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【结 构 式】 
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【分子编号】18522 【品名】3-amino-1-propanol 【CA登记号】156-87-6 |
【 分 子 式 】C3H9NO 【 分 子 量 】75.1106 【元素组成】C 47.97% H 12.08% N 18.65% O 21.3% |
合成路线1
该中间体在本合成路线中的序号：Title compound can be prepared as shown in Scheme: 1) 3,6-Dichloropyridazine (I) is converted to 3(2H)-pyridazinone (III) in two steps. 2) 3-N-(2-Benzo[1,4]dioxanylmethyl)amino-1-propanol (V), obtained by the reaction of (2-benzo[1,4]dioxanylmethyl)-4-toluenesulfonate (IV) with 3-amino-1-propanol, is N-benzylated to form the N-protected amino alcohol (VI), which on treatment with thionyl chloride affords the chloroalkyl derivative (VII). 3) Alkylation of 3(2H)-pyridazinone (III) with (VII) under phase-transfer catalysis conditions to the N-benzylated GYKI-12743 (VIII) and then removal of the N-benzyl group by hydrogenation gives GYKI-12743.
| 【1】 Kasztreiner, E.; Rabloczky, G.; Makk, N.; Jaszlits, L.; Matyus, P.; Cseh, G.; Pribusz, geb. Rapp, I.; Czakó, K.; Diesler, E.; Elekes, I.; Kaufer, L.; Kuhár, geb. Kürthy, M.; Kincsessy, J.; Kosáry, J.; Nagy, Gyöngyi geb. C. (Richter Gedeon Vegyeszeti); 3(2H)-Pyridazinone derivs., a process and intermediates for preparing them and medicaments containing them and/or other 3(2H)-pyridazinone derivatives. AU 8664496; EP 0220735; JP 87161768 . |
| 【2】 Kasztreiner, E.; Matyus, P.; Rabloczky, G.; Jaszlits, L.; GYKI-12743. Drugs Fut 1989, 14, 7, 622. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 18522 | 3-amino-1-propanol | 156-87-6 | C3H9NO | 详情 | 详情 | |
| 19171 | 1-(Chloromethyl)benzene; Benzyl chloride | 100-44-7 | C7H7Cl | 详情 | 详情 | |
| (I) | 11292 | 3,6-Dichloropyridazine | 141-30-0 | C4H2Cl2N2 | 详情 | 详情 |
| (II) | 20957 | 6-chloro-3(2H)-pyridazinone | C4H3ClN2O | 详情 | 详情 | |
| (III) | 20958 | 3(2H)-pyridazinone | C4H4N2O | 详情 | 详情 | |
| (IV) | 20959 | 2,3-dihydro-1,4-benzodioxin-2-ylmethyl 4-methylbenzenesulfonate | C16H16O5S | 详情 | 详情 | |
| (V) | 20960 | 3-[(2,3-dihydro-1,4-benzodioxin-2-ylmethyl)amino]-1-propanol | C12H17NO3 | 详情 | 详情 | |
| (VI) | 20961 | 3-[benzyl(2,3-dihydro-1,4-benzodioxin-2-ylmethyl)amino]-1-propanol | C19H23NO3 | 详情 | 详情 | |
| (VII) | 20962 | N-benzyl-3-chloro-N-(2,3-dihydro-1,4-benzodioxin-2-ylmethyl)-1-propanamine; N-benzyl-N-(3-chloropropyl)-N-(2,3-dihydro-1,4-benzodioxin-2-ylmethyl)amine | C19H22ClNO2 | 详情 | 详情 | |
| (VIII) | 20963 | 2-[3-[benzyl(2,3-dihydro-1,4-benzodioxin-2-ylmethyl)amino]propyl]-3(2H)-pyridazinone | C23H25N3O3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XVII)The condensation between 4-bromobutyronitrile (XVI) and 3-amino-1-propanol (XVII) gave the hydroxy amino nitrile (XVIII), which was further converted to the N,O-bis-tosylated derivative (XIX). Displacement of the tosylate ester group of (XIX) with NaI in boiling acetone afforded the alkyl iodide (XX). Alkylation of amine (XV) with iodide (XX) provided the secondary amine adduct (XXI). The p-toluenesulfonamido group of (XXI) was reductively removed by sodium in liquid ammonia, yielding diamine (XXII). Subsequent nitrile reduction by means of LiAlH4 furnished triamine (XXIII).
