合成路线1
该中间体在本合成路线中的序号:
(I) The condensation of 1-naphthol (I) with an excess of o-dichlorobenzene (II) at 100 C by means of anhydrous AlCl3 gives 4-(3,4-dichlorophenyl)-1-tetralone (III), which is allowed to react with N-methylhydroxylamine (IV) and NaOAc in refluxing ethanol, yielding the nitrone (V). The reduction of (V) with H2 over RaNi in methanol affords a racemic cis/trans (9:1) mixture of methylamines, which by crystallization of its hydrochloride in ethanol provides pure (racemic)-(cis)-(VI). Finally, the target (1S)-(cis)-compound is obtained by optical resolution of (VI) with (R)-(-)-mandelic acid.
【1】
Vukics, K.; et al.; Improved industrial synthesis of antidepressant sertraline. Org Process Res Dev 2002, 6, 1, 82.
|
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
(I) |
22935 |
alpha-naphthol; 1-naphthol
|
90-15-3 |
C10H8O |
详情 | 详情
|
(II) |
58592 |
1,2-Dichlorobenzene; chloroben; chloroden; cloroben; Dichloricide; Dichlorobenzol; dilantin db; dilatin db; dizene; dowtherm e; o-Dichlorobenzene; o-Dichlorobenzol; termitkil
|
95-50-1 |
C6H4Cl2 |
详情 | 详情
|
(III) |
30583 |
4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenone; 4-(3',4'-Dichlorophenyl)-1-tetralone
|
79580-19-3 |
C16H12Cl2O |
详情 | 详情
|
(IV) |
12690 |
(Hydroxyamino)methane; N-Methylhydroxylamine
|
593-77-1 |
CH5NO |
详情 | 详情
|
(V) |
58593 |
[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenylidene](methyl)ammoniumolate
|
|
C17H15Cl2NO |
详情 |
详情
|
(VI) |
58594 |
N-[(1S,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenyl]-N-methylamine; (1S,4S)-4-(3,4-dichlorophenyl)-N-methyl-1,2,3,4-tetrahydro-1-naphthalenamine
|
|
C17H17Cl2N |
详情 |
详情
|
合成路线2
该中间体在本合成路线中的序号:
(I) The reaction of 1-naphthol (I) with epichlorohydrin (II) in the presence of aqueous sodium hydroxide yields 1-(1-naphthyloxy)-2,3-epoxypropane (III). (III) is then reacted either in alcohol or without any solvent with 1-(2-methoxyphenyl)piperazine (IV).
【1】
Thiel, M.; Sponer, G.; Stach, K.; Witte, E.-C.; Roesch, E. (Roche Diagnostics GmbH); 1-[3-(Napht-1-yloxy)-2-hydroxypropyl]-piperazine c. GB 1445548; US 3997666 .
|
【2】
Prous, J.; Castaner, J.; Naftopidil. Drugs Fut 1987, 12, 1, 31.
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中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
(I) |
22935 |
alpha-naphthol; 1-naphthol
|
90-15-3 |
C10H8O |
详情 | 详情
|
(II) |
10146 |
Epichlorohydrin; 2-(Chloromethyl)oxirane
|
106-89-8 |
C3H5ClO |
详情 | 详情
|
(III) |
22937 |
2-[(1-naphthyloxy)methyl]oxirane; 1-naphthyl 2-oxiranylmethyl ether
|
|
C13H12O2 |
详情 |
详情
|
(IV) |
11882 |
1-(2-Methoxyphenyl)piperazine; Methyl 2-piperazinophenyl ether; 1-(2-Methoxyphenyl)-piperazine
|
35386-24-4 |
C11H16N2O |
详情 | 详情
|
合成路线3
该中间体在本合成路线中的序号:
(I) By condensation of 1-naphthol (I) with 2-(chloromethyl)quinoline (II) by means of NaH in DMF.
【1】
Marshall, L.A.; Wong, A.; Kreft, A.F.; Structure -activity relationships in the quinoline- containing class of inhibitors of 5-lipoxygenase (5-LO) enzyme translocation and activation. Drugs Fut 1994, 19, 3, 255.
|
【2】
Kreft, A.F.; Failli, A.; Musser, J.H.; et al.; Conversion of a cyclooxygenase (CO) inhibitor into a 5-lipoxygenase (LO) inhibitor - A general route to novel antiinflammatory and antiallergy drugs. Drugs Exp Clin Res 1991, 17, 381-387.
