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Product Details of [ 771-61-9 ]

CAS No. :771-61-9 MDL No. :MFCD00002156
Formula : C6HF5O Boiling Point : -
Linear Structure Formula :- InChI Key :XBNGYFFABRKICK-UHFFFAOYSA-N
M.W : 184.06 Pubchem ID :13041
Synonyms :
Chemical Name :2,3,4,5,6-Pentafluorophenol

Calculated chemistry of [ 771-61-9 ]

Physicochemical Properties

Num. heavy atoms : 12
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.0
Num. rotatable bonds : 0
Num. H-bond acceptors : 6.0
Num. H-bond donors : 1.0
Molar Refractivity : 28.26
TPSA : 20.23 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) : -5.13 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.36
Log Po/w (XLOGP3) : 3.23
Log Po/w (WLOGP) : 4.19
Log Po/w (MLOGP) : 3.64
Log Po/w (SILICOS-IT) : 3.53
Consensus Log Po/w : 3.19

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 2.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -3.39
Solubility : 0.0757 mg/ml ; 0.000411 mol/l
Class : Soluble
Log S (Ali) : -3.33
Solubility : 0.0865 mg/ml ; 0.00047 mol/l
Class : Soluble
Log S (SILICOS-IT) : -3.22
Solubility : 0.111 mg/ml ; 0.000604 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 2.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.34

Safety of [ 771-61-9 ]

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:

Application In Synthesis of [ 771-61-9 ]

* 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.

  • Upstream synthesis route of [ 771-61-9 ]
  • Downstream synthetic route of [ 771-61-9 ]

[ 771-61-9 ] Synthesis Path-Upstream   1~33

  • 1
  • [ 102741-63-9 ]
  • [ 1199-01-5 ]
  • [ 771-61-9 ]
Reference: [1] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1986, p. 163 - 168
  • 2
  • [ 4615-85-4 ]
  • [ 769-39-1 ]
  • [ 771-61-9 ]
Reference: [1] Journal of Fluorine Chemistry, 2013, vol. 149, p. 82 - 87
  • 3
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  • [ 64-19-7 ]
  • [ 19220-93-0 ]
Reference: [1] Chemistry - A European Journal, 2007, vol. 13, # 34, p. 9534 - 9541
[2] Patent: WO2009/12958, 2009, A2, . Location in patent: Page/Page column 42
  • 4
  • [ 771-61-9 ]
  • [ 108-24-7 ]
  • [ 19220-93-0 ]
Reference: [1] Synthesis, 2011, # 10, p. 1621 - 1625
[2] Organic and Biomolecular Chemistry, 2004, vol. 2, # 3, p. 397 - 401
[3] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1991, # 12, p. 1901 - 1908
  • 5
  • [ 771-61-9 ]
  • [ 75-36-5 ]
  • [ 19220-93-0 ]
Reference: [1] Chemistry - A European Journal, 2015, vol. 21, # 35, p. 12295 - 12298
[2] Journal of Organic Chemistry, 1988, vol. 53, # 14, p. 3321 - 3325
  • 6
  • [ 771-61-9 ]
  • [ 830-03-5 ]
  • [ 100-02-7 ]
  • [ 19220-93-0 ]
Reference: [1] Journal of the American Chemical Society, 1987, vol. 109, # 21, p. 6362 - 6368
[2] Journal of the American Chemical Society, 1987, vol. 109, # 21, p. 6362 - 6368
  • 7
  • [ 506-96-7 ]
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  • [ 19220-93-0 ]
Reference: [1] Journal of Organic Chemistry, 1979, vol. 44, p. 654 - 656
  • 8
  • [ 771-61-9 ]
  • [ 407-25-0 ]
  • [ 14533-84-7 ]
YieldReaction ConditionsOperation in experiment
