Structure of H-D-Ala-OiPr·HCl
CAS No.: 39613-92-8
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CAS No. : | 39613-92-8 |
Formula : | C6H14ClNO2 |
M.W : | 167.63 |
SMILES Code : | C[C@@H](N)C(OC(C)C)=O.[H]Cl |
MDL No. : | MFCD17976853 |
InChI Key : | YAQKNCSWDMGPOY-NUBCRITNSA-N |
Pubchem ID : | 51064150 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 10 |
Num. arom. heavy atoms | 0 |
Fraction Csp3 | 0.83 |
Num. rotatable bonds | 3 |
Num. H-bond acceptors | 3.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 41.91 |
TPSA ? Topological Polar Surface Area: Calculated from |
52.32 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
0.0 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.21 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.09 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.75 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
0.0 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
0.61 |
Log S (ESOL):? ESOL: Topological method implemented from |
-1.44 |
Solubility | 6.04 mg/ml ; 0.036 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-1.91 |
Solubility | 2.08 mg/ml ; 0.0124 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-0.43 |
Solubility | 61.9 mg/ml ; 0.369 mol/l |
Class? Solubility class: Log S scale |
Soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
Yes |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
No |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-6.46 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
1.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
0.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
1.68 |
* 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 |
---|---|---|
15 g | With triethylamine In dichloromethane; toluene at -25℃; for 1 h; | L-alanine isopropyl ester hydrochloride(52.5 g, 0.314 mol) was dissolved in dichloromethane(200 mL) solution, and then6-amino-9 - [(2R) -2 - [[chloro (phenoxy) phosphonoyl] methoxy] isopropyl] purine(Compound 2) (60 g of crude product) in toluene (300 mL) was added to the reaction solution,After completion of the addition, the mixture was cooled to -25 ° C and triethylamine (31.8 g, 0.314 mol)After the dropwise addition, the reaction was continued for 1 hour and the reaction was terminated.To the reaction solution was added 10percent aqueous sodium dihydrogenphosphate (400 mL)Fully stirred extraction layer,The organic phase was extracted with 15percent aqueous solution of potassium hydrogencarbonate (170 mL)The organic phase was washed successively with deionized water (150 mL x 1)Dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure(2S) -2 - [[[(1R) -2- (6-aminopurine-9-yl)1-methyl-ethoxy] methyl-phenoxy-phospho] amino]Isopropyl propionate(Compound 3) as a crude product.The crude product of compound 3 was added to a mixed solvent of acetonitrile (12 mL) and toluene (108 mL) (acetonitrile / toluene (v / v) = 1: 9). After stirring at room temperature for 6 hours, the solid was sufficiently precipitated, filtered, Washed with toluene (200 mL) and dried over the filter cake to give the purified product compound 3 (30 g, 35percent yield, 95.10percent HPLC purity, 96.04percent purity of the chiral HPLC diastereomer).Compound 3 (30 g) is added to acetonitrile (120 mL), heated to reflux for 1 hour, and then naturally cooled to room temperature, if desired, to obtain compound 3 with higher diastereomer purity, if necessary, After 6 hours of stirring, the solid was sufficiently precipitated and filtered. The filter cake was washed with acetonitrile (40 mL) and the cake was dried to give the purified product compound 3 (15 g, HPLC purity 99.40percent, chiral HPLC diastereomer purity 99.79 percent). |
33.4 g | With triethylamine In dichloromethane; toluene at -30 - 35℃; | In a round bottom flask equipped with reflux condenser, a suspension of monophenylPMPA (50 gms) in toluene (600 mL) was heated to 110°C and water removedazeotropically. The reaction was cooled to 50°C, and N, N-dimethyl formamide (0.5 mL) and thionyl chloride (25 gms) were added. The temperature of the reaction mixture was raised to 67-73°C and maintained at the same temperature for 12-24hrs. The reaction mixture was concentrated under vacuum and the residue obtained was co-evaporated withtoluene. To the resulting residue, toluene (250 mL) and dichloromethane (300 mL) were added and the resultant sluny was gradually cooled to -30°C. To the sluny, L-Alanine isopropyl