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CAS No. : | 23377-40-4 | MDL No. : | MFCD00171483 |
Formula : | C19H40O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | YDCSFYSJEYSCBP-UHFFFAOYSA-N |
M.W : | 300.52 | Pubchem ID : | 165753 |
Synonyms : |
|
Num. heavy atoms : | 21 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 1.0 |
Num. rotatable bonds : | 18 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 95.69 |
TPSA : | 29.46 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -2.81 cm/s |
Log Po/w (iLOGP) : | 4.97 |
Log Po/w (XLOGP3) : | 7.5 |
Log Po/w (WLOGP) : | 5.87 |
Log Po/w (MLOGP) : | 4.24 |
Log Po/w (SILICOS-IT) : | 6.56 |
Consensus Log Po/w : | 5.83 |
Lipinski : | 1.0 |
Ghose : | None |
Veber : | 1.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -5.24 |
Solubility : | 0.00173 mg/ml ; 0.00000575 mol/l |
Class : | Moderately soluble |
Log S (Ali) : | -7.95 |
Solubility : | 0.00000335 mg/ml ; 0.0000000112 mol/l |
Class : | Poorly soluble |
Log S (SILICOS-IT) : | -6.71 |
Solubility : | 0.0000589 mg/ml ; 0.000000196 mol/l |
Class : | Poorly soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 2.0 |
Synthetic accessibility : | 3.47 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88.4% | With potassium hydroxide In dimethyl sulfoxide; N,N-dimethyl-formamide at 20℃; for 16 h; | In a 1000ml round bottom flask,Add n-hexadecyl bromide (2) 97.5 g (0.32 mol, 1 eq), 1,3-propanediol (3) 73.5 g (0.96 mol, 3 eq),DMSO 200ml,DMF 200ml andPotassium hydroxide 72g (1.28mol, 4eq), stirred at room temperature16h.After completion of the reaction, 500 ml of water was added to the reaction solution, then the pH was adjusted to neutrality with a 5M hydrochloric acid solution, and the mixture was extracted with ethyl acetate (500 ml×2). The organic layers were combined and the organic layer was washed with saturated brine (500 ml×2). ), collecting organic phase,Dry with 10 g of anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain 102 g of a yellow solid.Recrystallization of petroleum ether yielded 85 g of white flake-like crystals with a yield of 88.4percent. |
77% | Stage #1: With sodium hydride In N,N-dimethyl-formamide; oil at 0 - 20℃; for 0.166667 h; Stage #2: With potassium iodide In N,N-dimethyl-formamide; oil at 95℃; for 4 h; |
General procedure: To a solution of 1,3-propanediol (19) (6.51 mL, 90 mmol) in dry DMF (40 mL) was added NaH (60percent oil dispersion; 1.20 g, 30 mmol) in installments at 0 °C and the mixture was stirred at room temperature for 10 min. Dodecyl bromide (4.80 mL, 20 mmol) and KI (3.32 g, 20 mmol) were added and the mixture was heated at 95 °C for 4 h. After cooling, the mixture was poured into ice-water and extracted with AcOEt. The extracts were washed with brine, dried over Na2SO4 and evaporated. The resulting residue was purified by flash CC (silica gel; AcOEt/hexane, 1:2) to provide dodecyl ether 20a (3.38 g, 69percent). Tetradecyl ether 20b (79percent) and hexadecyl ether 20c (77percent) were similarly prepared from 1,3-propanediol (19). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27% | With dmap; dicyclohexyl-carbodiimide; In N,N-dimethyl-formamide; at 20 - 80℃; | 9-(5-Phosphono-pent-2-en-l-yl)-adenine mono-(3-hexadecyloxy-l- propyl) phosphonoester (16)A solution of compound 13 (0.12Og, 0.424 mmol), 3-hexadecyloxy- propan-1-ol (HDPOH) (0.191g, 0.64 mmol) and DMAP (0.078g, 0.64 mmol) in DMF (10 mL) was treated with DCC (0.262g, 1.26 mmol) at room temperature. The reaction mixture was warmed up to 8O0C and stirred for overnight. After concentration, the residue was purified with a gradient mixture of chloroform, methanol, ammonia water and water (80:20:1 :1 to 100:40:3:3) by silica gel column chromatography to give 0.065g of product 16 (0.115 mmol, 27% yield); 1H NMR (MeOH-^) 58.21 (s, IH), 8.19 (s, IH) 5.84-5.74 (m, IH), 5.65-5.57 (m, IH), 4.92 (d, J = 7.0 Hz, 2H), 3.94 (q, J = 6.2 Hz, 2H), 3.52 (t, J = 6.2 Hz, 2H), 3.37 (t, J = 6.6 Hz, 2H), 2.58-2.44 (m, 2H), 1.90-1.78 (m, 2H), 1.74-1.62 (m, 2H), 1.54-1.43 (m, 2H), 1.36-1.14 (m, 12H), 0.89 (t, J = 7.0 Hz, 3H); 31P NMR (MeOH-^) 525.89; MS (ESI) m/z 566 (M+H)+, 564 (M-HV. