合成路线1

This compound can be obtained in two different ways: 1) By reaction of phthalic anhydride (I) with valeric anhydride (II) in the presence of sodium valerate (A). 2) By reaction of 2-iodobenzoic acid (III) with copper propylacetylide (IV).

合成路线2

The condensation of chiral tetraline (I) with phthalic anhydride (II) by means of AlCl3 at 180 C gives the naphthacenedione (III), which is ketalized at the acetyl group with ethylene glycol and p-toluenesulfonic acid yielding the dioxolane (IV). The hydroxylation of (IV) with Br2 and AIBN in CCl4/CHCl3 affords the 4-demethoxy-7-epidaunomycinone (V), which is isomerized with TFA yielding 4-demethoxydaunomycinone (VI) . The condensation of (VI) with the acylated hexopyranosyl chloride (VII) by means of CF3SO3Ag of Br2Hg affords the trifluoroacetylated 4-demethoxydaunomycin (VIII), which is finally treated with NaOH in order to eliminate the trifluoroacetyl groups

合成路线3

The reaction of aminomethansulfonic acid (I) with phthalic anhydride (II) by means of potassium acetate in refluxing acetic acid gives phthalimidomethansulfonic acid (III), which by reaction with PCl5 in refluxing benzene is converted into its acyl chloride (IV). The condensation of (IV) with tert-butylamine (A) in CHCl3 affords N-tert-butylphthalimidomethansulfonamide (V), which by reaction with hydrazine hydrate in refluxing ethanol yields 2-aminomethan-N-tert-butylsulfonamide (VI). The reaction of (VI) with CS2 and MeI by means of triethylamine in ethanol gives N-tert-butylsulfamoylmethyldithiocarbamic acid methyl ester (VII), which is cyclized with NaN3 in hot water to afford 1-(N-tert-butylsulfamoylmethyl)tetrazol-5-thiol (VIII). The hydrolysis of (VIII) with trifluoroacetic acid yields compound 1-sulfamoylmethyltetrazol-5-thiol (IX).

合成路线4

A novel solid-phase synthesis of thalidomide has been described: The coupling of phthalic anhydride (I) with hydroxymethyl polystyrene resin (II) by means of triethylamine and 4-dimethylaminopyridine (DMAP) in DMF affords the resin-linked acid (III), which is then condensed with alpha-aminoglutarimide (IV) by means of diisopropylcarbodiimide (DIC) and N-hydroxybenzotriazole (HOBt) in DMF to provide amide (V). Finally, thalidomide is obtained by treatment of resin (V) with TFA in refluxing toluene.

合成路线5

The esterification of N-(tert-butoxycarbonyl)-D-glutamic acid 5-O-benzyl ester (I) with phenol by means of DCC and pyridine in ethyl acetate gives the mixed ester (II), which is treated with H2 over Pd/C in methanol to yield the N-(tert-butoxycarbonyl)-D-glutamic acid 1-O-phenyl ester (III). The cyclization of (III) with O-benzylhydroxylamine (IV) by means of EDC, HOBT and TEA in dichloromethane affords N-[1-(benzyloxy)-2,6-dioxopiperidin-3(R)-yl]carbamic acid tert-butyl ester (V), which is treated with HCl gas in dichloromethane to provide 3(R)-amino-1-(benzyloxy)piperidine-2,6-dione (VI). The reaction of (VI) with phthalic anhydride (VII) by means of TEA in THF gives the phthalimido derivative (VIII), which is debenzylated with H2 over Pd/C in methanol to yield 1-hydroxy-3-(R)-(phthalimido)piperidine-2,6-dione (IX). Finally, the OH group of (IX) is eliminated by reaction with phenacyl bromide (X) and TEA in acetonitrile to afford the phenacyl ether (XI), which is submitted to a nucleophilic cleavage by means of DMAP as the base to obtain the target (R)-thalidomide.

