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Quality Control of [ 625095-57-0 ]

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Product Details of [ 625095-57-0 ]

CAS No. :625095-57-0 MDL No. :MFCD20484200
Formula : C9H11ClO2 Boiling Point : -
Linear Structure Formula :- InChI Key :VJGRFGFLZJIODS-VIFPVBQESA-N
M.W : 186.64 Pubchem ID :11446776
Synonyms :

Calculated chemistry of [ 625095-57-0 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 12
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.33
Num. rotatable bonds : 3
Num. H-bond acceptors : 2.0
Num. H-bond donors : 2.0
Molar Refractivity : 48.36
TPSA : 40.46 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.47 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.74
Log Po/w (XLOGP3) : 1.37
Log Po/w (WLOGP) : 1.43
Log Po/w (MLOGP) : 1.83
Log Po/w (SILICOS-IT) : 2.19
Consensus Log Po/w : 1.71

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 1.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -2.03
Solubility : 1.73 mg/ml ; 0.00928 mol/l
Class : Soluble
Log S (Ali) : -1.82
Solubility : 2.81 mg/ml ; 0.015 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -2.72
Solubility : 0.354 mg/ml ; 0.0019 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.87

Safety of [ 625095-57-0 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P264-P280-P302+P352-P305+P351+P338-P332+P313-P337+P313-P362 UN#:N/A
Hazard Statements:H315-H319 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 625095-57-0 ]

* 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.

  • Downstream synthetic route of [ 625095-57-0 ]

[ 625095-57-0 ] Synthesis Path-Downstream   1~61

  • 1
  • [ 777-52-6 ]
  • [ 625095-57-0 ]
  • [ 693223-08-4 ]
  • 2
  • [ 625095-57-0 ]
  • [ 625095-59-2 ]
  • <i>N</i>'-(9-{2-[4-(3-chloro-phenyl)-2-oxo-2λ5-[1,3,2]dioxaphosphinan-2-ylmethoxy]-ethyl}-9<i>H</i>-purin-6-yl)-<i>N</i>,<i>N</i>-dimethyl-formamidine [ No CAS ]
  • 3
  • [ 625095-56-9 ]
  • [ 625095-57-0 ]
YieldReaction ConditionsOperation in experiment
100% With borane-THF; In tetrahydrofuran; at 5 - 20℃; for 2h; Preparation of (S)-(-)-l-(3-chlorophenyl)-1,3-propanediol (3) The diol was prepared as described in U. S. PreGrant Published Application No. 20030225277 Al. A 12 L, 3-neck round bottom flask was equipped with a mechanical stirrer, addition funnel (2 L) and thermometer. The flask was flushed with nitrogen and charged with (S)-3-(3-chlorophenyl)-3-hydroxypropanoic acid 2 (206.7 g) and THF (850 mL), and the stirred solution was cooled to 5 C. (ice bath). AIM borane in THF solution (2.14 L) was charged to the addition funnel, and then added slowly with stirring maintaining the temperature at <10 C. After the addition was complete (approximately 1 h), the cooling bath was removed and the solution was stirred at ambient temperature for 1 h. The reaction solution was slowly and cautiously quenched with water (600 mL), followed by 3 M NaOH solution (850 mL). The mixture was stirred for 10 min. with an observed temperature increase to approximately 40 C, and then the mixture was transferred to a separatory funnel. The layers were separated and the aqueous phase was extracted again with ethyl acetate (600 mL). The combined organic phase was washed with approximately 10% NaCI solution (500 mL), dried (MgS04, 322 g), filtered and concentrated under reduced pressure to provide 189.0 g of a pale yellow oil (101%).
94% With borane; In tetrahydrofuran; at 5 - 20℃; for 2h; Example 3 Preparation of (S)-(-)-1-(3-Chlorophenyl)-1,3-propanediol (3) A 12 L, 3-neck round bottom flask was equipped with a mechanical stirrer, addition funnel (2 L) and thermometer. The flask was flushed with nitrogen and charged with (S)-3-(3-chlorophenyl)-3-hydroxypropanoic acid 2 (206.7 g) and THF (850 mL), and the stirred solution was cooled to 5 C. (ice bath). A 1 M borane in THF solution (2.14 L) was charged to the addition funnel, and then added slowly with stirring maintaining the temperature at <10 C. After the addition was complete (approximately 1 hour), the cooling bath was removed and the solution was stirred at ambient temperature for 1 hour. The reaction solution was slowly and cautiously quenched with water (600 mL), followed by 3 M NaOH solution (850 mL). The mixture was stirred for 10 minutes with an observed temperature increase to approximately 40 C., and then the mixture was transferred to a separatory funnel. The layers were separated and the aqueous phase was extracted again with ethyl acetate (600 mL). The combined organic phase was washed with approximately 10% NaCl solution (500 mL), dried (MgSO4, 322 g), filtered and concentrated under reduced pressure to provide 189.0 g of a pale yellow oil (101%). Preliminary analysis of the oil was by 1H-NMR (CDCl3). The oil was purified by vacuum distillation and the fraction at 125-155 C./0.15 mmHg was collected. Recovery=180.9 g
94% With borane-THF; In tetrahydrofuran; at 5 - 20℃; for 2h; A 12 L, 3-neck round bottom flask was equipped with a mechanical stirrer, addition funnel (2 L) and thermometer. The flask was flushed with nitrogen and charged with (S)-3-(3'-chlorophenyl)-3-hydroxypropanoic acid (206.7 g) and THF (850 mL), and the stirred solution was cooled to 5 C. (ice bath). A 1M borane in THF solution (2.14 L) was charged to the addition funnel, then added slowly with stirring maintaining the temperature <10 C. After the addition was complete (1 h), the cooling bath was removed and the solution was stirred at ambient temperature for 1 h. The reaction solution was slowly and cautiously quenched with water (600 mL), followed by 3 M NaOH solution (850 mL). The mixture was stirred for 10 min, then transferred to a separatory funnel. The layers were separated and the aqueous phase was back extracted with ethyl acetate (600 mL). The combined organic phase was washed with brine (500 mL), dried (MgSO4, 322 g), filtered and concentrated under reduced pressure to provide 189.0 g of a pale yellow oil (101%). The oil was purified by vacuum distillation and the fraction at 125-155 C./0.15 mmHg was collected to provide 180.9 g of a colorless oil (94.0%). [0344] The diol (5.0 mg, 0.026 mmol) was dissolved in dichloromethane (2.0 mL). Acetic anhydride (15 μL, 0.15 mmol) and 4-(dimethylamino)pyridine (13 mg, 0.10 mmol) were added and the solution was stirred at ambient temperature for 15 min. The reaction solution was quenched with 1 M HCl solution (3 mL) and the lower organic phase was separated, passed through a plug of MgSO4, and concentrated with a stream of nitrogen. The residue was dissolved in methanol (1 mL) and analyzed by chiral HPLC (see, Example 7; Step B). ee>98%.
