|
【结 构 式】 
|
【分子编号】20720 【品名】3,4-dihydro-1(2H)-naphthalenone 【CA登记号】529-34-0 |
【 分 子 式 】C10H10O 【 分 子 量 】146.1888 【元素组成】C 82.16% H 6.89% O 10.94% |
合成路线1
该中间体在本合成路线中的序号：(I)Reaction of alpha-tetralone (I) with formadehyde (II) and tyramine hydrochloride (III) in alcohol.
合成路线2
该中间体在本合成路线中的序号：(IV)A new synthesis of CGS-14824A is given: The reaction of 3-bromo-1-phenylpropane (I) with KCN gives 4-phenylbutyronitrile (II), which is hydrolyzed to the corresponding butyric acid (III). The cyclization of (III) with polyphosphoric acid affords 1-tetralone (IV), which is brominated to 2-bromo-1-tetralone (V) and treated with hydroxylamine to give the oxime (VI). The Beckman rearrangement of (VI) yields 3-bromo-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one (VII), which is treated with sodium azide to afford the azide derivative (VIII). The N-alkylation of (VIII) with ethyl bromoacetate (IX) by means of KOH and tetrabutylammonium bromide in THF gives the N-alkylated azide (X), which is reduced by catalytic hydrogenation to the corresponding amine (XI). The hydrolysis of the ester group of (XI) with NaOH yields the free acetic acid derivative (XII), which is finally reductocondensed with ethyl 2-oxo-4-phenylbutyrate (XIII) by means of sodium cyanoborohydride.
| 【1】 Chaudhuri, N.K.; Patera, R.; Markus, B.; Sung, M.-S.; Synthesis of 14C-labeled 3-([1-ethoxycarbonyl-3-phenyl-(1S)-propyl]amino)-2,3,4,5-tetrahydro-2-oxo-1H-1-(3S)-benzazepine-1-acetic acid hydrochloride ([14C]CGS 14824A). J Label Compd Radiopharm 1987, 24, 10, 1177-84. |
| 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) | 20884 | 1-(3-bromopropyl)benzene | 637-59-2 | C9H11Br | 详情 | 详情 |
| (II) | 20885 | 4-phenylbutanenitrile | 2046-18-6 | C10H11N | 详情 | 详情 |
| (III) | 20886 | Benzenebutyric acid; 4-Phenylbutyric acid | 1821-12-1 | C10H12O2 | 详情 | 详情 |
| (IV) | 20720 | 3,4-dihydro-1(2H)-naphthalenone | 529-34-0 | C10H10O | 详情 | 详情 |
| (V) | 20721 | 2-bromo-3,4-dihydro-1(2H)-naphthalenone | C10H9BrO | 详情 | 详情 | |
| (VI) | 20722 | 2-bromo-3,4-dihydro-1(2H)-naphthalenone oxime | C10H10BrNO | 详情 | 详情 | |
| (VII) | 20723 | 3-bromo-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one | C10H10BrNO | 详情 | 详情 | |
| (VIII) | 20891 | 3-azido-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one | C10H10N4O | 详情 | 详情 | |
| (IX) | 16640 | Ethyl 2-bromoacetate; Ethyl bromoacetate | 105-36-2 | C4H7BrO2 | 详情 | 详情 |
| (X) | 20893 | ethyl 2-(3-azido-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)acetate | C14H16N4O3 | 详情 | 详情 | |
| (XI) | 20894 | ethyl 2-[(3S)-3-amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]acetate | 109010-60-8 | C14H18N2O3 | 详情 | 详情 |
| (XII) | 20895 | 2-[(3S)-3-amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]acetic acid | C12H14N2O3 | 详情 | 详情 | |
| (XIII) | 20896 | Ethyl 2-oxo-4-phenylbutanoate; 2-Oxo-4-phenylbutyric acid ethyl ester | 64920-29-2 | C12H14O3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(IX)The Grignard condensation of 1-tetralone (IX) with 4-chloro-3-methoxyphenylmagnesium bromide (X) in THF followed by a treatment with TsOH gives 4-(4-chloro-3-methoxyphenyl)-1,2-dihydronaphthalene (XI), which is oxidized with oxone and TsOH yielding the 2-tetralone (XII). The condensation of (XII) with 2-aminoacetaldehyde dimethylacetal (XIII) in toluene affords the enamine (XIV), which is reduced with BH3 / t-Bu-NH2 and AcOH in dichloromethane to give a 9:1 mixture of cis (XV) and trans (XVI) isomers that is epimerized with t-BuOK in DMSO/DMF to a 15:85 mixture from which the desired trans-diastereomer (XVI) is isolated. The cyclization of (XVI) with CH3SO3H in dichloromethane affords the tetracyclic compound (XVII), which is hydrogenated with BH3 / t-Bu-NH2 to provide the intermediate (XVIII). Finally, this compound is methylated with formaldehyde and formic acid to obtain the previously reported rac-(VIII) compound.