合成路线6

The esterification of N-(tert-butoxycarbonyl)-L-glutamic acid 5-O-benzyl ester (I) with phenol by means of DCC and pyridine in ethyl acetate gives the mixed ester (II), which is treated with H2 over Pd/C in methanol to yield the N-(tert-butoxycarbonyl)-L-glutamic acid 1-O-phenyl ester (III). The cyclization of (III) with O-benzylhydroxylamine (IV) by means of EDC, HOBT and TEA in dichloromethane affords N-[1-(benzyloxy)-2,6-dioxopiperidin-3(S)-yl]carbamic acid tert-butyl ester (V), which is treated with HCl gas in dichloromethane to provide 3(S)-amino-1-(benzyloxy)piperidine-2,6-dione (VI). The reaction of (VI) with phthalic anhydride (VII) by means of TEA in THF gives the phthalimido derivative (VIII), which is debenzylated with H2 over Pd/C in methanol to yield 1-hydroxy-3-(S)-(phthalimido)piperidine-2,6-dione (IX). Finally the OH group of (IX) is eliminated by reaction with phenacyl bromide (X) and TEA in acetonitrile to afford the phenacyl ether (XI), which is submitted to a nucleophilic cleavage by means of DMAP as the base to obtain the target (S)-thalidomide. Alternatively, the phthalimido derivative (VIII) can also be obtained by reaction of 2(S)-(phthalimido)glutaric anhydride (XII) with O-benzylhydroxylamine (IV) by means of DCC and pyridine in dichloromethane.

合成路线7

By reaction of phthalic anhydride (I) with thiazolidine (II) in CH2Cl2.

合成路线8

The reaction of phthalic anhydride (I) with ethyl p-amino-alpha-ethylphenylacetate (II) in refluxing acetic acid gives ethyl alpha-[4-(1,3-dioxo-2-isoindolinyl)phenyl]-n-butyrate (III), which is reduced with Zn in refluxing acetic acid to the isoindolinone (IV). Finally, this compound is hydrolyzed with K2CO3 in refluxing ethanol - water.

合成路线9

This compound can be obtained in two related ways: 1) The cyclization of 4-acetamidocyclohexanone (I) with thiourea (II) by means of Br2 in hot acetic acid gives 6-acetamido-2-amino-4,5,6,7-tetrahydrobenzothiazole (III), which by hydrolysis with refluxing aqueous HBr yields racemic 2,6-diamino-4,5,6,7-tetrahydrobenzothiazole (racemic IV). Optical resolution with L-(+)-tartaric acid affords the (S)-(-)-isomer (IV), which is finally treated with propionaldehyde and LiBH4. 2) The reaction of 4-aminocyclohexanol (V) with phthalic anhydride (VI) in toluene gives the phthalimido derivative (VII), which is oxidized with potassium dichromate - H2SO4 to the corresponding cyclohexanone (VIII). The cyclization of (VIII) with thiourea (II) and Br2 as before affords 2-amino-6-phthalimido-4,5,6,7-tetrahydrobenzothiazole (IX), which is deprotected with hydrazine in refluxing ethanol yielding racemic (IV), already obtained.

合成路线10

(R)-2-acetyl-2-acetamido-5,8-dimethoxy-1,2,3,4-tetrahydronaphthalene (VI) is submitted to a Friedel-Crafts cyclocondensation with phthalic anhydride (VII) by means of anhydrous AlCl3 at 135 C to afford (R)-9-acetyl-9-acetamido-6,11-dihydroxy-7,8,9,10-tetrahydronaphthacene-5,12-dione (VIII). The protection of the acetyl group of (VIII) with ethylene glycol and p-toluenesulfonic acid gives the corresponding ketal (IX), which by cyclization with 1,3-dibromo-5,5-dimethylhydantoin (DDH) yields the pentacyclic oxazine (X). The hydrolysis of (X) with hot H2SO4 affords 9-amino-4-demethoxy-9-deoxydaunomycinone (XI), which is condensed with 3,4-di-O-acetyl-2-deoxy-beta-D-ribopyranosyl bromide (XII) (obtained from acetyl 3,4-di-O-acetyl-2-deoxy-beta-D-ribopyranoside (XIII) and trimethylsilyl bromide) by means of tetramethylurea in chloroform to give the 3',4'- di-O-acetyl derivative (XIV) of the desired product. Finally, this compound is deprotected by hydrolysis with anhydrous K2CO3 in methanol - dichloroethane.

