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Product Details of [ 321-28-8 ]

CAS No. :321-28-8 MDL No. :MFCD00000316
Formula : C7H7FO Boiling Point : -
Linear Structure Formula :- InChI Key :JIXDOBAQOWOUPA-UHFFFAOYSA-N
M.W : 126.13 Pubchem ID :67576
Synonyms :

Calculated chemistry of [ 321-28-8 ]

Physicochemical Properties

Num. heavy atoms : 9
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.14
Num. rotatable bonds : 1
Num. H-bond acceptors : 2.0
Num. H-bond donors : 0.0
Molar Refractivity : 32.89
TPSA : 9.23 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : Yes
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -5.55 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.93
Log Po/w (XLOGP3) : 2.14
Log Po/w (WLOGP) : 2.25
Log Po/w (MLOGP) : 2.24
Log Po/w (SILICOS-IT) : 2.26
Consensus Log Po/w : 2.17

Druglikeness

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

Water Solubility

Log S (ESOL) : -2.4
Solubility : 0.505 mg/ml ; 0.004 mol/l
Class : Soluble
Log S (Ali) : -1.97
Solubility : 1.36 mg/ml ; 0.0108 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -2.76
Solubility : 0.218 mg/ml ; 0.00173 mol/l
Class : Soluble

Medicinal Chemistry

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

Safety of [ 321-28-8 ]

Signal Word:Danger Class:3
Precautionary Statements:P210-P403+P235 UN#:1993
Hazard Statements:H225 Packing Group:
GHS Pictogram:

Application In Synthesis of [ 321-28-8 ]

* 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 [ 321-28-8 ]
  • Downstream synthetic route of [ 321-28-8 ]