| 【1】 Moriarty, R.M.; et al.; Synthesis of squalamine. A steroidal antibiotic from the shark. Tetrahedron Lett 1994, 35, 44, 8103. |
| 【2】 Moriarty, R.M.; Guo, L.; Tuladhar, S.M. (Genaera Corp.); Chemical synthesis of squalamine. WO 9419366 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XV) | 53701 | (3S,5R,7R,8R,9S,10S,13R,14S,17R)-3-amino-17-((1R)-4-{[tert-butyl(dimethyl)silyl]oxy}-1,5-dimethylhexyl)-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-7-ol | n/a | C33H63NO2Si | 详情 | 详情 |
| (XVI) | 34789 | 4-bromobutanenitrile | 5332-06-9 | C4H6BrN | 详情 | 详情 |
| (XVII) | 18522 | 3-amino-1-propanol | 156-87-6 | C3H9NO | 详情 | 详情 |
| (XVIII) | 53702 | 4-[(3-hydroxypropyl)amino]butanenitrile | n/a | C7H14N2O | 详情 | 详情 |
| (XIX) | 53703 | 3-{(3-cyanopropyl)[(4-methylphenyl)sulfonyl]amino}propyl 4-methylbenzenesulfonate | n/a | C21H26N2O5S2 | 详情 | 详情 |
| (XX) | 53704 | N-(3-cyanopropyl)-N-(3-iodopropyl)-4-methylbenzenesulfonamide | n/a | C14H19IN2O2S | 详情 | 详情 |
| (XXI) | 53705 | N-(3-{[(3S,5R,7R,8R,9S,10S,13R,14S,17R)-17-((1R)-4-{[tert-butyl(dimethyl)silyl]oxy}-1,5-dimethylhexyl)-7-hydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-yl]amino}propyl)-N-(3-cyanopropyl)-4-methylbenzenesulfonamide | n/a | C47H81N3O4SSi | 详情 | 详情 |
| (XXII) | 53706 | 4-[(3-{[(3S,5R,7R,8R,9S,10S,13R,14S,17R)-17-((1R)-4-{[tert-butyl(dimethyl)silyl]oxy}-1,5-dimethylhexyl)-7-hydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-yl]amino}propyl)amino]butanenitrile | n/a | C40H75N3O2Si | 详情 | 详情 |
| (XXIII) | 53707 | (3S,5R,7R,8R,9S,10S,13R,14S,17R)-3-({3-[(4-aminobutyl)amino]propyl}amino)-17-((1R)-4-{[tert-butyl(dimethyl)silyl]oxy}-1,5-dimethylhexyl)-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-7-ol | n/a | C40H79N3O2Si | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(III)Pyridazinone (I) was converted to 3,4,5-trichloropyridazine (VIII) on treatment with POCl3. Nucleophylic substitution in (II) with 3-aminopropanol (III) gave, after crystallization, the desired isomer (IV). Hydrolysis of the 3-chloro group of (IV) was carried out with AcOH and AcONa, resulting in the N,O-diacetyl derivative (V). Subsequent reaction of (V) with aqueous HBr provided bromide (VI), which was then treated with N-methyl homoveratrylamine (VII) to furnish the target compound (VIII). This compound was finally isolated as the fumarate salt on treatment with fumaric acid in EtOH (1).
