合成路线1

Antineopleston A10 (A10) can be obtained by two different ways: 1) A10 has been synthesized in two steps: Condensation of phenylacetic acid (I) with L-glutamine (V) to give phenylacetyl-L-glutamine (VI), followed by intramolecular cyclization of the latter. In the first step (I) is activated by reacting with various reagents such as HOSu (N-hydroxysuccinimide) (II) in the presence of DCC, DCC (N,N-dicyclohexylcarbodiimide) or 2-mercaptothiazoline (III) in the presence of DCC to afford the intermediates (IVa), (IVb) and (IVc), respectively. Without isolation, the intermediate (IVa), (IVb) or (IVc) is treated with a solution of L-glutamine in CH3CN:H2O (2:1) containing NaHCO3 to give (VI) in 60, 87 and 82% yields, respectively. In the second step (VI) is converted to the activated intermediate (IXa) or (IXb) by treatment with CDI (1,1'-carbonydiimidazole) (VII) or HOSu (VIII) in the presence of DCC. Finally, intramolecular cyclization of (IXa) or (IXb) is effected by treating the latter at 80 C to yield A10 in 85 or 82% yield, respectively. 2) Reaction of phenylacetyl chloride with L-glutamine in aqueous solution containing NaHCO3 affords phenylacetyl-L-glutamine (VI), which is heated at 160 C to give A10.

合成路线2

Antineoplaston AS2-5 (AS2-5) can be obtained in the following way (1,2): N-Phenylacetyl-L-glutamine sodium is synthesized in two steps. In the first step, phenylacetic acid (I) is treated with N-hydroxysuccinimide (B) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (A) in acetonitrile to give intermediate (Ia). In the second step, (Ia) is reacted without purification with L-glutamine (II) in the presence of NaHCO3 in 1:1 acetonitrile-water mixture to afford N-phenylacetyl-L-glutamine (III) in 87% yield. Compound (III) is then converted to sodium salt in aqueous solution by treatment with aqueous sodium hydroxide solution (pH 7). In a large scale preparation reaction of phenylacetyl chloride with L-glutamine in aqueous solution containing NaHCO3 affords N-phenyiacetyl L-glutamine sodium.

合成路线3

The alkylation of 2-phenylacetic acid (I) with 2-chloroethyl(methyl)sulfide (II) by means of lithium diisopropylamide (LDA) in THF gives 4-(methylsulfanyl)-2-phenylbutyric acid (III), which is esterified with methanol/H2SO4 yielding the methyl ester (IV). The transesterification of (IV) with quinuclidin-3(R)-ol (V) by means of NaH in refluxing toluene affords the 3(R)-quinuclidinyl ester (VI), which is hydroxymethylated with paraformaldehyde and NaH in DMF giving 2(RS)-(hydroxymethyl)-4-(methylsulfanyl)-2-phenylbutyric acid 3(R)-quinuclidinyl ester (VII) as a diastereomeric mixture. Chromatographic separation of (VII) over SiO2 using CHCl3/methanol/NH4OH as a gradient elution yields the 2(S)-hydroxymethyl isomer (VIII), which is oxidized with trifluoroperacetic acid in trifluoroacetic acid affording the corresponding sulfinyl derivative (IX) as a new diastereomeric mixture. Finally, this mixture is resolved by HPLC over Kromasil C-8 SiO2 using as eluant water/acetonitrile containing 1% trifluoroacetic acid.

合成路线4

The synthesis of rofecoxib can be performed by several different ways: 1) The condensation of phenylacetic acid (I) with ethyl bromoacetate (II) by means of triethylamine in THF yields 2-(phenylacetoxy)acetic acid ethyl ester (III), which is cyclized to the hydroxyfuranone (IV) by means of potassium tert-butoxide in tert-butanol. The reaction of (IV) with triflic anhydride and diisopropylethylamine in dichloro-methane affords the corresponding triflate (V), which by reaction with LiBr in hot acetone yields the bromofuranone (VI). The condensation of (VI) with 4-(methylsulfanyl)phenylboronic acid (VII) by means of Na2CO3 and Pd(Ph3P)4 in hot toluene gives 4-[4-(methylsulfanyl)-phenyl]-3-phenylfuran-2(5H)-one (VIII), which is finally oxidized with 2KHSO5.KHSO4.K2SO4 (oxone). 2) The intermediate (VIII) can also be obtained by condensation of triflate (V) with boronic acid (VII) by means of Na2CO3 and Pd(Ph3P)4 in hot toluene. 3) The intermediate (VIII) can also be synthesized by the reaction of triflate (V) with tetramethylammonium chloride, giving the chlorofuranone (IX), which is then condensed with boronic acid (VII) as before.