92.2% With borane-THF; In tetrahydrofuran; at 0 - 16℃; for 4.5h; A 22 L, 3-neck round bottom flask was equipped with a mechanical stirrer, thermowell/thermometer and nitrogen inlet (outlet to bubbler). The flask was charged with 2M borane-THF (3697 g, 4.2 L) and the stirred solution was cooled to 5 C. A solution of (S)-3-(3-chlorophenyl)-3-hydroxypropanoic acid (830 g) in THF (1245 mL) was prepared with stirring (slightly endothermic). The reaction flask was equipped with an addition funnel (1 L) and the hydroxyacid solution was slowly added to the stirred borane solution, maintaining the temperature <16 C. After the addition was complete (3 h), the mixture was stirred at ice bath temperature for 1.5 h. The reaction was quenched by careful addition of water (2.5 L). After the addition was complete (30 min), 3M NaOH solution (3.3 L) was added (temperature increased to 35 C.) and the resulting mixture was stirred for an additional 20 minutes (temperature=30 C.). The reaction mixture was transferred to a 5 gallon stationary separatory funnel and the layers were separated. The aqueous phase was extracted with MTBE (2.5 L) and the combined organic extracts (THF and MTBE) were washed with 20 wt % NaCl solution (2 L) and stirred with MgSO4 (830 g) for 30 minutes. The mixture was filtered through Celite and concentrated under reduced pressure to provide 735 g of a thick, brown oil. [0336] The oil was purified by vacuum distillation and the fraction at 135-140 C./0.2 mmHg was collected to provide 712.2 g of a colorless oil (92.2%). [0337] The diol was diacetylated and analyzed by chiral HPLC (e.e.=98%) (see Step B). Retention times: S-diol (diacetate)=12.4 min, R-diol (diacetate)=8.9 min. [α]D=-51.374 (5 mg/mL in CHCl3)
Step D: Preparation of (S)-(-)-1-(3-chlorophenyl)-1,3-propanediol: A 22 L, 3-neck round bottom flask was equipped with a mechanical stirrer, thermowell/thermometer and nitrogen inlet (outlet to bubbler). The flask was charged with 2 M borane-THF (3697 g, 4.2 L) and the stirred solution was cooled to 5 C. A solution of (S)-3-(3-chlorophenyl)-3-hydroxypropanoic acid (830 g) in THF (1245 mL) was prepared with stirring (slightly endothermic). The reaction flask was equipped with an addition funnel (1 L) and the hydroxyacid solution was slowly added to the stirred borane solution, maintaining the temperature <16 C. After the addition was complete (3 h), the mixture was stirred at ice bath temperature for 1.5 h. The reaction was quenched by careful addition of water (2.5 L). After the addition was complete (30 min), 3 M NaOH solution (3.3 L) was added (temperature increased to 35 C.) and the resulting mixture was stirred for an additional 20 min. (temperature=30 C.). The reaction mixture was transferred to a 5 gallon stationary separatory funnel and the layers were separated. The aqueous phase was extracted with MTBE (2.5 L) and the combined organic extracts (THF and MTBE) were washed with 20 wt % NaCl solution (2 L) and stirred with MgSO4 (830 g) for 30 min. The mixture was filtered through Celite and concentrated under reduced pressure to provide 735 g of a thick, brown oil. The oil was purified by vacuum distillation and the fraction at 135-140 C./0.2 mm Hg was collected to provide 712.2 g of a colorless oil. The diol was diacetylated and analyzed by chiral HPLC (e.e.=98%) (see Step B).

  • 5
  • [ 777-52-6 ]
  • [ 625095-57-0 ]
  • [ 883989-35-3 ]
YieldReaction ConditionsOperation in experiment
97% With triethylamine; In dichloromethane; at 20℃; for 1h; Compound 18A (1.3 g, 6.97 mmol) was dissolved in 10 mL of tetrahydrofuran, add triethylamine (2.1 g, 20.8 mmol), slowly add p-nitrophenyl dichlorophosphonic acid (2.1 g, 8.20 mmol) at room temperature, and stir at room temperature for 1 h. 20mL of water and 20mL of ethyl acetate were added for extraction. The organic layer was washed with a saturated aqueous sodium chloride solution (20 mL x 3), and dried over anhydrous sodium sulfate. Concentrated under reduced pressure, and the residue was further purified by silica gel column chromatography (ethyl acetate / petroleum ether = (v / v) 1/1 1/0),The title compound 18B was obtained as a pale yellow oil (2.5 g, 97% yield).
  • 6
  • [ 51699-45-7 ]
  • [ 632327-18-5 ]
  • [ 625095-57-0 ]
  • 7
  • [ 618-46-2 ]
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  • 8
  • [ 625095-57-0 ]
  • 1-{(2R,4R)-2-[(S)-4-(3-Chloro-phenyl)-2-oxo-2λ5-[1,3,2]dioxaphosphinan-2-yloxymethyl]-[1,3]dioxolan-4-yl}-5-methyl-1H-pyrimidine-2,4-dione [ No CAS ]
  • 11
  • [ 51699-40-2 ]
  • [ 625095-57-0 ]
  • 12
  • [ 13422-80-5 ]
  • [ 625095-57-0 ]
  • 13
  • [ 587-04-2 ]
  • Fmoc-L-tert-leucine on Wang resin [ No CAS ]
  • [ 625095-57-0 ]
  • 15
  • [ 625095-57-0 ]
  • [ 625095-60-5 ]
  • 16
  • [ 625095-57-0 ]
  • [ 693223-03-9 ]
  • 17
  • [ 625095-57-0 ]
  • [ 804561-62-4 ]
  • 20
  • [ 1056998-35-6 ]
  • [ 625095-57-0 ]
  • 9-{2-[2,4-trans(R)-(-)-4-(3-Chlorophenyl)-2-oxo-1,3,2-dioxaphosphorinan-2-yl]methoxyethyl}adenine [ No CAS ]
  • C22H28ClN6O4P [ No CAS ]
YieldReaction ConditionsOperation in experiment
With pyridine; triethylamine; In dichloromethane; at -71 - 0℃; for 1.75h; A 2 L, 3-neck round bottom flask was equipped with a mechanical stirrer, and addition funnel (1 L). The flask was flushed with nitrogen and charged with (S)-(-)-(3-chlorophenyl)-1,3-propanediol 3 (34.1 g), as a solution in dichloromethane (500 mL) and triethylamine (125 ml). A thermocouple probe was immersed in the reaction solution and the stirred contents were cooled to -71 C. (dry ice/isopropanol). The dichloridate solution 8 was charged to the addition funnel, then added slowly with stirring, maintaining the temperature <-67 C. After the addition was complete (1.25 h), the cooling bath was removed and the stirred mixture was warmed to 0 C. over 30 min. The reaction mixture was washed with water (550 mL) and the layers were separated. The dichloromethane phase was diluted with ethyl acetate (500 mL) and washed with 5% NaCl solution (600 mL). The organic phase was dried (MgSO4, 50 g), filtered through diatomaceous earth (Celite 521), and concentrated under reduced pressure to provide 108 g of a dark red sludge. The sample was dissolved in methanol. [0185] HPLC conditions: [0186] YMC-Pack R & D, R-33-5 S-5 120A, 250×4.6 mm; mobile phase: Solvent A=20 mM potassium phosphate, pH 6.2; Solvent B=acetonitrile; gradient: 10-60% B/15 min., 60-10% B/2 min., 10% B/3 min.; 1.4 mL/ min.; inj. vol.=10 μL; UV detection at 270 nm. [0187] Retention times: cis 13=12.5 min., trans 14=13.0 min. [CHEMMOL-00027] [0188] The material was dissolved in ethanol (500 mL) and transferred to a 2 L round bottom flask equipped with magnetic stirring, condenser and heating mantle. Acetic acid (55 mL) was added and the red solution was heated at reflux for 8 hours. HPLC indicated the reaction was complete. The sample was dissolved in methanol. [0189] HPLC conditions: [0190] YMC-Pack R & D, R-33-5 S-5 120A, 250×4.6 mm; mobile phase: Solvent A=20 mM potassium phosphate, pH 6.2; Solvent B=acetonitrile; gradient: 10-60% B/15 min., 60-10% B/2 min., 10% B/3 min.; 1.4 mL/ min.; inj. vol.=10 μL; UV detection at 270 nm. 6. [0191] Retention times: cis 15=9.5 min., trans. 16=9.8 min