[ 321-28-8 ] Synthesis Path-Upstream   1~43

  • 1
  • [ 321-28-8 ]
  • [ 133841-05-1 ]
Reference: [1] Tetrahedron Letters, 2004, vol. 45, # 8, p. 1769 - 1771
  • 2
  • [ 321-28-8 ]
  • [ 123-62-6 ]
  • [ 586-22-1 ]
Reference: [1] Journal of Organic Chemistry, 1953, vol. 18, p. 910,914
  • 3
  • [ 321-28-8 ]
  • [ 79-03-8 ]
  • [ 586-22-1 ]
  • [ 390-67-0 ]
Reference: [1] Journal of Organic Chemistry, 1954, vol. 19, p. 1562,1565
  • 4
  • [ 321-28-8 ]
  • [ 79-03-8 ]
  • [ 586-22-1 ]
Reference: [1] Helvetica Chimica Acta, 1966, vol. 49, # 5, p. 1543 - 1551
  • 5
  • [ 321-28-8 ]
  • [ 403-14-5 ]
Reference: [1] Journal of Organic Chemistry, 1953, vol. 18, p. 910,914
  • 6
  • [ 321-28-8 ]
  • [ 351-54-2 ]
Reference: [1] Monatshefte fuer Chemie, 1955, vol. 86, p. 511,515
[2] Chimica Therapeutica, 1968, vol. 3, p. 1 - 9
[3] Patent: US6028116, 2000, A,
[4] Patent: US5401774, 1995, A,
[5] Patent: EP485172, 1992, A2,
[6] Patent: US6232312, 2001, B1,
  • 7
  • [ 321-28-8 ]
  • [ 1191-17-9 ]
  • [ 351-54-2 ]
Reference: [1] Patent: US5998477, 1999, A,
[2] Patent: US5696159, 1997, A,
[3] Patent: US5776962, 1998, A,
  • 8
  • [ 321-28-8 ]
  • [ 100-97-0 ]
  • [ 351-54-2 ]
Reference: [1] Journal of Fluorine Chemistry, 2003, vol. 123, # 1, p. 101 - 108
  • 9
  • [ 321-28-8 ]
  • [ 75-36-5 ]
  • [ 455-91-4 ]
YieldReaction ConditionsOperation in experiment
95.2%
Stage #1: With aluminum (III) chloride In dichloromethane at 5 - 10℃; for 0.166667 h; Cooling with ice
Stage #2: at 5℃; for 1 h;
Under ice bath conditions,6.38 g (48 mmol) of aluminum trichloride and 40 mlDichloromethane is put into a 100ml round bottom flask, stirred and dissolved4.68 g (60 mmol) of acetyl chloride, maintaining the temperature at 5 to 10° C., stirring at 5° C. for 10 minutes, followed by dropwise addition of 2-fluoroanisole 5.04 g(40 mmol). The mixture is stirred at 5°C for 1 hour and then poured into 100 ml of ice-water. The aqueous layer is extracted with dichloromethane (2 x 30 ml). The combined organic phases are washed with water (2 x 30 ml), dried over anhydrous magnesium sulphate, filtered, and petroleum ether is used. The product was recrystallized from ethyl acetate in 92.4percent yield.
92%
Stage #1: With aluminum (III) chloride In chloroform at 5 - 10℃; for 0.166667 h;
Stage #2: at 0 - 10℃; for 1 h;
Step 1:
Preparation of 3'-fluoro-4'-methoxy-acetophenone.
acetyl chloride (51.0 g, 0.65 mol) was added dropwise to a stirred solution of aluminum chloride (80.0 g, 0.6 mol) and chloroform (750 ML), maintaining the temperature between 5-10° C.
The mixture was stirred for 10 minutes at 5 ° C. before the dropwise addition of 2-fluoroanisole (62.6 g, 0.5 mol)..
The mixture was stirred at 0-10° C. for 1 hour and poured into ice (1 L)..
The resultant layers were separated and the aqueous layer was extracted with dichloromethane (2*250 ML)..
The combined organic layers were washed with water (2*150 ML), dried over anhydrous MgSO4, filtered and concentrated in vacuo to a volume of 300 ML.
Hexanes were added and a white solid formed which was isolated by filtration and air dried..
This material was recrystallized from a mixture of dichloromethane and hexanes to afford (77.2 g, 92percent) of material suitable for use in the next step: mp 92-94° C.
75%
Stage #1: With aluminum (III) chloride In dichloromethane at 20℃; for 1 h;
Stage #2: at 20℃; for 16 h;
D2. 1 -( 3 -Fluoro-4-methoxy-ρhenvD-ethanoneTo a slurry of AICI3 (63.5g, 0.476mol) in dry dichloromethane (500ml) under nitrogen was added acetyl chloride (37.3g, 0.476mol) and the mixture was stirred for Ih at room temperature. To this was added a solution of l-fluoro-2-methoxybenzene (50g, 0.396mol) in dichloromethane (200ml) and the mixture was stirred at room temperature for 16h. This was then poured into ice-water (2L) and extracted with dichloromethane. The organic layer was washed with water, brine and dried. The solvent was removed under vacuum to afford 50g (75percent) of the title compound.
Reference: [1] Patent: CN107686465, 2018, A, . Location in patent: Paragraph 0041; 0053; 0054
[2] Patent: US6342510, 2002, B1, . Location in patent: Page column 28