合成路线11

1) The condensation of 2,4,5,6-tetraaminopyrimidine sulfate (I) with dihydroxyacetone dimer (II) in the presence of cysteine and O2 furnished 2,4-diamino-6-(hydroxymethyl)pteridine (III). Subsequent reaction of (III) with dibromotriphenylphosphorane in dimethylacetamide afforded bromide (IV) which, without isolation, was condensed with 4-aminobenzoic acid (V) in the presence of BaO to give 4-amino-4-deoxypteroic acid (VI). Formylation of (VI) with acetic-formic anhydride yielded formamide (VII), and subsequent activation as the 4-nitrophenyl ester (IX) was carried out upon reaction with bis(4-nitrophenyl)carbonate (VIII). Then Nd-Boc-L-ornithine, after conversion to the corresponding Na,O-bis(trimethylsilyl) derivative (X) by treatment with ClSiMe3 and triethylamine, was condensed with active ester (IX) to furnish amide (XI). Subsequent deprotection of the Boc group of (XI) with cold trifluoroacetic acid provided (XII), which was then condensed with phthalic anhydride (XIII) in the presence of triethylamine in N-methylpyrrolidinone, yielding the hemiphthaloyl amide (XIV). Finally, the formamide function was hydrolyzed with aqueous NaOH at r.t. to provide the target compound, after chromatographic separation of some phthaloyl-hydrolyzed byproduct.

合成路线12

Condensation of 7-hydroxy-1,8-naphthyridin-2-amine (I) with phthalic anhydride (II) in refluxing acetic acid gives N-(7-hydroxy-1,8-naphthyridin-2-yl)phthalimide (III), which is treated with refluxing POCl3 to yield the 7-chloro derivative (IV). Reduction of compound (IV) with KBH4 in dioxane affords 2-(7-chloro-1,8-naphthyridin-2-yl)-3-hydroxyisoindolin-1-one (V), which is condensed with 5-methyl-2-hexanone (VI) by means of NaH in DMF to give (±)-2-(7-chloro-1,8-naphthyridin-2-yl)-3-(5-methyl-2-oxohexyl)isoindolin-1-one (VII) (racemic pagoclone). The treatment of (VII) with NaOH in dioxane/water yields the racemic benzoic acid (VIII). Optical resolution of racemic (VIII) by means of (+)-ephedrine or cinchonine affords the (+)-isomer (IX), which is finally cyclized to the chiral (+)-indolinone derivative pagoclone by means of SOCl2 and imidazole in dichloromethane.

合成路线13

Reaction of 8-amino-6-methoxy-4-methyl-5-[3-(trifluoromethyl)phenoxy]quinoline (XIV) with phthalic anhydride (XV) affords the phthalimido derivative (XVI), which is oxidized with MCPBA to yield the quinoline N-oxide (XVII). Treatment of compound (XVII) with neutral alumina gives the quinolone derivative (XVIII), which by reaction with POCl3 in refluxing CHCl3 provides the 2-chloroquinoline derivative (XIX). Alternatively, reaction of the quinoline N-oxide (XVII) with POCl3 as before also gives the 2-chloroquinoline derivative (XIX) The removal of the phthalimido group of compound (XIX) by means of hydrazine in refluxing ethanol gives the chlorinated aminoquinoline (XX), which is finally treated with MeONa in hot DMF.

