Benzopyran derivatives

Leondardi etal, US Patent 6,403,594 (June 11, 2002) Assignee Recordati S.A. Chemical and Pharmaceutical Company Utility -Adrenergic Receptor Inhibitors 

To a solution of sodium ethoxide prepared using 4.6 g sodium and 100 ml ethyl alcohol was added 2-hydroxy-3-(l-propenyl)-propionphenone (10 g), 71.2g diethyl oxalate dissolved in 160 ml toluene, and the reaction stirred at 50°C 3.5 hours. Thereafter 16 ml 98% H2SO4 was added dropwise, the reaction stirred an addition 30 minutes at 50°C, cooled, and the organic phase washed 3 times with 200 ml water. The crude product was isolated in 62% yield, mp = 131-135 °C. 

The product from Step 1 (9.03 g) was dissolved 110 ml methyl alcohol and 90 ml 1 M NaOH, stirred at ambient temperature 3 hours, 100 ml water added, and the alcohol removed by vacuum distillation. The aqueous phase was kept at 50°C 24 hours, acidified with 1 M HCl, and the product isolated by filtration in 96% yield, mp = 224-228 °C. 

To the product from Step 2 (2.0 g) dissolved in 30 ml CH2CI2 and 1 ml DMF was added 0.66 ml thionyl chloride, the solution stirred for 2 hours at ambient temperature, and then sat overnight. Thereafter an additional 0.15 ml thionyl chloride was added and the solution stirred for 2 additional hours. The solvent was removed, the product extracted with CH2CI2, and evaporated to dryness. The residue was dissolved in THE, 5 ml 32% NH4OH added. 

To a solution of the product from Step 3 (0.6 g) dissolved in 30 ml acetone and 10 ml DMF was added 1.5 ml of aqueous 70% Na2Cr207 and 1.8 ml 70% H2SO4 and the solution stirred 4 hours at 50°C. Thereafter, an additional 3 ml of 70% Na2Cr207 and 3.6 ml 70% H2SO4 were added and the mixture heated 6 hours at 50°C and 6 hours at 70°C. The mixture was cooled, poured into 100 ml water containing sodium hydrosulfite, stirred for 30 minutes, and the product isolated by filtration in 83% yield, mp 250°C. 

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Related benzopyran derivatives include the compound CDRI-85/287 [130064-18-5]( >9) from the Central Dmg Research Institute (32). Analogues such as the pyrtohdinoethoxyphenyl have also been evaluated (33). An alternative series of basic ethers of 3-(p-halophenyl)-4-arylchrom-3-enes (40, X = F [128040-44-8] Cl, Br), has been synthesized and all found to be selective ligands for AEBS in vitro (34). 

A benzopyran derivative, RP-58866 (70) is under development by Rhone-Poulenc. Patch clamp studies in guinea-pig ventricular myocytes indicate that RP-58866 inhibits the inward rectifying potassium current (7ki) with no effects on the delayed rectifier, ATP-sensitive potassium currents or calcium currents [200]. RP-58866 increases APD90 of Purkinje fibres by about 45% at 0.3 yuM without affecting K ax [201]. The compound was effective... 

Baumy et al. (27) determined the binding constants for two 3,4-dihydro-2//-l-benzopyran derivatives of /3-CD. These binding constants were then used to calculate the optimal concentration of chiral selector for the enantioseparation of the two compounds. The calculation of the optimal concentration of the chiral selector was performed according to Eq. (18). Good agreement was found between the calculated and experimentally observed optimum concentrations for the two compounds. 

Levai, A., Utilization of the chiroptical spectroscopies for the structure elucidation of flavonoids and related benzopyran derivatives, Acta Chim. Slav., 45, 267, 1998. 

Benzopyran derivatives anthocyanins, flavonoids and related compounds ... 

A household microwave oven operating at 2450 MHz was used at its full power, 650 W. A neat mixture of benzopyran derivative 1 or 3 (1 mmol) and hydrazine (1.2-3 mmol) in a 10-mL glass beaker was thoroughly mixed for about 5 min, then it was placed in an alumina bath inside the household microwave oven and irradiated. Maximum temperature reached in the alumina after 10 min was about 150 °C. After cooling, methanol (ca. 4 mL) was added to the mixture and the separated solid was filtered off and washed with a small amount of methanol to give the products 2 and 4. 

Under the same conditions of NaH/THF, the ester 3 gave ltf-2-benzopyran derivative 5 in 60% yield, apparently by 6-endo-dig ring closure. Closer study of this latter transformation, however, revealed that the initial product of base-induced cyclisation was in fact the isobenzofuran 4, which was extremely labile, and that 5 was formed from 4 by acid-catalysed rearrangement during work-up of the reaction mixture. 

In order to meet the objective of a completely tissue-specific antiestrogen, a long series of benzopyran derivatives was synthesized with... 

Niwa, M., Ito, J., Terashima, K. and Aqil, M. (1994), Garcipyran, a novel 6-aryl-1,2-benzopyran derivative from Carcinia kola. Heterocycles 38(8), 1927-1932. 