ester hydrochloride (66 gms) and triethyl amine (40 gms) were sequentially added, temperature was allowed to raise to 25-35°C and stined at the same temperature. The mixture was cooled to 13°C and sequentially washed with aq NaH2PO4, aq NaHCO3and water. The resulting organic layer was dried over sodium sulphate and then concentrated under vacuum. The obtained residue was treated with a mixture of isopropyl alcohol (50 mL) and methyl tertiary butyl ether (200 mL) at RT, seeded with tenofovir alafenamide and stined for another 4-6hrs. The precipitated solid was filtered, and the wet material in a mixture of isopropyl alcohol (35 mL) and methyl tertiary butyl ether (140mL) was heated to a temperature of 55-61°C and stined for 3hrs. The reaction mass was cooled to room temperature and stined for 4hrs at the same temperature. The resulting solids were filtered and dried under vacuum at 45-55°C for 12-l6hrs to afford Tenofovir alafenamide (33.4 gms). HPLC purity: 99.4percent; RRS diastereomer: 0.5percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
190 g | Stage #1: With thionyl chloride In dichloromethane; toluene at 70 - 80℃; Inert atmosphere Stage #2: With potassium hydrogencarbonate In dichloromethane; toluene at 15 - 40℃; Inert atmosphere |
Acrylic chlorination step: 2.4 L of toluene was added to a 5 L reaction flask and TAF-Ml (400 g, prepared according to Example 1) was added,Heated to 70-80°C under nitrogen protection.Slowly add thionyl chloride (262g), add insulation 70-80°C, react for 40-50 hours, temperature below 75°C,Concentrate under reduced pressure until no significant distillate is produced, under nitrogen protection,Cool down to 20-40 °C, add 1600ml of methylene chloride, stir and disperse, wait for use;Dissociating step:Add 2.4L of methylene chloride to the 5L reaction flask, add TAF-SM2 (646g) and potassium bicarbonate (441g) at 15-25°C for 5-10 hours, filter, drain, and control the temperature at 30-40°C. Concentrate dry and press twice with fresh dichloromethane 400 ml*2 and add the residue to fresh dichloromethane 2.4L.Reaction steps:Under nitrogen protection cooling to -25 ~ -15 °C, slowly adding chlorine, adding insulation reaction for 1-2 hours, warming to 20-30 for 1-2 hours.Post-processing:Add 10percent of sodium dihydrogen phosphate aqueous solution 2000g, stir for 5-10 minutes, and stand for layering, the organic phase is respectively used 2000g 10percent sodium dihydrogen phosphate aqueous solution, 2000g*2 5percent potassium hydrogencarbonate aqueous solution, 2000g saturated chlorine The sodium solution and 2000 g of purified water were stirred for 5-10 minutes, and the mixture was allowed to stand for stratification. The organic phase was dried with 250 g-300 g of anhydrous sodium sulfate, filtered, and the mother liquor was dried under reduced pressure to obtain an oily substance under nitrogen protection. Add 400ml of acetonitrile and 1200ml of toluene, warm to 50-60°C, stir for 0.5-1 hour, clear the solution (about 20-30 minutes), slowly cool and crystallize (20-30°C, stir for 1-2 hours to start solidprecipitation) After precipitation of a large amount of solids, cool down to 0-10 °C for 1-2 hours, filter, drain, wash with toluene and dry to obtain crude product.Refining: Add the crude product to the reaction flask, add acetonitrile 1200ml, heat up to 60-70°C under nitrogen protectionSolution, the mother liquor slowly cooled and crystallized, 0-10 °C heat for 1-2 hours, filtered, pumped dry, filter cake 40-50 °C dried under reduced pressure for 10-12 hours to obtain the intermediate 190g TAF-M2. |
15 kg | Stage #1: With thionyl chloride In toluene at 70℃; for 50 h; Reflux; Inert atmosphere; Large scale Stage #2: With potassium hydrogencarbonate; sodium sulfate In dichloromethane at 20 - 70℃; for 24 h; Inert atmosphere; Large scale Stage #3: at 20℃; for 2 h; Inert atmosphere; Large scale |