| 【1】 Kotay-Nagy, P.; et al.; A new synthesis of EGIS-7229, a potent antiarrhythmic drug-candidate. 15th European Federation for Medicinal Chemistry International Symposium on Medicinal Chemistry (Sept 6 1998, Edinburgh) 1998, Abst P.151. |
| 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) | 24570 | 4,5-dichloro-3(2H)-pyridazinone | C4H2Cl2N2O | 详情 | 详情 | |
| (II) | 27529 | 3,4,5-trichloropyridazine | 14161-11-6 | C4HCl3N2 | 详情 | 详情 |
| (III) | 18522 | 3-amino-1-propanol | 156-87-6 | C3H9NO | 详情 | 详情 |
| (IV) | 27530 | 3-[(3,5-dichloro-4-pyridazinyl)amino]-1-propanol | C7H9Cl2N3O | 详情 | 详情 | |
| (V) | 27531 | 3-[acetyl(5-chloro-3-oxo-2,3-dihydro-4-pyridazinyl)amino]propyl acetate | C11H14ClN3O4 | 详情 | 详情 | |
| (VI) | 27532 | 4-[(3-bromopropyl)amino]-5-chloro-3(2H)-pyridazinone | C7H9BrClN3O | 详情 | 详情 | |
| (VII) | 18938 | 2-(3,4-dimethoxyphenyl)-N-methyl-1-ethanamine; N-(3,4-dimethoxyphenethyl)-N-methylamine | 3490-06-0 | C11H17NO2 | 详情 | 详情 |
| (VIII) | 27533 | 5-chloro-4-([3-[(3,4-dimethoxyphenethyl)(methyl)amino]propyl]amino)-3(2H)-pyridazinone | C18H25ClN4O3 | 详情 | 详情 | |
| (IX) | 23808 | Fumaric acid; (E)-2-butenedioic acid | 110-17-8 | C4H4O4 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XVI)Condensation between 2,5-dimethoxytetrahydrofuran (XIV), acetone-1,3-dicarboxylic acid (XV) and 3-amino-1-propanol (XVI), followed by acid decarboxylation of the intermediate adduct (XVII) furnished the tropinone analogue (XVIII). After conversion of (XVIII) to the corresponding oxime (XIX), its hydrogenation over PtO2 gave amine (XX). This was finally coupled with acid chloride (VIII) to give the title amide.
| 【1】 Yokomori, S.; Muramatsu, M.; Suzuki, M.; Ito, C.; Asanuma, H.; Isobe, Y.; Ohuchi, Y.; Kaneko, T.; Synthesis and evaluation of novel 2-oxo-1,2-dihydro-3-quinolinecarboxamide derivatives as potent and selective serotonin 5-HT4 receptor agonists. Chem Pharm Bull 2001, 49, 1, 29. |
| 【2】 Ohuchi, Y.; Suzuki, M.; Asanuma, H.; Yokomori, S.; Hatayama, K. (Taisho Pharmaceutical Co., Ltd.); Quinolinecarboxylic acid deriv.. EP 0710662; JP 1996034784; US 5753673; WO 9531455 . |
| 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) | 36336 | 1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarbonyl chloride | C13H12ClNO2 | 详情 | 详情 | |
| (XIV) | 12132 | 2,5-Dimethoxytetrahydrofuran; 5-Methoxytetrahydro-2-furanyl methyl ether | 696-59-3 | C6H12O3 | 详情 | 详情 |
| (XV) | 15530 | 1,3-Acetonedicarboxylic Acid; 3-Oxopentanedioic acid；3-oxoglutaric acid | 542-05-2 | C5H6O5 | 详情 | 详情 |
| (XVI) | 18522 | 3-amino-1-propanol | 156-87-6 | C3H9NO | 详情 | 详情 |
| (XVII) | 36340 | (1R,5S)-8-(3-hydroxypropyl)-3-oxo-8-azabicyclo[3.2.1]octane-2,4-dicarboxylic acid | C12H17NO6 | 详情 | 详情 | |
| (XVIII) | 36341 | (1R,5S)-8-(3-hydroxypropyl)-8-azabicyclo[3.2.1]octan-3-one | C10H17NO2 | 详情 | 详情 | |
| (XIX) | 36342 | (1R,5S)-8-(3-hydroxypropyl)-8-azabicyclo[3.2.1]octan-3-one oxime | C10H18N2O2 | 详情 | 详情 | |
| (XX) | 36343 | 3-[(1R,5S)-3-amino-8-azabicyclo[3.2.1]oct-8-yl]-1-propanol | C10H20N2O | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(II)Aldehyde (I) was condensed with 3-aminopropanol (II) in refluxing benzene using a Dean-Stark trap to give imine (III) which, without purification, was in turn condensed with a-mercaptoacetic acid (IV) to afford thiazolidinone (V). Treatment of alcohol (V) with PBr3 gave bromide (VI). Then, reaction of (VI) with amine (VII) in the presence of K2CO3 in refluxing acetone produced the target compound.
