合成路线1

The enantioselective condensation of 3-(trimethylsilyl)propynal (V) with allylmagnesium bromide (VI) by means of (+)-Ipc2B-OMe as chiral catalyst gives hex-5-en-1-yn-3(R)-ol (VII), which is silylated with Tbdps-Cl and imidazole to yield the silyl ether (VIII). The oxidation of the terminal double bond of (VII) by means of OsO4 and NaIO4 affords the aldehyde (IX), which is submitted to a Wittig condensation with the phosphorane (X) in benzene to provide the unsaturated ester (XI). The enantioselective dihydroxylation of the double bond of (XI) with AD-mix-beta in tert-butanol/water gives the dihydroxyester (XII), which is protected with 2-methoxypropene (XIII) and PPTS to yield the isopropylidene ketal (XIV). The bromination of the triple bond of (XIV), followed by selective hydrogenation, affords the cis-bromovinyl compound (XV), whose ester group is reduced with LiAlH4 in THF to provide the primary alcohol (XVI). The oxidation of (XVI) with (COCl)2 and TEA in DMSO gives the carbaldehyde (XVII), which is submitted to a Wittig condensation with the phosphorane (XVIII) in hot dichloromethane to yield the diunsaturated aldehyde (XIX). The enantioselective condensation of aldehyde (XIX) with allylmagnesium bromide catalyzed by (+)Ipc2-B-OMe affords the chiral alcohol (XX), which is esterified with acryloyl chloride (XXI) and DIEA in dichloromethane to provide the ester (XXII). Compound (XXII) is submitted to a ring-closing metathesis catalyzed by a Rh catalyst (Grubbs's catalyst), yielding the dihydropyran derivative (XXIII), which is submitted to cleavage of the acetonide group by means of Montmorillonite K 10 to afford the diol (XXIV). The condensation of the bromovinyl group of (XXIV) with the intermediate boronic ester (IV) by means of Pd(PPh3)4 and Ag2O gives compound (XXV) with the complete backbone of the target fostriecin. The selective monosilylation of (XXV) with Tbdps-OTf gives the intermediate (XXVI).

合成路线2

The reaction of the iodovinyl compound (I) with BuLi and MgBr2 gives the organometallic compound (II), which is condensed with the acetylenic ketone (III) to yield the tertiary alcohol (IV). The selective monodesilylation of (IV) by means of HF affords the diol (V), which is selectively monoesterified with acryloyl chloride (VI) by means of DIEA to provide the acrylate (VII). The silylation of the free OH group of (VIII) with Tes-OTf gives the desilylated compound (VIII), which is submitted to a ring closing metathesis by means of (Pcy3)2RuCl2(=CH-PH) and Ti(O-iPr)4 in dichloromethane to yield the dihydropyranone (IX). The iodination of the terminal acetylene group of (IX) by means of NIS and AgNO3 in acetone affords the iodoacetylene (X), which is selectively deprotected at the Pmb protecting group by means of DDQ to provide the alcohol (XI). Finally the triple bond of (XI) is reduced by means of o-(NO2)C6H4-SO2-N=NH to obtain the target iodovinyl intermediate (XII) (see scheme no. 09093803b, intermediate (XX)).

合成路线3

The reaction of 5-(benzyloxy)-3(E)-penten-2-one (I) with trimethylsilyl cyanide (II) by means of a chiral Ti catalyst gives the chiral pentenenitrile (III), which is treated with HCl in ethanol and reduced with DIBAL and NaBH4 in methanol to yield the chiral diol (IV). The selective monosilylation of (IV) by means of TipsCl and imidazole affords the secondary alcohol (V), which is protected with Mom-Cl and DIEA in dichloromethane to provide compound (VI). The debenzylation of (VI) by means of lithium di-t-butyl biphenylide (LiDBB) gives the primary alcohol (VII), which is oxidized with TPAP and NMO in dichloromethane to yield the carbaldehyde (VIII). The reductive allylation of (VIII) by means of allyl trimethoxy silane (IX), AgF and a chiral catalyst affords the secondary alcohol (X), which is esterified with acryloyl chloride (XI) and TEA to provide the acrylate ester (XII). Ester (XII) is submitted to a ring closing metathesis reaction, catalyzed by a Ru catalyst giving the dihydropyranone compound (XIII), which is desilylated by means of HF and TEA in THF to yield the primary alcohol (XIV). The oxidation of (XIV) with DMP in dichloromethane affords the aldehyde (XV), which is condensed with 4-(trimethylsilyl)-3-butyn-2-one (XVI), by means of a chiral La catalyst to provide the acetylenic hydroxyketone (XVII). The reaction of (XVII) with 2,2-dimethoxypropane (XVIII) by means of PPTS gives the acetonide (XIX), which is enantioselectively reduced and catalyzed by a chiral Ru catalyst to yield the secondary alcohol (XX). The reaction of (XX) with Tbdms-OTf affords the silyl ether (XXI), which is treated with NIS and AgNO3 to provide the iodoacetylene derivative (XXII). The diimide reduction of (XXII) using o-nitrobenzenesulfonyl hydrazide (NBSH) gives the cis-iodovinyl compound (XXIII).

合成路线4

The reaction of acryloyl chloride (I) with pentane-1,5-diol (II) by means of triethylamine and pyrogalol in hot benzene gives 1,5-pentamethylene diacrylate (III), which is condensed with tetrahydropapaverine (IV) in refluxing benzene to afford N,N'-4,10-dioxa-3,11-dioxotridecylene-1,13-bis(tetrahydropapaverine) (V). Finally, this compound is quaternized by treatment with methyl benzenesulfonate in acetonitrile.

合成路线5

The Keck's enantioselective allylation of dodecanal (I) with allyl bromide (II) employing a catalytic amount of (R)-BINOL and titanium tetraisopropoxide furnishes the chiral alcohol (III), which is esterified with acryloyl chloride (IV), TEA and DMAP to give the acrylate (V). The olefin metathesis of (V) by means of Grubbs' catalyst and Ti(O-iPr)4 in refluxing dichloromethane yields the dihydropyranone (VI), which is epoxidized with H2O2 and NaOH to afford the chiral epoxide (VII). The reductive cleavage of (VII) with diphenyl diselenide and NaBH4 gives the chiral tetrahydropyranone (VIII), which is silylated with Tbdms-Cl and DIEA, yielding the silyl ether (IX). Opening of the lactone ring of (IX) with TEA and methanol affords the hydroxyester (X), which is treated with dihydropyran and PPTS to provide the tetrahydropyranyl ether (XI). The desilylation of (XI) with TBAF in THF gives the beta-hydroxyester (XII), which is alkylated with hexyl iodide and LDA in THF, yielding the adduct (XIII). The cyclization of (XIII) by hydrolysis with LiOH, followed by treatment with Ph-SO2-Cl, affords the beta-lactone (XIV), which is treated with PPTS to eliminate the tetrahydropyranyl-protecting group and yield the secondary alcohol (XV). The esterification of (XV) with N-(benzyloxycarbonyl)-L-leucine (XVI) by means of DCC and DMAP affords the leucinate (XVII), which is deprotected with H2 over Pd/C, affording (XVIII) with a free amino group that is formylated with acetic formic mixed anhydride to furnish the target (-)-tetrahydrolipstatin.

合成路线6

The starting compounds (I) and (II) are obtained as follows: Aldehyde (I): The esterification of (R,R)-dihydrobenzoin (IX) with acryloyl chloride (X) by means of triethylamine in dichloromethane gives the corresponding diester (XI), which by bis-cyclization with butadiene (XII) by means of TiCl4 in dichloromethane yields the bis(3-cyclohexenecarboxylic acid) ester (XIII). The hydrolysis of (XIII) with LiOH in methanol affords (R)-3-cyclohexenecarboxylic acid (XIV), which by reaction with I2, KI and NaHCO3 is converted to the iodolactone (XV). The reaction of (XV) with 1,5-diazabicyclo[5.4.0]-5-undecene (DBU) in refluxing THF affords the unsaturated lactone (XVI), which by treatment with NaHCO3 in anhydrous methanol yields (1R,3R)-3-hydroxy-4-cyclohexenecarboxylic acid methyl ester (XVII). The methylation of (XVII) with methyl trifluoromethanesulfonate and 2,6-di-tert-butyl-4-methylpyridine (DBMP) in dichloromethane gives the 3-methoxy ester (XVIII), which is selectively hydroxylated with BH3, H2O2 and NaOH to (1R,3R,4R)-4-hydroxy-3-methoxycyclohexanecarboxylic acid methyl ester (XIX). The protection of (XIX) with triisopropylsilyl (TIPS) trifluoromethanesulfonate (XX) and triethylamine in dichloromethane affords the protected ester (XXI), which is reduced with dibutylaluminum hydride (DIBAL) in hexane to the corresponding aldehyde (XXII). Finally, this compound is condensed with the N-tert-butylimine of 2-(triethylsilyl)propanol (XXIII) by means of butyllithium in THF to afford the desired aldehyde (I).

