合成路线1

The condensation of 4-phenyl-1-butanol (I) with 1,6-dibromohexane (II) by means of NaH in THF gives the ether (III), which is condensed with benzylamine (IV) by means of NaI and TEA in DMSO to yield the secondary amine (V). The condensation of (V) with 5-(bromoacetyl)-2-hydroxybenzaldehyde (VI) in refluxing acetonitrile affords the tertiary amine (VII). The reduction of both carbonyl groups of (VII) by means of NaBH4 in methanol affords the dihydroxy amine (VIII), which is finally debenzylated by means of h2 over Pd/C in the same solvent to provide the target salmeterol. The intermediate 5-(bromoacetyl)-2-hydroxybenzaldehyde (VI) has been obtained by Friedel Crafts condensation of 2-hydroxybenzaldehyde (IX) with bromoacetyl chloride (X) by means of AlCl3 in dichloromethane.

合成路线2

This compound is obtained by condensation of 2(S)-(aminomethyl)-1-ethylpyrrolidine (I) with 5-(aminosulfonyl)-2-methoxybenzoyl chloride (II) by means of K2CO3 in acetone. The starting compounds (I) and (II) are obtained as follows: a) The acylation of 2(S)-(hydroxymethyl)pyrrolidine (III) with acetic anhydride in refluxing methanol gives 1-acetyl-2(S)-(hydroxymethyl)pyrrolidine (IV), which by reaction with SOCl2 in CHCl3 is converted into 1-acetyl-2(S)-(chloromethyl)pyrrolidine (V). The reaction of (V) with sodium azide in hot DMF affords the corresponding azide (VI), which is reduced with LiAlH4 in refluxing THF to yield the desired product (I). b) The methylation of 2-hydroxybenzaldehyde (VII) with dimethyl sulfate and K2SO3 in refluxing acetone gives 2-methoxybenzaldehyde (VIII), which is oxidized with KMnO4 in hot aqueous NaOH affording 2-methoxybenzoic acid (IX). The sulfonation of (IX) with hot chlorosulfonic acid yields 5-(chlorosulfonyl)-2-methoxybenzoic acid (X), which is finally treated with 28% aqueous NaOH to give the desired product (II).

合成路线3

meso-1,2-Bis(2,6-dichloro-4-hydroxyphenyl)ethylenediamine (I) is svnthesized by [3.3]sigmatropic diaza-Cope rearrangement according to the method of Vögtle and Goldschmitt by reaction of meso-1,2-bis(2-hydroxyphenyl)ethylenediamine (IV) with 2,6-dichloro-4methoxybenzaldehyde (V) at temperature below 120 C via the corresponding aldimine (VI) and subsequent ether cleavage with boron tribromide.

合成路线4

The condensation of 2-hydroxybenzaldehyde (I) with ethyl 2-bromobutyrate (II) by means of K2CO3 and NaI in DMF gives ethyl-2-(2-formylphenoxy) butyrate (III), which is reduced with NaBH4 and NaOEt in ethanol yielding the hydroxymethyl derivative (IV). The reaction of (IV) with SOCl2 affords the corresponding chloromethyl compound (V), which is cyclized by means of NaH in N-methylpyrrolidone to give 2-ethyl-2,3-dihydrobenzofuran-2-carboxylic acid ethyl ester (VI). The hydrolysis of the ethyl ester of (VI) with NaOH in methanol yields the expected carboxylic acid (VII), which is treated with SOCl2 and then with NH3 to afford the amide (VIII). This compound can also be obtained directly from ester (VI) by reaction with NH3. The dehydration of (VIII) by means of P2O5 or POCl3 gives the nitrile (IX), which is treated with HCl in ethanol yielding the carboxyimidate (X). Finally, this compound is cyclized with ethylenediamine (XI) in ethanol.

