合成路线1

The condensation of 2-bromo-6-methoxynaphthalene (I) with 3-buten-2-one (II) by means of PdCl2, PPh3 and K2CO3 in DMF at 132 C gives 4-(6-methoxy-2-naphthyl)-3-buten-2-one (III), which is then hydrogenated with H2 over Pd/C in DMF. The same condensation can be performed with PdCl2 , PPh3 and NaHCO3 in 1-methyl-2-pyrrolidone at 130 C. The reaction of 4-hydroxy-2-butanone (IV) with acetic anhydride or acetyl chloride gives 4-acetyl-2-butanone (V), which is condensed with 2-bromo-6-methoxynaphthalene (I) by means of PdCl2, PPh3 and K2CO3 in DMF at 132 C to yield the previously reported 4-(6-methoxy-2-naphthyl)-3-buten-2-one (III).

合成路线2

By condensation of 2-bromo-6-methoxynaphthalene (I) with 3-buten-2-ol (VI) catalyzed by Pd(OAc)2 or PdCl2, along with PPh3 and NaHCO3 in 1-methyl-2-pyrrolidone at 140 C. The reaction of 2-bromo-6-methoxynaphthalene (I) with Mg in THF gives the expected Grignard reagent (VII), which is then condensed with 3-buten-2-one (II) by means of ZnCl2-amine complex in the same solvent.

合成路线3

By reaction of methyl vinyl ketone (A) with 1,7,8,12b-tetrahydrobenzo[1,2] cyclohepta[3,4,5-d,e]isoquinoline hydrochloride (I) at 100 C to give trans-1,2,4,4a,8,9,13b,14-octahydro-3H-benzo[6,7]cyclopenta[1,2,3-d,e]pyrido[2,1-a]isoquinolin-3-one (II), m.p. 163-5 C, which is alkylated with tert-butyllithium in benzene.

合成路线4

The (+)-isolimonene (I) was submitted to a regioselective hydroboration with dicyclohexylborane to give the alcohol (II), which was oxidized with CrO3 to the corresponding carboxylic acid (III). The iodolactonization of (III) by means of KI, I2 and NaHCO3 yielded a separable, diastereomeric mixture of iodolactones (IV) + (V). The suitable isomer (IV) was condensed with methyl vinyl ketone (VI) by means of tris(trimethylsilyl)silane and AIBN in refluxing toluene to afford the alkylated lactone (VII) as an inseparable diastereomeric mixture. The ketonic group of (VII) was treated with ethanedithiol (VIII) and BF3/Et2O in dichloromethane to provide a separable mixture of thioketal lactones (IX)+(X). The suitable isomer (X) was hydrolyzed with NaOH in refluxing methanol to give the hydroxyacid (XI), which was treated with diazomethane to yield the corresponding methyl ester (XII). The oxidation of the OH group of (XII) by means of PCC affords the ketoester (XIII), which is submitted to a Wittig condensation with methoxymethyltriphenylphosphonium chloride (XIV) by means of KHMDS in THF/HMPA to provide the methoxymethylene derivative (XV). The cleavage of the dithioketal group of (XV) by means of HgCl2 and CaCO3 in acetonitrile regenerates the keto group giving compound (XVI), which is finally transformed into the target (+)-artemisinin by photooxidation with O2 in methanol in the presence of Rose Bengal, followed by a treatment with 70 % HClO4.

合成路线5

Nitration of 1,2-dimethoxybenzene (XXIX) with HNO3/AcOH gives 4,5-dimethoxy-1,2-dinitrobenzene (XXX), which is treated with ammonia in hot methanol to yield 4,5-dimethoxy-2-nitroaniline (XXXI). Cyclization of compound (XXXI) with buten-2-one (XXXII) by means of H3PO4 and H3AsO4 affords 5,6-dimethoxy-4-methyl-8-nitroquinoline (XXXIII), which is selectively mono-demethylated by means of HCl in ethanol to provide 5-hydroxy-6-methoxy-4-methyl-8-nitroquinoline (XXXIV). Reaction of quinoline (XXXIV) with POCl3 gives the corresponding 5-chloro derivative (XXXV), which is condensed with 3-(trifluoromethyl)phenol (IV) by means of KOH to yield the diaryl ether (XXXVI). Finally, the nitro group of (XXXVI) is reduced by means of H2 over PtO2 in THF or H2 over Raney nickel.