With triethylamine; In pyridine; dichloromethane; at -71 - 0℃; for 1.75h;Cooling with dry ice/isopropanol; A 2L, 3-neck round bottom flask was equipped with a mechanical stirrer, and addition funnel (1L). The flask was flushed with nitrogen and charged with (S)-(-)-(3'-chlorophenyl)-1,3-propanediol (34.1 g), as a solution in dichloromethane (500 mL) and triethylamine (125 ml). A thermocouple probe was immersed in the reaction solution and the stirred contents were cooled to -71 C. (dry ice/isopropanol). The dichloridate solution 11 was charged to the addition funnel, then added slowly with stirring, maintaining the temperature <-67 C. After the addition was complete (1.25 h), the cooling bath was removed and the stirred mixture was warmed to 0 C. over 30 min. The reaction mixture was washed with water (550 mL) and the layers were separated. The dichloromethane phase was diluted with ethyl acetate (500 mL) and washed with 5% NaCl solution (600 mL). The organic phase was dried (MgSO4, 50 g), filtered through diatomaceous earth (Celite 521), and concentrated under reduced pressure to provide 108 g of a dark red sludge. The samples were dissolved in methanol. [0369] HPLC Conditions: [0370] YMC-Pack R & D, R-33-5 S-5 120A, 250×4.6 mm; mobile phase: Solvent A=20 mM potassium phosphate, pH 6.2; Solvent B=acetonitrile; gradient: 10-60%B/15 min., 60-10%B/2 min., 10%B/3 min.; 1.4 mL/min.; inj. vol.=10 μL; UV detection at 270 nm. [0371] Retention Times: cis 14=12.5 min., trans 15=13.0 min. [0372] The material was dissolved in ethanol (500 mL) and transferred to a 2 L round bottom flask equipped with magnetic stirring, condenser and heating mantle. Acetic acid (55 mL) was added and the red solution was heated at reflux for 8 hours. HPLC indicated the reaction was complete. The samples were dissolved in methanol. [0373] HPLC Conditions: [0374] YMC-Pack R & D, R-33-5 S-5 120A, 250×4.6 mm; mobile phase: Solvent A=20 mM potassium phosphate, pH 6.2; Solvent B=acetonitrile; gradient: 10-60%B/15 min., 60-10%B/2 min., 10%B/3 min.; 1.4 mL/min.; inj. vol.=10 μL; UV detection at 270 nm. [0375] Retention Tmes: cis 16=9.5 min., trans 17=9.8 min.
  • 21
  • [ 108-24-7 ]
  • [ 632327-18-5 ]
  • [ 625095-57-0 ]
  • [ 625095-67-2 ]
  • [ 625095-68-3 ]
YieldReaction ConditionsOperation in experiment
With triethylamine;dmap; In dichloromethane;Product distribution / selectivity; Step D: To a solution of crude m-chloroepoxycinnamyl alcohol obtained from earlier reaction in dimethoxyethane (300 mL) was added a 65% Red-Al solution in toluene (18.63 mL, 60 mmol) dropwise under nitrogen at 0 C. After stirring at room temperature for 3 h, the solution was diluted with ethyl acetate (400 mL) and quenched with aq. saturated sodium sulfate solution (50 mL). After stirring at room temperature for 30 min, the resulting white precipitate formed was filtered and washed with ethylacetate. The filtrate was dried and concentrated. The crude product was distilled at 125-130 C./0.1 nm to give 3.75 g of enantioenriched (R)-1-(3'-chlorophenyl)-1,3-dihydroxypropane. (Rf=0.40 in 1:1 ethylacetate:dichloromethane). Enantiomeric excesses were defined as diacetates (prepared by treatment of diols with acetic anhydride, triethylamine, cat.DMAP in dichloromethane) by HPLC ((S,S) Whelko-0, 250 cm×4.0 mm ID purchased from Regis). (R)-1-(3'-chlorophenyl)-1,3-dihydroxypropane: 91% ee (+)Diisopropyltartrate provided >96% ee in (R)-1-(3'-chlorophenyl)-1,3-dihydroxypropane. (S)-1-(3'-chlorophenyl)-1,3-dihydroxypropane was also prepared under identical conditions via asymmetric epoxidation and reduction protocol utilizing (-)-tartrate in similar yields. (S)-3-(3'-chlorophenyl)-1,3-dihydroxypropane was obtained with 79% ee; Step D: Preparation of (S)-(-)-1-(3-chlorophenyl)-1,3-propanediol: A 22 L, 3-neck round bottom flask was equipped with a mechanical stirrer, thermowell/thermometer and nitrogen inlet (outlet to bubbler). The flask was charged with 2 M borane-THF (3697 g, 4.2 L) and the stirred solution was cooled to 5 C. A solution of (S)-3-(3-chlorophenyl)-3-hydroxypropanoic acid (830 g) in THF (1245 mL) was prepared with stirring (slightly endothermic). The reaction flask was equipped with an addition funnel (1 L) and the hydroxyacid solution was slowly added to the stirred borane solution, maintaining the temperature <16 C. After the addition was complete (3 h), the mixture was stirred at ice bath temperature for 1.5 h. The reaction was quenched by careful addition of water (2.5 L). After the addition was complete (30 min), 3 M NaOH solution (3.3 L) was added (temperature increased to 35 C.) and the resulting mixture was stirred for an additional 20 min. (temperature=30 C.). The reaction mixture was transferred to a 5 gallon stationary separatory funnel and the layers were separated. The aqueous phase was extracted with MTBE (2.5 L) and the combined organic extracts (THF and MTBE) were washed with 20 wt % NaCl solution (2 L) and stirred with MgSO4 (830 g) for 30 min. The mixture was filtered through Celite and concentrated under reduced pressure to provide 735 g of a thick, brown oil. The oil was purified by vacuum distillation and the fraction at 135-140 C./0.2 mm Hg was collected to provide 712.2 g of a colorless oil. The diol was diacetylated and analyzed by chiral HPLC (e.e.=98%) (see Step B). Retention times: S-diol (diacetate)=12.4 min, R-diol (diacetate)=8.9 min. [α]D=-51.374 (5 mg/mL in CHCl3)
  • 22
  • [ 110520-74-6 ]
  • [ 625095-57-0 ]
  • C10H11ClIO3P [ No CAS ]
  • C10H11ClIO3P [ No CAS ]
YieldReaction ConditionsOperation in experiment
With titanium tetrachloride; triethylamine; In dichloromethane; at 20 - 25℃; for 1.25h; Coupling of iodomethylphosphonic acid with (S)-(-)-I-(3- chlorophenyl)-1,3-propanediol A 500 mL 4-neck round bottom flask equipped with a heating mantle, mechanical stirring, an addition funnel, thermocouple, and a condenser with nitrogen inlet was charged with methylene chloride (80 mL), iodomethylphosphonic acid (9.88 g, 44.5 mmol), and N, N-diethylformamide (0.4 mL, 5.0 mol). The oxalyl chloride (9.0 mL, 103 mmol) was added via the addition funnel at such a rate as to maintain control over the gas evolution (0.25 h). The slurry was heated to reflux for 4 h during which time all of the solids had dissolved. The solution was cooled to room temperature. A 100 mL 3-neck round bottom flask equipped with a cooling bath, mechanical stirring, nitrogen inlet, thermocouple, and tubing adapter was charged with methylene chloride (70 mL), S (-)-1-(3-chlorophenyl)-1,3-propanediol (8.85 g, 44.6 mmol). The solution was cooled to < 10 C. Titanium tetrachloride (4.9 ml, 45.6 mmol) was added, and a heavy precipitate formed after approximately 5 min. Triethylamine (25 ml, 178 mmol) was added. The precipitate dissolved, and the solution turned to a purple color. After a few minutes, a light precipitate was observed forming. The diol/titanium tetrachloride solution was added to the dichloridate solution over 15 min; the initial temperature was 20 C and the final temperature was 25 C. The reaction was stirred at ambient temperature for 1 h, and then quenched with methanol (10 mL) and water (50 mL). After separation of layers, the aqueous phase was extracted with methylene chloride (50 mL). The combined organic layers were dried over MgS04, and concentrated to an oil (20 g). The ratio of major to minor isomer = 3.62:1.00 . by 3¹P NMR (DMSO) 8 = 91.0 (3.62 P), 88.6 (I.OOP).
