合成路线1

The cyclization of trifluoroacetylmethylpyridinium bromide (I) with 3-(4-trifluoromethylbenzoyl)acrylic acid (II) by means of ammonium acetate in refluxing methanol gives 2-trifluoromethyl-6-(4-trifluoromethylphenyl)isonicotinic acid (III), which by condensation with 2-bromopyridine (IV) by means of butyllithium in ethyl ether yields 2-trifluoromethyl-6-(4-trifluoromethylphenyl)4-pyridyl-2'-pyridyl ketone (V). Finally, this compound is reduced with H2 over Pt in aqueous concentrated HCl. The starting products are prepared as follows: 1) The acrylic acid (II) is obtained by condensation of maleic anhydride (VI) with 4-trifluoromethylphenylmagnesium bromide (VII) by means of ZnCl2 in refluxing ethyl ether. An alternative method is the condensation of 4-trifluoromethylacetophenone (VIII) with glyoxylic acid (IX) by means of triethylamine at 135 C. 2) The pyridinium salt (I) is prepared by bromination of 1,1,1-trifluoroacetone (X) giving 1,1,1-trifluoro-3-bromoacetone (XI), which is then condensed with pyridine.

合成路线2

The reaction of gamma-chlorobutyrophenone (I) with ethylene glycol (II) by means of p-toluenesulfonic acid in refluxing benzene gives the corresponding ethylene ketal (III), which is condensed with cis-2,6-dimethylpiperidine (IV) by means of Na and heat, and hydrolyzed with concentrated HCl yielding gamma-(cis-2,6-dimethyl-1-piperidyl)butyrophenone (V). Finally, this compound is condensed with 2-bromopyridine (VI) by means of butyllithium in THF.

合成路线3

The condensation of 7-amino-3-bromomethyl-3-cephem-4-carboxylic acid tert-butyl ester 1-oxide (I) with 2-(2-tritylamino-4-thiazolyl)-2-[2-(tert-butoxycarbonyl)-2-propyloxyimino]acetic acid (II) by means of dicyclohexylcarbodiimide in CH2Cl2 gives the corresponding amide (III), which is treated with N-allyl-pyridine-2-thione (IV) in dimethylacetamide yielding the pyridinium salt (V). Finally, this compound is deprotected by a treatment with HCl in formic acid. The thione (IV) is prepared as follows: The reaction of 2-bromopyridine (VI) with allyl bromide (VII) in acetone gives N-allyl-2-bromopyridinium bromide (VIII), which is then treated with potassium hydrosulfide in water.

合成路线4

The reduction of 1-(1-piperdinyl)acetone oxime (I) with LiAlH4 in ethyl ether, THF or dioxan gives 1-methyl2-(1-piperidinyl)ethylaine (II), which is acylated with propionyl chloride (III) in ether to afford propionamide (IV). The condensation of (IV) with 2-bromopyridine (V) by heating with K2CO3 and Cu (dust) provides compound (VI). Alternatively, (VI) can be obtained by heating N-[1-methyl-2-(1-piperidinyl)ethyl]-N-(2-pyridyl)amine (VII) with propionic anhydride (VIII). Finally, heating derivative (VI) with fumaric acid in acetone/EtOH allows formation of the desired compound as the corresponding fumarate salt.

合成路线5

The intermediate carbazate (VI) has been obtained as follows. The condensation of phenylboronic acid (I) with 2-bromopyridine (II) by means of Pd(PPh3)4 gives 4-(2-pyridyl)benzaldehyde (III), which is condensed with tert-butyl carbazate (IV) in hot toluene/isopropyl alcohol to yield the benzylidenehydrazone (V). Finally, this compound is reduced with sodium formate over Pd/C in ethanol to afford the target intermediate; the carbazate (VI). The selective monosilylation of the primary OH group of diol (VII) with Tbdms-Cl, TEA and DMAP followed by reaction of the secondary OH group with MsCl gives the protected mesylate (VIII), which is desilylated with NH4F and AcOH yielding the primary alcohol (IX). The epoxidation of (IX) with t-BuOK in isopropyl alcohol affords the chiral epoxide (X), which is condensed with the intermediate carbazate (VI) in refluxing isopropanol to provide the adduct (XI). Elimination of the two Boc protecting groups of (XI) with HCl in hot THF gives the diamino compound (XII), which is finally condensed with two moles of N-(methoxycarbonyl)-L-tert-leucine (XIII) by means of WSC, HOBt and DIEA in dichloromethane to provide the target Atazanavir.

