent / NaN3 / dimethylformamide / 26 h / 55 °C 3: 61 percent / H2; HCOOH / 10percent Pd/C / ethanol; tetrahydrofuran / 16 h / 2792.67 Torr 4: 75 percent / Et3N / dimethylformamide / 3 h / 60 °C 5: TFA / CH2Cl2 / 2 h 6: Et3N / dioxane; H2O / 16 h 7: NH2OK / methanol / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 7 steps 1: Et3N / CH2Cl2 / 20 °C 2: 59 percent / NaN3 / dimethylformamide / 26 h / 55 °C 3: 61 percent / H2; HCOOH / 10percent Pd/C / ethanol; tetrahydrofuran / 16 h / 2792.67 Torr 4: 75 percent / Et3N / dimethylformamide / 3 h / 60 °C 5: TFA / CH2Cl2 / 2 h 6: Et3N / dioxane; H2O / 16 h 7: 43 percent / NH2OK / methanol / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 8 steps 1: Et3N / CH2Cl2 / 20 °C 2: 59 percent / NaN3 / dimethylformamide / 26 h / 55 °C 3: 61 percent / H2; HCOOH / 10percent Pd/C / ethanol; tetrahydrofuran / 16 h / 2792.67 Torr 4: 98 percent / Et3N / CH2Cl2 / 18 h 5: 76 percent / DBU / dimethylformamide / 18 h 6: TFA / CH2Cl2 / 2 h 7: Et3N / dioxane; H2O / 16 h 8: NH2OK / methanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1: Et3N / CH2Cl2 / 20 °C 2: 59 percent / NaN3 / dimethylformamide / 26 h / 55 °C 3: 61 percent / H2; HCOOH / 10percent Pd/C / ethanol; tetrahydrofuran / 16 h / 2792.67 Torr 4: 75 percent / Et3N / dimethylformamide / 3 h / 60 °C 5: TFA / CH2Cl2 / 2 h 6: Et3N / dioxane; H2O / 16 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 7 steps 1: Et3N / CH2Cl2 / 20 °C 2: 59 percent / NaN3 / dimethylformamide / 26 h / 55 °C 3: 61 percent / H2; HCOOH / 10percent Pd/C / ethanol; tetrahydrofuran / 16 h / 2792.67 Torr 4: 98 percent / Et3N / CH2Cl2 / 18 h 5: 76 percent / DBU / dimethylformamide / 18 h 6: TFA / CH2Cl2 / 2 h 7: Et3N / dioxane; H2O / 16 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 8 steps 1: Et3N / CH2Cl2 / 20 °C 2: 59 percent / NaN3 / dimethylformamide / 26 h / 55 °C 3: 61 percent / H2; HCOOH / 10percent Pd/C / ethanol; tetrahydrofuran / 16 h / 2792.67 Torr 4: 98 percent / Et3N / CH2Cl2 / 18 h 5: 76 percent / DBU / dimethylformamide / 18 h 6: TFA / CH2Cl2 / 2 h 7: Et3N / dioxane; H2O / 16 h 8: NH2OK / methanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 7 steps 1: Et3N / CH2Cl2 / 20 °C 2: 59 percent / NaN3 / dimethylformamide / 26 h / 55 °C 3: 61 percent / H2; HCOOH / 10percent Pd/C / ethanol; tetrahydrofuran / 16 h / 2792.67 Torr 4: 75 percent / Et3N / dimethylformamide / 3 h / 60 °C 5: TFA / CH2Cl2 / 2 h 6: Et3N / dioxane; H2O / 16 h 7: NH2OK / methanol / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 85 percent / imidazole; DIEA / dimethylformamide 2: 89 percent / LiBH4 / tetrahydrofuran / 8 h / 20 °C | ||
Multi-step reaction with 2 steps 1: 1H-imidazole / dichloromethane / 18 h / 20 °C 2: sodium tetrahydroborate / tetrahydrofuran / 2 h / 70 °C | ||
Multi-step reaction with 2 steps 1.1: 1H-imidazole / dichloromethane / 18 h / 20 °C 2.1: sodium tetrahydroborate / tetrahydrofuran / 2 h / 70 °C 2.2: 20 °C |
Multi-step reaction with 2 steps 1: 1H-imidazole / dichloromethane / 18 h / 20 °C 2: sodium tetrahydroborate / tetrahydrofuran / 2 h / 70 °C | ||
Multi-step reaction with 2 steps 1: 1H-imidazole / dichloromethane / 18 h / 20 °C 2: sodium tetrahydroborate / tetrahydrofuran / 2 h / 70 °C | ||
Multi-step reaction with 2 steps 1: 1H-imidazole / N,N-dimethyl-formamide / 16.5 h / 0 - 20 °C 2: lithium borohydride / tetrahydrofuran / 16 h / 0 - 20 °C / Inert atmosphere | ||
Multi-step reaction with 2 steps 1: 1H-imidazole / N,N-dimethyl-formamide / 16.5 h / 0 - 20 °C 2: lithium borohydride / tetrahydrofuran / 16 h / 0 - 20 °C / Inert atmosphere | ||
Multi-step reaction with 2 steps 1: 1H-imidazole / dichloromethane / 0 - 20 °C 2: lithium borohydride / tetrahydrofuran / 0 - 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 10 steps 1.1: 85 percent / imidazole; DIEA / dimethylformamide 2.1: 89 percent / LiBH4 / tetrahydrofuran / 8 h / 20 °C 3.1: 97 percent / DIEA / CH2Cl2 / 0.67 h / 0 °C 4.1: 71 percent / NaN3 / dimethylformamide / 4 h / 90 °C 5.1: 100 percent / TFA / CH2Cl2 / 0.5 h / 20 °C 6.1: 91 percent / DIEA / tetrahydrofuran / 4 h / 20 °C 7.1: 76 percent / H2 / Pd/C / ethyl acetate / 20 °C 8.1: 88 percent / TBAF / tetrahydrofuran / 4 h / 20 °C 9.1: 74 percent / pyridine / 20 °C 10.1: K2CO3; Cs2CO3 / dimethylformamide / 0.08 h / 20 °C 10.2: 278 mg / dimethylformamide / 4 h / 20 - 80 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 7 steps 1: 85 percent / imidazole; DIEA / dimethylformamide 2: 89 percent / LiBH4 / tetrahydrofuran / 8 h / 20 °C 3: 97 percent / DIEA / CH2Cl2 / 0.67 h / 0 °C 4: 71 percent / NaN3 / dimethylformamide / 4 h / 90 °C 5: 100 percent / TFA / CH2Cl2 / 0.5 h / 20 °C 6: 91 percent / DIEA / tetrahydrofuran / 4 h / 20 °C 7: 76 percent / H2 / Pd/C / ethyl acetate / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 8 steps 1: 85 percent / imidazole; DIEA / dimethylformamide 2: 89 percent / LiBH4 / tetrahydrofuran / 8 h / 20 °C 3: 97 percent / DIEA / CH2Cl2 / 0.67 h / 0 °C 4: 71 percent / NaN3 / dimethylformamide / 4 h / 90 °C 5: 100 percent / TFA / CH2Cl2 / 0.5 h / 20 °C 6: 91 percent / DIEA / tetrahydrofuran / 4 h / 20 °C 7: 76 percent / H2 / Pd/C / ethyl acetate / 20 °C 8: 88 percent / TBAF / tetrahydrofuran / 4 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 9 steps 1: 85 percent / imidazole; DIEA / dimethylformamide 2: 89 percent / LiBH4 / tetrahydrofuran / 8 h / 20 °C 3: 97 percent / DIEA / CH2Cl2 / 0.67 h / 0 °C 4: 71 percent / NaN3 / dimethylformamide / 4 h / 90 °C 5: 100 percent / TFA / CH2Cl2 / 0.5 h / 20 °C 6: 91 percent / DIEA / tetrahydrofuran / 4 h / 20 °C 7: 76 percent / H2 / Pd/C / ethyl acetate / 20 °C 8: 88 percent / TBAF / tetrahydrofuran / 4 h / 20 °C 9: 74 percent / pyridine / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 11 steps 1.1: 85 percent / imidazole; DIEA / dimethylformamide 2.1: 89 percent / LiBH4 / tetrahydrofuran / 8 h / 20 °C 3.1: 97 percent / DIEA / CH2Cl2 / 0.67 h / 0 °C 4.1: 71 percent / NaN3 / dimethylformamide / 4 h / 90 °C 5.1: 100 percent / TFA / CH2Cl2 / 0.5 h / 20 °C 6.1: 91 percent / DIEA / tetrahydrofuran / 4 h / 20 °C 7.1: 76 percent / H2 / Pd/C / ethyl acetate / 20 °C 8.1: 88 percent / TBAF / tetrahydrofuran / 4 h / 20 °C 9.1: 74 percent / pyridine / 20 °C 10.1: K2CO3; Cs2CO3 / dimethylformamide / 0.08 h / 20 °C 10.2: 278 mg / dimethylformamide / 4 h / 20 - 80 °C 11.1: 195 mg / CH2Cl2 / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 12 steps 1.1: 85 percent / imidazole; DIEA / dimethylformamide 2.1: 89 percent / LiBH4 / tetrahydrofuran / 8 h / 20 °C 3.1: 97 percent / DIEA / CH2Cl2 / 0.67 h / 0 °C 4.1: 71 percent / NaN3 / dimethylformamide / 4 h / 90 °C 5.1: 100 percent / TFA / CH2Cl2 / 0.5 h / 20 °C 6.1: 91 percent / DIEA / tetrahydrofuran / 4 h / 20 °C 7.1: 76 percent / H2 / Pd/C / ethyl acetate / 20 °C 8.1: 88 percent / TBAF / tetrahydrofuran / 4 h / 20 °C 9.1: 74 percent / pyridine / 20 °C 10.1: K2CO3; Cs2CO3 / dimethylformamide / 0.08 h / 20 °C 10.2: 278 mg / dimethylformamide / 4 h / 20 - 80 °C 11.1: 195 mg / CH2Cl2 / 20 °C 12.1: Ba(OH)2 / H2O; tetrahydrofuran / 0.33 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: 22 percent 2: 81 percent 3: 99 percent / Cs2CO3 / dimethylformamide | ||