| 【1】 Kato, T.; Ozaki, T.; Tamura, K.; Suzuki, Y.; Akima, M.; Ohi, N.; Novel calcium antagonists with both calcium overload inhibition and antioxidant activity. 1. 2-(3,5-Di-tert-butyl-4-hydroxyphenyl)-3-(aminopropyl)thiazolidinones. J Med Chem 1998, 41, 22, 4309. |
| 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) | 14875 | 3,5-Bis(1,1-dimethylethyl)-4-hydroxybenzaldehyde; 3,5-di(tert-butyl)-4-hydroxybenzaldehyde; 3,5-Di-tert-butyl-4-hydroxybenzaldehyde | 1620-98-0 | C15H22O2 | 详情 | 详情 |
| (II) | 18522 | 3-amino-1-propanol | 156-87-6 | C3H9NO | 详情 | 详情 |
| (III) | 18523 | 2,6-di(tert-butyl)-4-[[(3-hydroxypropyl)imino]methyl]phenol | C18H29NO2 | 详情 | 详情 | |
| (IV) | 18524 | 2-sulfanylacetic acid | 68-11-1 | C2H4O2S | 详情 | 详情 |
| (V) | 18525 | 2-[3,5-di(tert-butyl)-4-hydroxyphenyl]-3-(3-hydroxypropyl)-1,3-thiazolidin-4-one | C20H31NO3S | 详情 | 详情 | |
| (VI) | 18526 | 3-(3-bromopropyl)-2-[3,5-di(tert-butyl)-4-hydroxyphenyl]-1,3-thiazolidin-4-one | C20H30BrNO2S | 详情 | 详情 | |
| (VIII) | 12561 | 2-(1,3-Benzodioxol-5-yloxy)-N-methyl-1-ethanamine; N-[2-(1,3-Benzodioxol-5-yloxy)ethyl]-N-methylamine | C10H13NO3 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：The enantiomerically pure benzodioxane derivative (VIII) was obtained in a straightforward route including five steps starting from pyrocatechin (I). Racemic (VI) was then resolved by means of crystallization with (-)-O,O'-dibenzoyl-L-tartaric acid.
| 【1】 Matyus, P.; GYKI-16084. Drugs Fut 1999, 24, 10, 1072. |
| 【2】 3(2H)-Pyridazinone derivs. and pharmaceutical compsns. containing these cpds.. WO 9638441 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 18522 | 3-amino-1-propanol | 156-87-6 | C3H9NO | 详情 | 详情 | |
| (I) | 11599 | o-Dihydroxybenzene; Catechol; Pyrocatechol | 120-80-9 | C6H6O2 | 详情 | 详情 |
| (II) | 10146 | Epichlorohydrin; 2-(Chloromethyl)oxirane | 106-89-8 | C3H5ClO | 详情 | 详情 |
| (III) | 28714 | 2,3-dihydro-1,4-benzodioxin-2-ylmethanol | 3663-82-9 | C9H10O3 | 详情 | 详情 |
| (IV) | 20959 | 2,3-dihydro-1,4-benzodioxin-2-ylmethyl 4-methylbenzenesulfonate | C16H16O5S | 详情 | 详情 | |
| (V) | 20960 | 3-[(2,3-dihydro-1,4-benzodioxin-2-ylmethyl)amino]-1-propanol | C12H17NO3 | 详情 | 详情 | |
| (VI) | 28715 | 3-chloro-N-(2,3-dihydro-1,4-benzodioxin-2-ylmethyl)-1-propanamine | C12H16ClNO2 | 详情 | 详情 | |
| (VII) | 16186 | (2R,3R)-2,3-bis(benzoyloxy)butanedioic acid | C18H14O8 | 详情 | 详情 | |
| (VIII) | 28716 | 3-chloro-N-[(2R)-2,3-dihydro-1,4-benzodioxin-2-ylmethyl]-1-propanamine | C12H16ClNO2 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(XV)Bromination of 4-bromo-3-methyl anisole derivative (I) by means of NBS and light in CH2Cl2 and (BzO)2 affords derivative (II), which is then treated with protected trifluoroethane derivative (III) in DMF to give (IV). Alternatively, (II) can be converted into (IV) by first treating with 2,2,2-trifluoroethylamine (V) in DMSO followed by N-protection by means of Boc2O in CH2Cl2. Treatment of (IV) with dimethyl itaconate (VII) in the presence of Pd(OAc)2, P(o-tol)3, DIEA and propionitrile yields intermediate (VIII), which is then reduced by hydrogenolysis over Pd/C in EtOAc to afford butanoate (IX). Removal of the Boc protecting group of (IX) by treatment with TFA and anisole provides derivative (X), which is then cyclized by means of tripropylamine in refluxing xylenes to afford benzazepine derivative (XI) in its racemic form. Separation of the two enantiomers of (XI) by chiral HPLC affords (S)-(XII), which is demethylated with BBr3 in CH2Cl2 to yield (XIII). Treatment of N-oxide derivative (XIV) with 3-amino-1-propanol (XV) in tert-amyl alcohol in the presence of NaHCO3 yields derivative (XVI), which is then reacted with phenol derivative (XIII) in a Mitsunobu reaction with PPh3 and DEAD in THF/DMF to give ether derivative (XVII). Reduction of (XVII) with cyclohexene in isopropanol in the presence of Pd/C affords methyl acetate (XVIII), which is finally hydrolyzed by means of aqueous NaOH in dioxane.