合成路线7

The condensation of sultam (XXII) with propenoyl chloride (XXIII) by means of TEA in dichloromethane gives the acryloyl sultam (XXIV), which is submitted to a Diels Alder cyclization with butadiene (XXV) by means of EtAlCl2 in dichloromethane to yield the chiral cyclohexenylcarbonyl derivative (XXVI). The hydrolysis of (XXVI) with LiOH in THF affords 3-cyclohexene-1(R)-carboxylic acid (XXVII), which is treated with I2, KI, NaHCO3 and DBU to provide the bicyclic lactone (XXVIII). The reduction of (XXVIII) with LiAlH4 in THF gives the chiral diol (XXIX), which is treated with diphenyl disulfide and tributylphosphine to yield the phenyl thioether (XXX). The methylation of the OH group of (XXX) with methyl iodide and KOH in DMSO afford the methoxy derivative (XXXI). The oxidation of (XXXI) with oxone in THF/methanol provides the sulfone (XXXII), which is submitted to hydroboration with BH3/Me2S and tBu-OOH in THF to give the chiral 4-hydroxy-3-methoxycyclohexylmethyl sulfone (XXXIII). The reaction of (XXXIII) with Tbdps-Cl and imidazole in DMF yields the silyl ether (XXXIV), which is condensed with the intermediate butyraldehyde (X) by means of BuLi in THF to afford the chiral pentanol derivative (XXXV). The oxidation of (XXXV) with TFAA and DMSO in dichloromethane provides the corresponding ketone (XXXVI), which is desulfonated by means of aluminum amalgam in refluxing THF/water to give the ketone (XXXVII). The reaction of (XXXVII) with Tf2N-Ph and KHMDS in THF yields the triflate enol ester (XXXVIII), which is methylated with Me-Li and CuI in THF to afford the unsaturated dithiane derivative (XXXIX). The reaction of (XXXIX) with NaH and Tips-OTf in HMPA provides the triisopropylsilyl ether (XL) (1) (Scheme 12407109c). The condensation of (XL) with the intermediate 14-iodo-10-tetradecenal dimethylacetal (XXI) by means of BuLi in THF/HMPA gives the adduct (XLI), which is desulfurized by means of NCS and AgNO3 in acetone/THF/water to yield the ketonic product (XLII). The cleavage of the 4-methoxybenzyl group of (XLII) by means of DDQ in dichloromethane affords the beta-hydroxyketone (XLIII). The reduction of the ketonic group of (XLIII) with LiAlH4 and LiI in ethyl ether provides the dihydroxy compound (XLIV), which is selectively monoprotected with Tips-OTf and 2,6-lutidine in dichloromethane to give the intermediate (XLV).

合成路线8

Treatment of 2,5-dihydroxybenzoic acid (I) with dimethyl sulfate and K2CO3 afforded methyl 2-hydroxy-5-methoxybenzoate (II). Condensation of (II) with dimethylthiocarbamoyl chloride gave the O-aryl thiocarbamate (III), which underwent thermal rearrangement to the S-aryl isomer (IV) upon heating at 265 C in diphenyl ether. Subsequent hydrolysis of the thiocarbamate group of (IV) furnished the desired thiophenol compound (V). Cyclization of the mercapto ester (V) with 2-chloroethylamine (VI) gave rise to the benzothiazepinone (VII), which was further reduced to the benzothiazepine (VIII) using LiAlH4. Acylation of (VIII) with acryloyl chloride (IX) provided the acrylamide (X). Finally, Michael addition of 4-benzylpiperidine (XI) to acrylamide (X) yielded the title compound.

