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CAS No. : | 33996-30-4 | MDL No. : | MFCD11506578 |
Formula : | C7H14ClNO3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | HHXSZDXMSRXWJV-IBTYICNHSA-N |
M.W : | 195.64 | Pubchem ID : | 12709304 |
Synonyms : |
|
Num. heavy atoms : | 12 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.86 |
Num. rotatable bonds : | 3 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 49.78 |
TPSA : | 58.56 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) : | -7.07 cm/s |
Log Po/w (iLOGP) : | 0.0 |
Log Po/w (XLOGP3) : | 0.6 |
Log Po/w (WLOGP) : | -0.31 |
Log Po/w (MLOGP) : | -0.16 |
Log Po/w (SILICOS-IT) : | 0.07 |
Consensus Log Po/w : | 0.04 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.23 |
Solubility : | 11.4 mg/ml ; 0.0585 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.4 |
Solubility : | 7.72 mg/ml ; 0.0395 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -0.47 |
Solubility : | 65.7 mg/ml ; 0.336 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.71 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-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 |
---|---|---|
100% | With triethylamine In ethanol; dichloromethane at 0 - 20℃; for 16.25 h; | Step 2:To a solution of compound 2 (HCI salt, 146.2 g, 0.747 mol) dissolved in CH2CI2 (1600 ml) and EtOH (100 ml) and cooled to 0 0C was added Et3N (113.4 g, 1.12 mol, 156.2 ml). t-BOC anhydride (195.6, 0.90 mol) was added portion-wise. The reaction mixture was stirred at 0 0C for 15 min, then at RT for 16 h. The resulting mixture was concentrated to ~ 800 ml volume and washed with water. The organic solution was dried (MgSO4), filtered, and concentrated. Purification by silica gel chromatography (eluant: 20percent EtOAc - CH2CI2) gave the product 3 (193.7 g, 100percent) as a yellow oil. MS (M+Na): m/e 282. 1H-NMR (CDCI3) δ 1.30 (t, 3H)1 1.45 (s, 9H), 1.75 (m, 1 H), 2.10 (m, 1 H), 2.30 (m, 1 H), 3.45 and 3.55 (d, 1 H for two rotamers), 3.65 (dd, 1 H), 4.25 (m, 2H), 4.40 and 4.45 (t, 1H for two rotamers), 4.55 (broad s, 1 H). |
100% | With triethylamine In ethanol; dichloromethane at 0 - 20℃; | Step 2:To a solution of compound 2 (HCl salt, 146.2 g, 0.747 mol) dissolved in CH2Cl2 (1600 ml) and EtOH (100 ml) and cooled to 0° C. was added Et3N (113.4 g, 1.12 mol, 156.2 ml). t-BOC anhydride (195.6, 0.90 mol) was added portionwise. The reaction mixture was stirred at 0° C. for 15 min, then at RT for 16 h. The resulting mixture was concentrated to 800 ml volume and washed with water. The organic solution was dried (MgSO4), filtered, and concentrated. Purification by silica gel chromatography (eluant: 20percent EtOAc-CH2Cl2) gave the product 3 (193.7 g, 100percent) as a yellow oil. MS (M+Na): m/e 282. 1H-NMR (CDCl3) δ 1.30 (t, 3H), 1.45 (s, 9H), 1.75 (m, 1H), 2.10 (m, 1H), 2.30 (m. 1H), 3.45 and 3.55 (d, 1H for two rotamers), 3.65 (dd, 1H), 4.25 (m, 2H), 4.40 and 4.45 (t, 1H for two rotamers), 4.55 (broad s, 1H). |
100% | Stage #1: With triethylamine In 1,4-dioxane; water at 0℃; for 0.166667 h; Stage #2: at 20℃; for 20 h; |
2B (13.4 g, 68.5 mmol) was dissolved in a mixed solution of 1,4-dioxane (50 mL) and water (50 mL) at room temperature and cooled to 0 ° C,Triethylamine (17.3 g, 0.171 mmol) was added and the mixture was stirred for 10 minutes.A mixture of di-tricarbonate (13.4 g, 68.5 mmol)In dichloromethane (50 mL) was added dropwise to the reaction solution and allowed to react at room temperature for 20 hours.Water (100 mL) was added to the reaction solution and extracted with dichloromethane (100 mL x 4).The organic phases were combined and washed with saturated brine solution (50 mL x 1). Dried over anhydrous magnesium sulfate,The filtrate was concentrated under reduced pressure to give pale yellow liquid 2C (18 g, yield 100percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With oxalyl dichloride; triethylamine; N,N-dimethyl-formamide 1.) CH2Cl2, reflux, 40 min, 2.) THF, 0 deg C, 30 min; Yield given. Multistep reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine In dichloromethane Ambient temperature; Yield given; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | With triethylamine In 1,4-dioxane; water for 120h; Ambient temperature; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With pyridine a) 0 deg C, 6 h, b) RT, 15 h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With thionyl chloride for 18h; Inert atmosphere; Reflux; | (2S,4R)-ethyl 4-hydroxypyrrolidine-2-carboxylate hydrochloride SI-3 Trans-4-hydroxy-L-proline (1.50 g, 1.15 mmol) was dissolved in dry EtOH (12 mL) under Ar, thionyl chloride (0.94 mL, 1.27 mmol) was added dropwise over 15 min and the the reaction heated to reflux for 18h. The reaction was concentrated in vacuo to give SI-3 as a white solid (2.23g, 100%) : dH (400 MHz; d6-DMSO) 9.77 (2H, br. s, NH2), 5.59 (1H, br. s., OH), 4.44 (1H, dd, J 10.8, 7.8, CHOH), 4.43-4.38 (1H, m, CHCO2Et), 4.21 (2H, q, J 7.2, CO2CH2), 3.36 (1H, dd, J 12.0, 4.4, NCHH), 3.07 (1H, d, J 12.0, NCHH), 2.20 (1H, ddt, J 13.4, 7.8, 1.4, 1.4, CHCHHCH), 2.08 (1H, ddd, J 13.4, 10.8, 4.8, CHCHHCH), 1.24 (3H, t, J 7.2, CH2CH3); m/z (ESI) (C7H14NO3 (M+H) requires 160.0968. Found 160.0968). |
