合成路线1

The reaction of 1-(4-bromophenyl)ethanol (IV) with 3,4-dihydro-2H-pyran (C) by means of HCl yields 2-[1-(4-bromophenyl)ethoxy]tetrahydro-2H-pyran (V); this product by condensation with 2-thiophenecarbonitrile (D) through its Grignard complex in THF gives [4-(1-hydroxyethyl)phenyl](2-thienyl)ketone (VI), which without purification is treated with SOCl2 in benzene to give [4-(1-chloroethyl)phenyl](2-thienyl)ketone (VII); then the halogen is substituted by CN with NaCN in DMSO to afford alpha-methyl-4-(2-thienylcarbonyl)benzeneacetonitrile (VIII), which, without purification, is hydrolyzed with H2SO4 and acetic acid.

合成路线2

This compound can be obtained by two related ways: 1) By reaction of adriamycin (I) with 2,3-dihydropyran (II) by means of p-toluenesulfonic acid as a catalyst in DMF. 2) The reaction of adriamycin (I) with 2,3-dihydropyran (II) under stronger conditions yields 14,4'-O-bistetrahydropyranyladriamycin (III), which is selectively hydrolyzed with aqueous 10% acetic acid.

合成路线3

1) By a stepwise conversion of spergualin to DSG in the following sequence: a) Protecting the primary and secondary amines of spergualin with N-(benzyloxycarbonyloxy)suc cinimide to form the N,N'-benzyloxycarbonyl derivative (I); b) protecting the 11-hydroxy group with 3,4-dihydro-2H-pyran to the 11-O tetrahydropyranyl derivative (II); c) converting the 1,5-hydroxy function of (II) to a 1,5-mesylate (III); d) halogenation of (III) with sodium iodide, followed by catalytic hydrogenation, to give 15-deoxy-1-O-tetrahydropyranylspergualin (IV); e) hydrolysis of (IV) with p-toluenesulfonic acid in water to yield 1,5-deoxyspergualin. The overall yield of DSG is 1.8%, based on the amount of spergualin used.

合成路线4

Synthesis of intermediate (XII). Ring cleavage and rearrangement of compound (VIII) affords enone (IXa) with an unprotected hydroxyl group. By stereoselective reduction of (IXa), diol (XIa) is obtained, which is finally protected by DHP to obtain intermediate (XII).

合成路线5

The reaction of 2-bromothiophene (I) with the monosodium salt of ethylene glycol (II) in the same solvent gives 2-(2-hydroxyethoxy)thiophene (III), which is condensed with 3,4-dihydro-2H-pyran (IV) by means of p-toluenesulfonic acid in THF yielding the corresponding tetrahydropyranyl ether (V). The reaction of (V) with N-(benzenesulfonyl)aziridine (VI) by means of BuLi in THF - hexane affords N-[2-[5-(2-hydroxyethoxy)thien-2-yl]ethyl]benzenesulfonamide (VII), which is finally oxidized with silver oxide in aqueous NaOH.

合成路线6

The intermediate 5-fluoro-3-[3-(1-piperazinyl)propyl]-1H-indole (V) has been obtained as follows: a) The condensation of 5-fluoro-1H-indole (VIII) with acrylic acid (IX) by means of acetic anhydride gives 3-(1H-indol-5-yl)propionic acid (X), which is reduced with LiAlH4 to 3-(1H-indol-5-yl)-1-propanol (XI). The tosylation of (XI) with tosyl chloride yields the tosylate (XII), which is condensed with 1-benzylpiperazine (XIII) in refluxing butyl acetate affording 3-[3-(4-benzylpiperazin-1-yl)propyl]-5-fluoro-1H-indole (XIV). Finally, this compound is debenzylated by hydrogenation with H2 over Pd/C yielding the target intermediate (V). b) The tosylate intermediate (XII) can also be condensed with ethyl piperazine-1-carboxylate (XVII) in refluxing butyl acetate giving 4-[3-(5-fluoro-1H-indol-3-yl)propyl]piperazine-1-carboxylic acid ethyl ester (XVIII), which is then decarboxylated with NaOH to the target intermediate (V). The intermediate 3-(1H-indol-5-yl)-1-propanol (XI) can also be obtained by direct cyclization of 4-fluorophenylhydrazine (XV) with dihydropyran (XVI) in hot propyleneglycol.

