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Product Details of [ 403-21-4 ]

CAS No. :403-21-4 MDL No. :MFCD01862092
Formula : C7H4FNO4 Boiling Point : -
Linear Structure Formula :- InChI Key :WVZBIQSKLXJFNX-UHFFFAOYSA-N
M.W :185.11 Pubchem ID :230653
Synonyms :

Calculated chemistry of [ 403-21-4 ]

Physicochemical Properties

Num. heavy atoms : 13
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.0
Num. rotatable bonds : 2
Num. H-bond acceptors : 5.0
Num. H-bond donors : 1.0
Molar Refractivity : 42.18
TPSA : 83.12 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : No
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.09 cm/s

Lipophilicity

Log Po/w (iLOGP) : 0.89
Log Po/w (XLOGP3) : 1.88
Log Po/w (WLOGP) : 1.85
Log Po/w (MLOGP) : 0.94
Log Po/w (SILICOS-IT) : -0.48
Consensus Log Po/w : 1.02

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 1.0
Bioavailability Score : 0.56

Water Solubility

Log S (ESOL) : -2.38
Solubility : 0.769 mg/ml ; 0.00415 mol/l
Class : Soluble
Log S (Ali) : -3.25
Solubility : 0.105 mg/ml ; 0.000565 mol/l
Class : Soluble
Log S (SILICOS-IT) : -1.43
Solubility : 6.85 mg/ml ; 0.037 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 2.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.57

Safety of [ 403-21-4 ]

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 [ 403-21-4 ]

* 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 [ 403-21-4 ]
  • Downstream synthetic route of [ 403-21-4 ]