99% at 40℃; for 18 h; A mixture of pentafluorophenol (50.0 g, 271 mmol) and trifluoroacetic anhydride (85.0 g, 404 mmol) was stirred at 4O0C for 18 h. The resulting mixture was fractionally distilled to afford pentafluorophenol trifluoroacetate as a colourless liquid (75.2 g, 99percent); bp 122-125°C.A solution of oleic acid (30.0 g, 106 mmol) in anhydrous DMF (100 mL) was added to a solution of pentfluorophenol trifluoroacetate (32.7 g, 116 mmol) in anhydrous DMF (100 mL), followed slowly by pyridine (9.16 g, 116 mmol). The resulting mixture was stirred at room temperature for 18 h, then diluted with ethyl acetate (200 mL) and washed successively with 0.1 N hydrochloric acid (1 x 100 mL), saturated aq. sodium bicarbonate solution (1 x 100 mL), and brine (1 x 50 mL). The organic solution was dried (MgSO4) and concentrated in vacuo to leave oleic acid pentafluoroacetate as a colourless viscous liquid (45.0 g, 95percent)
Reference: [1] Patent: WO2006/136460, 2006, A2, . Location in patent: Page/Page column 32
[2] Tetrahedron Letters, 1990, vol. 31, # 41, p. 5851 - 5852
  • 9
  • [ 354-32-5 ]
  • [ 771-61-9 ]
  • [ 14533-84-7 ]
Reference: [1] Canadian Journal of Chemistry, 1966, vol. 44, p. 2346 - 2348
  • 10
  • [ 56-23-5 ]
  • [ 771-61-9 ]
  • [ 59483-84-0 ]
  • [ 6161-53-1 ]
  • [ 120650-87-5 ]
Reference: [1] Journal of Organic Chemistry USSR (English Translation), 1988, p. 1362 - 1366[2] Zhurnal Organicheskoi Khimii, 1988, vol. 24, # 7, p. 1513 - 1517
[3] Journal of Organic Chemistry USSR (English Translation), 1988, p. 1362 - 1366[4] Zhurnal Organicheskoi Khimii, 1988, vol. 24, # 7, p. 1513 - 1517
  • 11
  • [ 56-23-5 ]
  • [ 771-61-9 ]
  • [ 36919-02-5 ]
  • [ 59483-84-0 ]
Reference: [1] Journal of Organic Chemistry USSR (English Translation), 1988, p. 1362 - 1366[2] Zhurnal Organicheskoi Khimii, 1988, vol. 24, # 7, p. 1513 - 1517
  • 12
  • [ 5070-13-3 ]
  • [ 771-61-9 ]
  • [ 100-02-7 ]
  • [ 59483-84-0 ]
Reference: [1] Journal of Organic Chemistry, 2001, vol. 66, # 20, p. 6571 - 6575
  • 13
  • [ 50903-47-4 ]
  • [ 16679-94-0 ]
  • [ 771-61-9 ]
  • [ 14719-37-0 ]
  • [ 1164-16-5 ]
Reference: [1] J. Gen. Chem. USSR (Engl. Transl.), 1983, vol. 53, # 12, p. 2505 - 2508[2] Zhurnal Obshchei Khimii, 1983, vol. 53, # 12, p. 2779 - 2783
  • 14
  • [ 50903-47-4 ]
  • [ 771-61-9 ]
  • [ 35150-09-5 ]
Reference: [1] J. Gen. Chem. USSR (Engl. Transl.), 1983, vol. 53, # 12, p. 2505 - 2508[2] Zhurnal Obshchei Khimii, 1983, vol. 53, # 12, p. 2779 - 2783
  • 15
  • [ 771-61-9 ]
  • [ 58-85-5 ]
  • [ 120550-35-8 ]
YieldReaction ConditionsOperation in experiment
90% With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 0 - 20℃; Inert atmosphere Biotin (2.95 g, 12.00 mmol) was dissolved in DMF (10 mL), and Pfp-OH (2.80 g, 15.20 mmol) was added to the biotin solution before EDC.HCl (5.70 g, 29.70 mmol) in DMF (15 mL) were added to the mixture at 0 °C over 30 min. The mixture stirred overnight at room temperature under nitrogen atmosphere. The product washed with DCM. White powder was obtained with a yield of 90percent (4.50 g). The product was used in the next step without further purification. 1H NMR (D2O): d 1.41-1.69 (m, 6H, CH2), 2.57 (d, 1H,CH2), 2.77-2.85 (m, 3H, CH2), 3.11-3.12 (m, 1H, CH), 4.14 (t, 1H, CH), 4.30 (t, 1H, CH), 6.37 (d, 2H, NH).