  • 23
  • C28H43Cl2O3PSi [ No CAS ]
  • [ 625095-57-0 ]
  • C37H52ClO5PSi [ No CAS ]
  • C37H52ClO5PSi [ No CAS ]
YieldReaction ConditionsOperation in experiment
With titanium tetrachloride; triethylamine; In dichloromethane; at 10 - 20℃; for 2.5h; Preparation of 4-{4-[2,4-cis-(,f)-4-(3-chlorophenyl)-2-oxo-2(at),5- (1,3,2]dioxaphosphinan-2-ylmethoxy]-2,6-dimethylbenzyl}-2- isopropylphenol A 500 ml 4-neck round bottom flask equipped with a heating mantle, mechanical stirring, an addition funnel, thermocouple, and a condenser with nitrogen inlet is charged with methylene chloride (190 ml), [4-(3-isopropyl-4- triisopropylsilanyloxy-benzyl) -3,5-dimethyl-phenoxymethyl]-phosphonic acid (55.1 mmol), and N,N -diethylformamide (5 mmol). Oxalyl chloride (115 mmol) is added via the addition funnel at a rate to control the gas evolution (0.5 h). The slurry is heated to reflux for 4 h. The solution is cooled to room temperature. A 250 ml 3-neck round bottom flask equipped with a cooling bath, mechanical stirring, nitrogen inlet, thermocouple, and tubing adapter is charged with methylene chloride (150 ml) and S(-)-1-(3-chlorophenyl)-1,3-propanediol (55.1 mmol). The solution is cooled to < 10 C. Titanium tetrachloride (56.0 mmol) is added, and a heavy precipitate forms after approximately 5 min. Triethylamine (222 mmol) is added. The precipitate dissolves, and the solution changes to a purple color. After a few minutes, a light precipitate forms. The diol/titanium tetrachloride solution is added to the dichloridate solution over 90 min. The reaction is stirred at ambient temperature for 1 h, and then is quenched with methanol (90 ml). The cis:trans ratio is approximately 3 to 1. The solution is poured into water (165 ml). The mixture is transferred to a separatory funnel, and the layers are separated. The organic phase is washed with 5% sodium chloride solution (300 ml) and is dried over MgS04. The methylene chloride is removed by vacuum distillation. THF (300 ml) and tetrethylammonium fluoride (56 mmol) is added. The solution is stirred for 1 h followed by quenching with water (50 ml). After separation of layers, the aqueous phase is extracted with ethyl acetate (50 ml). The combined organic layers are washed with brine (50 ml), dried over MgS04, and are concentrated. The product, 4-{4-[2,4-cis-(S)-4- (3-chlorophenyl)-2-oxo-2(at),5-[1,3,2]dioxaphosphinan-2-ylmethoxy]-2,6- dimethylbenzyl} -2-isopropylphenol is purified by crystallization or chromatography.
  • 24
  • C38H45Cl2N4O7P [ No CAS ]
  • [ 625095-57-0 ]
  • C48H56ClN4O9P [ No CAS ]
  • C48H56ClN4O9P [ No CAS ]
YieldReaction ConditionsOperation in experiment
With pyridine; dmap; triethylamine; In dichloromethane; at -78 - 20℃; To a solution of diacid (0.30 g, 0.41 mmol) in 3 mL of CHbCk at 0 C wasadded oxalyl chloride (0.74 mL, 8.20 mmol) and catalytic amount of DMF (100&L). The reaction mixture was stirred at 0 C for 0.5 h and warmed to roomtemperature for 0.5 h. The solvent was removed on rotavap, co-evaporatedT7Owith toluene, and dried under vacuum to give the dichloridate as a paleyellow solid which was dissolved in 2.0 mL of CfkCb, cooled to 0 C, andtreated slowly with pyridine (67 uL, 0.82 mmol). The above cold solution wasthen added slowly to a -78 C solution of diol (0.23 g, 1.23 mmol) andtriethylamine (0.40 mL, 2.87 mmol) in 1.0 mL CHzCk followed by addition ofDMAP (10 mg). The reaction mixture was stirred at -78 C for 0.5 h, warmed ,to 0 C for 1 h, and then warmed to room temperature and stirred overnight.The reaction mixture was poured into aqueous NH4C1 and extracted withCHbCk (3 x). The organic layers were washed with brine, dried with NazSCk,filtered and concentrated. The crude product was purified by columnchromatography on silica gel (2% MeOH/CHaCk) to give isomer A,compound 51 (50 mg, 14%) and isomer B, compound 52 (50 mg, 14%). *HNMR (CDsOD) for compound 51: 5 8.10 (m, 3H), 7.57 (m, 4H), 7.38 (m, 4H),7.23 (s, 1H), 7.05 (m, 1H), 6.70 (m, 1H), 5.95 (m, 2H), 5.57 (s, broad, 1H), 5.30(m, 1H), 5.10 (m, 1H), 4.85 (m, 1H), 4.70 (m, 1H), 4.60 (m, 2H), 4.30 (d, J = 9.3Hz, 1H), 4.00 (m, 4H), 2.75 (m, 1H), 2.30 (m, 2H), 2.10 (m, 1H), 1.60 (m, 12H),1.00 (s, 9H); 31P NMR (CDsOD) 5 15.98. LC/MS: 885 (M+ + 1). JH NMR(CDsOD) for compound 52: 5 8.10 (m, 3H), 7.57 (m, 4H), 7.38 (m, 4H), 7.23 (s,1H), 7.05 (m, 1H), 6.70 (m, 1H), 5.95 (m, 1H), 5.58 (m, 2H), 5.30 (m, 1H), 5.10(m, 1H), 4.70 (m, 1H), 4.60 (m, 2H), 4.30 (d, J = 9.3 Hz, 1H), 4.00 (m, 4H), 2.70(m, 1H), 2.50 - 2.08 (m, 3H), 1.60 (m, 12H), 1.00 (s, 9H); 31P NMR (CDsOD) 523.19. LC/MS: 885 (M+ +1).