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中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
(I) |
22935 |
alpha-naphthol; 1-naphthol
|
90-15-3 |
C10H8O |
详情 | 详情
|
(II) |
13162 |
2-(Chloromethyl)quinoline; alpha-Chloroquinaldine
|
4377-41-7 |
C10H8ClN |
详情 | 详情
|
合成路线4
该中间体在本合成路线中的序号:
(VII) The reaction of thiophene-2-carboxylic acid (I) with oxalyl chloride and PPh3 gives the corresponding acyl chloride (II), which is condensed with vinyltributylstannane to yield 1-(2-thienyl)-2-propen-1-one (III). The addition of HCl to the double bond of (III) affords 3-chloro-1-(2-thienyl)-1-propanone (IV), which is reduced with BH3 and the chiral (S)-oxazaborolidine catalyst (V) in THF to give the (R)-3-chloro-1-(2-thienyl)-1-propanol (VI). The condensation of (VI) with [1-14C]-1-naphthol (VII) by means of DEAD and PPh3 in THF affords the labeled naphthyl ether derivative (VIII), which is treated with NaI in acetone to give the labeled iodo derivative (IX). Finally, this compound is treated with methylamine in hot THF.
【1】
Wheeler, W.J.; Kuo, F.; Approaches to an asymmetric synthesis of duloxetine, a mixed uptake inhibitor of serotonin and norepinephrine, and its C-14 labeled analogs. Synthesis and Applications of Isotopically Labelled Compounds 1994, 597-603.
|
【2】
Sorbera, L.A.; Castaner, R.M.; Castaner, J.; Duloxetine oxalate. Drugs Fut 2000, 25, 9, 907.
|
【3】
Wheeler, W.J.; Kuo, F.; An asymmetric synthesis of duloxetine hydrochloride, a mixed uptake inhibitor of serotonin and norepinephrine, and its C-14 labeled isotopomers. J Label Compd Radiopharm 1995, 36, 3, 213.
|
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
(I) |
40505 |
2-thiophenecarboxylic acid
|
527-72-0 |
C5H4O2S |
详情 | 详情
|
(II) |
14103 |
2-Thiophenecarbonyl chloride
|
5271-67-0 |
C5H3ClOS |
详情 | 详情
|
(III) |
40506 |
1-(2-thienyl)-2-propen-1-one
|
|
C7H6OS |
详情 |
详情
|
(IV) |
40507 |
3-chloro-1-(2-thienyl)-1-propanone
|
|
C7H7ClOS |
详情 |
详情
|
(V) |
28292 |
(S)-Methyl oxazaborolidine; (3aS)-1-methyl-3,3-diphenyltetrahydro-3H-pyrrolo[1,2-c][1,3,2]oxazaborole
|
112022-81-8 |
C18H20BNO |
详情 | 详情
|
(VI) |
40512 |
(1R)-3-chloro-1-(2-thienyl)-1-propanol
|
|
C7H9ClOS |
详情 |
详情
|
(VII) |
22935 |
alpha-naphthol; 1-naphthol
|
90-15-3 |
C10H8O |
详情 | 详情
|
(VII) |
45152 |
1-naphthol
|
|
C10H8O |
详情 |
详情
|
(VIII) |
40513 |
(1S)-3-chloro-1-(2-thienyl)propyl 1-naphthyl ether; 2-[(1S)-3-chloro-1-(1-naphthyloxy)propyl]thiophene
|
|
C17H15ClOS |
详情 |
详情
|
(VIII) |
45153 |
(1S)-3-chloro-1-(2-thienyl)propyl 1-naphthyl ether; 2-[(1S)-3-chloro-1-(1-naphthyloxy)propyl]thiophene
|
|
C17H15ClOS |
详情 |
详情
|
(IX) |
40514 |
(1S)-3-iodo-1-(2-thienyl)propyl 1-naphthyl ether; 2-[(1S)-3-iodo-1-(1-naphthyloxy)propyl]thiophene
|
|
C17H15IOS |
详情 |
详情
|
(IX) |
45154 |
2-[(1S)-3-iodo-1-(1-naphthyloxy)propyl]thiophene; (1S)-3-iodo-1-(2-thienyl)propyl 1-naphthyl ether
|
|
C17H15IOS |
详情 |
详情
|
合成路线5
该中间体在本合成路线中的序号:
(VIII) The enantioselective reduction of 3-chloro-1-(2-thienyl)-1-propanone (I) by means of BH3 catalyzed by (R)-1-methyl-3,3-diphenyltetrahydropyrrolo[1,2-c][1,3,2]oxazaborole (II) in THF gives 3-chloro-1-(2-thienyl)propan-1(S)-ol (III), which is treated with methylamine and NaI in acetone/THF to yield (S)-N-methyl-N-[3-(2-thienyl)propyl]amine (IV). Finally, this compound is condensed with 1-fluoronaphthalene (V) by means of NaH in DMA to provide duloxetine.