Multi-step reaction with 3 steps 1.1: acetic acid; acetic anhydride / 6 h / Reflux 1.2: 3 h / Reflux 2.1: sodium hydrogencarbonate / water; 1,4-dioxane / 0 - 20 °C 3.1: acetone / 2 h / 20 °C / Alkaline conditions |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 9 steps 1: 99 percent / imidazole / dimethylformamide / 1.5 h / Ambient temperature 2: 93 percent / lithium borohydride / tetrahydrofuran / 16 h 3: 94 percent / triethylamine / CH2Cl2 / 15 h 4: lithium triethylborohydride / tetrahydrofuran / 2 h 5: tetra-n-butylammonium fluoride / tetrahydrofuran / 2.5 h 6: 16.1 g / triethylamine / CH2Cl2 / 14 h 7: 43 percent / tetra-n-butylammonium azide / acetonitrile / 3 h / 65 °C 8: hydrogen / 10percent palladium on carbon / methanol / 1 h / 3040 Torr 9: triethylamine / pyridine / 19 h / Ambient temperature |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 11 steps 1: 99 percent / imidazole / dimethylformamide / 1.5 h / Ambient temperature 2: 93 percent / lithium borohydride / tetrahydrofuran / 16 h 3: 94 percent / triethylamine / CH2Cl2 / 15 h 4: lithium triethylborohydride / tetrahydrofuran / 2 h 5: tetra-n-butylammonium fluoride / tetrahydrofuran / 2.5 h 6: 16.1 g / triethylamine / CH2Cl2 / 14 h 7: 43 percent / tetra-n-butylammonium azide / acetonitrile / 3 h / 65 °C 8: hydrogen / 10percent palladium on carbon / methanol / 1 h / 3040 Torr 9: triethylamine / pyridine / 19 h / Ambient temperature 10: trifluoroacetic acid / 0.25 h 11: triethylamine / pyridine / 48 h / 40 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 11 steps 1: 99 percent / imidazole / dimethylformamide / 1.5 h / Ambient temperature 2: 93 percent / lithium borohydride / tetrahydrofuran / 16 h 3: 94 percent / triethylamine / CH2Cl2 / 15 h 4: lithium triethylborohydride / tetrahydrofuran / 2 h 5: tetra-n-butylammonium fluoride / tetrahydrofuran / 2.5 h 6: 16.1 g / triethylamine / CH2Cl2 / 14 h 7: 43 percent / tetra-n-butylammonium azide / acetonitrile / 3 h / 65 °C 8: hydrogen / 10percent palladium on carbon / methanol / 1 h / 3040 Torr 9: triethylamine / pyridine / 19 h / Ambient temperature 10: trifluoroacetic acid / 0.25 h 11: triethylamine / pyridine / 48 h / 40 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 12 steps 1: 99 percent / imidazole / dimethylformamide / 1.5 h / Ambient temperature 2: 93 percent / lithium borohydride / tetrahydrofuran / 16 h 3: 94 percent / triethylamine / CH2Cl2 / 15 h 4: lithium triethylborohydride / tetrahydrofuran / 2 h 5: tetra-n-butylammonium fluoride / tetrahydrofuran / 2.5 h 6: 16.1 g / triethylamine / CH2Cl2 / 14 h 7: 43 percent / tetra-n-butylammonium azide / acetonitrile / 3 h / 65 °C 8: hydrogen / 10percent palladium on carbon / methanol / 1 h / 3040 Torr 9: triethylamine / pyridine / 19 h / Ambient temperature 10: trifluoroacetic acid / 0.25 h 11: triethylamine / pyridine / 48 h / 40 °C 12: 1.) aq. NaOH, 2.) aq. HCl / 1.) THF, 60 deg C, 4.5 h, 2.) 105 deg C, 17 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 12 steps 1: 99 percent / imidazole / dimethylformamide / 1.5 h / Ambient temperature 2: 93 percent / lithium borohydride / tetrahydrofuran / 16 h 3: 94 percent / triethylamine / CH2Cl2 / 15 h 4: lithium triethylborohydride / tetrahydrofuran / 2 h 5: tetra-n-butylammonium fluoride / tetrahydrofuran / 2.5 h 6: 16.1 g / triethylamine / CH2Cl2 / 14 h 7: 43 percent / tetra-n-butylammonium azide / acetonitrile / 3 h / 65 °C 8: hydrogen / 10percent palladium on carbon / methanol / 1 h / 3040 Torr 9: triethylamine / pyridine / 19 h / Ambient temperature 10: trifluoroacetic acid / 0.25 h 11: triethylamine / pyridine / 48 h / 40 °C 12: 1.) aq. NaOH, 2.) aq. HCl / 1.) THF, 60 deg C, 4.5 h, 2.) 105 deg C, 17 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 12 steps 1: 99 percent / imidazole / dimethylformamide / 1.5 h / Ambient temperature 2: 93 percent / lithium borohydride / tetrahydrofuran / 16 h 3: 94 percent / triethylamine / CH2Cl2 / 15 h 4: lithium triethylborohydride / tetrahydrofuran / 2 h 5: tetra-n-butylammonium fluoride / tetrahydrofuran / 2.5 h 6: 16.1 g / triethylamine / CH2Cl2 / 14 h 7: 43 percent / tetra-n-butylammonium azide / acetonitrile / 3 h / 65 °C 8: hydrogen / 10percent palladium on carbon / methanol / 1 h / 3040 Torr 9: triethylamine / pyridine / 19 h / Ambient temperature 10: trifluoroacetic acid / 0.25 h 11: triethylamine / pyridine / 48 h / 40 °C 12: 1.) aq. NaOH, 2.) aq. HCl / 1.) THF, 60 deg C, 4.5 h, 2.) 105 deg C, 17 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 10 steps 1: 99 percent / imidazole / dimethylformamide / 1.5 h / Ambient temperature 2: 93 percent / lithium borohydride / tetrahydrofuran / 16 h 3: 94 percent / triethylamine / CH2Cl2 / 15 h 4: lithium triethylborohydride / tetrahydrofuran / 2 h 5: tetra-n-butylammonium fluoride / tetrahydrofuran / 2.5 h 6: 16.1 g / triethylamine / CH2Cl2 / 14 h 7: 43 percent / tetra-n-butylammonium azide / acetonitrile / 3 h / 65 °C 8: hydrogen / 10percent palladium on carbon / methanol / 1 h / 3040 Torr 9: triethylamine / pyridine / 19 h / Ambient temperature 10: trifluoroacetic acid / 0.25 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 99 percent / imidazole / dimethylformamide / 1.5 h / Ambient temperature 2: 93 percent / lithium borohydride / tetrahydrofuran / 16 h | ||
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / dichloromethane / 3 h / -40 °C 2: lithium borohydride / tetrahydrofuran / 0 - 20 °C | ||
