|
【结 构 式】 
|
【分子编号】15530 【品名】1,3-Acetonedicarboxylic Acid; 3-Oxopentanedioic acid；3-oxoglutaric acid 【CA登记号】542-05-2 |
【 分 子 式 】C5H6O5 【 分 子 量 】146.09964 【元素组成】C 41.11% H 4.14% O 54.76% |
合成路线1
该中间体在本合成路线中的序号：(XII)The reaction of 5-chloro-2-hydroxybenzoic acid (I) with 2-methyl-2-propenyl chloride (II) by means of K2CO3 and KI in hot DMF gives 5-chloro-2-(2-methyl-2-propenyloxy)benzoic acid 2-methyl-2-propenyl ester (III), which is rearranged by heating at 190 C yielding 5-chloro-2-hydroxy-3-(2-methyl-2-propenyl)benzoic acid 2-methyl-2-propenyl ester (IV). The cyclization of (IV) with refluxing 90% formic acid affords 5-chloro-2,2-dimethyl-2,3-dihydrobenzofuran-7-carboxylic acid (V), which is treated with SOCl2 in DMF and condensed with endo-8-methyl-8-azabicyclo[3.2.1]octan-3-amine (VI). The acid intermediate (V) can also be obtained by hydrolysis of the ester (III) with NaOH and tetrabutylammonium bisulfate in refluxing water to give 5-chloro-2-(2-methyl-2-propenyloxy)benzoic acid (VII), which is rearranged by heating at 170 C yielding 5-chloro-2-hydroxy-3-(2-methyl-2-propenyl)benzoic acid (VIII). Finally, (VIII) is cyclized to acid intermediate (V) by a treatment with aqueous refluxing 2.7N HCl. The intermediate endo-8-methyl-8-azabicyclo[3.2.1]octan-3-amine (VI) has been obtained as follows: 2,5-dihydroxytetrahydrofuran (IX) or 2,5-dimethoxytetra-hydrofuran (X) with HCl give butanedialdehyde (XI), which, without isolation, is cyclized with 3-oxoglutaric acid (XII) and methylamine by means of NaOAc and HCl in hot water yielding 8-methyl-8-azabicyclo[3.2.1]octan-3-one (XIII). The reductocondensation of (XIII) with benzylamine by means of NaBH(OAc)3, followed by hydrogenolysis with H2 over Pd/C in basic water gives directly the amine (VI). The intermediate amine (VI) can also be obtained by condensation of bicyclooctanone (XIII) with benzylamine(A) to give the imine (XIV), which is reduced to the benzylamine (XV) with H2 over PtO2 in ethanol. Finally, this compound is debenzylated by hydrogenation over Pd/C in the same solvent yielding amine (VI).
| 【1】 Burks, J.E.; et al.; Development of a manufacturing process for zatosetron maleate. Org Process Res Dev 1997, 1, 3, 198. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 |
| (I) | 13895 | 5-Chloro-2-hydroxybenzoic acid; 5-Chlorosalicylic acid | 321-14-2 | C7H5ClO3 | 详情 | 详情 |
| (II) | 12127 | 3-Chloro-2-methyl-1-propene; Isobutenyl chloride | 563-47-3 | C4H7Cl | 详情 | 详情 |
| (III) | 36355 | 2-methyl-2-propenyl 5-chloro-2-[(2-methyl-2-propenyl)oxy]benzoate | C15H17ClO3 | 详情 | 详情 | |
| (IV) | 36356 | 2-methyl-2-propenyl 5-chloro-2-hydroxy-3-(2-methyl-2-propenyl)benzoate | C15H17ClO3 | 详情 | 详情 | |
| (V) | 13900 | 5-Chloro-2,2-dimethyl-2,3-dihydro-1-benzofuran-7-carboxylic acid | C11H11ClO3 | 详情 | 详情 | |
