合成路线1

A new short synthesis of troglitazone has been described: Condensation of the bromoacetal (I) with 4-hydroxybenzaldehyde (II) by means of K2CO3 and NaI in refluxing acetone gives the unsaturated ether (III), which is cyclized with trimethylhydroquinone (IV) by means of bis(trifluoromethylsulfonyl)imide in dichloromethane to yield the 6-hydroxybenzopyran (V). Acylation of (V) with acetic anhydride and DMAP in THF affords the expected acetoxybenzopyran (VI), which is condensed with thiazolidine-2,4-dione (VII) by means of piperidine in toluene to provide the 6-benzylidene-thiazolidine (VIII). The hydrogenation of (VIII) with H2 over Pd/C in methanol gives the corresponding benzyl derivative (IX), which is finally deacetylated with AcOH/HCl/water (3:1:1) in MeOH.

合成路线2

The condensation of 4-hydroxybenzaldehyde (I) with 2-(dimethylamino)ethyl chloride (II) by means of K2CO3 in hot isopropyl ether yields 4-[2-(dimethylamino)ethoxy]benzaldehyde (III), which is treated with hydroxylamine hydrochloride in refluxing ethanol to afford the corresponding oxime (IV). The hydrogenation of (IV) with H2 over RaNi in methanolic ammonia yields 4-[2-(dimethylamino)ethoxy]benzylamine (V), which is finally condensed with 3,4-dimethoxybenzoyl chloride (VI) (obtain303ed from the corresponding acid (VII) with SOCl2) in toluene.

合成路线3

BRL 35135 may be obtained by the following synthetic procedures: Alkylation of 4-hydroxybenzaldehyde (I) with methyl chloroacetate in boiling acetone in the presence of potassium carbonate and a catalytic quantity of potassium iodide gives methyl 4-formylphenoxyacetate (II), which is condensed with nitroethane in glacial acetic acid in the presence of n-butylamine to give the nitrostyrene (III). Reduction of nitrostyrene (III) with steel wool and glacial acetic acid/methanol leads to methyl 4-(2-oxopropyl)phenoxyacetate (IV). Condensation of (IV) with alpha-(aminomethyl-3-chlorobenzenemethanol (VI) and hydrogenation of the resultant imine with platinum in methyl acetate leads to a mixture of diastereomers (VII). Pure BRL 35135 can be obtained from this mixture of diastereomers by fractional crystallization, and subsequent recrystallization, of the hydrobromide salt from methyl acetate-methanol. The ethanolamine (VI) is prepared by addition of trimethylsilyl cyanide to 3-chlorobenzaldehyde (V) in diethyl ether in the presence of a catalytic amount of zinc iodide and subsequent reduction of the trimethylsilylcyanohydrin with lithium aluminum hydride.

合成路线4

Condensation of 2'-fluoroacetophenone (I) with 4-methoxybenzaldehyde (II) under acidic conditions afforded chalcone (III). This was subsequently demethylated with boron tribromide to yield the 4-hydroxy chalcone (IV). Alternatively, chalcone (IV) was also obtained by condensation of 2'-fluoroacetophenone (I) with 4-hydroxybenzaldehyde (V). Reaction of chalcone (IV) with 2-(dimethylamino)ethoxyamine dihydrochloride (VI) produced the corresponding oxime as a mixture of syn target compound and anti (VIII) isomers. The title syn isomer was isolated by fractional extraction at increasing pH values or, alternatively, by recrystallization as the corresponding hemifumarate salt. Optionally, the undesired anti compound (VIII) was isomerized by acidic treatment to produce a 45:55 mixture of target compound and (VIII).

合成路线5

Two new related syntheses of pioglitazone hydrochloride have been described: 1) The condensation of 2-(5-ethylpyridin-2-yl)ethanol (I) with 4-hydroxybenzaldehyde (II) by means of benzyltributylammonium chloride, NaOH and tosyl chloride gives 4-[2-(5-ethylpyridin-2-yl)ethoxy]benzaldehyde (III), which is condensed with thiazolidine-2,4-dione (IV) in basic medium to afford 5-[-4-[2-(5-ethylpyridin-2-yl)ethoxy]benzylidene]thiazolidine-2,4-dione (V). Finally, this compound is hydrogenated in the usual way. 2) The condensation of alcohol (I) with 4-fluorobenzonitrile (VI) by means of NaH gives 4-[2-(5-ethylpyridin-2-yl)ethoxy]benzonitrile (VII), which is reduced with Raney Nickel and formic acid to the aldehyde (III), already obtained.

