合成路线1

The reaction of 4-hydroxy-1-octyne (I), with chlorotrimethylsilane and imidazole in DMF gives 4-trimethylsilyloxy-1-octyne (II), which is converted into 1-iodo-4-trimethylsilyloxy-trans-1-octene (III) by reaction with bis(3-methyl-2-butyl)borane (A), trimethylamine oxide, NaOH and finally I2. The hydrolysis of (III) with acetic acid in THF affords 1-iodo-4-hydroxy-trans-1-octene (IV), which is oxidized with pyridinium chlorochromate in methylene chloride yielding 1-iodo-4-oxo-trans-1-octene (V). The Grignard reaction of (V) with vinylmagnesium bromide (B) in THF gives 4-hydroxy-4-vinyl-1-iodo-trans-1-octene (VI), which is protected with trimethylsilyl chloride as before yielding 4-trimethylsilyloxy-4-vinyl-1-iodo-trans-1-octene (VII). The reaction of (VII) with tert-butyllithium in ether and then with copper (1)-1-pentyne-tributylphosphine (C) in HMPT affords the copper salt (VIII), which is condensed with 2-(6-trimethylsilyloxycarbonyl-2-cis-hexenyl)-4-trimethylsilyloxycyclopent-2-en-1-one (IX) in ether - THF giving trimethylsilyl-9-oxo-11alpha,16-bistrimethylsilyloxy-16-vinyl-5-cis-13-trans-prostadienoate (X). The hydrolysis of (X) with acetic acid in THF-water yields 9-oxo-11alpha,16-dihydroxy-16-vinyl-5-cis-13-trans-prostadienoic acid (XI), which is finally methylated with diazomethane in ether.

合成路线2

The reaction of 4-hydroxy-1-octyne (I) with chlorotrimethylsilane and imidazole in DMF gives 4-trimethylsilyloxy-1-octyne (II), which is converted to 1-iodo-4-trimethylsilyloxy-trans-1-octene (III) by reaction with bis(3-methyl-2-butyl)borane, trimethylamine oxide, NaOH and finally I2. The hydrolysis of (III) with acetic acid in THF affords 1-iodo-4-hydroxy-trans-1-octene (IV), which is oxidized with pyridinium chlorochromate in methylene chloride yielding 1-iodo-4-oxo-trans-1-octene (V). The Grignard condensation of (V) with vinylmagnesium bromide in THF gives 4 hydroxy-4-vinyl-1-iodo-trans-1-octene (VI), which is protected with trimethylsilyl chloride as before yielding 4-trimethylsilyloxy-4-vinyl-1-iodo-trans-1-octene (VII). The reaction of (VII) with tert-butyllithium in ether and then with copper(I)-1-pentyne-tributylphosphine in HMPT affords the copper salt (VIII), which is condensed with 2-(6-trimethylsilyloxycarbonyl)-2-cis-hexenyl)-4-trimethylsilyloxycyclopent-2-en-1-one (IX) in ether-THF giving trimethylsilyl-9-oxo-11 alpha,16-bis(trimethylsilyloxy)-16-vinyl-5-cis-13-trans-prostadienoate (X). Finally, this compound is hydrolyzed with acetic acid in THF water.

合成路线3

The Diels-Alder cyclization of butadiene (VII) with 1,4-benzoquinone (VIII) in THF gives the naphthalenetrione (IX), which is acylated with acetic anhydride and TEA to yield the tetralone derivative (X). The Grignard reaction of (X) with vinylmagnesium bromide (XI) and CeCl3, followed by acylation with acetic anhydride, affords the tetraline derivative (XII), which is treated with NaBH4 and oxidized with cerium ammonium nitrate to provide the tetrahydronaphthoquinone (XIII). The cyclization of (XIII) with 4-acetoxy-3,4-dihydro-1H-2-benzopyran-1,3-dione (XIV) by means of NaH in THF gives the intermediate (XV), which rearranges to the tetracyclic dione (XVI). The palladium-catalyzed (PdCl2(MeCN)2) rearrangement of (XVI) in toluene yields the allyl acetate derivative (XVII), which is oxidized with peracetic acid and RuCl3 in water/acetonitrile/dichloromethane to afford the protected intermediate (XVIII). Finally, this compound is deprotected and simultaneously epimerized by a treatment with HCl in refluxing isopropanol/water to provide the desired target intermediate (II).

