van Zanten, B.; Nauta, W. Th. published the artcile< Synthesis of alkyl-substituted 3-phenyl-4-hydroxycoumarins>, Related Products of 112-63-0, the main research area is .
As part of a study into the relationship between chem. structure and biol. activity, a number of 3-phenyl-4-hydroxycoumarins with alkyl substituents in the 3-phenyl group were prepared to be used as anticoagulants. The principal methods of preparation of the compounds O.CO.CHR.CO.C:C.CH:CH.CH:CH (I) were reviewed. Use was made of the following methods for preparation of the I: (a) cyclization of compounds of the type 2-RCH2CO2C6H4CO2Me (II) (R is an aliphatic or aromatic group or H); (b) reaction of PhOH with monosubstituted malonic esters; (c) coupling aryldiazonium compounds with I (R = H) in an acid medium in the presence of CuCl2. The following RCH2CO2Et (III) required for method b were prepared by (d) esterification of the arylacetic acid by refluxing with EtOH and some H2SO4; (e) esterification of the arylacetonitrile by refluxing with 3:1 EtOH-H2SO4; (f) treatment of the arylcarboxylic chloride with CH2N2 and then with EtOH and Ag2O. The following III were prepared (R, method, % yield, b.p./mm., procedure used to prepare required intermediate given): 3-MeC6H4, e, 80, 115°/15, from m-xylene by treatment with SO2Cl2 to give 70% 3-MeC6H4CH2Cl, b10 90-2°, this converted with NaCN in aqueous EtOH to 86% nitrile, b10 125-30°; 2,3-Me2C6H3, f, 66, 132-45°/15, by diazotization of 2,3-Me2C6H3NH2 in 40% aqueous HBr, conversion with Cu bronze into 45% 2,3-Me2C6H3Br, b14 88-92°, treatment of the Grignard with solid CO2 to obtain 76% 2,3-Me2C6H3CO2H, m. 146°, and conversion with SOCl2 to 95% acid chloride, b11 107-11°; 2,4-Me2C6H3, e, 64, 138-40°/17, by chloromethylation of m-xylene with paraformaldehyde (IV) in concentrated HCl to obtain 72% 2,4-Me2C6H3CH2Cl, b12 99-102°, and conversion as before into 94% nitrile, b18 138-41°; 2,5-Me2C6H3, f, 67, 118-29°/12, by bromination of p-xylene to 80% 2,5-Me2C6H3Br, b10 80°, conversion to a Grignard compound and treatment with solid CO2 to obtain 75% 2,5-Me2C6H3CO2H, m. 133°, and conversion by SOCl2 to 90% acid chloride, b14 108°; 2,6-Me2C6H3, d, 87, 93-5°/2, by diazotizing 2,6-Me2C6H3NH2 and converting as above to 44% bromo compound, b20 90-3°, treatment of the Grignard with solid CO2 to obtain 70% 2,6-Me2C6H3CO2H, m. 116°, esterification with CH2N2 to 95% Me ester, b12 98-100°, reduction with LiAlH4 to 91% 2,6-Me2C6H3CH2OH, m. 91-2°, conversion by SOCl2 into 94% chloride, b13 96-7°, m. 31°, then into 93% nitrile, b11 125-7°, m. 36°, and saponification by 50% aqueous H2SO4 to 89% 2,6-Me2C6H3CH2CO2H, m. 130°; 3,4-Me2C6H3 (V), f, 30, 120-30°/7, by converting 3,4-Me2C6H3NH2 as above into 57% 3,4-Me2C6H3Br, b13 88-90°, treatment of the Grignard with solid CO2 to obtain 90% acid, m. 163-5°, and conversion by SOCl2 into 60% acid chloride, b17 119-22°; V, e, 67, 123-8°/10, by chloromethylation of o-xylene with MeOCH2Cl to 7% 3,4-Me2C6H3CH2Cl, b16 105-15°, and conversion to 85% nitrile, b10 123-8°; 3,5-Me2C6H3, e, 80, 130-4°/14, by conversion of 3,5-Me2C6H3NH2 to the bromo compound, b14 84-7°, treatment of the Grignard with IV to give 20% 3,5-Me2C6H3CH2OH, b2 83-5°, conversion to 90% chloride, b15 100-10°, and then to 60% nitrile, b15 128-32°; 2,4,6-Me3C6H2, d, 64, 115°/2, by treating 2,4,6-C6H3Me3 with IV in concentrated HCl to give 47% 2,4,6-Me3C6H2CH2Cl, b16 119-23°, converting into 84% nitrile, b18 147-56°, and saponifying to 87% 2,4,6-Me3C6H2CH2CO2H, m. 167°; 2-EtC6H4, e, 87, 134°/20, by converting 2-EtC6H4NH2 to 