98% | With hydrogenchloride for 3h; | |
98% | With thionyl chloride for 5h; Heating; |
98% | With thionyl chloride at 0℃; Reflux; | |
98% | With thionyl chloride at 105℃; for 4h; Inert atmosphere; Cooling with ice; | |
97% | With thionyl chloride at 0 - 15℃; for 2.5h; Heating / reflux; | 1.1 Example 1; Step 1 :To a mechanically stirred suspension of compound 1 (100.6 g, 0.767 mol) in EtOH (1000 ml) and cooled to O 0C was added SOCI2 (136.9 g, 1.15 mol, 84.0 ml) dropwise via addition funnel such that the internal temperature was < 15 0C. The reaction mixture was heated at reflux for 2.5 h, then cooled to O 0C. Ether (1000 ml) was added, and a white solid precipitated. The solid was isolated by vacuum filtration and washed with ether. The product 2 (HCI salt) was dried in a vacuum oven to give 146.3 g (97%) of a white solid. MS (M+1): m/e 160. 1H-NMR (DMSO) δ 1.25 (t, 3H), 2.05 (m, 1 H), 2.20 (m, 1 H)1 3.05 (d, 1 H), 3.40 (dd, 1 H), 4.20 (q5 2H), 4.45 (m, 2H)1 5.65 (broad s, 1 H). |
97% | With thionyl chloride at 0℃; Reflux; | 1.1 Step 1:To a mechanically stirred suspension of compound 1 (100.6 g, 0.767 mol) in EtOH (1000 ml) and cooled to 0° C. was added SOCl2 (136.9 g, 1.15 mol, 84.0 ml) dropwise via addition funnel such that the internal temperature was <15° C. The reaction mixture was heated at reflux for 2.5 h, then cooled to 0° C. Ether (1000 ml) was added, and a white solid precipitated. The solid was isolated by vacuum filtration and washed with ether. The product 2 (HCl salt) was dried in a vacuum oven to give 146.3 g (97%) of a white solid. MS (M+1): m/e 160. 1H-NMR (DMSO) δ 1.25 (t, 3H), 2.05 (m, 1H), 2.20 (m, 1H), 3.05 (d, 1H), 3.40 (dd, 1H), 4.20 (q, 2H), 4.45 (m, 2H), 5.65 (broad s, 1H). |
96% | With thionyl chloride for 4h; Reflux; | |
95% | With hydrogenchloride for 2h; Heating; | |
94% | With thionyl chloride | |
94% | With thionyl chloride Reflux; | 59.1 Example59: Compound 54 (2S,4S)-4-((benzyloxymethyl)-l-(2,2- diphenylacety l)pyrroIidine-2-carboxylic acid /. Procedure for the preparation of 54a To a stirred solution of traws-4-hydroxy-L-proline (100 g, 0.76 mol) in EtOH (1 L) was added SOCl2 (95.2 g, 0.8 mol) dropwise and the mixture was heated at reflux overnight. The mixture was cooled to RT and concentrated in vacuo to give 54a (140 g, 94%) as a white solid. LC-MS (Agilent): Rt 0.56 min; m/z calculated for C13H17NO3 [M+Hf 160.1 , found [M+H]+ 160.1. |
94% | With thionyl chloride for 4h; Reflux; | |
90% | With thionyl chloride at 0 - 78℃; for 8h; | 1 (2S,4R)-ethyl 4-hydroxypyrrolidine-2-carboxylate hydrochloride At room temperature,Trans-4-hydroxy-L-proline 2A (10.0 g, 76.3 mmol) was dissolved in absolute ethanol (100 mL)Cooling to 0 ,A solution of dichloroazepine (10.3 g, 86.2 mmol)The addition was completed temperature was raised to 78 , the reaction was refluxed for 8 hours.The reaction solution was lowered to -20 ° C, and a white solid was precipitated. Methyl tertiary butyl ether (15 mL) was added and stirring was continued for 30 minutes.The filter cake was washed with methyl tertiary butyl ether (30 mL x 2) and dried to give white solid 2B (13.4 g, 90% yield). |
88% | With thionyl chloride Cooling with ice; Reflux; | |
86% | With thionyl chloride for 6h; Heating; | |
80% | With thionyl chloride at 20℃; | |
With hydrogenchloride | ||
With thionyl chloride for 6h; Heating; | ||
With hydrogenchloride at 0℃; for 2h; Heating / reflux; | 23.A Example 23; (S)- {4- [5- (5-tert-Butyl- (lS, 4S) -2,5-diaza-bicyclo [2.2. 1] hept-2-yl)-imidazo [ 1, 2- c] pyrimidin-7-yl]-pyridin-2-yl}- (1-phcnyl-ethyl)-amine; Step A; To a 250 mL RBF, was added trans-4-hydroxy-L-proline, (2S, 4R)-4- hydroxy-pyrrolidine-2-carboxylic acid) (13.1 g, 100 mmol), and 50 mL absolute ethanol. The above mixture was cooled down to 0 °C and saturated with HC1 gas until all of the suspension was dissolved. The mixture was refluxed under nitrogen for 2 h. The mixture was cooled down to rt, and all solvent was removed by vacuum. The residue was kept in the refrigerator for 15 h, the white precipitate was filtered and washed with anhydrous ether 3 x 50 mL, to obtain the (2S, 4R)-4- hydroxy-pyrrolidine-2-carboxylic acid ethyl ester HC1 salt as a white solid. | |
With hydrogenchloride | ||