Alternatively, the enantioselective reduction of 3-chloro-1-(2-thienyl)-1-propanone (I) by means of BH3 catalyzed by (S)-1-methyl-3,3-diphenyltetrahydropyrrolo[1,2-c][1,3,2]oxazaborole (VI) in THF gives 3-chloro-1-(2-thienyl)propan-1(R)-ol (VII), which is condensed with 1-naphthol (VIII) by means of DEAD and PPh3 to yield the expected aryl ether (IX), with inversion of the configuration. Finally, this compound is treated with methylamine and NaI in acetone/THF to provide duloxetine.
【1】
Bymaster, F.P.; Beedle, E.E.; Findlay, J.; Gallagher, P.T.; Krushinski J.H.; Mitchell, S.; Robertson, D.W.; Thompson, D.C.; Wallace, L.; Wong, D.T.; Duloxetine (Cymbalta(TM)), a dual inhibitor of serotonin and norepinephrine reuptake. Bioorg Med Chem Lett 2003, 13, 24, 4477. |
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
(I) |
40507 |
3-chloro-1-(2-thienyl)-1-propanone
|
|
C7H7ClOS |
详情 |
详情
|
(II) |
20631 |
(R)-Methyl oxazaborolidine; (3aR)-1-methyl-3,3-diphenyltetrahydro-3H-pyrrolo[1,2-c][1,3,2]oxazaborole
|
112022-83-0 |
C18H20BNO |
详情 | 详情
|
(III) |
40509 |
(1S)-3-chloro-1-(2-thienyl)-1-propanol
|
|
C7H9ClOS |
详情 |
详情
|
(IV) |
40511 |
(1S)-3-(methylamino)-1-(2-thienyl)-1-propanol
|
116539-55-0 |
C8H13NOS |
详情 | 详情
|
(V) |
40503 |
1-fluoronaphthalene
|
321-38-0 |
C10H7F |
详情 | 详情
|
(VI) |
28292 |
(S)-Methyl oxazaborolidine; (3aS)-1-methyl-3,3-diphenyltetrahydro-3H-pyrrolo[1,2-c][1,3,2]oxazaborole
|
112022-81-8 |
C18H20BNO |
详情 | 详情
|
(VII) |
40512 |
(1R)-3-chloro-1-(2-thienyl)-1-propanol
|
|
C7H9ClOS |
详情 |
详情
|
(VIII) |
22935 |
alpha-naphthol; 1-naphthol
|
90-15-3 |
C10H8O |
详情 | 详情
|
(IX) |
40513 |
(1S)-3-chloro-1-(2-thienyl)propyl 1-naphthyl ether; 2-[(1S)-3-chloro-1-(1-naphthyloxy)propyl]thiophene
|
|
C17H15ClOS |
详情 |
详情
|
合成路线6
该中间体在本合成路线中的序号:
(XVIII) The synthesis of the [11C]-labeled compound was also reported. Selective tosylation of the primary hydroxyl of (R)-1-phenyl-1,3-propanediol (XVI) provided (XVII). From this, naphthyl ether (XIX) was prepared by Williamson's synthesis with the sodium alkoxide of 1-naphthol (XVIII). The remaining hydroxyl group of (XIX) was then converted to mesylate (XX) upon treatment with methanesulfonyl chloride and DMAP. Subsequent displacement with methylamine in a sealed vessel afforded the secondary amine (XXI). This was finally alkylated with 11CH3I to yield the target 11C-labeled compound.
【1】
Livni, E.; et al.; Synthesis of [11C]dapoxetine.HCl, a serotonin re-uptake inhibitor: biodistribution in rat and preliminary PET imaging in the monkey. Nucl Med Biol 1994, 21, 4, 669.
|
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
(XVI) |
59233 |
(R)-(+)-1-phenyl-1,3-propanediol; (R)-1-Phenyl-1,3-propanediol
|
103548-16-9 |
C9H12O2 |
详情 | 详情
|
(XVII) |
59234 |
(3R)-3-hydroxy-3-phenylpropyl 4-methylbenzenesulfonate
|
|
C16H18O4S |
详情 |
详情
|
(XVIII) |
22935 |
alpha-naphthol; 1-naphthol
|
90-15-3 |
C10H8O |
详情 | 详情
|
(XIX) |
59230 |
(1R)-3-(1-naphthyloxy)-1-phenyl-1-propanol
|
|
C19H18O2 |
详情 |
详情
|
(XX) |
59231 |
(1R)-3-(1-naphthyloxy)-1-phenylpropyl methanesulfonate
|
|
C20H20O4S |
详情 |
详情
|
(XXI) |
59232 |
N-methyl-N-[(1S)-3-(1-naphthyloxy)-1-phenylpropyl]amine; (1S)-N-methyl-3-(1-naphthyloxy)-1-phenyl-1-propanamine
|
|
C20H21NO |
详情 |
详情
|
合成路线7
该中间体在本合成路线中的序号:
(I) Esterification of 1-naphthol (I) with 3-methylcrotonic acid chloride (II) provides ester (III), which subsequently rearranges to the hydroxy ketone (IV). Cyclization of (IV) under acidic conditions provides the tricyclic system (V). Keto group reduction in (V) by means of LiAlH4 leads to alcohol (VI), which upon acidic treatment is dehydrated to olefin (VII). Further catalytic hydrogenation of (VII) in the presence of Pd/C yields the dihydro naphthopyran (VIII). Electrophilic nitration of (VIII) provides (IX). After reduction of nitro derivative (IX) to the corresponding amine (X) by means of Sn/HCl, acylation with acetic anhydride furnishes acetamide (XI). Finally, oxidation of (XI) with concentrated nitric acid gives rise to the target ortho-quinone .