合成路线14

In a different method, N-phthaloylglycine (VII) was obtained by melting a mixture of phthalic anhydride (V) and glycine (VI). Subsequent chlorination of (VII) using SOCl2 provided acid chloride (VIII). Condensation of (VIII) with the sodium derivative of the tricarboxylate compound (IX) gave the keto triester (X). Hydrogenolysis of the benzyl ester groups of (X), followed by decarboxylation in refluxing toluene, gave rise to delta-phthalimidolevulinic acid (XI). This was finally hydrolyzed to the title compound upon refluxing with 7 N HCl.

合成路线15

Tetrahydrofurfurylamine (XLVII) was converted into the corresponding phthalimide (XLVIII) by reaction of phthalic anhydride (V) in boiling chloroform. Subsequent ruthenium-catalyzed oxidation of (XLVIII) produced keto acid (XI), along with a pentanolide by-product, which was removed by column chromatography. Finally, acid hydrolysis of (XI) led to the desired compound. A closely related strategy was based in the ruthenium oxidation of N-benzoyl tetrahydrofurfurylamine (LXX), prepared from amine (XLVII) and benzoyl chloride (XLIX), to afford 5-benzoylaminolevulinic acid (XXXV), which was then hydrolyzed in boiling 6 N HCl .

合成路线16

The condensation of the labeled glycine (I) with phthalic anhydride (II) by heating at 160 C gives the labeled phthalimido acetic acid (III), which is treated with refluxing SOCl2 to yield the acyl chloride (IV). The condensation of (IV) with 3-iodopropionic acid ethyl ester (V) by means of the Zn/Cu couple and Pd(PPh3)4 in hot toluene affords the labeled 5-phthalimido-levulinate (VI), which is finally treated with refluxing 6N HCl to provide the target labeled aminolevulinic acid.

合成路线17

The condensation of phthalic anhydride (I) with glycine (II) by heating at 160 C gives 2-phthalimidoacetic acid (III), which is treated with refluxing SOCl2 to yield the acetyl chloride (IV). The condensation of (IV) with Meldrum's acid (V) by means of pyridine in dichloromethane, followed by a treatment with refluxing ethanol, affords 4-phthalimidoaetoacetic acid ethyl ester (VI), which is condensed with 1-13C-labeled 2-bromoacetic acid ethyl ester (VII) by means of NaH in dimethoxyethane to provide labeled 2-(2-phthalimidoacetyl)succinic acid diethyl ester (VIII). Finally, this compound is treated with HCl in refluxing acetic acid to give the target labeled aminolevulinic acid.

合成路线18

The condensation of phthalic anhydride (I) with 1-13C-labeled glycine (II) by heating at 160 C gives 2-phthalimidoacetic acid (III), which is treated with refluxing SOCl2 to yield the acetyl chloride (IV). The condensation of (IV) with Meldrum's acid (V) by means of pyridine in dichloromethane, followed by a treatment with refluxing ethanol affords 4-phthalimidoaetoacetic acid ethyl ester (VI). This compound is condensed with 2-bromoacetic acid ethyl ester (VII) by means of NaH in dimethoxyethane to provide labeled 2-(2-phthalimidoacetyl)succinic acid diethyl ester (VIII). Finally, the compound is treated with HCl in refluxing acetic acid to give the target labeled aminolevulinic acid.

合成路线19

The condensation of phthalic anhydride (I) with glycine (II) by heating at 160 C gives 2-phthalimidoacetic acid (III), which is treated with refluxing SOCl2 to yield the acetyl chloride (IV). The condensation of (IV) with Meldrum's acid (V) by means of pyridine in dichloromethane, followed by a treatment with refluxing ethanol affords 4-phthalimidoaetoacetic acid ethyl ester (VI). This compound is condensed with 2-13C-labeled 2-bromoacetic acid ethyl ester (VII) by means of NaH in dimethoxyethane to provide labeled 2-(2-phthalimidoacetyl)succinic acid diethyl ester (VIII). Finally, this compound is treated with HCl in refluxing acetic acid to give the target labeled aminolevulinic acid.