| 【1】 Berger, J.G.; Clader, J.W.; Chang, W.K.; Gold, E.H. (Schering Corp.); Fused benzazepines. EP 0230270; EP 0254737; JP 1988502348; WO 8704430 . |
| 【2】 Draper, R.W.; et al.; Novel stereoselective syntheses of the fused benzazepine dopamine D1 antagonist (6aS,13bR)-11-chloro-6,6a,7,8,9,13b-hexahydro-7-methyl-5-H-benzo[d]naphth[2,1-b]azepin-12-ol (Sch 39166): 1. Aziridinium salt based syntheses. Org Process Res Dev 1998, 2, 3, 175. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIII) | 31779 | (3aS,9bR)-12-chloro-11-methoxy-3-methyl-2,3,3a,4,5,9b-hexahydro-1H-naphtho[1,2-a][3]benzazepine; (3aS,9bR)-12-chloro-3-methyl-2,3,3a,4,5,9b-hexahydro-1H-naphtho[1,2-a][3]benzazepin-11-yl methyl ether | C20H22ClNO | 详情 | 详情 | |
| (IX) | 20720 | 3,4-dihydro-1(2H)-naphthalenone | 529-34-0 | C10H10O | 详情 | 详情 |
| (X) | 36624 | bromo(4-chloro-3-methoxyphenyl)magnesium | C7H6BrClMgO | 详情 | 详情 | |
| (XI) | 36625 | 4-(4-chloro-3-methoxyphenyl)-1,2-dihydronaphthalene; 2-chloro-5-(3,4-dihydro-1-naphthalenyl)phenyl methyl ether | C17H15ClO | 详情 | 详情 | |
| (XII) | 36626 | 1-(4-chloro-3-methoxyphenyl)-3,4-dihydro-2(1H)-naphthalenone | C17H15ClO2 | 详情 | 详情 | |
| (XIII) | 34158 | aminoacetaldehyde dimethylacetal; 2,2-dimethoxy-1-ethanamine; 2,2-dimethoxyethylamine | 22483-09-6 | C4H11NO2 | 详情 | 详情 |
| (XIV) | 36627 | N-[1-(4-chloro-3-methoxyphenyl)-3,4-dihydro-2-naphthalenyl]-N-(2,2-dimethoxyethyl)amine; 1-(4-chloro-3-methoxyphenyl)-N-(2,2-dimethoxyethyl)-3,4-dihydro-2-naphthalenamine | C21H24ClNO3 | 详情 | 详情 | |
| (XV) | 36628 | N-[(1R,2S)-1-(4-chloro-3-methoxyphenyl)-1,2,3,4-tetrahydro-2-naphthalenyl]-N-(2,2-dimethoxyethyl)amine; (1R,2S)-1-(4-chloro-3-methoxyphenyl)-N-(2,2-dimethoxyethyl)-1,2,3,4-tetrahydro-2-naphthalenamine | C21H26ClNO3 | 详情 | 详情 | |
| (XVI) | 36629 | (1S,2S)-1-(4-chloro-3-methoxyphenyl)-N-(2,2-dimethoxyethyl)-1,2,3,4-tetrahydro-2-naphthalenamine; N-[(1S,2S)-1-(4-chloro-3-methoxyphenyl)-1,2,3,4-tetrahydro-2-naphthalenyl]-N-(2,2-dimethoxyethyl)amine | C21H26ClNO3 | 详情 | 详情 | |
| (XVII) | 36630 | (3aS,9bR)-12-chloro-3a,4,5,9b-tetrahydro-3H-naphtho[1,2-a][3]benzazepin-11-yl methyl ether; (3aS,9bR)-12-chloro-11-methoxy-3a,4,5,9b-tetrahydro-3H-naphtho[1,2-a][3]benzazepine | C19H18ClNO | 详情 | 详情 | |
| (XVIII) | 36631 | (3aS,9bR)-12-chloro-2,3,3a,4,5,9b-hexahydro-1H-naphtho[1,2-a][3]benzazepin-11-yl methyl ether; (3aS,9bR)-12-chloro-11-methoxy-2,3,3a,4,5,9b-hexahydro-1H-naphtho[1,2-a][3]benzazepine | C19H20ClNO | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)Alkylation of the sodium salt of 1-naphthol with benzyl bromide provides DuP-654. Alternatively, condensation of 1-tetralone (I) with benzaldehyde (II) in the presence of potassium hydroxide yields 2-benzylidene-1-tetralone (III), which may be isomerized to DuP-654 using rhodium chloride or a soluble iridium complex. A mixture of (I) and (II) may also be directly converted to DuP-654 by treating with potassium tert-butoxide in refluxing tert-butanol.