| (VI) | 12412 | (1R,5S)-8-Methyl-8-azabicyclo[3.2.1]octan-3-amine; (1R,5S)-8-Methyl-8-azabicyclo[3.2.1]oct-3-ylamine | C8H16N2 | 详情 | 详情 | |
| (VII) | 36357 | 5-chloro-2-[(2-methyl-2-propenyl)oxy]benzoic acid | C11H11ClO3 | 详情 | 详情 | |
| (VIII) | 36358 | 5-chloro-2-hydroxy-3-(2-methyl-2-propenyl)benzoic acid | C11H11ClO3 | 详情 | 详情 | |
| (IX) | 36359 | tetrahydro-2,5-furandiol | C4H8O3 | 详情 | 详情 | |
| (X) | 12132 | 2,5-Dimethoxytetrahydrofuran; 5-Methoxytetrahydro-2-furanyl methyl ether | 696-59-3 | C6H12O3 | 详情 | 详情 |
| (XI) | 36360 | succinaldehyde | C4H6O2 | 详情 | 详情 | |
| (XII) | 15530 | 1,3-Acetonedicarboxylic Acid; 3-Oxopentanedioic acid；3-oxoglutaric acid | 542-05-2 | C5H6O5 | 详情 | 详情 |
| (XIII) | 16443 | (1R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-one | C8H13NO | 详情 | 详情 | |
| (XIV) | 36361 | N-benzyl-N-[(1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-ylidene]amine; N-[(1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-ylidene](phenyl)methanamine | C15H20N2 | 详情 | 详情 | |
| (XV) | 12413 | N-Benzyl-N-[(1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]amine; (1R,5S)-N-Benzyl-8-methyl-8-azabicyclo[3.2.1]octan-3-amine | C15H22N2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IV)The condensation of bromoacetaldehyde dimethyl acetal (I) with methylamine (II) by means of KOH in refluxing ethylene glycol gives bis(2,2-dimethoxyethyl)methylamine (III), which is cyclized with acetonedicarboxylic acid (IV) and more methylamine (II), yielding 3,9-dimethyl-3,9-diazabicyclo[3.3.1]nonan-7-one (V). The reaction of (V) with hydroxylamine affords the corresponding oxime (VI), which is reduced with H2 over RaNi in ethanol giving endo-3,9-dimethyl-3,9-diazabicyclo[3.3.1]nonan-7-amine (VII). Finally, this compound is condensed with 1H-indazole-3-carbonyl chloride (VIII) by means of dimethylaminopyridine (DMAP) in pyridine.
| 【1】 Castaner, J.; Rabasseda, X.; Mealy, N.; N-3389. Drugs Fut 1995, 20, 8, 780. |
| 【2】 Kikuchi, H.; Satoh, H.; Yahata, N.; Hagihara, K.; Hayakawa, T.; Mino, S.; Yanai, M. (Nisshin Flour Milling Co., Ltd.); Azabicyclo derivs. and their use as antiemetics. EP 0469449; JP 1993310749; US 5187166 . |
| 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) | 13183 | 2-Bromo-1,1-dimethoxyethane; 2-Bromo-1-methoxyethyl methyl ether; Bromoacetaldehyde dimethyl acetal | 7252-83-7 | C4H9BrO2 | 详情 | 详情 |
| (II) | 11021 | Methanamine; Methylamine | 74-89-5 | CH5N | 详情 | 详情 |
| (III) | 15529 | N-(2,2-dimethoxyethyl)-2,2-dimethoxy-N-methyl-1-ethanamine; N,N-bis(2,2-dimethoxyethyl)-N-methylamine; 2,2'-Methyliminobis-(acetaldehyde dimethyl acetal) | 70887-96-6 | C9H21NO4 | 详情 | 详情 |
| (IV) | 15530 | 1,3-Acetonedicarboxylic Acid; 3-Oxopentanedioic acid；3-oxoglutaric acid | 542-05-2 | C5H6O5 | 详情 | 详情 |
| (V) | 15531 | (1R,5S)-3,9-dimethyl-3,9-diazabicyclo[3.3.1]nonan-7-one | C9H16N2O | 详情 | 详情 | |
| (VI) | 15532 | (1R,5S)-3,9-dimethyl-3,9-diazabicyclo[3.3.1]nonan-7-one oxime | C9H17N3O | 详情 | 详情 | |