合成路线4

Synthesis of intermediate 1,4-bis(3,4,5-trimethoxyphenyl)butane-1,4-dione (V). This compound can be obtained by three related methods: 1. The Grignard reaction of 3,4,5-trimethoxybenzaldehyde (I) with vinylmagnesium bromide (II), followed by oxidation with MnO2, gives 1-(3,4,5-trimethoxyphenyl)-2-propen-1-one (III), which is then condensed with aldehyde (I) by means of the thiazolium salt (IV) to yield the target intermediate (V). 2. The condensation of 3,4,5-trimethoxyacetophenone (VI) with methylamine and formaldehyde gives 3-(dimethylamino)-1-(3,4,5-trimethoxyphenyl)-1-propanone (VII), which is treated with methyl iodide at 80 C to afford the previously reported propenone intermediate (III). 3.The direct dimerization of acetophenone (VI) by means of LDA and CuCl2 also gives the target intermediate (V). Synthesis of the target compound: The reduction of the butanedione intermediate (V) with LiAlH4 or NaBH4 gives (RS,RS)-1,4-bis(3,4,5-trimethoxyphenyl)butane-2,3-diol (IX), which is dehydrated to the target tetrahydrofuran by means of TFA, PdCl2/Cu(NO3)2 or MsCl/pyridine. Alternatively, the reduction of butanedione (V) can be performed stepwise, first with LiAlH(O-tBu)3 to give the intermediate hydroxyketone (VIII), which is reduced to the diol (IX). The isolation of the intermediate hydroxyketone (VIII) allows the separation of enantiomers offering the possibility of obtaining chiral forms of the target tetrahydrofuran.

合成路线5

The reaction of beta-ionon (X) with triethyl orthoformate (A) by means of H2SO4 in dioxane gives beta-ionon enolether (XI), which by reaction with NBS in CCl4 and hydrolysis with acetic acid is converted into 4-acetoxyonon (XII). The Grignard reaction of (XII) with vinylmagnesium bromide (B) in THF and hydrolysis with KOH in methanol gives 5-(3-hydroxy-2,6,6-trimethylcyclohex-1-en-1-yl)-3-methylpenta-1,4-dien-3-ol (XIII), which is oxidized with MnO2 in methylene chloride yielding 5-(3-oxo-2,6,6-trimethylcyclohex-1-en-1-yl)-3-methylpenta-1,4-dien-3-ol (XIV). Finally, this compound by reaction with triphenylphosphonium bromide (C) in DMF is converted into the phosphonium salt (VIII), which is finally condensed in a Wittig reaction with 2,7-dimethyl-2,4,6-octatriene-1,8-dial (IX) by means of sodium methoxide in dichloromethane.

合成路线6

A new synthetic route to famciclovir has been described: The alkylation of 2,2-dimethyl-1,3-dioxan-5-one (I) with vinylmagnesium bromide (II) in THF gives the 2,2-dimethyl-5-vinyl-1,3-dioxan-5-ol derivative (II), which is treated with methyl chloroformate in the same solvent to yield the mixed carbonate (IV). Condensation of (IV) with 6-chloropurine-2-amine (V) by means of 1,2-bis(diphenylphosphino)ethane (dppe) and tris(dibenzylideneacetone)dipalladium(0) [Pd2(dba)3] in DMF at 80 °C for 7.5 h affords a 5:95 mixture of the N-7 (VI) and N-9 (VII) regioisomers, respectively. Hydrogenation of regioisomer (VII) with H2 over Pd/C in THF eliminates the 6-chlorine atom and reduces the exocyclic double bond giving the 2-aminopurine derivative (VIII), which is treated with HCl in methanol to remove the acetonide group affording diol (IX). Finally, this compound is acylated with acetic anhydride and DMAP/TEA in dichloromethane.

合成路线7

The 1alpha,3beta-diol (Ia) derived from ergosterol was used as the starting material. The alcohol (Ia) was converted to methoxymethyl derivative (Ib) by reaction with chloromethyl methyl ether (4 eq) in dichloromethane for 16 h, which was oxidized with 3 eq of N-methylmorpholine N-oxide in the presence of osmium tetroxide (0.5 eq) in tert-butanol:tetrahydrofuran:water (10:3:1) for 4 h at room temperature to afford the 22,23-diol. The resulting diol was then cleaved by sodium metaperiodate (2.5 eq) in aqueous tetrahydrofuran (5 h, room temperature) to give the 22-aldehyde (IIa) in 30% yield from (Ia). Reaction of (IIa) with 6 eq of vinyl magnesium bromide (tetrahydrofuran, 0 C to room temperature, 2 h) gave the allyl alcohol (IIb) as a mixture of C-22 diastereoisomers. The Claisen reaction of (IIb) with 10 eq of triethyl orthopropionate and a catalytic amount of propionic acid (benzene reflux, 16 h) gave gamma,delta-unsaturated ester (IIa) in 70% yield from (IIa). The lithium enolate of (IIIa) generated by lithium N-isopropylcyclohexylamide in tetrahydrofuran at -78 C was reacted with oxygen for 1 h and subsequent reduction with triethyl phosphine at -78 C gave the 25-hydroxy ester (IIIb) in 87% yield. (IIIb) was shown to be a 1:1 mixture of C-25 diastereoisomers by high-pressure liquid chromatographic (HPLC) analysis. Alkaline hydrolysis (KOH, methanol, 60 C, 2.5 h) of the ester gave the hydroxy acid (IIIc) in 87% yield. (IIIc) was treated with 6 eq of I2 in dichloromethane in the presence of pyridine (15 eq) to give the iodolactone (IVa) in 74% yield, which was separated into isomers by silica gel column chromatography in a 1.5:1 ratio.