合成路线6

Nitration of 2-fluoroanisole (XXXVII) with HNO3/Ac2O gives 3-fluoro-4-methoxynitrobenzene (XXXVIII), which is reduced to the corresponding aniline (XXXIX) with SnCl2/HCl. Reaction of compound (XXXIX) with Ac2O yields the acetanilide (XL), which is nitrated with HNO3 to afford 5-fluoro-4-methoxy-2-nitroacetanilide (XLI). Hydrolysis of (XLI) with NaOH provides 5-fluoro-4-methoxy-2-nitroaniline (XLII), which is cyclized with buten-2-one (XXXII) by means of As2O5 and H3PO4 to furnish 5-fluoro-6-methoxy-4-methyl-8-nitroquinoline (XLIII). Condensation of quinoline (XLIII) with 3-(trifluoromethyl)phenol (IV) by means of K2CO3 gives the diaryl ether (XXXIV), which is finally reduced by means of H2 over PtO2 in THF.

合成路线7

The condensation of 3-buten-2-one (I) with the phosphonate (II) by means of LDA gives the alkylated thiazole (III), which is enantioselectively epoxidated to the chiral oxirane (V) by means of oxone and the chiral ketone (IV). Alternatively, the oxidation of the chiral epoxybutanol (VI) with CrO3 or SO3 /pyridine yields the epoxybutanone (VII), which is condensed with phosphorane (II) by means of LDA to afford the already reported chiral oxirane (V). The condensation of (V) with alkyl bromide (VIII) and propyne (IX) by means of Mg, CuBr and pentynyl lithium provides the undecatrienyl thiazole (X), which is treated with Tms-OTf in order to protect its OH group, yielding the silyl ether (XI). The oxidation of the terminal double bond of (XI) by means of (Ipc)2BH and CrO3 affords the carbaldehyde (XII), which is condensed with ketoacid (XIII) by means of LDA in THF to provide the undecadienoic acid (XIV). The cyclization of (XIV) by means of benzenesulfonyl chloride and pyridine gives the macrocyclic intermediate (XV), which is finally epoxidated by means of DMDO in acetone to furnish the target epothilone B.

合成路线8

The reduction of benzoin (XIII) with NaBH4 in ethanol/water gives the diol (XIV), which by a pinacol rearrangement by means of H2SO4 in hot acetic acid yields the diphenylacetaldehyde (XXV). The cyclization of (XV) with methyl vinyl ketone (XVI) by means of KOH in ethanol affords the cyclohexenone (XVII), which is reduced first with H2 over Pd/C in THF and then with NaBH4 in ethanol/water giving the 4,4-diphenylcyclohexanol (IX). The reaction of (IX) with PCl3 in THF yields the dichlorophosphite (XVIII), which is treated with imidazole (XIX) in THF affording the bis imidophosphite (XX). The condensation of (XX) with the previously obtained penta tert-butyl acetate compound (VI) in THF/heptane gives the imidophosphite (XXI), which is oxidized with sodium periodate yielding the phosphoric acid diester (XXII). Finally, the hydrolysis of (XXII) with HCl in ether/water eliminates the tert-butyl groups affording the desired chelating ligand (XII).