With thionyl chloride at 0℃; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With triethylamine In dichloromethane for 6h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | In dichloromethane |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With triethylamine In water; acetone at 20℃; for 3h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate In chloroform | R.2.2 REFERENCE EXAMPLE 2 (2) To a mixture of 10.0 g of (2S,4R)-2-ethoxycarbonyl-4-hydroxy pyrrolidine hydrochloride, 15.5 g of potassium carbonate and 50 ml of chloroform, 9.46 g of diethyl sulfate were dropwise added. At 40° C., the mixture was stirred for 4 hours and then allowed to cool, washed with water, added with an aqueous dilute HCl solution and the formed aqueous layer was separated. This aqueous layer was neutralized with potassium carbonate, extracted with chloroform and the extract was washed with water, dried and concentrated under reduced pressure to obtain (2S,4R)-2-ethoxycarbonyl-N-ethyl4-hydroxy pyrrolidine as an oily product. Yield 8.15 g. [α]D20 =-70.80 (c=1.06, MeOH). NMR (CDCl3)δ(TMS ppm): 1.07 (3H, t), 1.27 (3H, t), 1.9-3.1 (5H), 3.1-3.7 (3H), 4.16 (2H, q), 4.2-4.7 (1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With triethylamine In N,N-dimethyl-formamide at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
12.40 g | Stage #1: trans-4-hydroxy-L-proline ethyl ester hydrochloride; benzyl bromide With triethylamine In chloroform for 6h; Heating; Stage #2: With sodium hydroxide In chloroform at 20℃; | |
14.3 g | With N-ethyl-N,N-diisopropylamine In toluene at 110℃; for 6h; | 49 (3R,5S)-N- { 6,7-dimethoxy- 1 H,2H,3H-cyclopenta[b]quinolin-9-yl } -5-fluoropiperidin-3-amine Into a 500-mL round-bottom flask, was placed a mixture of ethyl (2S,4R)-4- hydroxypyrrolidine-2-carboxylate hydrochloride (10.0 g, 51.11 mmol, 1 eq.), BnBr (9.6 g, 0.06 mmol, 1.1 eq.), DIEA (16.5 g, 0.13 mmol, 2.5 eq.) and toluene (150 mL). The solution was stirred for 6 hours at 110 °C in an oil bath. The reaction was then quenched with 200 mL of saturated aqueous NaHC03, extracted with EtOAc, the combined organic layers were washed with brine, dried over anhydrous Na2S04 and concentrated to provide 14.3 g of ethyl (2S,4R)-l-benzyl-4-hydroxypyrrolidine-2- carboxylate as crude brown oil. LCMS (ES) [M+l]+ m/z 250.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine In dichloromethane at 0℃; for 3h; Title compound not separated from byproducts; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 7 steps 1: Et3N 2: Pb(NO3)2 3: 5 percent citric acid 4: (COCl)2, DMSO, Et3N / -60 °C 5: 96 percent / NaHMDS / tetrahydrofuran / -78 °C 6: 81 percent / Pd(PPh3)2 / dimethylformamide / 2 h / Heating 7: H2, Boc anhydride / Pd/C / 760 Torr |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: 70 percent / triethylamine / CH2Cl2 / 6 h / Heating 2: 1.) oxalyl chloride, dimethyl sulfoxide, 2.) triethylamine / 1.) CH2Cl2, -78 deg C, 30 min, 2.) CH2Cl2, from -78 deg C to RT 3: ethanol; H2O / 24 h / 55 - 60 °C 4: 65 percent / 6 N aq. HCl / 24 h / 130 °C 5: 74 percent / H2 / 20percent Pd(OH)2-C / aq. acetic acid / 10 h / 2280 Torr / Ambient temperature |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: 70 percent / triethylamine / CH2Cl2 / 6 h / Heating 2: 1.) oxalyl chloride, dimethyl sulfoxide, 2.) triethylamine / 1.) CH2Cl2, -78 deg C, 30 min, 2.) CH2Cl2, from -78 deg C to RT 3: ethanol; H2O / 24 h / 55 - 60 °C 4: 65 percent / 6 N aq. HCl / 24 h / 130 °C 5: 83 percent / H2 / 20percent Pd(OH)2-C / aq. acetic acid / 10 h / 2280 Torr / Ambient temperature |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 79 percent / anh. pyridine / a) 0 deg C, 6 h, b) RT, 15 h 2: 87 percent / LiAlH4 / tetrahydrofuran / a) 0 deg C, 3 h, b) RT, 3 h | ||
Multi-step reaction with 2 steps 2: 87 percent / LiAlH4 / tetrahydrofuran |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: 79 percent / anh. pyridine / a) 0 deg C, 6 h, b) RT, 15 h 2: 87 percent / LiAlH4 / tetrahydrofuran / a) 0 deg C, 3 h, b) RT, 3 h 3: 4-dimethylaminopyridine, Et3N / tetrahydrofuran / 16 h / Ambient temperature | ||
Multi-step reaction with 3 steps 2: 87 percent / LiAlH4 / tetrahydrofuran 3: 85 percent / tetrahydrofuran |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: 79 percent / anh. pyridine / a) 0 deg C, 6 h, b) RT, 15 h 2: 87 percent / LiAlH4 / tetrahydrofuran / a) 0 deg C, 3 h, b) RT, 3 h 3: 4-dimethylaminopyridine, Et3N / tetrahydrofuran / 16 h / Ambient temperature 4: 92 percent / anh. pyridine / 15 h / Ambient temperature | ||
Multi-step reaction with 4 steps 2: 87 percent / LiAlH4 / tetrahydrofuran 3: 85 percent / tetrahydrofuran 4: 92 percent |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 8 steps 1: 79 percent / anh. pyridine / a) 0 deg C, 6 h, b) RT, 15 h 2: 87 percent / LiAlH4 / tetrahydrofuran / a) 0 deg C, 3 h, b) RT, 3 h 3: 4-dimethylaminopyridine, Et3N / tetrahydrofuran / 16 h / Ambient temperature 4: 92 percent / anh. pyridine / 15 h / Ambient temperature 5: 70 percent / tetrahydrofuran; dioxane / a) 0 deg C, 2 h, b) RT, overnight 6: 10percent aq. H2O2 / methanol / a) 0 deg C, 1 h, b) RT, 1 h 7: HCl gas / methanol / 2 h / Ambient temperature 8: 91 percent / H2, 5percent Rh on Al2O3 powder / methanol / 48 h / 150 °C / 114000 Torr | ||