合成路线8

Compound (XIII) can follow two different routes for its conversion into the intermediate product (XXIV): i) Reaction of (XIII) with vinylmagnesium bromide (XXI) in THF provides vinyl derivative (XXII), which is then converted into aldehyde (XXIII) by ozonolysis, followed by addition of dimethylsulfide (DMS). Reduction of aldehyde (XXIII) by means of NaBH4 in MeOH affords alcohol (XXIV). Conversion of (XXII) into (XXIV) can also be achieved by first treatment with NaIO4 and OsO4 in MeOH/H2O followed by reduction with NaBH4 in MeOH. ii) Treatment of (XIII) with (dimethylisopropoxysilyl)-methylmagnesium chloride (XXVII) in THF provides derivative (XXVIII), which is then converted into (XXIV) by treatment with H2O2/NaHCO3 in MeOH-THF. Final conversion of (XXIV) into the target product is achieved by first mesylation of (XXIV) by means of MsCl and Et3N in EtOAc to yield mesylated derivative (XXV), followed by its reaction with 1H-1,2,4-triazole in DMF in the presence of K2CO3.

合成路线9

Montelukast can be obtained by two related ways: 1) The Grignard reaction of 3-[2(E)-(7-chloroquinolin-2-yl)vinyl]benzaldehyde (I) with vinylmagnesium bromide (II) in toluene/THF gives the expected secondary alcohol (III), which is condensed with methyl 2-bromobenzoate (IV) by means of palladium acetate and lithium acetate in DMF to yield methyl 2-[3-[3-[2(E)-(7-chloroquinolin-2-yl)vinyl]phenyl]-3-oxopropyl]benzoate (V). The enantioselective reduction of the keto group of (V) with (-)-B-chlorodiisopinocampheylborane in THF affords methyl 2-[3-[3-[2(E)-(7-chloroquinolin-2-yl)vinyl]phenyl]-3(S)-hydroxypropyl] benzoate (VI), which is reacted with methylmagnesium bromide in toluene/THF or methylmagnesium chloride/CeCl3 in THF to give the expected tertiary diol (VII). The selective esterification of (VII) with mesyl chloride and diisopropylethylamine in toluene/acetonitrile yields the expected secondary mesylate (VIII), which is condensed with 2-[1-(sulfanylmethyl)cyclopropyl]acetic acid (IX) by means of butyllithium in THF to afford the corresponding condensation product as free acid that is separated by addition of dicyclohexylamine and precipitates the corresponding salt (X). Finally, this dicyclohexylamine salt (X) is treated with NaOH in toluene/water. 2) The 2-[1-(sulfanylmethyl)cyclopropyl]acetic acid (IX) has been obtained as follows: The reaction of 1,1-cyclopropanedimethanol (XI) with SOCl2 or diisopropyl sulfite in dichloromethane gives 1,1-cyclopropanedimethanol cyclic sulfite (XII), which is treated with NaCN in dichloromethane yielding 2-[1-(hydroxymethyl)cyclopropyl]acetonitrile (XIII). The reaction of (XIII) with mesyl chloride and triethylamine affords the corresponding mesylate (XIV), which is treated with potassium thioacetate in isopropyl acetate giving 2-[1-(acetylsulfanyl)cyclopropyl]acetonitrile (XV). Finally, this compound is hydrolyzed with NaOH in toluene/water to afford (IX).

合成路线10

A new synthesis of FTY-720 has been reported: Condensation of 4-chlorobenzaldehyde (I) with octylzinc iodide (II) by means of Ni(0) gives 4-octylbenzaldehyde (III), which is treated with vinylmagnesium bromide (IV) to yield the allyl alcohol (V). Epoxidation of (V) with MCPBA affords the epoxide (VI), which is opened by means of NaNO2 and MgSO4 in refluxing methanol to provide 3-nitro-1-(4-octylphenyl)propane-1,2-diol (VII). Reaction of diol (VII) with trimethylsilyl chloride and NaI in acetonitrile gives 3-nitro-1-(4-octylphenyl)-1-propene (VIII), which is hydrogenated with H2 over Pd/C in ethanol yielding the corresponding nitropropane derivative (IX). The bis-formylation of compound (IX) with aqueous HCHO in the presence of Amberlyst A-21 in dichloromethane affords 2-nitro-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol (X), which is finally reduced with H2 over Ra-Ni to provide FTY-720.

合成路线11

The esterification of L-phenylglycine (I) with AcCl and methanol gives the methyl ester (II), which is N-protected by means of Boc2O and TEA to yield the N-Boc derivative (III). The reduction of (III) with NaBH4 in ethanol/THF affords the alcohol (IV), which is oxidized by means of (COCl)2 and DMSO to provide the carbaldehyde (V). The reaction of (V) with vinylmagnesium bromide (VI) in THF gives the allyl alcohol (VII), which is protected with Tbdms-Cl and imidazole to yield the silyl ether (VIII). The alkylation of (VIII) with allyl bromide (IX) and NaH in DMF affords the N-allyl derivative (X), which is desilylated by means of TBAF and AcOH in THF to provide the allyl alcohol (XI). The ring closing metathesis reaction of (XI) with a Grubbs' catalyst in dichloromethane gives the tetrahydropyridine (XII), which is treated with H2 over Pd/C in ethanol to yield the chiral protected piperidine (XIII). The condensation of (XIII) with 3,5-bis(trifluoromethyl)benzyl bromide (XIV) by means of NaH in DMF affords the benzyl ether (XV), which is finally deprotected with TFA to provide the target piperidine.

