合成路线1

The reaction of pregnenolone (I) with I2 and pyridine at 90 C gives (3beta-hydroxypregn-5-en-20-one-21-yl)pyridinium iodide (II), which by treatment with sodium methoxide in refluxing methanol is converted into methyl 5-androsten-3beta-ol-17beta-carboxylate (III). The Meerwein-Poundorf oxidation of (III) with cyclohexanone (A) and aluminum isopropoxide in refluxing toluene yields methyl 4-androsten-3-one-17beta-carboxylate (IV), which is hydrolyzed with KOH in refluxing methanol - water to the corresponding free acid (3-oxo-4-etienic acid) (V). The reaction of (V) with oxalyl chloride (B) and diethylamine in refluxing toluene affords 17beta-(N,N-diethylcarbamoyl)-4-androstene-3-one (VI), which is oxidized with O3 or with NaIO4 and KMnO4 giving 17beta-(N,N-diethylcarbamoyl)-5-oxo-3,5-secoandrostan-3-oic acid (VII). The cyclization of (VII) with methylamine ethylene glycol at 180 C in a pressure vessel affords 17beta-(N,N-diethylcarbamoyl)-4-methyl-4-aza-5-androsten-3-one (VIII), which is finally reduced with H2 over Pt in acetic acid. The cyclization of the acid (VII) with NH3 in ethanol at 180 C in a pressure vessel gives 17beta-(N,N-diethylcarbamoyl)-4-aza-5-androsten-3-one (IX), which is reduced with H2 over Pt in acetic acid yielding 17beta-(N,N-diethylcarbamoyl)-4-aza-5alpha-androstan-3-one (X). Finally, this compound is methylated with CH3I by means of NaH in toluene.

合成路线2

The oxidation of 3-oxo-4-etienic acid (V) with NaIO4 and KMnO4 in tert-butanol - water gives 5-oxo-3,5-secoandrostane-3,17beta-dioic acid (XI), which is cyclized with methylamine in ethanol at 180 C in a pressure vessel yielding 17beta-carboxy-4-methyl-4-aza-5-androsten-3-one (XII). The hydrogenation of (XII) with H2 over Pt in acetic acid affords 17beta-carboxy-4-methyl-4-azaandrostan-3-one (XIII), which is finally treated with oxalyl chloride (B) and diethylamine in toluene-THF. The amidation of (XIII) with oxalyl chloride (B) and NH3 in toluene-THF gives 17beta-carboxamide-4-methyl-4-azaandrostanone (XIV), which is alkylated with ethyl bromide and NaH in toluene. The amidation of (XIII) with ethylamine and oxalyl chloride (B) in toluene-THF gives 17beta-(N-ethylcarbamoyl)-4-methyl-4-azaandrostan-3-one (XV), which is finally alkylated with ethyl bromide and NaH in toluene.

合成路线3

The diazotation of 2,3-dichloroaniline (IX) with NaNO2 and HCl gives the corresponding diazonium chloride (X), which by a Sandmeyer reaction with CuCN yields 2,3-dichlorophenyl cyanide (XI). The Grignard reaction of (XI) with methylmagnesium bromide (A) in ether affords 2,3-dichloroacetophenone (XII), which by a Willgerodt reaction with S and morpholine is converted into 2,3-dichlorophenylacetic acid (XIII). The reaction of (XIII) with oxalyl chloride (B) in carbon tetrachloride affords the corresponding acyl chloride (XIV), which is cyclized with ethylene (C) by means of AlCl3 in methylene chloride yielding 7,8-dichloro-2-tetralone (XV). The reaction of (XV) with sodium azide in CHCl3 by means of H2SO4 gives 8,9-dichloro-2-benzazepin-3-one (XVI), which is finally reduced with diborane in THF.

合成路线4

The acid chloride (II) of isonicotinic acid is prepared by reaction of oxalyl chloride (A) with the potassium salt of isonicotinic acid (I). The acylation of 1,3-dihydro-4-ethyl-2H-imidazol-2-one (III) with acid chloride (II) under Friedel-Crafts' conditions gives 1,3-dihydro-4-isonicotinoyl-5-ethyl-2H-imidazol-2-one.