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; triethylamine; In dichloromethane; at -30 - 0℃; | General procedure: 4.1. General method A Bis isopropyl phosphonoethoxyethylchloride (1) (2.58 g,10.0 mmol) or bis isopropyl phosphonomethyltosylate (7) (3.50 g,10.0 mmol) in anhydrous acetonitrile (130 ml) was treated withbromotrimethylsilane (13 ml) overnight at room temperature.The mixture was then evaporated and codistilled with acetonitrile (3x25 mL), water (2x25 ml), ethanol (25 mL) and toluene (3 x 25 mL). The syrupy residue was dissolved in dichloromethane (50 ml) then DMF (0.1 ml) and oxalyl chloride (6.0 ml, 68.8 mmol) were added. The solution was gently refluxed (2 h), evaporated to dryness, and redissolved in dichloromethane (20 ml). The solution was cooled down to 0 C and treated slowly with pyridine (1.6 ml).The mixture was added to a cooled ( 30 C) solution of hexadecyloxypropanol (6.01 g, 20 mmol) in dichloromethane (100 ml) and triethylamine (8.7 ml). The mixture was allowed to reach 0C and kept at this temperature for3 h.The reactionmixturewas evaporated,codistilled with toluene (3 50 ml) and the residue was chromatographed on a silica gel column (400 g) in EtOAc/hexane (1:2/1:1). 4.1.2. Bis(hexadecyloxypropyl)phosphonomethyltosylate (8)Prepared similarly according to the published procedure [12]. Yield 6.94 g of syrup (83%). Identity was verified using authentic sample on TLC, Rf w0.3 (30% EtOAc/hexane). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; dicyclohexyl-carbodiimide; for 6h;Heating / reflux; | The phosphonate analog of AZT (3'-Azido-3'-5'-dideoxythymidine-5'-phosphonic acid) was synthesized using the published procedure: Hakimelahi, G. H.; Moosavi- Movahedi, A. A.; Sadeghi, M. M.; Tsay, S-C.; Hwu, J. R. Journal of Medicinal Chemistry, 1995 3 S, 4648-4659. The AZT phosphonate (1.65 g, 5 mmol) was suspended in dry pyridine (30 mL), then 3-hexadecyloxy-l-propanol (1.8 g, 6 mmol) and DCC (2.06 g, 10 mmol) were added and the mixture was heated to reflux and stirred for 6 h, then cooled and filtered. The filtrate was concentrated under reduced pressure and the residue was applied to a column of silica gel. Elution of the column with a 9:1 dichloromethane/methanol yielded 3'- azido-S'-S'-dideoxythymidine-S'-phosphonic acid, hexadecyloxypropyl ester. | |
With pyridine; dicyclohexyl-carbodiimide; for 6h;Heating / reflux; | [0106] The phosphonate analog of AZT (3'-Azido-3'-5'-dideoxythymidine-5'-phosphonic acid) was synthesized using the published procedure: Hakimelahi, G. H.; Moosavi-Movahedi, A. A.; Sadeghi, M. M.; Tsay, S-C.; Hwu, J. R. Journal of Medicinal Chemistry, 1995 38, 4648-4659. [0107] The AZT phosphonate (1.65 g, 5 mmol) was suspended in dry pyridine (30 mL), then <strong>[23377-40-4]3-hexadecyloxy-1-propanol</strong> (1.8 g, 6 mmol) and DCC (2.06 g, 10 mmol) were added and the mixture was heated to reflux and stirred for 6 h, then cooled and filtered. The filtrate was concentrated under reduced pressure and the residue was applied to a column of silica gel. Elution of the column with a 9:1 dichloromethane/methanol yielded 3'-azido-3'-5'-dideoxythymidine-5'-phosphonic acid, hexadecyloxypropyl ester. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; dicyclohexyl-carbodiimide; for 18h;Heating / reflux; | To a mixture of adefovir (1.36 g, 5 mmol) and 3-hexadecyloxy-l-propanol (1.8 g, 6 nunol) in dry pyridine was added DCC (2.06 g, 10 mmol). The mixture was heated to reflux and stirred 18 h then cooled and filtered. The filtrate was concentrated under reduced pressure and the residue was applied to a short column of silica gel. Elution of the column with 9:1 dichloromethane/methanol yielded hexadecyloxypropyl-adefovir (HDP-ADV) as a white powder. | |
With pyridine; dicyclohexyl-carbodiimide; for 18h;Heating / reflux; | [0104] To a mixture of adefovir (1.36 g, 5 mmol) and <strong>[23377-40-4]3-hexadecyloxy-1-propanol</strong> (1.8 g, 6 mmol) in dry pyridine was added DCC (2.06 g, 10 mmol). The mixture was heated to reflux and stirred 18 h then cooled and filtered. The filtrate was concentrated under reduced pressure and the residue was applied to a short column of silica gel. Elution of the column with 9:1 dichloromethane/methanol yielded hexadecyloxypropyl-adefovir (HDP-ADV) as a white powder. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With pyridine; dicyclohexyl-carbodiimide; In dichloromethane; at 0 - 20℃; | Part A. 3'-azido-3'-deoxy-5'-O-[(diethoxyphosphono)carbonyl]thymidine (2a in Above Scheme) [00143] To a stirred solution of diethylphosphonoformic chloride (1.0 g, 5 mmol) in dry pyridine (35 mL) was added a solution of AZT (1.0 g, 3.75 mmol) and dimethylaminopyridine (0.25 g, 2 mmol). The mixture was stirred overnight. The mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by flash column chromatography to yield 2a (1.29 g, 80%) as a foamy white solid. [00144] Part B. 3'-azido-3'-deoxy-5'-O-[(dihydroxyphosphono) carbonyl]thymidine (2b in above scheme) [00145] To a solution of diethyl phosphonate 2a (4.2 g, 9.7 mmol) in dry acetonitrile (30 mL) was added bromotrimethylsilane (10 g, 65 mmol) and the mixture was stirred one hour at room temperature. To the reaction mixture was added methanol (10 mL) and pyridine (5 mL) and the mixture was concentrated