Multi-step reaction with 2 steps 1: N,N-dimethyl-formamide / 4 h / 0 - 20 °C 2: lithium borohydride / tetrahydrofuran / 16 h / 0 - 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 12 steps 1: 99 percent / imidazole / dimethylformamide / 1.5 h / Ambient temperature 2: 93 percent / lithium borohydride / tetrahydrofuran / 16 h 3: 94 percent / triethylamine / CH2Cl2 / 15 h 4: lithium triethylborohydride / tetrahydrofuran / 2 h 5: tetra-n-butylammonium fluoride / tetrahydrofuran / 2.5 h 6: 16.1 g / triethylamine / CH2Cl2 / 14 h 7: 43 percent / tetra-n-butylammonium azide / acetonitrile / 3 h / 65 °C 8: hydrogen / 10percent palladium on carbon / methanol / 1 h / 3040 Torr 9: triethylamine / pyridine / 19 h / Ambient temperature 10: trifluoroacetic acid / 0.25 h 11: 78 percent / triethylamine / pyridine / 336 h / 65 °C 12: 1.) aq. NaOH, 2.) aq. hydrochloric acid / 1.) THF, 65 deg C, 4 h, 2.) 110 deg C, 15 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 11 steps 1: 99 percent / imidazole / dimethylformamide / 1.5 h / Ambient temperature 2: 93 percent / lithium borohydride / tetrahydrofuran / 16 h 3: 94 percent / triethylamine / CH2Cl2 / 15 h 4: lithium triethylborohydride / tetrahydrofuran / 2 h 5: tetra-n-butylammonium fluoride / tetrahydrofuran / 2.5 h 6: 16.1 g / triethylamine / CH2Cl2 / 14 h 7: 43 percent / tetra-n-butylammonium azide / acetonitrile / 3 h / 65 °C 8: hydrogen / 10percent palladium on carbon / methanol / 1 h / 3040 Torr 9: triethylamine / pyridine / 19 h / Ambient temperature 10: trifluoroacetic acid / 0.25 h 11: triethylamine / pyridine / 48 h / 40 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 11 steps 1: 99 percent / imidazole / dimethylformamide / 1.5 h / Ambient temperature 2: 93 percent / lithium borohydride / tetrahydrofuran / 16 h 3: 94 percent / triethylamine / CH2Cl2 / 15 h 4: lithium triethylborohydride / tetrahydrofuran / 2 h 5: tetra-n-butylammonium fluoride / tetrahydrofuran / 2.5 h 6: 16.1 g / triethylamine / CH2Cl2 / 14 h 7: 43 percent / tetra-n-butylammonium azide / acetonitrile / 3 h / 65 °C 8: hydrogen / 10percent palladium on carbon / methanol / 1 h / 3040 Torr 9: triethylamine / pyridine / 19 h / Ambient temperature 10: trifluoroacetic acid / 0.25 h 11: 78 percent / triethylamine / pyridine / 336 h / 65 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 9 steps 1: 93.9 percent / Ph3P, DEAD / tetrahydrofuran / 42 h / Ambient temperature 2: 97.4 percent / LiBH4 / tetrahydrofuran / Ambient temperature 3: 87.7 percent / Et3N / CH2Cl2; tetrahydrofuran / 43 h / Ambient temperature 4: 6.5 percent / triphenylphosphine, DEAD / tetrahydrofuran / 19 h / Ambient temperature 5: 80percent aq. acetic acid / Ambient temperature 6: H2O / 4 h / Heating 7: trifluoroacetic acid / 1 h / Ambient temperature 8: N-hydroxysuccinimide, dicyclohexylcarbodiimide / dimethylformamide / 1.) 0 deg C, 0.5 h, 2.) RT, 25 h 9: glacial acetic acid, H2 / 10percent Pd/C / 1 h / 760 Torr |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With diethylamino-sulfur trifluoride In dichloromethane at -78 - 20℃; for 42h; | 4 Add (diethylamino)sulfur trifluoride (3.9 mL, 29.8 mmol) to a -78 °C cooled solution of 4-(R)-hydroxypyrrolidine-N1,2-(R)-dicarboxylic acid 1-tert-butyl ester 2- methyl ester (3.81 g, 15.54 mmol) in dichloromethane (50 mL). Stir 2 h, then remove cold bath and stir 40 h at room temperature. Cool in ice bath and add saturated sodium bicarbonate solution. Warm to.room temperature, dry (magnesium sulfate), concentrate (350 mbar, 25°C) and purify (silica gel chromatography, eluting with diethyl ether and dichloromethane) to give the title compound as an oil (4.01 g, 97%). MS (ES): m/z = 148.1 [M+H, Product-Boc]. |
63% | With diethylamino-sulfur trifluoride In dichloromethane at -78 - 20℃; for 18h; | 41.1 Step 1: Synthesis of 1-tert-butyl 2-methyl (2R,4S)-4-fluoropyrrolidine-1,2-dicarboxylate To a solution of 1-tert-butyl 2-methyl (2R,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate (3 g, 12.2 mmol) in methylene chloride (30 mL) at -78 °C, was added diethyl amino sulfur trifluoride (2.40 mL, 18.2 mmol) drop wise. The mixture was stirred at -78 °C for 2 h and then at RT for another 16 h. After completion of the reaction, the reaction was quenched with NH4Cl aqueous solution (5 mL) and was extracted with DCM (25 mL x 3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a nutral alumina column chromatography (PE/EtOAc (v/v) = 20/1) to afford 1-tert-butyl 2-methyl (2R,4S)-4-fluoropyrrolidine- 1,2-dicarboxylate (1.89 g, 7.64 mmol, 63% yield) as a colour less liquid. TLC System: 10% EtOAc/Hexanes, Rf: 0.5.1H NMR (400 MHz, CDCl3): δ 5.28-5.13 (m, 1H), 4.49-4.38 (m, 1H), 3.95- 3.86 (m, 1H), 3.74 (s, 3H), 3.69-3.55 (dd, J = 12.8, 3.2 Hz, 1H), 2.62-2.54 (m, 1H), 2.19-2.02 (m, 1H), 1.42 (s, 9H). |
45% | With diethylamino-sulfur trifluoride In dichloromethane at -78 - 20℃; for 15h; | 2-18.1 Step 1 To a suspension of l-(/er/-butyl) 2-methyl (2R,4R)-4-hydroxypyrrolidine-l,2- dicarboxylate (0.5 g, 2.038 mmol) in DCM at -78 °C was added diethylaminosulfur trifluoride (0.53 mL, 4.076 mmol) dropwise and stirred at room temperature for 15 h. The reaction mass was quenched with saturated NaHCC solution (10 mL) and extracted with DCM (20 mL). The combined organic layers were dried over anhydrous NaiSCL and concentrated under reduced pressure. The crude product was purified by Biotage-Isolera using 10 g silica snap and was eluted with gradient 0-10% EtOAc in Hexane to afford l-(/er/-butyl) 2-methyl (2R,4S)-4- fluoropyrrolidine-l,2-dicarboxylate (0.23 g, 45%) as a colourless gum. NMR: (400 MHz, CDCb) d: 5.30 - 5.17 (m, 1H), 4.51 - 4.40 (m, 1H), 3.98 - 3.82 (m, 1H), 3.78 (s, 3H), 3.71 - 3.51 (m, 1H), 2.67 - 2.56 (m, 1H), 2.21 - 2.04 (m, 1H), 1.44 (s, 9H). |
15% | Stage #1: (2R,4R)-1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate With diethylamino-sulfur trifluoride In dichloromethane at -78 - 20℃; for 1.5h; Stage #2: With sodium hydrogencarbonate In dichloromethane; water | 90.3 Preparation of 1-(3,4-dimethoxy-5-trifluoromethylthiobenzoyl)-4S-fluoropyrrolidine-2R-carboxylic acid hydroxyamide; Step 3 To a stirred solution [OF 4R-HYDROXYPYRROLIDINE-1, 2R-DICARBOXYLIC] acid 1- [TERT-BUTYL] ester 2-methyl ester (1.62 g, 6.59 mmol, [1] eq. ) in CH2Cl2 (30 mL) at-78 [°C] was added DAST solution (1.0 M in [CH2C12,] 7.91 mL, 7.91 mmol, 1.2 eq. ). The resulting solution was stirred at-78 [°C] for 30 min, followed by room temperature for 60 min, then quenched with saturated aqueous [NAHCO3] (15 mL). The resulting mixture was partitioned between [H20] (100 mL) and [ET20] (150 mL). The layers were separated, the organic layer washed with brine (100 mL), dried MgS04 and concentrated invacuo. The product was purified via flash column chromatography on silica gel (40% EtOAc/hexanes as an eluent) to give 4S-fluoropyrrolidine- [1,] 2R-dicarboxylic acid [1-TERT-BUTYL] ester 2-methyl ester (248 mg, 1.00 mmol, 15% yield). ESMS: 270.5 [M+Na] |