合成路线12

Synthesis of the thiazole intermediate (XXVI): The Grignard reaction of 2-methyl-3-(2-methylthiazol-4-yl)-2(E)-propenal (XVII) with vinylmagnesium bromide (XVIII) in THF gives the racemic secondary alcohol (XIX), which is submitted to enzymatic optical resolution with Pseudomonas AK lipase and vinyl acetate to yield the desired (S)-secondary alcohol (XX) along with the (R)-acetate, which is easily separated by chromatography. The silylation of (XX) with Tbdms-Cl and imidazole in DMF affords the silyl ether (XXI). The selective hydroboration of the terminal double bond of (XXI) with dicyclohexylborane followed by oxidation with H2O2 provided the primary alcohol (XXII), which is oxidized with DMP in dichloromethane to give the corresponding aldehyde (XXIII). The reaction of (XXIII) with the iodomethyl phosphonium salt (XXIV) by means of NaHMDS in THF yields the cis-iodovinyl compound (XXV), which is desilylated with aqueous HF in acetonitrile, affording the corresponding alcohol (XXVI). Finally, this alcohol is treated with acetic anhydride, TEA and DMAP to provide the desired thiazole intermediate (XXVII).

合成路线13

Treatment of (R)-1-chloro-2,3-propanediol (I) with either K2CO3 or Cs2CO3 in CH2Cl2, followed by O-protection with Trt-Cl and Et3N in CH2Cl2, yields (S)-trityl glycidol (II). Alternatively, derivative (II) can also be obtained either by direct O-protection of (R)-glycidol (III) by means of Trt-Cl and Et3N in refluxing CH2Cl2 or by cyclization of protected propanediol derivative (IV)--obtained from treatment of compound (I) with Trt-Cl and Et3N in CH2Cl2--by means of KOH in EtOH. Reaction of (S)-trityl glycidol (II) with vinyl magnesium bromide (V) by means of CuI in THF provides (S)-1-(triphenylmethoxy)-4-penten-2-ol (VI), which is then condensed with allyl bromide (VII) with KOtBu or NaH in THF to afford compound (VIII). Ozonolysis of (VIII) in CH2Cl2/MeOH, followed by reductive quench with NaBH4 in NaOH, gives (S)-3-(2-hydroxyethoxy)-4-(triphenylmethoxy)-1-butanol (IX), which is then treated with MsCl/Et3N in CH2Cl2 to yield bismesylate (X). Coupling of compound (X) with 2,3-bis(1H-indol-3-yl)-N-methylmaleimide (XI) [obtained by treatment of dichloromaleic anhydride (XII) with methylamine hydrochloride by means of NaOMe in HOAc to furnish dichloro-N-methylmaleimide (XIII), followed by Grignard reaction of (XIII) with indole (XIV) in toluene/THF by means of EtMgBr in Et2O] by means of Cs2CO3 in DMF gives the 14-membered macrocycle (XV).

合成路线14

The reaction of 1,6:2,3-dianhydro-4-O-benzyl-beta-D-mannopyranose (I) with vinylmagnesium bromide in THF gives 1,6-anhydro-4-O-benzyl-2-deoxy-2-C-vinyl-beta-D-glucopyranose (II), which is treated with O3 and NaBH4 in EtOH/H2O yielding 1,6-anhydro-4-O-benzyl-2-deoxy-2-C-(hydroxymethyl)-beta-D-glucopyranose (III). The hydrolysis of (III) with aqueous refluxing H2SO4 affords 4-O-benzyl-2-deoxy-2-C-(hydroxymethyl)-D-glucopyranose (IV), which is oxidized with NaIO4 in MeOH giving 4-O-benzyl-2-deoxy-2-C-(hydroxymethyl)-D-xylo-pentodialdose (V). The reductocyclization of (V) with ammonia and H2 over Pd/C provides the benzylated target compound (VI), which is finally deprotected with H2 over Pd/C in EtOH/HCl furnishing the target compound as a single (R,R,R) enantiomer.