Reference: [1] Synthetic Communications, 1996, vol. 26, # 13, p. 2531 - 2547
[2] Journal of the American Chemical Society, 2009, vol. 131, p. 7954 - 7955
[3] Russian Journal of Bioorganic Chemistry, 1994, vol. 20, # 8-9, p. 520 - 528[4] Bioorganicheskaya Khimiya, 1994, vol. 20, # 8-9, p. 955 - 966
[5] Organic and biomolecular chemistry, 2003, vol. 1, # 6, p. 950 - 959
[6] Chinese Chemical Letters, 2017, vol. 28, # 4, p. 832 - 838
[7] Biomacromolecules, 2012, vol. 13, # 9, p. 2831 - 2842
[8] Organic Letters, 2008, vol. 10, # 20, p. 4453 - 4455
[9] Russian Journal of Bioorganic Chemistry, 2017, vol. 43, # 4, p. 386 - 396[10] Bioorg. Khim., 2017, vol. 43, # 4, p. 377 - 387,11
[11] Patent: WO2007/42469, 2007, A2, . Location in patent: Page/Page column 20
  • 16
  • [ 771-61-9 ]
  • [ 115520-21-3 ]
Reference: [1] Tetrahedron Letters, 1990, vol. 31, # 41, p. 5851 - 5852
  • 17
  • [ 771-61-9 ]
  • [ 35737-15-6 ]
  • [ 86069-87-6 ]
Reference: [1] Synthesis, 1983, # 4, p. 325 - 327
[2] Synthesis, 1986, # 4, p. 303 - 305
  • 18
  • [ 771-61-9 ]
  • [ 86069-87-6 ]
Reference: [1] Tetrahedron Letters, 1990, vol. 31, # 41, p. 5851 - 5852
  • 19
  • [ 771-61-9 ]
  • [ 103321-57-9 ]
  • [ 86060-92-6 ]
Reference: [1] Tetrahedron Letters, 1991, vol. 32, # 43, p. 6199 - 6202
  • 20
  • [ 771-61-9 ]
  • [ 35661-40-6 ]
  • [ 86060-92-6 ]
Reference: [1] Synthesis, 1983, # 4, p. 325 - 327
[2] Synthesis, 1986, # 4, p. 303 - 305
  • 21
  • [ 771-61-9 ]
  • [ 86060-92-6 ]
Reference: [1] Bulletin of the Academy of Sciences of the USSR Division of Chemical Science, 1989, vol. 37, # 12, p. 2539 - 2541
[2] Tetrahedron Letters, 1990, vol. 31, # 41, p. 5851 - 5852
  • 22
  • [ 771-61-9 ]
  • [ 98-74-8 ]
  • [ 244633-31-6 ]
Reference: [1] Tetrahedron Letters, 1999, vol. 40, # 32, p. 5939 - 5942
[2] Synthetic Communications, 2001, vol. 31, # 1, p. 61 - 70
  • 23
  • [ 771-61-9 ]
  • [ 35737-10-1 ]
  • [ 149303-38-8 ]
Reference: [1] Tetrahedron, 2002, vol. 58, # 27, p. 5427 - 5439
  • 24
  • [ 261909-49-3 ]
  • [ 771-61-9 ]
  • [ 1256490-52-4 ]
YieldReaction ConditionsOperation in experiment
100% With triethylamine In dichloromethane at 0 - 25℃; for 1 h; Inert atmosphere To a flask provided with mechanical stirrer, reflux condenser, thermometer and under nitrogen atmosphere is added a solution of (L)-alanine isopropyl ester hydrochloride (Q) (2.8 g, 16.8 mmol) obtained as described in example 1 and dichloromethane (21 mL). The resulting mixture is stirred at room temperature until obtaining a homogeneous suspension. The mixture is then cooled to between -65 °C and -55 °C by means of a bath of dry ice and acetone and triethylamine (3.9 g, 38.8 mmol) is added, keeping the temperature below -50 °C. At the end of the addition, the mixture is cooled to between -65 and -55 °C and a solution of phenyl dichlorophosphate (3.3 g, 15.6 mmol) in dichloromethane (1 1 mL) is added, keeping the temperature below -50 °C. The reaction mass is stirred between -65 and -55 °C up to complete conversion (about 1 hour). To a second flask provided with mechanical stirrer, reflux condenser, thermometer and under nitrogen atmosphere are added pentafluorophenol (2.4 g, 13.0 mmol) and dichloromethane (28 mL). The mixture is then cooled to between 0 and 5 °C and triethylamine (1 .6 g, 15.8 mmol) is added, keeping the temperature below 10 °C. At the end of the addition, the mixture is brought to 20-25 °C and kept under the same conditions for 1 hour, then added to the mixture prepared in the first flask, cooled to a temperature of between -15 and -10 °C, keeping the internal temperature below 5 °C. At the end of the addition, the resulting reaction mixture is brought to 0-5 °C and kept under the same conditions until the conversion is complete (about 1 hour). Water is added (8.7 mL) to the mass, keeping the temperature below 10 °C. It is heated to 20-25 °C, then the phases are separated, the organic phase is washed with water and is concentrated under vacuum to residue, removing the residual solvents by co-evaporation with /so-propyl acetate. 9.0 g of residue are obtained (quantitative yield) with a diastereomeric ratio of Sp:flp = 50:50.