With diethylamino-sulfur trifluoride In dichloromethane at -78 - 20℃; for 12h; Inert atmosphere; | 7.7.3 7.3 5 g of 1-tert-butyl 2-methyl (2R,4R)-4-hydroxypyrrolidine-1,2-carboxylate is dissolved in 100 ml of CH2Cl2 under an N2 atmosphere and cooled to -78° C. 3 ml of diethylaminosulfur trifluoride are subsequently slowly added dropwise. The reaction mixture is warmed to RT over 12 h. After aqueous work-up, the organic phase is dried over magnesium sulfate, evaporated in vacuo, and the 5.3 g of oily 1-tert-butyl 2-methyl (2R,4S)-4-fluoropyrrolidine-1,2-carboxylate obtained are reacted further in the next reaction without further purification. | |
With (bis-(2-methoxyethyl)amino)sulfur trufluoride In dichloromethane at -78 - 20℃; for 12h; | 1.2.3 [0297] To the alcohol 15 (5.0 g, 20.38 mmol) in DCM (50 ml) at -78UC, deoxofluor (Commercial source: sigma-aldrich) was added. Then the reaction mixture was allowed to come to rt and stirred at rt for 12h. Then the reaction mixture was quenched with saturated aq sodium carbonate solution at 0°C, warmed to rt. Then the reaction mixture was extracted with ethyl acetate. Organic layer was washed with water, brine and dried. Crude residue was column chromatographed to obtain 3.05 g of the ester 16. | |
With diethylamino-sulfur trifluoride In dichloromethane at -78 - 20℃; for 2.33333h; | 17.23a Example 17.23a. Synthesis of (2RAS)--tert-bxxiy 2-methyl 4-fluoropyrrolidine- 1,2-dicarboxylateTo a solution of (2/?,4/?)-l-ieri-butyl 2-methyl-4-hydroxypyrrolidine- 1,2-dicarboxylate (1.0 g, 4.1 mmol) in dichloromethane (20 mL) was added diethylaminosulfur trifluoride (2.0 g, 12.3 mmol) at -78 °C over 20 min. The reaction mixture was stirred at -78 °C for 1 h and then warmed to room temperature for 1 h. Then the reaction was quenched with aqueous sodium carbonate and extracted with dichloromethane (3 x lOOmL). The combined organic layers were washed with brine, dried over Na2SC>4, concentrated, and purified by column chromatography to give 670 mg of the desired product. MS (ESI): 248 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 20℃; for 8h; | 98.1 Preparation of 1-(3,4-dimethoxy-5-trifluoromethylthiobenzoyl)-4S- (naphthalene-2- yloxy) pyrrolidine-2R-carboxylic acid hydroxyamide; Step 1 To a stirred mixture of 4R-hydroxypyrrolidine-1,2R-dicarboxylic acid [1-] [TERT-BUTYL] ester 2-methyl ester [(1 0] g, 4.07 mmol, 1 [EQ. ;] Product from Step 2 of Example 90), 2- naphthol (1.19 g, 8.15 mmol, 2 eq. ), and [PH3P] (2. [38] g, 8.97 mmol, 2.20 [EQ.)] in dry THF (50 mL) at [0 °C] was added DIAD (1.86 mL, 8.97 mmol, 2.20 eq. ) dropwise. The reaction was allowed to warm to room temperature and stirred for 8 h. The solvent was removed in vacuo and the residue was pre-adsorbed in silica gel and chromatographed using 30% EtOAc in hexanes as an eluent to afford [4S-(NAPHTHALEN-2-YLOXY) PYRROLIDINE-1,] 2R-dicarboxylic acid 1-tert-butyl ester 2-methyl ester in 79% yield. ESMS: [M/Z] 394.5 [M+Na]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 20℃; for 8h; | 99.1 Preparation of 4S-(biphenyl-4-yloxy)-1-(3,4-dimethoxy-5-trifluorothiobenzoyl)-pyrrolidine-2R-carboxylic acid hydroxyamide; Step 1: To a stirred mixture [OF 4R-HYDROXYPYRROLIDINE-1, 2R-DICARBOXYLIC] acid 1- [TERT-BUTYL] ester 2-methyl ester (1.0 g, 4.07 mmol, 1 [EQ. ;] Product from Step 2 of Example 90), biphenyl-4-ol (1.43 g, 8.15 mmol, 2 eq. ), and Ph3P (2.38 g, 8.97 mmol, 2.20 [EQ.)] in dry THF (50 mL) at [0 °C] was added DIAD (1. [86] mL, 8.97 mmol, 2.20 eq. ) dropwise. The reaction was allowed to warm to room temperature and stirred for 8 h. The solvent was removed in vacuo and the residue was pre-adsorbed on to silica gel and to afford [4S- (BIPHENYL-4-YLOXY) PYRROLIDINE-1,] 2R-dicarboxylic acid 1- [TERT-BUTYL] ester 2-methyl ester in 47% yield. ESMS: mlz 420.6 [M+Na]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triphenylphosphine; diethylazodicarboxylate; In dichloromethane; at 25℃; for 2h; | Example 1 (4S)-4- ({4-[(3-Chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)-N- cyclopropyl-1-methyl-D-prolinamide Example 1 HATU (0.23g) was added to an agitated solution of (4Y)-4- ( {4- [ (3-CHLORO-2- fluorophenyl) AMINO]-7-METHOXYQUINAZOLIN-6-YL} OXY)-1-METHYL-D-PROLINE (7) (0.18g), cyclopropylamine (34.4mg) and DIPEA (156mg) IN METHYLENE CHLORIDE (5M1). After 16hrs the reaction mixture was reduced in vacuo. The residues were re-dissolved in methylene chloride and washed with sodium hydroxide solution (2M) and water. The organic phase was then purified by column chromatography on silica eluting with increasingly polar mixtures of METHANOL/METHYLENE CHLORIDE (0/100-10/90). THE fractions containing the desired product were combined and evaporated to a foam which was triturated with diethylether to give the title compound as a white solid. (0. 15G). LH NMR Spectrum : (DMSO d6) 0.40-0. 48 (m, 2H), 0.57-0. 64 (M, 2H), 2.05-2. 14 (M, 1H), 2.28 (s, 3H), 2.33-2. 45 (M, 1H), 2.48-2. 56 (M, 1H + DMSO), 2. 61-2. 70 (M, 1H), 3.08 (t, 1H), 3.64 (dd, 1H), 3.94 (s, 3H), 5.06 (M, 1H), 7.20 (s, 1H), 7.28 (t, 1H), 7.44-7. 56 (M, 2H), 7.65 (s, 1H), 7.87 (d, 1H), 8.35 (s, 1H), 9.63 (s, 1H); Mass SPECTRUM : (M+H) + 486. 44 The starting material 1, 2-PYRROLIDINEDICARBOXYLIC acid, 4-hydroxy-, 1- (1, 1-DIMETHYLETHYL) 2- methyl ester, (2R, 4R) (2) was prepared as follows: 1- [3- (DIMETHYLAMINO) PROPYL]-3-ETLIYLCARBODIIMIDE hydrochloride (14.73 g) was added to a stirred suspension of 1, 2-PYRROLIDINEDICARBOXYLIC acid, 4-hydroxy-, l- (l, l-dimethylethyl) ester, (2R, 4R) (1) (13.65 g), DIMETHYLAMINOPYRIDINE (21.65 g) and methanol (5.67 g) in methylene chloride (400 ml) and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was washed with citric acid (1.0 M), saturated aqueous sodium bicarbonate solution and saturated brine, dried over MgSO4, filtered and evaporated. The residues were then purified by column chromatography on silica eluting with increasingly polar mixtures of METHANOL/METHYLENE chloride (1/99-5/95). The desired product fractions were combined and evaporated to give 1, 2-PYNOLIDINEDICARBOXYLIC acid, 4-hydroxy-, L- (L, L-DIMETHYLETHYL) 2- methyl ester, (2R, 4R) (2) as a white crystalline solid, (5.9 g). 