合成路线15

The reaction of oxirane (I) with vinylmagnesium bromide in THF gives 1-(4-fluorophenoxy)-4-penten-2(S)-ol (II), which is treated with ethyl vinyl ether and mercuric trifluoroacetate to yield the vinyl ether (III). The cyclization of (III) by means of Grubb's catalyst in refluxing benzene affords the dihydrofuran (IV), which is treated with benzenesulfinic acid in dichloromethane to give the sulfone (V). The reaction of (V) with the acetylenic tetrahydropyranyl ether (VI) by means of isopropylmagnesium bromide in THF yields the expected addition product (VII), which is treated with TsOH to eliminate the tetrahydropyranyl group and provide the alcohol (VIII). The condensation of (VIII) with N,O-bis (phenoxycarbonyl)hydroxylamine (IX) by means of PPh3 and DEAD in THF affords the protected carbamate derivative (X), which is finally treated with ammonia in methanol.

合成路线16

Fischer esterification of 2,2,5,5-tetramethylhexanedioic acid (I) provided diethyl ester (II), which was subjected to acyloin condensation with sodium in xylene to furnish the alpha-hydroxy cyclohexanone (III). Further oxidation of (III) with CrO3 gave diketone (IV). This was condensed with 2,3-diaminopropionic acid (V) to afford, after esterification with MeOH and H2SO4, the quinoxaline ester (VI). Reduction of (VI) to alcohol (VII) employing diisobutylaluminum hydride, followed by Swern oxidation gave rise to aldehyde (VIII). Optionally, addition of vinylmagnesium bromide to (VIII), and further Swern oxidation of the allylic alcohol (IX) provided the alpha,beta-unsaturated ketone (X). Conversion to the required diketo precursor (XII) was achieved by two related strategies. Coupling of ethyl 4-formylbenzoate (XI) with the unsaturated ketone (X) using 3-benzyl-5-(2-hydroxyethyl)-4-ethylthiazolium chloride as the catalyst gave the 1,4-diketone (XII). Alternatively, addition of vinylmagnesium bromide to ethyl 4-formylbenzoate (XI) followed by oxidation with pyridinium dichromate gave unsaturated ketone (XIII). This was then coupled with quinoxaline aldehyde (VIII) in the presence of a thiazolium salt to furnish diketone (XII).

合成路线17

Protection of (R)-glycidol (I) with trityl chloride (II) and TEA in dichloromethane gives the trityl ether (III), which is condensed with vinylmagnesium bromide (IV) in THF to yield the pentenol (V). The alkylation of (V) with allyl bromide (VI) by means of NaH in THF affords the allyl ether (VII), which is oxidized with O3 in methanol/dichloromethane, giving dialdehyde (VIII). Reduction of (VIII) with NaBH4 in ethanol provides diol (IX), which is treated with mesyl chloride and TEA in dichloromethane to afford the fully protected alcohol (X). Cyclization of (X) with 3,4-bis(3-indolyl)-1-methyl-2,5-dihydro-1H-pyrrole-2,5-dione (XI) by means of Cs2CO3 in DMF yields the hexacyclic compound (XII), which is N-demethylated by reaction with KOH in refluxing ethanol to give the hexacyclic furan derivative (XIII), which is then treated with hexamethyldisilazane (HMDS) in hot methanol to afford the hexacyclic demethylated pyrrole (XIV). Elimination of the trityl protecting group of (XIV) with HCl in dichloromethane gives the methanol derivative (XV), which is treated with Br2, pyridine and triphenyl phosphite in dichloromethane to yield the bromomethyl derivative (XVI). Finally, this compound is treated with dimethylamine in DMF to provide LY-333531. Alternatively, compound (XV) is treated with methanesulfonic anhydride and pyridine in THF, giving the mesylate (XVII), which is then treated with dimethylamine as before.

合成路线18

Tetrahydrofuranone (XIII): The Grignard condensation of isobutyraldehyde (I) with vinylmagnesium bromide (II) in THF gives the magnesium alcoholate (III), which is condensed with ethyl malonyl chloride (IV) in the same solvent, yielding the mixed ester (V). Treatment of (V) with Ti(OEt)4 at 190 C affords 6-methyl-4(E)-heptenoic acid methyl ester (VI), which by reaction with (R,R)-(-)-pseudoephedrine (VII), oxalyl chloride and DMF in benzene gives the amide (VIII). The regiocontrolled addition of 4-fluorobenzyl chloride (IX) to the chiral amide (VIII) by means of BuLi and LiCl in THF yields the 2(S)-(4-fluorobenzyl)heptanamide (X), which by reaction with NBS in THF/water/acetic acid at 0 C, followed by reflux for 45 min, affords 5(S)-[1(R)-bromo-2-methylpropyl]-3(R)-(4-fluorobenzyl)tetrahydrofuran-2-one (XI). The reaction of (XI) with NaN3 in DMF gives the corresponding azide (XII), which is reduced with H2 over Pd/C, and the resulting amine is protected with tert-butoxycarbonyl anhydride to obtain the desired tetrahydrofuranone (XIII).