合成路线9

The reaction of 6-bromo-1,2,3,4-tetrahydronaphthalen-2-one (I) with 1(R)-phenylethylamine (II) by means of p-toluenesulfonic acid in refluxing toluene gives the enamine (III), which is methylated with lithium diisopropylamide and methyl iodide in THF yielding the 1-methyldihydronaphthalene (IV). The cyclization of (IV) with acryloyl chloride (V) in toluene affords the benzoquinoline derivative (VI), which is treated with triethylsilane and trifluoroacetic acid to eliminate the chiral auxiliar giving intermediate (VII). The methylation of (VII) with methyllithium in THF yields the N-methyl benzoquinoline (VIII), which is treated with N,N'-diisopropylthiuram disulfide (IX) and tert-butyllithium to afford the thiol derivative (X). Finally, this compound is condensed with 2-chloro-4-ethylbenzo thiazole (XI) by means of K2CO3 in hot DMF.

合成路线10

Reaction of 2-amino-5-nitrobenzonitrile (I) with N,N-dimethylformamide dimethylacetal at 100 C provided formamidine (II), which was cyclized with 3-bromoaniline (III) in refluxing AcOH yielding quinazoline (IV). The nitro group of (IV) was then reduced to amine (V) with iron powder and AcOH. The resulting amine (V) was finally coupled with either acryloyl chloride (VI) in pyridine or with acrylic acid (VII) in the presence of EDC.

合成路线11

The reaction of the chiral diol (XXIV) first with MsCl and TEA, and then with NaCN gives the chiral butyronitrile (XXV), which is reduced with DIBAL in dichloromethane to yield the butyraldehyde (XXVI). The reaction of (XXVI) with allyl tributyl tin (XXVII), (S)-BINOL and Ti(OiPr)4 affords the secondary alcohol (XXVIII), which is condensed with acetal (XXIX) by means of PPTS to provide the diene (XXX). A ring closing metathesis reaction in (XXX) by means of a Ru catalyst gives the dihydropyran derivative (XXXI). Alternatively, the reaction of (XXVIII) with propenoyl chloride (XXXII) by means of TEA gives the diene (XXXIII), which is submitted to a ring closing metathesis reaction as before to yield the dihydropyranone (XXXIV). The reduction of (XXXIV) with DIBAL, followed by treatment with CSA and ethanol affords the dihydropyran derivative (XXXV). The reaction of both acetals (XXXI) or (XXXV) with CH2=CH-O-Tbdms (XXXVI) in the presence of Montmorillonite as Lewis acid, followed by a treatment with NaBH4 provides the dihydropyran (XXXVII) as a single isomer.

合成路线12

The reaction of 5-amino-1H-imidazole-4-carboxamide (I) with acryloyl chloride (II) by means of Et3N or K2CO3 in acetonitrile gives the intermediate, not isolated compound (III), which cyclizes to the imidazopyrimidine (IV). Finally, this compound is treated with Lawesson's reagent in dioxane or xylene.

合成路线13

Treatment of Wang resin with acryloyl chloride (XI) in the presence of diisopropyl ethylamine produced the acrylate bound resin (XII). Conjugate addition of 3,4-dimethoxybenzylamine (XIII) to the acrylate (XII) afforded the beta-amino ester resin (XIV). This was coupled with the intermediate carboxylic acid (X) employing O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) to furnish (XV). The title compound was finally liberated from the resin (XV) by cleavage with trifluoroacetic acid.

合成路线14

The condensation between ethyl picolinate (VII) and phenethylamine (VIII) at 180 C produced amide (IX), which was subsequently cyclized to dihydroisoquinoline (X) either by heating with polyphosphoric acid or by chlorination with PCl5, followed by cyclization in the presence of AlCl3. Catalytic hydrogenation of (X) gave rise to the racemic tetrahydroisoquinoline, which was resolved employing D-(-)-tartaric acid. The desired (R)-enantiomer (XI) was acylated with acryloyl chloride (XII) to produce acrylamide (XIII). Finally, palladium-catalyzed coupling of (XIII) with aryl iodide (VI) furnished the title compound.

合成路线15

Heck reaction of 4,4'-dibromobenzil (VI) with tert-butyl acrylate (III) in the presence of palladium diacetate and tri(o-tolyl)phosphine afforded the arylacrylate ester (VII), which was subsequently condensed with the acrylamide (X) (prepared from acryloyl chloride (VIII) and hexadecylamine (IX)), to furnish adduct (XI). The condensation of diketone (XI) with aldehyde (V) in the presence of ammonium acetate in HOAc produced imidazole (XII). The tert-butyl ester groups of (XII) were finally cleaved by treatment with trifluoroacetic acid.