合成路线5

The decarboxylative hydrolysis of 2,4-dimethoxycarbonyl-3-(3-phenylpropyl)cyclopentanone (XIV) with HCl in acetic acid gives 4-carboxy-3-(3-phenylpropyl)cyclopentanone (XV), which by reaction with oxalyl chloride (B) is converted into the corresponding acyl chloride (XVI). The Arndt-Eistert carbon homologation in (XVI) with diazomethane and silver benzoate (C) in methanol affords 4-(methoxycarbonylmethyl)-4-(3-phenylpropyl)cyclopentanone (XVIIa), which is dehydrogenated by the sequence of reactions: N-bromosuccinimide and sodium selenofenolate (D) [to obtain intermediates (XVIIb) and (XVIIc), respectively], followed by reaction with hydrogen peroxide to give 4-(methoxycarbonylmethyl)-3-(3-phenylallyl)cyclopentanone (XVIIIa). Oxidation of (XVIIIa) first with osmium tetroxide and then with Jones reagent (CrO3) [to obtain intermediates (XVIIIb) and (XVIIIc), respectively], followed by methylation of (XVIIIc) with CH2N2 affords 3,4-di(methoxycarbonylmethyl)cyclopentanone (XIX), which is ketalized in the usual way to the ketal (XX). Finally, this compound is submitted to a Dieckmann condensation with sodium methoxide in DMS to yield the protected ketoester (IVa), the methyl ester analogue of the compound (IV) obtained in scheme 09083302a. This compound can then be used instead of (IV) in scheme 09083302a.

合成路线6

The synthesis of EO 122 starts from quinuclidine-3-carboxylic acid (I), which is converted to the acid chloride (II) by oxalyl chloride. The addition of 2,6-dimethylaniline (III) to the acid chloride yields EO-122.

合成路线7

The reaction of p-chlorobenzaldehyde (I) sodium cyanide and ethyl acetate gives ethyl 4-(p-chlorophenyl)-4-oxobutyrate (II), which is hydrolyzed with KOH to the corresponding free acid (III). The reduction of (III) with Zn and aqueous HCl affords 4-(p-chlorophenyl)butyric acid (IV), which is condensed with heptylamine (B) by means of oxalyl chloride (A) in refluxing benzene to yield N-heptyl-4-(p-chlorophenyl)butyramide (V), which is reduced with diborane in refluxing THF to afford N-heptyl-4-(p-chlorophenyl)butylamine (VI). The acetylation of (VI) with acetyl chloride (C) by means of Na2CO3 in acetone gives N-acetyl-N-heptyl-4-(p-chlorophenyl)butylamine (VII), which is reduced with diborane as before to yield N-ethyl-N-heptyl-4-(p-chlorophenyl)butylamine (VIII). The quaternization of (VIII) with refluxing ethyl bromide (D) gives N,N-diethyl-N-heptyl-4-(p-chlorophenyl)butylammonium bromide (IX), which by elution through a column with Dowex 1-X8, hydroxide form, resin is converted into N,N-diethyl-N-heptyl-4-(p-chlorophenyl)butyl ammonium hydroxide (X). Finally, this compound is salified with diluted aqueous phosphoric acid.

合成路线8

The cyctization of 4-chloro-2-(propylamino)aniline (I) with oxalyl chloride (II) in hot o-dichlorobenzene gives 1-propyl-7-chloroquinoxaline-2,3-dione (III), which by reaction with SOCl2 in DMF is converted to 3,7-dichloro-1-propyl-1H-quinoxalin-2-one (IV). The condensation of (IV) with ethyl carbazate (V) in refluxing acetonitrile affords ethyl 3-(7-chloro-1-propyl-2-oxo-1H-quinoxalin-3-yl)carbazate (VI), which is finally cyclized by heating at 260 C.

