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CAS No. : | 32233-40-2 | MDL No. : | |
Formula : | C8H12O4 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | VYTZWRCSPHQSFX-GBNDHIKLSA-N |
M.W : | 172.18 | Pubchem ID : | 2724453 |
Synonyms : |
Corey Lactone Diol
|
Num. heavy atoms : | 12 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.88 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 39.95 |
TPSA : | 66.76 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) : | -7.51 cm/s |
Log Po/w (iLOGP) : | 0.99 |
Log Po/w (XLOGP3) : | -0.22 |
Log Po/w (WLOGP) : | -0.71 |
Log Po/w (MLOGP) : | -0.16 |
Log Po/w (SILICOS-IT) : | 0.11 |
Consensus Log Po/w : | 0.0 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -0.7 |
Solubility : | 34.1 mg/ml ; 0.198 mol/l |
Class : | Very soluble |
Log S (Ali) : | -0.72 |
Solubility : | 32.4 mg/ml ; 0.188 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | 0.22 |
Solubility : | 288.0 mg/ml ; 1.67 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 3.34 |
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 |
---|---|---|
84% | In dichloromethane for 1.5h; Ambient temperature; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With Amberlite IR 120 resin In methanol at 70℃; for 8h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With pyridine at 60℃; for 1h; | |
94.55% | With pyridine at 65℃; for 4h; | Synthesis of (3aR,4S,5R,6aS)-hexahydro-4,5-ditriethylsilane-4-(methyl)cyclopenta[b]furan-2-one (8) To a solution of compound 7 (50 g, 1 mmol) in pyridine(500 mL), triethyl silylchloride (146 mL, 3 mmol)was added at room temperature and the mixture wasstirred at 65°C for 4 h. The solvent was removed underreduced pressure after completion of reaction, residuewas dissolved in water (400 mL) and extracted withdichloro methane (2 x 500 mL). The collected organicphases were washed with water followed by brine solution,dried over anhydrous Na2SO4 and concentratedunder reduced pressure. The crude product was purifiedby silica gel chromatography using ethyl acetateand hexane (10:90) to furnish desired compound 8 as a colorless liquid (110 g, 94.55%). 1H NMR (300 MHz,CDCl3): δ0.6 (m, 12H), 0.95 (J=15.9 Hz, t, 18H), 2 (m, 2H), 2.25 (m, 1H), 2.55 (dd, 1H), 2.75 (m,2H),3.55 (m,2H), 4.98 (m, 1H), 4.15 (m, 1H). 13C NMR(100 MHz, CDCl3): δ4.22 (3C), 4.63 (3C), 5.73 (2C),6.50 (2C), 6.65 (2C), 35.57, 39.26, 41.07, 56.99, 62.41,74.30, 84.07, 177.28. |
93% | With pyridine at 60℃; for 1h; |
93% | With pyridine at 60℃; for 1h; | 10 Example 10: Preparation and structural confirmation of disubstituted impurities ((-)-Corey Lactone primary and secondary alcohols) a 50ml three-neck bottle,Input (-)-Corey Lactone (2.0g, 11.62mmol)And dry pyridine(20.0ml),Triethylchlorosilane (4.0 g, 26.72 mmol) was added at room temperature.Warm up to 60 ° C and stir for one hour.The reaction solution was diluted with 40 ml of water.Extracted with 50 ml of dichloromethane, the extract was dried over anhydrous sodium sulfate and filtered.The filtrate was evaporated to dryness, and the obtained oil was purified by column chromatography (eluent: n-hexane,Ethyl acetate, 7:3),Obtained a colorless oily product (disubstituted impurity) 4.3g,Yield 93%, GC: 99.45%. |
With 1H-imidazole In N,N-dimethyl-formamide at 5℃; for 4h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With dmap; triethylamine In dichloromethane at 20℃; for 4h; Inert atmosphere; | 3 EXAMPLE 3 (3aR,4S,5R,6aS)-5-hydroxy-4-(trityloxymethyl)hexahydro-2H cyclopenta[b] furan-2-one [Show Image] (3aR,4S,5R,6aS)-4-(hydroxymethyl)-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl biphenyl-4-carboxylate (8.55 g, 0. 050 mol) was dissolved in dichloromethane (50 mL) under nitrogen atmosphere. Trityl chloride (15.2 g, 0.055 mol) was added followed by triethylamine (7.6 mL, 0.055 mol) dropwise and a solution of 4-(dimethylamino)pyridine (1.26 g, 0.010 mol) in dichloromethane (5 mL). While stirring at room temperature, the mixture turned into a red solution. The conversion of the starting material was monitored by TLC analysis for four hours. The mixture was washed with a 5% sodium bisulfate solution (40 mL) and the aqueous layer was then extracted with dichloromethane (3x 30 mL). The combined organic layers were washed with water (30 mL) and brine (30 mL). The organic layers were concentrated at 40°C under reduced pressure affording the crude product (25 g) which was suspended in n-hexane (100 mL) and stirred for 10 hours. After filtration the product was obtained as a pale yellow solid (24.8 g, quantitative). 1H-NMR {400MHz, CDCl3, δ (ppm)}: 7.42-7.39 (m, 5H, Ph), 7.33-7.23 (m, 10H, Ph), 4.85 (dt, J=2.8Hz, 6.8Hz, 1H, CH-O-C=O), 4.10 (q, J=6.0 Hz, 1H, CH-OH), 3.23 (dd, J=5.6, 9.6 Hz, CH2-O-C-Ph3), 3.12 (dd, J= 6.8, 9.6 Hz, CH2-O-C-Ph3), 2.70 (m, 1H, CH2-C=O), 2.53-2.29 (m, 4H, O-CH-CH2-CHO+CH2-C=O+OH+CH), 2.07-1.93 (m, 2H, O-CH-CH2-CH-O+CH). 13C-NMR {400MHz, CDCl3, δ (ppm)}: 35.3 (CH2), 39.9 (CH), 40.4 (CH2), 53.6 (CH), 64.2 (CH2), 75.3 (CH), 83.5 (C), 87.0 (CH), 127.2 (arom.CH), 127.3 (arom.CH), 127.7 (arom.CH), 127.8 (arom.CH), 127.9 (arom.CH), 128.0 (arom.CH), 128.4 (arom. CH), 143.6 (3x arom.C), 177.2 (C). HPLC-MS (ESI): [M+Na]+= 437; [2M+Na]+= 851. |
93% | With pyridine In dichloromethane | |
87% | With pyridine at 20℃; for 48h; |
87% | In pyridine at 20℃; for 48h; | |
With pyridine at 20℃; for 12h; Large scale; | 14 One-pot Preparation of (-) Corey lactone benzoate Add 30L of pyridine to the reactor with the filter element at the bottom, add (a) 4kg (leq) of the Corey lactone diol while stirring, add 7.13kg (1. leq) of triphenylchloromethane, and control the temperature at 20°C for 12h to complete In the reaction, 2.82 L (1.05 eq) of benzoyl chloride was added dropwise and the reaction was allowed to proceed at a controlled temperature of 30° C. for 4.5 h to complete the reaction; 44 L of pure water was added to the reaction vessel and stirred for 2 h to obtain a suspension. Nitrogen gas was introduced into the reaction vessel and passed through the reactor. The bottom of the filter will be suspended hydraulic filter, and then add isopropanol 40L to the reaction vessel, heated to reflux for 1h, the liquid pressure filter to obtain a solid powder; add 60L acetonitrile to the reaction vessel, add 30L of 3mol/L hydrochloric acid aqueous solution dropwise, control Temperature 45 ° C reaction 3.5h to complete reaction, the reaction system was cooled to 10 ° C, was added saturated aqueous sodium carbonate and neutralization reaction to ΡΗ = 7; the solvent acetonitrile in the reaction vessel was distilled off, and the resulting crude product was obtained by pressure filtration; 40K n-propyl ether was added to the reaction vessel, and the mixture was heated to reflux for 3 h, and then pressed and dried to give the product (-) Corey lactone benzoate, 6.4 Kg, a yield of 93.59%, and a purity of 99.03%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With oxalyl dichloride In dichloromethane; dimethyl sulfoxide at -78℃; for 1.03333h; | 1.1; 2.1; 3.1; 4.1; 5.1; 6.1; 7.1; 8.1; 9.1 (1) Synthesis of compound 2 At -78°C, a DCM solution (20 mL) of DMSO (3 ml, 42.2 mmol) was added dropwise to a DCM solution (20 mL) of oxalyl chloride (1.5 ml, 17.7 mmol).After stirring for 30 min, a solution of compound 1 (1.80 g, 10.5 mmol) in DCM (15 mL) was added dropwise to the above solution and stirred for 2 min. The reaction solution was kept at -78°C and stirred for 1 hour,Then TEA (12 mL, 86.0 mmol) was added dropwise to the above reaction liquid. After TEA was added dropwise, saturated NH4Cl solution (10 mL) was added to the reaction solution to quench the reaction. Then, the temperature of the reaction solution was raised to room temperature, and washed with saturated brine (3×20 mL),The organic phase was dried with anhydrous Na2SO4, filtered, concentrated, and purified by column chromatography to obtain compound 2 (1.7 g, 95%). |
95% | With oxalyl dichloride In dichloromethane; dimethyl sulfoxide at -78℃; for 1h; | 1.1; 2.1; 3.1; 4.1; 5.1; 6.1; 7.1; 8.1; 9.1 (1) Synthesis of compound 2 At -78°C, a DCM solution (20 mL) of DMSO (3 ml, 42.2 mmol) was added dropwise to a DCM solution (20 mL) of oxalyl chloride (1.5 ml, 17.7 mmol). After stirring for 30 min, a solution of compound 1 (1.80 g, 10.5 mmol) in DCM (15 mL) was added dropwise to the above solution and stirred for 2 min. Stir at -78°C for 1 h, and then add TEA (12 mL, 86.0 mmol) dropwise to the above reaction liquid. After TEA was added dropwise, saturated NH4Cl solution (10 mL) was added to the reaction solution to quench the reaction. Then, the temperature of the reaction solution was raised to room temperature, washed with saturated brine (3×20 mL), the organic phase was dried with anhydrous Na 2 SO 4, filtered, concentrated, and purified by column chromatography to obtain compound 2 (1.7 g, 95%). |
With oxalyl dichloride; triethylamine In dimethyl sulfoxide |
With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; iodobenzene diacetic acid In dichloromethane at 20℃; | 1 306 g of (-) - Corey lactone diol (Formula 1) (molecular weight: 172,0.06 mol)Mixed in 4680 ml of dichloromethane, stirred at room temperature,A mixture of 63 g of iodobenzene diacetate (molecular weight: 322, 1.1 eq) and 3.6 g of tetramethylpiperidine nitrogen oxide (molecular weight: 156, 0.13 eq) was added in portions, and the mixture was stirred at room temperature overnight.TLC to obtain a reaction solution containing a lactone aldehyde (Formula 2) in which methylene chloride is used as an organic solvent, iodobenzoacetate as a catalyst, tetramethylphosphine nitrogen oxide as an oxidizing agent. | |
501 g | Stage #1: (3aR,4S,5R,6aS)-5-hydroxy-4-(hydroxymethyl)hexahydro-2H-cyclopenta[b]furan-2-one With C10H16NO(1-); tetrabutylammomium bromide; sodium hydrogencarbonate; potassium bromide In dichloromethane at 0℃; for 0.166667h; Stage #2: With sodium chlorite In dichloromethane at 5℃; for 0.5h; | 1 Step (1) Preparation of Compound I In a constant pressure dropping funnel,Thermometer and mechanical stirring Corey lactone (500 g, 2.907 mol), DMN-AZADO (4.93 g, 0.02907 mol), respectively, in a 10 L three-necked flask,Potassium bromide KBr (34.59 g, 0.2907 mol), n-Bu4NBr (47.8g, 0.1454mol), dichloromethane (5L) and saturated sodium bicarbonate solution (400mL); then the above mixture system using ice salt bath, cooled to internal temperature ≤ 0 ° C, and stirred at constant temperature for 10 min; A solution of NaClO (3.4884 mol, used as an oxidizing agent) was slowly added dropwise to the reaction system, and the reaction temperature was controlled not higher than 5 ° C; the dropwise addition was completed, and the mixture was stirred at a constant temperature for 30 minutes. After completion of the reaction, the system was quenched by the addition of saturated Na 2 S 2 O 3 (neutral excess oxidant) (1000 mL), and the aqueous phase was extracted with dichloromethane (0.5 L*2). The combined organic phases were washed with a saturated sodium chloride solution, dried and concentrated to give a pale yellow compound I (501 g, purity 97%) which can be directly applied to the next step |