| (VII) | 15533 | (1R,5S)-3,9-dimethyl-3,9-diazabicyclo[3.3.1]non-7-ylamine; (1R,5S)-3,9-dimethyl-3,9-diazabicyclo[3.3.1]nonan-7-amine | C9H19N3 | 详情 | 详情 | |
| (VIII) | 15534 | 1H-indazole-3-carbonyl chloride | C8H5ClN2O | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XV)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4
该中间体在本合成路线中的序号：(I)Condensation of 1,3-acetonedicarboxylic acid (I) with pyridine-4-carboxaldehyde (II) and subsequent acid decarboxylation produced 1,5-dipyridylpentadienone (III), which was reduced to the saturated ketone (IV) by transfer hydrogenation using formic acid and Pd/C. Condensation of (IV) with benzyl amine (V) in benzene with azeotropical removal of water, followed by reduction of the intermediate imine with NaBH4 gave rise to the secondary amine (VI). Coupling of (VI) with N-Boc-N-methyl-L-4-chlorophenylalanine (VII) in the presence of EDC afforded amide (VIII). After Boc deprotection of (VIII) with trifluoroacetic acid, the resulting amine (IX) was coupled with 3,4,5-trimethoxybenzoylformic acid (X) to furnish the title compound.
| 【1】 Zelle, R.E.; Harding, M.W. (Vertex Pharmaceuticals Inc.); Novel amino acid derivs. with improved multi-drug resistance activity. EP 0797567; JP 1998509151; US 5543423; WO 9615101 . |
| 【2】 Zelle, R.E. (Vertex Pharmaceuticals Inc.); Methods and compsns. for stimulating neurite growth using cpds. with affinity for FKBP2 in combination with neurotrophic factors. WO 9820891 . |
| 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) | 15530 | 1,3-Acetonedicarboxylic Acid; 3-Oxopentanedioic acid；3-oxoglutaric acid | 542-05-2 | C5H6O5 | 详情 | 详情 |
| (II) | 17203 | 4-Pyridinecarboxaldehyde; isonicotinaldehyde | 872-85-5 | C6H5NO | 详情 | 详情 |
| (III) | 30040 | (1E,4E)-1,5-di(4-pyridinyl)-1,4-pentadien-3-one | C15H12N2O | 详情 | 详情 | |
| (IV) | 30041 | 1,5-di(4-pyridinyl)-3-pentanone | C15H16N2O | 详情 | 详情 | |
| (V) | 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 |
| (VI) | 30042 | N-benzyl-1,5-di(4-pyridinyl)-3-pentanamine; N-benzyl-N-[3-(4-pyridinyl)-1-[2-(4-pyridinyl)ethyl]propyl]amine | C22H25N3 | 详情 | 详情 | |
| (VII) | 30043 | (2S)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-(4-chlorophenyl)propionic acid | 125324-00-7 | C15H20ClNO4 | 详情 | 详情 |
| (VIII) | 30044 | tert-butyl (1S)-2-(benzyl[3-(4-pyridinyl)-1-[2-(4-pyridinyl)ethyl]propyl]amino)-1-(4-chlorobenzyl)-2-oxoethyl(methyl)carbamate | C37H43ClN4O3 | 详情 | 详情 | |
| (IX) | 30045 | (2S)-N-benzyl-3-(4-chlorophenyl)-2-(methylamino)-N-[3-(4-pyridinyl)-1-[2-(4-pyridinyl)ethyl]propyl]propanamide | C32H35ClN4O | 详情 | 详情 | |