[3] Patent: US5098602, 1992, A,
[4] Patent: WO2006/136829, 2006, A2, . Location in patent: Page/Page column 123
[5] Journal of Organic Chemistry, 1953, vol. 18, p. 910,914
[6] Patent: US6376528, 2002, B1,
[7] Patent: US6407140, 2002, B1,
[8] Patent: US5990148, 1999, A,
[9] Patent: US6136839, 2000, A,
[10] Patent: US5521207, 1996, A,
[11] Patent: US5700816, 1997, A,
[12] Patent: US5756529, 1998, A,
[13] Patent: US5756529, 1998, A,
[14] Patent: US5760068, 1998, A,
[15] Patent: US5760068, 1998, A,
[16] Patent: US6172096, 2001, B2,
  • 10
  • [ 321-28-8 ]
  • [ 455-91-4 ]
Reference: [1] Patent: US5180520, 1993, A,
[2] Patent: US5422037, 1995, A,
  • 11
  • [ 321-28-8 ]
  • [ 108-24-7 ]
  • [ 455-91-4 ]
Reference: [1] Journal of the American Chemical Society, 1940, vol. 62, p. 350,353
  • 12
  • [ 75-15-0 ]
  • [ 7446-70-0 ]
  • [ 321-28-8 ]
  • [ 108-24-7 ]
  • [ 455-91-4 ]
Reference: [1] Journal of the American Chemical Society, 1940, vol. 62, p. 350,353
  • 13
  • [ 321-28-8 ]
  • [ 454-16-0 ]
  • [ 455-93-6 ]
  • [ 484-94-6 ]
Reference: [1] Journal of Organic Chemistry, 1998, vol. 63, # 23, p. 8448 - 8454
[2] Journal of Organic Chemistry, 1998, vol. 63, # 23, p. 8448 - 8454
  • 14
  • [ 321-28-8 ]
  • [ 455-93-6 ]
Reference: [1] Journal of Medicinal Chemistry, 2000, vol. 43, # 24, p. 4701 - 4710
[2] Journal of the Chemical Society, 1926, p. 1332
[3] Chemische Berichte, 1933, vol. 66, p. 1180,1183
[4] Journal of the American Chemical Society, 1946, vol. 68, p. 1583[5] Chem.Abstr., 1947, p. 6274
[6] Journal of the American Chemical Society, 1941, vol. 63, p. 609
[7] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1980, p. 832 - 834
[8] Patent: US4431807, 1984, A,
  • 15
  • [ 321-28-8 ]
  • [ 454-16-0 ]
  • [ 455-93-6 ]
  • [ 484-94-6 ]
Reference: [1] Journal of Organic Chemistry, 1998, vol. 63, # 23, p. 8448 - 8454
[2] Journal of Organic Chemistry, 1998, vol. 63, # 23, p. 8448 - 8454
  • 16
  • [ 321-28-8 ]
  • [ 455-93-6 ]
  • [ 484-94-6 ]
Reference: [1] Journal of Organic Chemistry, 1998, vol. 63, # 23, p. 8448 - 8454
  • 17
  • [ 321-28-8 ]
  • [ 344-78-5 ]
  • [ 455-93-6 ]
Reference: [1] Chemische Berichte, 1933, vol. 66, p. 1180,1183
[2] Journal of the Chemical Society, 1926, p. 1332
  • 18
  • [ 321-28-8 ]
  • [ 7697-37-2 ]
  • [ 108-24-7 ]
  • [ 455-93-6 ]
Reference: [1] Chemische Berichte, 1933, vol. 66, p. 1180,1183
[2] Journal of the Chemical Society, 1926, p. 1332
[3] Journal of the Chemical Society, 1940, p. 810
[4] Journal of the American Chemical Society, 1940, vol. 62, p. 350,353
  • 19
  • [ 321-28-8 ]
  • [ 7697-37-2 ]
  • [ 344-78-5 ]
  • [ 455-93-6 ]
Reference: [1] Chemische Berichte, 1933, vol. 66, p. 1180,1183
[2] Journal of the Chemical Society, 1926, p. 1332
[3] Journal of the Chemical Society, 1940, p. 810
  • 20
  • [ 373-91-1 ]
  • [ 100-66-3 ]
  • [ 459-60-9 ]
  • [ 321-28-8 ]
  • [ 710-18-9 ]
Reference: [1] Journal of Fluorine Chemistry, 2012, vol. 140, p. 43 - 48
  • 21
  • [ 321-28-8 ]
  • [ 366-99-4 ]
Reference: [1] Journal of Medicinal Chemistry, 2000, vol. 43, # 24, p. 4701 - 4710
[2] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1980, p. 832 - 834
[3] Journal of the American Chemical Society, 1941, vol. 63, p. 609
[4] Chemische Berichte, 1933, vol. 66, p. 1180,1183
[5] Chemische Berichte, 1933, vol. 66, p. 1180,1183
  • 22
  • [ 321-28-8 ]
  • [ 350-29-8 ]
Reference: [1] Journal of Materials Chemistry, 2002, vol. 12, # 8, p. 2214 - 2220
[2] Monatshefte fuer Chemie, 1955, vol. 86, p. 511,515
  • 23
  • [ 321-28-8 ]
  • [ 404-90-0 ]
Reference: [1] Collection of Czechoslovak Chemical Communications, 1990, vol. 55, # 1, p. 296 - 306
  • 24
  • [ 321-28-8 ]
  • [ 94610-82-9 ]
Reference: [1] Helvetica Chimica Acta, 1984, vol. 67, p. 1572 - 1579
  • 25
  • [ 321-28-8 ]
  • [ 331-62-4 ]
Reference: [1] Journal of Materials Chemistry, 2002, vol. 12, # 8, p. 2214 - 2220
  • 26
  • [ 321-28-8 ]
  • [ 151-50-8 ]
  • [ 331-62-4 ]
Reference: [1] Tetrahedron, 1977, vol. 33, p. 779 - 786
  • 27
  • [ 50-00-0 ]
  • [ 321-28-8 ]
  • [ 331-61-3 ]
Reference: [1] DRP/DRBP Org.Chem.,
  • 28
  • [ 321-28-8 ]
  • [ 452-11-9 ]