合成路线9

The condensation of 3-buten-2-one (I) with the phosphonate (II) by means of LDA gives the alkylated thiazole (III), which is enantioselectively epoxidated to the chiral oxirane (V) by means of oxone and the chiral ketone (IV). Alternatively, the oxidation of the chiral epoxybutanol (VI) with CrO3 or SO3 /pyridine yields the epoxybutanone (VII), which is condensed with phosphorane (II) by means of LDA to afford the already reported chiral oxirane (V). The condensation of (V) with alkyl bromide (VIII) and propyne (IX) by means of Mg, CuBr and pentynyl lithium provides the undecatrienyl thiazole (X), which is treated with Tms-OTf in order to protect its OH group, yielding the silyl ether (XI). The oxidation of the terminal double bond of (XI) by means of (Ipc)2BH and CrO3 affords the carbaldehyde (XII), which is condensed with ketoacid (XIII) by means of LDA in THF to provide the undecadienoic acid (XIV). Finally, the cyclization of (XIV) by means of benzenesulfonyl chloride and pyridine gives the target epothilone D.

合成路线10

3-Methoxyphenethylamine (I) was converted into formamide (II) upon refluxing in ethyl formate. Subsequent cyclization of (II) in hot polyphosphoric acid produced the dihydroisoquinoline (III). This was subjected to a tandem Mannich-Michael condensations by refluxing in methyl vinyl ketone (IV) to yield the benzoquinolizinone system (V). The desired (S)-enantiomer (VI) was then isolated by crystallization of the diastereoisomeric salts with (-)-di-p-toluoyl-L-tartaric acid in EtOAc. Condensation of (VI) with methylamine in the presence of TiCl4, followed by reduction of the intermediate imine with NaBH4 provided amine (VII). This was finally converted to the target sulfonamide by treatment with methanesulfonyl chloride and Et3N.

合成路线11

Michael addition of methyl vinyl ketone (II) to phthalimide (I) in the presence of NaOEt afforded phthalimido ketone (III). Bromination of (III) in MeOH, followed by acid hydrolysis of the resulting dimethyl ketal provided bromo ketone (IV). Cyclization of bromo ketone (IV) with thiourea (V) yielded the amino thiazole (VI) and further deprotection of the phthalimido group of (VI) in refluxing HBr furnished diamine (VII). 3,4,5-Trimethoxyphenylacetic acid (VIII) was converted to the corresponding acid chloride (IX) using oxalyl chloride, and subsequently coupled with amine (VII) under Schotten-Baumann conditions to give amide (X). Cyclization of (X) to the thiazolopyridine (XI) was effected by the Bischler-Napieralski procedure employing POCl3 in acetonitrile. The imine double bond of (XI) was then reduced by means of NaBH4, and the resulting compound was finally converted to the dihydrochloride salt.

合成路线12

Michael addition of methyl vinyl ketone (II) to phthalimide (I) in the presence of NaOEt afforded phthalimido ketone (III). Bromination of (III) in MeOH, followed by acid hydrolysis of the resulting dimethyl ketal provided bromo ketone (IV). Cyclization of bromo ketone (IV) with thiourea (V) yielded the amino thiazole (VI) and further deprotection of the phthalimido group of (VI) in refluxing HBr furnished diamine (VII). 3,5-Diiodo-4-methoxyphenylacetic acid (VIII) was converted to the corresponding acid chloride (IX) using oxalyl chloride, and subsequently coupled with amine (VII) under Schotten-Baumann conditions to give amide (X). Cyclization of (X) to the thiazolopyridine (XI) was effected by the Bischler-Napieralski procedure employing POCl3 in acetonitrile. The imine double bond of (XI) was then reduced by means of NaBH4, and the resulting compound was finally converted to the dihydrochloride salt.

合成路线13

6-Methoxy-2-tetralone (I) was condensed with pyrrolidine (II) to produce enamine (III). Alkylation of (III) with benzyl bromide, followed by hydrolysis of the enamine function, furnished the 1-benzylnaphthalenone (IV). After formation of the chiral enamine (VI) with (S)-alpha-methylbenzylamine (V), enantioselective Michael addition of methyl vinyl ketone (VII) provided the (R)-diketone (VIII), which underwent ring closure to the phenanthrene derivative (IX) upon treatment with NaOMe. Methyl ether cleavage by using boron trichloride in the presence of tetrabutylammonium iodide afforded phenol (X). The conjugated ketone system of (X) was diastereoselectively reduced to the trans-phenanthrenone (XI) by means of lithium in liquid ammonia. Addition of the lithium acetylide of propyne (XII) to the ketone (XI) produced a diastereomeric mixture of carbinols from which the desired isomer (XIII) was isolated by flash chromatography. The phenol group of (XIII) was then converted to the aryl triflate (XIV) by reaction with trifluoromethanesulfonic anhydride and 2,6-lutidine.