合成路线6

This compound has been obtained by several different methods. The reaction of 2-(5-ethyl-2-pyridyl)ethanol (I) with Ts-Cl and NaOH in THF gives the corresponding tosylate (II), which is condensed with 4-hydroxybenzaldehyde (IV) by means of BnNBu3Cl and NaOH or K2CO3 to yield the aryl ether (V) (1-3). The condensation of (V) with thiazolidine-2,4-dione (VI) in refluxing ethanol affords the 5-benzylidenethiazolidinedione (VII), which is finally reduced with H2 over Pd/C in DMF or dioxane. The reaction of 2-(5-ethyl-2-pyridyl)ethanol (I) with Ms-Cl and TEA in dichloromethane THF gives the corresponding mesylate (III), which is condensed with 4-hydroxybenzaldehyde (IV) by means of K2CO3 to yield the already reported aryl ether (V). The condensation of 2-(5-ethyl-2-pyridyl)ethanol (I) with 4-fluorobenzonitrile (VIII) by means of NaH gives 4-[2-(5-ethyl-2-pyridyl)ethoxy]benzonitrile (IX), which is reduced with RaNi and HCOOH to yield the already reported 4-ethoxybenzaldehyde derivative (V).

合成路线7

3) The reaction of 4-hydroxybenzaldehyde (XII) with benzyl bromide and K2CO3 in acetone gives 4-(benzyloxy)benzaldehyde (XIII), which is condensed with 4-fluoroaniline (XIV) in isopropanol, yielding the imine (II). Cyclization of (II) with methyl 4-(chloroformyl)butyrate (XV) by means of tributylamine in toluene affords the trans-azetidinone (XVI), which is hydrolyzed with LiOH in THF/water to provide the propionic acid derivative (XVII). The reaction of (XVII) with oxalyl chloride in dichloromethane gives the corresponding acyl chloride (XVIII), which is condensed with 4-fluorophenylmagnesium bromide (XIX) by means of ZnCl2 and Pd(PPh3)4 in THF to yield a racemic mixture of saturated trans-azetidinones that was resolved by chiral HPLC to the trans-(3R,4S)-enantiomer (XX). The enantioselective reduction of (XX) with BH3 and the chiral oxaborole catalyst CBS gives the benzylated alcohol (XI), which is finally debenzylated as before with H2 over Pd/C in ethanol.

合成路线8

The enantioselective reduction of the oxazolidinone (I) with BH3/SMe2 and a chiral borinated catalyst gives the (S)-alcohol (II), which is condensed with the labeled imine (III) (prepared by reaction of 4-fluoroaniline (IV) and 13C-labeled 4-hydroxybenzaldehyde (V)) by means of TiCl4 in dichloromethane to yield the silylated adduct (VI) (previously the reactants are silylated with Tms-Cl and DIEA). Finally, adduct (VI) is resilylated with bis(trimethylsilyl)acetamide and cyclized and desilylated by treatment with TBAF in dichloromethane to afford the target 13C-labeled SCH-58235.

合成路线9

The enantioselective reduction of the oxazolidinone (I) with BH3/SMe2 and a chiral borinated catalyst gives the (S)-alcohol (II), which is condensed with the labeled imine (III) (prepared by reaction of 4-fluoroaniline (IV) and 14C-labeled 4-hydroxybenzaldehyde (V)) by means of TiCl4 in dichloromethane to yield the silylated adduct (VI) (previously the reactants are silylated with Tms-Cl and DIEA). Finally, adduct (VI) is resilylated with bis(trimethylsilyl)acetamide and cyclized and desilylated by treatment with TBAF in dichloromethane to afford the target 14C-labeled SCH-58235.