Stage #1: (3aR,4S,5R,6aS)-5-hydroxy-4-(hydroxymethyl)hexahydro-2H-cyclopenta[b]furan-2-one With DMN-AZADO; tetrabutylammomium bromide; sodium hydrogencarbonate; potassium bromide In 1,2-dichloro-ethane at 0℃; for 0.166667h; Stage #2: With sodium hypochlorite In dichloromethane at 5℃; for 0.5h; | 1 (1) Preparation of Compound I In a constant pressure dropping funnel,Add a left-handed spine to the thermometer and mechanically stirred 3L three-necked bottleCoryrolactone diol (100 g, 0.5814 mol), DMN-AZADO (0.986 g, 0.0058 mol),Potassium bromide KBr (6.918 g, 0.058 mol),Tetrabutylammonium bromide (n-Bu4NBr, 9.56g, 0.029mol),Dichloromethane (1 L) and saturated sodium bicarbonate solution (100 mL).Then, the above mixed system is cooled to an internal temperature ≤ 0 ° C, and stirred at a constant temperature for 10 min.A NaOCl (0.70 mol) solution was slowly added dropwise to the reaction system.The reaction temperature was controlled to be not higher than 5 °C. The addition was completed, and the mixture was stirred at a constant temperature for 30 min.After the reaction was completed, the system was quenched by the addition of saturated Na 2 S 2 O 3 (200 mL).The aqueous phase was extracted with dichloromethane (0.2 L*2).The organic phases are combined and washed with a saturated sodium chloride solution.Drying over anhydrous sodium sulfate and filtering to obtain a solution of Compound I in dichloromethane.Directly applied to the next step of the reaction. | |
With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; [bis(acetoxy)iodo]benzene In dichloromethane; N,N-dimethyl acetamide at 20℃; for 6h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | Stage #1: Formic acid (3aR,4S,5R,6aS)-4-formyloxymethyl-2-oxo-hexahydro-cyclopenta[b]furan-5-yl ester With sodium methylate In methanol at 25℃; Stage #2: With acetic acid In methanol at 25℃; stereoselective reaction; | |
With sodium methylate In methanol | ||
6.2 g | With sodium In methanol at 0℃; for 0.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride In tetrahydrofuran at 25℃; Yield given; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20% | With sodium hydroxide; Soerensen phosphate buffer In methanol at 36℃; for 24h; subtilisin DY; Further byproducts given. Yields of byproduct given; | |
16% | With sodium hydroxide; Soerensen phosphate buffer In methanol at 36℃; for 24h; subtilisin DY; Further byproducts given. Yields of byproduct given; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With Amberlite IR 120 resin In methanol at 70℃; for 8h; | |
79% | With resin Wofatit SBW (OH-) In methanol for 2h; Ambient temperature; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With toluene-4-sulfonic acid In methanol at 75 - 80℃; for 4h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With Amberlite IR 120 resin In methanol at 70℃; for 8h; | |
82.1% | With hydrogenchloride In methanol; water for 4h; Reflux; | 7 Example 7, Synthesis of Compound 8 2 g of compound 7, 30 ml of methanol was added to a 100 ml three-necked flask, and 3 mL of hydrochloric acid was added thereto with stirring, and the mixture was heated under reflux for 4 hours. The reaction solution was cooled to 0 °C with an ice salt bath, neutralized with a saturated sodium hydrogen carbonate solution to pH = 4, and the solvent was removed by a reduced pressure distillation.The residue was dissolved in methylene chloride, insoluble matter was filtered off hot, the filtrate is cooled to precipitate a white solid Compound 8 1.1g, 82.1% yield |
With DBN In methanol at 20℃; for 12h; | (3aR,4S,5R,6aS)-5-hydroxy-4-(hydroxymethyl)hexahydro-2H-cyclopenta[b]furan-2-one (3):2 To a solution of Corey lactone bis-acetate 2 (2 g, 7.8 mmol) in MeOH (12 mL) at room temperature was added DBN (0.19 mL, 1.53 mmol). The reaction mixture was stirred for 12 h, and then the solvent was removed under reduced pressure. The crude was purified by column chromatography eluting with dichlorometane/MeOH 9/1 to give the beige solid 3 (1.08 g, 80%). Rf 0.44 (DCM/MeOH 9/1); m.p. 115-117 ºC; [α]D -43.4 (c 1.12, MeOH). IR (KBr) cm-1: 3354.09, 2942.36, 2891.59, 2862.67, 2809.36, 1740.34 1H NMR (500 MHz, CDCl3) δ= 2.0 (m, 4H), 2.42 (td, J=5.4, 15 Hz, 1H), 2.53 (dd, J=2.4 Hz, 1H), 2.63 (m, 1H), 2.81 (dd, J=9.6 Hz, 1H), 3.65 (m, 2H), 4.18 (q, J=6.3 Hz, 1H), 4.94 (td, J=6.9, 2.3 Hz, 1H) ppm. 13C NMR (125 MHz, CDCl3) δ= 35.2 (CH2), 39.4 (CH), 40.7 (CH2), 55.1 (CH), 63.7 (CH2), 75.6 (CH), 83.4 (CH), 177.02 (C=O) ppm. MS [EI+] m/z (%): 173 (M++1), 154 (10), 126 (35), 95 (18), 82 (42), 67 (25), 54 (100), 41 (30). |
28 g | With methanol at 25 - 65℃; | 18 Example 18 Preparation of (3aR,4S, 5R,6aS)-hexahydro-5-hydroxy-4-(hydroxymethyl)-2H-cyclopenta[b]furan-2-one. Example 18 Preparation of (3aR,4S, 5R,6aS)-hexahydro-5-hydroxy-4-(hydroxymethyl)-2H-cyclopenta[b]furan-2-one. Methanol (500 mL), (3aR,4S, 5R,6aS)-5-(acetyloxy)-4-[(acetyloxy)methyl]hexahydro-2H-cyclopenta[b]furan-2-one (100 g) and Indion 225 H resin (100 g) are charged in to the round bottom flask at 25-35° C. and stirred for 15 minutes. The reaction mixture is heated to 60-65° C. and maintained for 35-40 hours. The reaction mixture is cooled to 25-35° C., filtered through the hyflow bed and washed with methanol (200 mL). The resultant filtrate is concentrated completely under reduced pressure at below 50° C. The obtained reaction mass is subjected to column chromatography by using n-hexane/acetone. The collected fractions are evaporated completely under reduced pressure at 45-50° C. to afford 28.0 g of the title compound. Purity by HPLC: 95.7% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With potassium carbonate In tetrahydrofuran; methanol for 4h; Ambient temperature; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 44% 2: 13% 3: 8% 4: 19% | With 2,2'-azobis(isobutyronitrile); tri-n-butyl-tin hydride In benzene Heating; Further byproducts given; | |
1: 40% 2: 19% | With 2,2'-azobis(isobutyronitrile); tri-n-butyl-tin hydride In benzene Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96.3% | With 1H-imidazole In N,N-dimethyl-formamide at 0 - 10℃; for 2h; | 1 Compound 1 (50g, 0.29mol) was dissolved in DMF (200mL), cooled to 0 ° C, imidazole (47.5g, 0.70mol) was added , and TBSCl (52.3g, 0.35mol) in DMF (200mL) solution was then added slowly, the temperature was maintained such that it does not exceed 10 ° C, after the addition was completed, stirred at 0 ~ 5 ° C for 2h, saturated ammonium chloride (200 mL) was added to quench the reaction, and extracted with dichloromethane. The aqueous layer was washed twice with citric acid (10%, 200mL) , the organic phase was separated, washed with saturated NaCl solution (200 mL) and saturated sodium bicarbonate solution (200 mL) and saturated brine (200 mL), dried over anhydrous sodium sulfate, concentrated and purified by column chromatography to obtain the product (80g, yield 96.3%). |
94.5% | With 1H-imidazole In dichloromethane at 20℃; | |
89% | With 1H-imidazole In N,N-dimethyl-formamide at 0℃; for 1h; |
84% | With 1H-imidazole In N,N-dimethyl-formamide at 0℃; for 1h; | |
75% | Stage #1: (3aR,4S,5R,6aS)-5-hydroxy-4-(hydroxymethyl)hexahydro-2H-cyclopenta[b]furan-2-one With 1H-imidazole In N,N-dimethyl-formamide at 20℃; for 0.333333h; Inert atmosphere; Stage #2: tert-butyldimethylsilyl chloride In N,N-dimethyl-formamide for 8h; Inert atmosphere; | (3aR,4S,5R,6aS)-4- ((tert-butyldimethylsilyloxy)methyl)-5- hydroxyhexahydro-2H-cyclopenta[b] furan-2-one (4):3 To a solution of Corey lactone diol 3 (0.9 g, 5.23 mmol) in anhydrous DMF (1.8 mL) was added imidazole (0.88 g, 13.06 mmol). The solution was stirred for 20 min at room temperature under nitrogen atmosphere. Then tert-butyldimethylsilyl chloride (0.86 g, 5.74 mmol) was added in solution. The reaction mixture was stirred for 8 h, and then brine (~40 mL) was added to the reaction mixture and washed with EtOAc (3×10 mL). The organic layer was dried (Na2SO4) and the solvent was evaporated under reduced pressure. The crude product was purified by column chromatography eluting with ethyl acetate/hexane 1/1 to give the white solid 4 (1.11 g, 75%). Rf 0.4 (EtOAc/Hex 1/1); m.p. 61 ºC; [α]D -14.9 (c. 1.05, CHCl3) IR (KBr) cm-1: 3370.1, 2940.81, 2885.8, 1739.37. 1H NMR (500 MHz, CDCl3) δ= 4.9 (dt, J = 6.7 Hz, 1H), 4.15 (q, J = 10.0, Hz, 1H), 3.7 (d, J = 12.4 Hz, 1H), 3.6 (d, J = 12.4 Hz, 1H), 2.8 (m, 1H), 2.65-2.3 (m, 3H), 2.0 (m, 2H), 0.89 (s, 9H), 0.06 (s, 6H) ppm. 13C NMR (125 MHz, CDCl3) δ= -5.5 (2xCH3), 1.8 (C), 25.8 (3xCH3), 35.3 (CH2), 39.6 (CH), 40.8 (CH2), 55.3 (CH), 63.9 (CH2), 75.5 (CH), 83.8 (CH), 177 (C=O) ppm. MS [EI+] m/z (%): 287 (M++1), 229 (15), 183 (12), 137 (47), 75 (100), 41 (7). |
With 1H-imidazole In N,N-dimethyl-formamide at -15 - 0℃; Inert atmosphere; | 1 EXAMPLE 1 (3aR,4S,5R,6aS)-4-[(tert-butyldimethylsilyloxy)methyl]-5-(tert-butyldiphenyl-silyloxy) hexahydro-2H-cyclopenta[b]furan-2-one [Show Image] In a round bottom flask (3aR,4S,5R,6aS)-5-hydroxy-4-(hydroxymethyl)hexahydro-2H-cyclopenta[b]furan-2-one (100.0 g, 0.581 mol) was dissolved in anhydrous N,N-dimethylformamide (500 mL) under nitrogen atmosphere. The flask was cooled to 15°C and imidazole (42.31 g, 0.621 mol) was added followed by tert-butyldimethylsilyl chloride (91.91 g, 0.619 mol). The mixture was stirred at -13°C for one hour, then the temperature was allowed to reach 0°C and stirred overnight. After checking the selective protection of the primary hydroxyl group by TLC analysis, imidazole (63.26 g, 0.929 mol) and tert-butyl(chloro)diphenylsilane (175.2 mL, 185.19 g, 0.674 mol) were added at 0°C and the mixture was stirred at the same temperature for one hour and subsequently at room temperature. The reaction was checked by TLC and quenched by addition of ethyl acetate (1.00 L), water (1.00 L) and 5% sodium bisulfate solution (300 mL). The phases were separated and the aqueous one was extracted with ethyl acetate (330 mL). The combined organic layers were washed with water (3x 330 mL), brine (460 mL, 160 mL) and dried over magnesium sulfate. After filtration the organic solvent was removed at 40°C under reduced pressure. The crude product was obtained as a yellow oil (357.88 g) and was used in the subsequent step without further purification. A sample (5.50 g, corresponding to 0.009 mol of starting diol) was purified by column chromatography on silica gel (eluent: n-hexane: ethyl acetate from 95:5 to 80:20) affording the product (4.50 g, 0.0086 mol, 95%) as a colorless oil which was used for the characterization. 1H-NMR {400MHz, CDCl3, δ (ppm)}: 7.25-7.65 (m, 10 H, Ph), 4.84 (m, 1H, CH-O-C=O), 4.09 (m, 1H, CH-O-Si), 3.40 (dd, J=5.2, 10.0Hz, 1H, CH2-O-Si), 3.27 (dd, J=6.0, 10.0Hz, 1H, CH2-O-Si), 2.80 (dd, J=11.2, 18.8 Hz, 1H, CH2-C=O), 2.64 (m, 2H, -O-CH-CH2-CH-O+ CH2-C=O), 1.90-2.10 (m, 3H, -O-C H-CH2-CH-O+CH+CH), 1.04 (s, 9H, (CH3)3C), 0.79 (s, 9H, (CH3)3C), 0.08 (s, 3H, (CH3)Si), 0.07 (s, 3H, (CH3)Si). 13C-NMR {400MHz, CDCl3, δ (ppm)}: 177.2 (C), 135.8 (2x arom.CH), 135.7 (2x arom.CH), 133.6 (C), 133.5 (C), 129.8 (arom.CH), 129.7 (arom.CH), 127.6 (2x arom.CH), 127.5 (2x arom.CH), 84.2 (CH), 76.2 (CH), 63.2 (CH2), 57.1 (CH), 41.0 (CH2), 39.8 (CH), 35.8 (CH2), 26.8 (3x CH3), 25.7 (3x CH3), 18.9 (C), 18.0 (C), -5.7 (2x CH3). HPLC-MS (ESI): [M-(t-Bu(CH3)3Si) +H2O]+ = 428; [M-(t-Bu(CH3)3Si)+Na]+ = 433. | |