合成路线9

The cyclization of diethyl malonate (I) with cis-1,4-dichloro-2-butene (II) by means of LiH in DMF gives 3-cyclopentene-1,1-dicarboxylic acid diethyl ester (III), which is monodecarboxylated by hydrolysis with NaOH in ethanol, followed by heating at 170-180 C to yield 3-cyclopentene-1-carboxylic acid (IV). The reaction of (IV) with SOCl2 affords the acyl chloride (V), which by reaction with ethanol provides the ethyl ester (VI). The oxidation of (VI) with OsO4 and N-methylmorpholine N-oxide (NMMO) in acetone/water gives the dihydroxy compound (VII), which is further oxidized with NaIO4 in THF to yield the dialdehyde (VIII). The cyclization of (VIII) by means of glycine ethyl ester and acetonedicarboxylic acid affords the 9-azabicyclo[3,3,1]nonan-3-one derivative (IX), which is reduced with NaBH4 in ethanol to provide the corresponding alcohol (X). The protection of the OH group of (X) with dihydropyran and methanesulfonic acid gives the tetrahydropyranyl ether (XI), which is cyclized by means of tBuO-K in hot toluene, yielding the tricyclic ketone (XII). The deprotection of (XII) with 5N HCl affords the alcohol (XIII), which is finally esterified with 1H-indole-3-carbonyl chloride (XIV) by means of tetrafluoroboric acid and silver tetrafluoroborate in nitroethane. Alternatively, 1H-indole (XV) is condensed with oxalyl chloride (XVI) to give 3-indolylglyoxylyl chloride (XVII), which is used to acylate the alcohol (XIII) by means of tetrafluoroboric acid and silver tetrafluoroborate as before. Simultaneous decarbonylation takes place in this acylation reaction.

合成路线10

Treatment of 4-(chloromethyl)-5-methyl-1,3-dioxol-2-one (XXII) with potassium formate (XXIII) by means of KI and NaHCO3 in DMF affords the formyloxymethyl derivative (XXIV), which is converted into the hydroxymethyl derivative (XXV) by refluxing in MeOH. Coupling of compound (XXV) with oxalyl chloride (XXVI) in dichloromethane furnishes compound (XXVII), which is then condensed with protected azetidinone (VI) by means of Et3N in dichloromethane to yield compound (XXVIII). Intramolecular Wittig cyclization of compound (XXVIII) by means of triethyl phosphite in refluxing xylene provides the silylated faropenem daloxate (XXIX), which is finally deprotected by means of either Et3N tris(hydrogen fluoride) in ethyl acetate or tetrabutylammonium fluoride (TBAF) and AcOH in THF.

合成路线11

The acylation of 2-(4-chlorophenyl)ethylamine (I) with Ac2O in toluene gives the acetamide (II), which is cyclized with oxalyl chloride (III) in dichloromethane to yield the oxazolidinedione (IV). The cyclization of (IV) by means of FeCl3 in dichloromethane affords the oxazolo-isoquinoline (V), which is hydrolyzed with hot H2SO4 in methanol or AcOH to provide 7-chloro-1-methyl-3,4-dihydroisoquinoline (VI). The cyclization of (VI) with 3-(dimethylamino)-2-phenylacrylic acid ethyl ester (VII) in hot AcOH gives the benzoquinolizine (VIII), which is brominated with NBS in hot AcOH to yield the 1-bromo compound (IX). Finally, this compound is condensed with 3(S)-ethoxypyrrolidine (XIII) and carbon monoxide by means of Pd(OAc)2 dppp in hot acetonitrile to furnish the target acyl pyrrolidine compound. Alternatively, bromocompound (IX) is condensed with CO by means of Pd(OAc)2 dppp in hot DMSO to give the carboxylic acid (XI), which is treated with oxalyl chloride and DMAP in hot ethyl acetate to yield the corresponding acyl chloride (XII). Finally, this compound is condensed with 3(S)-ethoxypyrrolidine (XIII) by means of TEA in toluene. In a further method, the bromocompound (IX) is condensed with CO by means of Pd(OAc)2 dppp in hot methanol to yield the methyl ester (X), which is hydrolyzed with KOH in methanol/water to the already reported carboxylic acid (XI). A third method is also reported: The condensation of carboxylic acid (XI) with 3(S)-hydroxypyrrolidine (XIV) by means of NMM and HBTU in DMF gives the corresponding acyl pyrrolidine (XV), which is finally alkylated with ethyl iodide and KOH in DMF. The intermediate 3-(dimethylamino)-2-phenylacrylic acid ethyl ester (VII) has been obtained by condensation of 2-phenylacetic acid ethyl ester (XVI) with dimethylformamide diethylacetal (XVII) at 150 C.

合成路线12

The cyclization of 4-chloro-3,3-dimethylbutyronitrile (I) with benzylmagnesium chloride (II) in ethyl ether containing some iodine gives 2-benzyl-4,4-dimethyl-1-pyrroline (III), which is cyclized with 4'-chlorophenacyl bromide (IV) by means of NaHCO3 in methanol, yielding 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro.1H-pyrrolizine (V). The condensation of (V) with oxalyl chloride (VI) in THF affords 2-[6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl]-2-oxoacetyl chloride (VII), which is finally reduced and hydrolyzed with hydrazine in hot diethyleneglycol to provide the target licofelone.

合成路线13

Condensation of 2-(4-methylphenyl)ethanol (I) with t-Bu-bromoacetate (II) in toluene in the presence of NaOH and tetrabutylammonium bromide (TBAB) provides ethoxyacetic acid derivative (III), which is converted into acetamide (V) by reaction with oxalyl chloride (IV) in toluene/DMF followed by treatment with NH4OH. Reduction of (V) by reaction with borane-tetrahydrofuran (BH3·THF) in THF yields ethanamine (VI), which is then coupled to chlorosulfonyl derivative (VII) in CH2Cl2 in the presence of TEA to afford compound (VIII). Reduction of the ester group of (VIII) by treatment with diisobutylaluminium hydride (DIBAL) in toluene furnishes aldehyde (IX), which is finally subjected to a reductive amination with benzothiazol derivative (X) by means of NaCNBH3 in MeOH/HOAc.

合成路线14

A new strategy for the synthesis of a key intermediate in the preparation of LY-333531 has been described: Condensation of indole (I) with the tosylate (II) by means of NaH in DMF gives 4-(1-indolyl)butane-1,2-diol (III), which is monotritylated with trityl bromide yielding ether (IV). Alkylation of compound (IV) with tert-butyl bromoacetate (V) and NaH in THF affords the hydroxyacetic derivative (VI), which is reduced with LiBH4 in THF/EtOH to provide the carbinol (VII). Reaction of compound (VII) with Ms2O and pyridine in THF gives the mesylate (VIII), which is condensed with oxalyl chloride (IX) in ethyl ether to yield the oxoacetyl chloride (X). The alcoholysis of (X) with NaOMe in methanol affords the oxoacetate (XI), which is finally cyclized with 2-(3-indolyl)acetamide (XII) by means of NaH in DMF to provide the target intermediate (XIII).

合成路线15

The intermediate N-Boc-amino acid (VII) was synthesized as shown in Scheme 25409101a. Treatment of 3-(tert-butoxycarbonylamino)-3-methylbutanoic acid (I) with ethyl chloroformate and Et3N, followed by reduction of the resulting mixed anhydride (II) with LiBH4, provided alcohol (III). Then, oxidation of (III) under Swern conditions yielded aldehyde (IV). Subsequent Horner-Emmons condensation of (IV) with triethyl phosphonoacetate (V) in the presence of potassium tert-butoxide gave ester (VI), which was saponified with LiOH to provide the required carboxylic acid (VII).

合成路线16

Condensation between 5-bromoindole (I) in ether and oxalyl chloride (II) in dichloromethane followed by treatment with dimethylamine provides N,N-dimethyaminoglyoxyl derivative (III), which is then reduced with LiAlH4 in THF to yield compound (IV). Coupling of (IV) with benzoyl chloride (V) by means of Et3N and DMAP in dichloromethane affords benzoylindole derivative (VI), which is then subjected to reaction with tributylstannyl derivative (VII) in toluene in the presence of Pd(PPh3)4 to furnish compound (VIII). Treatment of (VIII) with NaOH in refluxing MeOH gives indole (IX), which is converted into the final product by reduction with LiAlH4 in refluxing THF) and treatment with HCl for the formation of the corresponding hydrochloride salt. Alternatively, the target compound can be obtained as follows: treatment of (IV) with KH in ether and tert-butyllithium in pentane followed by reaction with N-methylpiperidinone (X) affords hydroxy derivative (XI), which is finally converted into the desired product.