合成路线10

Acetylation of N-benzoylaspartic acid beta-methyl ester (I) with acetic anhydride and subsequent decarboxylation gave the 3-benzoylamino-4-oxovalerate (II). The methyl oxazolylacetate (III) was prepared by cyclization of 4-oxovalerate (II) in the presence of Ac2O. Ester (III) was then reduced to alcohol (IV) with LiBH4 and further converted to mesylate (V) with methanesulfonyl chloride and Et3N. Coupling between mesylate (V) and 4-hydroxybenzaldehyde (VI) gave ether (VII). Knoevenagel condensation of (VII) with dimethyl malonate using piperidine acetate produced the benzylidene malonate (VIII). Finally, catalytic hydrogenation with Pd/C furnished JTP-20993. The title compound (JTT-501) is obtained by reaction of JTP-20993 with NH2OH.

合成路线11

Friedel-Crafts reaction between 4-hydroxyphenylacetic acid (I) and resorcinol (II) by means of BF3.Et2O provides trihydroxydeoxy benzoin (III), which is then protected with dihydropyran (IV) in the presence of TsOH to give the bis-THP ether (V). Knoevenagel reaction of (V) with 4-hydroxybenzaldehyde (VI) in the presence of piperidine in refluxing benzene, followed by alkylation with 1-(2-chloroethyl)piperidine (VII) in the presence of Cs2CO3 in refluxing acetone:H2O to yield chromanone (VIII). Alternatively, (VIII) can be synthesized by reaction of (V) with compound (IX) (obtained in turn from reaction between aldehyde (VI) and chloro derivative (VII) with K2CO3 in DMF) by means of piperidine in refluxing toluene, followed by treatment with NaOAc in refluxing MeOH. Chromanone (VIII) is then alkylated either with MeLi or with methylmagnesium bromide in THF and then dehydrated and deprotected in HOAc furnishing chromene (X). Racemic compound (X) is then resolved to afford enantiomer (XI) either by preparative chiral HPLC or by chemical resolution of the corresponding diastereomeric salt obtained by reaction with (+)-CSA in DMF/CH2Cl2, and treatment of the resulting salt with saturated K2CO3 . Finally, the target product is obtained by acylation of (XI) by reaction with pivaloyl chloride (XII) and Et3N in CH2Cl2.

合成路线12

4-Hydroxybenzaldehyde (I) was alkylated with 2,2,3,3-tetrafluoropropyl tosylate (A) to give ether (II). Subsequent Horner-Emmons condensation of (II) with triethyl phosphonocrotonate (III) provided dienoate (IV), that was further reduced to alcohol (V) by means of DIBAL. Oxidation of (V) with activated MnO2 then gave aldehyde (VI).

合成路线13

By condensation of 4-(2-quinolinylmethoxy)benzaldeyde (I) with 2-hydroxy-5(1H-tetrazol-5-yl)acetophenone (II) by means of KOH in ethanol/water. The intermediates (I) and (II) have been obtained as follows: Benzaldehyde (I): By condensation of 2-(chloromethyl)quinoline (III) with 4-hydroxybenzaldehyde (IV) by means of K2CO3 in hot DMF. Acetophenone (II): The acetylation of 4-hydroxybenzonitrile (V) with acetic anhydride/sulfuric acid and AlCl3 gives 5-cyano-2-hydroxyacetophenone (VI), which is then cyclized with sodium azide and ammonium chloride in hot DMF.

合成路线14

Alkylation of 4-hydroxybenzaldehyde (I) with chloro derivative (II) by means of K2CO3 in DMF at reflux affords benzaldehyde derivative (III), which is reduced with NaBH4 in MeOH to provide the benzylic alcohol (IV) --alternatively, alcohol (IV) can be obtained by reaction of 4-hydroxybenzyl alcohol (V) with chloro derivative (II) by means of NaOH and benzyltriethylammonium bromide in toluene--. Alcohol (V) is treated with HCl in THF and then chlorinated with SOCl2 to furnish hydrochloride salt (VI), which is condensed with the indole derivative (VII) – produced by condensation of the bromo ketone (VIII) and 4-benzyloxyaniline hydrochloride (IX) either refluxing by with DMF or with Et3N in refluxing DMF – by means of NaH in DMF to give the N-alkylated indole (X). Finally, the O-benzyl protecting groups of (X) are removed by transfer hydrogenolysis using cyclohexadiene and Pd/C.