合成路线6

Deprotonation of 2-bromopyridine (V) with LDA and subsequent quenching with dimethylformamide provided 2-bromo-3-formylpyridine (VI). Nucleophilic substitution of the bromine of (VI) with N-Boc-4-(methylamino)piperidine (VII) in diisopropylethylamine at 100 C in a sealed tube yielded aminopyridine derivative (VIII). Then, Wittig olefination of (VIII) with the ylide resulting from isopropyl triphenylphosphonium iodide and n-BuLi introduced the isobutenyl substituent giving (IX), and further catalytic hydrogenation furnished the isobutyl derivative (X). The Boc group of (X) was deprotected by treatment with HCl in dioxan to give piperidine (XI). Finally, coupling of (XI) with indolecarboxylic acid (IV) via activation with carbonyl diimidazole yielded the title carboxamide.

合成路线7

Lithiation of 2-bromopyridine (II) with BuLi, followed by addition to 1-phenylcyclopropanecarbonitrile (I), gave rise to ketone (III). Electrophilic nitration of the phenyl ring of (III) produced the nitro derivative (IV). The nitro group of (IV) was subsequently reduced by catalytic hydrogenation over Raney Ni to afford aniline (V), which was further acylated with trifluoroacetic anhydride, yielding amide (VI). A second nitration reaction in (VI) with HNO3-H2SO4 provided the nitro anilide (VII). Amide (VII) N-alkylation by means of iodomethane and K2CO3 gave the corresponding N-methyl derivative (VIII). The trifluoroacetamide function of (VIII) was then hydrolyzed under basic conditions to furnish the nitro aniline (IX), which was reduced to the phenylenediamine (X) by catalytic hydrogenation in the presence of Raney Ni. Acylation of (X) by N-(4-cyanophenyl)glycine (XI) yielded amide (XII). Benzimidazole (XIII) was then obtained by cyclization of (XII) in refluxing HOAc. The keto group of (XIII) was converted to the oxime derivative (XV) by condensation with ethyl (aminooxy)acetate (XIV). Finally, Pinner reaction of nitrile (XV) with ethanolic HCl, followed by treatment of the resulting imidate with ammonium carbonate provided the target amidine.

合成路线8

Lithiation of 2-bromopyridine (VI), followed by addition to diethyl oxalate leads to ketoester (VII). Subsequent fluorination of (VII) by means of diethylaminosulfur trifluoride gives rise to the difluoro ester (VIII). Reduction of ester (VIII) by using NaBH4 yields alcohol (IX), which is then activated as the triflate (X) with trifluoromethanesulfonic anhydride. Displacement of triflate (X) with NaN3 in hot DMF produces azide (XI). The pyridine ring of (XI) is converted into the corresponding N-oxide (XII) by treatment with m-chloroperbenzoic acid. Reduction of azide (XII) by means of triphenylphosphine in moist THF leads to amine (XIII). Coupling of amine (XIII) with the bromopyrazinone (XIV) provides the aminopyrazinone adduct (XV), which is further chlorinated to (XVI) employing N-chlorosuccinimide. Saponification of the ethyl ester group of (XVI) provides carboxylic acid (XVII). This is finally coupled to the benzylic amine (V) in the presence of EDC/HOAt to furnish the title amide.