合成路线5

The iodination of 2-hydroxybenzaldehyde (I) with iodine chloride in dichloromethane gives 2-hydroxy-5-iodobenzaldehyde (II), which is protected with Mem-Cl by means of NaH and 1,3-dimethylperhydropyrimidin-2-one (DMPU) in THF yielding the ether derivative (III). The reduction of (III) with NaBH4 in THF affords the benzyl alcohol (IV), which is brominated with NBS and triphenylphosphine in THF to give the benzyl bromide (V). The condensation of (V) with the protected aminopyrrolidinone (VI) by means of NaH and DMPU in THF yields the benzylpyrrolidinone (VII), which is treated with Zn(CN)2 and palladium tetrakis(triphenylphosphine) in DMF to provide the benzonitrile (VIII). The deprotection of (VIII) with HCl gas in ethyl acetate gives the primary amine (IX), which is sulfonated with 5-(3-pyridyl)thiophene-2-sulfonyl chloride (X) in pyridine yielding the sulfonamide (XI). Finally, this compound is treated first with HCl gas in ethanol, and then with NH3 in methanol to convert the cyano group of (XI) into the amidino group of the target compound. The intermediate sulfonyl chloride (X) has been obtained as follows: The condensation of 3-bromopyridine (XII) with 2-bromothiophene (XIII) by means of Mg and NiCl2 in refluxing ethyl ether gives 2-(3-pyridyl)thiophene (XIV), which is chlorosulfonated by means of BuLi, SO2 and SO2Cl2 in THF to yield intermediate (X).

合成路线6

The intermediate 1,2,3,4-tetrahydrobenzofuro[3,2-c]pyridine (VIII) has been obtained by three different ways: 1) The cyclization of 2-hdroxybenzaldehyde (I) with ethyl 2-bromoacetate (II) by means of K2CO3 in DMF gives ethyl benzofuran-2-carboxylate (III), which is reduced with LiAlH4 in refluxing THF to the carbinol (IV). The reaction of (IV) with acetone cyanohydrin (V), PPh3 and DEAD yields the acetonitrile (VI), which is reduced with H2 over Raney-Ni to afford the ethylamine (VII). Finally, this compound is cyclized with formaldehyde in refluxing water to provide the desired intermediate (VIII). 2) The intermediate ethyl benzofuran-2-carboxylate (III), is hydrolyzed with NaOH to the corresponding free acid (IX), which is decarboxylated with Cu at 240 C in quinoline to yield benzofuran (X). The reaction of (X) with oxirane (XI) by means of n-BuLi in ethyl ether affords 2-(2-benzofuryl)ethanol (XII), which is treated first with MsCl and TEA, and then with NaI in refluxing acetone to provide the 2-(2-iodoethyl)benzofuran (XIII). The reaction of (XIII) with hexamethylenetetramine (HMT) gives the adduct (XIV), which is finally cyclized to the target intermediate (VIII) by means of HCl in refluxing ethanol. 3) The target intermediate (VIII) can also be obtained by cyclization of O-phenylhydroxylamine (XV) with 4-piperidone (XVI) in refluxing isopropanol. Finally, intermediate (VIII) is condensed with 3-(2-chloroethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidine (XVII) by means of Na2CO3 and KI in a refluxing organic solvent such as 4-methyl-2-pentanone.

合成路线7

Salicylaldehyde (I) was alkylated with 1,3-dibromopropane (II) to provide bromopropyl ether (III). Furter displacement of the bromine of (III) with the potassium salt of 2-mercaptoimidazole (IV) gave thioether (V). Condensation of methyl cyanoacetate (VI) with 3-chlorobenzylamine (VII) at 120 C afforded cyanoacetamide (VIII). Finally, Knoevenagel reaction of (VIII) with benzaldehyde (V) in the presence of beta-alanine furnished the title compound.

合成路线8

Condensation of salicylaldehyde (I) with 2-bromoacetophenone (II) produced benzofuranyl phenyl ketone (III), which was reduced to 2-benzyl benzofuran (IV) under Wolff-Kishner conditions. Subsequent Friedel-Crafts acylation of (IV) with anisoyl chloride (V) employing SnCl4 afforded ketone (VI). Methyl ether cleavage in (VI) with concomitant intramolecular cyclization, followed by dehydration by means of BBr3 gave rise to benzo naphthofuran (VII). This was brominated in AcOH to yield tribromo derivative (VIII). Mitsunobu coupling of (VIII) with (S)-methyl-2-hydroxy-3-phenylpropionate (IX) furnished ether (X). Finally, the methyl ester group of (X) was hydrolyzed with KOH.