合成路线15

The reaction of 2-(4-hydroxyphenyl)ethyl alcohol (I) with Ms-Cl and TEA in dichloromethane gives the bis-methanesulfonate (II), which is condensed with 4-hydroxybenzaldehyde (III) by means of K2CO3 in acetonitrile to yield the substituted benzaldehyde (IV). The condensation of (IV) with phosphonium salt (V) by means of tetramethylguanidine (TMG) in chloroform affords the acrylic ester (VI), which is reduced with H2 over Pd/C in ethyl acetate to provide the propionic ester (VII). The hydrolysis of (VII) with LiOH in THF/water gives the propionic acid (VIII) as a racemic mixture, which is condensed with (R)-phenylglycinol (IX) by means of EDC, HOBt and DIEA in dichloromethane to yield the amide (X) as a diastereomeric mixture that is separated by crystallization and chromatography. The desired (S)-isomer (XI) is treated with H2SO4 in hot dioxane/water to furnish the target propionic acid.

合成路线16

Treatment of chromane (I) with metanesulfonyl chloride in pyridine at 0 C afforded mesylate (II), which was treated with 2-methylaminoethanol (III) to afford tertiary amine (IV). Reaction with SOCl2 gave chloride (V), and further reaction with p-hydroxybenzaldehyde (VI) provided (VII). Aldehyde (VII) was then condensed with 2,4-thiazolidinedione (VIII) in the presence of piperidine benzoate in toluene to furnish (IX). Finally, the benzyl protecting group was removed by treatment with acetic acid-hydrochloric acid at 60 C to give the title compound.

合成路线17

3,5-Di-tert-butyl-4-hydroxybenzoic acid (I) was converted to amide (III) via activation as the acyl imidazole (II) followed by treatment with aqueous ammonia. Subsequent condensation of (III) with ethyl 4-chloroacetoacetate (IV) produced oxazole (V). Basic hydrolysis of the ethyl ester of (V) yielded carboxylic acid (VI), which was reduced to alcohol (VII) with borane in THF. Treatment of (VII) with methanesulfonyl chloride and triethylamine generated mesylate (VIII). This was coupled with 4-hydroxybenzaldehyde (IX), yielding ether (X). Finally, reductive condensation of (X) with ethyl methylamine in the presence of NaBH3CN furnished the corresponding tertiary amine.

合成路线18

The target compound was obtained by several related ways. Indolylethanol (III) was either prepared by alkylation of indole (I) with methyl bromoacetate, followed by reduction of the resulting indolylacetate (II) with LiAlH4 or by alkylation of (I) with 2-bromoethanol. Alkylation of (III) with 4-fluorobenzaldehyde (IV) in the presence of NaH or condensation with 4-hydroxybenzaldehyde (V) under Mitsunobu conditions provided ether (VII). Alternatively, (VII) was prepared by alkylation of indole (I) with 4-(bromoethoxy)benzaldehyde (VI). Then, Knoevenagel condensation of aldehyde (VII) with 2,4-thiazolidinedione (VIII) in the presence of piperidinium benzoate in refluxing toluene with azeotropic removal of water yielded benzylidene compound (IX). Reduction of the olefinic double bond by either hydrogenation in the presence of an excess of Pd/C or by chemical reduction with Mg in MeOH provided the target benzyl compound. Alternatively, indolylethanol (III) was condensed with hydroxybenzyl compound (X) in the presence of tributyl phosphine and 1,1'-(azodicarbonyl)dipiperidine (ADDP) in benzene to give (XI), which was finally deprotected by hydrogenation in the presence of an excess of Pd/C in dioxan.

合成路线19

Acetylation of N-benzoylaspartic acid beta-methyl ester (I) with acetic anhydride and subsequent decarboxylation gave the 3-benzoylamino-4-oxovalerate (II). The methyl oxazolylacetate (III) was prepared by cyclization of 4-oxovalerate (II) in the presence of Ac2O. Ester (III) was then reduced to alcohol (IV) with LiBH4 and further converted to mesylate (V) with methanesulfonyl chloride and Et3N. Coupling between mesylate (V) and 4-hydroxybenzaldehyde (VI) gave ether (VII). Knoevenagel condensation of (VII) with dimethyl malonate using piperidine acetate produced the benzylidene malonate (VIII). Finally, catalytic hydrogenation with Pd/C furnished the title compound.