[ 403-21-4 ] Synthesis Path-Upstream   1~23

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Reference: [1] Journal of the American Chemical Society, [2] Journal of the American Chemical Society, 2009, vol. 131, p. 5564 - 5572
[3] Journal of Medicinal Chemistry, 2015, vol. 58, # 7, p. 3002 - 3024
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Reference: [1] Journal of the American Chemical Society, 1944, vol. 66, p. 1631
[2] Patent: WO2006/136402, 2006, A1,
  • 3
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  • [ 455-87-8 ]
YieldReaction ConditionsOperation in experiment
98.6% With palladium on activated charcoal; hydrogen In tetrahydrofuran; methanol at 20℃; for 15 h; In a 1000 mL round bottom single-necked flask, palladium on carbon (2 g)And the mixture was dissolved in 300 ml of a mixed solvent of methanol and tetrahydrofuran,Further 3-fluoro-4-nitrobenzoic acid (30 g, 190 mmol, leq) was added,The reaction system was filled with hydrogen gas and stirred at room temperature for 15 hours.After completion of the reaction, the reaction solution was filtered through Celite to obtain a filtrate, and the filtrate was dried to obtain a white solid,Dry the solids in an oven to give a dry white solid (24. 86 g, 98.6percent).
98% With 5%-palladium/activated carbon; hydrogen In ethanolFlow reactor General procedure: Before each run, the system (see Fig.4) was allowed to equilibrate by pumping solvent through for 30min with the Tube-in-Tube device at 16bar of hydrogen. An omnifit cartridge (20.0mm OD, 15.0mm ID) containing 1g of Pd-C catalyst was used. To avoid an overpressure of the system in the event of blockage, the upper pressure cut-off limit on the Knauer pump was set to 25bar. With the injection loop disconnected from the flow line, the loop was opened and filled manually (using a syringe) with 3.6mL of a 0.076M solution of starting material in ethanol (excess starting material solution exiting the loop was recovered for reuse). The injection loop was then closed off and switched into the flow stream. The outlet from the system (downstream of the back-pressure regulator) was collected for 120min. The solvent was removed under reduced pressure (using a rotary evaporator followed by a 2-stage rotary vane pump) to afford the product.
Reference: [1] Patent: CN105294567, 2016, A, . Location in patent: Paragraph 0033-0036
[2] Tetrahedron, 2018, vol. 74, # 47, p. 6795 - 6803
[3] Journal of the American Chemical Society, 1944, vol. 66, p. 1631
[4] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 12, p. 2697 - 2706
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  • [ 7439-89-6 ]
  • [ 455-87-8 ]
Reference: [1] Patent: US6201007, 2001, B1,
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  • [ 74-89-5 ]
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YieldReaction ConditionsOperation in experiment
100%
Stage #1: at 20℃; for 1 h;
Stage #2: With potassium hydrogensulfate In water
Step 1: 4- (METHYLAMINO)-3-NITROBENZOIC acid (279) [0435] A 40percent solution of methylamine in water (11 mL; 128MMOL) (or any other primary amine) was slowly added to a stirring suspension of 4-fluoro-3-nitrobenzoic acid (278,6. 1G ; 32. 9mmol) in DMF (20mL) at room temperature. After the addition was completed the mixture was stirred at the same temperature for 60min ; concentrated in vacuo, and suspended in 5percent KHSO4 (final pH=2). The suspension was stirred overnight; the precipitate was collected by filtration, washed with water, then with ether and dried to afford the title compound 279 (6.5g ; 100percent YIELD). 1H NMR: (400.2 MHz, DMSO) 8 (ppm): 12.8 (bs; 1H). 8.59 (d, J= 2.0 Hz; 1H); 8.55 (q, J= 5.0 Hz; 1H); 7.96 (dd, J= 2.0, 9.1 Hz; 1H); 7.04 (d, J= 9.1 Hz; 1H); 3.00 (d, J= 5. 0 Hz; 3H). MS: CALC : 196.2 ; found: 197.1 (M+H)
Reference: [1] Patent: WO2005/30704, 2005, A1, . Location in patent: Page/Page column 244
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  • [ 75-65-0 ]
  • [ 658700-15-3 ]
  • [ 2369-13-3 ]
YieldReaction ConditionsOperation in experiment