in vacuo to give the phosphonate 2b as a foamy solid which was used in the next step without further purification. [00146] Part C. 3'-azido-3'-deoxy-5'-)-[(hexadecyloxypropy)(hydroxy) phosphono(carbonyl]thymidine (2c in above scheme) [00147] To a solution of the free phosphate 2b (0.5 g, 1.3 mmol) in pyridine (30 mL) was added <strong>[23377-40-4]3-hexadecyloxy-1-propanol</strong> (0.75 g, 2.3 mmol) and the solution was cooled in an ice bath. A solution of dicyclohexyldiimide (1.0 g, 5 mmol) in dichloromethane (7 mL) was added dropwise with stirring and the mixture was left at room temperature overnight. The reaction mixture was filtered and the filtrate was concentrated in vacuo and the residue was purified by flash chromatography over silica gel using 80:20 (by vol.) CH2Cl2/MeOH to elute the coupled product 2c (540 mg, 63%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With triethylamine; In dichloromethane; at -20 - 20℃; for 2.5h; | Part A. (Hexadecyloxypropoxy)dimethoxyphosphite (3a in Above Scheme) [00150] To a stirred solution of dimethylphosphorochloridite (0.9 g, 7 mmol) in dry CH2Cl2 (30 mL) cooled to -20 C. was added dropwise a CH2Cl2 solution of <strong>[23377-40-4]3-hexadecyloxy-1-propanol</strong> (2.1 g, 7 mmol) and triethylamine (0.9 g, 0.9 mmol) over 30 minutes. The mixture was allowed to warm to room temperature over 2 hours, then vacuum filtered to remove triethylamine hydrochloride. The filtrate was concentrated in vacuo and the residue purified by flash chromatography over silica gel using 9:1 (by vol.) hexane/ethyl acetate as the eluting solvent. Evaporation of the pure fractions yielded 1.96 g of 3a as a colorless oil (70%). [00151] Part B. (Hexadecyloxypropoxy)(methoxy)ethyloxycarbonylphosphonate (3b in Above Scheme) [00152] A mixture of 3a (1.96 g, 5 mmol) and ethyl chloroformate (10 mL) was stirred for 5 hours at room temperature. The ethyl chloroformate was evaporated in vacuo and the residue was purified by flash column chromatography over silica gel using 9:1 hexane:ethyl acetate to elute 1.8 g of 3b as a colorless oil (80%). [00153] Part C. Sodium 3'-azido-3'-deoxy-5'-O-(hexadecyloxypropoxy) (carbonyloxyphosphinyl)thymidine (3d in above scheme) [00154] PCl5 (0.9 g, 4.2 mmol) was added to a solution of 3b (1.8 g, 4 mmol) in dry CCl4 (15 mL) and the reaction mixture was heated to reflux for 3 hours. The unreacted PCl5 was decomposed by passing dry SO2 gas through the solution at room temperature for 5 minutes and the CCl4, SOCl2, and POCl3 were distilled off under high vacuum (40 C., 0.01-0.05 Torr). The residue was taken up in dry DMF (20 mL), and the solution was cooled to -50 C. in a dry ice-acetone bath. AZT (anhydrous, 1.07 g, 4 mmol) was dissolved in dry DMF (5 mL), and the solution was added all at once to the stirred DMF solution of the phosphonyl chloride reagent. When addition was complete, the reaction mixture was allowed to warm to room temperature and stirring was continued for 24 hours. The solvent was evaporated under reduced pressure, and the residue was purified by flash chromatography on silica gel (95:5 CHCl3/MeOH) to obtain 0.56 g of PFA-AZT triester 3c as a colorless solid (yield 20%). [00155] Aqueous sodium hydroxide (0.1 N, 0.5 mL) was added to a stirred suspension of the PFA-AZT triester 3c (560 mg) in ethanol (0.5 mL) and stirred for 1 hour at room temperature. The solid was collected by vacuum filtration, rinsed thoroughly with cold ethanol and recrystallized from ethanol to give 550 mg (90%) 3d as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | In toluene; at 20℃; | To a solution of pyridinium toluenesulfonyloxymethylphosphonate (1. 0 g, 3. 0 mmol) in dry toluene (20 mL) was added oxalyl chloride (0. 39 mL, 4. 5 mmol) and N, N-DMF (0. 02 mL, 0. 3 mmol) in one portion. The solution was stirred at room temperature for 1 hour. Toluene and the excess oxalyl chloride were removed under vacuum. The residue was redissolved in toluene (10 mL). 3-Hexadecyloxy-1-propanol (0. 81 g, 2. 7 mmol) was added. The mixture was stirred at room temperature overnight. Triethyl ammonium hydrogen carbonate buffer (10 mL) was added to the mixture which was stirred for 30 min. Solvents were evaporated. The residue was dissolved in CHOC13 (50 mL), washed with water (2 x 10 mL) and the solvent evaporated to give 1 gram of crude product. The impurities were removed by flash column chromatography (silica gel, 15% EtOH/CH2Cl2) Yield = 0. 60 g (40%). IH NMR : (CDCl3)No. 0. 88 (t, 3H), 1. 25 (br s, 26H), 1. 46 (m, 2H), 1. 71 (p, 2H), 2. 46 (s, 3H), 3. 34 (t, 2H), 3. 80 (dd, 2H), 3. 98 (d, 2H), 7. 37 (d, 2H), 7. 