合成路线19

Isobutyraldehyde (I) was condensed with vinylmagnesium bromide (II) to provide allylic alcohol (III). Condensation of (III) with diethyl malonate (IV) in the presence of titanium ethoxide, followed by Claisen rearrangement at 190 C gave malonate (V). Subsequent basic hydrolysis of (V) with concomitant decarboxylation yielded 6-methyl-4-heptenoic acid (VI). This was transformed to the corresponding acid chloride by means of SOCl2 and then coupled with (1R,2R)-(-)-pseudoephedrine (VII) to produce the chiral amide (VIII). Alkylation of the dianion of (VIII) with benzyl bromide (IX) in the presence of LiCl afforded the benzylated compound (X). Further treatment of (X) with N-bromosuccinimide and AcOH in THF generated the bromolactone (XI). The bromo group of (XI) was then displaced with NaN3, and the resulting azide (XII) was hydrogenated in the presence of di-tert-butyl dicarbonate to provide carbamate (XIII). Basic hydrolysis of the lactone (XII) gave hydroxyacid (XIV), which was oxidized to ketoacid (XV) by means of N-methylmorpholine-N-oxide and tetrapropyl ammonium perruthenate.

合成路线20

Isobutyraldehyde (I) was condensed with vinylmagnesium bromide (II) to provide allylic alcohol (III).Transesterification with diethyl malonate (IV) in the presence of titanium ethoxide, followed by Claisen rearrangement at 190 C gave malonate (V). Subsequent basic hydrolysis of (V) with concomitant decarboxylation yielded 6-methyl-4-heptenoic acid (VI). This was transformed to the corresponding acid chloride by means of SOCl2 and then coupled with (1R,2R)-(-)-pseudoephedrine (VII) to produce the chiral amide (VIII). Alkylation of the dianion of (VIII) with 4-methylbenzyl bromide (IX) in the presence of LiCl afforded the benzylated compound (X). Further treatment of (X) with N-bromosuccinimide and AcOH in THF generated the bromolactone (XI). The bromo group of (XI) was then displaced with NaN3, and the resulting azide (XII) was hydrogenated in the presence of di-tert-butyl dicarbonate to provide carbamate (XIII). Basic hydrolysis of the lactone (XIII) gave hydroxyacid (XIV), which was oxidized to ketoacid (XV) by means of N-methylmorpholine-N-oxide and tetrapropyl ammonium perruthenate.

合成路线21

Isobutyraldehyde (I) was condensed with vinylmagnesium bromide (II) to provide allylic alcohol (III).Transesterification with diethyl malonate (IV) in the presence of titanium ethoxide, followed by Claisen rearrangement at 190 C gave malonate (V). Subsequent basic hydrolysis of (V) with concomitant decarboxylation yielded 6-methyl-4-heptenoic acid (VI). This was transformed to the corresponding acid chloride by means of SOCl2 and then coupled with (1R,2R)-(-)-pseudoephedrine (VII) to produce the chiral amide (VIII). Alkylation of the dianion of (VIII) with 4-flourobenzyl bromide (IX) in the presence of LiCl afforded the benzylated compound (X). Further treatment of (X) with N-bromosuccinimide and AcOH in THF generated the bromolactone (XI). The bromo group of (XI) was then displaced with NaN3, and the resulting azide (XII) was hydrogenated in the presence of di-tert-butyl dicarbonate to provide carbamate (XIII). Basic hydrolysis of the lactone (XIII) gave hydroxyacid (XIV), which was oxidized to ketoacid (XV) by means of N-methylmorpholine-N-oxide and tetrapropyl ammonium perruthenate.

合成路线22

The addition of 2-(trimethylsilyl)ethylmercaptane (I) to 2,4-hexadiyn-1,6-diol (II) catalyzed by KOH in DMF gives the addition product (III), which is oxidized with Dess-Martin periodinane in dichloromethane or oxalyl chloride in DMSO yielding the dialdehyde (IV). The condensation of (IV) with tetrabromomethane by means of triphenylphosphine in dichloromethane affords the tetrabromo derivative (V), which is treated with butyllithium in THF to give the diacetylenic dianion (VI). The reaction of (V) with methyl iodide yields the mono methylated compound (VII), which is condensed with cis-1,2-dichloroethylene (VIII) by means of Pd(PPh3)4/CuI/butylamine in benzene affording the cis-chlorovinyl compound (IX). THe reaction of (IX) with vinylmagnesium bromide (X) catalyzed by Pd(PPh3)4 in benzene gives precursor (XI), which is finally submitted to an oxidative cyclization by means of tetrabutylammonium fluoride/trifluoroacetic acid and iodine.

合成路线23

This compound has been obtained by two related ways: 1) The Grignard reaction of 5,8-dimethylnaphthalene-2-carbaldehyde (I) with vinylmagnesium bromide in ether/THF gives the expected carbinol (II), which is oxidized with MnO2 in dichloromethane yielding the propenone (III). The condensation of (III) with 4-formylbenzoic acid methyl ester (IV) by means of 3-benzyl-5-(hydroxymethyl)-4-methylthiazolium chloride (BHMT) in refluxing ethanol affords the 1,4-butanedione (V), which is cyclized with ammonium acetate in refluxing methanol to give the substituted pyrrole (VI). Finally, the ester group of (V) is hydrolyzed with NaOH in refluxing ethanol/water. 2) 1,4-Butanedione (V) can also be obtained by condensation of 5,8-dimethylnaphthalene-2-carbaldehyde (I) with 4-acryloylbenzoic acid methyl ester (VII) by means of BHMT in hot DMF.