合成路线20

The condensation of phthalic anhydride (I) with glycine (II) by heating at 160 C gives 2-phthalimidoacetic acid (III), which is treated with refluxing SOCl2 to yield the acetyl chloride (IV). The condensation of (IV) with 2-13C-labeled Meldrum's acid (V) by means of pyridine in dichloromethane, followed by a treatment with refluxing ethanol affords 4-phthalimidoaetoacetic acid ethyl ester (VI). This compound is condensed with 2-bromoacetic acid ethyl ester (VII) by means of NaH in dimethoxyethane to provide labeled 2-(2-phthalimidoacetyl)succinic acid diethyl ester (VIII). Finally, the ester is treated with HCl in refluxing acetic acid to give the target labeled aminolevulinic acid.

合成路线21

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22

An alternative procedure for the chiral hydroxy sulfoxide (XIX) involved a lipase-catalyzed kinetic resolution. Transesterification of racemic hydroxy sulfoxide (XXII) with isopropenyl acetate (XXIII) catalyzed by lipase AL yielded the acetate ester of the required (S)-isomer (XXIV), along with the unreacted (R)-alcohol (XXV). Separation was achieved upon treatment with phthalic anhydride (XXVI) in the presence of DMAP and pyridine to produce the phthalic acid derivative (XXVII) of the unreacted alcohol, which could be separated from the desired acetate ester (XXIV) by means of selective extraction. The target enantiomerically pure (S)-hydroxy sulfoxide intermediate (XIX) was then obtained by methanolysis of the acetate ester (XXIV) with K2CO3, followed by two recrystallizations from EtOAc. The corresponding (R)-alcohol was recovered by NaOH hydrolysis of the phthalate ester (XXVII), and was completely racemized by treatment with aqueous HCl.

合成路线23

Pyrroline (III) was prepared by Favorskii rearrangement of 3,5-dibromo-2,2,6,6-tetramethylpiperidinone (I) in the presence of 1,3-diaminopropane (II). Acylation at the primary amino group of (III) with phthalic anhydride (IV) gave the 2-carboxybenzamide (VI), which was cyclized to the target phthalimide (VII) by refluxing in toluene in the presence of Et3N. Alternatively, the phthalimido derivative (VII) was obtained by condensation of amine (III) with phthalimide (V) at 150 C. The target compound was then isolated as the hydrochloride salt upon treatment with HCl in EtOH-Et2O.

合成路线24

Phthalic anhydride (I) was condensed with 2,6-diisopropyl-aniline (II) to give the N-aryl phthalimide (III), which was then treated with diphosphorus pentasulfide in boiling xylene to afford the title thiocarbonyl analogue.

合成路线25

Michael addition of itaconic acid (II) to 4-tert-butylaniline (I), and further lactamization afforded pyrrolidone carboxylic acid (III). This was esterified with H2SO4 in MeOH, and the resulting methyl ester (IV) was reduced to alcohol (V) with NaBH4 in boiling tetrahydrofuran. Optical resolution of (V) was achieved by condensation with phthalic anhydride (VI) to give amide (VII), followed by coupling of the remaining carboxylic acid group of (VII) with chiral alpha-methylbenzyl amine (VIII) yielding (IX). After separation of the diastereomeric mixture (IX), hydrolysis of the phthalate ester furnished the required (S)-alcohol (X) (2). Mesylate (XI), prepared from alcohol (X) and MsCl in the presence of Et3N, was condensed with methyl 4-hydroxybenzoate (XII) to afford ether (XIII). Then, basic hydrolysis of the methyl ester of (XIII) provided the title compound.