76 (d, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Preferable examples of Compound (I) are as follows: Compound 1: 2-Hexadecyloxy-3-methoxy-1-propanol 1-Hexadecyloxy-3-methoxy-2-propanol 3-Hexadecyloxy-1-propanol 1-(2,3-Dimethoxypropoxy)hexadecane 2-Methoxy-1-eicosanol 3-Hydroxy-2-methoxypropyl stearate 2-Hexadecyloxy-1,3-propanediol 2,2-Dimethyl-3-octadecyloxy-1-propanol 1,2-eicosanediol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | [0092] A. Hexadecyloxypropyl Methyl Phosphite (b) [0093] Hexadecyloxypropyl methyl phosphite was prepared using the method described in: Kers, A., Kers, I., Stawinski, J., Sobkowski, M., Kraszewski, A. Synthesis April 1995, 427-430. To a solution of diphenylphosphite (14 g, 60 mmol) in pyridine (50 mL) maintained at 0 C. was slowly added to a solution of hexadecyloxypropan-1-ol (6.0 g, 20 mmol) in pyridine (25 mL). The mixture was stirred one hour before anhydrous methanol (10 mL) was added. After stirring an additional hour, the solvent was evaporated the residue was adsorbed on silica gel and chromatographed, using gradient elution (hexanes to 20% ethyl acetate/80% hexanes), to afford pure compound 2 as a waxy, low-melting solid (4.5 g, 60% yield). 1H NMR (CDCl3) delta 6.79 (d, 1H, J=696 Hz), 4.19 (q, 2H), 3.78 (d, 3H), 3.51 (t, 3H), 3.40 (t, 2H), 1.95 (pent, 2H), 1.25 (broad s, 28H), 0.88 (t, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With toluene-4-sulfonic acid; In toluene;Reflux; | L-alanine (25 g, 280.6 mmol, 1 equiv.) was suspended in toluene (700 niL), p- toluenesulfonic acid (58.7 g, 308.7 mmol, 1.1 equiv.) and HDP-OH (169 g, 561.2 mmol, 2 equiv.), were added and the resulting mixture was heated at reflux with Dean-Stark trap overnight. The reaction mixture was evaporated in vacuo. The crude solid was triturated in hexanes, filtered and dried to afford 13O g (85% yield) of slightly impure N as the tosylate salt. This material was used without further purification. Step 2: Preparation of phenyl phosphorodichloridate, O. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium tert-butylate; 1,3-bis(cyclohexyl)imidazolium tetrafluoroborate; In tetrahydrofuran; at 20℃; for 24h;Molecular sieve; Inert atmosphere; | To a tetrahydrofuran (THF) (1 mL/mmol) solution of l,3-bis(cyclcohexyl) imidazolium tetrafluoroborate (ICyHBF4) salt (0.05 eq.) and molecular sieves (0.5g/mmol), under argon, is added tBuOK (0.9 eq.) and stirred for 10 min. Lipophilic alcohol (1 eq.) and dialkyl H-phosphonate (2 eq.) are added and the reaction stirred at room temperature for 24h. The reaction is quenched with a saturated solution of ammonium chloride (5 mL/mmol) and filtrate on celite. Ethylacetate (AcOEt) (10 mL/mmol) is added to the solution then the organic and aqueous layers are separated. Aqueous phase is then extracted with AcOEt (10 mL/mmol) and the combinated organic layers are evaporated under vaccum. The corresponding alkyl/lipophilic chain H-phosphonate is finally purified by chromatography on silica gel.Example 2 : Synthesis of Bn/HDP H-phosphonateCompound 1 is synthesized according to procedure 1.4. from dibenzylphosphite as reported by the scheme 1. Scheme 11H NMR (400 MHz, CDCl3) delta = 7.74 (s, 0.5H, H-P), 7.41-7.33 (m, 5H, HA1), 5.99 (s, 0.5H, H-P), 5.11 (d, J = 9.5 Hz, 3H, OCH3), 4.20-4.07 (m, 2Eta, P-O-CH2-CH2-CH2-O), 3.46 (t, J = 6.1Hz, 2H, P-O-CH2-CH2-CH2-O), 3.37 (t, J = 6.7 Hz, 2H, 0-CH2-CH2-(CH2)I3-CH3), 1.90 ( p, J = 6.2 Hz, 2H, P-O-CH2-CH2-CH2-O), 1.53 (p, J = 6.9 Hz, 2H, 0-CH2-CH2-(CH2) ?- CH3), 1.35-1.19 (m, 26H, 0-CH2-CH2-(CH2)^-CH3), 0.87 (t, J = 6.4 Hz, 3H, 0-CH2-CH2- 13C NMR (100 MHz, CDCl3) delta = 136.6, 128.7, 128.6, 127.9, 126.9 (CA1), 71.2 (0-CH2-CH2- (CH2)I3-CH3), 67.2 (2C, CH2-Ph), 66.3 (P-O-CH2-CH2-CH2-O), 63.1, 63.0 (P-O-CH2-CH2- CH2-O), 31.9, 30.6 (2C), 29.7, 29.6 (2C), 29.5, 29.3, 26.1, 22.7 (CH2-P, P-O-CH2-CH2-CH2- O, 0-CH2-CH2-(CH2)^-CH3), 14.1 (O-CH2-CH2-(CH2)13-CH3).3 '11P NMR (162 MHz, CDCl3): delta = 10.05. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; for 48h;Reflux; Inert atmosphere; | To a dichloromethane (DCM) (5mL/mmol) solution of dialkyl allylphosphonate (1 eq.) was added oxalyl chloride (3 eq.), and gently reflux for 24h under positive pressure of dry argon. This solution was evaporated under reduced pressure and diluted in DCM (5mL/mmol). Lipophilic alcohol (1.05 eq.) and dry triethylamine (1.5 eq.) were then added and the solution was refluxed for 48h under positive pressure of dry argon. Volatiles were evaporated and the residue purified by chromatography on silica gel to give the corresponding alkyl/lipophilic chain alkylphosphonate.; Compound 3 is synthesized according to procedure 1.1. from dibenzyl methylphosphonate as reported by the scheme 3.1. Oxalyl chloride CH2Cl2, 24h reflux2. HDPOH, Et3N CH2Cl2, 48h reflux Scheme 3 1U NMR (400 MHz, CDCl3) delta = 7.41-7.28 (m, IH), 5.11-4.99 (m, 2H, CH2-Ph), 4.15-3.99 (m, 2Eta, P-O-CH2-CH2-CH2-O), 3.45 (t, J = 6.3 Hz, 2H, P-O-CH2-CH2-CH2-O), 3.36 (t, J = 6.7 Hz, 2H, 0-CH2-CH2-(CH2)I3-CH3), 1.87 (p, J = 6.3 Hz, 2H, P-O-CH2-CH2-CH2-O), 1.53 (p, J = 6.9 Hz, 2H, 0-CH2-CH2-(CH2)I3-CH3), 1.46 (d, J = 17.6 Hz, 3H, CH3-P), 1.32-1.20 (m, 26Eta, 0-CH2-CH2-(CH2)^-CH3), 0.87 (t, J = 6.4 Hz, 3H, 0-CH2-CH2-(CH2)I3-CH3). 