4-Fluoro-δ-oxobenzenepentanoic acid

Off-White Solid

To a stirred suspension of aluminum chloride (205.85g, 1. 54MOL) in dichloromethane(500ML) was added a solution of glutaric anhydride (80g, 0. 7MOL) indichloromethane (125ML) at 0C. The reaction mass was stirred for30minutes and fluorobenzene (67.36g, 0. 7MOL) was added to the reactionmass slowly. The reaction was monitored for completion by TLC and thenpoured into ice cold water (2000ML) under stirring and the separatedsolids were collected by filtration. The solids were dissolved in 3percentaqueous sodium hydroxide solution (1100ML) and washed withdichloromethane (300ML). The aqueous layer was acidified to give aprecipitate. The solids were filtered and washed with water andvacuum-dried to yield the title product (125g, yield: 85percent). LHNMR(CDC13) 8 : 8.027-7. 98 (M, 2H), 7.17-7. 11 (M, 2H), 3.067 (t, 2H), 2.52(t, 2H), 2.14-2. 04 (M, 2H).In a milliliter three-necked flask, 200 ml of fluorobenzene was added, Then aluminum trichloride (59.4 g, 0.45 mol) was added, And cooled to 15 ° C with an ice bath, Then, the solution of glutaric anhydride (30 g, 0.3 mol) in fluorobenzene (100 ml) was added dropwise at 15 ° C, After completion of the dropwise reaction at 30 ° C for 5 hours, Cold to about 0 deg C, Dropping 200 ml of 1 M hydrochloric acid, Note that the temperature during the dropwise process does not exceed 20 ° C. After completion of the dropwise addition, the reaction solution was added to a large amount of ice water, Precipitation of solids, filter, Wash the filter cake with steamed water, The filter cake was then added to 800 ml of saturated sodium bicarbonate solution and stirred at room temperature for 1 h, filter, The filtrate was added with activated carbon decolorization. Concentrated hydrochloric acid to adjust the PH value to 1, Solid precipitation, Filter and wash the filter cake with water, After drying, 51.7 g of white solid compound I, Yield 82percent.EXAMPLES; Starting materials useful in the processes of the present invention can be made by the following procedures: Preparation of 4-(4-fluorobenzoyl)butyric acid; Charged 250 g of anhydrous AlClCharge 250 g of anhydrous AlClA flask was charged with AlCl3 (77.17 mmol, 10.29 g, 2.15 equiv) and dry CH2Cl2 (25 ml) under calcium chloride guard tube and the formed suspension was stirred on ice bath. Subsequently, a solution of glutaric anhydride 10 (35.8 mmol, 4.08 g) in dry CH2Cl2 (12 ml) was added dropwise (t < 8 °C). The resulting mixture was stirred on ice bath for 30 minutes and fluorobenzene 11c (35.1 mmol, 3.37 g, 1.0 equiv) was carefully added afterwards. The cooling bath was removed and the mixture was stirred at room temperature for 19 hours, then it was carefully quenched with ice water (20 ml), conc. H2SO4 (10 ml) and again with ice water (60 ml), the aqueous layer was extracted with ethyl acetate (1 x 200 ml, 1 x 100 ml, 1 x 70 ml), the combined organics were washed with half-saturated brine (200 ml), dried over Na2SO4, filtered and concentrated. The crude product was crystallized from ethyl acetate to provide 5-(4-fluorophenyl)-5-oxopentanoic acid (3.80 g, 51percent) as a yellow-brown powder;3 mp 141-142 °C; 1H NMR (300 MHz, CDCl3): δ = 2.08 (m, 2H), 2.51 (t, J = 7.2 Hz, 2H), 3.05 (t, J = 7.2 Hz, 2H), 7.13 (m, 2H), 7.99 (m, 2H). 5-(4-Fluorophenyl)-5-oxopentanoic acid (16.7 mmol, 3.50 g), paraformaldehyde (50.0 mmol, 1.50 g, 3.0 equiv) and piperidine (0.32 ml, 0.2 equiv) were dissolved/suspended in pyridine (15 ml) and stirred at 70 °C for 21 hours. Afterwards, the mixture was poured into 1M H2SO4 (340 ml), the aqueous layer was extracted with ethyl acetate (4 x 100 ml), the combined organics were dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel (EA/hexanes = 1/1 + 0.5percent AcOH). The obtained product was repeatedly coevaporated with toluene (4 x 25 ml) under reduced pressure to remove the residual AcOH, yielding 4-(4-fluorobenzoyl)pent-4-enoic acid 9c (3.33 g, 90percent) as an orange solid; mp 81-82 °C; 1H NMR (300 MHz, CDCl3): δ = 2.62 (t, J = 7.2 Hz, 2H), 2.80 (t, J = 7.2 Hz, 2H), 5.65 (s, 1H), 5.92 (s, 1H), 7.12 (dd, J = 8.7, 8.7 Hz, 2H), 7.78 (dd, J = 5.7, 8.7 Hz, 2H), 10.74 (bs, 1H); 13C NMR (75 MHz, CDCl3): δ = 27.3, 32.5, 115.3 (d, JCF = 21.8 Hz), 126.7, 132.0 (d, JCF = 9.0 Hz), 133.7, 145.9, 165.3 (d, JCF = 252.5 Hz), 178.9, 196.2To a suspension of aluminum chloride (205.85 g, 1.54 mol) in dichloromethane (500 mL) was added a solution of glutaric anhydride (80 g, 0.7 mol) in dichloromethane (125 mL) at 0° C. 25 gms of Aluminium chloride was added to 50 ml of dichloromethane and 4.5 ml of fluorobenzene. To this a solution of 50 ml of dichloromethane containing 10 gms of glutaric anhydride and 4.5 ml of fluorobenzene was added. Reaction mass was stirred at room temperature. After completion of reaction, reaction mass was quenched with ice& HCl solution at 0-10° C. Filtered the reaction mass. The obtained wet solid was dissolved in eq NaHCOPreparation of 4-(4-fluorobenzoyl)butyric acid:

Molecular Weight:210.20
XLogP3:1.8
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:5
Exact Mass:210.06922237
Monoisotopic Mass:210.06922237
Topological Polar Surface Area:54.4
Heavy Atom Count:15
Complexity:232
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes