合成路线1

A new synthesis of 13C- or 14C-labeled SKF-86466 has been described: The Friedel Craft's condensation of labeled benzene (I) with oxalyl chloride by means of AlCl3 in CS2 yields benzoic acid (II), which is chlorinated by means of cupric chloride and thallium (III) trifluoroacetate in trifluoroacetic acid to give 2-chlorobenzoic acid (III). The reduction of (III) by means of borane/THF complex in THF affords 2-chlorobenzyl alcohol (IV), which is treated with hot concentrated HCl to afford 2-chlorobenzyl chloride (V). The Grignard condensation of (V) with N-methyloxazolidine (VI) by means of Mg in ether gives N-[2-(2-chlorophenyl)ethyl]-N-methyl-2-hydroxyethylamine (VII), which is finally cyclized by treatment with PCl5 in hot trichlorobenzene followed by addition of AlCl3 and heating at 215-25 C.

合成路线2

Treatment of carboxy polystyrene resin (I) with oxalyl chloride in dichloromethane, followed by reaction with Bu4NNCS in THF/DCM, affords isothiocyanate resin (II), to which 2-amino-4,5-dimethoxybenzonitrile (III) is attached by means of NMP to provide derivative (IV). Treatment of resin (IV) with 1-(2-furoyl)-piperazine (V) and EDC in chloroform in the presence of DIEA furnishes resin-bound guanidine (VI), from which prazosin is obtained as its trifluoroacetic acid salt (VII) by acidolysis with TFA/H2O at 80 C. Finally, the hydrochloride salt of prazosin can be obtained by treatment with HCl.

合成路线3

The Grignard reaction of phenylmagnesium bromide (I) with 11C labeled CO2 (II) in THF gives the radiolabeled benzoic acid (III), which is treated with phthaloyl dichloride (IV) in the same solvent to yield radiolabeled benzoyl chloride (V). Finally, this compound is treated with N-debenzoylated paclitaxel (VI) in acetonitrile to afford the target radiolabeled paclitaxel.

合成路线4

The reaction of [benzene-U-13C]benzoic acid (I) with SOCl2 gives the corresponding acyl chloride (II), which is cyclized with the ethanolamine (III) to yield the oxazoline (IV).The chlorination of (IV) with sec-BuLi and hexachloroethane in toluene affords the 2-chlorophenyl derivative (V), which is methylated with MeI to provide the oxazolinium salt (VI). The reduction of (VI) with NaBH4 in ethanol yields the oxazolidine (VII), which is hydrolyzed with HCl to afford the labeled 2-chlorobenzaldehyde (VIII). The condensation of aldehyde (VIII) with the tetrahydrothienopyridine (IX) by means of acetone cyanohydrine in hot toluene affords the substituted acetonitrile (X), which is hydrolyzed to the substituted acetamide (XI) with HCl in methanol. Finally, this compound is treated with H2SO4 in refluxing methanol to afford the target labeled methyl ester as a racemic mixture.

合成路线5

The synthesis of baogongteng A has been published: The alkylation of 3-hydroxypyridine (I) with benzylbromide (II) gives 1-benzyl-3-hydropyridinium bromide (III), which is condensed with acrylonitrile (IV) by means of triethylamine at reflux temperature, yielding the bicyclic nitrile (V). The reduction of (V) with LiAlH4 gives the bicyclic hydroxy nitrile (VII), also obtained by stepwise reduction of (V) with H2 over Pd/C to (VI) and posterior reduction to (VII) with NaBH4. The protection of (VII) with trimethylsilyl chloride and triethylamine affords the silyloxy derivative (VIII), which is treated with methylmagnesium iodide to yield the acetyl derivative (IX). Oxidation of (IX) with m-chloroperbenzoic acid (MCPBA) in CHCl3 affords the acetoxy compound (X), which is finally debenzylated by hydrogenation with H2 and Pd/C in ethanol to give the free base (XI). This is then treated with benzoic acid.

合成路线6

The synthesis of ring labeled [14C]-atorvastatin has been described: The Grignard reaction of phenylmagnesium chloride (I) with [14C]-labeled CO2 (II) in THF/ethyl ether gives the benzoic acid (III), which is reduced with LiAlH4 in ethyl ether to the benzyl alcohol (IV). The oxidation of (IV) with pyridinium dichromate affords the benzaldehyde (V), which is condensed with the isobutyrylacetamide (VI) by means of beta-alanine in acetic acid yielding a mixture of the cis- and trans-benzylidene derivatives (VII). The condensation of (VII) with 4-fluorobenzaldehyde (VIII) by means of triethylamine and a thiazolium bromide catalyst affords the 1,4-dione (IX), which is cyclized with the chiral amino ester (X) in hot heptane/toluene/THF providing the protected pyrroloheptanoic ester (XI). The deprotection of (XI) in acidic medium, followed by the hydrolysis of the ester group with NaOH affords the sodium salt (XII), which is finally treated with calcium acetate in THF/water.