| (X) | 30046 | 2-oxo-2-(3,4,5-trimethoxyphenyl)acetic acid | C11H12O6 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(I)Acetonedicarboxylic acid (I) was converted to the monomethyl ester (III) via the cyclic anhydride (II). Dialdehyde (V), prepared in situ by acid hydrolysis of 2,5-dimethoxydihydrofuran (IV), was subjected to a double Mannich condensation with keto ester (III) and methylamine to produce a mixture of tropane derivatives. Column chromatography of the obtained crude product provided a mixture of 7-hydroxy- (VI) and 6-hydroxy- (VII) tropanes, which were separated from the minor 6- and 7-methoxy analogues. Treatment of alcohols (VI) and (VII) with dimethoxymethane and p-toluenesulfonic acid generated the corresponding mixture of mixed acetals, from which the desired 7-methoxymethyl isomer (VIII) was isolated by column chromatography. Conversion of (VIII) to the enol triflate (IX) was achieved with N-phenyltrifluoromethanesulfonimide and sodium bis(trimethylsilyl)amide at low temperature. The aryl tropene (XI) was then obtained by Suzuki coupling of triflate (IX) with 3,4-dichlorophenylboronic acid (X), followed by trimethylsilyl bromide-promoted deprotection of the methoxymethyl group. Resolution of the racemic tropenol (XI) was effected by esterification with (1S)-(-)-camphanic chloride followed by separation of the resulting diastereomeric mixture. The desired isomer (XII) was then hydrolyzed with LiOH to provide the enantiopure (1S)-alcohol (XIII). Then, reduction to the saturated tropane derivative by means of samarium iodide at low temperature produced a diastereomeric mixture of 3-aryltropanes from which the title 3alpha-isomer was isolated by flash chromatography.
| 【1】 Meltzer, P.C.; et al.; Synthesis of 6- and 7-hydroxy-8-azabicyclo[3.2.1]octanes and their binding affinity for the dopamine and serotonin transporters. J Med Chem 2001, 4, 16, 2619. |
| 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) | 15530 | 1,3-Acetonedicarboxylic Acid; 3-Oxopentanedioic acid；3-oxoglutaric acid | 542-05-2 | C5H6O5 | 详情 | 详情 |
| (II) | 49965 | 2H-pyran-2,4,6(3H,5H)-trione | C5H4O4 | 详情 | 详情 | |
| (III) | 49966 | 5-methoxy-3,5-dioxopentanoic acid | C6H8O5 | 详情 | 详情 | |
| (IV) | 49967 | 2,5-dimethoxy-2,5-dihydrofuran | 332-77-4 | C6H10O3 | 详情 | 详情 |
| (V) | 49968 | (Z)-2-butenedial | C4H4O2 | 详情 | 详情 | |
| (VI) | 49969 | methyl (1S,2R,5S,7R)-7-hydroxy-8-methyl-3-oxo-8-azabicyclo[3.2.1]octane-2-carboxylate | C10H15NO4 | 详情 | 详情 | |
| (VII) | 49970 | methyl (1R,2R,5R,6S)-6-hydroxy-8-methyl-3-oxo-8-azabicyclo[3.2.1]octane-2-carboxylate | C10H15NO4 | 详情 | 详情 | |
| (VIII) | 49971 | methyl (1S,2R,5S,7R)-7-(methoxymethoxy)-8-methyl-3-oxo-8-azabicyclo[3.2.1]octane-2-carboxylate | C12H19NO5 | 详情 | 详情 | |
| (IX) | 49972 | methyl (1S,5S,7R)-7-(methoxymethoxy)-8-methyl-3-[[(trifluoromethyl)sulfonyl]oxy]-8-azabicyclo[3.2.1]oct-2-ene-2-carboxylate | C13H18F3NO7S | 详情 | 详情 | |
| (X) | 34040 | 3,4-Dichlorophenylboronic acid | 151169-75-4 | C6H5BCl2O2 | 详情 | 详情 |
| (XI) | 49973 | (rac)-methyl (1S,5R,7R)-3-(3,4-dichlorophenyl)-7-hydroxy-8-methyl-8-azabicyclo[3.2.1]oct-2-ene-2-carboxylate | C16H17Cl2NO3 | 详情 | 详情 | |