With dmap; triethylamine In dichloromethane at -5 - 25℃; for 14h; | (Preparation of starting materials): Compound (IV) used in the present invention: 7-[(1R,2R,3R,5S)-2-(4,4-difluoro-3-hydroxyoctyl)-5-hydroxy-3-(2-tetrahydrogen) Pyryloxy)cyclopentyl]heptanoic acid is prepared by the following method: At -5°C,Slowly add 125 mL of dichloromethane solution containing 43.7 g of TBSCl to 50 g of compound 1,375 mL of dichloromethane, 29.4 g of a mixture of triethylamine and 3.57 g of DMAP.After the addition was complete, the mixture was stirred for 2.0 hours.Warm to 25°C and stir for 12 hours.The reaction was complete, and 175 ml of water was added to the reaction solution.After the addition is complete, stir for 10-20 minutes to separate the organic phase.It was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give compound 2 as 88.89 g of an oily product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With 1H-imidazole In N,N-dimethyl-formamide at -40℃; for 2h; | |
With 1H-imidazole In N,N-dimethyl-formamide at 0℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With Dowex 50wX8 In tetrahydrofuran; water at 20℃; for 3h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With hydrogen In dichloromethane at 20℃; for 0.833333h; atmospheric pressure; | |
Multi-step reaction with 2 steps 1: 90 percent / PPTS / 1,2-dichloro-ethane / 2 h / Ambient temperature 2: 3,4-Dihydro-2H-pyran / TsOH |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: (COCl)2, NEt3 / dimethylsulfoxide 2: 50percent aq. NaOH, BuNEt3Cl / CH2Cl2 3: (i-Bu)2Al-O-C6H2-(2,6-di-t-Bu,4-Me) / CH2Cl2 / -78 °C 4: (i-Bu)2AlH | ||
Multi-step reaction with 5 steps 1: C21H21NOSi; copper dichloride; N-ethyl-N,N-diisopropylamine / acetonitrile; dichloromethane / 14 h / -20 °C 2: 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; carbonic acid dimethyl ester; trichloroisocyanuric acid / ethyl acetate 3: sodium hydroxide / dichloromethane; water 4: D-Glucose; nicotinamide adenine dinucleotide phosphate / aq. phosphate buffer / pH 7 / Enzymatic reaction 5: potassium carbonate / methanol; dichloromethane | ||
Multi-step reaction with 5 steps 1: C21H21NOSi; copper dichloride; N-ethyl-N,N-diisopropylamine / acetonitrile; dichloromethane / 14 h / -20 °C 2: 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; carbonic acid dimethyl ester; trichloroisocyanuric acid / ethyl acetate 3: sodium hydroxide / dichloromethane; water 4: D-Glucose; nicotinamide adenine dinucleotide phosphate / aq. phosphate buffer; dimethyl sulfoxide / pH 7 5: potassium carbonate / methanol; dichloromethane |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: 97 percent / pyridine / 1 h / 60 °C 2: 62 percent / oxalyl chloride, DMSO / CH2Cl2 / 0.67 h / -60 °C 3: 72 percent / 50percent NaOH, triethylbenzylammonium chloride / 0.5 h / Ambient temperature 4: 93 percent / 40percent HF / acetonitrile / 0.25 h / Ambient temperature | ||
Multi-step reaction with 4 steps 1: 90 percent / 1 h / 145 °C 2: CrO3/pyridine, activated silica gel / CH2Cl2 / 0.42 h 3: KOH / CH2Cl2 / 0.33 h / 20 °C 4: 1 N hydrochloric acid / acetone / 0.17 h / 20 °C | ||
Multi-step reaction with 4 steps 1: 93 percent / pyridine / 1 h / 60 °C 2: 1.) DMSO, (COCl)2, 2.) Et3N / 1.) CH2Cl2, -60 deg C, 40 min, 2.) -60 deg C to room temp. 3: 72 percent / 50percent aq. NaOH / Et3BnN(+)cL(-) / CH2Cl2 / 0.5 h / Ambient temperature 4: 87 percent / 40percent aq. HF / acetonitrile / 0.25 h / Ambient temperature |
Multi-step reaction with 2 steps 1: iodobenzene diacetic acid; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical / dichloromethane / 20 °C 2: sodium thiosulfate / 0.5 h | ||
Multi-step reaction with 2 steps 1.1: C10H16NO(1-); potassium bromide; tetrabutylammomium bromide; sodium hydrogencarbonate / dichloromethane / 0.17 h / 0 °C 1.2: 0.5 h / 5 °C 2.1: lithium hydroxide monohydrate / acetonitrile / 1.5 h / 20 °C 2.2: Horner-Wadsworth-Emmons Olefination / 1 h / 20 °C | ||
Multi-step reaction with 2 steps 1.1: [bis(acetoxy)iodo]benzene; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical / dichloromethane; N,N-dimethyl acetamide / 6 h / 20 °C 2.1: sodium hydride / tetrahydrofuran / 1 h / 0 °C / Inert atmosphere 2.2: 6 h / 0 - 20 °C / Inert atmosphere | ||
Multi-step reaction with 2 steps 1.1: oxalyl dichloride / dimethyl sulfoxide; dichloromethane / 1 h / -78 °C 2.1: potassium hexamethylsilazane / tetrahydrofuran / 0.5 h / -78 °C / Inert atmosphere 2.2: 4 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 97 percent / pyridine / 1 h / 60 °C 2: 62 percent / oxalyl chloride, DMSO / CH2Cl2 / 0.67 h / -60 °C | ||
Multi-step reaction with 2 steps 1: 93 percent / pyridine / 1 h / 60 °C 2: 1.) DMSO, (COCl)2, 2.) Et3N / 1.) CH2Cl2, -60 deg C, 40 min, 2.) -60 deg C to room temp. | ||
Multi-step reaction with 2 steps 1: pyridine / 4 h / 65 °C 2: oxalyl dichloride; dimethyl sulfoxide; triethylamine / dichloromethane / 4 h / -72 °C |
Multi-step reaction with 2 steps 1: 1H-imidazole / N,N-dimethyl-formamide / 4 h / 5 °C / Inert atmosphere 2: oxalyl dichloride; triethylamine / dichloromethane; dimethyl sulfoxide / 4 h / -72 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: 97 percent / pyridine / 1 h / 60 °C 2: 62 percent / oxalyl chloride, DMSO / CH2Cl2 / 0.67 h / -60 °C 3: 72 percent / 50percent NaOH, triethylbenzylammonium chloride / 0.5 h / Ambient temperature | ||
Multi-step reaction with 3 steps 1: 93 percent / pyridine / 1 h / 60 °C 2: 1.) DMSO, (COCl)2, 2.) Et3N / 1.) CH2Cl2, -60 deg C, 40 min, 2.) -60 deg C to room temp. 3: 72 percent / 50percent aq. NaOH / Et3BnN(+)cL(-) / CH2Cl2 / 0.5 h / Ambient temperature | ||
Multi-step reaction with 3 steps 1.1: oxalyl dichloride / dimethyl sulfoxide; dichloromethane / 1 h / -78 °C 2.1: potassium hexamethylsilazane / tetrahydrofuran / 0.5 h / -78 °C / Inert atmosphere 2.2: 4 h / 20 °C 3.1: 1H-imidazole / N,N-dimethyl-formamide / 8 h / 0 - 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 92 percent / conc. sulfuric acid / 1.) 80 deg C, 5 h, 2.) RT, 12 h 2: 6.2 g / sodium / methanol / 0.5 h / 0 °C | ||
Multi-step reaction with 2 steps 1: H2SO4 2: MeONa / methanol | ||
Multi-step reaction with 2 steps 1: 9.5 percent / glacial acetic acid, sulfuric acid / 24 h / 75 - 80 °C 2: 78 percent / p-toluenesulfonic acid / methanol / 4 h / 75 - 80 °C |
Multi-step reaction with 2 steps 1: sulfuric acid / 24 h / 50 - 80 °C / Sealed tube 2: DBN / methanol / 12 h / 20 °C | ||
Multi-step reaction with 2 steps 1.1: sulfuric acid / 70 °C / 12751.3 Torr 2.1: sodium methylate / methanol / 25 °C 2.2: 25 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 97 percent / H2 / Pd/C / CH2Cl2 / 0.03 h / 20 °C / atmospheric pressure 2: 99 percent / H2 / Pd/C / CH2Cl2 / 0.83 h / 20 °C / atmospheric pressure |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: 65 percent / CH3ONa / methanol / 1.33 h / Ambient temperature 2: 90 percent / PPTS / 1,2-dichloro-ethane / 2 h / Ambient temperature 3: 3,4-Dihydro-2H-pyran / TsOH |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: 84 percent / p-TsOH / CH2Cl2 / 1.5 h / Ambient temperature 2: 94 percent / DIBAL-H / diethyl ether / 0.33 h 3: 61 percent / RhCl (PPh)3 / benzene / 11 h / Heating |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 84 percent / p-TsOH / CH2Cl2 / 1.5 h / Ambient temperature 2: 94 percent / DIBAL-H / diethyl ether / 0.33 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: 84 percent / p-TsOH / CH2Cl2 / 1.5 h / Ambient temperature 2: 94 percent / DIBAL-H / diethyl ether / 0.33 h 3: 61 percent / RhCl (PPh)3 / benzene / 11 h / Heating 4: 94 percent / Collins reagent / CH2Cl2 / 19 h / Ambient temperature |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: 84 percent / p-TsOH / CH2Cl2 / 1.5 h / Ambient temperature 2: 94 percent / DIBAL-H / diethyl ether / 0.33 h 3: 61 percent / RhCl (PPh)3 / benzene / 11 h / Heating 4: 94 percent / Collins reagent / CH2Cl2 / 19 h / Ambient temperature 5: 88 percent / aq. HCl; tetrahydrofuran / 72 h / Ambient temperature |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 9 steps 1: 1.) NBS 2.) H2O / 2.) heated 2: 35 percent / methanol; pyridine / 0.33 h / Ambient temperature 3: 85 percent / AcONH4, 15percent aq. TiCl3 / tetrahydrofuran; H2O / 1 h / 60 °C 4: p-toluene sulfonic acid / 6 h / Ambient temperature 5: tetramethylguanidine 6: LiAlH(Ot-Bu)3 / tetrahydrofuran / 1.) 18 h, RT 2.) 3 h, 60 deg C 7: 70 percent / NH4OAc, 15percent aq. TiCl3 / tetrahydrofuran / Ambient temperature 8: NaBH4 / methanol / 2 h / Ambient temperature 9: 5percent HCl / tetrahydrofuran / 25 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 8 steps 1: 35 percent / methanol; pyridine / 0.33 h / Ambient temperature 2: 85 percent / AcONH4, 15percent aq. TiCl3 / tetrahydrofuran; H2O / 1 h / 60 °C 3: p-toluene sulfonic acid / 6 h / Ambient temperature 4: tetramethylguanidine 5: LiAlH(Ot-Bu)3 / tetrahydrofuran / 1.) 18 h, RT 2.) 3 h, 60 deg C 6: 70 percent / NH4OAc, 15percent aq. TiCl3 / tetrahydrofuran / Ambient temperature 7: NaBH4 / methanol / 2 h / Ambient temperature 8: 5percent HCl / tetrahydrofuran / 25 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1: p-toluene sulfonic acid / 6 h / Ambient temperature 2: tetramethylguanidine 3: LiAlH(Ot-Bu)3 / tetrahydrofuran / 1.) 18 h, RT 2.) 3 h, 60 deg C 4: 70 percent / NH4OAc, 15percent aq. TiCl3 / tetrahydrofuran / Ambient temperature 5: NaBH4 / methanol / 2 h / Ambient temperature 6: 5percent HCl / tetrahydrofuran / 25 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: tetramethylguanidine 2: LiAlH(Ot-Bu)3 / tetrahydrofuran / 1.) 18 h, RT 2.) 3 h, 60 deg C 3: 70 percent / NH4OAc, 15percent aq. TiCl3 / tetrahydrofuran / Ambient temperature 4: NaBH4 / methanol / 2 h / Ambient temperature 5: 5percent HCl / tetrahydrofuran / 25 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 7 steps 1: 85 percent / AcONH4, 15percent aq. TiCl3 / tetrahydrofuran; H2O / 1 h / 60 °C 2: p-toluene sulfonic acid / 6 h / Ambient temperature 3: tetramethylguanidine 4: LiAlH(Ot-Bu)3 / tetrahydrofuran / 1.) 18 h, RT 2.) 3 h, 60 deg C 5: 70 percent / NH4OAc, 15percent aq. TiCl3 / tetrahydrofuran / Ambient temperature 6: NaBH4 / methanol / 2 h / Ambient temperature 7: 5percent HCl / tetrahydrofuran / 25 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With pyridine at 0 - 20℃; for 3h; | 1 Preparation of (3aR,4S,5R,6aS)-5-p-toluenesulfoxy-4-[(p-toluenesulfoxy)methyl]hexahydrocyclopenta[b]furan-2-one (Compound 2) Example 1 Preparation of (3aR,4S,5R,6aS)-5-p-toluenesulfoxy-4-[(p-toluenesulfoxy)methyl]hexahydrocyclopenta[b]furan-2-one (Compound 2) To a 200 mL-three-neck flask attached with a dropping funnel were added p-toluenesulfonyl chloride (37.0 g, 190 mmol), and 60 mL of pyridine, and the mixture was cooled on an ice bath. The mixture was added dropwise with a solution of (3aR,4S,5R,6aS)-5-hydroxy-4-hydroxymethylhexahydrocyclopenta[b]furan-2-one (Compound 1, 8.6 g, 50 mmol) in 40 mL of pyridine, stirred for 30 minutes, then warmed to room temperature, and further stirred for 2.5 hours. The mixture was again cooled on an ice bath, and slowly added with 50 mL of ice water. The mixture was stirred at room temperature for 10 minutes, and then added with 80 mL of ethyl acetate, the layers were separated, and further the aqueous layer was extracted twice with 30 mL of ethyl acetate. The organic layers were combined, and washed five times with 50 mL of diluted hydrochloric acid and once with 40 mL of saturated brine in this order. The organic layer was dried over anhydrous magnesium sulfate, and after the drying agent was removed by filtration, concentrated in an evaporator. The residue was added with 150 mL of methanol, and the mixture was stirred at 70° C. for 30 minutes with heating, and then crystallized at 5 to 10° C. by cooling. The precipitated solid was collected by filtration, and dried in a desiccator to obtain (3aR,4S,5R,6aS)-5-p-toluenesulfoxy-4-[(p-toluenesulfoxy)methyl]hexahydrocyclopenta-[b]furan-2-one (Compound 2) as white crystals (17.5 g, yield: 73%). 