Reference: [1] Patent: WO2016/151542, 2016, A1, . Location in patent: Page/Page column 23; 24
[2] Patent: WO2014/62596, 2014, A1, . Location in patent: Page/Page column 60
[3] Patent: US2014/206640, 2014, A1, . Location in patent: Paragraph 0286; 0287
[4] Patent: CN106543253, 2017, A, . Location in patent: Paragraph 0086-0089
[5] Patent: WO2018/48937, 2018, A1, . Location in patent: Page/Page column 220; 221
  • 25
  • [ 771-61-9 ]
  • [ 770-12-7 ]
  • [ 39613-92-8 ]
  • [ 1256490-52-4 ]
YieldReaction ConditionsOperation in experiment
48%
Stage #1: With N-ethyl-N,N-diisopropylamine In dichloromethane at -78℃; for 0.5 h;
Stage #2: at -10℃; for 3.5 h;
200 mL of methylene chloride, 50 g of L-alanine isopropyl ester hydrochloride and 38.3 g of DIPEA were added to the reaction flask and stirredMixed, cooled to -78 ° C, the reaction 30min, and then dropping phenol dichlorophosphate dichloromethane solution (63g / 120mL); dropAnd the reaction was stirred for 30 minutes. Then, the temperature was raised to -10 ° C for 3 hours. 55.4 gPerfluorophenol,35.2 g of DIPEA was dissolved200mL dichloromethane, drop to the reaction solution; drop finished, stirring reaction, TLC monitoring reaction; reaction is complete, filtration, filtrationThe cake was washed with 50 mL of methylene chloride and the organic phases were combined, concentrated under reduced pressure and dissolved with 500 mL of methyl tert-butyl ether.The filter cake was washed with 50 mL of methyl t-butyl ether and the organic phases were combined and concentrated under reduced pressure to give 123.5 g of crude off-white. The crude with BEthyl acetate and n-hexane purification, 65.6 fine. Yield: 48percent
40%
Stage #1: With triethylamine In dichloromethane at -78 - 20℃;
Stage #2: With triethylamine In dichloromethane at 20℃; for 4 h;
General procedure: 11. Preparation of chiral phosphorus reagents 21To a solution of PhOPOCl2 (19, 6.14 g, 40 mmol) in CH2C12 (80 mL) was added L-alanyl isopropyl ester hydrochloride (20, 6.7 g, 40 mmol) then a solution of Et3N (80 mmol) in CH2C12 (10 mL) at -78 °C. The mixture was stirred at room temperature for overnight. To the mixture was added a solution of pentafluorophenol (7.36 g, 40 mmol) and Et3N (80 mmol) in CH2CI2 (10 mL) and the mixture was stirred at room temperature for 4h. Filtered and the cake was washed with CH2CI2. The filtrate was evaporated and the residue was dissolved in EtOAc (200 mL). The solution was washed with Aq. NaHC03, brine and dried over Na2S04. Solvent was evaporated and the residue was purified by silica gel column chromatography (5-50percent EtOAc in hexanes) to give a mixture of diastereomers of compound 21. The mixture was recrystallized from EtOAc-hexane to give single isomer 21 (25-40percent yield). <¾ (CDCI3): m/z: 539 [M+H]+.