合成路线9

Reaction of salicylaldehyde (I) with iodine monochloride produced 2-hydroxy-5-iodobenzaldehyde (II), which was protected with (2-methoxyethoxy) methyl chloride to give ether (III). Reduction of the aldehyde group of (III) with NaBH4 yielded alcohol (IV) and subsequent treatment with N-bromosuccinimide and triphenylphosphine generated bromide (V). N-Boc-3-aminopyrrolidinone (VII) was prepared by cyclization of (S)-alpha-Boc-2,4-diaminobutyric acid (VI) in the presence of EDC and HOBt. Subsequent alkylation of (VII) with bromide (V) produced the N-benzylpyrrolidinone derivative (VIII). Displacement of iodide group of (VIII) by zinc cyanide gave nitrile (IX). Then, acid cleavage of both Boc and MEM protecting groups furnished intermediate (X).

合成路线10

Reaction of salicylaldehyde (I) with iodine monochloride produced 2-hydroxy-5-iodobenzaldehyde (II), which was protected with (2-methoxyethoxy) methyl chloride to give ether (III). Reduction of the aldehyde group of (III) with NaBH4 yielded alcohol (IV) and subsequent treatment with N-bromosuccinimide and triphenylphosphine generated bromide (V). N-Boc-3-aminopyrrolidinone (VII) was prepared by cyclization of (S)-alpha-Boc-2,4-diaminobutyric acid (VI) in the presence of EDC and HOBt. Subsequent alkylation of (VII) with bromide (V) produced the N-benzylpyrrolidinone derivative (VIII). Displacement of iodide group of (VIII) by zinc cyanide gave nitrile (IX). Then, acid cleavage of both Boc and MEM protecting groups furnished intermediate (X).

合成路线11

Treatment of salicylaldehyde (I) with methyl chloroacetate (II) in DMF in the presence of potassium carbonate provides methyl o-formylphenoxyacetate (III), which is converted into methyl 2-benzofuranecarboxylate (IV) by reaction with DBU in toluene. Reduction of (IV) by means of LiAlH4 in ether yields hydroxy derivative (V), which then reacts with SOCl2 in ether/DMF to furnish chloro derivative (VI). Treatment of (VI) with NaCN in DMSO affords cyano derivative (VII), which is converted into 2-benzofuraneacetic acid (VIII) by treatment with NaOH in boiling water. Esterification of (VIII) by treatment with HCl in refluxing MeOH affords methyl acetate derivative (IX), which is condensed with p-anisoyl chloride (X) by means of SnCl4 in 1,2-dichloroethane to yield compound (XI). Treatment of (XI) with aluminum powder and iodine crystals (to generate AlI3) in refluxing benzene gives acetic acid derivative (XII), which is iodinated with iodine and K2CO3 in H2O to give derivative (XIII). Esterification of (XIII) by means of iPrOH and H2SO4 provides isopropyl acetate derivative (XIV), which is finally converted into the desired product by reaction with diethylaminoethyl chloride (XV) in NaOH and CH2Cl2 in the presence of benzyltriethylammonium chloride.

合成路线12

By cyclization of 2-hydroxybenzaldehyde (I) with 4-(cyanacetamido)benzoic acid ethyl ester (II) catalyzed by piperidine in ethanol.

合成路线13

The cyclization of 2-hydroxybenzaldehyde (I) with 2-(cyanacetamido)benzoic acid methyl ester (II) catalyzed by piperidine in ethanol gives the 2-imino-1-benzopyran (III), which is then hydrolyzed to the target benzopyranone with HCl in refluxing ethanol/water.

合成路线14

The cyclization of 2-hydroxybenzaldehyde (I) with 4-(cyanacetamido)benzoic acid ethyl ester (II) catalyzed by piperidine in ethanol gives the 2-imino-1-benzopyran (III), which is then hydrolyzed to the target benzopyranone with HCl in refluxing ethanol/water.

合成路线15