Multi-step reaction with 8 steps 2: 87 percent / LiAlH4 / tetrahydrofuran 3: 85 percent / tetrahydrofuran 4: 92 percent 5: 70 percent / dioxane; tetrahydrofuran 6: 10percent H2O2 / methanol 7: 3percent HCl / methanol 8: 91 percent / H2 / Rh-Al2O3 / methanol / 48 h / 150 °C / 114000 Torr |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 7 steps 1: 79 percent / anh. pyridine / a) 0 deg C, 6 h, b) RT, 15 h 2: 87 percent / LiAlH4 / tetrahydrofuran / a) 0 deg C, 3 h, b) RT, 3 h 3: 4-dimethylaminopyridine, Et3N / tetrahydrofuran / 16 h / Ambient temperature 4: 92 percent / anh. pyridine / 15 h / Ambient temperature 5: 70 percent / tetrahydrofuran; dioxane / a) 0 deg C, 2 h, b) RT, overnight 6: 10percent aq. H2O2 / methanol / a) 0 deg C, 1 h, b) RT, 1 h 7: HCl gas / methanol / 2 h / Ambient temperature | ||
Multi-step reaction with 7 steps 2: 87 percent / LiAlH4 / tetrahydrofuran 3: 85 percent / tetrahydrofuran 4: 92 percent 5: 70 percent / dioxane; tetrahydrofuran 6: 10percent H2O2 / methanol 7: 3percent HCl / methanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 9 steps 1: 79 percent / anh. pyridine / a) 0 deg C, 6 h, b) RT, 15 h 2: 87 percent / LiAlH4 / tetrahydrofuran / a) 0 deg C, 3 h, b) RT, 3 h 3: 4-dimethylaminopyridine, Et3N / tetrahydrofuran / 16 h / Ambient temperature 4: 92 percent / anh. pyridine / 15 h / Ambient temperature 5: 70 percent / tetrahydrofuran; dioxane / a) 0 deg C, 2 h, b) RT, overnight 6: 10percent aq. H2O2 / methanol / a) 0 deg C, 1 h, b) RT, 1 h 7: HCl gas / methanol / 2 h / Ambient temperature 8: 91 percent / H2, 5percent Rh on Al2O3 powder / methanol / 48 h / 150 °C / 114000 Torr 9: 96 percent / pyridine / a) 0 deg C, 3 h, b) RT, 14 h | ||
Multi-step reaction with 9 steps 2: 87 percent / LiAlH4 / tetrahydrofuran 3: 85 percent / tetrahydrofuran 4: 92 percent 5: 70 percent / dioxane; tetrahydrofuran 6: 10percent H2O2 / methanol 7: 3percent HCl / methanol 8: 91 percent / H2 / Rh-Al2O3 / methanol / 48 h / 150 °C / 114000 Torr 9: 96 percent |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 14 steps 1: 79 percent / anh. pyridine / a) 0 deg C, 6 h, b) RT, 15 h 2: 87 percent / LiAlH4 / tetrahydrofuran / a) 0 deg C, 3 h, b) RT, 3 h 3: 4-dimethylaminopyridine, Et3N / tetrahydrofuran / 16 h / Ambient temperature 4: 92 percent / anh. pyridine / 15 h / Ambient temperature 5: 70 percent / tetrahydrofuran; dioxane / a) 0 deg C, 2 h, b) RT, overnight 6: 10percent aq. H2O2 / methanol / a) 0 deg C, 1 h, b) RT, 1 h 7: HCl gas / methanol / 2 h / Ambient temperature 8: 91 percent / H2, 5percent Rh on Al2O3 powder / methanol / 48 h / 150 °C / 114000 Torr 9: 96 percent / pyridine / a) 0 deg C, 3 h, b) RT, 14 h 10: dimethylformamide; dioxane; tetrahydrofuran / 13 h / -20 °C 11: 10percent aq.H2O2 / methanol / a) 0 deg C, 0.5 h, b) RT, 0.5 h 12: 65 percent / 48percent HBr, phenol / 10 h / Heating 13: HSiCl3, Et3N / acetonitrile / 3 h / Heating 14: Et3N / CH2Cl2 / 2 h / Ambient temperature |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 10 steps 1: 79 percent / anh. pyridine / a) 0 deg C, 6 h, b) RT, 15 h 2: 87 percent / LiAlH4 / tetrahydrofuran / a) 0 deg C, 3 h, b) RT, 3 h 3: 4-dimethylaminopyridine, Et3N / tetrahydrofuran / 16 h / Ambient temperature 4: 92 percent / anh. pyridine / 15 h / Ambient temperature 5: 70 percent / tetrahydrofuran; dioxane / a) 0 deg C, 2 h, b) RT, overnight 6: 10percent aq. H2O2 / methanol / a) 0 deg C, 1 h, b) RT, 1 h 7: HCl gas / methanol / 2 h / Ambient temperature 8: 91 percent / H2, 5percent Rh on Al2O3 powder / methanol / 48 h / 150 °C / 114000 Torr 9: 96 percent / pyridine / a) 0 deg C, 3 h, b) RT, 14 h 10: dimethylformamide; dioxane; tetrahydrofuran / 13 h / -20 °C | ||
Multi-step reaction with 10 steps 2: 87 percent / LiAlH4 / tetrahydrofuran 3: 85 percent / tetrahydrofuran 4: 92 percent 5: 70 percent / dioxane; tetrahydrofuran 6: 10percent H2O2 / methanol 7: 3percent HCl / methanol 8: 91 percent / H2 / Rh-Al2O3 / methanol / 48 h / 150 °C / 114000 Torr 9: 96 percent |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 11 steps 1: 79 percent / anh. pyridine / a) 0 deg C, 6 h, b) RT, 15 h 2: 87 percent / LiAlH4 / tetrahydrofuran / a) 0 deg C, 3 h, b) RT, 3 h 3: 4-dimethylaminopyridine, Et3N / tetrahydrofuran / 16 h / Ambient temperature 4: 92 percent / anh. pyridine / 15 h / Ambient temperature 5: 70 percent / tetrahydrofuran; dioxane / a) 0 deg C, 2 h, b) RT, overnight 6: 10percent aq. H2O2 / methanol / a) 0 deg C, 1 h, b) RT, 1 h 7: HCl gas / methanol / 2 h / Ambient temperature 8: 91 percent / H2, 5percent Rh on Al2O3 powder / methanol / 48 h / 150 °C / 114000 Torr 9: 96 percent / pyridine / a) 0 deg C, 3 h, b) RT, 14 h 10: dimethylformamide; dioxane; tetrahydrofuran / 13 h / -20 °C 11: 10percent aq.H2O2 / methanol / a) 0 deg C, 0.5 h, b) RT, 0.5 h | ||
Multi-step reaction with 11 steps 2: 87 percent / LiAlH4 / tetrahydrofuran 3: 85 percent / tetrahydrofuran 4: 92 percent 5: 70 percent / dioxane; tetrahydrofuran 6: 10percent H2O2 / methanol 7: 3percent HCl / methanol 8: 91 percent / H2 / Rh-Al2O3 / methanol / 48 h / 150 °C / 114000 Torr 9: 96 percent |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 8 steps 1: 79 percent / anh. pyridine / a) 0 deg C, 6 h, b) RT, 15 h 2: 87 percent / LiAlH4 / tetrahydrofuran / a) 0 deg C, 3 h, b) RT, 3 h 3: 100 percent / pyridine / a) -25 deg C, 15 h, b) 0 deg C, 4 h, c)RT, 1 h 4: 100 percent / pTsOH monohydrate / CH2Cl2 / 3 h / Ambient temperature 5: 67 percent / tetrahydrofuran; dioxane / a) 0 deg C, 6 h, b) RT, 13 h 6: 10percent aq. H2O2 / methanol / 1 h / Ambient temperature 7: pTsOH monohydrrate / methanol; H2O / 1 h / Heating 8: 96 percent / H2, 5percent Rh on Al2O3 powder / methanol / 48 h / 150 °C / 114000 Torr | ||