Reference: [1] Journal of the American Chemical Society, 1941, vol. 63, p. 609
  • 29
  • [ 321-28-8 ]
  • [ 2357-52-0 ]
YieldReaction ConditionsOperation in experiment
94% With sodium bicarbonate; bromine; sodium hydrogensulfite In chloroform; water Synthesis of 3-fluoro-4-methoxybromobenzene
Into a flask of 5 l were charged 384 g (3.04 mol) of 2-fluoroanisole and 2.5 l of chloroform, to which was added dropwise 504 g (3.16 mol) of bromine over about 3 hours while cooling on an ice water bath at 10° C.
The resulting mixture was stirred at room temperature over a night and heated under reflux for 8 hours.
After the air cooling, the product was added with 1 l of water and 50 g of sodium bisulfite and sufficiently shaken to separate into two layers.
The resulting organic layer was washed with an aqueous solution of 5percent sodium hydrogen carbonate and further with 1 l of water and dried on magnesium sulfate.
After magnesium sulfate was filtered off, the filtrate was concentrated and distilled under a reduced pressure (4 mmHg, bp: 93-°96° C.) to obtain 585 g (yield: 94percent) of 3-fluoro-4-methoxybromobenzene.
92.3% With sodium hydroxide; bromine In chloroform (a)
Synthesis of STR7
A reaction vessel was charged with 128 g (1.016 mol) of 2-fluoroanisole and 250 ml of chloroform.
To this mixture was added dropwise under agitation at room temperature 177 g (1.106 mol) of bromine over the period of at least 3 hours.
The reaction liquid was poured into a diluted aqueous solution of NaOH, and the chloroform layer was separated, washed with a solution of edible salt and dried over Glauber's salt.
The solvent was distilled off and the residue was distilled under reduced pressure to obtain 2-fluoro-4-bromoanisole.
Yield 192 g (yield rate: 92.3percent)
b.p. 107°-116° C./25-31 mmHg
91% With sodium hydroxide; bromine In chloroform (a)
Synthesis of 3-fluoro-4-methoxybenzamidine hydrochloride:
306 g of 2-fluoroanisole was dissolved in 750 ml of chloroform.
To the resulting solution, was added dropwise 389 g of bromine under stirring at room temperature.
After the completion of the addition, the reaction mixture was heated under reflux for nine hours and then allowed to cool to room temperature.
The mixture was washed with 500 ml of a 5percent aqueous solution of sodium hydroxide and then the organic layer was washed with 500 ml portions of water thrice.
The organic layer was separated and dried over anhydrous sodium sulfate.
After distilling off the solvent, the residue was purified by distillation (main fraction: 14 mmHg, 98°-100° C.) to thereby give 454 g of 2-fluoro-4-bromoanisole. Yield: 91percent.
86% With N-Bromosuccinimide In acetonitrile at 70℃; for 3 h; The crude product (1.0 g, 7.9 mmol) was dissolved in acetonitrile (15 mL) and N-bromosuccinimide (1.4 g, 8.7 mmol) was added and reacted at 70 ° C for 3 h. After the reaction was completed, most of the acetonitrile was distilled off, 30 mL of water was added, the mixture was stirred for 10 min and extracted with ethyl acetate (3 × 20 mL). The combined organic phases were dried over anhydrous magnesium sulfate and separated by column chromatography (pure petroleum ether as eluent) The brominated product (intermediate A_2c) was obtained as a light yellow oily liquid (1.4 g, yield 86percent) oA-2c: SH (300 MHz; CDCl 3) 7.23-7.16 (2H, m), 6.82 (D, J = 8.7Hz), 3.86 (3H, s); δ (75ΜΗζ; CDC13) 152.3 (d, Jc, F = 249.0Hz), 147.1 (d, 119.6 (d, J = 21.1 Hz), 114.6 (d, J = 2.2 Hz), 111.9 (d, J = 8.2 Hz), 56.4
73.4% With sodium hydroxide; bromine In chloroform; water Example 21
[Synthesis of 3'-fluoro-4'-dodecyloxybiphenyl-4-carboxylic acid]
2-Fluoroanisole (266 g) was dissolved in 700 ml of chloroform and 337 g of bromine was added dropwise to the solution.
The mixture was reacted under reflux at 67° to 68° C. for 1 hour, subsequently left to cool, washed with a 5percent aqueous solution of sodium hydroxide and then with water, and dried with anhydrous sodium sulfate.
After the solvent was distilled off under reduced pressure, the residue was distilled (95° to 96° C./12 mmHg) to obtain 317 g of 4-bromo-2-fluoroanisole (yield 73.4percent).