合成路线7

Treatment of (1E,3S)-1-iodo-3-(tert-butyldimethylsilyloxy)-1-octene (I) with BuLi in ethyl ether, followed by reaction with 7-[3(R)-(tert-butyldimethylsilyloxy)-5-oxo-1-cyclopenten-1-yl] heptanoic acid butyl ester (II) by means of tributylphosphine-copper(I) iodide complex and tributylphosphine in ethyl ether provides the protected nonisolated intermediate (III), which is treated with butyric anhydride (IV) to afford derivative (V). Finally, this compound is converted into the desired product by removal of the TBDMS groups by means HF in acetonitrile/H2O (1). Alternatively, the synthesis can be performed by following a different protection strategy: Esterification of carboxylic acid (VI) with butyl iodide in DMSO by means of diisopropylamine provides derivative (VII), which is then protected by reaction with 3,4-dihydro-2H-pyran (VIII) to furnish compound (IX). Next, coupling of (IX) with iodo derivative (I) by means of tert-BuLi, tributylphosphine - copper (I) iodide complex and tributylphosphine in ethyl ether gives the adduct (X), which by reaction with butyric anhydride (IV) affords derivative (XI). Finally, this compound is converted into the desired product by following this deprotection protocol: 1) Bu4NF in THF; 2) Ac2O, DMAP in CH2Cl2 in the presence of pyridine; and finally 3) pyridinium p-toluenesulfonate (PPTS) in EtOH.

合成路线8

Reaction of 3,4-dihydro-2H-pyran (I) with potassium cyanide, HCl/HOAc and KOH in H2O, followed by treatment with ammonium carbonate in H2O provides hydantoin (II). Hydrolysis of compound (II) with LiOH in H2O at 135 C gives the racemic lithium salt (III), which by treatment with methyl trifluoroacetate and Li2CO3 in a refluxing mixture of BuOH/MeOH followed by enzymatic resolution with acylase I leads to the optically pure (S)-enantiomer (IV). Compound (IV) is converted into its corresponding methyl ester (V) using trimethyl orthoformate and HCl in refluxing MeOH. The ester (V) is then coupled with N-phthaloyl-L-phenylalanine acid chloride (VI) by means of NMM in DMF/CH2Cl2 to provide the alpha-amino-omega-hydroxyhexanoic acid derivative (VII). Compound (VI) is prepared separately from L-phenylalanine (VIII) by reaction with phthalic anhydride (IX) in refluxing toluene or DMF to yield compound (X), which is treated with oxalyl chloride in refluxing toluene in the presence of DMF or in DMF/CH2Cl2. Oxidation of (VII) under Swern conditions [(COCl)2, DMSO and Et3N] followed by treatment with Oxone (potassium peroxymonosulfate) provides aldehyde (XI), which is then subjected to cyclization by means of TFA in CH2Cl2 to furnish the tetrahydropyridine derivative (XII).

合成路线9

Alternatively, intermediate (XIII) can be obtained as follows: Heating of ethyl (S)-lactate (XIV) with morpholine affords amide (XVI), which then reacts with 3,4-dihydro-2H-pyran (A) in the presence of p-TsOH to give protected derivative (XVII). Grignard reaction between (XVII), bromo derivative (XVIII) and Mg turnings in THF yields protected ketone (XIX), which is treated with pyridinium p-toluenesulfonate (PPTS) (THP group removal) and reprotected by means of Tf2O and DIEA to give triflate derivative (XX). Conversion of (XX) into intermediate (XIII) is achieved by reaction with triazolone (VII) and NaH in THF.

合成路线10

Synthesis of intermediate (XI): Treatment of 2,4-difluorophenol (I) with triethylamine and ethyl chloroformate (II) in dichloromethane yields O-ethoxycarbonyl-2,4-difluorophenol (III), which is then nitrated by means of HNO3/H2SO4 and hydrolyzed with Na2CO3 or NaHCO3 in MeOH/H2O to provide (IV). The nitro group of (IV) is then hydrogenated over Pd/C in EtOAc to afford 5-amino-2,4-difluorophenol (V), which is N-protected by reaction with pivaloyl chloride (VI) in pyridine to furnish pivaloylamino derivative (VII). Treatment of (VII) with 3,4-dihydro-2H pyran (VIII) and camphorsulfonic acid (CSA) in dichloromethane gives O-protected derivative (IX), which is converted into ethyl benzoate (X) by first reaction in THF with hexamethylphosphoric triamide (HMPA) and n-BuLi in hexane, followed by treatment with ethyl chloroformate (II). Finally, methylation of (X) by means of iodomethane (MeI) and LDA in THF/hexane yields intermediate (XI). Alternatively, intermediate (XI) can be also obtained by following this pathway: lithiation of derivative (IX) with LDA followed by treatment with TMSCl in THF affords trimethylsilylated compound (XII), which is converted into ethyl benzoate (XIII) by reaction with BuLi and ethyl chloroformate (II). Finally, TMS removal of (XIII) is achieved by treatment with tetrabutyl ammonium fluoride (TBAF) in THF to furnish derivative (X), which is methylated as described above.