Reference: [1] ACS Medicinal Chemistry Letters, 2016, vol. 7, # 12, p. 1197 - 1201
[2] Patent: CN104610404, 2016, B, . Location in patent: Paragraph 0037; 0038
[3] Patent: WO2013/13009, 2013, A2, . Location in patent: Page/Page column 25; 26
[4] Patent: CN104151352, 2017, B, . Location in patent: Paragraph 0025; 0047-0051
  • 26
  • [ 771-61-9 ]
  • [ 39825-33-7 ]
  • [ 770-12-7 ]
  • [ 1256490-52-4 ]
Reference: [1] Patent: US2016/257706, 2016, A1, . Location in patent: Paragraph 0579; 0580
  • 27
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  • [ 1256490-52-4 ]
Reference: [1] Patent: WO2016/181313, 2016, A1,
  • 28
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  • [ 770-12-7 ]
  • [ 39613-92-8 ]
  • [ 1334513-02-8 ]
YieldReaction ConditionsOperation in experiment
61.6%
Stage #1: With triethylamine In dichloromethane at -78 - 20℃; for 2 h;
Stage #2: With triethylamine In dichloromethane at -78 - 20℃; for 3 h;
A flask containing (S)-isopropyl 2-aminopropanoate hydrochloride (72.0 g, 430 mmol) was charged with phenyl phosphorodichloridate (64.2 mL, 430 mmol) and dichloromethane (DCM, 1200 mL). The mixture was cooled to -70 to -78°C with dry-ice acetone bath and then treated with drop wise addition of triethylamine (120 mL, 859 mmol) over a period of 30 minutes. The mixture was stirred at -70 to -78°C for 30 more minutes and then was allowed to warm to ambient temperature and stirred for lh. (0555) The reaction mixture was then cooled to 0-5 °C in ice-bath and added to a solution of 2,3,4,5, 6-pentafluorophenol (79 g, 430 mmol) and triethylamine (59.9 mL, 430 mmol) in 100 mL DCM over a period of 30 minutes. The resulting mixture was stirred at -70 to -78°C for 30 more minutes, then was warmed to ambient temperature and stirred for 2h. (0556) The solids were filtered off and solid cake was washed with 200 mL ethyl acetate. (0557) The filtrate and washes were concentrated by vacuum distillation until a semi-solid residue remained. The semi-solid residue was dissolved in 500 mL ethyl acetate and washed with water and brine. The washes were re-extracted with 50 mL of ethyl acetate. The combined organic layer was dried over anhydrous MgSCn and concentrated to give crude racemic product 210 g (100percent yield). Based on the NMR characterization, the racemic product appears to be a 1 : 1 mixture of two diastereomers. (0558) Kinetic resolution of the racemic product to produce the desired SS diastereomer was accomplished by the following protocol. (0559) 1) The crude racemic mixture was slurried in 500 mL of 20percent ethyl acetate/ hexanes and was added to a solution of 5 g of pentafluorophenol, 10 mL of triethylamine, and 100 mg of dimethylaminopyridine in 20 mL of 20percent ethyl acetate/hexanes. The reaction mixture was warmed to 45-50 °C for 30 minutes, and the slurry was allowed to stir overnight. The white solid was collected by filtration and was washed with 200 mL of 20percent ethyl acetate/hexanes and 100 mL of hexanes. The product was dried at 40 °C under vacuum to give a white solid (weight: 98 g). Based on the NMR characterization, the product appears to be substantially the SS diastereomer. (0560) 2) The filtrate and washings from the above reaction were combined and concentrated to give a semi solid which was mainly the SS diastereomer as shown by NMR along with other impurities. This residue was dissolved in 150 mL ethyl acetate and washed with 50 mL of IN HC1, water and 5percent K2CO3 solution. The organic layer was dried and concentrated. The white residue was slurred in 100 mL of 20percent ethyl acetate /hexanes, and the solid was collected by filtration. The cake was then washed with 20percent ethyl acetate /hexanes, hexanes and dried. The weight of the resulting white solid was 22 g. Based on the - and 1P-NMR characterization, the product appears to be substantially the SS diastereomer. Total weight of the product after resolution: 120g (61.6percent yield).
56%
Stage #1: With triethylamine In dichloromethane at -20 - 0℃; for 2.16667 h; Inert atmosphere
Stage #2: With triethylamine In dichloromethane at -8 - 5℃;