Analogous reactions have been performed in similar benzo- and naphthopy-rane series [101]. Oxidation of benzopyrane derivatives YIII/174 with chromic acid/acetic acid, chromic acid anhydride/acetic acid anhydride, Jones reagent, or ozone gave only complex mixtures of products. Only raefa-chloroperoxyben-zoic acid in dichloromethane was successful (VIII/175 as naphthoketolactones with n = 4, 5, 6 in 70, 49, and 60% yield). 

Substituted benzopyran derivatives, (IV), prepared by Ohara (4) were effective as potassium Kvl.5 channel blockers and used in the treatment of arrhythmic events. 

The preparation of bicyclicheterocyclic- and N-phenylaminoalkyl benzopyran derivatives is described, (1), (2), respectively. 

H-benzofuro[3,2-c][l] benzopyran derivatives were also prepared by the authorin the current invention using coumestrol, (III), directly or by reacting tetralone or indanone with the appropriate phenol. 

The use of im-butyl /V./V-dichlorocarbamate allows the preparation of the corresponding A -Boc-protcctcd amines, from which the free amines can be conveniently obtained by mild acidic treatment. The addition to indene, and 1,2-dihydronaphthalene and benzopyran derivatives gave exclusively the tram-adducts, from which amines, diamines, aziridines, and oxazo-lidinones were in turn prepared79. 

Cloricromsn [inn] is a benzopyran derivative, a NITRIC OXIDE SYNTHASE INHIBITOR, coronary VASODILATOR. PLATELET AGGREGATION INHIBITOR and antischaemic. It has possible ANTIINFLAMMATORY / IMMUNOSUPPRESSANT properties, and has been used to treat arterial vascular disorders where there is a... 

Heterocycliz/oHon. Indoles are obtained when anilines and trialkanolamines are treated with RuClj, PhjP, and SnCl2-2H20 in dioxane," and dihydrobenzofurans from 2-allylphenols with RuClj hydrate, AgOTf, Cu(OTf)j, and PhjP. It appears that 2-(3-butenyl)phenol also undergoes cyclization to give benzopyran derivatives. 

Contino M, Cantore M, Capparelli E, Perrone MG, Niso M, Inglese C et al (2012) A benzopyrane derivative as a P-glycoprotein stimulator A potential agent to decrease (l-amyloid accumulation in Alzheimer s disease. Chem Med Chem 7 391-395... 

Isomerization of phenols 137 over sUica gel in the solid phase furnishes the corresponding 2,3-dihydro-4-oxo-4//-l-benzopyrane derivatives 138 (equation 60) ° . The cascades of the charge-accelerated rearrangements of the ortl o-(l,l-dimethylpropenyl)phenol 139 catalyzed by Bronsted acid (e.g. trifluoroacetic acid, equation 61) as well as by Lewis acids (anhydrous AICI3 or TiCLj, equations 62 and 63) proceed via the common intermediate 140 . 

The titled reactions are employed for synthesis of benzopyrane derivatives. Thus, the racemic cordiachromene 202 (from the cannabinoid class) was prepared starting from 6-methylhept-5-en-2-one 200 using the Claisen rearrangement of the intermediate propargyl ether 201 in an overall yield of 50% (equation 93) . 

The synthesis of a variety of other heterocycles has been achieved using similar methodology [108], For example, benzopyran derivatives are readily prepared from 2-allyl phenols [110] note that the Pd( 0) precatalyst is oxidized to Pd(ll) by air before the reaction commences. Nitrogen heterocycles are also accessible from Wacker-type transformations, as demonstrated by the Hegedus indole synthesis described below in Section 1.10. 

Chantegrel, B., Deshayes, C., and Laure, R., Tandem Wolff rearrangement- fert-amino effect sequence. Synthesis of 2-oxoindolinium enolate and l//-2-benzopyrane derivatives. Tetrahedron Lett., 36, 7859, 1995. 

The results are reported in Table 3. The first attempt was not successful. In fact, bridging the carbon atom in ortho position of the phenyl ring with the distal carbon atom on the bridge (way a in Figure 1) to obtain the benzopyran derivative 22, resulted in a sharp decrease in selectivity due to a decrease in I receptor affinity and an increase in a2-adrenergic receptor affinity. Another way of... 

Furobenzo-y-pyrone (furochromen-4-one) derivatives are shown in the chalcone-flavone and flavone-chalcone series. These series includes (I-P,0,II-7 I-a, II-6)-chalcone-flavone dimers (310,311) (1-6,0,Il-a I-7,II-P)-flavone-chalcone dimers (312-314) and (I-6,0,II-P I-7,II-a)-flavone-chalcone dimers (315). Fm-o[2,3-/]chromanone derivatives comprise a (I-6,II-a I-5,0,II-P)-flavanone-chalcone dimer (316) dihydrofuro[3,2-g]chromanone derivatives comprise (I-7,0,II-P I-6,II-a)-flavanone-dihydrochalcone dimers (317) and furo[2,3-/ ]benzopyran derivatives (I-a,II-8 I-p,0,II-7)-chalcone-flavan dimers (318,319). 

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