合成路线20

The reaction of 4-hydroxybenzaldehyde (I) with cyanacetic acid (II) by means of pyridine in toluene gives the 3-(4-hydroxyphenyl)propenenitrile (III), which by reaction first with methanolic HCl and then with methanolic ammonia is converted into the amidine (IV). Finally, this compound is condensed with 2-furylcarbonyl chloride (V) in pyridine and treated with methanesulfonic acid to afford the target sulfonate.

合成路线21

4-Bromophenol (I) was acetylated with Ac2O and Et3N, and the resulting 4-bromophenyl acetate (II) was rearranged to 5'-bromo-2'-hydroxyacetophenone (III) in the presence of AlCl3 at 120 C. Subsequent nitration of (III) produced the 3'-nitroacetophenone (IV). The catalytic hydrogenation of the nitro group of (IV), with simultaneous halogen hydrogenolysis, furnished 3'-amino-2'-hydroxyacetophe-none (V). Then, diazotization of the amine group of (V), followed by treatment with KI and Cu powder gave iodide (VI). Coupling of 4-phenyl-1-butanol (VII) with 4-hydroxybenzaldehyde (VIII) under Mitsunobu conditions provided 4-(4-phenylbutoxy)benzaldehyde (IX). Further Wittig reaction of (IX) with methylene triphenylphosphorane (X) gave the styrene (XI). This was condensed with the iodoacetophenone (VI) in the presence of Pd(OAc)2 to produce the stilbene derivative (XII). The benzopyranone (XIII) was prepared by condensation of hydroxyacetophenone (XII) with diethyl oxalate in the presence of NaOEt, followed by acid cyclization. After conversion of the ester function of (XIII) to the corresponding amide with methanolic ammonia, dehydration using POCl3 in DMF afforded nitrile (XIV). The required tetrazole ring was finally obtained by reaction with NaN3 and NH4Cl in DMF at 100 C.

合成路线22

Alkylation of p-hydroxybenzaldehyde (I) with 1-(2-chloroethyl)piperidine (II) afforded 4-(2-piperidinylethoxy)benzaldehyde (III). Aldehyde function reduction using NaBH4 provided the benzylic alcohol (IV). Alternatively, alcohol (IV) can be obtained by reaction of 4-hydroxybenzyl alcohol (A) with 1-(2-chloroethyl)piperidine hydrochloride (II) by means of NaOH and benzyl triethylammonium bromide in toluene.The hydrochloride salt of (IV) was then treated with SOCl2 to furnish chloride (V).

合成路线23

The known benzofuran carbinol (I) was converted to mesylate (II) upon treatment with methanesulfonyl chloride and triethylamine and then condensed with (S)-prolinol (III) at 120 C to afford adduct (IV). Subsequent chlorination of (IV) with concomitant rearrangement by means of thionyl chloride in benzene produced the 3-chloropiperidine derivative (V). The reaction of (V) with 4-hydroxybenzaldehyde (VI) in the presence of K2CO3 in DMF at 80 C furnished a mixture of six- and five-membered ring products (VII) and (VIII), which were separated by column chromatography. Condensation of the required aldehyde (VIII) with thiazolidinedione (IX) using piperidinium benzoate in refluxing toluene provided the target benzylidene thiazolidine, which was finally converted to the corresponding maleate salt.

合成路线24

Alkylation of 4-hydroxybenzaldehyde (I) with 1-(2-chloroethyl)piperidine hydrochloride (II) in the presence of K2CO3 yielded (piperidinylethoxy)benzaldehyde (III), which was further reduced to the benzylic alcohol (IV) with methanolic NaBH4. Coupling of (IV) with thioacetic acid according to the Mitsunobu procedure yielded thioacetate ester (V), which was converted to the corresponding thiol (VI) by reductive cleavage of the thioester group with LiAlH4.