| 【1】 Miller, W.H.; Bhatnager, P.K.; Alberts, D.P.; et al.; Discovery of orally active nonpeptide vitronectin receptor antagonists based on a 2-benzazepine gly-asp mimetic. J Med Chem 2000, 43, 1, 22. |
| 【2】 Callahan, J.F.; Cousins, R.D.; Keenan, R.M.; Kwon, C.; Miller, W.H.; Uzinkas, I.N. (SmithKline Beecham plc); Vitronectin receptor antagonists. EP 0957917; WO 9814192 . |
| 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) | 42539 | 4-bromo-3-methylphenyl methyl ether; 1-bromo-4-methoxy-2-methylbenzene | 27060-75-9 | C8H9BrO | 详情 | 详情 |
| (II) | 27552 | 1-bromo-2-(bromomethyl)-4-methoxybenzene | C8H8Br2O | 详情 | 详情 | |
| (III) | 42540 | C7H11F3NNaO2 | 详情 | 详情 | ||
| (IV) | 42541 | tert-butyl 2-bromo-5-methoxybenzyl(2,2,2-trifluoroethyl)carbamate | C15H19BrF3NO3 | 详情 | 详情 | |
| (V) | 42542 | 2,2,2-trifluoroethylamine; 2,2,2-trifluoro-1-ethanamine | 753-90-2 | C2H4F3N | 详情 | 详情 |
| (VI) | 42543 | N-(2-bromo-5-methoxybenzyl)-2,2,2-trifluoro-1-ethanamine; N-(2-bromo-5-methoxybenzyl)-N-(2,2,2-trifluoroethyl)amine | C10H11BrF3NO | 详情 | 详情 | |
| (VII) | 21416 | dimethyl 2-methylenesuccinate | 617-52-7 | C7H10O4 | 详情 | 详情 |
| (VIII) | 42544 | dimethyl 2-[(E)-(2-[[(tert-butoxycarbonyl)(2,2,2-trifluoroethyl)amino]methyl]-4-methoxyphenyl)methylidene]succinate | C22H28F3NO7 | 详情 | 详情 | |
| (IX) | 42545 | dimethyl 2-(2-[[(tert-butoxycarbonyl)(2,2,2-trifluoroethyl)amino]methyl]-4-methoxybenzyl)succinate | C22H30F3NO7 | 详情 | 详情 | |
| (X) | 42546 | dimethyl 2-(4-methoxy-2-[[(2,2,2-trifluoroethyl)amino]methyl]benzyl)succinate | C17H22F3NO5 | 详情 | 详情 | |
| (XI) | 42547 | methyl 2-[8-methoxy-3-oxo-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-2-benzazepin-4-yl]acetate | C16H18F3NO4 | 详情 | 详情 | |
| (XII) | 42548 | methyl 2-[(4S)-8-methoxy-3-oxo-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-2-benzazepin-4-yl]acetate | C16H18F3NO4 | 详情 | 详情 | |
| (XIII) | 42549 | methyl 2-[(4S)-8-hydroxy-3-oxo-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-2-benzazepin-4-yl]acetate | C15H16F3NO4 | 详情 | 详情 | |
| (XIV) | 34524 | 2-chloro-1-pyridiniumolate | 2402-95-1 | C5H4ClNO | 详情 | 详情 |
| (XV) | 18522 | 3-amino-1-propanol | 156-87-6 | C3H9NO | 详情 | 详情 |
| (XVI) | 34525 | 2-[(3-hydroxypropyl)amino]-1-pyridiniumolate | C8H12N2O2 | 详情 | 详情 | |
| (XVII) | 42550 | 2-[(3-[[(4S)-4-(2-methoxy-2-oxoethyl)-3-oxo-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-2-benzazepin-8-yl]oxy]propyl)amino]-1-pyridiniumolate | C23H26F3N3O5 | 详情 | 详情 | |
| (XVIII) | 42551 | methyl 2-[(4S)-3-oxo-8-[3-(2-pyridinylamino)propoxy]-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-2-benzazepin-4-yl]acetate | C23H26F3N3O4 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(III)Curtius rearrangement of arachidonic acid (I) in the presence of diphenyl phosphoryl azide in hot benzene gave isocyanate (II), which was coupled with ethanolamine (III) to yield the title urea.