1H NMR Spectrum : (DMSO d6) 1.32 + 1.38 (2s, 9H), 1.76-1. 87 (M, 1H), 2.24-2. 28 (M, 1H), 3.06-3. 15 (M, 1H), 3.42- 3. 51 (m, 1H), 3.60 + 3.63 (2s, 3H), 4.15-4. 24 (M, 2H), 4.92-5. 00 (M, 1H). Starting material 1, 2-Pyrrolidinedicarboxylic acid, 4-hydroxy-1- (1, 1-dimethylethyl) ester, (2R, 4R), (1), (Boc-D-cis-hyp-OH) is commercially available Starting material (3) was prepared as follows: 6-Acetoxy-4-chloro-7-methoxyquinazoline, (Example 25-5 of in W001/66099 ; 10. 0g, 39.6 MMOLE) was added in portions to a stirred 7N methanolic ammonia solution (220 ML) cooled to 10C in an ice/water bath. After stirring for one hour the precipitate was filtered, washed with diethylether and dried thoroughly under high vacuum to give 4-chloro-7- METHOXYQUINAZOLIN-6-OL (3) (5.65g, 67.8%) ; 1H NMR Spectrum : (DMSO d6) 3.96 (s, 3H); 7.25 (s, 1H); 7.31 (s, 1H); 8.68 (s, 1H) ; Mass Spectrum: (M+H) + 211. The starting material (4) was prepared as follows: Di-ethyl azodicarboxylate (5.71g) was added slowly to a stirred suspension of 1,2- PYNOLIDINEDICARBOXYLIC acid, 4-hydroxy-, L- (L, L-DIMETHYLETHYL) 2-methyl ester, (2R, 4R) (2) (5.9g), 4-CHLORO-7-METHOXYQUINAZOLIN-6-OL (3) (4.6g) AND TRIPHENYLPHOSPHINE (8.6g) in methylene chloride (400 ML) at 25C under an atmosphere of nitrogen and the reaction mixture was stirred for 2 hours. The reaction mixture was then evaporated to ½ volume and purified by column chromatography on silica eluting with increasingly polar mixtures of METHANOL/METHYLENE chloride (1/99-3/97). The desired product fractions were combined and evaporated to give 1-tert-butyl 2-methyl (2R, 4S)-4-[(4-chloro-7-methoxyquinazolin-6- yl) oxy] pyrrolidine-1, 2-dicarboxylate (4) as a pale yellow gum. This was used in the preparation of (5) without further purification. The starting material methyl (4S)-4-({4-[(3-CHLORO-2-FLUOROPHENYL) AMINO]-7- METHOXYQUINAZOLIN-6-YL} OXY)-D-PROLINATE HYDROCHLORIDE (5) was prepared as follows: 4. 0M HCl in Dioxane (15 ml) was added to a suspension of 1-tert-butyl 2-methyl (2R, 4S)-4- [(4-chloro-7-methoxyquinazolin-6-yl0 oxy] pyrrolidine-1, 2-dicarboxylate (4) AND 3-CHLORO-2- fluoroaniline (2.89g) in acetonitrile (400 ML) and the reaction mixture was stirred and heated at 70C for 3 hours. The resulting precipitate was filtered hot and washed with acetonitrile and diethylether and dried under vacuum to give methyl (4S)-4- (14- [ (3-CLILORO-2- FLUOROPHENYL) AMINO]-7-METHOXYQUINAZOLIN-6-YL} OXY)-D-PROLINATE HYDROCHLORIDE (S) as an off- white solid, (6. 3G). TH NMR Spectrum : (DMSO D6) 2.46-2. 60 (M, 2H), 3.37-3. 46 (M, 1H), 3.71 (s, 3H), 3.89-3. 98 (m, 4H), 4.53 (t, 1H), 5.42 (M, 1H), 7.29 (t, 1H), 7.38-7. 48 (M, 2H), 7.55 (t, 1H), 8.64 (s, 1H), 8.75 (s, 1H)... |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In methanol; toluene at 0℃; for 2h; | 1 Trimethylsilyl diazomethane (3.89 mmol) was slowly added to an ice cooled solution of (4R)-1-[(1,1-dimethylethyl)oxy]carbonyl}-4-hydroxy-D-proline (0.75 g, 3.25 mmol), 60 mL toluene and 20 mL of methanol. The reaction was stirred for 2 hours on the ice bath, was warmed to room temperature, and was concentrated to give 0.89 g of the title compound as a clear yellow oil. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.4 (m, 9 H), 1.8 (dt, J=12.8, 4.9 Hz, 1 H), 2.4 (m, 1 H), 3.1 (m, 1 H), 3.5 (dd, J=10.8, 5.7 Hz, 1 H), 3.6 (s, 3 H), 4.2 (m, 2 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 16h; | 1 Example 1 (4S)-4- ({4-[(3-Chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)-N- cyclopropyl-1-methyl-D-prolinamide Example 1 HATU (0.23g) was added to an agitated solution of (4Y)-4- ( {4- [ (3-CHLORO-2- fluorophenyl) AMINO]-7-METHOXYQUINAZOLIN-6-YL} OXY)-1-METHYL-D-PROLINE (7) (0.18g), cyclopropylamine (34.4mg) and DIPEA (156mg) IN METHYLENE CHLORIDE (5M1). After 16hrs the reaction mixture was reduced in vacuo. The residues were re-dissolved in methylene chloride and washed with sodium hydroxide solution (2M) and water. The organic phase was then purified by column chromatography on silica eluting with increasingly polar mixtures of METHANOL/METHYLENE CHLORIDE (0/100-10/90). THE fractions containing the desired product were combined and evaporated to a foam which was triturated with diethylether to give the title compound as a white solid. (0. 15G). LH NMR Spectrum : (DMSO d6) 0.40-0. 48 (m, 2H), 0.57-0. 64 (M, 2H), 2.05-2. 14 (M, 1H), 2.28 (s, 3H), 2.33-2. 45 (M, 1H), 2.48-2. 56 (M, 1H + DMSO), 2. 61-2. 70 (M, 1H), 3.08 (t, 1H), 3.64 (dd, 1H), 3.94 (s, 3H), 5.06 (M, 1H), 7.20 (s, 1H), 7.28 (t, 1H), 7.44-7. 56 (M, 2H), 7.65 (s, 1H), 7.87 (d, 1H), 8.35 (s, 1H), 9.63 (s, 1H); Mass SPECTRUM : (M+H) + 486. 44 The starting material 1, 2-PYRROLIDINEDICARBOXYLIC acid, 4-hydroxy-, 1- (1, 1-DIMETHYLETHYL) 2- methyl ester, (2R, 4R) (2) was prepared as follows: 1- [3- (DIMETHYLAMINO) PROPYL]-3-ETLIYLCARBODIIMIDE hydrochloride (14.73 g) was added to a stirred suspension of 1, 2-PYRROLIDINEDICARBOXYLIC acid, 4-hydroxy-, l- (l, l-dimethylethyl) ester, (2R, 4R) (1) (13.65 g), DIMETHYLAMINOPYRIDINE (21.65 g) and methanol (5.67 g) in methylene chloride (400 ml) and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was washed with citric acid (1.0 M), saturated aqueous sodium bicarbonate solution and saturated brine, dried over MgSO4, filtered and evaporated. The residues were then purified by column chromatography on silica eluting with increasingly polar mixtures of METHANOL/METHYLENE chloride (1/99-5/95). The desired product fractions were combined and evaporated to give 1, 2-PYNOLIDINEDICARBOXYLIC acid, 4-hydroxy-, L- (L, L-DIMETHYLETHYL) 2- methyl ester, (2R, 4R) (2) as a white crystalline solid, (5.9 g). 1H NMR Spectrum : (DMSO d6) 1.32 + 1.38 (2s, 9H), 1.76-1. 87 (M, 1H), 2.24-2. 28 (M, 1H), 3.06-3. 15 (M, 1H), 3.42- 3. 51 (m, 1H), 3.60 + 3.63 (2s, 3H), 4.15-4. 24 (M, 2H), 4.92-5. 00 (M, 1H). Starting material 1, 2-Pyrrolidinedicarboxylic acid, 4-hydroxy-1- (1, 1-dimethylethyl) ester, (2R, 4R), (1), (Boc-D-cis-hyp-OH) is commercially available Starting material (3) was prepared as follows: 6-Acetoxy-4-chloro-7-methoxyquinazoline, (Example 25-5 of in W001/66099 ; 10. 