  • 25
  • [ 625095-57-0 ]
  • C7H17N*C9H10ClO2P [ No CAS ]
YieldReaction ConditionsOperation in experiment
With N,N-diisopropylphosphoramide dichloride; triethylamine; In tetrahydrofuran; at -78 - 20℃; To a solution of commercially available diisopropyl phosphoramidous dichloride (1 mmol) in THF (5 mL) was added 1,3-diol (1 mmol) and triethylamine (4mmol) in THF (5 mL) at -78 0C over 30 min. The reaction was slowly warmed to room temperature and left stirring overnight. Reaction mixture was filtered to remove salts and filtrate was concentrated to give crude product. Silica gel column chromatography provided pure cyclic diisopropyl phosphoramidite of 1 ,3-diol.
  • 26
  • [ 777-52-6 ]
  • [ 625095-57-0 ]
  • [ 883989-27-3 ]
YieldReaction ConditionsOperation in experiment
A solution of 1 -(3 -chlorophenyl)- 1,3 -propane diol (25 g, 134 mmol) and triethylamine (62.5 mL, 442 mmol) in THF was added to a solution of 4-nitrophenyl- phosphorodichloridate (37.7 g, 147 mmol) in THF at room temperature and the resulting solution was heated at reflux. After 2 h, TLC indicated complete consumption of the starting diol and formation of the cis and trans isomers in a 60/40 ratio (HPLC). The clear yellow solution was cooled to 30 0C, sodium 4-nitrophenoxide (56 g, 402 mmol)) was added and the reaction mixture was heated at reflux. After 90 min. the reddish reaction mixture was cooled to room temperature and stirred at room temperature for 2 h then placed in the refrigerator overnight. The final ratio was determined by HPLC to be 96/4 translcis. The reaction mixture was quenched with a saturated solution of ammonium chloride and diluted with ethyl acetate. The layers were separated and the organics were washed 4 times with 0.3 N sodium hydroxide to remove the nitrophenol, then saturated sodium chloride and dried over sodium sulfate. The filtered solution was concentrated under reduced pressure and the resulting solid was recrystallized from ethyl acetate to give large off white needles (45 g, mp = 115-116 0C, purity 98 A%).1HNMR (CDCl3, Varian Gemini 200 MHz): C'-proton: cis-isomer 5.6-5.8 (m, IH), trans- isomer 5.5-5.6 9 (m, IH).TLC conditions: Merck silica gel 60 F254 plates, 250 mum thickness; mobile phase = 60/40 hexanes/ethyl acetate; Rf: diol = 0.1, cis-phosphate = 0.2, trans-phosphate = 0.35. HPLC conditions: Column = Waters mu Bondapack Cl 8 3.9 x 300 mm; mobile phase = 40/60 acetonitrile/phosphate buffer pH 6.2; flow rate = 1.4 mL/min; detection = UV @ EPO <DP n="116"/>270 nm; retention times in min: cis-isomer = 14.46, trans-isomer = 16.66, 4-nitrophenol =4.14.
  • 27
  • [ 40620-64-2 ]
  • [ 625095-57-0 ]
YieldReaction ConditionsOperation in experiment
A 22 L, 3 -neck round bottom flask was equipped with a mechanical stirrer, thermo well/thermometer and nitrogen inlet (outlet to bubbler). The flask was charged with 2 M borane-THF (3697 g, 4.2 L) and the stirred solution was cooled to 5 C. A solution of (5)-3-(3-chlorophenyl)-3-hydroxypropanoic acid (830 g) in THFf(1245 mL) was prepared with stirring (slightly endothermic). The reaction flask was equipped with an addition funnel (1 L) and the hydroxyacid solution was slowly added to the stirred borane solution, maintaining the temperature < 16 C. After the addition was complete (3 h), the mixture was stirred at ice bath temperature for 1.5 h. The reaction was quenched by careful addition of water (2.5 L). After the addition was complete (30 min), 3 MNaOH solution (3.3 L) was added (temperature increased to 35 C) and the resulting mixture was stirred for an additional 20 min. (temperature = 30 0C). The reaction mixture was transferred to a 5 gallon stationary separatory funnel and the layers were separated.The aqueous phase was extracted with MTBE (2.5 L) and the combined organic extracts(THF and MTBE) were washed with 20 wt% NaCl solution (2 L) and stirred with MgSO4(830 g) for 30 min. The mixture was filtered through Celite and concentrated under reduced pressure to provide 735 g of a thick, brown oil.The oil was purified by vacuum distillation and the fraction at 135-140 0C/ 0.2 mm Hg was collected to provide 712.2 g of a colorless oil.The diol was diacetylated and analyzed by chiral HPLC (e.e. = 98%) (see Step B).Retention times: S-diol (diacetate) = 12.4 min, i?-diol (diacetate) = 8.9 min.[α]D= -51.374 (5 mg/mL in CHCl3)
  • 28
  • (2S,7S,10R)-2-(3-chlorophenyl)-7-isopropyl-10-methyl-1,5-dioxa-spiro[5.5]undecane [ No CAS ]
  • [ 625095-57-0 ]
  • 29
  • [ 142341-38-6 ]
  • [ 625095-57-0 ]
  • [ 625095-60-5 ]
  • 30
  • [ 852948-11-9 ]
  • [ 625095-57-0 ]
  • trans (S)-2-[4,6-dichloro-3-fluoro-5-(4'-hydroxy-3'-iso-propylphenoxy)-pyrid-2-ylaminomethyl]-4-(3-chlorophenyl)-2-oxo-2λ5-[1,3,2]-dioxaphosphonane [ No CAS ]
  • cis (S)-2-[4,6-dichloro-3-fluoro-5-(4'-hydroxy-3'-iso-propylphenoxy)-pyrid-2-ylaminomethyl]-4-(3-chlorophenyl)-2-oxo-2λ5-[1,3,2]-dioxaphosphonane [ No CAS ]
YieldReaction ConditionsOperation in experiment
22%; 33% With pyridine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20 - 68℃; for 16h; To a stirring solution of [4,6-dichloro-3-fluoro-5- (4'-hydroxy-3'-iso- propylphenoxy) -pyrid-2-ylamino] methylphosphonic (0.2 g, 0.47 mmol, US,6747048 B2) and (S)-1-(3-chlorophenyl)-1, 3-propanediol (0.18 g, 0.94 mmol) in DMF (6 mL) at room temperature was add pyridine (0.46 mL, 5.64 mmol) and EDCI (0.27 g, 1.41 mmol). The reaction mixture was stirred at68 C for 16 hrs. The solvent was removed under reduced pressure, and the residue was partitioned between EtOAc and water. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with ethyl acetate to afford: Compound13-12-trans : (60 mg, 22%) : 1H NMR (300 MHz, DMSO-d6) :8 9.20 (s,1 H), 7.67 (t, J= 6.0 Hz,1 H), 7.36-7. 48 (m, 4 H), 6.81 (d, J= 3.0 Hz,1 H), 6.69 (d, J= 9.0 Hz,1 H), 6.44 (dd,J= 3.0, 9.0 Hz,1 H), 5.78 (t,J= 7.5 Hz,1 H), 4.71 (m,1 H), 4.45 (m,1 H), 4.11 (m, 2 H), 3.17 (m,1 H), 2.19 (s,1 H), 1.14 (d,J= 6.9 Hz, 6 H); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase = ethyl acetate-hexanes (2: 1);Rf= 0.44 ;LC-MS mlz = 576[C24H23Cl3FN205P +H] + ; Anal Calcd for(C24H23C13FN205P +0. 2CH2CI2 + 0.3H20) : C, 48.58 ; H, 4.04 ; N, 4.68. Found: C, 48.64 ; H, 3.66 ; N, 4.83. Compound13-12-cis : (90 mg, 33%): IH NMR (200 MHz, DMSO-d6) :8 9.20 (s,1 H), 7.67 (t, J= 6.0 Hz,1 H), 7.21-7. 37 (m, 4 H), 6.71 (d,J= 3.0 Hz,1 H), 6.63 (d, J= 9.0 Hz,1 H), 6.34 (dd,J= 3.0, 9.0 Hz,1 H), 5.65 (d,J= 10.4 Hz,1 H), 4.21-4. 61 (m, 2 H), 4.11 (m,1 H),3. 80 (m,1 H), 3.07 (m,1 H), 2.11 (m, 1 H), 1. 88 (m,1 H), 1.04 (m, 6 H); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase = ethyl acetate; Rf= 0.53 ; LC-MSm/z = 576[C24H23C13FN205P + H]+ ; Anal Calcd for(C24H23Cl3FN205P +O.1CH2Cl2 + 0.4H20) : C, 48.94 ; H, 4.09 ; N, 4.74. Found: C, 48.57 ; H, 3.69 ; N, 4.92.