合成路线7

1) The iodination of 4-(1,2,4-triazol-1-ylmethyl)aniline (I) with ICl and CaCO3 in methanol/water gives the 2-iodoaniline (II), which is cyclized with 1-(triethylsilyl)-4-(triethylsilyloxy)-1-butyne (III) by means of paladium acetate and Na2CO3 in hot DMF yielding 5-(1,2,4-triazol-1-ylmethyl)-3-[2-(triethylsilyloxy)ethyl]-1H-indole (IV). The desilylation of (IV) with HCl in methanol affords the corresponding alcohol (V), which is condensed with dimethylamine by means of methanesulfonyl chloride and triethylamine to give MK-0462 free base (VI). Finally, this compound is treated with benzoic acid in isopropyl alcohol/isopropyl acetate solution.

合成路线8

The reaction of bromobenzene (I) with 14CO2 by means of Mg in ether gives the corresponding benzoic acid (II), which is treated with SOCl2 and DMAP to yield the benzoyl chloride (III). The homologation of (III) with diazomethane in ether affords the phenacyl chloride (IV), which is enantioselectively reduced with borane and a chiral borolidine catalyst in THF to give (R)-2-chloro-1-phenylethanol (V). The cyclization of (V) by means of NaOH in ethyl ether yields the oxirane (VI), which by reaction with ammonia is converted into the (R)-2-amino-1-phenylethanol (VII). The condensation of (VII) with 4'-chlorobiphenyl-4-carboxylic acid (VIII) by means of CDI in DMF provides the amide (IX), which is cyclized to the oxazoline (X) by means of methanesulfonic anhydride and TEA in THF. Finally, this compound is condensed with imidazole (XI) by heating at 125 C.

合成路线9

YM-905 has been obtained by two related ways: 1) The benzoylation of 2-phenylethylamine (I) with benzoyl chloride (II) and triethylamine in chloroform, or with benzoic acid (III), DPPA and triethylamine in DMF, gives the corresponding benzamide (IV), which is cyclized by means of POCl3 and P2O5 in refluxing xylene and reduced with NaBH4 in ethanol, yielding racemic 1-phenyl-1,2,3,4-tetrahydroisoquinoline (V). The reaction of (V) with ethyl chloroformate by means of K2CO3 in chloroform affords racemic 1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid ethyl ester (VI), which is transesterified with quinuclidine-3(R)-ol (VII) by means of NaH in refluxing toluene to provide the quinuclidinyl ester (VIII) as a diastereomeric mixture. This mixture is resolved by chiral HPLC, giving the target compound as a pure enantiomer. 2) The racemic 1-phenyl-1,2,3,4-tetrahydroisoquinoline (V) can also be submitted to optical resolution with (+)-tartaric acid to give 1(S)-phenyl-1,2,3,4-tetrahydroisoquinoline (IX), which is condensed with ethyl chloroformate by means of K2CO3 in chloroform to afford 1(S)-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid ethyl ester (VI). This compound is transesterified with quinuclidine-3(R)-ol (VII) by means of NaH in refluxing toluene to directly provide the pure enantiomer.

合成路线10

The reaction of the chiral hydroxyaldehyde (I) with the phenyllithium derivative (II) gives the condensation product (III), which is protected with methylboronic acid yielding the cyclic boronate (IV). The cyclization of (IV) by means of TiCl4 followed by a treatment with HF affords the tricyclic tetrol (V), which is finally selectively benzoylated with benzoic acid and DCC to give the target monobenzoate.

合成路线11

The title compound is prepared by two alternative methods. Sulfonation of benzoic acid (I) with hot chlorosulfonic acid affords 3-carboxybenzenesulfonyl chloride (II). After conversion of (II) to the pyridine complex, coupling with prednisolone (III) produces the target 21-sulfobenzoate ester, which is finally isolated as the title sodium salt by treatment with aqueous NaOH.

合成路线12

2) Propiophenone derivative (XXV) - prepared according to a procedure similar to that described for compound (XIX) - is subjected to a Grignard reaction with (chloromethyl)trimethylsilane (XXVI) and Mg in ether to give the silyl alcohol (XXVII), which by treatment with p-toluenesulfonic acid in MeOH undergoes b-elimination and deprotection to yield the allylic alcohol (XXVIII). Epoxidation of (XXVIII) with tert-butyl hydroperoxide and catalytic oxyvanadium acetylacetonate gives the epoxy-alcohol (XXIX), which is subjected to a Mitsunobu reaction with benzoic acid (XXX) by means of DEAD and PPh3 in THF to provide benzoate (XXXI). Solvolysis of compound (XXXI) in MeOH with catalytic NaOMe yields the epoxyalcohol (XXXII), which is mesylated with methanesulfonyl chloride and triethylamine in CH2Cl2 to afford the protected alcohol (XXXIII). Finally, treatment of compound (XXXIII) with 1H-1,2,4-triazole (XXIV) and NaH in DMF affords the desired intermediate (IX).

合成路线13