Multi-step reaction with 6 steps 1: 2.) LiAlH4 2: 100 percent / pyridine / -25 °C 3: 100 percent / p-toluenesulfonic acid 4: 67 percent / dioxane; tetrahydrofuran / Ambient temperature 5: 1.) 10 percent H2O2; 2.) PTSA / 1.) methanol; 2.) methanol 6: 96 percent / H2 / 5 percent Rh-Al2O3 / methanol / 48 h / 150 °C / 114000 Torr |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 9 steps 1: 79 percent / anh. pyridine / a) 0 deg C, 6 h, b) RT, 15 h 2: 87 percent / LiAlH4 / tetrahydrofuran / a) 0 deg C, 3 h, b) RT, 3 h 3: 100 percent / pyridine / a) -25 deg C, 15 h, b) 0 deg C, 4 h, c)RT, 1 h 4: 100 percent / pTsOH monohydrate / CH2Cl2 / 3 h / Ambient temperature 5: 67 percent / tetrahydrofuran; dioxane / a) 0 deg C, 6 h, b) RT, 13 h 6: 10percent aq. H2O2 / methanol / 1 h / Ambient temperature 7: pTsOH monohydrrate / methanol; H2O / 1 h / Heating 8: 96 percent / H2, 5percent Rh on Al2O3 powder / methanol / 48 h / 150 °C / 114000 Torr 9: 88 percent / pyridine | ||
Multi-step reaction with 7 steps 1: 2.) LiAlH4 2: 100 percent / pyridine / -25 °C 3: 100 percent / p-toluenesulfonic acid 4: 67 percent / dioxane; tetrahydrofuran / Ambient temperature 5: 1.) 10 percent H2O2; 2.) PTSA / 1.) methanol; 2.) methanol 6: 96 percent / H2 / 5 percent Rh-Al2O3 / methanol / 48 h / 150 °C / 114000 Torr 7: 88 percent |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 12 steps 1: 79 percent / anh. pyridine / a) 0 deg C, 6 h, b) RT, 15 h 2: 87 percent / LiAlH4 / tetrahydrofuran / a) 0 deg C, 3 h, b) RT, 3 h 3: 100 percent / pyridine / a) -25 deg C, 15 h, b) 0 deg C, 4 h, c)RT, 1 h 4: 100 percent / pTsOH monohydrate / CH2Cl2 / 3 h / Ambient temperature 5: 67 percent / tetrahydrofuran; dioxane / a) 0 deg C, 6 h, b) RT, 13 h 6: 10percent aq. H2O2 / methanol / 1 h / Ambient temperature 7: pTsOH monohydrrate / methanol; H2O / 1 h / Heating 8: 96 percent / H2, 5percent Rh on Al2O3 powder / methanol / 48 h / 150 °C / 114000 Torr 9: 88 percent / pyridine 10: dioxane; tetrahydrofuran; dimethylformamide / -30 °C 11: 10 percent aq. H2O2 / methanol 12: 73 percent / 48percent HBr, phenol / 10 h / Heating | ||
Multi-step reaction with 9 steps 1: 2.) LiAlH4 2: 100 percent / pyridine / -25 °C 3: 100 percent / p-toluenesulfonic acid 4: 67 percent / dioxane; tetrahydrofuran / Ambient temperature 5: 1.) 10 percent H2O2; 2.) PTSA / 1.) methanol; 2.) methanol 6: 96 percent / H2 / 5 percent Rh-Al2O3 / methanol / 48 h / 150 °C / 114000 Torr 7: 88 percent 9: 73 percent / 48 percent HBr, phenol / Heating |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 11 steps 1: 79 percent / anh. pyridine / a) 0 deg C, 6 h, b) RT, 15 h 2: 87 percent / LiAlH4 / tetrahydrofuran / a) 0 deg C, 3 h, b) RT, 3 h 3: 100 percent / pyridine / a) -25 deg C, 15 h, b) 0 deg C, 4 h, c)RT, 1 h 4: 100 percent / pTsOH monohydrate / CH2Cl2 / 3 h / Ambient temperature 5: 67 percent / tetrahydrofuran; dioxane / a) 0 deg C, 6 h, b) RT, 13 h 6: 10percent aq. H2O2 / methanol / 1 h / Ambient temperature 7: pTsOH monohydrrate / methanol; H2O / 1 h / Heating 8: 96 percent / H2, 5percent Rh on Al2O3 powder / methanol / 48 h / 150 °C / 114000 Torr 9: 88 percent / pyridine 10: dioxane; tetrahydrofuran; dimethylformamide / -30 °C 11: 10 percent aq. H2O2 / methanol | ||
Multi-step reaction with 8 steps 1: 2.) LiAlH4 2: 100 percent / pyridine / -25 °C 3: 100 percent / p-toluenesulfonic acid 4: 67 percent / dioxane; tetrahydrofuran / Ambient temperature 5: 1.) 10 percent H2O2; 2.) PTSA / 1.) methanol; 2.) methanol 6: 96 percent / H2 / 5 percent Rh-Al2O3 / methanol / 48 h / 150 °C / 114000 Torr 7: 88 percent |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 13 steps 1: 79 percent / anh. pyridine / a) 0 deg C, 6 h, b) RT, 15 h 2: 87 percent / LiAlH4 / tetrahydrofuran / a) 0 deg C, 3 h, b) RT, 3 h 3: 4-dimethylaminopyridine, Et3N / tetrahydrofuran / 16 h / Ambient temperature 4: 92 percent / anh. pyridine / 15 h / Ambient temperature 5: 70 percent / tetrahydrofuran; dioxane / a) 0 deg C, 2 h, b) RT, overnight 6: 10percent aq. H2O2 / methanol / a) 0 deg C, 1 h, b) RT, 1 h 7: HCl gas / methanol / 2 h / Ambient temperature 8: 91 percent / H2, 5percent Rh on Al2O3 powder / methanol / 48 h / 150 °C / 114000 Torr 9: 96 percent / pyridine / a) 0 deg C, 3 h, b) RT, 14 h 10: dimethylformamide; dioxane; tetrahydrofuran / 13 h / -20 °C 11: 10percent aq.H2O2 / methanol / a) 0 deg C, 0.5 h, b) RT, 0.5 h 12: 65 percent / 48percent HBr, phenol / 10 h / Heating 13: HSiCl3, Et3N / acetonitrile / 3 h / Heating |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 10 steps 1: 2.) LiAlH4 2: 100 percent / pyridine / -25 °C 3: 100 percent / p-toluenesulfonic acid 4: 67 percent / dioxane; tetrahydrofuran / Ambient temperature 5: 1.) 