Phenyl dichlorophosphate (62.88 g, 0.298 mol, 1 .0 eq) was added under nitrogen to a solution of L-alanine isopropylester hydrochloride (50.0 g, 0.298 mol) in DCM (310 ml_) at 0 °C - the addition was completed by wash with DCM (39 ml_). The mixture was cooled and triethylamine (63.35 g, 0.626 mol, 2.1 eq) was added over a period of 70 minutes with cooling keeping the temperature not higher than -14 °C, the addition was completed by wash with DCM (39 ml_). The mixture was stirred for one hour at -15 to -20 °C, then heated to -8 °C and a solution of pentafluorophenol (60.38 g, 0.328 mol, 1 .1 eq) and triethylamine (33.19 g, 0.328 mol, 1 .1 eq) in DCM (78 ml_) was added over a period of 42 minutes with cooling keeping the temperature not higher than 0 °C - the addition was completed by wash with DCM (39 ml_). The mixture was stirred for one hour at 0 °C and then over night at +5 °C. The formed precipitate was removed by filtration, and the filter cake washed with DCM (95 ml_). The combined filtrates were washed at 5 °C with water (2x190 ml_). The organic phase was distilled at 32 - 38°C at reduced pressure (650 - 600 mBar), and distillation was continued until a residual volume of approx. 170 ml_ partly crystallized mass was obtained. Ethyl acetate (385 ml_) was added, and the resulting clear solution was distilled at 43 - 45°C under reduced pressure (300 - 250 mBar). Distillation was continued until a residual volume of approx. 345 ml_ was obtained. The clear solution was cooled to 36°C, and crystallization is induced by addition of seed crystals of (S)-isopropyl 2- (((S)-(perfluorophenoxy)(phenoxy)phosphoryl)amino)propanoate (20 mg) prepared as described in J. Org. Chem., 201 1 , 76, 831 1 - 8319. The mixture was cooled to 27 °C over a period of one hour, then n-heptane (770 ml_) was added over a period of 47 minutes, and the mixture was stirred for an additional period of 37 minutes. Triethylamine (6.03 g, 0.2 eq) was added, and the mixture was stirred at 23 - 25 °C over night. The precipitate was isolated by filtration. The filter cake was washed with ethyl acetate:n-heptane (1 :9, 80 ml_) and dried to constant under reduced pressure (below 0.1 mBar) without heating, which gave the title compound (75.64 g, 56percent) as a white crystalline material. 1 H NMR (CDCI3, 300 MHz) δ 7.38-7.32 (m, 2 H), 7.27-7.24 (m, 2 H), 7.23-7.19 (m, 1 H), 5.10- 4.98 (m, 1 H), 4.20-4.08 (m, 1 H), 4.03-3.96 (m, 1 H), 1 .46 (dd, 7.2, 0.6 Hz, 3 H), 1 .26-1 .23 (2xd, 6 H); 13CNMR (CDCI3, 100 MHz) δ 172.7 (d, J = 8.8 Hz), 150.4 (d, J = 7.1 Hz), 143.4-143.0 (m), 141 .0-140.2 (m), 140.0-139.8 (m), 137.6-137.2 (m), 136.8-136.2 (m), 130.0 (d, J = 0.82 Hz), 125.8 (d, J = 1 .4 Hz), 120.3 (d, J = 5.0 Hz), 69.8, 50.6, (d, J = 1 .9 Hz), 21 .8 (d, J = 1 .9 Hz), 21 .2 (d, J = 4.4 Hz); The crystallization properties and NMR spectral data of the title compound were in agreement with published data (J. Org. Chem., 201 1 , 76, 831 1 -8319), thus confirming the S stereochemistry of the phosphorus atom of the title compound.
56%
Stage #1: With triethylamine In dichloromethane at -20 - 0℃; for 1 h; Inert atmosphere
Stage #2: With triethylamine In dichloromethane at -8 - 5℃;
At 0 ° C under nitrogen atmosphere, phenyl dichlorophosphate (62.88 g, 0.298 mol, 1.0 eq.) was added to a solution of L-alanine isopropyl ester hydrochloride (50.0 g, 0.298 mol) in DCM (310 mL) was added - completion by washing with DCM (39 mL). The mixture was cooled and triethylamine (63.35 g, 0.626 mol, 2.1 eq.) Was added over a period of 70 minutes while keeping the temperature cool to -14 ° C and complete by washing with DCM (39 mL). The mixture was stirred at -15 to -20 ° C for one hour then warmed to -8 ° C and pentafluorophenol (60.38 g, 0.328 mol, 1.1 eq.) And triethylamine (33.19 g, 0.328 mol, 1.1 eq.) In DCM (78 mL) while cooling to keep the temperature below 0 ° C. - added by washing with DCM (39 mL). The mixture was stirred at 0 ° C for one hour and then at + 5 ° C overnight. The formed precipitate was removed by filtration, then the filter cake was washed with DCM (95 mL). The combined filtrates were washed with water (2x190 mL) at 5 ° C. The organic phase is distilled under reduced pressure (650-600 mbar) at 32-38 ° C and distillation is continued until a residual volume of about 170 mL to obtain a partially crystalline material. Ethyl acetate (385 mL) was added and the resulting clear solution was distilled under reduced pressure (300-250 mbar) at 43-45 ° C. Distillation was continued until a residual volume of about 345 mL was obtained. The clear solution was cooled to 36 ° C and was quenched by the addition of (S)-2-(((S)(perfluorophenoxy)(phenoxy)phosphoryl)amino)propanoic acid isopropyl ester (20 mg)as described in J. Org. Chem., 2011, 76, 8311-8319. The mixture was cooled to 27 ° C over a period of one hour, then n-heptane (770 mL) was added over a period of 47 minutes, and the mixture stirred for an additional 37 minutes. Triethylamine (6.03 g, 0.2 eq) was added and the mixture was stirred at 23-25 ° C overnight. The precipitate is isolated by filtration. The filter cake was washed with ethyl acetate: n-heptane (1: 9, 80 mL) and dried under reduced pressure (0.1 mbar or less) to constant weight without heating to give the title compound (75.64 g, 56percent) as a white crystalline material.