合成路线14

6-Methoxy-2-tetralone (I) is converted into enamine (II) by treatment with pyrrolidine in toluene by azeotropic removal of water. Alkylation of (II) with benzyl bromide, followed by hydrolysis of the enamine, provides the 1-benzyl tetralone (III). This is then condensed with (S)-alpha-methylbenzylamine (IV), and the resultant imine (V) is treated with methyl vinyl ketone (VI) to furnish, after hydrolysis of the chiral auxiliary, the tricyclic ketone (VII). Rearrangement of (VII) in the presence of NaOMe results in the phenanthrenone (VIII). Cleavage of the methyl ether of (VIII) is accomplished by treatment with boron trichloride and tetrabutylammonium iodide to form phenol (IX). Reduction of enone (IX) with lithium metal in liquid ammonia leads to the saturated ketone (X). Finally, addition of the lithium acetylide of propyne (XI) to the ketone (X) affords the title carbinol adduct.

合成路线15

合成路线16

Cyclization of 4-bromoaniline (Ia) with methyl vinyl ketone (II) by means of H2SO4 in refluxing dioxane affords 6-bromo-4-methylquinoline (IIIa) (1). Similarly, cyclization of 4-aminobenzonitrile (Ib) with methyl vinyl ketone (II) by means of HCl and chloranil in EtOH gives 4-methyl-6-quinolinecarbonitrile (IIIb) (2). Condensation of 4-methylquinolines (IIIa) or (IIIb) with methyl 6-methylpyridine-2-carboxylate (IV) by means of KHMDS in THF at –70 °C or t-BuONa in THF (2) produces the 2-(4-quinolinyl)-1-(pyridyl)ethanone derivatives (Va) (1) or (Vb) (2), respectively. Subsequent condensation of ketone (Va) with 1-amino-2-pyrrolidinone hydrochloride (VIa) in pyridine yields acyl hydrazone (VIIa), which is cyclized by means of Cs2CO3 in DMF at 100 °C, leading to the pyrrolopyrazole derivative (IXa) (1). Alternatively, condensation of ketone (Vb) with 1-amino-2-pyrrolidinone p-toluenesulfonate (VIb) [prepared by the hydrolysis of hydrazone (VIII) with p-TsOH·H2O in toluene] in the presence of 2,6-lutidine in refluxing DMF/toluene provides the acyl hydrazone (VIIb), which cyclizes to the pyrrolopyrazole derivative (IXb) by treatment with K2CO3 (2). Finally, methoxycarbonylation of bromoquinoline (IXa) under CO atmosphere in the presence of Pd(dppf)2Cl2 and NaOAc in MeOH at 80 °C gives the methyl ester (X), which is submitted to ammonolysis with NH3 in MeOH at 90 °C. Alternatively, nitrile (IXb) is hydrolyzed by means of H2O2 and K2CO3 in DMSO/H2O .