0g, 39.6 MMOLE) was added in portions to a stirred 7N methanolic ammonia solution (220 ML) cooled to 10°C in an ice/water bath. After stirring for one hour the precipitate was filtered, washed with diethylether and dried thoroughly under high vacuum to give 4-chloro-7- METHOXYQUINAZOLIN-6-OL (3) (5.65g, 67.8%) ; 1H NMR Spectrum : (DMSO d6) 3.96 (s, 3H); 7.25 (s, 1H); 7.31 (s, 1H); 8.68 (s, 1H) ; Mass Spectrum: (M+H) + 211. The starting material (4) was prepared as follows: Di-ethyl azodicarboxylate (5.71g) was added slowly to a stirred suspension of 1,2- PYNOLIDINEDICARBOXYLIC acid, 4-hydroxy-, L- (L, L-DIMETHYLETHYL) 2-methyl ester, (2R, 4R) (2) (5.9g), 4-CHLORO-7-METHOXYQUINAZOLIN-6-OL (3) (4.6g) AND TRIPHENYLPHOSPHINE (8.6g) in methylene chloride (400 ML) at 25°C under an atmosphere of nitrogen and the reaction mixture was stirred for 2 hours. The reaction mixture was then evaporated to ½ volume and purified by column chromatography on silica eluting with increasingly polar mixtures of METHANOL/METHYLENE chloride (1/99-3/97). The desired product fractions were combined and evaporated to give 1-tert-butyl 2-methyl (2R, 4S)-4-[(4-chloro-7-methoxyquinazolin-6- yl) oxy] pyrrolidine-1, 2-dicarboxylate (4) as a pale yellow gum. This was used in the preparation of (5) without further purification. The starting material methyl (4S)-4-({4-[(3-CHLORO-2-FLUOROPHENYL) AMINO]-7- METHOXYQUINAZOLIN-6-YL} OXY)-D-PROLINATE HYDROCHLORIDE (5) was prepared as follows: 4. 0M HCl in Dioxane (15 ml) was added to a suspension of 1-tert-butyl 2-methyl (2R, 4S)-4- [(4-chloro-7-methoxyquinazolin-6-yl0 oxy] pyrrolidine-1, 2-dicarboxylate (4) AND 3-CHLORO-2- fluoroaniline (2.89g) in acetonitrile (400 ML) and the reaction mixture was stirred and heated at 70°C for 3 hours. The resulting precipitate was filtered hot and washed with acetonitrile and diethylether and dried under vacuum to give methyl (4S)-4- (14- [ (3-CLILORO-2- FLUOROPHENYL) AMINO]-7-METHOXYQUINAZOLIN-6-YL} OXY)-D-PROLINATE HYDROCHLORIDE (S) as an off- white solid, (6. 3G). TH NMR Spectrum : (DMSO D6) 2.46-2. 60 (M, 2H), 3.37-3. 46 (M, 1H), 3.71 (s, 3H), 3.89-3. 98 (m, 4H), 4.53 (t, 1H), 5.42 (M, 1H), 7.29 (t, 1H), 7.38-7. 48 (M, 2H), 7.55 (t, 1H), 8.64 (s, 1H), 8.75 (s, 1H), 12.28 (bs, 1H); Mass Spectrum : (M+H) + 446.96 Compound (6) was prepared as follows: Methyl (4S)-4-({4-[(3-CHLORO-2-FLUOROPHENYL) AMINO]-7-METHOXYQUINAZOLIN-6-YL} OXY)-D- PROLINATE HYDROCLULORIDE (S) (6.3g), PARAFORMALDEHYDE (3.9g), sodium cyanoborohydride (3. 28G) and magnesium sulphate (3.13g) were suspended in methanol (50ml) and heated to 45°C for 4 hours under an atmosphere of nitrogen. The reaction mixture was filtered, evaporated and partitioned between ethylacetate and saturated aqueous sodium bicarbonate solution. The organics were then washed with saturated brine, dried over MGS04, filtered and evaporated. The residues were then purified by column chromatography on silica eluting with increasingly polar mixtures of methanol/methylene chloride (2-3%) to give methyl (4S)-4-({4-[(3-CHLORO-2- FLUOROPHENYL) AMINO]-7-METHOXYQUINAZOLIN-6-YL} OXY)-1-METHYL-D-PROLINATE (6) as a yellow foam, (4.19 G). LH NMR Spectrum: (DMSO d6) 2.14-2. 23 (M, 1H), 2.34 (s, 3H), 2.53-2. 60 (M, 2H), 3.36 (t, 1H), 3.61 (dd, 1H), 3.66 (s, 3H), 3.94 (s, 3H), 5.08 (M, 1H), 7.20 (s, 1H), 7.27 (t, 1H), 7.44-7. 54 (M, 2H), 7.68 (s, 1H), 8.36 (s, 1H), 9.62 (s, 1H); Mass Spectrum : (M+H) + 460.9 Compound (7) was prepared as follows: Sodium hydroxide 2M (7 ml) was added to a stirred solution of methyl (4S)-4-({4-[(3-CHLORO- 2-fluorophenyl) AMINO]-7-METHOXYQUINAZO] IN-6-YL} OXY)-1-METHYL-D-PROLINATE (4.18g) in methanol (20 ML) and THF (10 ML) at 25°C and the reaction mixture was stirred for 4 hours. The reaction mixture was evaporated and the residue re-dissolved in water. The pH of this solution was then adjusted to 6 by the dropwise addition OF 2M HC1 (AQ) to give (4S)-4- (F 4- [ (3-CHLORO-2-FLUOROPHENYL) AMINO]-7-METHOXYQUINAZOLIN-6-YL} OXY)-1-METHYL-D-PROLINE (7) as a pale yellow solid which was filtered and washed with water and dried, (3.5 G). 1H NMR Spectrum : (DMSO d6) 2. 21-2. 31 (M, 1H), 2.35-2. 49 (M, 1H), 2.50 (s, 3H), 2.78 (dd, 1H), 3.42 (t, 1H), 3.77 (dd, 1H), 3.94 (s, 3H), 5.08 (M, 1H), 7.20 (s, 1H), 7.27 (t, 1H), 7.44-7. 54 (M, 2H), 7.74 (s, 1H), 8.37 (s, 1H), 9.75 (s, 1H) ; Mass Spectrum : (M+H) + 446. 9 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34% | With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 20℃; for 18h; | 15 To an ice cold solution of (2R,4S)-4-hydroxypyrrolidine-1,2-dicarboxylic acid 1- tert-butyl ester 2-methyl ester (1.15 g, 4.69 mmol) and 3-methoxyphenol (0.56 mL, 5.158 mmol) in THF (10 mL) is added triphenylphosphine (1.84 g, 7.03 mmol) followed by the dropwise addition of diisopropyl-azodicarboxylate (1.40 mL, 7.03 mmol). Warm to room temperature and stir for 18 h. Dilute the reaction with ethyl acetate and wash with 1 N HCI, saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, dry (magnesium sulfate) and purify (silica gel chromatography, eluting with dichloromethanelethyl acetate mixtures) to give the title compound (0.57 g, 34%). MS (ES): m/z = 252.1 [M+H, Product-Boc insitu]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With formic acid; triphenylphosphine In tetrahydrofuran | P.7.B.1 Step B-1. Step B-1. Substitution for a formyloxy group To a solution of (2R,4R)-1-t-butoxycarbonyl-4-hydroxy-2-methoxycarbonylpyrrolidine (2.45 g: 10 mmole) in tetrahydrofuran (10 ml), formic acid (453 μl: 12 mmole), triphenylphosphine (3.15 g: 12 mmole), and diethyl azodicarboxylate (1.89 ml: 12 mmole) are successively is added in a nitrogen atmosphere under ice cooling. The mixture is stirred for 30 minutes at the same temperature to give (2R,4S)-1-t-butoxycarbonyl-4-formyloxy-2-methoxycarbonylpyrrolidine (2.17 g). Yield: 79%. Colorless oil. NMR δ(CDCl3) ppm: 1.44(d, J=7.8 Hz, 9H), 2.1 to 2.6(m, 2H), 3.5 to 3.9(m, 5H), 4.4(m, 1H), 5.4(m, 1H), 8.0(s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With diisopropyl (E)-azodicarboxylate In tetrahydrofuran at 0 - 20℃; for 16h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | In acetone at 20℃; for 2h; Alkaline conditions; | |