| (XII) | 49974 | methyl (1S,5R,7R)-3-(3,4-dichlorophenyl)-8-methyl-7-([[(4R)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]hept-1-yl]carbonyl]oxy)-8-azabicyclo[3.2.1]oct-2-ene-2-carboxylate | C26H29Cl2NO6 | 详情 | 详情 | |
| (XIII) | 49975 | methyl (1S,5R,7R)-3-(3,4-dichlorophenyl)-7-hydroxy-8-methyl-8-azabicyclo[3.2.1]oct-2-ene-2-carboxylate | C16H17Cl2NO3 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(XIII)The precursor 4-bromo-2,6-diethylpyridine (V) can be prepared by several methods. Condensation of 3-oxoglutaric acid (XIII) with propionic anhydride (XIV) in the presence of H2SO4, followed by cyclization with HCl at 100 °C leads to 2,6-diethyl-4-pyranone (XV). Subsequent treatment of pyranone (XV) with NH4OH at 50 °C yields 2,6-diethyl-4-pyridinol (XVI) , which is finally brominated with PBr5 in CHCl3 or POBr3 in DMF at 120 °C .
Alternatively, substitution of 2,6-dichloropyridine (XVII) with ethylmagnesium bromide (XVIII) in the presence of NiCl2(dppp) in Et2O gives 2,6-diethylpyridine (XIX), which can also be obtained by Wolff- Kishner reduction of 2,6-diacetylpyridine (XX) with NH2NH2 in the presence of NaOH in diethylene glycol at 120 °C. Oxidation of 2,6-diethylpyridine (XIX) with mCPBA in CHCl3, followed by nitration of the resulting 2,6-diethylpyridine-1-oxide (XXI) with HNO3 and H2SO4 at 90 °C provides the 4-nitro derivative (XXII). Substitution of nitropyridine (XXII) using AcBr in AcOH at 90 °C affords 4-bromo-2,6-diethylpyridin-1-oxide (XXIII), which is finally reduced with PBr3 in CH2Cl2 .
| 【1】 Gonzalez, J., Jewell, T.M., Li, H., Linton, A., Tatlock, J.H. (Pfizer, Inc.; Agouron Pharmaceuticals, Inc.). Inhibitors of hepatitis C virus RNAdependent RNA polymerase, and compositions and treatments using the same. EP 1781662, JP 2008509984, US 2006122399, US 7151105, US 8268835, WO 2006018725. |
| 【2】 Li, H., Tatlock, J., Linton, A. et al. Discovery of (R)-6-cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl)ethyl)-3-((5,7-dimethyl-(1,2,4)triazolo(1,5-a)pyrimidin-2-yl)methyl)-4-hydroxy-5,6-dihydropyran-2-one (PF-00868554) as a potent and orally available hepatitis C virus polymerase inhibitor. J Med Chem 2009, 52(5): 1255-8. |
| 【3】 Johnson, S., Drowns, M., Tatlock, J. et al. Synthetic route optimization of PF-00868554, an HCV polymerase inhibitor in clinical evaluation. Synlett 2010(5): 796-800. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (V) | 68333 | 4-bromo-2,6-diethylpyridine | 877133-54-5 | C9H12BrN | 详情 | 详情 |
| (XIII) | 15530 | 1,3-Acetonedicarboxylic Acid; 3-Oxopentanedioic acid；3-oxoglutaric acid | 542-05-2 | C5H6O5 | 详情 | 详情 |
| (XIV) | 20095 | propionic anhydride | 123-62-6 | C6H10O3 | 详情 | 详情 |
| (XV) | 68342 | 2,6-diethyl-4H-pyran-4-one | C9H12O2 | 详情 | 详情 | |
| (XVI) | 68343 | 2,6-diethyl-4-pyridinol;2,6-diethylpyridin-4-ol | C9H13NO | 详情 | 详情 | |