  • 31
  • [ 627082-36-4 ]
  • [ 625095-57-0 ]
  • cis-2-[4,6-dichloro-3-fluoro-5-(4'-hydroxy-3'-iso-propylphenoxy)-pyrid-2-ylaminomethyl]-4-(3-chlorophenyl)-2-oxo-2λ5-[1,3,2]-dioxaphosphonane [ No CAS ]
  • trans-2-[4,6-dichloro-3-fluoro-5-(4'-hydroxy-3'-iso-propylphenoxy)-pyrid-2-ylaminomethyl]-4-(3-chlorophenyl)-2-oxo-2λ5-[1,3,2]-dioxaphosphonane [ No CAS ]
YieldReaction ConditionsOperation in experiment
33%; 22% With pyridine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20 - 68℃; for 16h; To a stirring solution of [4,6-dichloro-3-fluoro-5-(4'-hydroxy-3'-iso-propylphenoxy)-pyrid-2-ylamino]methylphosphonic (0.2 g, 0.47 mmol, U.S. Pat. No. 6,747,048 B2) and (S)-1-(3-chlorophenyl)-1,3-propanediol (0.18 g, 0.94 mmol) in DMF (6 mL) at room temperature was add pyridine (0.46 mL, 5.64 mmol) and EDCI (0.27 g, 1.41 mmol). The reaction mixture was stirred at 68 C. for 16 hrs. The solvent was removed under reduced pressure, and the residue was partitioned between EtOAc and water. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with ethyl acetate to afford:Compound 13-12-trans (60 mg, 22%): 1H NMR (300 MHz, DMSO-d6): δ 9.20 (s, 1H), 7.67 (t, J=6.0 Hz, 1H), 7.36-7.48 (m, 4H), 6.81 (d, J=3.0 Hz, 1H), 6.69 (d, J=9.0 Hz, 1H), 6.44 (dd, J=3.0, 9.0 Hz, 1H), 5.78 (t, J=7.5 Hz, 1H), 4.71 (m, 1H), 4.45 (m, 1H), 4.11 (m, 2H), 3.17 (m, 1H), 2.19 (s, 1H), 1.14 (d, J=6.9 Hz, 6H); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=ethyl acetate-hexanes (2:1); Rf=0.44; LC-MS m/z=576 [C24H23Cl3FN2O5P+H]+; Anal Calcd for (C24H23Cl3FN2O5P+0.2CH2Cl2+0.3H2O): C, 48.58; H, 4.04; N, 4.68. Found: C, 48.64; H, 3.66; N, 4.83.
  • 32
  • [ 852947-39-8 ]
  • [ 625095-57-0 ]
  • [ 852948-13-1 ]
  • [ 852948-12-0 ]
YieldReaction ConditionsOperation in experiment
Compound of Formula 9 (1.20 g), dicyclohexylcarbodiimide (DCC) (2.03 g), pyridine (5.72 g) and N,N-dimethylformamide (6 ml) were added to a 25 ml reaction flask and stirred at room temperature for 10 minutes. Compound of Formula 10 (0.62 g) was added dropwise and heated to 65 C. After the reaction, 1 ml water was added to quench the reaction, and 20 ml dichloromethane was added to extract the reaction. The extract was detected by HPLC and showed that cis:trans≈1.7:1. Compound of Formula I was obtained by column chromatography (0.25 g, yield: 15%).
  • 33
  • C13H12Cl2NO2PS [ No CAS ]
  • [ 625095-57-0 ]
  • [ 1229578-27-1 ]
  • [ 1229578-26-0 ]
  • 34
  • [ 1224724-29-1 ]
  • [ 625095-57-0 ]
  • [ 1224724-30-4 ]
YieldReaction ConditionsOperation in experiment
A suspension of 2-(5-biphenyl-4-yl-6-chloro~ IH- benzoimidazol-2-ylsulfanylmethyl)-phosphonic acid (Example 29) in thionyl chloride (5 mL) was heated to reflux. After 45 minutes, the resulting suspension was evaporated by rotary evaporation. Toluene (5 mL) was added to residue and promptly removed by rotary evaporation. The resulting residue was diluted with DCM (2.5 mL), cooled to 00C, and treated with a solution of (S)-l-(3-chloro-phenyl)-propane-l ,3-diol (115 mg, 0.62 mmol) in DCM (1 mL).Diisopropylethylamine (0.31 mL, 1.9 mmol) was then added. After 2 hours, the reaction was quenched with saturated aqueous ammonium chloride and extracted twice with EtOAc. The EtOAc extracts were washed with brine and dried with MgSO4. Following rotary evaporation of the combined EtOAc extracts, the resulting residue was purified by flash chromatography using an eluent gradient of up to 65 % EtOAc in DCM to isolate the title compound. LRMS (API-ES) m/e for C29H23Cl2N2O3PS (M+H)+, calcd 581.46, found 583.6. Anal. Calcd for C29H23Cl2N2O3PS + 1 H2O + 0.5 MeOH: C, 57.57; H5 4.42; N, 4.55. Found: C5 57.68; H, 4.24; N, 4.42.