1H NMR (CDCl3, 300 MHz): δ 7.77-7.72 (m, 4H), 7.40-7.33 (m, 4H), 4.87-4.76 (m, 2H), 4.04-3.94 (m, 2H), 2.81-2.73 (m, 2H), 2.48 (s, 3H), 2.46 (s, 3H), 2.44-2.26 (m, 3H), 2.26-2.04 (m, 1H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | In toluene at 120℃; for 3h; Dean-Stark apparatus; | Protected Diol 16. To a suspension of 12 (5.0 g, 29 mmol, 1 equiv) in toluene (100 mL) was added anisaldehyde dimethyl acetal (14) (7.4 mL, 44 mmol, 1.5 equiv) and p-methoxy benzoic acid (44 mg, 0.29 mmol, 0.01 equiv). A condenser and a Dean-Stark apparatus were attached and the mixture was heated at 120° C. for 3 h while removing methanol by the Dean-Stark apparatus (approximately 2 mL). The reaction mixture was removed from the oil bath and stirred at room temperature for 15 min. Methyl tert-butyl ether (100 mL) was added and the mixture was cooled in an ice bath for 45 min. The resulting suspension was filtered, washed with methyl tert-butyl ether, and dried under vacuum for 10 min to afford 7.3 g of 16 (87%) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | Corey Lactone Diol 12. To a suspension of 12 (15 g, 54 mmol, 1 equiv) in methanol (75 mL) was added sodium methoxide (25percent wt in methanol, 1.2 mL, 5.4 mmol, 0.1 equiv). The mixture was stirred at room temperature for 1.5 h and then hydrochloric acid solution (4 M in dioxane, approximately 1 mL) was added until the pH was 3-4. The solution was stirred at room temperature for 10 min and then concentrated to dryness under vacuum on a rotary evaporator. The resulting white solid was suspended in methyl tert/butyl ether (150 mL) and stirred at room temperature for 1 h. The solid was filtered, washed with methyl tert-butyl ether, and dried under vacuum for 10 min to afford 9.1 g of 12 (97percent) as a white solid. | |
95% | With sodium methylate; In methanol; at 20℃; for 2h; | The corrie lactone benzoate (2) (100 g) was suspended in the methanol (500 mL). Next, the sodium methoxide (2 g) was melted in the methanol (10 mL) and it dipped at a temperature of 20 to 25 and the progressing of reaction was observed in the room temperature for 2 hours after doing the mixing with the thin-layer chromatography (hexane : ethyl acetate = 1 : 5). 4M- hydrochloric acid solution (8 mL) diluted in 1,4- dioxane was added and the pH was fitted after the reaction completion with 3 through 4. It was stirred for 10 minutes and the methyl tert-butyl ether (400 mL) was put after doing the concentration and it concentrated after doing suspension. Next, the methyl tert-butyl ether (1000 mL) was put and solid was filtered and it washed in the room temperature for 1 hour after doing the mixing to the methyl tert-butyl ether. Solid vacuum was dried and circle (3) (59 g, 95percent) 2 H were obtained by (3aR,4S,5R,6aS) -5- hydroxy -4 - (hydroxymethyl) *** of the white solid with the cyclopenta [b] furan. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With 1H-imidazole In dichloromethane for 15h; | 1 To a suspension of compound 2 (60.5 g, 0.352 mol) in dichloromethane (5 vol) was added imidazole (28.8 g, 0.422 mol) followed by TIPS-CI (78.2 ml_, 0.37 mol). The suspension was stirred for about 15h. After the consumption of the starting material, the reaction mixture was cooled to 00C, water (2 vol) was added and the pH adjusted to 3-4 using 1 N HCI. The organic layer was separated, washed with water (to pH 5-6), and brine, dried over Na2SO4 and then concentrated to dryness to yield(3a/?,4S,5/:?,6aS)-hexahydro-5-hydroxy-4-(triisopropylsilyloxymethyl)-2H-cyclo penta[b]furan-2-one (3, R8 is TIPS) as a clear oil in quantitative yield. 1H NMR (CDCI3): δ 1.05 (m, 21 H), 1.99 (m, 2H), 2.42-2.55 (m, 3H), 2.65 (m, 1 H), 2.78 (m, 1 H), 3.69 (m, 1 H), 3.79 (m, 1 H), 4.12 (m, 1 H), 4.85 (m, 1 H). |
100% | Stage #1: (3aR,4S,5R,6aS)-5-hydroxy-4-(hydroxymethyl)hexahydro-2H-cyclopenta[b]furan-2-one; triisopropylsilyl chloride With 1H-imidazole In dichloromethane for 15h; Stage #2: With hydrogenchloride In dichloromethane; water at 0℃; | 1 Example 1 :Preparation of APO-II:To a suspension of compound 2[(3af?,4S,5R,6aS)-hexahydro-5-hydroxy-4-(hydroxymethyl)-2H-cyclopenta[0]f uran-2-one] (250g, 1.45 mol) in dichloromethane (5 volumes) was added imidazole (118.6 g, 1.74 mol) followed by triisopropylsilyl chloride (TIPS-CI) (308 mL, 1.60 mol). The suspension was stirred for about 15 hours. After the consumption of the starting material, the reaction mixture was cooled to 0°C, water (2 volumes) was added and the pH adjusted to 3-4 using 1 N hydrochloric acid. The organic layer was separated, washed with water (to pH 5-6) and brine, dried over sodium sulfate and concentrated to dryness to yield compound 3[(3af?,4S,5R,6aS)-hexahydro-5-hydroxy-4-(triisopropylsilyloxymethyl)-2H-cycl openta[6]furan-2-one] as a clear oil in quantitative yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 10 steps 1.1: 1H-imidazole / dichloromethane / 15 h 1.2: 0 °C / pH 3 - 4 2.1: sodium hydride / tetrahydrofuran; mineral oil / 1.5 h / 0 - 20 °C 2.2: 15 h / 0 - 20 °C 3.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 0 °C 4.1: oxalyl dichloride / dichloromethane; dimethyl sulfoxide / 0.75 h / -78 °C 4.2: 0.5 h / -78 °C 5.1: zinc(II) hydroxide / water; tert-butyl methyl ether / 1 h / Inert atmosphere 5.2: 24 h 6.1: diisobutylaluminium hydride / dichloromethane; toluene / -78 °C 6.2: 1 h / 20 °C 7.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 0.83 h / 0 - 20 °C 7.2: 3 h 8.1: Dess-Martin periodane / dichloromethane / 2 h 9.1: hydrogen / palladium 10% on activated carbon / dichloromethane / 15 h / 103.43 Torr 10.1: <i>tert</i>-butylamine / ethyl acetate / 20 °C 10.2: pH 5 | ||
Multi-step reaction with 14 steps 1.1: triethylamine; dmap / dichloromethane / 24 h / 20 °C / Inert atmosphere 1.2: 3 h / 20 °C 2.1: diisobutylaluminium hydride / toluene / 1 h / -75 °C / Inert atmosphere 3.1: lithium hexamethyldisilazane / tetrahydrofuran / 0.5 h / -5 °C / Inert atmosphere 3.2: 2 h / 0 °C / Inert atmosphere 4.1: triethylamine / dichloromethane / 5 h / 20 °C / Inert atmosphere 5.1: palladium 10% on activated carbon; hydrogen / methanol / 8 h / 20 °C / 760.05 Torr 6.1: Dess-Martin periodane / dichloromethane / 0.5 h / 20 °C 7.1: dichloromethane / 6 h / 20 °C 8.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 15 h / 20 °C 9.1: Dess-Martin periodane / dichloromethane / 0.5 h / 20 °C 10.1: lithium hydroxide / tert-butyl methyl ether / 1 h / 20 °C / Inert atmosphere 10.2: 36 h / 45 °C 11.1: palladium 10% on activated carbon / water; ethyl acetate / 2 h / 20 °C 12.1: lithium hydroxide / tetrahydrofuran; water; ethanol / 2 h / 20 °C 13.1: Dess-Martin periodane / dichloromethane / 0.5 h / 20 °C / Inert atmosphere 14.1: phosphoric acid / water; acetonitrile / 2 h / 0 - 5 °C | ||
Multi-step reaction with 10 steps 1.1: dmap; triethylamine / dichloromethane / 14 h / -5 - 25 °C 2.1: pyridinium p-toluenesulfonate / dichloromethane / 3 h / 50 °C 3.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 12 h / 20 °C 4.1: Dess-Martin periodane / dichloromethane / 12 h / 20 °C 5.1: lithium hydroxide monohydrate / tert-butyl methyl ether / 1 h / 20 °C / Inert atmosphere 5.2: 24 h / 45 °C 6.1: diisobutylaluminium hydride / toluene; hexane / 2 h / -78 °C / Inert atmosphere 6.2: 3 h / 20 °C / Inert atmosphere 7.1: lithium hexamethyldisilazane / tetrahydrofuran / 0 °C 7.2: 0.83 h / 20 °C 8.1: palladium 10% on activated carbon; hydrogen / 2 h / 20 °C / 760.05 Torr 9.1: Dess-Martin periodane / dichloromethane / 14 h / 20 °C 10.1: phosphoric acid / acetonitrile; water / 2 h / 0 - 5 °C |
Multi-step reaction with 9 steps 1.1: 1H-imidazole / N,N-dimethyl-formamide; toluene / 6 h / 20 - 40 °C 1.2: 5 h / 130 °C 2.1: diisobutylaluminium hydride / toluene / 2 h / -22 °C / Inert atmosphere 3.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 1 h / Cooling with ice; Inert atmosphere 3.2: 3.17 h / Cooling with ice 4.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 3 h / 45 °C 5.1: hydrogen; sodium hydroxide; 5%-palladium/activated carbon / acetonitrile; water / 18 h / 25 °C 6.1: potassium carbonate / acetone / 4 h / Reflux 7.1: triethylamine; sulfur trioxide pyridine complex / dichloromethane; dimethyl sulfoxide / 2 h / Cooling with ice 8.1: zinc(II) hydroxide / water; tert-butyl methyl ether / 1 h / 25 °C 8.2: 15 h 9.1: hydrogen; 20% palladium hydroxide-activated charcoal / isopropyl alcohol / 3 h / 25 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 9 steps 1.1: dmap; triethylamine / dichloromethane / 4 h / 20 °C / Inert atmosphere 2.1: 1H-imidazole / N,N-dimethyl-formamide / Inert atmosphere 3.1: sulfuric acid / methanol / 4 h / 20 °C / Inert atmosphere 4.1: 1-hydroxy-3H-benz[d][1,2]iodoxole-1,3-dione / dimethyl sulfoxide / 4 h 5.1: triethylamine; lithium chloride / tetrahydrofuran / 1.5 h / -10 °C / Inert atmosphere 5.2: 2.42 h / -10 °C / Inert atmosphere 6.1: (-)-diisopinocamphenylborane chloride / tetrahydrofuran / 2 h / 0 °C / Inert atmosphere 7.1: diisobutylaluminium hydride / toluene; tetrahydrofuran / 3.5 h / -78 °C / Inert atmosphere 7.2: -78 - 20 °C 8.1: tetrabutyl ammonium fluoride / water; tetrahydrofuran / 4 h / 0 °C 9.1: triethylamine; hydrogen / platinum on carbon / methanol / 24.25 h / 20 °C | ||
Multi-step reaction with 9 steps 1.1: 1H-imidazole / N,N-dimethyl-formamide / -15 - 0 °C / Inert atmosphere 2.1: 1H-imidazole / N,N-dimethyl-formamide / 0 - 20 °C / Inert atmosphere 3.1: sulfuric acid / water; methanol / 6 h / 20 °C 4.1: 1-hydroxy-3H-benz[d][1,2]iodoxole-1,3-dione / dimethyl sulfoxide / 4 h 5.1: triethylamine; lithium chloride / tetrahydrofuran / 1.5 h / -10 °C / Inert atmosphere 5.2: 2.42 h / -10 °C / Inert atmosphere 6.1: (-)-diisopinocamphenylborane chloride / tetrahydrofuran / 2 h / 0 °C / Inert atmosphere 7.1: diisobutylaluminium hydride / toluene; tetrahydrofuran / 3.5 h / -78 °C / Inert atmosphere 7.2: -78 - 20 °C 8.1: tetrabutyl ammonium fluoride / water; tetrahydrofuran / 4 h / 0 °C 9.1: triethylamine; hydrogen / platinum on carbon / methanol / 24.25 h / 20 °C | ||
Multi-step reaction with 5 steps 1.1: [bis(acetoxy)iodo]benzene; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical / dichloromethane; N,N-dimethyl acetamide / 6 h / 20 °C 2.1: sodium hydride / tetrahydrofuran / 1 h / 0 °C / Inert atmosphere 2.2: 6 h / 0 - 20 °C / Inert atmosphere 3.1: C20H35B / tetrahydrofuran; hexane / 12 h / -40 °C 4.1: 5%-palladium/activated carbon; hydrogen; sodium hydroxide / ethanol / 5 h / 20 °C / 760.05 Torr 5.1: diisobutylaluminium hydride / dichloromethane / 2 h / -78 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 8 steps 1.1: dmap; triethylamine / dichloromethane / 4 h / 20 °C / Inert atmosphere 2.1: 1H-imidazole / N,N-dimethyl-formamide / Inert atmosphere 3.1: sulfuric acid / methanol / 4 h / 20 °C / Inert atmosphere 4.1: 1-hydroxy-3H-benz[d][1,2]iodoxole-1,3-dione / dimethyl sulfoxide / 4 h 5.1: triethylamine; lithium chloride / tetrahydrofuran / 1.5 h / -10 °C / Inert atmosphere 5.2: 2.42 h / -10 °C / Inert atmosphere 6.1: (-)-diisopinocamphenylborane chloride / tetrahydrofuran / 2 h / 0 °C / Inert atmosphere 7.1: diisobutylaluminium hydride / toluene; tetrahydrofuran / 3.5 h / -78 °C / Inert atmosphere 7.2: -78 - 20 °C 8.1: tetrabutyl ammonium fluoride / water; tetrahydrofuran / 4 h / 0 °C | ||