合成路线25

Alkylation of 4-hydroxybenzaldehyde (I) with iodoacetic acid in the presence of K2CO3 afforded ether (II). Subsequent condensation of (II) with 5,6-diamino-1,3-dipropyluracil (III) gave imine (IV). Oxidative ring closure by means of FeCl3 in boiling EtOH, with concomitant esterification, furnished xanthine (V). The ethyl ester of (V) was then displaced by hydrazine to yield hydrazide (VI). Finally, condensation of (VI) with dimethylmaleic anhydride (VII) gave rise to the corresponding maleimide.

合成路线26

Mesylate (I) is heated with L-prolinol (II) to furnish pyrrolidine derivative (III), which can be converted into (VII) by different ways: 1) Treatment of (III) with t-BuOK and reaction with 4-fluorobenzaldehyde (IV) in DMF. 2) Conversion of (III) into chloropiperidine derivative (V) by means of SOCl2 in benzene, followed by reaction with 4-hydroxyaldehyde (VI) and K2CO3 in DMF in and chromatographic separation. 3) Mitsunobu reaction between (III) and 4-hydroxyaldehyde (VI) by treatment with PPh3 and DEAD in THF, followed by chromatographic separation. Derivative (VII) is condensed with 2,4-thiazolidinedione (VIII) in toluene in the presence of piperidine and benzoic acid to afford (IX), which is finally converted into its maleate form by treatment with maleic acid in Et2O.

合成路线27

Intermediate (VIII) can be obtained as follows: Bromination of glucuronate derivative (X) by means of TiBr4 in CH2Cl2 followed by reaction with p-hydroxybenzaldehyde (XI) in acetonitrile in the presence of Ag2O affords derivative (XII), whose aldehyde moiety is then reduced by means of NaBH4 and silica gel in isopropanol/CHCl3 to provide benzyl alcohol (XIII). Finally, O-acetyl groups of (XIII) are cleaved by means of NaOMe in MeOH to furnish intermediate (VIII).

合成路线28

Treatment of glucuronic acid gamma-lactone (I) with sodium methoxide in methanol affords methyl glucuronate (II), which is further acylated by acetic anhydride to form the tetraacetate ester (III). Bromination of (III) with TiBr4, followed by coupling of the resultant bromide (IV) with p hydroxybenzaldehyde (V) in the presence of Ag2O yields the peracetylated glucuronide (VI). Aldehyde (VI) reduction employing NaBH4 in the presence of silica gel leads to the benzyl alcohol (VII). The acetate ester groups of (VII) are then removed with sodium methoxide in methanol to furnish (VIII).

合成路线29

Reduction of 3-(4-fluorobenzoyl)propionic acid (I) by means of AlCl3 in CH2Cl2 and borane/tert-butylamine complex yields alcohol (II), which is then converted into aldehyde (IV) by reaction with 4-hydroxybenzaldehyde (III) in presence of PPh3 in THF and diethyl azodicarboxylate. Treatment of (IV) with a solution of methyltriphenylphosphonium bromide in THF and a solution of n-BuLi in hexane affords styrene derivative (V), which couples with 2’-hydroxy-3’-iodoacetophenone (VI) in presence of Et3N and Pd(OAc)2 in CH3CN to provide (VII). Cyclization of (VII) by means of a first treatment with NaOEt in EtOH followed by reaction with diethyl oxalate in Et2O/EtOH yields benzopyrane derivative (VIII) which is then hydrolyzed with NaOH in THF/MeOH to give (IX). Carboxylic acid (IX) is first converted into carboxamide (X) by treatment with a saturated NH3 solution in MeOH and then into carbonitrile (XI) by means of POCl3 in DMF. Finally, treatment of (XI) with a solution of NaN3, NH4Cl and DMF leads to the formation of the desired product.

合成路线30

Alkylation of 4-hydroxybenzaldehyde (I) with iodoacetic acid afforded 4-formylphenoxyacetic acid (II). This was condensed with 5,6-diamino-1,3-dipropyluracil (III) to produce imine (IV), which was oxidatively cyclized to xanthine (V) in the presence of ferric chloride. After activation of (V) as the corresponding acid chloride (VI), coupling with 4-aminobenzonitrile (VII) furnished the title amide.