32% With diphenyl phosphoryl azide; triethylamine In 1,4-dioxane at 95℃; for 48 h; Diphenylphosphorylazide (5.5 mmol, 1.5 g) was added to a solution of 3-fluoro-4- nitrobenzoic acid (5.4 mmol, [1] g) and triethylamine (5.6 mmol, 0.8 mL) in a 1: 1 mixture of [TERT-BUTYL] alcohol/dioxane (60 mL). The reaction mixture was refluxed for 2 days at 95 [C] and the solvent was evaporated to give an oily residue. The residue was taken up in ethyl acetate (100 mL) and washed with 10percent citric acid, IN NaOH, brine and H20. Evaporation of solvent afforded an orange residue that was subsequently purified by flash chromatography eluting with ethyl acetate/hexane to afford [(TERT-BUTOXY)-N- (3-FLUORO-4-] nitrophenyl) carboxamide (1. [75MMOL,] 0.45g, yield 32percent). 3-Fluoro-4-nitroaniline (0.36 g, 2.3 mmol) was isolated as a byproduct. Treatment of [(TERT-BUTOXY)-N- (3-FLUORO-4-] nitrophenyl) carboxamide with trifluoroacetic acid in methylene chloride afforded additional [3-FLUORO-4-NITROANILINE.]
Reference: [1] Patent: WO2004/14905, 2004, A1, . Location in patent: Page 157-158
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YieldReaction ConditionsOperation in experiment
83% With potassium dichromate; sulfuric acid In acetic acid at 120℃; for 2 h; 2-Fluoro-4-methyl-l-nitro-benzene (1.0 g, 12.9 mmol) was added portion- wise to a suspension of potassium dichromate (5.04 g, 17.16 mmol) in glacial acetic acid (8 mL) follow by concentrated sulfuric acid (3.6 mL). The reaction mixture was heated to 1200C for 2 h and then allowed to cool to ambient temperature. The reaction was quenched with crushed ice and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 3-fluoro-4-nitro-benzoic acid (1.9 g, 83percent) as a white solid.
82.9% With potassium permanganate In ethyl acetate Reference Example 39
An aqueous solution (50 mL) containing 3-fluoro-4-nitrotoluene (2.0 g, 12.9 mmol) and potassium permanganate (4.07 g, 25.8 mmol) was heated under reflux for 15 hours.
The reaction solution was cooled and then aqueous phase was washed with ethyl acetate.
The aqueous phase was acidified with 4 N aqueous hydrochloric acid solution, and the precipitated crystals were collected by filtration.
The filtrate was extracted with ethyl acetate five times.
The crystals collected by filtration were dissolved in ethyl acetate, and combined with the ethyl acetate extraction solution.
The ethyl acetate layer combined was washed with water and then with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure, to obtain 3-fluoro-4-nitrobenzoic acid (1.07 g, 82.9percent) as pale yellow crystals.
1H-NMR(CDCl3)δ:8.01-8.06(1H,m),8.12-8.18 (1H,m) ppm
FABMS:186(M+1)
68% With sodium dichromate; sulfuric acid In water at 0 - 90℃; for 4.3 h; (a)
Synthesis of 3-fluoro-4-nitrobenzoic acid
Sodium dichromate (6.50 g, 21.8 mmol) was added to a suspension of 3-fluoro-4-nitrotoluene (2.50 g, 16.0 mmol) in water (19 ml) under ice-cooling, and concentrated sulfuric acid (14.7 ml) was added dropwise thereto at 6°C over a period of 2 hours.
After completion of the dropwise addition, an ice-water bath was removed and the mixture obtained was allowed to stand for 20 minutes until its temperature became room temperature.
Thereafter, the mixture was heated and then stirred at 90°C for 2 hours.
After completion of the reaction, water (50 ml) was poured into the reaction mixture under ice-cooling, and the resulting mixture was stirred at room temperature for a while.
This mixture was extracted twice with ethyl acetate and then the organic layer was washed three times with a 2N-aqueous sodium hydroxide solution.
The aqueous layer was acidified with 6N-hydrochloric acid and extracted with ethyl acetate.
The organic layer was washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and then filtered.
The filtrate was concentrated and the crude product thus obtained was purified by a silica gel column chromatography (eluent: chloroform/methanol = 8/2) to obtain 3-fluoro-4-nitrobenzoic acid (2.00 g, 68percent).
58% With potassium permanganate In water for 6 h; Heating / reflux Stage 1:
3-fluoro-4-nitrobenzoic acid
A mixture of 3-fluoro-4-nitrotoluene (10 g, 1 eq) and potassium permanganate (25.5 g, 2.5 eq) in water (1 L) is heated under reflux for 6 hours then cooled down to ambient temperature.
The mixture is filtered on celite and the aqueous phase is washed twice with diethyl ether (2*300 ml).
The aqueous phase is acidified, at 0° C., with a solution of concentrated hydrochloric acid then concentrated under reduced pressure at 40° C. to a volume of approximately 300 ml.
The precipitate formed is filtered then washed with petroleum ether and dried in order to produce the expected compound in the form of a white solid (6.9 g; 58percent yield).
NMR (1H, 400 MHz, DMSO-d6): δ 7.93 (m, 2H), 8.25 (m, 1H), 13.95 (m, 1H).
58%
Stage #1: With potassium permanganate In water for 6 h; Reflux
Stage #2: at 0℃;