合成路线24

The Grignard reaction of 7-fluoro-4-(trifluoromethyl)benzofuran-2-carbaldehyde (I) with vinylmagnesium bromide in ether/THF gives the expected carbinol (II), which is oxidized with MnO2 in dichloromethane yielding the propenone (III). The condensation of (III) with 4-formylbenzoic acid methyl ester (IV) by means of 3-benzyl-5-(hydroxymethyl)-4-methylthiazolium chloride (BHMT) in refluxing ethanol affords the 1,4-butanedione (V), which is cyclized with ammonium acetate in refluxing methanol to give the substituted pyrrole (VI). Finally, the ester group of (V) is hydrolyzed with NaOH in refluxing ethanol/water.

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The silylation of the acetonide (XVIII) with Tms-Cl and LDA in THF gives dienolate (XIX), which is enantioselectively condensed with acrolein (XX) by means of Carreira's Ti catalyst in ethyl ether to yield the chiral allyl alcohol (XXI). The reaction of (XXI), N,O-dimethylhydroxylamine (XXII) and Me2AlCl affords the amide (XXIII), which is selectively reduced with Me4NBH(OAc)3 in HOAc/acetonitrile to provide the dihydroxyamide (XXIV). The silylation of the OH groups of (XXIV) with Tbdms-Cl and imidazole gives the disilylated compound (XXV), which is submitted to a Grignard reaction with vinylmagnesium bromide (XXVI) in THF to yield the vinyl ketone (XXVII). The Michael addition reaction with Ph2P(O)-Li and simultaneous triflation with (XXVIII) in THF affords the enol triflate (XXIX), which is cyclized by means of Pd(OAc)2, PPh3 and TEA in THF to provide the phosphorane (XXXa-b) as an inseparable mixture of the (Z)- and (E)-isomers. Finally, this mixture is submitted to photochemical isomerization with a medium-pressure UV mercury lamp in the presence of 9-fluorenone, furnishing the target intermediate, the (Z)-isomer (X) with a 95 % yield.

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Addition of vinylmagnesium bromide to diisopropyl ketone (I) produced carbinol (II). Subsequent oxidation of (II) with pyridinium chlorochromate gave unsaturated aldehyde (III), which was further hydrogenated to the saturated aldehyde (IV). Optionally, oxidation with sodium chlorite produced carboxylic acid (V), which was converted to acid chloride (VI) using oxalyl chloride and pyridine.

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The synthesis of intermediate (VIII) can be achieved by following two different routes: 1) Treatment of 2-bromo-5-methylnitrobenzene (I) with vinyl magnesium bromide (II) in THF yields bromoindole derivative (III), which is then converted into carboxylic acid (IV) by means of BuLi and CO2 in THF. Treatment of (IV) with diphenylphosphoryl azide (DPPA) and Et3N converts the carboxylic group into an amine intermediate which is then treated with hot t-BuOH to afford derivative (V). Formylation of (V) by means of DMF, POCl3 and aqueous NaOH provides aldehyde (VI), which is then treated with hydroxylamine (NH2OH), pyridine and N,N'-carbonyldiimidazole (CDI) and then heated with Et3N to furnish cyano derivative (VII). Finally, removal of the Boc group of (VII) by treatment with TFA in CH2Cl2 gives intermediate (VIII). 2) Alternatively, conversion of 5-methyl-2-nitroaniline (IX) into hydrazone derivative (XI) is achieved by first reaction with NaNO2 in hydrochloric acid media followed by condensation with ethyl 2-methylacetoacetate (X) in EtOH and aqueous KOH. Treatment of (XI) with refluxing H3PO4 in xylene yields indole derivative (XII), which is hydrolyzed by means of aqueous NaOH in THF to afford carboxylic acid (XIII). Decarboxylation of (XIII) with CuCO3 in 1,3-dimethyl-2-imidazolidinone furnishes 4-methyl-7-nitro-1H-indole (XIV), which is then formylated by means of DMF, POCl3 and aqueous NaOH to give aldehyde (XV). Conversion of formyl derivative (XV) into cyano derivative (XVI) is achieved by treatment with hydroxylamine (NH2OH), pyridine and N,N'-carbonyldiimidazole (CDI) followed by heating with Et3N. Finally, hydrogenation of the nitro group of (XVI) over PtO2 affords the target intermediate (VIII).

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From the starting carbaldehyde (I) two different pathways can be followed: 1) A solution of carbaldehyde (I) in ether is treated with the vinyl Grignard reagent (A) in THF and oxidized with activated manganese dioxide to afford enone derivative (II). The derivative is then coupled with methyl 4-formylbenzoate (III) in refluxing ethanol in presence of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazolium chloride (B) to yield diketone (IV). 2) Methyl 4-formylbenzoate (III) is treated with vinylmagnesium bromide (A) in THF, and oxidized with pyridinium dichromate to give methyl 4-acryloylbenzoate (V), which is coupled with carbaldehyde (I) by means of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazolium chloride (B) and triethylamine in DMF to yield directly diketone (IV). The final step is the cyclization of diketone (IV) to afford the pyrrole-benzoic acid derivative by treatment of the diketone with ammonium acetate in refluxing methanol and hydrolysis with NaOH in refluxing ethanol followed by neutralization with dilute HCl.