| 【1】 Batt, D.G. (E.I. Du Pont de Nemours & Co.); 2-Substituted-1-naphthols as 5-lipoxygenase inhibitors. AU 8657186; EP 0201071; ES 8801780; US 4833164 . |
| 【2】 Harris, R.R.; Batt, D.G.; Galbraith, W.; Gans, K.R.; Jaffee, B.D.; Kerr, J.S.; Ackerman, N.R.; Mackin, W.M.; DuP-654. Drugs Fut 1989, 14, 11, 1040. |
合成路线5
该中间体在本合成路线中的序号：(IV)2) The chiral intermediates the amine (I) and the acid (II) have been obtained as follows: 2a) The bromination of 1-tetralone (IV) with Br2 in methanol gives the 2-bromotetralone (V), which is treated with hydroxylamine yielding the corresponding oximae (VI). The isomerization of (V) with polyphosphoric acid (PPA) at 80 C affords the benzazepinone (VII), which is treated with potassium phthalimide (VIII) in DMF to give the corresponding phthalimido derivative (IX). The reaction of (IX) with tert-butyl bromoacetate (X) by means of potassium tert-butoxide in DMF yields the benzazepinoacetic ester (XI), which is treated with hot ethanolamine to eliminate the phthalimido group yielding racemic (I). Finally, this racemate is submitted to optical resolution with L-(+)-tartaric acid to afford the chiral (S)-intermediate (I).
| 【1】 Waldeck, H.; Höltje, D.; Messinger, J.; Antel, J.; Wurl, M.; Thormählen, D. (Kali-Chemie AG); Benzazepin-, benzoxazepin- and benzothiazepin-N-acetic acid-derivs., their preparation and their pharmaceutical compsns.. CA 2172354; EP 0733642; JP 1996269011; US 5677297 . |
| 【2】 Rozsa, S.; Gy Papp, J.; Thormahlen, D.; Waldeck, H. (Solvay SA); Drugs for increasing gastrointestinal blood supply. DE 19638020; EP 0830863; JP 1998101565 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| rac-(I) | 20728 | tert-butyl 2-(3-amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)acetate | C16H22N2O3 | 详情 | 详情 | |
| (I) | 20717 | tert-butyl 2-[(3S)-3-amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]acetate | C16H22N2O3 | 详情 | 详情 | |
| (IV) | 20720 | 3,4-dihydro-1(2H)-naphthalenone | 529-34-0 | C10H10O | 详情 | 详情 |
| (V) | 20721 | 2-bromo-3,4-dihydro-1(2H)-naphthalenone | C10H9BrO | 详情 | 详情 | |
| (VI) | 20722 | 2-bromo-3,4-dihydro-1(2H)-naphthalenone oxime | C10H10BrNO | 详情 | 详情 | |
| (VII) | 20723 | 3-bromo-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one | C10H10BrNO | 详情 | 详情 | |
| (VIII) | 10926 | (1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)potassium | C8H4KNO2 | 详情 | 详情 | |
| (IX) | 20725 | 2-(2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl)-1H-isoindole-1,3(2H)-dione | C18H14N2O3 | 详情 | 详情 | |
| (X) | 17430 | 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate | 5292-43-3 | C6H11BrO2 | 详情 | 详情 |
| (XI) | 20727 | tert-butyl 2-[3-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]acetate | C25H26N2O5 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(IV)2a) The chiral intermediate amine (I) has been obtained as follows: The bromination of 1-tetralone (IV) with Br2 in methanol gives the 2-bromotetralone (V), which is treated with hydroxylamine yielding the corresponding oximae (VI). The isomerization of (V) with polyphosphoric acid (PPA) at 80 C affords the benzazepinone (VII), which is treated with potassium phthalimide (VIII) in DMF to give the corresponding phthalimido derivative (IX). The reaction of (IX) with tert-butyl bromoacetate (X) by means of potassium tert-butoxide in DMF yields the benzazepinoacetic ester (XI), which is treated with hot ethanolamine to eliminate the phthalimido group yielding racemic (I). Finally, this racemate is submitted to optical resolution with L-(+)-tartaric acid to afford the chiral (S)-intermediate (I).