375 g
Stage #1: With trimethylamine In dichloromethane at -60 - -50℃;
Stage #2: With triethylamine In dichloromethane at -60 - 20℃;
L-alanine isopropyl ester hydrochloride (218.5 g) and toluene (1250 mL) were heated to reflux azeotropically till complete removal of water. The reaction mass was then cooled to 50°C and solvent was removed under reduced pressure. MDC was charged into the resultant mass was cooled to -60° to -50°C. Phenyldichloro phosphate (250.0 g) was charged into the reaction mass at -60°C to -50°C followed by trimethylamine (263.75 g) was added and the reaction mass was stirred for 2-3 hours at -60° to -50°C. Pentafluorophenol (240.0 g) was charged into the reaction mass followed by addition of triethylamine (143.39 g) at -60° to -50°C. The reaction mixture was allowed to warm to room temperature (RT) and stirred for 2-3 hours at RT. The reaction was monitored by HPLC (Distereomeric ratio of (Sp) : (Rp) = 35 : 65). The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Paraffin oil (1250 mL) was charged into the residual mass and the reaction mixture was heated to 60°C. The reaction mixture was stirred for 3 hours at 60°C. The reaction was monitored by HPLC (Distereomeric ratio of (Sp) : (Rp) = 99.67 : 0.37). The reaction mixture was filtered and washed with n-heptane (750 mL). The filtered solid was stirred with saturated bicarbonate solution (2500 mL) for 1 hour and filtered. The filtered solid was stirred with water (2500 mL) for 1 hour and filtered. The material was dried at 50-55°C in ATD to get pure (Sp)-isomer: (S)-2-[(S)-(2,3,4,5,6-pentafluoro-phenoxy)-phenoxy- phosphorylamino]propionic acid isopropyl ester (375 g) wherein (Rp)-isomer is 0.37 percent on chiral HPLC.
51.8 g
Stage #1: With triethylamine In dichloromethaneReflux
Stage #2: at 20℃;
Phenyl dichlorophosphate (50 g, 0.24 mol) and pentafluorophenol (43.6 g, 0.24 mol)Adding to 150 mL of dichloromethane, adding triethylamine (79.4 g, 0.79 mol) dropwise;The temperature was raised to reflux, and the temperature was lowered to room temperature after stirring for 7 to 8 hours.Add L-alanine isopropyl ester hydrochloride (40 g, 0.24 mol),Stir at room temperature for 4 to 5 hours; suction filtration, and concentrate the filtrate under reduced pressure.The concentrated residue was recrystallized from n-hexane and ethyl acetate:The residue can be dissolved in an appropriate amount of ethyl acetate, and then n-hexane is added dropwise at 30 to 40 ° C until turbidity occurs.Lowering the temperature to cause crystallization;Alternatively, the residue may be added to a mixed solvent of ethyl acetate and n-hexane in a volume ratio of 1:4.Then heated to dissolve, and then cooled to crystallization; collect crystals, vacuum dry,N-[(S)-(2,3,4,5,6-pentafluorophenoxy)phenoxyphosphoryl]-L-alanine isopropyl ester (compound of formula I)51.8g, the molar yield is 48percent,The HPLC purity was 99.1percent.