| (XVII) | 13573 | 2,6-Dichloropyridine | 2402-78-0 | C5H3Cl2N | 详情 | 详情 |
| (XVIII) | 24239 | bromo(ethyl)magnesium；ethylmagnesium bromide | 925-90-6 | C2H5BrMg | 详情 | 详情 |
| (XIX) | 68344 | 2,6-diethylpyridine | 935-28-4 | C9H13N | 详情 | 详情 |
| (XX) | 48515 | 2,6-Diacetylpyridine | 1129-30-2 | C9H9NO2 | 详情 | 详情 |
| (XXI) | 68345 | 2,6-diethylpyridine-1-oxide | C9H13NO | 详情 | 详情 | |
| (XXII) | 68346 | 2,6-diethyl-4-nitropyridine 1-oxide | C9H12N2O3 | 详情 | 详情 | |
| (XXIII) | 68347 | 4-bromo-2,6-diethylpyridin-1-oxide | C9H12BrNO | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(XIX)Reaction of 2-aminobenzyl alcohol (I) with acetone in aqueous AcOH affords 2,2-dimethyl-1,4-dihydro-2H-3,1-benzoxazine, which is reduced with LiAlH4 in THF, producing 2-(isopropylamino)benzyl alcohol (II). After oxidation of alcohol (II) to the corresponding benzaldehyde (III) by means of MnO2 in toluene at 117 °C, Knoevenagel condensation with Meldrum’s acid (IV) in the presence of AcOH and ethylenediamine in MeOH gives 1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (V) . Chlorination of acid (V) with SOCl2 in toluene at 95 °C and subsequent coupling of the resulting acid chloride with N-Boc-endo-3-aminotropane (VI) in the presence of NaOH in toluene/water affords the corresponding amide (VII). Deprotection of the N-Boc-tropane derivative (VII) by means of TFA in CH2Cl2 furnishes the corresponding amine TFA salt (VIII) (1-9), which is then N-alkylated with 1-chloro-3-(N-Boc-N-methylamino)propan-2(S)-ol (IX) [prepared by condensation of (S)-epichlorohydrin (X) with Nmethylbenzylamine in hexane and subsequent hydrogenolysis of the obtained benzylamine derivative (XI) in the presence of Pd(OH)2/C and Boc2O in EtOAc] in the presence of DIEA in MeOH at 80 °C to give the N-Boc-methylamine derivative (XII). Deprotection of this compound by means of TFA in CH2Cl2 and N-sulfonylation of the obtained free amine (XIII) with methanesulfonyl chloride (XIV) in the presence of DBU in CH2Cl2 then affords velusetrag. Alternatively, reaction of amine (VIII) with N-[(S)-glycidyl]-N-methylmethanesulfonamide (XV) [prepared by alkylation of N-methylmethanesulfonamide (XVI) with (S)-epichlorohydrin (XVII) using aqueous NaOH] in the presence of NaOH in MeOH yields velusetrag . N-Boc-endo-3-aminotropane (VI) is prepared by hydrolysis of 2,5-dimethoxytetrahydrofuran (XVIII) with aqueous HCl, followed by Mannich reaction of the resulting succinaldehyde with BnNH2 and 1,3-acetonedicarboxylic acid (XIX) in the presence of HCl in H2O to give N-benzyl-8-azabicyclo[3.2.1]octan-3-one (XX). Treatment of this compound with H2 over Pd(OH)2/C and Boc2O in EtOAc yields N-Boc-8-azabicyclo[3.2.1]octan-3-one (XXI), which is then converted to the desired amine (VI) by reductive amination with HCOONH4 in the presence of Pd/C in MeOH/H2O .