Multi-step reaction with 8 steps 1.1: 1H-imidazole / N,N-dimethyl-formamide / -15 - 0 °C / Inert atmosphere 2.1: 1H-imidazole / N,N-dimethyl-formamide / 0 - 20 °C / Inert atmosphere 3.1: sulfuric acid / water; methanol / 6 h / 20 °C 4.1: 1-hydroxy-3H-benz[d][1,2]iodoxole-1,3-dione / dimethyl sulfoxide / 4 h 5.1: triethylamine; lithium chloride / tetrahydrofuran / 1.5 h / -10 °C / Inert atmosphere 5.2: 2.42 h / -10 °C / Inert atmosphere 6.1: (-)-diisopinocamphenylborane chloride / tetrahydrofuran / 2 h / 0 °C / Inert atmosphere 7.1: diisobutylaluminium hydride / toluene; tetrahydrofuran / 3.5 h / -78 °C / Inert atmosphere 7.2: -78 - 20 °C 8.1: tetrabutyl ammonium fluoride / water; tetrahydrofuran / 4 h / 0 °C | ||
Multi-step reaction with 4 steps 1.1: [bis(acetoxy)iodo]benzene; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical / dichloromethane; N,N-dimethyl acetamide / 6 h / 20 °C 2.1: sodium hydride / tetrahydrofuran / 1 h / 0 °C / Inert atmosphere 2.2: 6 h / 0 - 20 °C / Inert atmosphere 3.1: C20H35B / tetrahydrofuran; hexane / 12 h / -40 °C 4.1: diisobutylaluminium hydride / dichloromethane / 2 h / -78 °C |
Multi-step reaction with 4 steps 1.1: oxalyl dichloride / dichloromethane; dimethyl sulfoxide / 1.03 h / -78 °C 2.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 0.5 h / 0 °C / Inert atmosphere 2.2: 6 h / 20 °C / Inert atmosphere 3.1: chlorobis(2,6,6-trimethylbicyclo[3.1.1]heptan-3-yl)borane / tetrahydrofuran / 12 h / -40 °C 3.2: 0.5 h / 20 °C 4.1: diisobutylaluminium hydride / dichloromethane / 2 h / -78 °C 4.2: 0.25 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 10 steps 1.1: dmap; triethylamine / dichloromethane / 4 h / 20 °C / Inert atmosphere 2.1: 1H-imidazole / N,N-dimethyl-formamide / Inert atmosphere 3.1: sulfuric acid / methanol / 4 h / 20 °C / Inert atmosphere 4.1: 1-hydroxy-3H-benz[d][1,2]iodoxole-1,3-dione / dimethyl sulfoxide / 4 h 5.1: triethylamine; lithium chloride / tetrahydrofuran / 1.5 h / -10 °C / Inert atmosphere 5.2: 2.42 h / -10 °C / Inert atmosphere 6.1: (-)-diisopinocamphenylborane chloride / tetrahydrofuran / 2 h / 0 °C / Inert atmosphere 7.1: diisobutylaluminium hydride / toluene; tetrahydrofuran / 3.5 h / -78 °C / Inert atmosphere 7.2: -78 - 20 °C 8.1: tetrabutyl ammonium fluoride / water; tetrahydrofuran / 4 h / 0 °C 9.1: triethylamine; hydrogen / platinum on carbon / methanol / 24.25 h / 20 °C 10.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 0.75 h / 0 °C / Inert atmosphere 10.2: -15 - -10 °C / Inert atmosphere | ||
Multi-step reaction with 10 steps 1.1: 1H-imidazole / N,N-dimethyl-formamide / -15 - 0 °C / Inert atmosphere 2.1: 1H-imidazole / N,N-dimethyl-formamide / 0 - 20 °C / Inert atmosphere 3.1: sulfuric acid / water; methanol / 6 h / 20 °C 4.1: 1-hydroxy-3H-benz[d][1,2]iodoxole-1,3-dione / dimethyl sulfoxide / 4 h 5.1: triethylamine; lithium chloride / tetrahydrofuran / 1.5 h / -10 °C / Inert atmosphere 5.2: 2.42 h / -10 °C / Inert atmosphere 6.1: (-)-diisopinocamphenylborane chloride / tetrahydrofuran / 2 h / 0 °C / Inert atmosphere 7.1: diisobutylaluminium hydride / toluene; tetrahydrofuran / 3.5 h / -78 °C / Inert atmosphere 7.2: -78 - 20 °C 8.1: tetrabutyl ammonium fluoride / water; tetrahydrofuran / 4 h / 0 °C 9.1: triethylamine; hydrogen / platinum on carbon / methanol / 24.25 h / 20 °C 10.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 0.75 h / 0 °C / Inert atmosphere 10.2: -15 - -10 °C / Inert atmosphere | ||
Multi-step reaction with 6 steps 1.1: [bis(acetoxy)iodo]benzene; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical / dichloromethane; N,N-dimethyl acetamide / 6 h / 20 °C 2.1: sodium hydride / tetrahydrofuran / 1 h / 0 °C / Inert atmosphere 2.2: 6 h / 0 - 20 °C / Inert atmosphere 3.1: C20H35B / tetrahydrofuran; hexane / 12 h / -40 °C 4.1: 5%-palladium/activated carbon; hydrogen; sodium hydroxide / ethanol / 5 h / 20 °C / 760.05 Torr 5.1: diisobutylaluminium hydride / dichloromethane / 2 h / -78 °C 6.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 0.67 h / 0 °C / Inert atmosphere 6.2: 2 h / 0 - 20 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 11 steps 1.1: dmap; triethylamine / dichloromethane / 4 h / 20 °C / Inert atmosphere 2.1: 1H-imidazole / N,N-dimethyl-formamide / Inert atmosphere 3.1: sulfuric acid / methanol / 4 h / 20 °C / Inert atmosphere 4.1: 1-hydroxy-3H-benz[d][1,2]iodoxole-1,3-dione / dimethyl sulfoxide / 4 h 5.1: triethylamine; lithium chloride / tetrahydrofuran / 1.5 h / -10 °C / Inert atmosphere 5.2: 2.42 h / -10 °C / Inert atmosphere 6.1: (-)-diisopinocamphenylborane chloride / tetrahydrofuran / 2 h / 0 °C / Inert atmosphere 7.1: diisobutylaluminium hydride / toluene; tetrahydrofuran / 3.5 h / -78 °C / Inert atmosphere 7.2: -78 - 20 °C 8.1: tetrabutyl ammonium fluoride / water; tetrahydrofuran / 4 h / 0 °C 9.1: triethylamine; hydrogen / platinum on carbon / methanol / 24.25 h / 20 °C 10.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 0.75 h / 0 °C / Inert atmosphere 10.2: -15 - -10 °C / Inert atmosphere 11.1: caesium carbonate / N,N-dimethyl-formamide / 3 h / 40 °C | ||
Multi-step reaction with 11 steps 1.1: 1H-imidazole / N,N-dimethyl-formamide / -15 - 0 °C / Inert atmosphere 2.1: 1H-imidazole / N,N-dimethyl-formamide / 0 - 20 °C / Inert atmosphere 3.1: sulfuric acid / water; methanol / 6 h / 20 °C 4.1: 1-hydroxy-3H-benz[d][1,2]iodoxole-1,3-dione / dimethyl sulfoxide / 4 h 5.1: triethylamine; lithium chloride / tetrahydrofuran / 1.5 h / -10 °C / Inert atmosphere 5.2: 2.42 h / -10 °C / Inert atmosphere 6.1: (-)-diisopinocamphenylborane chloride / tetrahydrofuran / 2 h / 0 °C / Inert atmosphere 7.1: diisobutylaluminium hydride / toluene; tetrahydrofuran / 3.5 h / -78 °C / Inert atmosphere 7.2: -78 - 20 °C 8.1: tetrabutyl ammonium fluoride / water; tetrahydrofuran / 4 h / 0 °C 9.1: triethylamine; hydrogen / platinum on carbon / methanol / 24.25 h / 20 °C 10.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 0.75 h / 0 °C / Inert atmosphere 10.2: -15 - -10 °C / Inert atmosphere 11.1: caesium carbonate / N,N-dimethyl-formamide / 3 h / 40 °C | ||
Multi-step reaction with 10 steps 1.1: pyridine / 4 h / 65 °C 2.1: oxalyl dichloride; dimethyl sulfoxide; triethylamine / dichloromethane / 4 h / -72 °C 3.1: lithium hydroxide monohydrate / tert-butyl methyl ether / 1 h / 20 °C 3.2: 0.92 h / 5 °C 4.1: nickel(II) chloride hexahydrate; sodium tetrahydroborate / methanol / 3 h / 0 °C 5.1: triethylamine / dichloromethane / 5 h / 5 - 10 °C 6.1: diisobutylaluminium hydride / tetrahydrofuran / 1 h / -70 °C 7.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 6 h / 5 °C 8.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetone / 16 h / 30 °C 9.1: triethylamine / dichloromethane / 6 h / 5 - 10 °C 10.1: acetic acid / water; tetrahydrofuran / 8 h / 30 °C |
Multi-step reaction with 7 steps 1.1: [bis(acetoxy)iodo]benzene; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical / dichloromethane; N,N-dimethyl acetamide / 6 h / 20 °C 2.1: sodium hydride / tetrahydrofuran / 1 h / 0 °C / Inert atmosphere 2.2: 6 h / 0 - 20 °C / Inert atmosphere 3.1: C20H35B / tetrahydrofuran; hexane / 12 h / -40 °C 4.1: 5%-palladium/activated carbon; hydrogen; sodium hydroxide / ethanol / 5 h / 20 °C / 760.05 Torr 5.1: diisobutylaluminium hydride / dichloromethane / 2 h / -78 °C 6.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 0.67 h / 0 °C / Inert atmosphere 6.2: 2 h / 0 - 20 °C / Inert atmosphere 7.1: caesium carbonate / N,N-dimethyl-formamide / 18 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89.4% | With 2,6-dimethylpyridine In dichloromethane at -20 - 20℃; Inert atmosphere; | 1 Example 1Synthetic Route to the Single Isomer of a Compound of Formula (I) Preparation of (2); A 1-L, three-necked, round-bottomed flask equipped with a mechanical stirrer, a dropping funnel, a thermocouple and an argon inlet-outlet adapter connected to a bubbler was charged with Corey lactone (1) (10 g), anhydrous dichloromethane (100 mL), and 2,6-lutidine (27 mL) under argon. A solution of t-butyldimethyl trifluoromethane sulfonate (37.4 mL) in dichloromethane (50 mL) was added to the reaction mixture drop-wise, while keeping the temperature between -10° C. to -20° C. over a period of 20-40 minutes. After complete addition, the reaction mixture was allowed to warm-up to ambient temperature. After 2-4 h, the progress of the reaction was monitored by thin-layer chromatography. After completion of the reaction, the reaction mixture was concentrated in vacuo to obtain a crude product. The crude product was chased with MTBE to remove dichloromethane completely. The crude product was dissolved in MTBE (100-150 mL) and washed with water (1×100 mL), saturated sodium bicarbonate (1×100 mL), brine (1×150 mL), dried over anhydrous sodium sulfate (10 g), and filtered. The filtrate was evaporated in vacuo to a afford crude, viscous liquid (30.4 g). The crude product was purified by column chromatography using 230-400 mesh silica gel. A solvent gradient of ethyl acetate in hexanes (2-12%) was used to elute the product from the column. All fractions containing the desired product were combined and concentrated in vacuo to give pure product (2) as a white solid (20.8 g, 89.4%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: 2,6-dimethylpyridine / dichloromethane / -20 - 20 °C / Inert atmosphere 2.1: diisobutylaluminium hydride / toluene / -70 - -50 °C / Inert atmosphere 2.2: -20 °C 3.1: triethylamine; methanesulfonyl chloride / dmap / dichloromethane / -20 °C / Inert atmosphere; Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: 2,6-dimethylpyridine / dichloromethane / -20 - 20 °C / Inert atmosphere 2.1: diisobutylaluminium hydride / toluene / -70 - -50 °C / Inert atmosphere 2.2: -20 °C 3.1: triethylamine; methanesulfonyl chloride / dmap / dichloromethane / -20 °C / Inert atmosphere; Reflux 4.1: tris{3-(heptafluoropropylhydroxymethylene)-(+)-camphorato}europium(III) / toluene; 1,2-dichloro-ethane / Inert atmosphere; Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1.1: 2,6-dimethylpyridine / dichloromethane / -20 - 20 °C / Inert atmosphere 2.1: diisobutylaluminium hydride / toluene / -70 - -50 °C / Inert atmosphere 2.2: -20 °C 3.1: triethylamine; methanesulfonyl chloride / dmap / dichloromethane / -20 °C / Inert atmosphere; Reflux 4.1: tris{3-(heptafluoropropylhydroxymethylene)-(+)-camphorato}europium(III) / toluene; 1,2-dichloro-ethane / Inert atmosphere; Reflux 5.1: 5% Pd-C / toluene / Inert atmosphere; Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1.1: 2,6-dimethylpyridine / dichloromethane / -20 - 20 °C / Inert atmosphere 2.1: diisobutylaluminium hydride / toluene / -70 - -50 °C / Inert atmosphere 2.2: -20 °C 3.1: triethylamine; methanesulfonyl chloride / dmap / dichloromethane / -20 °C / Inert atmosphere; Reflux 4.1: tris{3-(heptafluoropropylhydroxymethylene)-(+)-camphorato}europium(III) / toluene; 1,2-dichloro-ethane / Inert atmosphere; Reflux 5.1: 5% Pd-C / toluene / Inert atmosphere; Reflux 6.1: diisobutylaluminium hydride / toluene / -50 - -25 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 7 steps 1.1: 2,6-dimethylpyridine / dichloromethane / -20 - 20 °C / Inert atmosphere 2.1: diisobutylaluminium hydride / toluene / -70 - -50 °C / Inert atmosphere 2.2: -20 °C 3.1: triethylamine; methanesulfonyl chloride / dmap / dichloromethane / -20 °C / Inert atmosphere; Reflux 4.1: tris{3-(heptafluoropropylhydroxymethylene)-(+)-camphorato}europium(III) / toluene; 1,2-dichloro-ethane / Inert atmosphere; Reflux 5.1: 5% Pd-C / toluene / Inert atmosphere; Reflux 6.1: diisobutylaluminium hydride / toluene / -50 - -25 °C / Inert atmosphere 7.1: manganese(IV) oxide / dichloromethane / 20 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 8 steps 1.1: 2,6-dimethylpyridine / dichloromethane / -20 - 20 °C / Inert atmosphere 2.1: diisobutylaluminium hydride / toluene / -70 - -50 °C / Inert atmosphere 2.2: -20 °C 3.1: triethylamine; methanesulfonyl chloride / dmap / dichloromethane / -20 °C / Inert atmosphere; Reflux 4.1: tris{3-(heptafluoropropylhydroxymethylene)-(+)-camphorato}europium(III) / toluene; 1,2-dichloro-ethane / Inert atmosphere; Reflux 5.1: 5% Pd-C / toluene / Inert atmosphere; Reflux 6.1: diisobutylaluminium hydride / toluene / -50 - -25 °C / Inert atmosphere 7.1: manganese(IV) oxide / dichloromethane / 20 °C / Inert atmosphere 8.1: potassium carbonate / methanol / 16 h / 20 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With copper(ll) sulfate pentahydrate In methanol at 100℃; for 0.25h; Microwave irradiation; | Microwave irradiation procedure General procedure: A 10 mL reaction vessel was charged with amagnetic stir bar, 0.4 mmol of TBDMS ether, and 20 mol % CuSO45H2O in 2mLof MeOH. A septum cap was affixed; the vessel was placed in the microwavecavity of an Anton-Paar microwave equipment. The stirring reaction mixturewas irradiated at 100 C for 15 min. After cooling to room temperature, TLCindicated the disappearance of starting material. The solid cupric sulfate wasfiltered off and the solvent was removed under reduced pressure. Columnchromatography afforded the pure alcohol. All products were spectrallyidentical with authentic alcohols. |
96% | With cerium (IV) sulfate tetrahydrate In methanol at 60℃; for 12h; | |
95% | With aluminium(III) chloride hexahydrate In methanol at 100℃; for 0.25h; Microwave irradiation; Sealed tube; chemoselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; triethylamine In tetrahydrofuran at 35 - 65℃; Inert atmosphere; Molecular sieve; | 19 Example 19 Preparation of (3aR,5R,6aS)-hexahydro-5-hydroxy-4-[(triphenylmethoxy)methyl]-2H-cyclopenta[b]furan-2-one. Example 19 Preparation of (3aR,5R,6aS)-hexahydro-5-hydroxy-4-[(triphenylmethoxy)methyl]-2H-cyclopenta[b]furan-2-one. A solution of (3aR,4S,5R,6aS)-hexahydro-5-hydroxy-4-(hydroxymethyl)-2H-cyclopenta[b]furan-2-one (27 g) solution in tetrahydrofuran (418.5 mL) is charged in to a round bottom flask under nitrogen atmosphere at 27° C. The reaction mixture is heated to 60-65° C. The reaction mixture is cooled to 35-40° C., molecular sieves (13.5 g) is charged to the reaction mixture and stirred for 15-30 minutes. Dimethyl amino pyridine (3.82 g) and triethyl amine (130 mL) are charged to the reaction mixture at 35-40° C. under nitrogen atmosphere. A solution of triphenyl methyl chloride (48 g) in tetrahydrofuran (81 mL) is added to the reaction mixture at 35-40° C. under nitrogen atmosphere. The reaction mixture is heated to 60-65° C. and maintained for 20-24 hours. The reaction mixture is cooled to 25-35° C., filtered through the hyflow bed and washed with ethyl acetate (81 mL). The resultant filtrate is washed with water (270 mL). The aqueous layer is extracted with ethyl acetate (2*135 mL). The combined organic layer is washed with water (135 mL). The solvent from the organic layer is evaporated completely under reduced pressure at below 55° C. to afford 61.5 g of the title compound. Purity by HPLC: 68%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: methyl (5-chloro-3-hydroxy-2-hydroxymethyl-cyclopentyl)-acetate With water; sodium hydroxide In methanol for 3h; Stage #2: With hydrogenchloride In methanol; water for 2h; | 5-hydroxy-4-hydroxymethyl-hexahydro-cyclopenta[b]furan-2-one, (21). 50 mmoles enantiomer Chloroester 20 dissolved in1 35 mL methanol were treated with a solution of 2.5 equivalents (5.0 g, 125 mmoles) NaOH in 32 mL water, monitoring the reaction by TLC (ethyl acetate-hexane-aceticacid, 5:4:0.1; Rf in = 0.62, Rf fin = 0.00). After all starting compound 20 reacted, methanol was removed at reduced pressure, the aqueous solution was acidulated with conc. HCl to pH ~4, stirred for 2 hours, concentrated to remove water, co-evaporated with ethanol and the product was extracted with hot ethanol. Crude product (9.2 g) was crystallized from ethanol and had physical characteristics identical with those published |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine In dichloromethane at -78 - 20℃; for 2.5h; Inert atmosphere; | 1.1 Under the nitrogen atmosphere, in dichloromethane (50mL) solution the triethylamine (2. 5mL) was added to compound IV(1. 0g,purchased from Shanghai Dragon Drug Research and Development Co., Ltd.). thereaction system was cooled down to -78 ° C, in dichloromethane (10 mL)solution triisopropylsilyl trifluoromethanesulfonate(2. 9g) was added. After twohours , the cooling bathwas removed and the reaction was stirred for 30 minutes at 20 ° C . under reduced pressure the reaction system was concentrated and to givecompound Vaa the residue was purified by column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With 1H-imidazole In N,N-dimethyl-formamide for 3h; Inert atmosphere; | |
95% | With 1H-imidazole In dichloromethane at 0 - 40℃; for 24h; Inert atmosphere; | 2.1 (3aR,4S,5R,6aS)-5-((tert-butyldimethylsilyl)oxy)-4-(((tert-butyldimethylsilyl)oxy)methyl)hexahydro-2H-cyclopenta[b]furan-2-one (11) To a solution of (-)-Corey lactone diol (6) (31.0 g, 0.18 mol) in DCM (0.25 L) was added Imidazole (49.0 g, 0.72 mol) and a solution of TBSCl (108.5 g, 0.72 mol) in DCM (0.3 L) at 0 °C under N2 atmosphere. After being stirred at 0 °C for 20 mins, the reaction temperature was raised to 40 °C and then the reaction mixture was stirred at 40 °C for 24 hours. The reaction mixture was added H2O (0.3 L) and the aqueous and organic layers were separated. The aqueous layer was further extracted with DCM (0.3 L) and the combined organic extracts were dried over Na2SO4, filtrated and concentrated in vacue to give the crude. The crude was purified by silical gel chromatography (Hexane/EA=6/1) to afford intermediate (11) (68.5 g). Yield: 95%. White solid. [α]25 589: -31.3° (C=1 in CHCl3). MS (ES+): 401.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 4.91 (t, J = 6.8 Hz, 1H), 4.11 (q, J = 4.8 Hz, 1H), 3.54 (dd, J = 10.4, 5.6 Hz, 1H), 3.47 (dd, J = 10.4, 5.6 Hz, 1H), 2.78 (dd, J = 17.6, 10.4 Hz, 1H), 2.66-2.62 (m, 1H), 2.53 (d, J = 17.6 Hz, 1H), 2.25-2.18 (m, 1H), 1.98-1.94 (m, 2H), 0.87 (s, 9H), 0.85 (s, 9H), 0.03 (s, 12H) ppm. 13C NMR (100 MHz, CDCl3) δ 176.8, 83.7, 74.1, 62.1, 56.4, 40.6, 38.7, 35.1, 25.4, 25.2, 17.7, 17.4, -5.1, -5.5, -5.9, -6.0 ppm. |
340 g | With 1H-imidazole; dmap In dichloromethane at 0 - 30℃; for 16h; | 2 150 g of (3aR, 4S, 5R, 6aS) -5-hydroxy-4-hydroxymethylhexahydro-2H-cyclopenta [b] furan-2-one was suspended in 2 liters of dichloromethane,Adding 237 g of imidazole,3 g of DMAP (4-dimethylaminopyridine),A solution of 390 g of TBSCl (tert-butyldimethylchlorosilane) and 600 ml of methylene chloride was added dropwise at 0 ° C,Add 25-30 degrees after mixing 16 hours,Washed with 2 L X2 saturated brine,Dried over anhydrous sodium sulfate,Concentrated to get(3aR, 4S, 5R, 6aS) -5- tert-butyldimethylsilyloxy-4-tert-butyldimethylsilyloxy -2H- hexahydro-cyclopenta [b] furan-2-one |
23 g | With 1H-imidazole In dichloromethane at 40℃; Inert atmosphere; | 1 Example 1 Synthesis of compound of formula IV-1 Under the protection of nitrogen, add colinolide diol (III) (10.0g, 58.1mmol) and imidazole (15.8g, 0.23mol) into dichloromethane (DCM) (150ml), and dissolve in 70ml dichloromethane dropwise (DCM) tert-butyldimethylchlorosilane (TBSCl) (35g, 0.23mol), heated to 40°C and reacted overnight. Add 100ml of water to quench, separate the layers, extract the aqueous phase with dichloromethane (DCM) (100ml), combine the organic phases, wash with water (100ml) and saturated brine (100ml) successively, dry with anhydrous Na2SO4, filter, and reduce the filtrate Press and concentrate to obtain a white flocculent solid (23.0 g), which was directly used in the next step without purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3.52 g | Stage #1: (3aR,4S,5R,6aS)-5-hydroxy-4-(hydroxymethyl)hexahydro-2H-cyclopenta[b]furan-2-one; tert-butyldimethylsilyl chloride With dmap; triethylamine In dichloromethane at -20 - 20℃; for 24h; Inert atmosphere; Stage #2: 3,4-dihydro-2<i>H</i>-pyran With pyridinium p-toluenesulfonate In dichloromethane at 20℃; for 3h; Inert atmosphere; | 1.1 Under the protection of N2, Corey lactone XVII (1.72 g, purchased from Taizhou Aoxiang Pharmaceutical Technology Co., Ltd.) was suspended in dichloromethane (60 mL), 4 dimethylaminopyridine (122 mg), tris (13.4 mL), cooled to -20 ° C and slowly dropwise a solution of tert-butyldimethylchlorosilane embankment (1.48 g) in dichloromethane (20 mL) and then raised to 20 ° C for 24 hours TheAfter completion of the reaction, methyl t-butyl ether (50 mL) and saturated ammonium chloride (50 mL), separated, the organic phase was washed with saturated brine, dried over anhydrous of Na2the S04dried, filtered, and concentrated to give a white solid.The white solid (2.86 g) was dissolved in dichloromethane (30 mL), PPTS (500 mg), DHP (4.6 mL) was added and reacted at 20 ° C for 3 hours.After completion of the reaction, methyl t-butyl ether and saturated NaHC03solution, separated, the organic phase was washed with saturated brine, dried over anhydrous of Na2the S04dried, filtered and concentrated to give the product isolated XVIa 3.52 g. |