合成路线9

2-Bromopyridine (I) is metalated by means of butyllithium and subsequently condensed with diethyl oxalate (II) to produce the keto ester adduct (III). Reaction of (III) with hot diethylaminosulfur trifluoride gives rise to the difluoro ester (IV), which is further reduced to alcohol (V) employing NaBH4 in EtOH. Treatment of (V) with triflic anhydride and 2,6-di-t-butyl-4-methylpyridine in CH2Cl2 yields the corresponding triflate (VI), which is then converted into azide (VII) by reaction with NaN3 in DMF. The pyridine ring of (VII) is oxidized by means of m-chloroperbenzoic acid to produce the N-oxide (VIII). Then, azido group reduction with PPh3 in moist THF leads to the primary amine (IX)

合成路线10

合成路线11

Condensation of 5-bromoanthranilic acid (I) with the lithium derivative of 2-bromopyridine (II) in cold THF/ethyl ether gives the diaryl ketone (III). N-Fmoc-L-glutamic acid 5-methyl ester (IV) is chlorinated with oxalyl chloride and catalytic DMF to produce the acid chloride (V), which is then coupled with the amino ketone (III) in boiling chloroform to afford amide (VI). Base-mediated deprotection of amine (VI), followed by cyclization by treatment with AcOH in dichloroethane leads to the benzodiazepinone (VII). Subsequent treatment of lactam (VII) with bis-morpholinophosphorochloridate and NaH affords the imino phosphate (VIII), which is then condensed with 1-amino-2-propanol (IX) producing amidine (X). Finally, remimazolam is obtained by Swern oxidation of the secondary alcohol of (X), followed by cyclization under acidic conditions .

合成路线12

Selective bromide displacement in 2,5-dibromopyridine (I) with NaOMe in refluxing MeOH affords 5-bromo-2-methoxypyridine (II) (1), which alternatively can be obtained by bromination of 2-methoxypyridine (III) with elemental bromine in the presence of NaOAc in EtOAc at 50 °C (2). Metalation of 5-bromo-2-methoxypyridine (II) with BuLi in THF at –75 °C followed by addition of trimethyl borate and aqueous acidic hydrolysis leads to (6-methoxy-3-pyridyl)boronic acid (IV). Subsequent Suzuki coupling of boronic acid (IV) with 2-bromopyridine (V) in the presence of Pd(OAc)2, PPh3 and K2CO3 in DME/H2O at reflux provides 6-methoxy-3,2’-bipyridine (VI) (1). In an alternative method, bipyridine (VI) can be obtained by metalation of 5-bromo-2-methoxypyridine (II) with BuLi in THF at –75 °C followed by condensation with 2-(phenylsulfonyl)pyridine (VII) . Hydrolysis of 6-methoxy-3,2’-bipyridine (VI) by means of aqueous HCl at reflux yields 5-(2-pyridyl)-2-pyridone (VIII) . In a related method, Stille coupling of 5-bromo-2-methoxypyridine (II) with (2-pyridyl)tributyltin (IX) in the presence of Pd(Ph3)4 in DMF at 120 °C followed by methoxy group hydrolysis with concentrated HBr at 110 °C leads to 5-(2-pyridyl)-2-pyridinone (VIII) . N-Arylation of pyridone (VIII) with either phenylboronic acid (X) or its trimeric anhydride 2,4,6-triphenylboroxine (XI) in the presence of Cu(OAc)2 in pyridine/DMF under air blowing conditions gives 1-phenyl-5-(2-pyridyl)-2-pyridinone (XII), which is brominated using NBS in DMF or EtOAc to yield the 3-bromopyridone derivative (XIII). Finally, this compound is subjected to Suzuki coupling with 2-(2-cyanophenyl)-1,3,2-dioxaborinane (XIV) by means of Pd(OAc)2, PPh3, CuI and K2CO3 in DME .
In a different synthetic strategy, Suzuki coupling of 5-bromo-6-methoxy-3,2’-bipyridine (XV) with 2-(2-cyanophenyl)-1,3,2-dioxaborinane (XIV) using Pd(PPh3)4 and Cs2CO3 in DMF at 140 °C gives 3-(2-cyanophenyl)-5-(2-pyridyl)-2-methoxypyridine (XVI), which undergoes methoxy group hydrolysis by means of ClSiMe3 and NaI in acetonitrile to produce the pyridone derivative (XVII). Finally, subsequent N-arylation of pyridone (XVII) with phenylboronic acid (X) in the presence of Cu(OAc)2 and Et3N in CH2Cl2 furnishes perampanel