EXAMPLE A1; N,N-bis(3-methylbutyl)-11-oxo-5-(3-piperidin-1-ylpropyl)-5,11-dihydrothieno[3',2':4,5]pyrimido[1,2-a]benzimidazole-7-carboxamide hydrochloride; Stage 1: 3-fluoro-4-nitrobenzoic acid; A mixture of 3-fluoro-4-nitrotoluene (10 g, 1 eq) and potassium permanganate (25.5 g, 2.5 eq) in water (1 L) is heated under reflux for 6 hours then cooled down to ambient temperature. The mixture is filtered on celite and the aqueous phase is washed twice with diethyl ether (2.x.300 ml). The aqueous phase is acidified, at 0° C., with a solution of concentrated hydrochloric acid then concentrated under reduced pressure at 40° C. to a volume of approximately 300 ml. The precipitate formed is filtered then washed with petroleum ether and dried in order to produce the expected compound in the form of a white solid (6.9 g; 58percent yield).NMR (1H, 400 MHz, DMSO-d6): δ 7.93 (m, 2H), 8.25 (m, 1H), 13.95 (m, 1H).
58% With potassium permanganate In water for 6 h; Heating / reflux Stage 1:
3-fluoro-4-nitrobenzoic acid
A mixture of 3-fluoro-4-nitrotoluene (10 g, 1 eq) and potassium permanganate (25.5 g, 2.5 eq) in water (1 l) is heated to reflux for 6 hours then cooled down to ambient temperature.
The mixture is filtered on celite and the aqueous phase is washed twice with diethyl ether (2*300 ml).
The aqueous phase is acidified with an aqueous solution of concentrated hydrochloric acid (12N) then concentrated under reduced pressure at 40° C. to a volume of approximately 300 ml.
The precipitate formed is filtered then washed with petroleum ether and dried in order to produce the expected compound in the form of a white solid (6.9 g; 58percent yield).
NMR 1H (400 MHz, DMSO-d6): δ7.93 (m, 2H), 8.25 (m, 1H), 13.95 (m, 1H).
24% With sodium dichromate; sulfuric acid In water at 90 - 100℃; for 1 - 2 h; Concentrated H2SO4 (190 mL) was added dropwise to a cooled solution of 3-fluoro-4- nitrotoluene (161.2 mmol, 25 g) and sodium dichromate dihydrate (225.6 mmol, 67.2 g) in water (200 mL). The addition was carried out while maintaining the temperature of the reaction mixture below 10 [C.] Once the addition was complete, the solution was refluxed at 100 [C] for approximately 2 h. The reaction mixture was cooled to room temperature, diluted with H20 (200 mL) and the product extracted with ethyl acetate. The organic extracts were combined and extracted with a solution of 2N sodium hydroxide. The basic phase was acidified with concentrated [HC1] to afford (65.9 mmol, 12.2 g) as an off-white solid precipitate (yield: 40.8percent). The precipitate was further purified by recrystallization from an ethanol/water mixture to afford 3-fluoro-4- nitrobenzoic acid as white crystals.To a solution [OF 3-FLUORO-4-NITROTOLUENE] (22.45 g, 144.7 mmol) and sodium dichromate dihydrate (60.38 g, 202.6 mmol) in water at [0 C] was added concentrated sulfuric acid (140 mL) dropwise over 3 h. When the addition was complete, the solution was allowed to warm to room temperature over [1] h, and then brought to 90 C for 1 h. The mixture was allowed to cool to room temperature, diluted with 300 mL water and extracted with ethyl acetate (3 x 250 mL). The combined organic extracts were concentrated down to 300 mL and extracted with [1] N NaOH (3 x 250 mL). The aqueous extracts were acidified with 6 N [HC1] and extracted with ethyl acetate (3 x 300 mL). The combined organic extracts were dried over [MGS04] and concentrated to give a gummy solid. Trituration with hexane gave the [3-FLUORO-4-NITROBENZOIC] acid as a solid that was collected by filtration (6.51 g, 24percent).
68% With Na2Cr2O7; sulfuric acid In sodium hydroxide; water Example 8
Synthesis of 3-Fluoro-4-[3-Pentyl-3-(5,5,8,8-Tetramethyl-5,6,7,8-Tetrahydro-Naphthalen-2-yl)-Ureido]-Benzoic Acid
A solution of 3-fluoro-4-nitrotoluene (2 g, 12.82 mmole) in 13 mL water, containing 5.72 g of Na2Cr2O7, was treated dropwise with 14.2 mL of concentrated sulfuric acid, stirred at room temperature for one hour and then diluted with 20 mL of water.
The mixture was filtered and the recovered solid was gently heated in 50 mL 2percent sodium hydroxide solution.
The resulting solution was cooled and filtered and the filtrate was acidified with concentrated HCl.
The aqueous phase was extracted with two 100 mL portions of ethyl acetate, the combined extracts were washed with 100 mL of aqueous saturated sodium chloride solution, dried over MgSO4, filtered and concentrated in vacuo to give 1.6 g (68percent) of 3-fluoro-4-nitrobenzoic acid as a yellow solid.