13C NMR (100 MHz, CDCl3) delta = 136.4 (2C), 128.5, 128.3, 127.8 (CM), 71.2 (0-CH2-CH2- (CH2)I3-CH3), 67.0 (2C, CH2-Ph), 66.5 (P-O-CH2-CH2-CH2-O), 62.9, 62.8 (P-O-CH2-CH2- CH2-O), 31.9, 30.8, 30.7, 30.3 (2C), 29.7, 29.6 (3C), 29.5, 29.3, 26.1, 22.6(CH2-P, P-O-CH2- CH2-CH2-O, 0-CH2-CH2-(CH2)^-CH3), 14.1 (0-CH2-CH2-(CH2)I3-CH3), 11.9, 10.4 (CH3-P). 31P NMR (162 MHz, CDCl3): delta = 31.23 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | Oxalylchloride (2.04 mL, 3 eq., 23.8 mmol) was added to a solution of dimethyl allylphosphonate (1 .19 g, 1 eq., 7.9 mmol) in dichloromethane (35 mL). This mixture was gently refluxed during 3 days at 45C. After evaporation of all volatiles, the crude compound was diluted in 35 mL of dichloromethane. Hexadecyloxypropyl alcohol (2.5 g, 1 .05 eq., 8.3mmol) and freshly distilled triethylamine (1 .6 mL, 1 .5 eq., 20 mmol) were then added subsequently and the resulting solution was refluxed during 3 days at 45C. The volatiles were removed under reduced pressure, and the residue was purified by flash column chromatography (eluting PE/EtOAc 9:1 - 6:4 - 0:1 ) to afford 209 as a white amorphous solid. (2.52 g, 76%) 1H NMR (400 MHz, CDCI3) d 5.75 (m, 1 H, CH=CH2), 5.23 (m, 2H, CH2-CH=CH2), 4.13 (dt, J = 6.5, 1 .7 Hz, 2H, He), 3.73 (d, J = 10.9 Hz, 3H, 0-CH3), 3.48 (t, J = 6.2 Hz, 2H, Ha), 3.38 (t, J = 6.7 Hz, 2H, CH2-0), 2.62 (ddt, J = 22.0, 7.4, 1 .1 Hz, 2H, CH2-P), 1 .91 (p, J = 6.3Hz, 2H, CH2-b), 1 .54 (p, J = 6.9 Hz, 2H, CH2-CH2-0), 1 .32-1 .22 (m, 26H, CH2), 0.87 (t, J= 6.8 Hz, 3H, CH3). 31P NMR (162 MHz, CDC ) d 28.3. CAS: 1258789-65- 9 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | Under N2 atmosphere, commercial 1 ,3-propanediol (9.02 ml_, 5 eq., 124.8 mmol) was dissolved in 200 ml_ DMF, and sodium hydride (60% in oil, 2.49 g, 2.5 eq., 62.4 mmol) was carefully added. The solution was stirred 30 minutes at room temperature, followed by the addition of 207 (8 g, 1 eq., 25 mmol). This mixture was stirred overnight at room temperature, and the crude product was quenched with cold water (200 ml_), dissolved in EtOAc (100 ml_), extracted 5 times with water (5 x 100 ml_), washed with brine (100 ml_) and dried over MgS04. After evaporation of all volatiles, the product was purified by flash column chromatography (PE/EtOAc 8:2) to give compound 208 as a white powder. (7.12 g, 95%) 1H NMR (400 MHz, CDCI3) d 3.75 (q, J = 5.5 Hz, 2H, Ha), 3.58 (t, J = 5.6 Hz, 2H, Hc), 3.40 (t, J = 6.6 Hz, 2H, CH2), 2.46 (t, J = 5.5 Hz, 1 H, OH), 1 .80 (p, J = 5.6 Hz, 2H, Hb), 1 .23 (s, 26H, CH2), 0.85 (m, 3H, CH3). CAS: 23377-40-4 | |
Under an inert atmosphere, e.g., nitrogen, a reactor was charged with 1,3-propanediol (4.07 kg) and NMP (30 L). The reaction was cooled to -5 to 5 C. and kept under a nitrogen atmosphere. Sodium hydride (1.07 kg, 60% in mineral oil) was cautiously added portion-wise. After the addition was complete, the reaction was stirred at room temperature for an additional 2 hours. A solution of hexadecyl methanesulfonate 4 (4.39 kg) dissolved in NMP (10 L) was added slowly to the reaction mixture at 20 to 55 C. The resulting solution was stirred for 12 to 28 hours at 20 to 35 C. The reaction was monitored by GC-MS and was considered complete when the conversion rate was >95%. The reaction mixture was cooled down to -5 to 5 C. and slowly diluted with water (15 L). The reaction was extracted with ethyl acetate (2×25 L). The organic phase was washed with water (20 L), dried over Na2SO4 and concentrated to give a brown oil. The crude product was dissolved in methanol (20 L) and aged at 20 to 30 C. for 12 hours. The resulting solid impurities were filtered and discarded and the filtrate was concentrated. Acetonitrile (40 L) was added to the concentrate and the mixture was aged 5 to 15 C. for 16 hours. The solid was filtered and dried at 25 to 30 C. to afford 5 as a white solid (3.1 kg, 77%). Typical HPLC (AUC) purity was >95%. 1H-NMR was consistent with structure. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Synthesis of toluenesulfonyloxymethylphosphonate, hexadecyloxypropyl ester (HDP-TsOMPA): To a solution of pyridinium toluenesulfonyloxymethylphosphonate (1.0 g, 3.0 mmol) in dry toluene (20 mL) was added oxalyl chloride (0.39 mL, 4.5 mmol) and DMF (0.02 mL, 0.3 mmol) in one portion. The solution was stirred at room temperature for 1 hour. Toluene and the excess oxalyl chloride were removed under vacuum. The residue was re-dissolved in toluene (10 mL). 