With potassium carbonate In acetone for 6h; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 18h; | 79.1 To a mixture of (2R,4R)-1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate (2.12 g, 8.65 mmol) and N,N-diisopropylethylamine (3.01 mL, 17.3 mmol) in dichloromethane (30 mL) was added benzyl chloromethyl ether (2.71 g, 17.3 mmol). After stirring at room temperature for 18 h, the mixture was poured into water. The aqueous layer was extracted with dichloromethane three times. The combined organic layers were dried over magnesium sulfate and concentrated in vacuo to afford an oil. The residual oil was purified by silica gel column chromatography (ethyl acetate/hexane 1:4 to 1:3) to give 2.29 g (72%) of the title compound as a colorless oil.MS (ESI) m/z: 366 (M+H) +. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: 1H-imidazole / dichloromethane / 18 h / 20 °C 2.1: sodium tetrahydroborate / tetrahydrofuran / 2 h / 70 °C 3.1: sodium hydride / tetrahydrofuran / 2 h / 20 °C 3.2: 183 h / 23 °C 4.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 2 h / 23 °C | ||
Multi-step reaction with 4 steps 1.1: 1H-imidazole / dichloromethane / 18 h / 20 °C 2.1: sodium tetrahydroborate / tetrahydrofuran / 2 h / 70 °C 2.2: 20 °C 3.1: sodium hydride / tetrahydrofuran; mineral oil / 2 h / 20 °C 3.2: 183 h / 23 °C 4.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 2 h / 23 °C | ||
Multi-step reaction with 4 steps 1.1: 1H-imidazole / dichloromethane / 18 h / 20 °C 2.1: sodium tetrahydroborate / tetrahydrofuran / 2 h / 70 °C 3.1: sodium hydride / tetrahydrofuran / 2 h / 20 °C 3.2: 183 h / 23 °C 4.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 2 h / 23 °C |
Multi-step reaction with 4 steps 1.1: N,N-dimethyl-formamide / 4 h / 0 - 20 °C 2.1: lithium borohydride / tetrahydrofuran / 16 h / 0 - 20 °C 3.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 °C 3.2: 4 h / 20 °C 4.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 5 h / 20 °C | ||
Multi-step reaction with 4 steps 1.1: 1H-imidazole / dichloromethane / 18 h / 20 °C 2.1: sodium tetrahydroborate / tetrahydrofuran / 2 h / 70 °C 3.1: sodium hydride / tetrahydrofuran / 2 h / 20 °C 3.2: 183 h / 23 °C 4.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 2 h / 23 °C | ||
Multi-step reaction with 4 steps 1.1: 1H-imidazole / N,N-dimethyl-formamide / 16.5 h / 0 - 20 °C 2.1: lithium borohydride / tetrahydrofuran / 16 h / 0 - 20 °C / Inert atmosphere 3.1: sodium hydride / tetrahydrofuran; mineral oil / 1 h / 0 °C / Inert atmosphere 3.2: 3 h / 0 - 20 °C / Inert atmosphere 4.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 3 h / 0 - 20 °C | ||
With lithium aluminium tetrahydride In tetrahydrofuran at 0℃; for 1h; | ||
Multi-step reaction with 4 steps 1.1: 1H-imidazole / N,N-dimethyl-formamide / 16.5 h / 0 - 20 °C 2.1: lithium borohydride / tetrahydrofuran / 16 h / 0 - 20 °C / Inert atmosphere 3.1: sodium hydride / tetrahydrofuran / 1 h / 0 °C / Inert atmosphere 3.2: 3 h / 0 - 20 °C / Inert atmosphere 4.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 3 h / 0 - 20 °C | ||
Multi-step reaction with 4 steps 1.1: 1H-imidazole / dichloromethane / 0 - 20 °C 2.1: lithium borohydride / tetrahydrofuran / 0 - 20 °C 3.1: sodium hydride / tetrahydrofuran / 0.5 h / 20 °C 3.2: 12 h / 20 °C 4.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 16 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With sodium hydride; sodium iodide In N,N-dimethyl-formamide; mineral oil at 0℃; for 4h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With water; sodium hydroxide In methanol at 60℃; for 2h; | 1.A Step A: (2R,4R)-1-(tert-Butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid To an aqueous solution of NaOH (2 N, 1100 mL, 2275 mmol) was added to methyl (2R,4R)-1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate (279 g, 1140 mmol, Oakwood) followed by MeOH (3300 mL). The mixture was stirred at about 60° C. for about 2 h and the mixture was partially concentrated in vacuo removing ˜3 L of solvent. The remaining solution was cooled in an ice bath and concentrated HCl was used to adjust the pH to between 2 and 3 while maintaining the temperature at about 15° C. The resulting precipitate was collected by filtration and rinsed with DCM (2*100 mL). The combined filtrate was separated and the organic phase was dried over MgSO4, filtered and concentrated in vacuo. This material was combined with the solids collected in the first filtration to provide (2R,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid: LC/MS (Table 3, Method b) Rt=1.10 min.; MS m/z: 232 (M+H)+. | |
Stage #1: (2R,4R)-1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate With sodium hydroxide In methanol; water at 60℃; for 2h; Stage #2: With hydrogenchloride In methanol; water at 15℃; | Step A: (2R,4R)-l-(tert-Butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid To an aqueous solution of NaOH (2 N, 1100 mL, 2275 mmol) was added to methyl (2R,4R)-l-tert-butyl 2-methyl 4-hydroxypyrrolidine-l,2-dicarboxylate (279 g, 1140 mmol, Oakwood) followed by MeOH (3300 mL). The mixture was stirred at about 60 °C for about 2 h and the mixture was partially concentrated in vacuo removing ~3 L of solvent. The remaining solution was cooled in an ice bath and concentrated HCl was used to adjust the pH to between 2 and 3 while maintaining the temperature at about 15 °C. The resulting precipitate was collected by filtration and rinsed with DCM (2xl00mL). The combined filtrate was separated and the organic phase was dried over MgS04, filtered and concentrated in vacuo. This material was combined with the solids collected in the first filtration to provide (2R,4R)-l-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2- carboxylic acid: LC/MS (Table 3, Method b) Rt = 1.10 min.; MS m/z: 232 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