| 【1】 Aung, M.M.; Abood, M.E.; Martin, B.R.; Razdan, R.K.; Ng, E.W.; Unique analogues of anandamide: Arachidonyl ethers and carbamates and norarachidonyl carbamates and ureas. J Med Chem 1999, 42, 1975. |
| 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) | 21406 | (5Z,8Z,11Z,14Z)-5,8,11,14-icosatetraenoic acid | 7771-44-0 | C20H32O2 | 详情 | 详情 |
| (II) | 26237 | (4Z,7Z,10Z,13Z)-1-isocyanato-4,7,10,13-nonadecatetraene; (4Z,7Z,10Z,13Z)-4,7,10,13-nonadecatetraenyl isocyanate | C20H31NO | 详情 | 详情 | |
| (III) | 18522 | 3-amino-1-propanol | 156-87-6 | C3H9NO | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(XII)Condensation of 2-chloropyridine-N-oxide hydrochloride (XI) with 3-amino-1-propanol (XII) in boiling tert-amyl alcohol provided the aminopyridine N-oxide (XIII). Subsequent Mitsunobu coupling of (XIII) with the chiral phenol (X) in the presence of diisopropyl azodicarboxylate and triphenyl phosphine produced ether (XIV). The N-oxide group of (XIV) was then reduced by transfer hydrogenation using cyclohexene and Pd/C to yield pyridine (XV). Finally, saponification of the ethyl ester of (XV) furnished the title compound.
| 【1】 Drake, F.H. (SmithKline Beecham plc); Method for stimulating bone formation. EP 0946180; WO 9815278 . |
| 【2】 Miller, W.H.; Samanen, J.M.; Heerding, D.; Bondinell, W.E. (SmithKline Beecham Corp.); Vitronectin receptor antagonists. EP 1025090; WO 9915508 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (X) | 34523 | ethyl 2-[(10S)-3-hydroxy-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-10-yl]acetate | C19H20O3 | 详情 | 详情 | |
| (XI) | 34524 | 2-chloro-1-pyridiniumolate | 2402-95-1 | C5H4ClNO | 详情 | 详情 |
| (XII) | 18522 | 3-amino-1-propanol | 156-87-6 | C3H9NO | 详情 | 详情 |
| (XIII) | 34525 | 2-[(3-hydroxypropyl)amino]-1-pyridiniumolate | C8H12N2O2 | 详情 | 详情 | |
| (XIV) | 34526 | 2-[(3-[[(10S)-10-(2-ethoxy-2-oxoethyl)-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-3-yl]oxy]propyl)amino]-1-pyridiniumolate | C27H30N2O4 | 详情 | 详情 | |
| (XV) | 34527 | ethyl 2-[(10S)-3-[3-(2-pyridinylamino)propoxy]-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-10-yl]acetate | C27H30N2O3 | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(III)Treatment of cyclohexanecarboxaldehyde (I) with sulfur monochloride produced the dimeric disulfide (II). After condensation of (II) with 3-amino-1-propanol (III), reduction with NaBH4 afforded diamine (IV). Subsequent N-methylation of (IV) to give (VI) was achieved by condensation with formaldehyde, followed by NaBH4 reduction of the resulting oxazine (V). Reductive cleavage of the disulfide group of (VI) using LiAlH4 provided thiol (VII). Optionally, nitrosation of the sulfhydryl group of (VII) by means of tert-butyl nitrite gave rise to the nitrosothio derivative (VIII). Further coupling of this compound with diclofenac (IX) in the presence of DCC and DMAP furnished the title ester. Alternatively, the title compound was prepared by esterification of mercapto alcohol (VII) with diclofenac, followed by S-nitrosation of the resulting ester (X).