| 【1】 Sorbera, L.A.; Leeson, P.A.; Castañer, J.; SLV-306. Drugs Fut 2002, 27, 1, 27. |
| 【2】 Waldeck, H.; Höltje, D.; Messinger, J.; Antel, J.; Wurl, M.; Thormählen, D. (Kali-Chemie AG); Benzazepin-, benzoxazepin- and benzothiazepin-N-acetic acid-derivs., their preparation and their pharmaceutical compsns.. CA 2172354; EP 0733642; JP 1996269011; US 5677297 . |
| 【3】 Rozsa, S.; Gy Papp, J.; Thormahlen, D.; Waldeck, H. (Solvay SA); Drugs for increasing gastrointestinal blood supply. DE 19638020; EP 0830863; JP 1998101565 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| rac-(I) | 20728 | tert-butyl 2-(3-amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)acetate | C16H22N2O3 | 详情 | 详情 | |
| (I) | 20717 | tert-butyl 2-[(3S)-3-amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]acetate | C16H22N2O3 | 详情 | 详情 | |
| (IV) | 20720 | 3,4-dihydro-1(2H)-naphthalenone | 529-34-0 | C10H10O | 详情 | 详情 |
| (V) | 20721 | 2-bromo-3,4-dihydro-1(2H)-naphthalenone | C10H9BrO | 详情 | 详情 | |
| (VI) | 20722 | 2-bromo-3,4-dihydro-1(2H)-naphthalenone oxime | C10H10BrNO | 详情 | 详情 | |
| (VII) | 20723 | 3-bromo-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one | C10H10BrNO | 详情 | 详情 | |
| (VIII) | 10926 | (1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)potassium | C8H4KNO2 | 详情 | 详情 | |
| (IX) | 20725 | 2-(2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl)-1H-isoindole-1,3(2H)-dione | C18H14N2O3 | 详情 | 详情 | |
| (X) | 17430 | 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate | 5292-43-3 | C6H11BrO2 | 详情 | 详情 |
| (XI) | 20727 | tert-butyl 2-[3-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]acetate | C25H26N2O5 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(III)Sodium azide (I) is treated with sulfuric acid to give hydrazoic acid (II), which is condensed with 1-tetralone (III) in hot aqueous sulfuric acid yielding 2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (IV). The bromination of (IV) with Br2 in chloroform affords the 3-bromo derivative (V), which is treated with sodium azide in DMSO to give the corresponding azido derivative (VI). The condensation of (VI) with ethyl 2-bromoacetate (VII) by means of KOH and tetrabutylammonium bromide in THF yields the adduct (VIII). The azido group of (VIII) is reduced with H2 over Pd/C in ethanol the amine (IX) as a racemic mixture, which is submitted to optical resolution with L-tartaric acid affording the desired (S)-enantiomer (X). The condensation of intermediate (X) with 2(R)-benzyl-3-benzyloxyamino)propionic acid (XI) by means of HOBT and EDAC in dichloromethane provides the amide (XII), which is formylated with formic acid and acetic anhydride yielding the formamide (XIII). The debenzylation of (XIII) with H2 over Pd/C in methanol affords the intermediate (XIV), which is finally hydrolyzed with NaOH in methanol.