40% bromo compound, b16 79-80°, treating the Grignard with solid CO2 to obtain 89% acid, m. 68°, esterifying to 96% Et ester, b16 114-16°, reducing by LiAlH4 to 100% 2-EtC6H4CH2OH, converting into 94% chloride (VI), b20 105°, and then into 96% nitrile, b20 138-40° (treatment of the Grignard of VI with Ac2O gave 52% 2-EtC6H4Ac, b13 99-103°; n25D 1.5222); 4-EtC6H4, e, 78, 152-4°/35, by chloromethylation of EtPh to 60% 4-EtC6H4CH2Cl, b16 100-2°, and conversion to 85% nitrile, b16 148-51°, n20D 1.5172; 2,6-Et2C6H3, d, 96, 135-6°/10, by converting 2,6-Et2C6H3NH2 to 52% 2,6-Et2C6H3Br, b16 109-14°, treating the Grignard with solid CO2 to give 86% 2,6-Et2C6H3CO2H, m. 85°, converting to 75% Me ester, b13 115-21°, reducing with LiAlH4 to 90% 2,6-Et2C6H3CH2OH, m. 65°, converting with SOCl2 to 98% chloride, b11 117°, and via the nitrile to 73% 2,6-Et2C6H3CH2CO2H, m. 72°; 2-iso-PrC6H4, e, 80, 135-6°/17, by conversion of 2-iso-PrC6H4NH2 to 46% 2-iso-PrC6H4Br, b15 90-3°, treatment of the Grignard reagent with solid CO2 to give 83% 2-iso-PrC6H4CO2H, m. 69°, conversion to 95% Et ester, b15 119-20°, reduction with LiAlH4 to 98% 2-iso-PrC6H4CH2OH, conversion by SOCl2 to 91% chloride, b20 109-11°, and conversion to 94% nitrile, b16 133-9°; 4-iso-PrC6H4, e, 81, 139-41°/15, by treating 4-iso-PrC6H4Me with SO2Cl2 to give 4-iso-PrC6H4CH2Cl, b17 112-14°, and converting to 92% nitrile, b10 130-3°; 2,6-iso-Pr2C6H3, e, 90, 108-9°/0.5, by conversion of 2,6-iso-Pr2C6H3NH2 to 44% 2,6-iso-Pr2C6H3Br, b15 128-30°, then as usual to 68% 2,6-iso-Pr2C6H3CO2H, esterification (Newman, CA 35, 73844) to 81% Me ester, b20 136-8°, m. 31°, reduction as usual to 98% 2,6-iso-Pr2C6H3CH2OH, b20 146-8°, m. 98°, conversion to 92% chloride, b18 136-7°, and then to 97% nitrile, b0.5 116-18°, m. 60°; 2-tert-BuC6H4, d, 90, 153-4°/19, by conversion of 2-tert-BuC6H4Br (VII) (b11 97°) (Crawford and Stewart, CA 48, 6398b) to 80% 2-tert-BuC6H4CO2H, m. 68°, esterification to 90% Me ester, b15 120-3°, reduction to 100% 2-tert-BuC6H4CH2OH, b16 130-3°, conversion to 90% chloride (VIII), b16 116-21°, conversion of VIII to 72% nitrile, b18 148-54°, n20D 1.5230, and saponification to 99% acid (IX), m. 84° [treatment of the Grignard reagent of X with CO2 gave only 20% IX, the main product obtained was 50% (2-tert-BuC6H4CH2)2, b0.001 140-50°, m. 83-4°; oxidation of 2-tert-BuC6H4CH2CH:CH2, b13 102-5° (obtained in 57% yield by coupling the Grignard (X) of VII with CH2:CHCH2Br in C6H6) did not yield IX; treatment of X with Ac2O at -20° gave 40% 2-tert-BuC6H4Ac, b12 112-22°, which did not give IX on oxidation]; 4-tert-BuC6H4, d, 88, 134-7°/8, by conversion of tech. 4-tert-BuC6H4CO2H into 93% Me ester, b16 136-8°, reduction to 95% 4-tert-BuC6H4CH2OH, conversion into 80% chloride, b16 122-30°, then to 90% nitrile, b16 149-52°, and saponification to 95% acid, m. 78-9°; 1-C10H7, e, 72, 140-5°/3, by chloromethylation of C10H8 to 65% 1-C10H7CH2Cl, b5 130-5°, and conversion to 83% nitrile, b2 155-65°; 2-C10H7, d, 90, 135-8°/2, by converting C10H8 to 80% 2-C10H7Ac, b11 155-61°, m. 30°, treating with S and morpholine to 84% crude thiomorpholide of 2-C10H7CH2CO2H (XI), and saponifying with AcOH and H2SO4 to 72% XI, m. 140-3°. The III (0.37 mole) and 0.70 mole (CO2Et)2 added at 40-50° during 1 min. with stirring to 0.40 mole NaOEt from which all traces of EtOH were removed in vacuo while distilling any volatiles formed, the mixture stirred and distilled while the temperature was raised to 130° and then to 180° at 10-20 mm., cooled, treated with 200 ml. H2O, 12-15 ml. concentrated H2SO4, and 500 ml. Et2O, the