| 【1】 Bandarage, U.K.; et al.; Nitrosothiol esters of diclofonecac: Synthesis and pharmacological characterization as gastrointestinal-sparing prodrugs. J Med Chem 2000, 43, 21, 4005. |
| 【2】 Bandarage, U.K.; et al.; NMI-377, a nitric oxide-donating diclofenac derivative with gastroprotective properties. 217th ACS Natl Meet (March 21 1999, Anaheim) 1999, Abst MEDI 81. |
| 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) | 33694 | cyclohexanecarbaldehyde | 2043-61-0 | C7H12O | 详情 | 详情 |
| (II) | 33695 | 1-[(1-formylcyclohexyl)disulfanyl]cyclohexanecarbaldehyde | C14H22O2S2 | 详情 | 详情 | |
| (III) | 18522 | 3-amino-1-propanol | 156-87-6 | C3H9NO | 详情 | 详情 |
| (IV) | 33696 | 3-[([1-[(1-[[(3-hydroxypropyl)amino]methyl]cyclohexyl)disulfanyl]cyclohexyl]methyl)amino]-1-propanol | C20H40N2O2S2 | 详情 | 详情 | |
| (V) | 33697 | bis[1-(1,3-oxazinan-3-ylmethyl)cyclohexyl] disulfide; 3-[(1-[[1-(1,3-oxazinan-3-ylmethyl)cyclohexyl]disulfanyl]cyclohexyl)methyl]-1,3-oxazinane | C22H40N2O2S2 | 详情 | 详情 | |
| (VI) | 33698 | 3-[([1-[(1-[[(3-hydroxypropyl)(methyl)amino]methyl]cyclohexyl)disulfanyl]cyclohexyl]methyl)(methyl)amino]-1-propanol | C22H44N2O2S2 | 详情 | 详情 | |
| (VII) | 33699 | 3-[methyl[(1-sulfanylcyclohexyl)methyl]amino]-1-propanol | C11H23NOS | 详情 | 详情 | |
| (VIII) | 33700 | 1-[[(3-hydroxypropyl)(methyl)amino]methyl]-N-oxocyclohexanesulfenamide | C11H22N2O2S | 详情 | 详情 | |
| (IX) | 33701 | Diclofenac; 2-[2-(2,6-Dichloroanilino)phenyl]acetic acid | C14H11Cl2NO2 | 详情 | 详情 | |
| (X) | 33702 | 3-[methyl[(1-sulfanylcyclohexyl)methyl]amino]propyl 2-[2-(2,6-dichloroanilino)phenyl]acetate | C25H32Cl2N2O2S | 详情 | 详情 |
合成路线11
该中间体在本合成路线中的序号：(XX)The precursor aminopropiophenone (XXVII) was synthesized as follows: 3-Amino-1-propanol (XX) was converted to the N-Boc derivative (XXI) and subsequently sulfonylated with p-toluenesulfonyl chloride to afford tosylate (XXII). Addition of vinylmagnesium bromide to 5-hydroxy-2-nitrobenzaldehyde (XXIII) provided the allyl alcohol (XXIV). The phenolic hydroxyl of (XXIV) was then alkylated with tosylate (XXII), yielding ether (XXV). The oxidation of the OH group of (XXV) with MnO2 gave the unsaturated ketone (XXVI). Catalytic hydrogenation of the olefin and nitro groups of (XXVI) provided the aminopropiophenone (XXVII).