| 【1】 Asaad, M.M.; Robl, J.A.; Simpkins, L.M.; N-Formyl hydroxylamine containing dipeptides: Generation of a new class of vasopeptidase inhibitors. Bioorg Med Chem Lett 2000, 10, 3, 257. |
| 【2】 Robl, J.A. (Bristol-Myers Squibb Co.); N-Formyl hydroxylamine containing cpds. useful as ACE inhibitors and/or NEP inhibitors. WO 9738705 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 37288 | 1H-triazirine | HN3 | 详情 | 详情 | |
| (III) | 20720 | 3,4-dihydro-1(2H)-naphthalenone | 529-34-0 | C10H10O | 详情 | 详情 |
| (IV) | 30511 | 1,3,4,5-tetrahydro-2H-1-benzazepin-2-one | C10H11NO | 详情 | 详情 | |
| (V) | 20723 | 3-bromo-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one | C10H10BrNO | 详情 | 详情 | |
| (VI) | 20891 | 3-azido-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one | C10H10N4O | 详情 | 详情 | |
| (VII) | 16640 | Ethyl 2-bromoacetate; Ethyl bromoacetate | 105-36-2 | C4H7BrO2 | 详情 | 详情 |
| (VIII) | 20893 | ethyl 2-(3-azido-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)acetate | C14H16N4O3 | 详情 | 详情 | |
| (IX) | 37292 | ethyl 2-(3-amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)acetate | C14H18N2O3 | 详情 | 详情 | |
| (X) | 20894 | ethyl 2-[(3S)-3-amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]acetate | 109010-60-8 | C14H18N2O3 | 详情 | 详情 |
| (XI) | 37283 | (2R)-2-benzyl-3-[(benzyloxy)amino]propionic acid | C17H19NO3 | 详情 | 详情 | |
| (XII) | 37289 | ethyl 2-[(3S)-3-([(2R)-2-benzyl-3-[(benzyloxy)amino]propanoyl]amino)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]acetate | C31H35N3O5 | 详情 | 详情 | |
| (XIII) | 37290 | ethyl 2-[(3S)-3-([(2R)-2-benzyl-3-[(benzyloxy)(formyl)amino]propanoyl]amino)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]acetate | C32H35N3O6 | 详情 | 详情 | |
| (XIV) | 37291 | ethyl 2-[(3S)-3-([(2R)-2-benzyl-3-[formyl(hydroxy)amino]propanoyl]amino)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]acetate | C25H29N3O6 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(I)The Stobbe-type condensation of tetralone (I) with diethyl succinate (II) by means of potassium tert-butoxide in tert butanol and subsequent hydrolysis/decarboxylation in HOAc/HCl gives the propionic acid (III), which is asymmetrically reduced with H2 over a chiral ruthenium catalyst in methanol to afford (S)-3-(1,2,3,4-tetrahydronaphthalen-1-yl)propionic acid (S)-(IV). The cyclization of (IV) by means of PPA at 130 C provides the hexahydrophenalen-1-one (V), which by reaction with hydroxylamine is converted into the oxime (VI). The reduction of (VI) with H2 over Raney Ni in methanol yields the corresponding amine (VII), which is condensed with the piperidinium iodide (VIII) by means of K2CO3 in refluxing ethanol to afford a diastereomeric mixture from which the desired enantiomer (IX) is separated by column chromatography. A Strecker reaction of (IX) with aniline and Tms-CN in HOAc gives the anilino nitrile (X), which is finally cyclized by reaction with formic acid, Ac2O and formamide at 200 C to yield the target spiro compound. Alternatively, the anilino nitrile (X) is hydrolyzed with formic acid/Ac2O to give the formylated carboxamide (XI), which is finally cyclized with refluxing triethyl orthoformate, followed by reduction with NaBH4 in methanol.