3-Hexadecyloxy-1-propanol (5) (0.81 mL, 2.7 mmol) was added. The mixture was stirred at room temperature overnight. Triethyl ammonium hydrogen carbonate buffer (10 mL) was added to the mixture which was stirred form 30 min. Solvents were evaporated. The residue was dissolved in chloroform (50 mL), washed with water (2?10 mL) and the solvent evaporated to give 1 gram of crude product. The impurities were removed by flash column chromatography (silica gel, 15% EtOH/dichloromethane) Yield=0.60 g (40%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Under an inert atmosphere, e.g., nitrogen, a reactor was charged with diethyl (tosyloxy)methyloxyphosphonate (6, 4.00 kg) and anhydrous acetonitrile (36 L). Bromotrimethylsilane (6.65 kg) was cautiously added to the reaction. Once the addition was complete, the reaction was stirred at 20 to 30 C. for 1 hour and then heated to 55 C. and stirred for an additional two hours. The mixture was cooled to 20 to 30 C. and concentrated in vacuo. The concentrate was dissolved in anhydrous dichloromethane (36 L) and oxalyl chloride (5.52 kg) was added slowly over two hours. Excessive gas evolution was observed from the reaction. The reaction was stirred for two hours and N,N-dimethylformamide (DMF) (2.0 mL) was added. After the DMF addition, the reaction was stirred for 12 to 16 hours. The reaction mixture was concentrated to give (dichlorophosphoryl)methyl 4-methylbenzenesulfonate (7) as a brown oil. 7 was dissolved in anhydrous dichloromethane (36 L) and <strong>[23377-40-4]3-(hexadecyloxy)propan-1-ol</strong> (5) (3.25 kg) was added. The reaction was cooled to -5 to 5 C. and pyridine (2.56 kg) was added dropwise. After the reaction was complete, the mixture was stirred at 20 to 30 C. for two hours and then quenched by the slow addition of water (5.0 L). The first 500 mL of water was added over 30 minutes due to a strong exotherm. The remainder of the water was added over 15 minutes. A saturated solution of sodium bicarbonate was added over 30 minutes and stirring was continued for one hour. The mixture was pH adjusted to 2.0 with 6N hydrochloric acid. The organic layer was separated and the aqueous phase was extracted with dichloromethane (10 L). The combined organic layers were washed with water (2×10 L), dried over sodium sulfate and concentrated to afford a brown oil. The crude product was dissolved in 2-propanol (50 L) and 6N sodium hydroxide (4.0 mL) was added. The solution was kept at 20 to 30 C. for three days. The precipitate was collected by filtration and washed with 2-propanol (12 L). The filter cake was dried in vacuo to give CMX203 as a white solid (4.50 kg, 73% based on <strong>[23377-40-4]3-(hexadecyloxy)propan-1-ol</strong> (5)). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With diphenyl phosphoryl azide; 1,8-diazabicyclo[5.4.0]undec-7-ene; In N,N-dimethyl-formamide; at 90℃; for 3h; | General procedure: To a solution of the alcohol 20a (2.44 g, 10 mmol) and DPPA (2.59 mL, 12 mmol) in dry DMF (20 mL) was added DBU (1.79 mL, 12 mmol) and the mixture was heated at 90 C for 3 h. After cooling, the mixture was diluted with AcOEt and washed with brine, dried over Na2SO4 and evaporated. The resulting residue was purified by flash CC (silica gel; AcOEt/hexane, 8:92) to provide the azide 21a (2.39 g, 89%). Azides 21b (94%) and 21c (81%) were similarly prepared from alcohols 20b and 20c. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; triethylamine; In dichloromethane; at -30 - 0℃; | General procedure: 4.1. General method A Bis isopropyl phosphonoethoxyethylchloride (1) (2.58 g,10.0 mmol) or bis isopropyl phosphonomethyltosylate (7) (3.50 g,10.0 mmol) in anhydrous acetonitrile (130 ml) was treated withbromotrimethylsilane (13 ml) overnight at room temperature.The mixture was then evaporated and codistilled with acetonitrile (3x25 mL), water (2x25 ml), ethanol (25 mL) and toluene (3 x 25 mL). The syrupy residue was dissolved in dichloromethane (50 ml) then DMF (0.1 ml) and oxalyl chloride (6.0 ml, 68.8 mmol) were added. The solution was gently refluxed (2 h), evaporated to dryness, and redissolved in dichloromethane (20 ml). The solution was cooled down to 0 C and treated slowly with pyridine (1.6 ml).The mixture was added to a cooled ( 30 C) solution of hexadecyloxypropanol (6.01 g, 20 mmol) in dichloromethane (100 ml) and triethylamine (8.7 ml). The mixture was allowed to reach 0C and kept at this temperature for3 h.The reactionmixturewas evaporated,codistilled with toluene (3 50 ml) and the residue was chromatographed on a silica gel column (400 g) in EtOAc/hexane (1:2/1:1). 