合成路线26

Protection of 3-amino-5-methylphenol (I) with phthalic anhydride (II) provided the phthalimido derivative (III), which was alkylated with ethyl 4-bromobutyrate (IV) in the presence of K2CO3 to give the corresponding ether (V). Hydrazinolysis of the phthalimido group of (V) afforded the primary amine (VI), which was condensed with benzenesulfonyl chloride (VII), yielding sulfonamide (VIII). Saponification of the ethyl ester of (VIII) gave carboxylic acid (IX). After conversion to the mixed anhydride with isobutyl chloroformate and N-methylmorpholine, treatment with methanolic ammonia furnished amide (X). This was reduced to amine (XI) using LiAlH4 in THF. Finally, reaction of (XI) with S-methylisothiouronium sulfate (XII) in refluxing EtOH provided the target guanidine.

合成路线27

Reaction of glycine (II) with phthalic anhydride (I) in a microwave oven gave phthaloylglycine (III). Subsequent condensation with phenylamidoxime (IV) in the presence of DCC in dimethoxyethane afforded the O-acyl intermediate (V), which on heating cyclized to the title oxadiazole.

合成路线28

Condensation of phthalic anhydride (I) with 4-methylpyridine (II) and heating with NH2-NH2 hydrate yields phthalazine (III) which is converted into chloro derivative (IV) by directly heating in presence of POCl3 or alternatively by heating a solution of (IV) in CH3CN with HCl/dioxane and POCl3. Phthalazine (III) is added to a melt formed by 4-chloroaniline (V), P2O5 and Et3N.HCl to afford the desired product. Alternatively the final product is obtained by heating (V) with (IV) in EtOH or 1-butanol.

合成路线29

The D-(threo)-1-p-substituted-phenyl-2-dichloroacetamido-3-fluoro-1-propanol derivatives were prepared according to the following reaction sequence: The amino group of (I) was protected with phthalicanhydride (II), followed by substitution of the primary hydroxy group with diethylamine - sulfur-trifluoride to (III), deprotection with hydrazine to the amine (IV) and acetylation with methyldichloro-acetate (B) to the target compounds.

合成路线30

The reaction of cyanosafracin B (I) with Boc2O in ethanol gives the amino protected compound (II), which is treated with Mom-Br, DIEA and DMAP in acetonitrile yielding the O-protected compound (III). The demethylation of (III) with NaOH in methanol affords the hydroxyquinone (IV), which is reduced with H2 over Pd/C and cyclized with bromochloromethane and Cs2CO3 in hot DMF providing the methylenedioxy compound (V). The reaction of (V) with acetyl chloride and pyridine in dichloromethane gives the acetate (VI), which is treated with TFA, phenyl isothiocyanate and HCl yielding the primary amine (VII). Finally, this compound is treated with phthalic anhydride (VIII) and CDI in dichloromethane to afford the target phthalimide (phthalascidin Pt-650).

合成路线31

The starting product dibenzo[a,d]cyclohepta-1,4,6-triene-5-one (I) is prepared by condensation of phthalic anhydride (X) with phenylacetic acid (XI) by means of sodium acetate at 240 C that gives benzalphthalide (XII). This compound is reduced with red phosphorus in refluxing aqueous HI yielding 2-(2-phenylethyl)benzoic acid (XIII), which is then cyclized with polyphosphoric acid at 175 C afforing dibenzo[a,d]cyclohepta-1,4-diene-5-one (XIV). The ketone (XIV) is brominated with NBS in CCl4 to the bromo ketone (XV) and finally dehydrobrominated with triethylamine.

合成路线32

Ftalic anhydride (I) id treated with butyric anhydride (II) and sodium butyrate to obtain lactone (IV), which is hydrogenated to target compound by means H2 Nickel Raney.

合成路线33

The condensation between 2-chloro-4-nitroaniline (II) and phthalic anhydride (I) in refluxing acetic acid produced phthalimide (III). The nitro group was then reduced to the desired aniline by transfer hydrogenation employing cyclohexene in the presence of Pd/C.