| 【1】 Hennig, M.; Adam, G.; Wichmann, J.; Cesura, A.M.; Dautzenberg, F.M.; Scalone, M.; Jenck, F.; Rover, S.; Synthesis of (1S,3aS)-8-(2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one, a potent and selective orphanin FQ (OFQ) receptor agonist with anxiolytic properties. Eur J Med Chem 2000, 35, 9, 839. |
| 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) | 20720 | 3,4-dihydro-1(2H)-naphthalenone | 529-34-0 | C10H10O | 详情 | 详情 |
| (II) | 12313 | diethyl succinate | 123-25-1 | C8H14O4 | 详情 | 详情 |
| (III) | 51989 | 3-(3,4-Dihydronaphthalen-1-yl)propionic acid | C13H14O2 | 详情 | 详情 | |
| (IV) | 51990 | 3-[(1S)-1,2,3,4-tetrahydro-1-naphthalenyl]propionic acid | C13H16O2 | 详情 | 详情 | |
| (V) | 51991 | (3aS)-2,3,3a,4,5,6-hexahydro-1H-phenalen-1-one | C13H14O | 详情 | 详情 | |
| (VI) | 51992 | (3aS)-2,3,3a,4,5,6-hexahydro-1H-phenalen-1-one oxime | C13H15NO | 详情 | 详情 | |
| (VII) | 51993 | (3aS)-2,3,3a,4,5,6-hexahydro-1H-phenalen-1-amine; (3aS)-2,3,3a,4,5,6-hexahydro-1H-phenalen-1-ylamine | C13H17N | 详情 | 详情 | |
| (VIII) | 51994 | 1-ethyl-1-methyl-4-oxopiperidinium iodide | C8H16INO | 详情 | 详情 | |
| (IX) | 51995 | 1-[(1S,3aS)-2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl]-4-piperidinone | C18H23NO | 详情 | 详情 | |
| (X) | 51996 | 1-[(1S,3aS)-2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl]-4-anilino-4-piperidinecarbonitrile | C25H29N3 | 详情 | 详情 | |
| (XI) | 51997 | 1-[(1S,3aS)-2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl]-4-(formylanilino)-4-piperidinecarboxamide | C26H31N3O2 | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(I)The condensation of 1-tetralone (I) with 2-oxoacetic acid (II) by means of KOH gives 2-(1-oxo-1,2,3,4-tetrahydronaphthalen-2-ylidene)acetic acid (III), which is cyclized with hydrazine in hot butanol to yield the tricyclic pyridazinone (IV). The treatment of (IV) with hot POCl3 gives the chloropyridazine derivative (V), which is treated with hydrazine in boiling water to provide the hydrazino derivative (VI). The hydrogenation of (VI) with H2 over Ni in methanol gives the aminopyridazine derivative (VII), which is condensed with ethyl 11-bromoundecanoate (VIII) (prepared by esterification of the corresponding acid (IX) with Et-OH/HCl) in hot DMF to yield the adduct (X). The hydrolysis of (X) with HCl in hot HOAc affords the corresponding acid (XI), which is finally condensed with 1-(2-pyrimidinyl)piperazine (XII) by means of HOBt and EDC in DMF to provide the target amide.
| 【1】 Mirzoeva, S.; Zasadzki, M.; Sawkar, A.; et al.; Discovery of a 3-amino-6-phenyl-pyridazine derivative as a new synthetic antineuroinflammatory compound. J Med Chem 2002, 45, 3, 563. |
| 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) | 20720 | 3,4-dihydro-1(2H)-naphthalenone | 529-34-0 | C10H10O | 详情 | 详情 |
| (II) | 15618 | 2-Oxoacetic acid; Glyoxylic Acid | 298-12-4 | C2H2O3 | 详情 | 详情 |
| (III) | 56768 | 2-[1-oxo-3,4-dihydro-2(1H)-naphthalenylidene]acetic acid | C12H10O3 | 详情 | 详情 | |
| (IV) | 56769 | 5,6-dihydrobenzo[h]cinnolin-3(2H)-one | C12H10N2O | 详情 | 详情 | |
| (V) | 56770 | 3-chloro-5,6-dihydrobenzo[h]cinnoline | C12H9ClN2 | 详情 | 详情 | |
| (VI) | 56771 | 3-hydrazino-5,6-dihydrobenzo[h]cinnoline | C12H12N4 | 详情 | 详情 | |
| (VII) | 56772 | 5,6-dihydrobenzo[h]cinnolin-3-ylamine; 5,6-dihydrobenzo[h]cinnolin-3-amine | C12H11N3 | 详情 | 详情 | |
| (VIII) | 56773 | Ethyl omega-bromoundecanoate; Ethyl 11-bromoundecanoate | 6271-23-4 | C13H25BrO2 | 详情 | 详情 |
| (IX) | 56774 | 11-Bromoundecanoic acid | 2834-05-1 | C11H21BrO2 | 详情 | 详情 |
| (X) | 56775 | ethyl 11-[3-imino-5,6-dihydrobenzo[h]cinnolin-2(3H)-yl]undecanoate | C25H35N3O2 | 详情 | 详情 | |
| (XI) | 56776 | 11-[3-imino-5,6-dihydrobenzo[h]cinnolin-2(3H)-yl]undecanoic acid | C23H31N3O2 | 详情 | 详情 | |
| (XII) | 11175 | 2-(1-Piperazinyl)pyrimidine; 2-Piperazinopyrimidine; N-(Pyrimidinyl)piperazine | 20980-22-7 | C8H12N4 | 详情 | 详情 |