4.1.1. Bis(hexadecyloxypropyl)phosphonoethoxyethylchloride (2) Yield 6.50 g of syrup (88%). The crude product was used without further purification procedures. ESI-MS, m/z: 753.6 (53) [M th H]th, 775.6 (100) [M th Na]th, 791.5 (22) [M th K]th, 812.7 (28); ESI-HRMS calcd for C42H87O6ClP 753.59233, found: 753.59185 [M th H]th. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; In dichloromethane; at 20℃; for 3h; | Example 12 Ethyl 3-(hexadecyloxy)propyl {3-[({4-hydroxy-5H-pyrrolo[3,2-d]pyrimidin-7- yl}methyl)amino]propyl}phosphonate (65), Scheme 12Scheme 12 (3-[(Benzyloxy)carbonyl]amino}propyl)(ethoxy)phosphinic acid (56) (0.52 g) is evaporated twice with MeCN then dissolved in dry DCM (5 mL) and dry DMF (5 pL). This solution is then added to oxalyl chloride (574 muIota, 5 eq.) in dry DCM (5 mL) under Ar, stirred at room temperature for 2 h and then evaporated twice from dry DCM. The resulting crude phosphonyl chloride (57) in dry DCM (5 mL) is added to a solution of 3- hexadecyloxypropan-1-ol (504 mg, 1.3 eq.) and dry pyridine (1 mL) in dry DCM (3 mL). The mixture is stirred at room temperature for 3 h and then treated with saturated sodium bicarbonate solution, extracted with DCM, dried and evaporated. Flash chromatography (hexanes- EtOAc, followed by 5% v/v MeOH in EtOAc) gives benzyl N-(3-{ethoxy[3- (hexadecyloxy)propoxy]phosphoryl}propyl)carbamate (62) (110 mg). 1H NMR (500 MHz, CDCI3) delta 7.36-7.26 (m, 5H), 5.09 (s, 2H), 4.12-4.08 (m, 2H), 3.49-3.47 (m, 2H), 3.40-3.37 (m, 2H), 3.32-3.25 (m, 2H), 1.92-1.89 (m, 2H), 1.79-1.75 (m, 2H), 1.58-1.54 (m, 2H), 1.32-1.25 (m, 30H), 0.89-0.87(m, 3H). 3C NMR (125MHz, CDCI3) delta 156.4,136.6,128.5, 128.1 , 71.2, 66.6, 62.9, 61.7, 31.9, 30.9, 29.7, 29.5, 29.3, 26.2, 22.7, 16.4, 14.1. 31P NMR (202 MHz, CDCI3 ) delta 31.7. ESI-HRMS for C32H58N06PNa [M+Na]+ calcd 606.3899; found 686.3904. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 2,4,6-triisopropylphenylsulfonyl chloride;1-methyl-1H-imidazole; In dichloromethane; at 20℃; | Example 6 Hexadecyloxypropyl-2',3'-isopropylideneuridin-5'-yl-vinyphosphonate TPSCl (5.54 g, 18.3 mmol) is added to the mixture of vinylphosphonic acid from the example 1 (1.8 g, 6.1 mmol), hexadecyloxypropanol (1.45 g, 3.05 mmol), and 1-methylimidazole (1.45 ml, 18.3 mmol) in DCM (60 ml). The reaction mixture is stirred overnight at rt, then extracted/washed with saturated solution of NaHCO3 (2 x 100 ml), 3% aqueous citric acid (2 x 100 ml) and dried over Na2SO4. The organic phase is concentrated in vacuo and the product is obtained by flash chromatography on silica gel using linear gradient of ethanol in chloroform in 71% yield (1.42 g, 2.16 mmol) in the form of colorless wax. A mixture of diastereoisomers ~ 1:1 1H NMR (500.0 MHz, CDCl3): 0.88 (m, 6H, CH3(CH2)15); 1.23-1.33 (m, 52H, CH3(CH2)13CH2CH2-O); 1.348, 1.352 (2 * q, 2 * 3H, 4J= 0.6, (CH3)2C); 1.54 (m, 4H, CH3(CH2)13CH2CH2O); 1.57 (s, 6H, (CH3)2C); 1.92, 1.94 (2 * p, 2 * 2H, Jvic = 6.1, OCH2CH2CH2OC16H33); 3.38, 3.39 (2 * t, 2 * 2H, Jvic, = 6.7, CH3(CH2)13CH2CH2O); 3.48, 3.49 (2 * t, 2 * 2H, Jvic = 6.1, OCH2CH2CH2OC16H33); 4.13, 4.15 (2 * td, 2 * 2H, Jvic = 6.1, JH,P = 4.8, OCH2CH2CH2OC16H33); 4.20-4.30 (m, 4H, H-5'); 4.34-4.38 (m, 2H, H-4'); 4.85, 4.86 (2 * dd, 2 * 1H, J3',2' = 6.5, J3',4' = 3.6, H-3'); 4.92 (dd, 2H, J2',3' = 6.5, J2',1' = 2.3, H-2'); 5.700, 5.704 (2 * d, 2 * 1H, J5,6 = 8.1 H-5); 5.74, 5.76 (2 * d, 2 * 1H, J1',2' = 2.3, H-1'); 6.03, 6.05 (2 * ddd, 2 * 1H, JH,P = 22.9, Jtrans = 18.4, Jcis = 12.7, =CHP); 6.16, 6.18 (2 * ddd, 2 * 1H, JH,P = 51.8, Jcis = 12.7, Jgem = 1.9, CHcisHtrans=CHP); 6.33, 6.35 (2 * ddd, 2 * 1H, JH,P = 25.5, Jtrans = 18.4, Jgem = 1.9, CHcisHtrans=CHP); 7.34, 7.39 (2 * d, 2 * 1H, J6,5 = 8.1, H-6). 13C NMR (125.7 MHz, CDCl3): 14.07 (CH3(CH2)15); 22.62 (CH3(CH2)13CH2CH2O); 25.19, 25.21 ((CH3)2C); 26.08 (CH3(CH2)14CH2O); 27.04, 27.06 ((CH3)2C); 29.29, 29.45, 29.55, 29.57, 29.58, 29.63 (CH3(CH2)14CH2O); 30.66, 30.68 (d, JC,P = 6.4, OCH2CH2CH2OC16H33); 31.85 (CH3(CH2)13CH2CH2O); 63.56 63.57 (d, JC,P = 5.5, OCH2CH2CH2OC16H33); 64.92, 65.01 (d, JC,P = 5.5, CH2-5'); 66.32, 66.36 (OCH2CH2CH2OC16H33); 71.15, 71.16 (CH3(CH2)14CH2O); 80.60, 80.67 (CH-3'); 84.44, 84.53 (CH-2'); 85.38, 85.62 (d, JC,P = 7.1, CH-4'); 93.82, 94.12 (CH-1'); 102.57, 102.64 (CH-5); 114.42, 114.46 (C(CH3)2); 124.75, 124.80 (d, JC,P = 184.0, =CHP); 136.75, 136.77 (d, JC,P = 1.9, CH2=CHP); 141.43, 141.48 (CH-6); 150.16 (C-2); 163.29, 163.32 (C-4). 