| 【1】 Tsujihara, K.; Kawaguchi, T.; Okuno, S.; Yano, T. (Tanabe Seiyaku Co., Ltd.); Camptothecin derivs.. CA 2182244; EP 0757049; JP 1998072467; US 5837673 . |
| 【2】 Nomura, S.; Tsujihara, K.; Kawaguchi, T. (Tanabe Seiyaku Co., Ltd.); S type 2-substd. hydroxy-2-indolidinylbutyric ester cpds. and process for preparation thereof. US 6277992 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XX) | 18522 | 3-amino-1-propanol | 156-87-6 | C3H9NO | 详情 | 详情 |
| (XXI) | 10260 | tert-butyl N-(3-hydroxypropyl)carbamate | 58885-58-8 | C8H17NO3 | 详情 | 详情 |
| (XXII) | 49950 | 3-[(tert-butoxycarbonyl)amino]propyl 4-methylbenzenesulfonate | C15H23NO5S | 详情 | 详情 | |
| (XXIII) | 14942 | 5-hydroxy-2-nitrobenzaldehyde | 42454-06-8 | C7H5NO4 | 详情 | 详情 |
| (XXIV) | 49951 | 3-(1-hydroxy-2-propenyl)-4-nitrophenol | C9H9NO4 | 详情 | 详情 | |
| (XXV) | 49952 | tert-butyl 3-[3-(1-hydroxy-2-propenyl)-4-nitrophenoxy]propylcarbamate | C17H24N2O6 | 详情 | 详情 | |
| (XXVI) | 49953 | tert-butyl 3-(3-acryloyl-4-nitrophenoxy)propylcarbamate | C17H22N2O6 | 详情 | 详情 | |
| (XXVII) | 49954 | tert-butyl 3-(4-amino-3-propionylphenoxy)propylcarbamate | C17H26N2O4 | 详情 | 详情 |
合成路线12
该中间体在本合成路线中的序号：(XXII)The intermediate aldehyde (XXV) has been prepared by two related procedures. Benzylic bromination of o-tolylacetic acid (XIV) employing NBS and AIBN leads to bromo acid (XV), which is further converted into the tert-butyl ester (XVI) upon treatment with isobutylene and sulfuric acid. Bromide group displacement in (XVI) with NaN3 in hot DMF affords azide (XVII). This is then reduced by catalytic hydrogenation to the corresponding primary amine, which can be isolated as the more stable oxalate salt (XVIII). After protection of amine (XVIII) as the N-Boc derivative (XIX), selective reduction of the ester function employing LiAlH4 in cold Et2O gives rise to alcohol (XX). Further bromination of alcohol (XX) to produce (XXI) is accomplished by treatment with CBr4 and PPh3. Bromide (XXI) is condensed with 3-amino-1-propanol (XXII) yielding amino alcohol (XXIII), which is subsequently protected as the di-Boc derivative (XXIV). Swern oxidation of alcohol (XXIV) generates the required aldehyde intermediate (XXV).
| 【1】 Selnick, H.G.; Newton, R.C.; Newton, C.L.; Barrow, J.C.; Nantermet, P.G. (Merck & Co., Inc.); Thrombin inhibitors. WO 0311222 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIV) | 64207 | 2-(2-methylphenyl)acetic acid | C9H10O2 | 详情 | 详情 | |
| (XV) | 64208 | 2-[2-(bromomethyl)phenyl]acetic acid | C9H9BrO2 | 详情 | 详情 | |
| (XVI) | 64209 | tert-butyl 2-[2-(bromomethyl)phenyl]acetate | C13H17BrO2 | 详情 | 详情 | |
| (XVII) | 64210 | tert-butyl 2-[2-(azidomethyl)phenyl]acetate | C13H17N3O2 | 详情 | 详情 | |
| (XVIII) | 64211 | tert-butyl 2-[2-(aminomethyl)phenyl]acetate | C13H19NO2 | 详情 | 详情 | |
| (XIX) | 64212 | tert-butyl 2-(2-{[(tert-butoxycarbonyl)amino]methyl}phenyl)acetate | C18H27NO4 | 详情 | 详情 | |
| (XX) | 64213 | tert-butyl 2-(2-hydroxyethyl)benzylcarbamate | C14H21NO3 | 详情 | 详情 | |
| (XXI) | 64214 | tert-butyl 2-(2-bromoethyl)benzylcarbamate | C14H20BrNO2 | 详情 | 详情 | |
| (XXII) | 18522 | 3-amino-1-propanol | 156-87-6 | C3H9NO | 详情 | 详情 |
| (XXIII) | 64215 | tert-butyl 2-{2-[(3-hydroxypropyl)amino]ethyl}benzylcarbamate | C17H28N2O3 | 详情 | 详情 | |
| (XXIV) | 64216 | tert-butyl 2-{[(tert-butoxycarbonyl)amino]methyl}phenethyl(3-hydroxypropyl)carbamate | C22H36N2O5 | 详情 | 详情 | |
| (XXV) | 64217 | tert-butyl 2-{[(tert-butoxycarbonyl)amino]methyl}phenethyl(3-oxopropyl)carbamate | C22H34N2O5 | 详情 | 详情 |