10 percent H2O2; 2.) PTSA / 1.) methanol; 2.) methanol 6: 96 percent / H2 / 5 percent Rh-Al2O3 / methanol / 48 h / 150 °C / 114000 Torr 7: 88 percent 9: 73 percent / 48 percent HBr, phenol / Heating 10: HSiCl3, Et3N, 30 percent NaOH / toluene |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 11 steps 1: 2.) LiAlH4 2: 100 percent / pyridine / -25 °C 3: 100 percent / p-toluenesulfonic acid 4: 67 percent / dioxane; tetrahydrofuran / Ambient temperature 5: 1.) 10 percent H2O2; 2.) PTSA / 1.) methanol; 2.) methanol 6: 96 percent / H2 / 5 percent Rh-Al2O3 / methanol / 48 h / 150 °C / 114000 Torr 7: 88 percent 9: 73 percent / 48 percent HBr, phenol / Heating 10: HSiCl3, Et3N, 30 percent NaOH / toluene 11: 65 percent |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 1.) oxalyl chloride, DMF, 2.) triethylamine / 1.) CH2Cl2, reflux, 40 min, 2.) THF, 0 deg C, 30 min 2: 1.) Na2S2SO4, 2.) aq. HCl / 1.) THF, H2O, room temp., 1.5 d, 2.) THF, H2O, room temp., 2 d |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 7 steps 1: 1.) oxalyl chloride, DMF, 2.) triethylamine / 1.) CH2Cl2, reflux, 40 min, 2.) THF, 0 deg C, 30 min 2: 1.) Na2S2SO4, 2.) aq. HCl / 1.) THF, H2O, room temp., 1.5 d, 2.) THF, H2O, room temp., 2 d 3: 89 percent / H2 / Pd/C / methanol / 5 h / 60 °C / 2068.6 Torr 4: 79.4 percent / 24 h / Heating 5: 70 percent / oxalyl chloride, DMSO / CH2Cl2 / 1 h / -78 °C 6: 90 percent / pyridine / CH2Cl2 / 3 h / Ambient temperature 7: 50 percent / DABCO / (CH3CN)2PdCl2 / methanol / 45 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: 1.) oxalyl chloride, DMF, 2.) triethylamine / 1.) CH2Cl2, reflux, 40 min, 2.) THF, 0 deg C, 30 min 2: 1.) Na2S2SO4, 2.) aq. HCl / 1.) THF, H2O, room temp., 1.5 d, 2.) THF, H2O, room temp., 2 d 3: 89 percent / H2 / Pd/C / methanol / 5 h / 60 °C / 2068.6 Torr |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 9 steps 1: 1.) oxalyl chloride, DMF, 2.) triethylamine / 1.) CH2Cl2, reflux, 40 min, 2.) THF, 0 deg C, 30 min 2: 1.) Na2S2SO4, 2.) aq. HCl / 1.) THF, H2O, room temp., 1.5 d, 2.) THF, H2O, room temp., 2 d 3: 89 percent / H2 / Pd/C / methanol / 5 h / 60 °C / 2068.6 Torr 4: 79.4 percent / 24 h / Heating 5: 70 percent / oxalyl chloride, DMSO / CH2Cl2 / 1 h / -78 °C 6: 90 percent / pyridine / CH2Cl2 / 3 h / Ambient temperature 7: 50 percent / DABCO / (CH3CN)2PdCl2 / methanol / 45 °C 8: 99 percent / NaBH4 / methanol / 4.5 h 9: 0.1 M aq. HCl / 2 h / Ambient temperature |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: 1.) oxalyl chloride, DMF, 2.) triethylamine / 1.) CH2Cl2, reflux, 40 min, 2.) THF, 0 deg C, 30 min 2: 1.) Na2S2SO4, 2.) aq. HCl / 1.) THF, H2O, room temp., 1.5 d, 2.) THF, H2O, room temp., 2 d 3: 89 percent / H2 / Pd/C / methanol / 5 h / 60 °C / 2068.6 Torr 4: 79.4 percent / 24 h / Heating 5: 70 percent / oxalyl chloride, DMSO / CH2Cl2 / 1 h / -78 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 7 steps 1: 1.) oxalyl chloride, DMF, 2.) triethylamine / 1.) CH2Cl2, reflux, 40 min, 2.) THF, 0 deg C, 30 min 2: 1.) Na2S2SO4, 2.) aq. HCl / 1.) THF, H2O, room temp., 1.5 d, 2.) THF, H2O, room temp., 2 d 3: 89 percent / H2 / Pd/C / methanol / 5 h / 60 °C / 2068.6 Torr 4: 79.4 percent / 24 h / Heating 5: 70 percent / oxalyl chloride, DMSO / CH2Cl2 / 1 h / -78 °C 6: 90 percent / pyridine / CH2Cl2 / 3 h / Ambient temperature 7: 60 percent / LiCl / (Ph3P)4Pd / tetrahydrofuran / Heating |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: 1.) oxalyl chloride, DMF, 2.) triethylamine / 1.) CH2Cl2, reflux, 40 min, 2.) THF, 0 deg C, 30 min 2: 1.) Na2S2SO4, 2.) aq. HCl / 1.) THF, H2O, room temp., 1.5 d, 2.) THF, H2O, room temp., 2 d 3: 89 percent / H2 / Pd/C / methanol / 5 h / 60 °C / 2068.6 Torr 4: 79.4 percent / 24 h / Heating |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 7 steps 1: 1.) oxalyl chloride, DMF, 2.) triethylamine / 1.) CH2Cl2, reflux, 40 min, 2.) THF, 0 deg C, 30 min 2: 1.) Na2S2SO4, 2.) aq. HCl / 1.) THF, H2O, room temp., 1.5 d, 2.) THF, H2O, room temp., 2 d 3: 89 percent / H2 / Pd/C / methanol / 5 h / 60 °C / 2068.6 Torr 4: 79.4 percent / 24 h / Heating 5: 70 percent / oxalyl chloride, DMSO / CH2Cl2 / 1 h / -78 °C 6: 90 percent / pyridine / CH2Cl2 / 3 h / Ambient temperature 7: 65 percent / LiCl / (Ph3P)4Pd / tetrahydrofuran / Heating |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 8 steps 1: 1.) oxalyl chloride, DMF, 2.) triethylamine / 1.) CH2Cl2, reflux, 40 min, 2.) THF, 0 deg C, 30 min 2: 1.) Na2S2SO4, 2.) aq. HCl / 1.) THF, H2O, room temp., 1.5 d, 2.) THF, H2O, room temp., 2 d 3: 89 percent / H2 / Pd/C / methanol / 5 h / 60 °C / 2068.6 Torr 4: 79.4 percent / 24 h / Heating 5: 70 percent / oxalyl chloride, DMSO / CH2Cl2 / 1 h / -78 °C 6: 90 percent / pyridine / CH2Cl2 / 3 h / Ambient temperature 7: 50 percent / DABCO / (CH3CN)2PdCl2 / methanol / 45 °C 8: 99 percent / NaBH4 / methanol / 4.5 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1: 1.) oxalyl chloride, DMF, 2.) triethylamine / 1.) CH2Cl2, reflux, 40 min, 2.) THF, 0 deg C, 30 min 2: 1.) Na2S2SO4, 2.) aq. HCl / 1.) THF, H2O, room temp., 1.5 d, 2.) THF, H2O, room temp., 2 d 3: 89 percent / H2 / Pd/C / methanol / 5 h / 60 °C / 2068.6 Torr 4: 79.4 percent / 24 h / Heating 5: 70 percent / oxalyl chloride, DMSO / CH2Cl2 / 1 h / -78 °C 6: 90 percent / pyridine / CH2Cl2 / 3 h / Ambient temperature |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 69.6 percent / Et3N / dioxane; H2O / 15 h / 50 °C 2: 81 percent / LiAlH4 / tetrahydrofuran / 1.) 0 deg C, 1 h, 2.) room temperature, 15 h | ||