Reference: [1] Journal of Organic Chemistry, 2018, vol. 83, # 2, p. 930 - 938
[2] Patent: US5098602, 1992, A,
[3] Helvetica Chimica Acta, 1984, vol. 67, p. 1572 - 1579
[4] Patent: US5397504, 1995, A,
[5] Patent: US4997942, 1991, A,
[6] European Journal of Organic Chemistry, 2016, vol. 2016, # 7, p. 1429 - 1438
[7] Patent: CN104557654, 2017, B, . Location in patent: Paragraph 0082; 0083; 0085
[8] Patent: US4828754, 1989, A,
[9] Journal fuer Praktische Chemie (Leipzig), 1935, vol. <2> 143, p. 18,24
[10] Journal of Materials Chemistry, 2002, vol. 12, # 8, p. 2214 - 2220
[11] Journal of Medicinal Chemistry, 2003, vol. 46, # 22, p. 4790 - 4798
  • 30
  • [ 321-28-8 ]
  • [ 454-16-0 ]
  • [ 455-93-6 ]
  • [ 484-94-6 ]
Reference: [1] Journal of Organic Chemistry, 1998, vol. 63, # 23, p. 8448 - 8454
[2] Journal of Organic Chemistry, 1998, vol. 63, # 23, p. 8448 - 8454
  • 31
  • [ 321-28-8 ]
  • [ 455-93-6 ]
  • [ 484-94-6 ]
Reference: [1] Journal of Organic Chemistry, 1998, vol. 63, # 23, p. 8448 - 8454
  • 32
  • [ 321-28-8 ]
  • [ 458-09-3 ]
Reference: [1] Collection of Czechoslovak Chemical Communications, 1990, vol. 55, # 1, p. 296 - 306
[2] Monatshefte fuer Chemie, 1955, vol. 86, p. 511,515
[3] Monatshefte fuer Chemie, 1955, vol. 86, p. 511,515
[4] Monatshefte fuer Chemie, 1955, vol. 86, p. 511,515
  • 33
  • [ 321-28-8 ]
  • [ 452-14-2 ]
Reference: [1] Collection of Czechoslovak Chemical Communications, 1990, vol. 55, # 1, p. 296 - 306
[2] Monatshefte fuer Chemie, 1955, vol. 86, p. 511,515
  • 34
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  • [ 82380-18-5 ]
Reference: [1] Helvetica Chimica Acta, 1984, vol. 67, p. 1572 - 1579
  • 35
  • [ 321-28-8 ]
  • [ 67475-55-2 ]
YieldReaction ConditionsOperation in experiment
87% With chlorosulfonic acid In chloroform at 20℃; for 14 h; A stirred solution of 2-fluoroanisole (33.7 mL, 301 MMOL) in chloroform (250 mL) was cooled to 0°C and treated drop-wise with chlorosulfonic acid (50.0 mL, 752 MMOL). After stirring at room temperature for 14 hours, the reaction mixture was poured into ice-water (700 mL) and the separated, aqueous phase extracted with chloroform (2 x 200 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated IN VACUO TO YIELD 3-FLUORO-4- METHOXYBENZENESULFONYL CHLORIDE as a fine, white solid (58.6 g, 87percent), m. p. 80°C ; 1H NMR (400 MHz, DMSO-d6) 5 : 7.32 (m, 1H), 7.25 (dd, J= 11.5, 2.0 Hz, 1H), 7.05 (t, J = 8. 5 HZ, 1 H), 3.78 (s, 3H).
Reference: [1] Patent: WO2004/50631, 2004, A1, . Location in patent: Page 122-123
  • 36
  • [ 321-28-8 ]
  • [ 68-12-2 ]
  • [ 103438-88-6 ]
YieldReaction ConditionsOperation in experiment
64%
Stage #1: With N,N,N,N,-tetramethylethylenediamine; sec.-butyllithium In tetrahydrofuran; cyclohexane at -78℃; for 2 h;
Stage #2: at -78℃; for 0.166667 h;
Stage #3: With acetic acid In tetrahydrofuran; cyclohexane; water at 20℃;