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4) The oxidation of 4-(methylsulfanyl)acetophenone (X) with monoperoxyphthalic acid (MMPP) in dichloro-methane/methanol gives the corresponding sulfone (XI), which is brominated with Br2/AlCl3 in chloroform, yielding the expected phenacyl bromide (XII). Finally, this compound is cyclocondensed with phenylacetic acid (I) by means of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and triethylamine in acetonitrile. 5) Reaction of [4-(methylsulfonyl)phenyl]phenylacetyl-ene (XIII) with CO catalyzed by Rh4(CO)12 in THF at 100 C in a stainless steel autoclave at 100 Atm pressure, followed by a chromatographic separation in a silicagel column to eliminate the undesired regioisomer.

合成路线6

The Friedel Crafts acylation of thioanisole (I) with acetyl chloride (II) and AlCl3 in chloroform gives 4-(methylsulfanyl)acetophenone (III), which is oxidized with monoperoxyphthalic acid (MMPP) in methanol/dichloromethane to yield 4-(methylsulfonyl)acetophenone (IV). The bromination of (IV) with Br2 and AlCl3 in chloroform affords 4-(methylsulfonyl)phenacyl bromide (V), which is finally cyclized by means of DBU and TEA in acetonitrile to provide the target furanone derivative.

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Condensation of phenylacetic acid (XI) with methoxyamine gave hydroxamate (XII). After N-chlorination of (XII) with tert-butyl hypochlorite, Ag(I)-catalyzed ring closure of the intermediate (XIII) produced N-(methoxy)oxindole (XIV). Amide reduction of (XIV) with LiAlH4 gave hemiaminal (XV), which was converted to the racemic tryptophan derivative (XVII) by reaction with alpha-acetamidoacrylic acid (XVI) in AcOH-Ac2O. Optical resolution of (XVII) by enantioselective enzymatic hydrolysis of the acetamide group using Acylase I from Aspergillus sp. afforded N1'-methoxy-L-tryptophan (XVIII), which was protected as the N-Boc derivative (XIX) and N-methylated by means of MeI and NaH yielding (XX). The resulting N-methyl amino acid (XX) was esterified upon treatment with (trimethylsilyl)diazomethane giving (XXI), and the N-Boc group was removed with HCl in EtOAc to provide the tryptophan derivative (XXII).

合成路线8

Coumarin (III) was prepared by condensation of benzophenone (I) with phenylacetic acid (II) in the presence of Ac2O and Et3N. Reduction of the lactone function of (III) with LiAlH4, followed by acidic treatment furnished diaryl chromene (IV). Subsequent hydrogenation of (IV) over Pd/C gave rise to the racemic cis chromane (V), which was O-alkylated with 1-(2-chloroethyl) pyrrolidine (VI) producing the corresponding (pyrrolidinyl)ethoxy derivative. Resolution by means of active ditoluoyl tartaric acid yielded the desired (-)-enantiomer (VII). Finally, cleavage of the methoxy group using pyridine hydrochloride at 150 C provided the title compound.

合成路线9

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10

Alkylation of phenylacetic acid (VII) with allyl bromide (VIII) using lithium bis(trimethylsilyl)amide furnished 2-phenyl-4-pentenoic acid (IX). Reduction of the carboxylate group of (IX) by means of LiAlH4 and AlCl3 gave rise to alcohol (X), which was subsequently converted to triflate (XI). The triflate group of (XI) was then displaced with benzimidazole (XII) to produce adduct (XIII). Dihydroxylation of the double bond of (XIII) with N-methylmorpholine-N-oxide in the presence of OsO4, followed by oxidative cleavage with NaIO4, yielded aldehyde (XIV). Finally, aldehyde (XIV) was reductively condensed with piperidine (VI) in the presence of sodium triacetoxyborohydride.

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