Reference: [1] Patent: WO2017/223421, 2017, A1, . Location in patent: Page/Page column 68; 69
[2] Patent: WO2016/30335, 2016, A1, . Location in patent: Page/Page column 51
[3] Patent: CN107405356, 2017, A, . Location in patent: Paragraph 0209; 0210; 0213; 0214; 0215; 0216; 0217
[4] Journal of Organic Chemistry, 2011, vol. 76, # 20, p. 8311 - 8319
[5] Patent: WO2016/99982, 2016, A2, . Location in patent: Page/Page column 55
[6] Patent: CN106366146, 2017, A, . Location in patent: Paragraph 0111; 0112; 0113; 0114; 0115
[7] Patent: CN104672288, 2017, B, . Location in patent: Paragraph 0083; 0101-0103
[8] Patent: WO2018/25195, 2018, A1, . Location in patent: Page/Page column 9; 10
[9] Patent: CN104761582, 2018, B, . Location in patent: Paragraph 0017; 0030-0037
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YieldReaction ConditionsOperation in experiment
28 % de With triethylamine In dichloromethane at -15 - 5℃; for 1 h; Inert atmosphere To a flask provided with mechanical stirrer, reflux condenser, thermometer and under nitrogen atmosphere is added a solution of (L)-alanine isopropyl ester hydrochloride (Q) (2.8 g, 16.8 mmol) obtained as described in example 1 and /'so- propyl acetate (21 mL). The resulting mixture is stirred at room temperature until a homogeneous suspension is obtained. The mixture is then cooled to between -65 °C and -55 °C by means of a bath of dry ice and acetone and triethylamine (3.9 g, 38.8 mmol) is added, keeping the temperature below -50 °C. At the end of the addition, the mixture is cooled to between -65 and -55 °C and a solution of phenyl dichlorophosphate (3.3 g, 15.6 mmol) in dichloromethane (1 1 imL) is added, keeping the temperature below -50 °C. The reaction mass is stirred between -65 e -55 °C until the conversion is complete (about 1 hour). To a second flask provided with mechanical stirrer, reflux condenser, thermometer and under nitrogen atmosphere, are added pentafluorophenol (2.4 g, 13.0 mmol) and dichloromethane (28 imL). The mixture is then cooled to between 0 and 5 °C and triethylamine (1 .6 g, 15.8 mmol) is added, keeping the temperature below 10 °C. At the end of the addition, the mixture is brought to 20-25 °C and kept under the same conditions for 1 hour, then added to the mixture prepared in the first flask, cooled to a temperature of between -15 and -10 °C, keeping the internal temperature below 5 °C. At the end of the addition, the resulting reaction mixture is brought to 0-5 °C and kept under the same conditions until the conversion is complete (about 1 hour). Water is added (8.7 imL) to the mass, keeping the temperature below 10 °C. It is heated to 20-25 °C, then the phases are separated, the organic phase is washed with water and concentrated under vacuum to residue, moving the residual solvents by co-evaporation with /'so-propyl acetate. 9.0 g of residue (quantitative yield) are obtained of a product with a diastereomeric ratio of Sp:flp = 64:36.
Reference: [1] Patent: WO2012/142085, 2012, A1, . Location in patent: Page/Page column 74-75
[2] Patent: US2014/364446, 2014, A1, . Location in patent: Paragraph 0318; 0319; 0320; 0321; 0322
[3] Patent: WO2016/151542, 2016, A1, . Location in patent: Page/Page column 25; 26
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  • [ 771-61-9 ]
  • [ 770-12-7 ]
  • [ 39613-92-8 ]
  • [ 1334513-02-8 ]
  • [ 1337529-56-2 ]
Reference: [1] Patent: CN104151352, 2017, B, . Location in patent: Paragraph 0025; 0047-0051
[2] Patent: CN107868105, 2018, A, . Location in patent: Paragraph 0022-0025
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YieldReaction ConditionsOperation in experiment
10.8 g
Stage #1: With triethylamine In dichloromethane at 0 - 20℃; for 1 h;
Stage #2: With triethylamine In dichloromethane at 20℃; for 5 h; Cooling with ice
Step b) The crude compound (12.4 g, 50 mmol) of the compound of formula II in step a)Adding 50 ml of methylene chloride, cooling the ice bath, controlling the temperature of 0 ° C, adding phenol slowly (4.7 g, 50 mmol)(10.1 g, 100 mmol) was added dropwise, and the mixture was gradually added to room temperature and allowed to react at room temperature for 1 hour. The reaction mixture was cooled in an ice bath and gradually added with five Fluorophenol (9.2 g, 50 mmol) and triethylamine (10.1 g, 100 mmol) in dichloromethane was added dropwise,Room temperature reaction for 5 hours. After completion of the reaction, 100 ml of ice water was added to the reaction solution,The dichloromethane phase was washed once with saturated aqueous sodium bicarbonate and once with saturated brine,The organic phases were combined and dried over anhydrous sodium sulfate. Filtering, and concentrating under reduced pressure to obtain the crude product;Step c) The concentrated crude product was recrystallized using n-hexane: ethyl acetate (4: 1)To obtain 10.8 g of N - [(S) - (2,3,4,5,6-pentafluorophenoxy)] phenoxyphosphoryl-L-alanine isopropyl ester,Yield 48percent, HPLC purity 99.3percent.
Reference: [1] Patent: CN106432328, 2017, A, . Location in patent: Paragraph 0042; 0043; 0051-0053; 0058-0061
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Reference: [1] Patent: US2016/16986, 2016, A1, . Location in patent: Paragraph 0684-0685
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Reference: [1] Patent: US2016/257706, 2016, A1,
[2] Patent: WO2016/181313, 2016, A1,
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