合成路线34

Conversion of 4-hydroxy-L-proline (I) into the corresponding cis-N-Boc-4-hydroxy-L-proline methyl ester (II) is performed as follows: Treatment of (I) with SOCl2 in MeOH followed by reaction with Boc2O and Et3N in EtOAc affords the corresponding protected acid chloride; then the methyl ester moiety is formed under Mitsunobu conditions with formic acid, DIAD and PPh3 in THF followed by treatment with NaOH in MeOH. The OH group of (II) is converted into thioether (IV) by first mesylation with MsCl and Et3N in toluene followed by reaction with triphenylmethanethiol (III) in THF in the presence of NaH. Reduction of the methyl ester of (IV) with LiBH4 in THF provides alcohol (V), which is mesylated with MsCl and Et3N in THF and then treated with NaN3 and HMPA to furnish azide (VI). Boc removal in (VI) is performed by treatment with HCl in EtOAc to give derivative (VII), which is then converted into compound (VIII) by condensation with 2-(2,4-difluorobenzoyl)benzoic acid (XI) by means of water-soluble carbodiimide (WSC) and HOBt in DMF (compound (XI) can be obtained by Friedel-Crafts reaction between phthalic anhydride (IX) and 1,3-difluorobenzene (X) in the presence of AlCl3). Reduction of the azido moiety of (VIII) by means of SnCl2 and NaOH in EtOH furnishes amine (XII), which is finally converted into the desired product by condensation with carboxylic acid (XIII) by means of WSC and HOBt (derivative (XIII) can be obtained by Knoevenagel reaction between 4-formyl-benzoic acid (XIV) and 2,4-thiazolidinedione (XV) in refluxing 2-methoxyethanol in the presence of piperidine).

合成路线35

The condensation of phthalic anhydride (I) with aniline (II) in refluxing HOAc produced N-phenyl phthalimide (III). Aromatic sulfonation of (III) with chlorosulfonic acid in the presence of PCl5 afforded the sulfonyl chloride (IV). This was finally condensed with thiomorpholine (V) to furnish the target sulfonamide.

合成路线36

The primary amino group of 4-(aminomethyl)piperidine (I) was protected by conversion to the phthalimide (III) upon heating with phthalic anhydride (II). After coupling of piperidine (III) with 1-naphthylacetic acid (IV) to give amide (V), hydrazinolysis of the phthalimido group of (V) liberated the primary amine (VI). Alkylation of (VI) with N-(4-bromobutyl)phthalimide (VII) furnished the secondary amine (VIII), which was further protected with a tert-butoxycarbonyl group to provide (IX). The phthaloyl group of (IX) was then removed by hydrazinolysis, yielding amine (X). This was subjected to reductive alkylation with cyclohexanecarboxaldehyde (XI) in the presence of NaBH4 to afford the cyclohexylmethyl amine (XII). After purification as the di-Boc derivative, acid cleavage of the tert-butyl carbamate groups provided the title compound.

合成路线37

Treatment of beta-alanine (I) with phthalic anhydride (II) in refluxing toluene provides phthalimidopropionic acid (III), which upon cyclocondensation with 2-aminophenol (IV) in hot polyphosphoric acid provides the benzoxazole derivative (V). Hydrazinolysis of phthalimide (V) affords the primary amine (VI), which is finally condensed with pyrazole-1-carboxamidine hydrochloride (VII) in DMF to produce the target guanidine compound.

合成路线38

合成路线39

The intermediate N-(2-ethoxy-4-nitrophenyl)phthalimide (IV) is prepared by N-protection of 2-amino-5-nitrophenol (XVII) with phthalic anhydride (XVIII) in the presence of AcOH at 115-120 °C to give the corresponding phthalimide (XIX), which is then alkylated at the phenolic hydroxyl with ethyl bromide (XX) in the presence of K2CO3 in DMF .

合成路线40