Multi-step reaction with 2 steps 1: sodium hydrogencarbonate / 1,4-dioxane; water / 0 - 20 °C 2: lithium borohydride / tetrahydrofuran / 0 - 20 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 12 steps 2: 87 percent / LiAlH4 / tetrahydrofuran 3: 85 percent / tetrahydrofuran 4: 92 percent 5: 70 percent / dioxane; tetrahydrofuran 6: 10percent H2O2 / methanol 7: 3percent HCl / methanol 8: 91 percent / H2 / Rh-Al2O3 / methanol / 48 h / 150 °C / 114000 Torr 9: 96 percent 12: HSiCl3-NEt3, 30percent NaOH / acetonitrile / Heating |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With dmap; triethylamine In dichloromethane at 20℃; for 48h; | |
In pyridine |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With triethylamine; In ethanol; dichloromethane; at 0 - 20℃; for 16.25h; | Step 2:To a solution of compound 2 (HCI salt, 146.2 g, 0.747 mol) dissolved in CH2CI2 (1600 ml) and EtOH (100 ml) and cooled to 0 0C was added Et3N (113.4 g, 1.12 mol, 156.2 ml). t-BOC anhydride (195.6, 0.90 mol) was added portion-wise. The reaction mixture was stirred at 0 0C for 15 min, then at RT for 16 h. The resulting mixture was concentrated to ~ 800 ml volume and washed with water. The organic solution was dried (MgSO4), filtered, and concentrated. Purification by silica gel chromatography (eluant: 20% EtOAc - CH2CI2) gave the product 3 (193.7 g, 100%) as a yellow oil. MS (M+Na): m/e 282. 1H-NMR (CDCI3) delta 1.30 (t, 3H)1 1.45 (s, 9H), 1.75 (m, 1 H), 2.10 (m, 1 H), 2.30 (m, 1 H), 3.45 and 3.55 (d, 1 H for two rotamers), 3.65 (dd, 1 H), 4.25 (m, 2H), 4.40 and 4.45 (t, 1H for two rotamers), 4.55 (broad s, 1 H). |
100% | With triethylamine; In ethanol; dichloromethane; at 0 - 20℃; | Step 2:To a solution of compound 2 (HCl salt, 146.2 g, 0.747 mol) dissolved in CH2Cl2 (1600 ml) and EtOH (100 ml) and cooled to 0 C. was added Et3N (113.4 g, 1.12 mol, 156.2 ml). t-BOC anhydride (195.6, 0.90 mol) was added portionwise. The reaction mixture was stirred at 0 C. for 15 min, then at RT for 16 h. The resulting mixture was concentrated to 800 ml volume and washed with water. The organic solution was dried (MgSO4), filtered, and concentrated. Purification by silica gel chromatography (eluant: 20% EtOAc-CH2Cl2) gave the product 3 (193.7 g, 100%) as a yellow oil. MS (M+Na): m/e 282. 1H-NMR (CDCl3) delta 1.30 (t, 3H), 1.45 (s, 9H), 1.75 (m, 1H), 2.10 (m, 1H), 2.30 (m. 1H), 3.45 and 3.55 (d, 1H for two rotamers), 3.65 (dd, 1H), 4.25 (m, 2H), 4.40 and 4.45 (t, 1H for two rotamers), 4.55 (broad s, 1H). |
100% | 2B (13.4 g, 68.5 mmol) was dissolved in a mixed solution of 1,4-dioxane (50 mL) and water (50 mL) at room temperature and cooled to 0 C,Triethylamine (17.3 g, 0.171 mmol) was added and the mixture was stirred for 10 minutes.A mixture of di-tricarbonate (13.4 g, 68.5 mmol)In dichloromethane (50 mL) was added dropwise to the reaction solution and allowed to react at room temperature for 20 hours.Water (100 mL) was added to the reaction solution and extracted with dichloromethane (100 mL x 4).The organic phases were combined and washed with saturated brine solution (50 mL x 1). Dried over anhydrous magnesium sulfate,The filtrate was concentrated under reduced pressure to give pale yellow liquid 2C (18 g, yield 100%). |
With sodium hydroxide; In water; at 0 - 20℃; for 1h; | Step B; The mixture of 19.5 g (100 mmol) (2S, 4R)-4-hydroxy-pyrrolidine-2- carboxylic acid ethyl ester HCl salt in 250 mL 1 N NaOH was cooled down to 0 C and stirred under nitrogen. The mixture was treated with 26 g (Boc) 20, and the mixture was stirred at 0 C to rt for 1 h. The mixture was quenched with 100 mL sat. NH4C1, extracted with ethyl acetate 3 x 100 mL. The combined organic was washed with brine 50 mL, and dried over anhydrous Na2S04. After purification by flash chromatography, obtained (2S, 4R) 4-hydroxy-pyrrolidine-1, 2-dicarboxylic acid 1- tert-butyl ester 2-ethyl ester 23 g as white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With triethylamine In methanol at 0 - 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With 1H-imidazole In dichloromethane at 0 - 25℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 70% 2: 7% | Stage #1: trans-4-hydroxy-L-proline ethyl ester hydrochloride With dmap; triethylamine In dichloromethane for 1.16667h; Inert atmosphere; Stage #2: methyl chloroformate In dichloromethane at 0℃; for 110h; Inert atmosphere; Reflux; | (2S,4R)-2-ethyl 1-methyl 4-(methoxycarbonyloxy)pyrrolidine-1,2-dicarboxylate (9) and (2S,4R)-2-ethyl 1-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate (SI-4) SI-3 (2.15 g, 11.0 mmol) was dissolved in