  • 35
  • [ 100-02-7 ]
  • [ 777-52-6 ]
  • [ 625095-57-0 ]
  • [ 693223-08-4 ]
  • 36
  • [ 625095-57-0 ]
  • [ 1233960-52-5 ]
  • 37
  • [ 625095-57-0 ]
  • cis-3-O-[4-(S)-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphorinan-2-yl]-18β-glycyrrhetinic acid sodium salt [ No CAS ]
  • 38
  • [ 108-05-4 ]
  • [ 587-04-2 ]
  • [ 632327-18-5 ]
  • [ 625095-57-0 ]
  • 39
  • [ 632327-19-6 ]
  • [ 625095-57-0 ]
  • 40
  • 8-nitroquinolin-3-yl phosphonic dichloride [ No CAS ]
  • [ 625095-57-0 ]
  • (4S)-4-(3-chlorophenyl)-2-(8-nitroquinolin-3-yl)-1,3,2-dioxaphosphinan-2-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
35.5 g <strong>[625095-57-0](S)-1-(3-chlorophenyl)propane-1,3-diol</strong> (36.95 g) 20 was added to CH2Cl2 (540 mL). Then TiCl4 was added (22 mL) dropwise under -78 C. The mixture was stirred for 5 minutes, and then stirred for 5 minutes under ice bath. TEA (110 mL) was added to the mixture. The resulting mixture was added dropwise to the solution of compound 12c in dichloromethane. After the addition was complete, the resulting mixture reacted at room temperature for overnight. The reaction mixture was diluted with CH2Cl2 (700 mL), charged with 10% tartaric acid (210 mL), and stirred for 2 minutes. The mixture was filtered through celite, extracted with CH2Cl2. The organic layer was dried over Na2SO4, and the solvent removed. The residue was recrystallized twice from CH3CN. A yellow solid 13c 35.5 g was given in 44%. m/z: 405.1 [M+1];
  • 41
  • [ 135505-20-3 ]
  • [ 625095-57-0 ]
YieldReaction ConditionsOperation in experiment
85.5% With sodium tetrahydroborate; water; In butan-1-ol; at 90℃; for 4.5h;Cooling with ice; The preparation of (1S)-1-(3-chlorophenyl)propane-1,3-diol (20) Sodium borohydride (1.84 g) and water (0.62 mL) were added to 1-butanol (37.5 mL), and then the solution of compound 19 (10.4 g) in 1-butanol (3.8 mL) was added dropwise to under ice bath. After addition was complete, the mixture was stirred for 0.5 h, and reacted at 90 C. for 4 h. The reaction mixture was cooled to room temperature, charged with aqueous potassium carbonate solution (10%, 23 mL), and stirred for 10 min. The organic layers were separated, washed with aqueous potassium carbonate solution (10 wt/vol %, 8 mL) and brine (8 mL), dried over anhydrous Na2SO4, filtered, evaporated to dryness, and purified with chromatography (DCM:CH3OH=30:1). A yellow oil 20 7.75 g was given in 85.5%. 1H NMR (300 MHz, CDCl3) δ 7.36 (s, 1H), 7.30-7.20 (m, 3H), 4.92 (q, J=4.5□Hz, 7.8 Hz, 1H), 3.90-3.79 (m, 2H), 2.82 (s, 2H), 2.03-1.85 (m, 2H).
  • 42
  • [ 625095-57-0 ]
  • (4S)-4-(3-chlorophenyl)-2-(8-aminoquinolin-3-yl)-1,3,2-dioxaphosphinan-2-one [ No CAS ]
  • 43
  • [ 625095-57-0 ]
  • (4S)-4-(3-chlorophenyl)-2-(8-((2,2-dimethyl-1,3-dioxane-4,6-dione)-5-methylene)aminoquinolin-3-yl)-1,3,2-dioxaphosphinan-2-one [ No CAS ]
  • 44
  • [ 625095-57-0 ]
  • (4S)-4-(3-chlorophenyl)-2-(7-hydroxy-1,10-phenanthrolin-3-yl)-1,3,2-dioxaphosphinan-2-one [ No CAS ]
  • 45
  • [ 625095-57-0 ]
  • 3-((4S)-4-(3-chlorophenyl)-1,3,2-dioxaphosphinan-2-one-2-yl)-1,10-phenanthrolin-7-yl phosphoric acid diethyl ester [ No CAS ]
  • 46
  • [ 625095-57-0 ]
  • di-t-butyl (3-((4S)-4-(3-chlorophenyl)-1,3,2-dioxaphosphinan-2-one-2-yl)-1,10-phenanthrolin-7-oxy)-7-methyl phosphate [ No CAS ]
  • 47
  • [ 625095-57-0 ]
  • 3-((4S)-4-(3-chlorophenyl)-1,3,2-dioxaphosphinan-2-one-2-yl)-1,10-phenanthrolin-7-yl phosphoric acid [ No CAS ]
  • 48
  • [ 625095-57-0 ]
  • disodium 3-((4S)-4-(3-chlorophenyl)-1,3,2-dioxaphosphinan-2-one-2-yl)-1,10-phenanthrolin-7-yl phosphate [ No CAS ]
  • 49
  • [ 625095-57-0 ]
  • di-t-butyl (3-((4S)-4-(3-chlorophenyl)-1,3,2-dioxaphosphinan-2-one-2-yl)-1,10-phenanthrolin-7-one)-10(7H)-methyl phosphate [ No CAS ]
  • 50
  • [ 625095-57-0 ]
  • (3-((4S)-4-(3-chlorophenyl)-1,3,2-dioxaphosphinan-2-one-2-yl)-1,10-phenanthrolin-7-oxy)-7-methyl phosphoric acid [ No CAS ]
  • 51
  • [ 625095-57-0 ]
  • (3-((4S)-4-(3-chlorophenyl)-1,3,2-dioxaphosphinan-2-one-2-yl)-1,10-phenanthrolin-7-one)-10(7H)-methyl phosphoric acid [ No CAS ]
  • 52
  • [ 625095-57-0 ]
  • 4-[3-chloro-4-(cyclopropylcarbamoylamino)phenoxy]-N-[(4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphinan-2-yl]-7-methoxyquinoline-6-carboxamide [ No CAS ]
  • 53
  • [ 110-17-8 ]
  • [ 147127-20-6 ]
  • [ 625095-57-0 ]
  • C18H23ClN5O4P*C4H4O4 [ No CAS ]
YieldReaction ConditionsOperation in experiment
Ca. 15 g Add 18.6g of diol and 90mL of dichloromethane to a dry and clean 250mL reaction flask, Stir and lower the temperature to 05 and start adding 19.0g of titanium tetrachloride dropwise to the reaction system. Then 42.0 g of triethylamine was added dropwise to the reaction solution, and the addition was completed, which was recorded as reaction solution A. Add 370 mL of dichloromethane to the 1.0L reaction flask at room temperature, Turn on the stirring and add 28.7g of Tenofovir and 50.8g of DEF. Add 10.9g of oxalyl chloride dropwise at 1025. After the addition is complete, turn on heating to reflux; reflux reaction for 23h, stop heating, Drop the reaction solution A to 1.0L reaction system when the temperature is lowered to 10C; After the addition is complete, the reaction is stirred for 1 hour. Add methanol and water to the reaction system, stir for 5 min, separate the liquids, The aqueous phase was extracted 4 times with dichloromethane, Combine the organic phases and wash with saturated brine, Separate the liquids, dry the organic phase with anhydrous magnesium sulfate; filter, wash the filter cake with dichloromethane, The filtrate was concentrated under reduced pressure to no fraction; Add the concentrated solution to ethanol to dissolve, transfer to a 500mL reaction flask, And add 32mL of acetic acid and heat to reflux for 5-6h. Concentrate under reduced pressure at 60-70C to almost no fraction, Add methanol and succinic acid, stir and react for 1h; Stir and cool to crystallize, filter, filter cake 5565 blast drying material for 5h, 30g succinate is obtained. Add 300L water to the reaction flask, add 30g HTS succinate, 200mL acetone, After the temperature was raised to 30-40C to dissolve, it was extracted with methyl tert-butyl ether. Discard the organic phase and adjust the Ph of the aqueous phase to 8-9 with saturated sodium bicarbonate solution; The aqueous phase was extracted with dichloromethane. Combine the organic phases and wash once with saturated sodium chloride, The organic phase is dried by adding anhydrous magnesium sulfate, Filter and wash the filter cake with dichloromethane. The filtrate was concentrated under reduced pressure at 30-40C to no fraction. Approximately 18 g of oil is obtained, which is added to the reaction flask after being dissolved in methanol, and about 11.6 g of fumaric acid is added under stirring, and the reaction is stirred for 30 minutes below 30C. Stir and cool to crystallize, filter, and bake the filter cake at 5565 for more than 10h. About 15 g of white powder is obtained.