合成路线16

The reaction of 4-aminobenzoic acid ethyl ester (I) with acryloyl chloride (II) by means of TEA in dichloromethane gives the corresponding acrylamide (III), which is condensed with 4,5,6,7-tetrahydro-1H-indol-4-one (IV) by means of K2CO3 in hot DMF to yield NEO-339. (1,2)

合成路线17

2-Methyl-3-(methylaminomethyl)indole (II) was obtained by the reductive amination of indole aldehyde (I) with methylamine. Acylation of amine (II) with acryloyl chloride (III) furnished the corresponding acrylamide (IV).

合成路线18

The reaction of 1,3-benzodioxol-5-ylmethylamine (I) with acryloyl chloride (II) by means of TEA gives the acrylamide (III), which is reductocondensed with perhydroazepine (IV) by means of LiAlH4 or BH3/THF in THF to yield the secondary amine (V). Finally this compound is condensed with 5-chloro-3-(3,5-difluorophenyl)isoxazole (VI) by means of BuLi in diethyl ether to afford the target tertiary amine. The intermediate 5-chloro-3-(3,5-difluorophenyl)isoxazole (VI) has been obtained by two related ways: The condensation of 3.5-difluorobenzoyl chloride (VII) with malonic acid monoethyl ester (VIII) by means of BuLi gives 2-(3,5-difluorobenzoyl)acetic acid ethyl ester (IX), which is cyclized with hydroxylamine in HOAc to yield 3-(3,5-difluorophenyl)isoxazol-5-ol (X). Finally this compound is treated with POCl3 to afford the desired 5-chloro-3-(3,5-difluorophenyl)isoxazole (VI) intermediate. Alternatively, the reaction of 3,5-difluoroacetophenone (XI) with diethyl carbonate (XII) by means of NaH yields also the already reported intermediate 2-(3,5-difluorobenzoyl)acetic acid ethyl ester (IX)

合成路线19

N-Methyl-(1,2,7-trimethylindol-3-ylmethyl)amine (VII) is condensed with acryloyl chloride (VIII) to form the corresponding acrylamide (IX). Then, Heck coupling between acrylamide (IX) and bromonaphthyridine (VI) in the presence of palladium acetate and tri-o-tolyl phosphine gives rise to the title compound.

合成路线20

Rociletinib is prepared by condensation of 2,4-dichloro-5-trifluoromethylpyrimidine (I) with N-Boc-1,3-diaminobenzene (II) in the presence of DIEA in BuOH to give the secondary amine (III), which is N-deprotected using TFA in CH2Cl2 yielding the primary amine (IV).Coupling of amine (IV) with acryloyl chloride (V) in CH2Cl2 affords amide (VI), which is condensed with intermediate (VII) by means of TFA in dioxane at 50 °C to provide rociletinib trifluoroacetate (VIII) . Finally, rociletinib trifluoroacetate (VIII) is treated with Na2CO3 in CH2Cl2 , followed by treatment of the obtained free base with HBr.

合成路线21

Chlorination of 4-phenoxybenzoic acid (I) with refluxing SOCl2 gives the corresponding acid chloride (II), which is then condensed with malononitrile (III) in the presence of DIEA in toluene/THF, followed by treatment with H2So4 to yield the enol derivative (IV). Methylation of the hydroxy group of compound (IV) by means of Me3SiCHn2 and DIEA in ace tonitrile/MeoH provides the 2-methoxyethene derivative (V), which by cyclization with hydrazine in EtoH affords the pyrazole derivative (VI). Cyclization of compound (VI) with formamide at 180 °C gives 4-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidine (VII) (1), which is submitted to Mitsunobu coupling with N-Boc-3(S)-hydroxypiperidine (VIII) in THF using DIAD and either polymer-bound triphenylphosphine or PPh3 to provide the 1-[N-Boc-3(R)-piperidinyl]pyrazolopyrimidine derivative (IX). Deprotection of intermediate (IX) by treatment with HCl in dioxane or TFA in CH2Cl2 leads to the free piperidine derivative (X), which is finally acylated with acryloyl chloride (XI) by means of Et3n in CH2Cl2 .

合成路线22