21% | Stage #1: (2R,4R)-1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate With sodium hydride In tetrahydrofuran; mineral oil at 0 - 20℃; for 0.25h; Inert atmosphere; Stage #2: 2-Bromoethyl methyl ether In tetrahydrofuran; mineral oil at 0 - 20℃; for 72h; Inert atmosphere; | 7A 7A. (4R)-1-tert-Butyl 2-methyl 4-(2-methoxyethoxy)pyrrolidine-1,2-dicarboxylate To a solution of (2i?,4i?)-l-fert-butyl 2-methyl 4-hydroxypyrrolidine-l,2- dicarboxylate (0.500 g, 2.04 mmol) in THF (8.2 mL) at 0 °C under argon was added 95%> NaH (0.108 g, 4.28 mmol). The reaction mixture was warmed to rt and stirred for 15 min, The reaction mixture was cooled to 0 °C, l-bromo-2-methoxy ethane (0.62 g, 4.5 mmol) was added, and the reaction mixture was warmed to rt and stirred for 72 h. The reaction was quenched with sat. aq. NH4C1 (5 mL) and extracted with EtOAc/Et20 (1 : 1 v/v, 3 x 5 mL). The combined organic layers were washed with water (2 x 5 mL), brine (5 mL), dried (Na2SC"4), and concentrated. The crude product was purified by silica chromatography to give 7A (0.128 g, 0.423 mmol, 21%> yield) as a colorless oil. LC-MS Anal. Calc'd Ci4H25N06: 303.35, found [M+H-Boc] 204.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90.45% | With N-ethyl-N,N-diisopropylamine In dichloromethane at -40℃; for 3h; | 2.1 Synthesis of (2R,4R)-1-tert-butyl 2-methyl 4-((tert-butyldimethylsilyl)oxy)pyrrolidine-1,2-dicarboxylate (2R, 4R) -1- tert-butyl-4-hydroxy-2-methyl pyrrolidine-1,2-carbonate (5g, 20.40mmol) was dissolved in dichloromethane (40 mL) in, DIPEA (7.46mL, 44.87mmol), cooled to -40 , stirring was continued after dropwise tert-butyldimethylsilyl triflate (5.63mL, 24.48mmol) 3h.Large amount of water was added to quench the reaction, methylene chloride was added and extracted, dried over anhydrous sodium sulfate, concentrated and purified by column, eluent: PE / EA = 3/1, to give the desired product 6.63g, yield 90.45% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With magnesium(II) perchlorate | 50.2 Synthesis of (2R,4R)-l-tert-butyl 2-methyl 4-(tert-butoxy)pyrrolidine- 1 ,2-dicarboxylate (50b) To a solution of compound 50a (16.06 g; 65.48 mmol) in DMF (100 mL), Mg(C104)2 (1.46 g; 6.55 mmol) was added, followed by B0C2O (32.87 g; 150.60 mmol) and reaction was stirred overnight. Next day another portion of Mg(C104)2 and B0C2O (44.30 g; 203,03 mmol) and reaction was stirred overnight after which time LCMS control indicated completion of the reaction. Reaction mixture was filtrated and evaporated to dryness. Product was purified by column chromatography (hexane/EtOAc 9/1) and was obtained as a white crystalline solid (13.51 g; 68% yield).ESI-MS m/z for C15H27NO5 found 302,4.2 (M+l)+, 324.3 (M+Na)+. NMR (DMSO-d6+D20, 700 MHz) δ: 4.24-4.19 (m, 1H), 4.17-4.13 (m, 1H), [3.61 (s); 3.58 (s); 3H], 3.54-3.51 (m, 1H), 2.99-2.94 (m, 1H), 2.38-2.30 (m, 1H), 1.75-1.71 (m, 1H), [1.36 (s); 1.29 (s); 9H], [1.08 (s); 1.07 (s); 9H]. |
68% | With magnesium(II) perchlorate In dichloromethane Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74.8% | In tetrahydrofuran at 0℃; for 3h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62.7% | Stage #1: 2-fluoro-4-iodophenol; (2R,4R)-1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate With triphenylphosphine In tetrahydrofuran at 0℃; for 0.25h; Inert atmosphere; Stage #2: With di-isopropyl azodicarboxylate In tetrahydrofuran at 20℃; Inert atmosphere; | 5.1 Step 1. Synthesis of compound 5-2 Add 2-fluoro-4-iodophenol 5-1a (1.43g, 6mmol) and triphenylphosphine (1.62g, 6mmol) into a 250ml three-necked flask, deoxygenate and protect with nitrogen, and put it into the three-necked flask under ice bath conditions. Add 100ml of ultra-dry tetrahydrofuran and stir until the reactants are completely dissolved. After dissolving, add (2R, 4R)-1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate 5-1 (1.47g, 6mmol) dissolved in ultra-dry tetrahydrofuran. Add it to a three-necked flask and stir well for about 15 minutes, then slowly add DIAD (1.21g, 6mmol) dropwise to the reaction flask. Stir overnight under nitrogen protection. After the reaction, it was extracted with water and ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to obtain the product (2R, 4S)-1-tert-butyl 2-methyl 4-( 2-Fluoro-4-iodophenol)pyrrolidine-1,2-dicarboxylate 5-2 (1.75 g, 62.7%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; dmap; triethylamine | 52 1-(tert-Butyl) 2-methyl (2R,4R)-4-(tosyloxy)pyrrolidine-1,2-dicarboxylate (100) 1-(tert-Butyl) 2-methyl (2R,4R)-4-(tosyloxy)pyrrolidine-1,2-dicarboxylate (100) In a 100 ml round-bottomed flask were dissolved 3.13 g (99) (12.8 mmol), 1.71 g DMAP (14.0 mmol) and 1.97 ml Et3N (14.0 mmol) in 40 ml DCM and 2.68 g TsCI (14 mmol) were added subsequently under ice cooling. After 30 min, the cooling bath was removed and the mixture was stirred at ambient temperature overnight. The mixture was diluted with DCM and poured on 2N HCl. The phases were separated and the organic phase was washed once more with 2N HCl. The organic phase was further washed with water and brine before it was dried over Na2SO4 and concentrated under reduced pressure. The title compound was yielded as 4.78 g (94%) as a yellow sticky syrup. 1H NMR (400 MHz, CDCl3) δ 7.72 (d, J = 8.0 Hz, 2H), 7.32 (d, J = 8.0 Hz, 2H), 5.07 - 4.96 (m, 1H), 4.42 - 4.26 (m, 1H), 3.72 - 3.59 (m, 3H), 3.62 (s, J = 12.4 Hz, 1H), 3.59 - 3.51 (m, 1H), 2.42 (s, 3H), 2.48 - 2.27 (m, 2H), 1.42 - 1.33 (m, 9H). 13C NMR (101 MHz, CDCl3) δ 172.0, 171.6, 153.8, 153.4, 145.2, 133.8, 130.0, 127.8, 80.6, 78.9, 77.7, 57.5, 57.1, 52.2, 52.1, 51.6, 37.0, 36.0, 28.3, 21.7. ESI-MS m/z: 422.4 [M+Na]+ HPLC tret = 7.72 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With palladium on activated charcoal; hydrogen; Sodium hydrogenocarbonate In methanol; lithium hydroxide monohydrate at 40 - 45℃; Autoclave; | 5-6 Synthesis of compound 7 In the 500mL autoclave, add 300mL methanol, 60mL water, compound 6 obtained in 30g embodiment 4, 31.5g Boc acid anhydride, 15g sodium bicarbonate, 3.2g palladium carbon, after nitrogen replacement, add 4.5-5.0Mpa of hydrogen, and heat up 40-45 of reaction for more than 24h, the TLC raw material reaction was completed, the reaction solution was taken out, concentrated to remove methanol, extracted with MTBE, dried, filtered, and concentrated to obtain an oily substance, and petroleum ether was crystallized to obtain compound 7 (target product), off-white solid 24.1g, yield: 82%, purity: 99.6%. |
[ 145681-01-2 ]
1-tert-Butyl 2-methyl pyrrolidine-1,2-dicarboxylate
Similarity: 0.95
[ 87691-27-8 ]
(2S,4S)-1-(tert-Butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid
Similarity: 0.95
[ 1218998-83-4 ]
rel-(2R,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid
Similarity: 0.95
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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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