Reference: [1] Patent: WO2009/130481, 2009, A1, . Location in patent: Page/Page column 145
[2] Journal of Medicinal Chemistry, 2005, vol. 48, # 6, p. 1729 - 1744
[3] Patent: EP1820799, 2007, A1,
[4] Patent: WO2006/51851, 2006, A1, . Location in patent: Page/Page column 60-61
[5] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 5, p. 1386 - 1391
[6] Patent: EP1500643, 2005, A1, . Location in patent: Page 39
[7] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 4, p. 1043 - 1046
[8] European Journal of Medicinal Chemistry, 1999, vol. 34, # 3, p. 225 - 234
[9] Patent: US2005/65179, 2005, A1, . Location in patent: Page/Page column 9
[10] Patent: US2009/209531, 2009, A1, . Location in patent: Page/Page column 5
[11] Patent: US2006/281784, 2006, A1, . Location in patent: Page/Page column 8
[12] Bioorganic and Medicinal Chemistry, 2009, vol. 17, # 13, p. 4345 - 4359
[13] Patent: US4483986, 1984, A,
[14] Patent: WO2004/14905, 2004, A1, . Location in patent: Page 157; 157
[15] Journal of the American Chemical Society, 1944, vol. 66, p. 1631
[16] Journal of Medicinal Chemistry, 1983, vol. 26, # 8, p. 1193 - 1196
[17] Patent: US2003/158226, 2003, A1,
[18] Patent: US5624957, 1997, A,
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YieldReaction ConditionsOperation in experiment
92% With jones reagent; calcium carbonate In water; acetone at 0℃; for 0.5 h; In the step D-3, to a solution of 3-fluoro-4-nitrobenzyl alcohol (2. 97 g) in acetone (60 ml) was added Jones reagent (13 ml), prepared from CHROMIC acid (26.7 g) and sulfuric acid (23 ml) in water (100 ml), dropwise at 0C. The mixture was stirred on a ice-bath for 0.5 hours and quenched with isopropanol (20 ml) to be concentrated in vacuo. The residue was dissolved in ethyl acetate (30 ml) and washed with water (30 ml X 3), and brine (30 ml X 1), successively. The organic layer was dried over sodium sulfate and concen- trated in vacuo to obtain a yellow solid, that was triturated with hexane to give 3-FLUORO-4-NITROBENZOIC acid as a pale yellow solid (2.94 g, 92percent).
Reference: [1] Patent: WO2004/58764, 2004, A1, . Location in patent: Page 39
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Reference: [1] Tetrahedron, 2001, vol. 57, # 22, p. 4753 - 4757
[2] Journal of Organic Chemistry, 2002, vol. 67, # 2, p. 394 - 400
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Reference: [1] Journal of Organic Chemistry, 2002, vol. 67, # 2, p. 394 - 400
[2] Tetrahedron, 2001, vol. 57, # 22, p. 4753 - 4757
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Reference: [1] Patent: US2006/14807, 2006, A1, . Location in patent: Page/Page column sheet 2; 44-45
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  • [ 160538-51-2 ]
Reference: [1] Patent: WO2005/121147, 2005, A1,
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  • [ 5081-36-7 ]
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  • [ 185629-32-7 ]
Reference: [1] Patent: US2003/158226, 2003, A1,
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Reference: [1] Patent: WO2012/87520, 2012, A1,
[2] Patent: WO2012/87519, 2012, A1,
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YieldReaction ConditionsOperation in experiment
97% for 15 h; Heating / reflux Step 1 :; 10 N HCI (2 mL) was added to a solution of 3-fluoro-4-nitro-benzoic acid (29-1) (10 g, 54.0 mmol) in 300 mL of MeOH and the solution was refluxed for 15 h. The mixture was then concentrated, the residue was diluted with EtOAc, and the organic phase was washed with 2 X water and saturated aqueous NaHC03, dried (MgS04), filtered and evaporated to give 10.45 g (97 percent yield) of compound 29-2 as a white solid. The compound was used as such for the next reaction.
96% With hydrogenchloride In diethyl ether for 16 h; Heating / reflux EXAMPLE 2; 4-FIuoro-N-isopropyl-6-(4-phenyloxazol-5-yl)benzo [d]thiazol-2-amine;1. Methyl 3-fluoro-4-nitrobenzoate[00154] ;A mixture of 3-fluoro-4-nitrobenzoic acid (5.00 g, 27.0 mmol), Methanol (40 mL), and 2 N HCl in Et2O was heated at reflux for 16 hr. Volatile material was removed under vacuum. The residue was diluted with AcOEt (150 mL), washed successively with saturated NaHCO3 solution and brine, and dried over anhydrous MgSO4. Evaporation of solvent under vacuum gave the title compound-(5.18 g, 96percent yield) as a pale yellow solid.
95% at 0 - 60℃; for 24 h; To a solution of compound 53 (5.0 g, 27.01 mmol) in MeOH (12.9 mL) was added SOCl2 (4.1 mL, 56.72 mmol) at 0 °C.
The mixture was heated to 60 °C for 24 h and monitored by TLC. Upon completion, the solvent was evaporated.
The residue was basified with saturated NaHCO3 to pH 7-8, diluted with water and extracted with EtOAc (3 * 40 mL).
Combined organic layers were washed with brine, and dried with Na2SO4 to afford compound 54 (5.11 g, 25.68 mmol, 95percent yield) as a light yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.11 (t, J = 7.8 Hz, 1H), 7.97 (s, 1H), 7.94 (d, J = 3.0 Hz, 1H), 3.98 (s, 3H); MS m/z (EI) found [M]+ 199; retention time 3.28 min, > 95percent pure.
93% Heating / reflux In the step D-4, to a solution of 3-fluoro-4-nitrobenzoic acid (5.00 g) in methanol (50 ml) was added 98percent sulfuric acid (1 ml). The mixture was refluxed overnight and concentrated in vacuo. The residue was dissolved in ethyl acetate (30 ml) and washed with saturated sodium bicarbonate water solution (30 ml) and brine (30 ml), successively. The organic layer was dried over sodium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane/ethyl acetate = 5/1) to give methyl 3-fluoro-4-nitrobenzoate (5.0 g, 93percent) as a colorless solid.
93% With hydrogenchloride In water for 18 h; Reflux 12 M HCI (5.00 mL) was added to a solution of 3-fluoro-4-nitro-benzoic acid (25.0 g, 135 mmol) in MeOH (400 mL). The reaction mixture was refluxed for 18 h. After cooling, the mixture was concentrated in vacuo. The residue was diluted with EtOAc and water. The organic layer was separated, washed with saturated aqueous solution of NaHC( and brine, dried over MgSC>4 and concentrated in vacuo to give methyl 3-fluoro-4-nitrobenzoicacidmethylester (25.5 g, 93percent) as a colorless solid. 1H NMR (300 MHz, CDC13) δ 3.98 (s, 3 H), 7.94 (d, J= 2.8 Hz, 1 H), 7.96 (s, 1 H), 8.08-8.12 (m, 1 H).
89% for 5.5 h; Heating / reflux Preparation of methyl 3-fluoro-4-nitrobenzoate; <n="55"/>3-Fluoro-4-nitrobenzoic acid (8.15 g, 44.0 mmol) was dissolved in 100 mL anhydrous methanol under a nitrogen atmosphere, added 1 mL concentrated sulfuric acid, and subsequently heated at reflux for 5.5 hours. The reaction mixture was cooled to ambient temperature, concentrated in vacuo. Re-dissolved in diethyl ether (250 mL), washed with saturated sodium bicarbonate (3 x 100 mL), brine, dried with magnesium sulfate, filtered and concentrated in vacuo to yield title compound. (7.8 g, 89percent): APCI" 199.3; Anal. HPLC Retention time = 16.6 minutes (>99percent pure).