DCM (40 mL) under Ar, TEA (17.9 mL, 88.2 mmol) and DMAP (133 mg, 1.10 mmol) were added over 10 min and the reaction mixture stirred for 1 h. Methyl chloroformate (5.15 mL, 66.1 mmol) was added dropwise at 0°C over 1.5 h and the reaction mixture heated to reflux for 18 h. Methyl chloroformate (5.00 mL, 64.1 mmol) was added dropwise over 0.5 h and the reaction mixture heated to reflux for a further 72 h. The reaction mixture was diluted with DCM (60 mL), washed with NH4Cl (2 x 20 mL), brine (20 mL), dried over Na2SO4, filtered and evaporated to give a colourless oil, 3.52 g. This was purified by flash column chromatography, eluted with petrol:EtOAc 1-0:1 to give 9 as a colourless oil (2.11 g, 70%) and SI-4 as a colourless oil (167 mg, 7%): 9: [a]D21 -48.05 (c 1.30 in CHCl3); nmax/cm-1 (CHCl3) 3011, 2959, 1747, 1704, 1455, 1394, 1274, 1193; dH (400 MHz; CDCl3, 2:1 mixture rotamers) 5.20 (1H, app. sxt, J 2.0, CHOCO2Me), 4.46 (0.67H, t, J 8.0, CHCO2Et), 4.41 (0.33H, t, J 8.0, CHCO2Et), 4.21 (1.33H, t, J 6.9, CH2CH3), 4.21 (0.67H, t, J 6.9, CH2CH3), 3.86 (0.67H, dt, J 12.7, 1.8, NCHH), 3.80 (3H, br. s, CO2CH3), 3.78-3.72 (1.33H, m, NCH2), 3.72 (2H, s, CO2CH3), 3.68 (1H, s, CO2CH3), 2.58-2.43 (1H, m, CHCHHCH), 2.30-2.15 (1H, m, CHCHHCH), 1.28 (2H, q, J 6.9, CH2CH3), 1.27 (1H, q, J 6.9, CH2CH3); dC (100 MHz; CDCl3) 172.1, 172.0 (C), 155.1, 155.0 (C), 154.8, 153.6 (C), 76.3, 75.5 (C), 61.5, 61.4 (CH2), 57.8, 57.5 (CH), 55.0 (CH3), 52.8 (CH3), 52.5, 51.9 (CH2), 36.5, 35.6 (CH2), 14.2, 14.1 (CH3); m/z (ESI) (C11H18NO7 (M+H) requires 276.1078. Found 276.1076, C11H17NNaO7 (M+Na) requires 298.0897. Found 298.0894). SI-4: [a]D22 -67.63 (c 1.25 in CHCl3); nmax/cm-1 (CHCl3) 3467 (br), 3011, 2958, 1743, 1701, 1456, 1394, 1192; dH (400 MHz; CDCl3, 1:1 mixture of rotamers) 4.57-4.50 (1H, m, CHOH), 4.49 (0.5H, t, J 8.2, CHCO2Et), 4.44 (0.5H, t, J 8.2, CHCO2Et), 4.21 (1H, q, J 7.2, CH2CH3), 4.21 (1H, q, J 7.2, CH2CH3), 3.73 (1.5H, s, CO2CH3), 3.69 (1.5H, s, CO2CH3), 3.72-3.66 (1H, m, NCHH), 3.64 (0.5H, br. d, J 11.5, NCHH), 3.52 (0.5H, d, J 11.5, NCHH), 2.40-2.24 (1H, m, CHCHHCH), 2.16-2.06 (1H, m, CHCHHCH), 1.77 (1H, br. s., OH), 1.29 (1.5H, t, J 7.2, CH2CH3), 1.28 (1.5H, t, J 7.2, CH2CH3); dC (100 MHz; CDCl3) 172.9, 172.8 (C), 155.7, 155.4 (C), 69.7, 68.9 (CH), 61.5, 61.2 (CH2), 58.0, 57.7 (CH), 55.0, 54.5 (CH2), 52.9, 52.6 (CH3), 39.0, 38.2 (CH2), 14.1, 14.0 (CH3); m/z (ESI) (C9H16NO5 (M+H) requires 218.1023. Found 218.1025, C9H15NNaO5 (M+Na) requires 240.0842. Found 240.0841). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With potassium carbonate In diethyl ether; water at 0 - 20℃; for 2h; | 59.2 2. Procedure for the preparation of 54b To a stirred mixture 54a (60.0 g, 0.30 mol) in diethyl ether/0 (100 mL/600 mL) at 0°C was added K2C03 (104 g, 0.75 mol) and CbzCl (48.0 g, 0.28 mol) dropwise and the mixture was stirred at RT for 2 h, TLC (PE:EA=2:1) showed that a major new product was formed. The layers were separated and the aqueous phase was extracted with EA (100 mL x 2) and the combined organic extracts were washed with brine, dried over Na2S04i filtered and concentrated in vacuo to give 54b (75.0 g, 83%) as a yellow oil. LC-MS (Agilen, P- 2): R, 2.86 min; m/z calculated for C 5H 19NO5 [M+H]+ 294.1, [M+Naf 316.1 , found [M+Hf 294.1 , [M+Na]+ 316.1. |
60 mg | With triethylamine In dichloromethane at 20℃; | 106.1 Step 1: Preparation of 1 -benzyl 2-ethyl (2S,4R)-4-hydroxypyrrolidine- 1 ,2-dicarboxylate Cbz-Cl (70 g, 410.33 mmol, 2.00 equiv) in dichloromethane (50 mL) was added dropwise into a mixture of ethyl (2S,4R)-4-hydroxypyrrolidine-2-carboxylate hydrochloride (40 g, 204.45 mmol, 1.00 equiv) and TEA (83 g, 820.24 mmol, 4.00 equiv) in dichloromethane (400 mL) at room temperature. The resulting solution was stirred overnight at room temperature. The mixture was diluted with water and extracted with ethyl acetate. The combined extracts were washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by a silica gel column eluting with ethyl acetate/petroleum ether (2:1) to afford the title compound (60 g) as light yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | Stage #1: bromobenzene With magnesium In diethyl ether Inert atmosphere; Stage #2: trans-4-hydroxy-L-proline ethyl ester hydrochloride In diethyl ether at 20℃; Inert atmosphere; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | In diethyl ether for 5h; Reflux; |
Tags: 33996-30-4 synthesis path| 33996-30-4 SDS| 33996-30-4 COA| 33996-30-4 purity| 33996-30-4 application| 33996-30-4 NMR| 33996-30-4 COA| 33996-30-4 structure
[ 440678-43-3 ]
(2S,4S)-Ethyl 4-hydroxypyrrolidine-2-carboxylate
Similarity: 0.98
[ 61478-25-9 ]
(2S,4R)-Ethyl 4-hydroxypyrrolidine-2-carboxylate
Similarity: 0.98
[ 440678-43-3 ]
(2S,4S)-Ethyl 4-hydroxypyrrolidine-2-carboxylate
Similarity: 0.98
[ 61478-25-9 ]
(2S,4R)-Ethyl 4-hydroxypyrrolidine-2-carboxylate
Similarity: 0.98
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P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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