A solution of 2 fluoro-anisole (6. 0 g, 47 mmol) and N, N, N', N'-teteramethylethylenediamine in THF (250 mL) was cooled to-78°C and treated dropwise with sec-butyl lithium (1.3 M/CYCLOHEXANE, 37.9 mL, 49 mmol). The mixture was stirred for 2 hours at- 78°C and then treated with dimethylformamide (3.6 mL, 47 mmol). Stirring continued for an additional 10 minutes and then acetic acid (20 mL) followed by water (150 mL) was added to the reaction. The reaction was warmed to ambient temperature and then diluted with ethyl acetate. The organic layer was extracted first with IN HCL, and then with brine. The solution was dried over MgSO4 and concentrated under reduced pressure to afford crude 2 flouro-3- methoxybenzaldehyde (4.7 g, 64percent). In a manner analogous to that described in Intermediate 13,2 flouro-3-methoxybenzaldehyde (4.7 g, 30 mmol), malonic acid (4.76 g, 45 mmol), pyridine (50 mL) and piperidine (1. 5 mL) afforded the title product (2.5g, 42percent). IH-NMR- (400 MHZ, D6 DMSO) 8, 7.65 (d, J=16. 1HZ, LH), 7. 34 (m, LH), 7.18 (m, 2H), 6.58 (d, J= 16. 1Hz, 1H), 3.83 (s, 3H).
Reference: [1] Patent: WO2005/34939, 2005, A1, . Location in patent: Page/Page column 67
[2] Patent: WO2005/23800, 2005, A1, . Location in patent: Page/Page column 54
[3] Patent: EP2168960, 2010, A1, . Location in patent: Page/Page column 141
[4] Patent: WO2015/13318, 2015, A1, . Location in patent: Paragraph 0234
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  • [ 68-12-2 ]
  • [ 74266-68-5 ]
  • [ 103438-88-6 ]
Reference: [1] Journal of Organic Chemistry, 1988, vol. 53, # 14, p. 3145 - 3147
  • 38
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  • [ 459-60-9 ]
  • [ 321-28-8 ]
  • [ 134364-69-5 ]
Reference: [1] Journal of Fluorine Chemistry, 2004, vol. 125, # 12, p. 1873 - 1877
  • 39
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  • [ 124-38-9 ]
  • [ 137654-20-7 ]
Reference: [1] Journal of Organic Chemistry, 2007, vol. 72, # 4, p. 1271 - 1275
[2] Bioorganic and Medicinal Chemistry Letters, 2000, vol. 10, # 18, p. 2115 - 2118
[3] Patent: WO2004/11443, 2004, A1, . Location in patent: Page 122
  • 40
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  • [ 137654-20-7 ]
YieldReaction ConditionsOperation in experiment
51% With n-butyllithium; potassium <i>tert</i>-butylate In tetrahydrofuran; water Step 1.
Preparation of 2-fluoro-3-methoxybenzoic acid.
A mixture of potassium tert-butoxide (30.80 g, 274 mmol) and anhydrous tetrahydrofuran (300 mL) was cooled to -78° C. and treated with a 1.6M solution of n-butyllithium (172 mL, 275 mmol) in hexanes.
After stirring for 15 minutes, 2-fluoroanisole (31.35 g, 248 mmol) was added and the reaction was stirred an additional 1.8 hours.
The reaction was poured into a 2 L Erlenmeyer flask containing dry ice and warmed to room temperature.
Water (250 mL) was added and after extracting with ether (160 mL), the aqueous layer was acidified with concentrated hydrochloric acid, and filtered to give 2-fluoro-3-methoxybenzoic acid (21.43 g, 51percent) as a yellow solid: mp 155°-160° C.; 1 H NMR (acetone-d6) 300 MHz 7.46 (ddd, J=6.0 Hz J=1.8 Hz J=1.4 Hz, 1H) 7.36 (dt, J=1.6 Hz J=8.1 Hz, 1H) 7.20 (dt, J=1.4 Hz J=8.1 Hz, 1H) 3.92 (s, 3H); 19 F NMR (acetone-d6) 300 MHz -134.04(m).
Mass spectrum: M+H=171.
Reference: [1] Patent: US5547975, 1996, A,
  • 41
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  • [ 169590-41-4 ]
Reference: [1] Patent: CN107686465, 2018, A,
  • 42
  • [ 321-28-8 ]
  • [ 351210-06-5 ]
Reference: [1] Tetrahedron Letters, 2004, vol. 45, # 8, p. 1769 - 1771
  • 43
  • [ 109-72-8 ]
  • [ 121-43-7 ]
  • [ 321-28-8 ]
  • [ 352303-67-4 ]
Reference: [1] Patent: US2002/132820, 2002, A1,
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