Reference: [1] Bioorganic and Medicinal Chemistry, 2009, vol. 17, # 5, p. 2017 - 2029
[2] Patent: WO2005/80388, 2005, A1, . Location in patent: Page/Page column 88-89
[3] Patent: WO2007/16392, 2007, A2, . Location in patent: Page/Page column 47
[4] European Journal of Medicinal Chemistry, 2018, vol. 150, p. 156 - 175
[5] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 4, p. 1043 - 1046
[6] Patent: WO2004/58764, 2004, A1, . Location in patent: Page 39
[7] Patent: WO2015/161142, 2015, A1, . Location in patent: Paragraph 00254
[8] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 5, p. 1386 - 1391
[9] Patent: WO2008/84300, 2008, A1, . Location in patent: Page/Page column 52-53
[10] Bioorganic and Medicinal Chemistry, 2009, vol. 17, # 13, p. 4345 - 4359
[11] Patent: US2007/232603, 2007, A1, . Location in patent: Page/Page column 19
[12] Patent: WO2012/87519, 2012, A1, . Location in patent: Page/Page column 84; 85
[13] Patent: WO2012/87520, 2012, A1, . Location in patent: Page/Page column 43
[14] Patent: WO2011/56635, 2011, A1, . Location in patent: Page/Page column 105
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YieldReaction ConditionsOperation in experiment
97% With thionyl chloride In methanol; hexane; N,N-dimethyl-formamide; toluene Synthesis of 3-fluoro-4 nitro benzoic acid methylester
To a 500 ml flask under nitrogen atmosphere was charged 3-fluoro-4-nitro benzoic acid (10 g, 0.054 mol, 1 eq) and 250 ml of Toluene followed by DMF (210 ul, 3.7 mmol, 0.05 eq) and was heated to 70° C. At 40° C. thionyl chloride (8.0 ml, 0.11 mol, 2.0 eq) was added and the reaction was allowed to stir at 70° C. for 16 hours.
The reaction was removed from the heat and placed in an ambient temperature bath.
100 ml of anhydrous methanol was added and then concentrated on rotary evaporator under reduced pressure, and bath temp of 45° C.
The final volume was reduced to ~70 ml and slowly add hexane 100 ml with stiring to yield a light yellow solid, yield 97percent. 1H NMR (Solvent CDCl3), Singlet, 3 H, 3.99 ppm, Doublet of Doublets, 2H, 7.95 ppm, Triplet, 1H, 8.15 ppm.
Thin Layer Chromatography elution 5percent methanol/dichloromethane, Rf=0.9.
Reference: [1] Patent: US2003/119754, 2003, A1,
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  • [ 18107-18-1 ]
  • [ 185629-31-6 ]
YieldReaction ConditionsOperation in experiment
100% at 20℃; for 0.666667 h; Compound 236a: 3-Fluoro-4-nitro-benzoic acid methyl ester: A solution of 3-fluoro-4-nitro-benzoic acid (3.0 g, 16.12 mmol, 1.0 eq) in 4:1 DCM/MeOH (50 ml) was stirred at room temperature for 5 minutes and a 2.0M solution of TMS-diazomethane in hexanes (8.1 ml, 16.12 mmol, 1.0 eq) was added drop-wise over 10 minutes, the reaction then stirred at room temperature for 30 minutes. The reaction was quenched with a few drops of acetic acid and the solvent removed in vacuo to give the title compound (3.4 g, 17.09 mmol, 100percent corrected). 1H NMR shows the desired product in ca. 90percent purity.
100% at 0 - 20℃; for 1 h; Compound 153a: 3-Fluoro-4-nitro-benzoic acid methyl ester: A solution of 3-fluoro-4-nitrobenzoic acid (0.5 g, 2.7 mmol, 1.0 eq) in 3:1 toluene/methanol (8 ml) was cooled to 00C and 2.0M TMS-diazomethane/Et2O (1.8 ml, 3.5 mmol, 1.3 eq) was added dropwise. The reaction was stirred for 1 hour and allowed to warm to room temperature. The solvent was removed in vacuo to give the title compound as a yellow solid (0.54 g, 2.7 mmol, 100percent). 1H NMR shows product in >95percent purity.
99% at 0℃; for 0.583333 h; (MRS-2-33) 3-Fluoro-4-nitrobenzoic acid (720 mg, 3.89 mmol) was dissolved in PhMe:MeOH (8 mL ea) and cooled to 0 °C. ( Diazomethyl ) trimethylsilane (4.3 mL, 8.56 mmol, 2.2 equiv, 2 M in n-hexane) was added dropwise over 5 minutes. The reaction mixture was stirred 30 minutes, then quenched with slow addition of AcOH. Solvent was removed in vacuo and the residue purified by flash chromatography (Si02, 10percent EtOAc/hexanes) to give 770 mg (99percent) of the methyl ester .
87% With acetic acid In methanol; hexane Stage 1:
methyl 3-fluoro-4-nitrobenzoate
A solution of trimethylsilyldiazomethane (2M in hexane, 50 ml, 4 eq) is slowly added to a solution of 3-fluoro-4-nitrobenzoic acid (4.7 g, 1 eq) in methanol (70 ml) until the gas evolution ceases.
The excess trimethylsilyldiazomethane is consumed by the dropwise addition of acetic acid until the solution becomes discoloured.
The mixture is then concentrated under reduced pressure at a temperature of approximately 40° C. Water (200 ml) and dichloromethane (300 ml) are added to the residue.
After decantation and extractions, the combined organic phases are washed with salt water, dried over Na2SO4 then concentrated under reduced pressure at 40° C.
The solid obtained is washed with petroleum ether and dried (4.4 g; 87percent yield).
NMR (1H, 400 MHz, CDCl3): δ 4.0 (s, 3H), 7.97 (m, 2H), 8.11 (d, 1H).