合成路线11

Activation of butyric acid derivative (I) with isobutyl chloroformate (II) by means of Et3N in THF, followed by coupling with ethylamine (III) in THF in the presence of Et3N, yields butyramide derivative (IV). Reduction of (IV) by means of (-)-B-chlorodiisopinocampheylborane (Ipc2BCl) in THF, followed by reaction with diethanolamine (A), affords hydroxy derivative (V), whose carbonyl group is removed by means of sodium bis(2-methoxyethoxy)aluminum hydride (Red-Al) in toluene/THF, followed by treatment with H2SO4 to provide compound (VI) . Separately, the synthesis of intermediate (XIV) is performed as follows: condensation of pentamethylene chlorohydrin (VII) with 3,4-dihydro-2H-pyran (VIII) by means of p-toluenesulfonic acid in Et2O furnishes 5-chloropentyl-2-tetrahydropyranyl ether (IX), which is then subjected to reaction with acetone (X) in THF by means of Mg in the presence of 1,2-dibromoethane (B) to provide tetrahydropyranyl ether (XI). Conversion of hydroxy derivative (XI) into the corresponding fluoro derivative (XII) is performed by reaction with diethylaminosulfur trifluoride (DAST) in CH2Cl2, and posterior reaction of (XII) with pyridinium p-toluenesulfonate in EtOH furnishes 6-fluoro-6-methyl-1-heptanol (XIII). Finally, intermediate (XIV) is obtained by reaction of (XIII) with NBS and PPh3 in benzene. Condensation of secondary amine (VI) with intermediate (XIV) by means of NaHCO3 in refluxing acetonitrile provides methanesulfonamide (XV), which is finally converted into the target product by formation of the hemifumarate salt by treatment with fumaric acid (XVI) in acetone.

合成路线12

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13

3-Mercapto-3-methylbutyric acid (I) was protected as the tetrahydropyranyl derivative (III) using dihydropyran (II) and HCl. Subsequent treatment of (III) with triphosgene and triethylamine generated the acid anhydride (IV). Condensation of yohimbine (V) with anhydride (IV) in the presence of dimethylaminopyridine provided ester (VI). Further acetylation of (VI) with acetyl chloride in acetic acid gave rise to the N,S-diacetyl compound (VII), which was selectively deacetylated with mercuric trifluoroacetate, yielding thiol (VIII). Finally, reaction of (VIII) with NaNO2 and HCl furnished the corresponding S-nitrosyl derivative.

合成路线14

The condensation of (R)-lactic acid (I) with morpholine (II) gives the corresponding morpholide (III), which is protected at the hydroxyl position with dihydropyran (IV) to yield the tetrahydropyranyl ether (V). The Grignard reaction of (V) with 2,4-difluorophenylmagnesium bromide (VI) affords the chiral 1-propanone (VII), which by a Corey's diastereoselective epoxidation with trimethylsulfoxonium iodide is converted into the oxirane (VIII). The opening of the oxirane ring of (VIII) by means of 1,2,4-triazole (IX) and NaH provides the tertiary alcohol (X), which is treated with pyridine p-toluenesulfonate to give the deprotected diol (XI) as a (2R,3R) and (2R,3S) 4:1 diastereomeric mixture, from which the desired (2R,3R)-isomer (XII) was isolated by crystallization. The reaction of (XII) with Ms-Cl and TEA, followed by cyclization with NaOMe, yields the oxirane (XIII), which is finally condensed with 7-chloroquinazolin-4(3H)-one (XIV) by means of K2CO3 in hot NMP.

合成路线15

Rearrangement of leinamycin (I) to thioester (III) was achieved by treatment with 4-chloromethyl-5-methyl-2-oxo-1,3-dioxolene (II) in the presence of KI and K2CO3. The required tetrahydropyranyl ether was then obtained by condensation of (III) with dihydropyran (IV) employing camphorsulfonic acid as the catalyst.

合成路线16

Sharpless epoxidation of 3-methyl-2-buten-1-ol (I) using L-(+)-diisopropyl tartrate provided the (2S)-epoxide (II). Treatment of (II) with methyl isocyanate gave the corresponding carbamate (III). Subsequent base-catalyzed epoxide opening generated oxazolidinone (IV), which smoothly rearranged to the more stable isomer (V) under the reaction conditions. Protection of the primary alcohol of (V) as the tetrahydropyranyl ether (VII) was followed by hydrolysis of the carbamate group with KOH in aqueous ethylene glycol at 150 C. The resulting amine (VIII) was coupled with Boc-glycyl-sarcosine (IX) using EDC and HOAt to furnish amide (X). Acid-catalyzed removal of the tetrahydropyranyl group of (X) gave alcohol (XI), which was oxidized to carboxylic acid (XII) by means of RuO2-NaIO4. Exchange of the Boc protecting group for a Fmoc group in (XII) was effected by acid cleavage of the tert-butyl carbamate, followed by treatment with Fmoc-chloride. Esterification of the the resulting acid (XIII) with the functionalized dipeptide (XIV) was achieved with DCC-DMAP to produce (XV).