  • 54
  • [ 625095-57-0 ]
  • C9H10ClO3P [ No CAS ]
YieldReaction ConditionsOperation in experiment
Purge 30L double-layer glass reactor with nitrogen for 5min, add 4L DCM,Cool down the low-temperature coolant circulation pump to -20C, and add PCl3 (558.6g, 4.07mol);Take <strong>[625095-57-0](S)-1-(3-chlorophenyl)propane-1,3-diol</strong>(IV-a1, 721.4g, 3.87mol),Pyridine (612 g, 7.74mol) was dissolved in 2L DCM, and under mechanical stirring,Maintain the internal temperature at -20, quickly add the mixed solution dropwise, and continue stirring for 1 hour after the drop.Dissolve tert-butanol (458.0g, 4.64mol) in 2L DCM, and under mechanical stirring,Maintain the internal temperature at -20C, add tert-butanol in DCM solution dropwise, continue to stir for 1h after the drop,HPLC monitors the end of the reaction; pour 10 L of ice water into the reaction solution, stir and separate,The organic phase was washed with 8L saturated brine, stirred and separated, and the organic phase was dried by adding anhydrous sodium sulfate.Suction filtration, concentration of the filtrate under reduced pressure, recovery of DCM;Obtained 818 g of colorless and transparent oil (compound III-a2 and III'-a2 diastereomer mixture) with a yield of 91%;HPLC purity: the peak area percentages of compound III'-a2 and compound III-a2 at 220 nm ultraviolet wavelength are: 21.4%, 67.1%.
  • 55
  • [ 625095-57-0 ]
  • C30H35ClN2O8P2 [ No CAS ]
  • 56
  • [ 625095-57-0 ]
  • C21H16ClN2O4P [ No CAS ]
  • 57
  • [ 625095-57-0 ]
  • C22H19ClN2O8P2 [ No CAS ]
  • 58
  • [ 852947-39-8 ]
  • [ 625095-57-0 ]
  • [ 852948-13-1 ]
YieldReaction ConditionsOperation in experiment
15% Add the compound of formula 9 (1.20g), dicyclohexylcarbodiimide (DCC) (2.03g), pyridine (5.72g), N,N-dimethylformamide (6ml) into a 25ml reaction flask, at room temperature Stir for 10 minutes. The compound of formula 10 (0.62g) was added dropwise, after the dropping was completed, it was heated to 65C for reaction. After the reaction was completed, 1 ml of water was added to quench the reaction, and 20 ml of dichloromethane was added to extract the reaction. The extract was tested by HPLC and showed that cis: trans ≈1.7:1. The compound of formula 1 (0.25 g, yield: 15%) was obtained through column chromatography.
  • 59
  • C19H23Cl2O3P [ No CAS ]
  • [ 625095-57-0 ]
  • [ 852948-13-1 ]
YieldReaction ConditionsOperation in experiment
75% Compound of formula 9 (673 g) was dissolved in dichloromethane (4.139 Kg) and DMF (0.005 Kg, 0.04 eq.), SOCl2 (0.949 Kg) was added. Then the mixture was heated to 35-45 C. for 4-6 h. The reaction solution is concentrated to dryness under reduced pressure at 10-30 C. to give phosphonyl chloride intermediate 11 as an oil, which was dissolved in methylene chloride (6.912 Kg) for later use. Compound of formula 10 (415 g, 1.2 eq.) was dissolve in dichloromethane (9.22 Kg), add TiCl4 (424 g, 1.2 eq.) at -15-5 C. After the addition, triethylamine (471 g, 2.6 eq.) was added at -15-5 C. and the mixture was maintained for 0.5-1.5 h. The resulting solution was added dropwise to the solution of phosphonyl chloride intermediate 11 at -60-40 C., and maintained for 3-6 hours. After the reaction was completed by HPLC monitoring, the reaction solution was quenched with water (1.467 Kg). Then anhydrous Na2SO4 (4.657 Kg) and dichloromethane (3.483 Kg) was added and stirred for 30-40 min. The organic phase was washed with brine twice and concentrated under reduced pressure at 25-35 C. to dryness to give the crude compound of Formula I, which was purified by column chromatography (200-300 mesh) to give solvate target compound. The solvate compound was purified further by recrystallization from EtOAc/MTBE/n-heptane and EtOAc/MTBE successively to give MTBE solvate compound. The MTBE was substituted by EtOH under reduced pressure to give pure product (695 g, yield: 75%).
65% The compound of formula 9 (1.4g) was dissolved in tetrahydrofuran (14ml), DMF (5.6mg, 0.02eq.) was added, SOCl2 (0.82g, 2.5eq.) was added dropwise, and the reaction was refluxed overnight. The reaction solution was decompressed to dryness. The oily phosphonic chloride intermediate 11 is dissolved in 14 mL of tetrahydrofuran and set aside. The compound of formula 10 (0.72g, 1.0eq.) was dissolved in 10ml of tetrahydrofuran, TiCl4 (0.874g, 1.2eq.) was added dropwise at 1015, and after the dripping, at 05, triethylamine ( 0.97g, 2.5eq.), incubate the reaction for 20min. The resulting solution was added dropwise to the solution of the phosphonic chloride intermediate 11 at -40 C., and reacted at this temperature for 2 h. TLC monitored until the reaction no longer proceeded. The reaction solution was determined by HPLC method to show cis: trans ≈ 6:1 (the HPLC determination method is the same as in Example 1), add 10ml of water to quench the reaction, extract, decompress the organic phase to dryness, and obtain the target compound of formula 1 by column chromatography (1.3g, yield: 65%).
  • 60
  • C19H23Cl2O3P [ No CAS ]
  • [ 625095-57-0 ]
  • [ 852948-13-1 ]
  • [ 852948-12-0 ]
YieldReaction ConditionsOperation in experiment
Compound of Formula 9 (1.4 g) was dissolved in dichloromethane (14 ml) and DMF (5.6 mg, 0.02 eq.), SOCl2 (0.82 g, 2.5 eq.) was added. Then the mixture was heated to reflux overnight. The reaction solution is concentrated to dryness to give phosphonyl chloride intermediate 11 as an oil, which was dissolved in 14 mL methylene chloride for later use. Compound of formula 10 (0.72 g, 1.0 eq.) was dissolve in 10 ml dichloromethane, add TiCl4 (0.874 g, 1.2 eq.) at 10-15 C. After the addition, triethylamine (0.97 g, 2.5 eq.) was added at 0-5 C. and the mixture was maintained for 20 min. The resulting solution was added dropwise to the solution of phosphonyl chloride intermediate of Formula 11 at -40 C., and maintained for 2 hours. After the reaction was completed by TLC monitor. HPLC showed cis:trans≈6:1 in the reaction solution. The reaction solution was quenched with 10 ml water. The organic phase was concentrated to dryness to give the target compound of Formula I by column chromatography (1.3 g, yield: 65%).
  • 61
  • [ 921-26-6 ]
  • [ 625095-57-0 ]
  • C15H23ClNO2P [ No CAS ]
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