Reference: [1] Patent: WO2006/136402, 2006, A1, . Location in patent: Page/Page column 119
[2] Patent: WO2006/136402, 2006, A1, . Location in patent: Page/Page column 87
[3] Patent: WO2014/131023, 2014, A1, . Location in patent: Page/Page column 147
[4] Journal of Medicinal Chemistry, 2016, vol. 59, # 10, p. 4812 - 4830
[5] Patent: US2005/65179, 2005, A1, . Location in patent: Page/Page column 18
  • 18
  • [ 403-21-4 ]
  • [ 75-36-5 ]
  • [ 185629-31-6 ]
Reference: [1] Patent: US5624957, 1997, A,
  • 19
  • [ 18166-02-4 ]
  • [ 403-21-4 ]
  • [ 185629-31-6 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 16, p. 4464 - 4470
  • 20
  • [ 403-21-4 ]
  • [ 503315-74-0 ]
YieldReaction ConditionsOperation in experiment
97% With dimethylsulfide borane complex In tetrahydrofuran at 0 - 65℃; for 21 h; Part A. Preparation of (3-fluoro-4-nitrophenyl)methanol.; [00722]To a solution of 3-fluoro-4-nitrobenzoic acid (2.0 g, 10.8mmol) in TηF (50ml) at O0C was addedBH3-Me2S complex (2.215ml, 22.15mmol) drop-wise. The mixture was stirred at O0C for 3h, and was then stirred at 650C for 18h. To the cooled mixture was added ice (5Og), followed by 1 ν aq. HCl(100ml), and the resulting mixture was extracted with EtOAc (200ml). The organic layer was dried overνa24, filtered and concentrated in vacuo to provide the title compound as a white solid (1.79g, 97percent).
94%
Stage #1: With benzotriazol-1-ol; dicyclohexyl-carbodiimide In tetrahydrofuran at 20℃; for 1 h;
Stage #2: With sodium tetrahydroborate In tetrahydrofuran at 20℃; for 2 h;
Stage #3: With hydrogenchloride In tetrahydrofuran; water
General method for the synthesis of 4-nitro-benzyl alcohols (III)To a solution of substituted 4-nitrobenzoic acid II (1.0 mmol) in THF (10 mL) was added HOBt (135 mg, 1.0 mmol) and DCC (227 mg, 1.1 mmol). The resulting mixture was stirred at room temperature for 1 h. The white precipitates were filtered off and rinsed with THF (2 x 5 mL). The filtrate was added dropwise to a suspension of NaBH4 (38 mg, 1.0 mmol) in THF (10 mL) over 30 min. The reaction was carried out at room temperature for additional 1.5 h and quenched by adding 10 mL 1.0 N HC1. After evaporation of THF under reduced pressure, the remaining aqueous solution was extracted EtOAc (3 x 20 mL). The combined EtOAc phase was washed with water and brine, and dried over Na2S04. After removal of Na2S04 via filtration, the filtrate was concentrated to dryness. The crude product was purified by flash column chromatography (hexane to 50percent EtOAc/hexane) to afford the desired alcohol III.3-Fluoro-4-nitrobenzyl alcohol. A yellow solid (161 mg, 94percent); 1H NMR (200 MHz, CDC13): δ 8.01 (t, 1H, J= 7.8 Hz), 7.29 (d, 1H, J= 1 1.8 Hz), 7.22 (d, 1H, J= 8.4 Hz), 4.77 (s, 2H), 2.00 (s, -OH); 13C NMR (50 MHz, CDC13): 155.7 (d, J= 265.0 Hz), 150.3 (t, J= 8.0 Hz), 136.9 (t, J= 8.0 Hz), 126.2 (d, J= 2.0 Hz), 121.7 (d, J= 4.0 Hz), 115.8 (d, J= 21.0 Hz), 63.4; lR (KBr): 2146, 1691 , 1432, 1298 cm"1.
92% With sodium tetrahydroborate; boron trifluoride diethyl etherate In tetrahydrofuran at 20℃; TO AN ICE-COOLED SUSPENSION OF NABH4 (204MG, 5.4MMOL, 2EQ. ) IN THF (LOML) WAS ADDED
DROPWISE 3-FLUORO 4-NITRO BENZOIC ACID (500MG, 2. 7MMOL, LEQ. ) IN THF (IOML) OVER 30] minutes. BF3-Et20 (7.3mmol, 2.7eq.) was then added dropwise over 30 minutes. The solution was stirred at room temperature over night. IN [HC1] was added dropwise to quench NaBH4 excess. The solvent was [REMOVED IN VACTIO,] the residue dissolved in DCM, washed with water, brine. The organic layer was then dried over [MGS04] and the solvent removed in vacuo to give 425 mg of 3-fluoro 4-nitro benzyl alcohol (92percent yield). The compound was used in the following step with no further purification. [1H NMR] : [8=] (400 MHz, [CDC13)] : 7.97 [(M,] 1H), 7.28 [(M,] 1H), 7.18 [(M,] 1H), 4.75 [(M,] 2H).