3.52 g | Stage #1: (3aR,4S,5R,6aS)-5-hydroxy-4-(hydroxymethyl)hexahydro-2H-cyclopenta[b]furan-2-one; tert-butyldimethylsilyl chloride With dmap; triethylamine In dichloromethane at 20℃; for 24h; Inert atmosphere; Stage #2: 3,4-dihydro-2<i>H</i>-pyran With pyridinium p-toluenesulfonate In dichloromethane at 20℃; for 3h; | 1.1 N2 protection,Corey lactone XVII (1.72 g, purchased from Taizhou Aoxiang Pharmaceutical Technology Co., Ltd.) was suspended in dichloromethane (60 mL)A solution of t-butyldimethylchlorosilane (1.48 g) in dichloromethane (20 mL) was slowly added dropwise to a solution of 4-dimethylaminopyridine (122 mg) and triethylamine (13.4 mL) And the reaction was carried out at 20 ° C for 24 hours.After completion of the reaction, methyl tert-butyl ether (50 mL) and saturated ammonium chloride (50 mL) were added. The organic phase was washed with saturated brine, dried over anhydrous Na2SO4 and concentrated by filtration to give a white solid.The white solid (2.86 g) was dissolved in dichloromethane (30 mL), PPTS (500 mg), DHP (4.6 mL) was added and reacted at 20 ° C for 3 hours.After completion of the reaction, methyl tert-butyl ether and saturated NaHCO3 solution were added and the phases were separated. The organic phase was washed with saturated brine, dried over anhydrous Na2SO4 and concentrated by filtration to give 3.52 g of product XVIa. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With ALPS at 40℃; for 24h; | 2 (3aR,4S,5R,6aS) The tetrahydrofuran (1719 mL) was put into the circle (3) (59 g) in -5- hydroxy -4 - (hydroxymethyl) *** with 2 H and it suspended. After the vinyl acetate (31.7 mL) was added and the ALPS (34.4 g) was put the progressing of reaction was observed with the thin-layer chromatography (hexane : ethyl acetate = 1 : 5) while it was stirred in 40 for 24 hours. It filtered through the Celite pad and it concentrated after the reaction completion among the vacuum. The mixture was refined through the column chromatography (hexane : ethyl acetate = 1 : 5) and 4 -yl methyl acetate (4)) (66.3 g, 90%) 2 H were obtained by the pure product ((3aR, 4S, 5R, 6aS) -5-hydroxy-2-oxohexa-2-yl-cyclopenta [b] furan-4-yl) methyl acetate with the cyclopenta [b] furan. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93.45% | Into a reaction vessel with a filter element at the bottom, 40 L of pyridine was added, and (-) Cretocene diol 4 kg (1 eq) was added under stirring, and 6.48 kg (1 eq) of triphenylchloromethane was added.The temperature was controlled at 20 C for 12h to complete the reaction. 5.54kg (1.1eq) of biphenyl-4-formyl chloride was added. The temperature was controlled at 30 C for 4.5h to complete the reaction.40L of pure water was added to the reaction vessel and stirred for 2 hours to obtain a suspension. Nitrogen gas was introduced into the reaction vessel, and the suspension was filtered through a filter element.Ethanol 40L was added to the reaction vessel, and the mixture was heated to reflux for 1 hour. The liquid was pressure filtered to obtain a solid powder.60L of tetrahydrofuran was added to the reaction vessel, 30L (4mol/L) hydrochloric acid aqueous solution was added dropwise, and the reaction was completed at a temperature of 45 C. for 3.5 h to complete reaction. The reaction system was cooled to 10 C., and saturated aqueous sodium carbonate was added to neutralize the reaction to PH=7.;The solvent in the reactor was evaporated under reduced pressure and the crude product was obtained by pressure filtration.50L of n-propyl ether was added to the reaction vessel, and the mixture was heated to reflux for 3 hours, and then dried by pressure filtration to give the product (-)biphenyl-4-formyl-colyactone 7.66 kg. The yield was 93.45%, and the purity was 99.41%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With N-ethyl-N,N-diisopropylamine In dichloromethane at 20 - 30℃; for 2h; | 1-9 Example 9: Preparation and structural confirmation of (-)-Corey Lactone primary alcohol triethylsilane Into a 50ml three-necked flask, put 1.72g (1eq) (-)-Corey Lactone,Add 20 ml of dichloromethane, stir and mix.Add 3.4 ml of diisopropylethylamine (2.5 eq, stirring, at room temperatureThe temperature was lowered to 20 ° C, and 1.66 g (1.1 eq) of triethylchlorosilane was slowly added dropwise.The reaction mixture was kept at 20-30 ° C for 2 hours, and the reaction liquid was poured into 20 ml of ice water, the aqueous layer was separated, dried over anhydrous sodium sulfate, filtered, evaporated, evaporated,(-)-Corey Lactone primary alcohol triethylsilane (2.63 g, yield: 92%, GC: 98.7%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: (S)-6,6'-bis(2,4,6-triisopropylphenyl)-1,1'-spirobiindane-7,7'-diyl hydrogenphosphate; dihydrogen peroxide / chloroform; water / -15 °C / Schlenk technique 2.1: ammonium chloride; zinc / methanol / 3 h / 70 °C 3.1: formic acid; sulfuric acid / 24 h / 80 °C 3.2: 2 h / 0 - 20 °C | ||
Multi-step reaction with 3 steps 1.1: (S)-6,6'-bis(2,4,6-triisopropylphenyl)-1,1'-spirobiindane-7,7'-diyl hydrogenphosphate; dihydrogen peroxide / chloroform; water / 48 h / 0 °C / Schlenk technique 2.1: ammonium chloride; zinc / methanol / 3 h / 70 °C 3.1: formic acid; sulfuric acid / 24 h / 80 °C 3.2: 2 h / 0 - 20 °C | ||
Multi-step reaction with 5 steps 1.1: dihydrogen peroxide; sodium hydroxide / methanol; water / -5 - 30 °C 2.1: zinc; ammonium chloride / methanol / Cooling; Reflux 3.1: sodium hydroxide / water / 2 h / 30 °C 3.2: 1 h / Acidic conditions 4.1: sulfuric acid / 24 h / Reflux 4.2: 5 h / Reflux 5.1: hydrogenchloride / methanol; water / 4 h / Reflux |
Multi-step reaction with 4 steps 1.1: D-Glucose; nicotinamide adenine dinucleotide phosphate; oxygen / aq. phosphate buffer; tert-butyl methyl ether / 760.05 Torr / pH 7.5 / Enzymatic reaction 2.1: acetic acid; zinc / tetrahydrofuran / 70 °C / 5250.53 Torr 3.1: sulfuric acid / 70 °C / 12751.3 Torr 4.1: sodium methylate / methanol / 25 °C 4.2: 25 °C | ||
Multi-step reaction with 4 steps 1.1: D-Glucose; nicotinamide adenine dinucleotide phosphate; oxygen / aq. phosphate buffer; 2-methoxy-ethanol / 760.05 Torr / pH 7.5 / Enzymatic reaction 2.1: acetic acid; zinc / tetrahydrofuran / 70 °C / 5250.53 Torr 3.1: sulfuric acid / 70 °C / 12751.3 Torr 4.1: sodium methylate / methanol / 25 °C 4.2: 25 °C | ||
Multi-step reaction with 4 steps 1.1: dihydrogen peroxide / 2,2,2-trifluoroethanol / -5 - 5 °C 2.1: ammonium chloride; zinc / methanol / 3 h / 70 °C / Inert atmosphere 3.1: sodium hydroxide / tetrahydrofuran; water / 2 h / 0 - 20 °C 3.2: 12 h / 4 °C 4.1: formic acid; sulfuric acid / 80 °C / Cooling with ice |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With formic acid; sulfuric acid at 80℃; Cooling with ice; | 5 Example 5 Preparation of corey lactone diol (I) Under ice bath, disperse compound (VII) (0.5g, 4.0mmol) and paraformaldehyde (0.4g, 13.3mmol) (analytical purity, content >95%, Shanghai Zhanyun Chemical Co., Ltd.) with 4mL anhydrous formic acid evenly , And then slowly add concentrated sulfuric acid (125μL, 2.3mmol) to it, then place it in a pressurized reaction flask, slowly raise the temperature to 80°C, and stir for 20-24h.Adjust the pH to 8-9 with saturated sodium bicarbonate. At this time, EtOAc extracts the reaction solution (30mL×3) and combines the organic phases, dried over anhydrous sodium sulfate and spin-dried, and then disperse the resulting yellow oil in hydrochloric acid with a mass concentration of 6%. In the methanol solution (6mL), the temperature was slowly raised to 65°C and stirred for 3 to 4 hours.After the solvent was spin-dried, the white solid Corey lactone diol (I) was obtained by recrystallization from chloroform, 0.53 g, with a yield of 85% and an optical purity of 99%ee.Corey lactone diol (I): |
79% | Stage #1: formaldehyd; (-)-(1S,5R)-2-oxabicyclo[3.3.0]oct-6-en-3-one With formic acid; sulfuric acid at 80℃; for 24h; Stage #2: With potassium carbonate In methanol at 0 - 20℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: ammonium chloride; zinc / methanol / 3 h / 70 °C 2.1: formic acid; sulfuric acid / 24 h / 80 °C 2.2: 2 h / 0 - 20 °C | ||
Multi-step reaction with 3 steps 1.1: acetic acid; zinc / tetrahydrofuran / 70 °C / 5250.53 Torr 2.1: sulfuric acid / 70 °C / 12751.3 Torr 3.1: sodium methylate / methanol / 25 °C 3.2: 25 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | Stage #1: (3aR,4S,5R,6aS)-5-hydroxy-4-(hydroxymethyl)hexahydro-2H-cyclopenta[b]furan-2-one; triisopropylsilyl chloride With 1H-imidazole In N,N-dimethyl-formamide; toluene at 20 - 40℃; for 6h; Stage #2: benzyl bromide With N-ethyl-N,N-diisopropylamine; potassium iodide at 130℃; for 5h; | 1 Production Example 1:(3aR, 4S, 5R, 6aS) -5- (benzyloxy) -4-(((triisopropylsilyl) oxy) methyl) hexahydro-2H-cyclopenta [b] furan-2-oneSynthesis of To a 1000 mL four-necked flask equipped with a thermometer(3aR, 4S, 5R, 6aS) -hexahydro-5-hydroxy-4- (hydroxymethyl) -2H-cyclopenta [b] furan-2-one 50.0 g (290 mmol),35.6 g of imidazole(523 mmol), N, N-dimethylformamide 200 mL, and toluene 300 mL were added and stirred.61.6 g (1.1 eq., 319 mmol) of chlorotriisopropylsilane was added so that the internal temperature was 20 ° C.After stirring at an internal temperature of 20 to 40 ° C. for 6 hours, the reaction solution was ice-cooled,400 mL of water 39.5 g of potassium dihydrogen phosphateWhat was dissolved in was added. After adding 50 mL of toluene, liquid separation was performed,Extract the aqueous layer again with 200 mL of toluene,The organic layers were combined and washed with 50 mL of water.After drying the organic layer with magnesium sulfate,Concentration under reduced pressure with an evaporator gave 102.4 g of the concentrate. 1000mL with a thermometer installed as it isIn addition to a four-necked flask, ethyl diisopropylamine150.1 g (1161 mmol), potassium iodide19.3 g (116 mmol), 149 g of benzyl bromide(871 mmol) was added,After stirring for 5 hours at an internal temperature of 130 ° C.,Cool the reaction to 17 ° C.After adding 250 mL of water and 150 mL of toluene for liquid separation,The aqueous layer was further extracted twice with 100 mL of toluene.The organic layers were combined, washed once with 100 mL of saturated aqueous ammonium chloride solution, once with 100 mL of 1M hydrochloric acid, and 100 mL of water,The organic layer was dried over magnesium sulfate and concentrated under reduced pressure using an evaporator. By recrystallizing the concentrated residue with hexane,(3aR, 4S, 5R, 6aS) -5- (benzyloxy) -4-(((triisopropylsilyl) oxy) methyl) hexahydro-2H-cyclopenta [b] furan-2-one69.3g(Yield 57%, (-)-corey lactone basis) was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With 1H-imidazole In dichloromethane at 20℃; for 8h; | 1.1; 2.1 (1) Synthesis of compound 2a Corinolone(20g, 116.2mmol) in dichloromethane (200ml) was added TBSCl (52.6g, 350mmol, 3.0eq), and imidazole (25.0g, 360mmol, 3.0eq), reacted at room temperature for 8h, suction filtered, added to the organic phase 10% hydrochloric acid solution (80mL), then react at room temperature for 5h, quench the reaction with saturated ammonium chloride solution (150ml), concentrate, add dichloromethane (200ml) and water (200ml), let stand for layer separation, the aqueous phase uses two Chloromethane (150ml*3) was extracted, washed with saturated brine (100ml), dried over anhydrous sodium sulfate, filtered, concentrated, and recrystallized from ethyl acetate (180ml) to obtain white solid compound 2 (27.4g, 83%). |