31P NMR (202.3 MHz, CDCl3): 18.64, 18.80. IR vmax(KBr) 2925 (vs), 2854 (s), 1709 9vs, sh), 1696 (vs), 1630 (w), 1459 (m), 1421 (m), 1400 (w, sh), 1381 (m), 1270 (m, sh), 1250 (m, sh), 1109 (s), 1078 (s), 1028 (s), 1012 (s), 972 (m, sh), 859 (m), 762 (w), 548 (w), 514 (w) cm-1. HR-ESI C33H58O9N2P (M+H)+ calcd 657.3874; found 657.3876 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 2,4,6-triisopropylphenylsulfonyl chloride;1-methyl-1H-imidazole; In dichloromethane; at 20℃; | Example 8 Hexadecyloxypropyl 4-N-Benzoyl-2',3'-isopropylidenecytidin-5'-yl vinylphosphonate TPSCl (1.24 g, 4.08 mmol) is added to the mixture of vinylphosphonic acid from the example 7 (0.65 g, 1.36 mmol), hexadecyloxypropanol (0.81 g, 2.7 mmol), and 1-methylimidazole (1.45 ml, 18.3 mmol) in DCM (60 ml). The reaction mixture is stirred overnight at rt, then extracted/washed with saturated solution of NaHCO3 (2 x 100 ml), 3% aqueous citric acid (2 x 100 ml) and dried over Na2SO4. Organic phase is concentrated in vacuo and product is obtained by flash chromatography on silica gel using linear gradient of ethanol in chloroform in 78% yield (0.81 g, 1.06 mmol) in the form of colorless wax. A mixture of diastereoisomers ~ 1:1 1H NMR (600.1 MHz, CD3OD): 0.895 (m, 6H, CH3(CH2)15); 1.24-1.35 (m, 52H, CH3(CH2)13CH2CH2O); 1.368, 1.371 (2 * q, 2 * 3H, 4J = 0.6, (CH3)2C); 1.51 (m, 4H, CH3(CH2)13CH2CH2O); 1.57 (s, 6H, (CH3)2C); 1.89, 1.91 (2 * p, 2 * 2H, Jvic = 6.1, OCH2CH2CH2OCl6H33); 3.38, 3.39 (2 * t, 2 * 2H, Jvic = 6.7, CH3(CH2)13CH2CH2O); 3.47 (td, 2H, Jvic = 6.1, JH,P = 1.2, OCH2CH2CH2OC16H33); 3.49 (t, 2H, Jvic = 6.1, OCH2CH2CH2OC16H33); 4.09-4.16 (m, 4H, OCH2CH2CH2OC16H33); 4.27-4.36 (m, 4H, H-5'); 4.48 (m, 2H, H-4'); 4.91 (dd, 2H, J3',2' = 6.2, J3',4' = 3.6, H-3'); 5.06, 507 (2 * dd, 2 * 1H, J2',3' = 6.2, J2',1' = 1.8, H-2'); 5.87, 5.88 (2 * d, 2 * 1H, J1',2' = 1.8, H-1'); 6.145, 6.17 (2 * ddd, 2 * 1H, JH,P = 24.0, Jtrans = 18.4, Jcis = 12.8, =CHP); 6.257, 6.261 (2 * ddd, 2 * 1H, JH,P = 52.0, Jcis = 12.8, Jgem = 2.1, CHcisHtrans=CHP); 6.30, 6.31 (2 * ddd, 2 * 1H, JH,P = 26.0, Jtrans = 18.4, Jgem = 2.1, CHcisHtrans=CHP); 7.54 (m, 4H, H-m-Bz); 7.59 (d, 2H, J5,6 = 7.7, H-5); 7.64 (m, 2H, H-p-Bz); 7.99 (m, 4H, H-o-Bz); 8.16, 8.17 (2 * d, 2 * 1H, J6,5 = 7.7, H-5). 13C NMR (150.9 MHz, CD3OD): 14.48 (CH3(CH2)15); 23.75 (CH3(CH2)13CH2CH2O); 25.46, 25.48 ((CH3)2C); 27.27 (CH3(CH2)14CH2O); 27.43 ((CH3)2C); 30.49, 30.61, 30.78, 30.80, 30.81 (CH3(CH2)14CH2O); 31.70 (d, JC,P = 6.5, OCH2CH2CH2OC16H33); 33.09 (CH3(CH2)13CH2CH2O); 64.96, 64.98 (d, JC,P = 5.7, OCH2CH2CH2OC16H33); 66.97, 67.04 (d, JC,P = 5.6, CH2-5'); 67.42, 67.43 (OCH2CH2CH2OC16H33); 72.10 (CH3(CH2)14CH2O); 82.64, 82.635, 82.644 (CH-3'); 86.57, 86.58 (CH-2'); 88.23, 88.30 (d, JC,P = 7.2, CH-4'); 97.60, 97.71 (CH-1'); 98.51, 98.54 (CH-5); 115.10, 115.11 (C(CH3)2); 125.63, 125.67 (d, JC,P = 183.9, =CHP); 129.25 (CH-o-Bz); 129.83 (cH-m-Bz); 134.14 (CH-p-Bz); 134.70 (C-i-Bz); 138.01, 138.04 (d, JC,P = 1.9, CH2=CHP); 148.26, 148.34 (CH-6); 157.58, 157.60 (C-2); 165.58 (C-4); 169.19 (CO-Bz). 31P NMR (202.3 MHz, CD3OD): 19.62, 19.72. IR vmax(CHCl3) 3406 (w), 2928 (s), 2856 (m), 1703 (m), 1670 (s), 1628 (m), 1603 (w), 1554 (m), 1582 (w), 1497 (m, sh), 1480 (vs), 1455 (w, sh), 1400 (m), 1385 (m), 1377 (m), 1301 (m), 1248 (s, sh), 1186 (w), 1158 (m), 1121 (m), 1110 (m), 1078 (s), 1070 (s), 1028 (m), 1003 (m, sh), 989 (m), 909 (w), 865 (w), 842 (vw), 708 (w), 687 (w), 512 (w) cm-1. HR-EI C40H62N3O9P (M+H)+ calcd 759.4224; found 759.4225 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50.1% | With Jones reagent; In acetone; at 0℃; for 1h; | A 2.7 M solution of Jones reagent (2.0 mL) was added dropwise into a stirred solution of compound 14 (0.124 g, 0.4 mmol) in acetone (20 mL) at 0 C. The reaction was monitored by TLC and was completed after 1 h. Isopropyl alcohol was added dropwise until a stable green color appeared, to remove the excess of CrO3. The organic solvent was removed under reduced pressure. The solid was dissolved in water, and then compound 15 was extracted using ethyl acetate. The combined organic layers were washed by brine, dried using MgSO4 and concentrated under reduced pressure. The compound 15 was purified by silica gel column flash chromatography (4:1 hexane/ethyl acetate) to yield white solid (63 mg, 50.1%). 1H-NMR (CDCl3): delta = 3.72 (t, J = 6.3 Hz,2H, -CH2-COOH), 3.48 (t, J = 6.7 Hz, 2H, -OCH2-CH2-COOH), 2.65 (t, J = 6.3 Hz, 2H, -OCH2-CH2-(CH2)13), 1.59 (m, 2H, -CH2-(CH2)13), 1.23-1.34 (brs, 26H, -(CH2)13 0.90 (t, J = 6.9 Hz, 3H, CH3).ESMS: calcd for C19H38O3Na+ m/z 337.3; found: m/z [M+Na]+ 337.4 |
Tags: 23377-40-4 synthesis path| 23377-40-4 SDS| 23377-40-4 COA| 23377-40-4 purity| 23377-40-4 application| 23377-40-4 NMR| 23377-40-4 COA| 23377-40-4 structure
[ 5306-85-4 ]
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P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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