Reference: [1] Patent: WO2009/39135, 2009, A1, . Location in patent: Page/Page column 140
[2] Journal of Medicinal Chemistry, 2018, vol. 61, # 3, p. 1153 - 1163
[3] Patent: WO2011/66416, 2011, A1, . Location in patent: Page/Page column 16
[4] Patent: WO2004/7491, 2004, A1, . Location in patent: Page 65
[5] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 13, p. 3986 - 3991
  • 21
  • [ 403-21-4 ]
  • [ 6638-79-5 ]
  • [ 863604-64-2 ]
YieldReaction ConditionsOperation in experiment
83% With 4-methyl-morpholine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 17 h; To a solution of CH2C12 (1L) was addded 3-fluoro-4-nitrobenzoic acid (100 g, 540 mmol) and EDCI (155.3 g, 810 mmol) followed by NMM (178 mL, 1.62 mol) and N-methoxymethanamine hydrochloride (79.0 g, 810 mmol). The solution was allowed to stir under N2 at rt for 17h. The reaction mixture was then diluted with IN HCI (1 L), transferred to separatoiy funnel, and separated. The organic phase was washed with IN NaOH (2 x 500 mL) and water (250 mL). All aqueous layers were back extracted with EtOAc (2 x 500 mL). The organic layers were combined, dried (MgS04), filtered, and concentrated in vacuo. to afford 102.3 g of the above compound as a yellow solid (448 mmol, yield 83percent). (at)H-NMR (DMSO-d6) No. 8.22 to 8.18 (t, J = 8.0 Hz, 1H), 7.79 to 7.76 (d, J = 11.5 Hz, 1H), 7.60 to 7.58 (d, J = 8.3 Hz, 1H), 3.56 (s, 3H), 3.28 (s, 3H) ; MS [M+H]+ = 229.1; LCMS RT = 2.27 min.
56% With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; N-[methyl]-N-[methoxy] 3-fluoro-4-nitrobenzamide; Dissolve 3-Fluoro-4-nitro-benzoic acid (10. 7 g, 57. 71 mmol) in 1000 mL anhydrous dichloromethane. Add N, O-Dimethylhydroxylamine hydxochloride (4. 5 g, 46. 17 mmol), followed by 1- (3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (16. 60 g, 86. 57 mmol) and and 4-dimethylaminopyridine (6. 77 g, 55. 4 mmol). Stir at room temperature under nitrogen atmosphere overnight. Concentrate under reduced pressure and partition the residue between ethyl acetate (300 mL) and water (lOOmL). Wash the organic layer with saturated aqueous sodium chloride (4x 30mL) and dry over magnesium sulfate. Concentrate under reduced pressure to provide the desired compound (7. 4 g, 56percent). MS (ES) : m/z = 229. 1; N- [Methyl]-N-[methoxy]-3-fluoro-4-nitrobenzamide; Add triethylamine (17 mL, 120 mmol) dropwise to a stirring solution of 3-fluoro- 4-nitrobenzoic acid (17. 8 g, 96 mmol), 1- (3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (23 g, 120 mmol), N, O-dimethylamine hydrochloride (11. 25 g, 115. 2 moles) and 4-N, N-dimethylaminopyridine (1, 17 g, 9. 6 mmol) in 300 mL dry dichloromethane under a nitrogen atmosphere. Stir at room temperature overnight. Add 10percent hydrochloric acid (200 mL), dichloromethane (200 mL) and water (200 mL). Separate the phases and extract the aqueous phase twice with dichloromethane. Wash the combined organic phases sequentially with 10 percent aqueous hydrochloric acid, water, and saturated aqueous sodium chloride. Dry over magnesium sulfate and concentrate under reduced pressure to provide the desired compound (90percent).
Reference: [1] Patent: WO2005/121147, 2005, A1, . Location in patent: Page/Page column 105; 106
[2] Patent: WO2005/80380, 2005, A1, . Location in patent: Page/Page column 21;26
[3] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 15, p. 4050 - 4054
  • 22
  • [ 403-21-4 ]
  • [ 72802-25-6 ]
Reference: [1] Patent: WO2016/145092, 2016, A1,
[2] Patent: WO2017/87428, 2017, A1,
  • 23
  • [ 403-21-4 ]
  • [ 924287-65-0 ]
Reference: [1] Patent: WO2012/87520, 2012, A1,
[2] Patent: WO2012/87519, 2012, A1,
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