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The reaction of the chiral dibenzoyloxy-dihydropyran (LXV) with H2SO4 and HgSO4 gives the unsaturated aldehyde (LXVI), which is condensed with the phosphorane (LXVII) to yield the hepatdienoic ester (LXVIII). The hydrogenation of (LXVIII) with H2 over Pd/C affords the heptanoic ester (LXIX), which is treated with Ts-Cl and pyridine to provide the tosyloxy derivative (LXX). The cyclization of (LXX) by means of K2CO3 gives the chiral epoxide (LXXI), which is condensed with vinylmagnesium bromide (LXXII) to yield 6(S)-hydroxy-8-nonenoic acid methyl ester (LXXIII). The oxidation of the terminal double bond of (LXXIII) with ozone affords the carbaldehyde (LXXIV), which is reduced with NaBH4 to provide 6(S),8-dihydroxyoctanoic acid methyl ester (XLVIII). The reaction of (XLVIII) with Ms-Cl and pyridine gives the dimesylate (XLIX), which is treated with Na2S2 to yield the lipoic acid methyl ester (L), which is hydrolyzed to the target acid with KOH in H2O.

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Synthesis of the thiazole intermediate (XXVI): The Grignard reaction of 2-methyl-3-(2-methylthiazol-4-yl)-2(E)-propenal (XVII) with vinylmagnesium bromide (XVIII) in THF gives the racemic secondary alcohol (XIX), which is submitted to enzymatic optical resolution with Pseudomonas AK lipase and vinyl acetate to yield the desired (S)-secondary alcohol (XX) along with the (R)-acetate, which is easily separated by chromatography. The silylation of (XX) with Tbdms-Cl and imidazole in DMF affords the silyl ether (XXI). The selective hydroboration of the terminal double bond of (XXI) with dichlohexylborane followed by oxidation with H2O2 provides the primary alcohol (XXII), which is oxidized with DMP in dichloromethane to give the corresponding aldehyde (XXIII). The reaction of (XXIII) with the iodomethyl phosphonium salt (XXIV) by means of NaHMDS in THF yields the cis-iodovinyl compound (XXV), which is desilylated with aqueous HF in acetonitrile affording the corresponding alcohol (XXVI). Finally, this alcohol is treated with acetic anhydride, TEA and DMAP to provide the desired thiazole intermediate (XXVII).

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Nucleophilic substitution of 2,6-dichloro-3-nitrobenzonitrile (I) with methylamine provided the 2-(methylamino) regioisomer (II). The remaining chloride was subsequently displaced with the potassium enolate of ethyl 2-methylacetoacetate (III), yielding adduct (IV). After catalytic hydrogenation of the nitro group of (IV), the resulting amine (V) was condensed with 2,6-dichlorophenyl isothiocyanate (VI) to produce thiourea (VII), which was further cyclized to the benzimidazole (VIII) upon desulfuration with mercuric oxide. Decarbethoxylation and simultaneous cyclization between keto and cyano groups of (VIII) under acidic conditions gave rise to the fused pyridone system (IX). Regioselective oxidation of one methyl group of (IX) using selenium dioxide in hot dioxan furnished aldehyde (X). To this was added the vinyl Grignard reagent (XI), producing the allyl alcohol (XII), which was further esterified to acetate (XIII) with acetic anhydride and triethylamine. Finally, palladium-catalyzed displacement of the acetate group of (XIII) with diethylamine, with concomitant double bond rearrangement, produced the title allylic amine.

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Nucleophilic substitution of 2,6-dichloro-3-nitrobenzonitrile (I) with methylamine provided the 2-(methylamino) regioisomer (II). The remaining chloride was subsequently displaced with the potassium enolate of ethyl 2-methylacetoacetate (III), yielding adduct (IV). After catalytic hydrogenation of the nitro group of (IV), the resulting amine (V) was condensed with 2,6-dichlorophenyl isothiocyanate (VI) to produce thiourea (VII), which was further cyclized to the benzimidazole (VIII) upon desulfuration with mercuric oxide. Decarbethoxylation and simultaneous cyclization between keto and cyano groups of (VIII) under acidic conditions gave rise to the fused pyridone system (IX). Regioselective oxidation of one methyl group of (IX) using selenium dioxide in hot dioxan furnished aldehyde (X). To this was added the vinyl Grignard reagent (XI), producing the allyl alcohol (XII), which was further esterified to acetate (XIII) with acetic anhydride and triethylamine. Finally, palladium-catalyzed displacement of the acetate group of (XIII) with dimethylamine, with concomitant double bond rearrangement, produced the title allylic amine.

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