82% | With 1H-imidazole In dichloromethane at 20℃; for 8h; | 1 To a solution of Coryrolactone (10 g, 58.1 mmol) in dichloromethane (100 mL) was added TBSCI (26.3 g, 175 mmol, 3.0 eq)And imidazole (12.5 g, 180 mmol, 3.0 eq),After reacting for 8 h at room temperature, suction-filtering, 10% hydrochloric acid solution (50 mL, 2.8 eq) was added to the organic phase, then reacted at room temperature for 5 h, quenched with saturated ammonium chloride solution (100 mL), concentrated, and then added dichloromethane (100 mL) Water (100mL), standing layered,The aqueous phase was extracted with dichloromethane (100 mL*3).Wash with saturated brine (100 mL) and dry over anhydrous sodium sulfate.Filtered, concentrated,Ethyl acetate (100ml)Recrystallization gave Compound 2a (13.6 g, 82%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With thionyl chloride at 0 - 20℃; for 7h; | Methyl (1R,2R,3R,5R)-(5-chloro-2-chloromethyl-3-hydroxycyclopentyl)acetate (5). A solution of (-)-Corey lactone diol 4 (1.6 g) in methanol (5 mL) was added dropwise to a solution of thionyl chloride (10 mL) in methanol (15 mL) at 0 °C. The reaction mixture was stirred at room temperature for 7 h, neutralized with saturated aqueous NaHCO3 to p 6.5-7, and concentratedin vacuo. The residue was extracted with EtOAc, the extract was dried with Na2SO4, concentrated in vacuo, and purified by column chromatography (EtOAc-petroleum ether, 3 : 7) to obtain methyl ester 5 (2.1 g, 92%) as a colorless liquid, Rf = 0.4 (EtOAc-petroleum ether, 1 : 1), [α]D20 -186.0 ( 1.0,MeOH). 1H NMR (CDCl3), δ: 2.05 (m, 1 H, H(1)); 2.15(m, 1 H, H(2)); 2.25 (m, 2 H, CH2CO2); 2.45 (br.s, H); 2.58(dd, 1 H, (4), J = 6.9 Hz, J = 16.1 Hz); 2.68 (dd, 1 H, H(4),J = 5.4 Hz, J = 16.1 Hz); 3.57 (dd, 1 H, CH2Cl, J = 7.0 Hz,J = 11.1 Hz); 3.69 (s, 3 H, Me); 3.75 (dd, 1 H, CH2Cl,J = 5.0 Hz, J = 11.1 Hz); 4.20 (dt, 1 H, H(3), J = 8.0 Hz,J = 7.6 Hz); 4.29 (m, 1 H, H(5)). 13C NMR (CDCl3), δ: 35.82(CH22), 44.00 (C(4)), 45.98 (2Cl), 48.03 (C(1)), 51.93(), 54.21 (C(2)), 60.31 (C(5)), 73.76 (C(3)), 172.47 (CO2).IR, /cm-1: 3437, 2954, 1734, 1718, 1437, 1297, 1199, 1080,728. MS, m/z: 239 [M - H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20% | Stage #1: (3aR,4S,5R,6aS)-5-hydroxy-4-(hydroxymethyl)hexahydro-2H-cyclopenta[b]furan-2-one With sodium hydride In N,N-dimethyl-formamide at 0℃; for 1h; Stage #2: p-methoxybenzyl chloride In N,N-dimethyl-formamide at 0℃; for 12h; | Synthesis of hydroxy-lactone 14 3.16 g (1.3 equiv., 79.1 mmol) of sodium hydride and 60 mL ofDMF were introduced in a flame dried 500 mL flask. A solution of compound 11 in 20 mL of DMF was added dropwise to the mixture at 0 °C (ice-bath). After 1 h, p-methoxybenzyl chloride (24.7 mL, 3 equiv., 237.4 mmol) was added to the reaction mixture and the allowed to run for 12 h at the same temperature. The reaction was quenched by slow addition of water and the resulting mixture was extracted with ethyl acetate (3x). The organic phase was washed with brine and dried over MgSO4. After evaporation of the volatile material, the crude residue was purified by chromatography over silica gel (petroleum ether: ethyl acetate 95:5 to 80:20) to yield 20% of pure compound 14 as yellow oil; TLC (petroleum ether: ethylacetate, 4:1) Rf 0.4; 1H NMR (300 MHz, CDCl3): d 2.08-2.17 (m, 1H), 2.40 (d, J 15.3 Hz, 1H), 2.58 (dd, J 18.4, 3.3 Hz, 1H), 2.90 (dd,J 18.4, 11.0 Hz, 1H), 3.05-3.06 (m, 1H), 3.27-3.36 (m, 1H), 3.83 (s,3H), 4.31-4.33 (m, 1H), 4.31 (d, J 11.4 Hz, 1H), 4.54 (d, J 11.4 Hz,1H), 5.11 (t, J 6.6 Hz, 1H), 6.9 (d, J 8.7 Hz, 2H), 7.25 (d, J 8.6 Hz,2H) ppm.; 13C NMR (75 MHz, CDCl3): d 35.5, 37.3, 40.3, 55.3, 56.9, 70.9, 82.1, 84.3, 113.9, 129.3, 129.5, 159.4, 176.5, 177.4 ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With triethylamine In N,N-dimethyl-formamide at 0 - 20℃; Inert atmosphere; | Synthesis of hydroxy-lactone 12 Method b. A solution of TIPSOTf was prepared by dropwise addition of TIPSH (1.15 equiv, 333.9 mmol, 68.4 mL) to a solution of TfOH (28.3 mL, 1.1 equiv, 319.4 mmol) in 100 mL of dry DCM at 0 °C under argon atmosphere. The ice bath was maintained until complete formation of H2 gas. The reaction mixture was stirred for an additional hour at room temperature. Then it was cannulated at 0 °C under inert atmosphere into a flask containing 50 g of diol 11 (290.4 mmol), 60.8 mL of Et3N (1.5 equiv, 435.6 mmol) and 300 mLof anhydrous DMF. The reaction mixture was stirred overnight at room temperature. After addition of water (7-10 vol), the crude mixture was extracted with ethyl acetate. The extract was washed with brine and dried over MgSO4. Evaporation of the solvent quantitatively yielded 12 as an oil which was more than did not need further purification (purity > 95%). It was directly used in the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With triethylamine In dichloromethane at 20℃; for 0.5h; Inert atmosphere; enantioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
14.8 mg | With potassium fluoride; dihydrogen peroxide In water; N,N-dimethyl-formamide at 40℃; for 1h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: C21H21NOSi; copper dichloride; N-ethyl-N,N-diisopropylamine / acetonitrile; dichloromethane / 14 h / -20 °C 2: 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; carbonic acid dimethyl ester; trichloroisocyanuric acid / ethyl acetate |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: C21H21NOSi; copper dichloride; N-ethyl-N,N-diisopropylamine / acetonitrile; dichloromethane / 14 h / -20 °C 2: 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; carbonic acid dimethyl ester; trichloroisocyanuric acid / ethyl acetate 3: sodium hydroxide / dichloromethane; water |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: C21H21NOSi; copper dichloride; N-ethyl-N,N-diisopropylamine / acetonitrile; dichloromethane / 14 h / -20 °C 2: 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; carbonic acid dimethyl ester; trichloroisocyanuric acid / ethyl acetate 3: sodium hydroxide / dichloromethane; water |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: C21H21NOSi; copper dichloride; N-ethyl-N,N-diisopropylamine / acetonitrile; dichloromethane / 14 h / -20 °C 2: 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; carbonic acid dimethyl ester; trichloroisocyanuric acid / ethyl acetate 3: sodium hydroxide / dichloromethane; water |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: C21H21NOSi; copper dichloride; N-ethyl-N,N-diisopropylamine / acetonitrile; dichloromethane / 14 h / -20 °C 2: 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; carbonic acid dimethyl ester; trichloroisocyanuric acid / ethyl acetate 3: sodium hydroxide / dichloromethane; water |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: C21H21NOSi; copper dichloride; N-ethyl-N,N-diisopropylamine / acetonitrile; dichloromethane / 14 h / -20 °C 2: 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; carbonic acid dimethyl ester; trichloroisocyanuric acid / ethyl acetate 3: sodium hydroxide / dichloromethane; water 4: D-Glucose; nicotinamide adenine dinucleotide phosphate / aq. phosphate buffer / pH 7 / Enzymatic reaction |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: C21H21NOSi; copper dichloride; N-ethyl-N,N-diisopropylamine / acetonitrile; dichloromethane / 14 h / -20 °C 2: 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; carbonic acid dimethyl ester; trichloroisocyanuric acid / ethyl acetate 3: sodium hydroxide / dichloromethane; water 4: D-Glucose; nicotinamide adenine dinucleotide phosphate / aq. phosphate buffer; dimethyl sulfoxide / pH 7 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: C21H21NOSi; copper dichloride; N-ethyl-N,N-diisopropylamine / acetonitrile; dichloromethane / 14 h / -20 °C 2: 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; carbonic acid dimethyl ester; trichloroisocyanuric acid / ethyl acetate 3: sodium hydroxide / dichloromethane; water 4: D-Glucose; nicotinamide adenine dinucleotide phosphate / aq. phosphate buffer / pH 7 / Enzymatic reaction |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: C21H21NOSi; copper dichloride; N-ethyl-N,N-diisopropylamine / acetonitrile; dichloromethane / 14 h / -20 °C 2: 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; carbonic acid dimethyl ester; trichloroisocyanuric acid / ethyl acetate 3: sodium hydroxide / dichloromethane; water 4: D-Glucose; nicotinamide adenine dinucleotide phosphate / aq. phosphate buffer / pH 7 / Enzymatic reaction |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: C21H21NOSi; copper dichloride; N-ethyl-N,N-diisopropylamine / acetonitrile; dichloromethane / 14 h / -20 °C 2: 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; carbonic acid dimethyl ester; trichloroisocyanuric acid / ethyl acetate 3: sodium hydroxide / dichloromethane; water 4: D-Glucose; nicotinamide adenine dinucleotide phosphate / aq. phosphate buffer / pH 7 / Enzymatic reaction |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: C21H21NOSi; copper dichloride; N-ethyl-N,N-diisopropylamine / acetonitrile; dichloromethane / 14 h / -20 °C 2: 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; carbonic acid dimethyl ester; trichloroisocyanuric acid / ethyl acetate 3: sodium hydroxide / dichloromethane; water 4: D-Glucose; nicotinamide adenine dinucleotide phosphate / aq. phosphate buffer / pH 7 / Enzymatic reaction 5: potassium carbonate / methanol; dichloromethane |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1: C21H21NOSi; copper dichloride; N-ethyl-N,N-diisopropylamine / acetonitrile; dichloromethane / 14 h / -20 °C 2: 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; carbonic acid dimethyl ester; trichloroisocyanuric acid / ethyl acetate 3: sodium hydroxide / dichloromethane; water 4: D-Glucose; nicotinamide adenine dinucleotide phosphate / aq. phosphate buffer / pH 7 / Enzymatic reaction 5: potassium carbonate / methanol; dichloromethane 6: caesium carbonate / dichloromethane; N,N-dimethyl-formamide |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 73% 2: 9 %Spectr. | With C21H21NOSi; N-ethyl-N,N-diisopropylamine; copper dichloride In dichloromethane; acetonitrile at -20℃; for 14h; stereoselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28.4 g | In dichloromethane at 20℃; for 1h; | 3.1; 4.1 1) Primary alcohol protection reaction of Corylactone: Add 100 mL of dichloromethane to a four-necked flask at room temperature,Add 17.2 g of Coryllactone and 17.2 g of triethylamine as shown in formula IV,Stir well, then add 15.7g of N-(2-chloroethyl)-morpholine,Stir and mix, react at room temperature for 1 hour,The obtained reaction solution was poured into 40 ml of ice water, and the water layer was separated. The organic phase was added with Na SO After drying, the solution was filtered, desolvated under reduced pressure, and concentrated to obtain 28.4 g of the compound of formula III in an amorphous state, which was detected by high performance liquid chromatography (HPLC). Purity 98.9%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
29.9 g | In dichloromethane at 20℃; for 2h; | 1.1; 2.1 1) Primary alcohol protection reaction of Corylactone: Add 100 mL of dichloromethane to a four-necked flask at room temperature,Add 17.2g of Coryllactone as shown in formula IV,17.2 g of N-(3-chloropropyl)-morpholine were added,Stir and mix, react at room temperature for 2 hours,The resulting reaction solution was poured into 20 ml of ice water,The aqueous layer was separated, the organic phase was dried by adding Na2SO4, and filtered.Precipitated under reduced pressure and concentrated to obtain 29.9 g of the compound of formula III in an amorphous state,The purity detected by high performance liquid chromatography (HPLC) was 99.3%. |
Tags: 32233-40-2 synthesis path| 32233-40-2 SDS| 32233-40-2 COA| 32233-40-2 purity| 32233-40-2 application| 32233-40-2 NMR| 32233-40-2 COA| 32233-40-2 structure
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H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
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