【1】
Amaral, A.C.F.; Barnes, R.A.; The total synthesis of beta-lapachone. J Heterocycl Chem 1992, 29, 1457.
|
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
(I) |
22935 |
alpha-naphthol; 1-naphthol
|
90-15-3 |
C10H8O |
详情 | 详情
|
(II) |
17810 |
3-methyl-2-butenoyl chloride; 3,3-Dimethylacryloyl chloride
|
3350-78-5 |
C5H7ClO |
详情 | 详情
|
(III) |
60270 |
1-naphthalenyl 3-methyl-2-butenoate
|
|
C15H14O2 |
详情 |
详情
|
(IV) |
60271 |
1-(1-hydroxy-2-naphthalenyl)-3-methyl-2-buten-1-one
|
|
C15H14O2 |
详情 |
详情
|
(V) |
60272 |
2,2-dimethyl-2,3-dihydro-4H-benzo[h]chromen-4-one
|
|
C15H14O2 |
详情 |
详情
|
(VI) |
60273 |
2,2-dimethyl-3,4-dihydro-2H-benzo[h]chromen-4-ol
|
|
C15H16O2 |
详情 |
详情
|
(VII) |
60274 |
2,2-dimethyl-2H-benzo[h]chromene
|
|
C15H14O |
详情 |
详情
|
(VIII) |
60275 |
2,2-dimethyl-3,4-dihydro-2H-benzo[h]chromene
|
|
C15H16O |
详情 |
详情
|
(IX) |
60276 |
2,2-dimethyl-6-nitro-3,4-dihydro-2H-benzo[h]chromene
|
|
C15H15NO3 |
详情 |
详情
|
(X) |
60277 |
2,2-dimethyl-3,4-dihydro-2H-benzo[h]chromen-6-amine; 2,2-dimethyl-3,4-dihydro-2H-benzo[h]chromen-6-ylamine
|
|
C15H17NO |
详情 |
详情
|
(XI) |
60278 |
N-(2,2-dimethyl-3,4-dihydro-2H-benzo[h]chromen-6-yl)acetamide
|
|
C17H19NO2 |
详情 |
详情
|
合成路线8
该中间体在本合成路线中的序号:
(I) Alkylation of 1-napthol (I) with 1,2-dibromoethane provides the (naphthyloxy)ethyl bromide (II), which is condensed with p-nitrophenethylamine (III) to afford the secondary amine (IV). After acetylation of amine (IV) to produce acetamide (V), the nitro group of (V) is reduced by means of iron and HCl, yielding aniline (VI). Finally, acylation of the amino group of (VI) with methanesulfonyl chloride furnishes the target sulfonamide.
【1】
Liu, H.; et al.; New p-methylsufonamido phenylamine analogues as class III antiarrhythmic agents: Design, synthesis, biological assay, and 3D-QSAR analysis. J Med Chem 2002, 45, 14, 2953.
|
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
(I) |
22935 |
alpha-naphthol; 1-naphthol
|
90-15-3 |
C10H8O |
详情 | 详情
|
(II) |
57707 |
2-bromoethyl 1-naphthyl ether; 1-(2-bromoethoxy)naphthalene
|
|
C12H11BrO |
详情 |
详情
|
(III) |
26560 |
4-nitrophenethylamine
|
24954-67-4 |
C8H10N2O2 |
详情 | 详情
|
(IV) |
57708 |
2-(1-naphthyloxy)-N-(4-nitrophenethyl)-1-ethanamine; N-[2-(1-naphthyloxy)ethyl]-N-(4-nitrophenethyl)amine
|
|
C20H20N2O3 |
详情 |
详情
|
(V) |
57709 |
N-[2-(1-naphthyloxy)ethyl]-N-(4-nitrophenethyl)acetamide
|
|
C22H22N2O4 |
详情 |
详情
|
(VI) |
57710 |
N-(4-aminophenethyl)-N-[2-(1-naphthyloxy)ethyl]acetamide
|
|
C22H24N2O2 |
详情 |
详情
|