合成路线17

Condensation of 2-formylcycloheptanone (I) with ethyl 3-aminocrotonate (II) provides ethyl carboxylate (III), which is then converted into carbonylguanidine (VI) by reaction with free guanidine (V) (obtained from guanidine hydrochloride (IV) by treatment with Na/MeOH) in refluxing isopropanol. Alternatively, carbonylguanidine (VI) can also be obtained by saponification of ethyl ester (III) with refluxing NaOH to yield carboxylic acid (VII), which is then activated with oxalyl chloride (A) in CH2Cl2 or with CDI in THF to allow condensation with guanidine (V) in THF. Finally, the corresponding maleate can be obtained by reaction of carbonylguanidine (VI) with maleic acid (VIII) in MeOH.

合成路线18

6-Nitroindole (I) was methylated using iodomethane and NaH and the resulting 1-methyl-6-nitroindole (II) was acylated with oxalyl chloride in dichloromethane to furnish the glyoxylyl chloride (III). Subsequent condensation of (III) with 1-methylindole-3-acetic acid (IV) in the presence of Et3N gave the bisindolylmaleic anhydride (V). This was finally converted into the target maleimide by heating with ammonia in aqueous DMF in a sealed vessel at 140 C.

合成路线19

This compound has been obtained by two similar ways: The condensation of 6-iodo-1-methyl-1H-indole (I) with imidazole (II) by means of copper trifluoromethanesulfonate, 1,10-phenanthroline, Cs2CO3 and dibenzylideneacetone gives 6-(1-imidazolyl)-1-methyl-1H-indole (III), which is condensed with oxalyl chloride (IV) in dichloromethane to yield the adduct (V). Finally, this compound is cyclized with 2-(1-methyl-1H-indol-3-yl)acetimidic acid isopropyl ester (VI) by means of TEA in dichloromethane to afford the target pyrrolinedione. Alternatively, indole (I) and imidazole (II) are condensed by means of Pd2(dba)3, BINAP and tBu-ONa to give 6-(1-imidazolyl)-1-methyl-1H-indole (III), which is condensed with methoxalyl chloride (VII) in dichloromethane to yield the adduct (VIII). The reduction of (VIII) with NaH2PO2 affords the methyl acetate derivative (IX), which is treated with NH4OH to provide the acetamide derivative (X). Finally, this compound is cyclized with the methoxalyl derivative (XI) (obtained by condensation of 1-methyl-1H-indole (XII) with methoxalyl chloride (VII)) by means of tBu-ONa in THF to afford the target pyrrolinedione.

合成路线20

Condensation of oxalyl chloride (XI) with N,O-dimethylhydroxylamine produces N,N'-dimethyl-N,N'-dimethoxy oxamide (XII). This is then condensed with cyclobutylmethylmagnesium bromide (XIII) to afford the ketoamide (XIV). Asymmetric keto group reduction employing (R)-alpine borane leads to the (S)-alcohol (XV) in 91% enantiomeric excess. Hydrolysis of the N-methoxyamide function of (XV) to provide hydroxyacid (XVI) is then accomplished employing potassium tert-butoxide in the presence of the equimolecular amount of H2O in THF. Alkylation of hydroxyacid (XVI) with benzyl bromide and Et3N furnishes the corresponding benzyl ester (XVII). Treatment of (XVII) with trifluoromethanesulfonic anhydride gives rise to triflate (XVIII), which is further condensed with pyrrolidine (X) to produce (XIX). After desilylation of (XIX) with tetrabutylammonium fluoride, the resultant alcohol (XX) is oxidized to aldehyde (XXI) under Swern conditions.

合成路线21