合成路线17

The synthesis of suvorexant by the medicinal route starts with conjugate addition of monoprotected diamine (I) to methyl vinyl ketone (II) in Et2O, followed by in situ trapping with benzyl chloroformate in the presence of Et3N to yield the fully protected diaminoketone (III), from which the Boc-protecting group is cleaved by means of HCl in EtOAc to provide primary amine (IV). Intramolecular reductive cyclization of amino ketone (IV) in the presence of NaBH(OAc)3 and AcOH in CH2Cl2 affords benzyl 5-methyl-1,4-diazepane-1-carboxylate (V), which is then N-protected with di-tert-butyl dicarbonate in the presence of Et3N in CH2Cl2 to give the diprotected diazepine derivative (VI). Resolution of racemic diazepine (VI) by means of chiral HPLC provides the desired (R)-enantiomer (VII), which is then N-deprotected with HCl in EtOAc to afford benzyl 5(R)-methyl-1,4-diazepane-1-carboxylate (VIII). Coupling of cyclic amine (VIII) or its hydrochloride with 5-methyl-2-(1,2,3-triazol-2-yl)benzoic acid (IX) [prepared by condensation of 2-iodo-5-methylbenzoic acid (X) with 1,2,3-triazole (XI) in the presence of Cs2CO3, CuI and t-DAMCH in DMF at 120 °C] using EDC, HOAt and NMM in DMF produces the corresponding amide (XII). N-Deprotection of N-Cbz-amine (XII) by means of H2 over Pd(OH)2/C in EtOAc/MeOH or EtOAc generates the 7(R)-methyldiazepane derivative (XIII), which is finally condensed with 2,5-dichloro-1,3-benzoxazole (XIV) [prepared by the chlorination of 5-chloro-2-mercaptobenzoxazole (XV) with POCl3 and PCl5 in CH2Cl2] in the presence of Et3N in DMF at 75 °C .

合成路线18

Enantioselective synthesis of suvorexant is based on enzymatic transamination and described as follows. Cyclization of 2-amino-4-chlorophenol (XVI) with trimethyl orthoformate HC(OMe)3 in the presence of p-TsOH in THF provides 5-chlorobenzoxazole (XVII), which subsequently reacts with LiHMDS in THF followed by bromination of the resulting anion with NBS to afford 2-bromo-5-chlorobenzoxazole (XVIII). Condensation of crude bromo derivative (XVIII) with ethanolamine (XIX) in acetonitrile gives 2-(5-chloro-2-benzoxazolylamino)ethanol (XX), which is subjected to aza-Michael addition with methyl vinyl ketone (II) in the presence of NaOH in DMF to yield the β-amino ketone (XXI). Activation of crude alcohol (XXI) with MsCl in the presence of Et3N in i-PrOAc provides keto mesylate (XXII), which by transamination and cyclization with i-PrNH2 in the presence of CDX-017 enzyme and pyridoxal phosphate in DMSO, and subsequent acidification with HCl, provides the (R)-azepane derivative (XXIII). Finally, Schotten-Baumann acylation of amine (XXIII) with 5-methyl-2-(1,2,3-triazol-2-yl)benzoyl chloride (XXIV) in the presence of K2CO3 in i-PrOAc/H2O affords suvorexant. Chloride (XXIV) was prepared from 5-methyl-2-(1,2,3-triazol-2-yl)benzoic acid (IX) by treatment with (COCl)2 in the presence of DMF in i-PrOAc .

合成路线19

Process route to suvorexant starts with treatment of dichlorobenzoxazole (XIV) with N-Boc-ethylenediamine (I) in the presence of Et3N to provide 82% yield of 2-aminobenzoxazole (XXV), which by reaction with methyl vinyl ketone (II) in the presence of DBU in acetonitrile provides intermediate (XXVI) in a high yield. Clean deprotection of (XXVI) is achieved with methanesulfonic acid in THF to give 94% of aminoketone in the form of salt (XXVII). Reductive cyclization of this salt by means of Na(OAc)3BH in the presence of NaOAc in CH2Cl2 provides 98% yield of racemic diazepane (XXVIII). An extensive screening of classical resolution methods for racemate (XXVIII) led to optimal conditions based on resolution with dibenzoyl-L-tartaric acid in THF/CH2Cl2, giving 39% yield (74% ee). Recrystallization of this salt in a 4:1 mixture of i-PrAc/MeOH then provided a 70% yield (96% ee). Treatment of the tartrate salt with NaOH provided the free base (XXIX), which is finally condensed with acid chloride (XXIV) in the presence of Et3N, giving a 95% yield of suvorexant .