合成路线17

Hydrogenation of p-nitroacetanilide (I) over Pd/C afforded p-aminoacetanilide (II), which was converted to triazolylacetanilide (III) upon treatment with N,N-dimethylformamide azine and p-toluenesulfonic acid. Acid hydrolysis of the acetamide (III) provided triazolylaniline (IV). Subsequent diazotization of (IV), followed by SnCl2 reduction of the diazonium salt furnished hydrazine (V). Fischer indole synthesis employing (V) and dihydropyran (VI) gave rise to the indolylpropanol (VII), which was converted to the intermediate mesylate (VIII) using CH3SO2Cl and Et3N.

合成路线18

The known chiral epoxide (IX) can be synthesized by several different ways shown in the following: 1) 2(S)-Acetoxypropionic acid (XII) is treated first with oxalyl chloride in DMF/CH2Cl2, and then the resultant acyl chloride is submitted to a Friedel-Crafts reaction with 1,3-difluorobenzene (XIII) by means of AlCl3 to provide a 1:1 mixture of a(S)-acetoxypropiophenone (XIV) and a(S)-hydroxy-propiophenone (XV). This mixture is treated with H2SO4 in MeOH to give the pure alcohol (XV). Tosylation of alcohol (XV) with p-toluenesulfonyl chloride in pyridine furnishes tosylate (XVI), which is converted into a(R)-hydroxypropiophenone (XVII) by an SN2 displacement reaction with LiOH in DMF/H2O. Reaction of the hydroxy group of (XVII) with 2,3-dihydropyran (XVIII) and pyridi-nium p-toluenesulfonate (PPTS) in CH2Cl2 gives the protected compound (XIX), which is converted into the silyl alcohol (XXI) by a Grignard reaction with (chloro-methyl)dimethylisopropoxysilane (XX) in the presence of Mg and a small amount of MeI. Oxidative desilylation of (XXI) by means of NaHCO3 and H2O2 in THF/MeOH, followed by hydrolysis with TsOH in MeOH, affords the triol (XXII), which is then mesylated with methanesulfonyl chloride in pyridine to provide the dimesylate (XXIII). Finally, nucleofilic substitution of one mesylate group of (XXIII) with 1H-1,2,4-triazole (XXIV) by means of NaH in DMF with concomitant epoxide formation affords the desired intermediate (IX).

合成路线19

It can be prepared in several different ways: 1) By reaction of the 1-(2-cyanophenoxy)-2-hydroxy-3-bromopropane (I) with N,N'-di-tert-butylurea (A) in tetralin at 200 C. 2) By condensation of the 1-(2-cyanophenoxy)-2-hydroxy-3-bromopropane (I) with dihydropyrane (B) to the corresponding tetrahydropyranyl ether (III), which is condensed with tert-butylamine (C) in benzene to 1-(2-cyanophenoxy)-3-tert-butylaminopropanol-2-tetrahydropyranyl ether (IV) (oxalate, m.p. 102-5 C), which is finally hydrolyzed with diluted HCl at 100 C.

合成路线20

4-Chloro-1-butanol (I) is protected as the tetrahydropyranyl ether (III) by treatment with dihydropyran (II) in the presence of pyridinium p-toluenesulfonate (PPTS). Alkylation of the sodium derivative of phenothiazine (IV) with chloride (III) yields adduct (V), which is subsequently deprotected to alcohol (VI) with PPTS in MeOH-THF. The free alcohol (VI) is then chlorinated to (VII) by using SOCl2 in benzene. Finally, condensation of chloride (VII) with pyrrolidine (VIII) in THF at 100 C in a sealed tube provides the title compound.

合成路线21

Reaction of 2',5'-dihydroxyacetophenone (I) with dihydropyran (II) and pyridinium p-toluenesulfonate gives the protected bis-tetrahydropyranyl ether (III), which is submitted to Claisen-Schmidt condensation with 2-chlorobenzaldehyde (IV) in the presence of barium hydroxide, yielding the chalcone (V). Finally, the tetrahydropyranyl protecting groups of (V) are removed by acidic hydrolysis with p-toluenesulfonic acid in MeOH.

合成路线22