250kg of toluene was pumped into 500L reactor I.Add the above TAF-IM vapor to reflux.The glass return pipe receives water from the bottle and no longer separates the water.After 2 hours of continuous cooling to room temperature,Nitrogen protection,Thionyl chloride 31kg in the high tank,Slowly and repeatedly into the kettle,Leave it at 70°C for 50 hours.Concentrate under reduced pressure to a thick state,After cooling down to room temperature, add 200 kg of n-heptane.Under nitrogen protection filter rejection to dryness,Collect solids,Dissolve complete solids with 200 kg of methylene chloride and transfer to the upper tank.Distill 250kg of dichloromethane into 500L reactor II.Add potassium bicarbonate 50kg,Anhydrous sodium sulfate 10kg and L-alanine isopropyl ester hydrochloride 75kg,Stir for 24 hours under nitrogen protection.Pump down to 500L reactor III.Proline catalyst SA (0.05 eq) was added.The nitrogen protection adds the batches in the high tank to the reactor III in multiple batches.Every time triethylamine 2kg is added,Total added 6kg,After the addition was completed, the mixture was stirred at room temperature for 2 hours.10percent aqueous solution of sodium dihydrogen phosphate in a concentration of 10percentSaturated brine extractionAfter drying over anhydrous sodium sulfate,Suction filtration to 500L dry clean reactorConcentrate under reduced pressure to 60L,Add 100kg of toluene,Then concentrate under reduced pressure to 100L.Then add 100kg of toluene and 50kg of acetonitrile.The solid precipitated slowly at room temperature.The frozen liquid is circulated and incubated for 4 hours.Rejection filter to dry,Acetonitrile beating,Agitate and rinse with acetonitrile.Rejection filter to dry,Drying at 40 °C under reduced pressure to obtain white solid TAF-II M15kg,Yield 45percent (calculated on the basis of "Tenofovir"). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
[00134] L-Alanine isopropyl ester hydrochloride (21.82 g, 0.1303 mol) was charged under nitrogen atmosphere into a round bottom flask, tert-butyl methyl ether (98 mL) was added and the mixture was cooled to 0 °C. Dichlorophenylphosphate (26.2 g, 0.124 mol) was added. The reaction solution was cooled to -10 °C to 0 °C and triethylamine (38.38 mL, 0.248 mol) in tert-butyl methyl ether (98 mL) was added at - 10 °C to 0 °C. The reaction mixture was allowed to stir at 0 °C for 4 h. [00135] In a separate round bottom flask, a 3,5-diiodo-4-hydroxy methylbenzoate (DIHMB - 30 g, 0.074 mol) and tert-butyl methyl ether (98 mL) mixture was prepared under nitrogen atmosphere. This mixture was cooled to -5 to 0 °C and triethylamine (17.42 mL, 0.124 mol) was added. This solution was added to the previous reaction mixture at 0 to 5 °C under nitrogen atmosphere and stirred for 1 to 2 h at 0 °C. After stirring for 2 h, water (66 mL) was added and the organic layer was twice washed with 2.5percent Na2C03 (aq) solution (66 mL), followed by 6percent NaHCC (aq) solution (500 mL). The organic layer was concentrated under vacuum to give a solid residue (60 g). This solid was stirred in hexanes (85 mL) and filtered. The obtained solid was dried at 35 °C under vacuum to give the desired product as an off-white solid (43.49 g, 80percent yield; >90percent purity) as 1 : 1 mixture of diastereomers. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
11.5 g | Phosphorus oxychloride (5 g, 3.04 ml, 32.6 mmol) was added to the reaction flask.Add acetonitrile 200mL,Cool to -70 C,Slowly add K11 (9.8g, 32.6mmol)And a solution of triethylamine (3.3 g, 4.53 ml, 32.6 mmol) in acetonitrile (60 mL).After the dropwise addition was completed, the temperature was slowly raised to room temperature, and the reaction was continued overnight.Cool the above mixture to 0 C,Add HA30 (4.93g, 29.4mmol),Cool to -70 C,60 mL of a solution of triethylamine (7.3 g, 10 ml, 72 mmol) in acetonitrile was added dropwise.After the addition, warm up to 0 C,Pentafluorophenol (5.4 g, 29.4 mmol) was reacted for 3 hours.And 60 mL of a solution of triethylamine (7.3 g, 10 ml, 72 mmol) in acetonitrile was added dropwise to the above solution.Stir at 0 C for 1 hour,Raise to room temperature and stir overnight.After adding 100 ml of dichloromethane and 100 ml of water, the organic phase was separated, dried over anhydrous sodiumThe residue was separated on a silica gel column (0-30% ethyl acetate /hexane)11.5g of white solid,The solid was recrystallized from 10% t-butyl methyl ether / hexane.Obtained white solid FP130-2 (4.5g),The mother liquor was separated on a silica gel column (50% ethyl acetate /hexane) to give FP130-1 (3.4 g) and FP130-2 (0.6 g).Both FP130-2 and FP130-1 are more than 99% pure. |
Tags: 39613-92-8 synthesis path| 39613-92-8 SDS| 39613-92-8 COA| 39613-92-8 purity| 39613-92-8 application| 39613-92-8 NMR| 39613-92-8 COA| 39613-92-8 structure
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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 |
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