合成路线31

The title compound was synthesized by two related methods. Stobbe condensation between 4-hydroxybenzaldehyde (I) and diethyl succinate (II) in the presence of NaOEt afforded the benzylidenesuccinate monoester (III). Coupling of (III) with cis-hexahydroisoindoline (IV) gave the amidoester (V). The phenolic hydroxyl group of (V) was then alkylated with tosylate (VI) to provide the corresponding ether (IX). Alternatively, intermediate (IX) was obtained by initial alkylation of 4-hydroxybenzaldehyde (I) with tosylate (VI). The resultant alkyloxy benzaldehyde (VII) was then subjected to Stobbe condensation with diethyl succinate (II) to afford the benzylidenesuccinate (VIII), which was further coupled with the bicyclic amine (IV) to produce (IX). Finally, ester (IX) obtained by either synthetic method was hydrolyzed with NaOH to furnish the target carboxylic acid.

合成路线32

Acetylation of aniline (I) with acetic anhydride (Ac2O) in HOAc followed by reaction with mercurium acetate (Hg(OAc)2) and HClO4 in HOAc provides derivative (II), which is first subjected to dimerization by treatment with Cu and PdCl2 in pyridine and then nitrated by means of HNO3 in HOAc to afford substituted biphenyl (III). Hydrolysis of (III) with H2SO4 gives 4,4'-diamino-3,3'-dinitrobiphenyl (IV), which is converted into tetraaminobiphenyl (V) by hydrogenation over Raney-Ni in acetone. Mitsunobu reaction between p-hydroxybenzaldehyde (VI) and 3-dimethylamino propan-1-ol (VII) with PPh3 and DEAD in THF gives substituted benzaldehyde (VIII), which is finally cyclized with biphenyl derivative (V) by heating in nitrobenzene to furnish the target product.

合成路线33

Treatment of 4-hydroxybenzaldehyde (I) with O-ethylhydroxylamine produced the corresponding O-ethyloxime (II). Coupling of (II) with alcohol (III) under Mitsunobu conditions then gave the title ether.

合成路线34

The condensation of 2,4,6-trihydroxyacetophenone (IV) with tetraacetylbromoglucose (V) by means of NaOH in acetone-water gives tetraacetylphloracetophenone-4-O-glucoside (VI), which is condensed with 4-hydroxybenzaldehyde (VII), by means of KOH in alcohol yielding the chalcone derivative (VIII). Finally, this compound is cyclized and deprotected by a treatment with refluxing aqueous HCl.

合成路线35

The intermediate aldehyde (IX) was synthesized by alkylation of the sodium salt of 4-hydroxybenzaldehyde (VII) with methyl 8-bromooctanoate (VIII).

合成路线36

4-Hydroxybenzaldehyde (I) was acetylated using Ac2O in pyridine. The resultant 4-(acetyloxy)benzaldehyde (II) was then subjected to a Wadsworth-Emmons condensation with trimethyl phosphonoacetate to afford methyl 4-(acetyloxy)cinnamate (III). After catalytic double bond hydrogenation, the resultant saturated ester (IV) was reduced by LiAlH4 to furnish 3-(4-hydroxyphenyl)-1-propanol (V) –alternatively (V) can be obtained by reduction with LiAlH4 of the propionic acid derivative (VI) (isolated from Asplenium onopteris)-. Methylation of the phenolic hydroxyl group of (V) with iodomethane and K2CO3 in acetone gave the methyl ether (VII). Then, oxidation of alcohol (VII) to 3-(4-methoxyphenyl)propanal (VIII) was accomplished by means of pyridinium chlorochromate.

合成路线37

Knoevenagel condensation of 4-hydroxybenzaldehyde (I) with dimethyl malonate in the presence of pyridinium acetate affords the benzylidene malonate (II), which is further hydrogenated over Pd/C to furnish dimethyl (4-hydroxybenzyl)malonate (III). Then, Mitsunobu coupling between phenol (III) and 4-chlorophenethyl alcohol (IV) gives rise to the title compound.

合成路线38