Et2O layer separated, the aqueous layer extracted 4 times with Et2O, the combined Et2O layers washed with 2N Na2CO3 and with H2O until neutral to litmus, evaporated, the residue dried azeotropically with C6H6, mixed with porcelain powder, heated in a bath at 180° at 10-20 mm. until CO no longer was evolved, and the residue twice distilled gave the following RCH(CO2Et)2 (XII) (R, % yield, and b.p./mm. given): 3-MeC6H4, 52, 125-32°/2; 2,3-Me2C6H3, 42, 127°/1; 2,4-Me2C6H3, 94, 151°/4; 2,5-Me2C6H3, 40, 128°/1.5; 2,6-Me2C6H3, 57, 122-8°/1; 3,4-Me2C6H3, 49, 137°/2; 3,5-Me2C6H3, 52, 127°/1.5; 2,4,6-Me3C6H2, 65, 150-60°/2 (m. 46-7°); 2-EtC6H4, 63, 117-18°/1; 4-EtC6H4, 60, 122-4°/1; 2,6-Et2C6H3, 42, 132-3°/1; 2-iso-PrC6H4, 75, 121°/1; 4-iso-PrC6H4, 68, 130°/1; 2,6-iso-Pr2C6H3, 36, 137-9°/1; 2-tert-BuC6H4 (XIII), 17, 130°/1 [an unsuccessful attempt to prepare XIII was made by coupling X with OC(CO2Et)2 at -70° to obtain 57% 2-tert-BuC6H4C(OH)(CO2Et)2, b0.05 158-62°, and converting with SOCl2 to 55% chloride, b0.01 130°, but the chloride could not be catalytically reduced]; 4-tert-BuC6H4, 57, 149-52°/1; 1-C10H7, 68, 176-7°/1 (m. 62°); 2-C10H7, 39, 180°/2 (m. 96-7°). Treatment of RCH2COCl with 2-HOC6H4CO2Me (XIV) (method g) or RCH2CO2H with XIV (method h) (Stahmann, et al., CA 38, 7417) gave the following II (R, method, % yield, m.p., b.p./mm., procedure used to obtain required intermediate given): Ph, g, 50, 54-5°, 160°/0.8, by conversion of PhCH2CO2H with SOCl2 to 90% PhCH2COCl, b20 99-102°; H, h, 90, 47-9°, -, S., et al., loc. cit.; 2-MeC6H4, g, 74, 58-61°, 180-95°/0.1, by treating PhCH2MgCl with IV to obtain 50% 2-MeC6H4CH2OH, b17 112°, converted successively into 85% chloride, b15 82-6°, 93% nitrile, b15 115-28°, 68% acid, m. 88-9°, and 85% acid chloride, b15 108-9°; 4-MeC6H4, g, 55, -, 175-200°/0.05, by chlorination of p-xylene with SO2Cl2 to obtain 79% 4-MeC6H4CH2Cl, b8 70-4°, converted successively to 80% nitrile, b12 115°, 80% acid, m. 90-1°, and 90% acid chloride, b9 98-9°; 2,4,6-Me3C6H2, g, 61, 64-5°, 175-85°/0.03, by converting 2,4,6-Me3C6H2CH2CO2H to 72% acid chloride, b15 134-7°. The procedures (a, b, c) used to obtain the I were as follows. (a) Na (0.2 g. atom) in 200 ml. paraffin oil heated to 250°, 0.2 mole II was added with stirring, the mixture heated and stirred 1 hr. at 250°, the paraffin oil decanted, the residue washed with petr. ether, dissolved in 600 ml. H2O, the solution acidified to pH 6-7, extracted with Et2O, and adjusted to pH 1-2 with acid gave the I. (b) The XII (0.1 mole) and 0.1 mole PhOH dried azeotropically with C6H6, the mixture heated 24-72 hrs. at 250-300° until a drop of the mixture solidified on cooling, poured into 400 ml. 5% aqueous NaHCO3, boiled 1 hr., the solution filtered, the filtrate acidified to pH 6-7, extracted with C6H6 or Et2O, and acidified to pH 1-2 gave the I. (c) PhNH2 (0.03 mole) in 12 ml. 12N HCl and 18 ml. H2O diazotized with 3 g. NaNO2 at -5°, the diazonium solution added slowly at -5° with stirring to 6 g. NaOAc and 5 g. I (R = H) in 20 ml. Me2CO, the mixture treated with 1 g. CuCl2, heated to 40-50°, heated and stirred 30 min. at 40-50°, the Me2CO distilled, the residue acidified, the precipitate filtered off, dissolved in 5% aqueous NaHCO3, and the solution treated as in b gave the I.
Recueil des Travaux Chimiques des Pays-Bas et de la Belgique published new progress about Blood coagulation. 112-63-0 belongs to class esters-buliding-blocks, and the molecular formula is C19H34O2, Related Products of 112-63-0.
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