Velusetrag can be converted to its salts, including hydrochloride, citrate,adipate, phosphate, sulfate, tartrate, malate, hydrobromide and mesylate, by treatment with the respective acids .
| 【1】 Marquess, D., Fatheree, P.R., Turner, D.S., Long, D.D., Choi, S.-K., Goldblum, A.A., Genov, D. (Theravance, Inc.). Quinolinone-carboxamide compounds as 5-HT4 receptor agonists. EP 1735304, JP 2007535546, JP 2008174569, US 2005228014, US 2007281970, US 7375114, US 7728006, WO 2005100350. |
| 【2】 Marquess, D., Fatheree, P.R., Turner, S.D., Long, D.D., Choi, S., Goldblum, A.A., Genov, D. (Theravance, Inc.). Quinolinone-carboxamide compounds as 5-HT4 receptor agonists. US 2007270457, US 7592355. |
| 【3】 Marquess, D., Fatheree, P.R., Turner, S.D., Long, D.D., Choi, S., Goldblum, A.A., Genov, D. (Theravance, Inc.). Quinolinone-carboxamide compounds as 5-HT4, receptor agonists. US 2008176895, US 7763637. |
| 【4】 Choi, S.-K., Fatheree, P., Goldblum, A.A., Jiang, L., Long, D.D., Marquess, D., Turner, S.D. (Theravance, Inc.). 5-HT4 receptor agonist compounds. US 2008255187, US 7534889. |
| 【5】 Marquess, D., Fatheree, P.R., Turner, S.D., Long, D.D., Choi, S.-K., Goldblum, A.A., Genov, D. (Theravance, Inc.). Quinolinone-carboxamide compounds as 5-HT4 receptor agonists. US 2010285519. |
| 【6】 Marquess, D., Fatheree, P.R., Turner, S.D., Long, D.D., Choi, S.-K., Goldblum, A.A., Genov, D. (Theravance, Inc.). Quinolone-carboxamide compounds as 5-HT4 receptor agonists. US 2010311979. |
| 【7】 Choi, S.-K., Fatheree, P., Goldblum, A.A., Jiang, L., Long, D.D., Marquess, D., Turner, S.D. (Theravance, Inc.). 5-HT4 receptor agonist compounds. EP 1807422, JP 2008518965, US 2006100236, US 7399862, WO 2006052640. |
| 【8】 Fatheree, P.R., Turner, S.D., Goldblum, A., Chao, R., Genov, D. (Theravance, Inc.). Crystalline form of a quinolinone-carboxamide compound. EP 1874766, JP 2008535848, US 2006229332, US 7728004, WO 2006108127. |
| 【9】 Genov, D., Lee, J., Liu, J. (Theravance, Inc.). Process for preparing intermediates to 5-HT4 receptor agonist compounds. EP 1984362, JP 2009526852, US 2007191355, WO 2007097976. |
| 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) | 18619 | (2-aminophenyl)methanol; 2-Amino-benzenemethanol；2-Hydroxymethyl aniline;2-aminobenzyl alcohol;o-Aminobenzyl 2-aminobenzylalcohol;alcohol; 2-aminobenzenemethanol; 2-aminobenzyl alcohol | 5344-90-1 | C7H9NO | 详情 | 详情 |
| (II) | 36334 | [2-(isopropylamino)phenyl]methanol；2-(isopropylamino)benzyl alcohol;(2-(isopropylamino)phenyl)methanol | C10H15NO | 详情 | 详情 | |
| (III) | 36335 | 2-(isopropylamino)benzaldehyde | C10H13NO | 详情 | 详情 | |
| (IV) | 14738 | Meldrum's acid; 2,2-dimethyl-1,3-dioxane-4,6-dione；Malonic acid cyclic isopropylidene ester | 2033-24-1 | C6H8O4 | 详情 | 详情 |
| (V) | 36333 | 1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxylic acid | C13H13NO3 | 详情 | 详情 | |
| (VI) | 68799 | (1R,3r,5R)-tert-butyl 3-amino-8-azabicyclo[3.2.1]octane-8-carboxylate | C12H22N2O2 | 详情 | 详情 | |
| (VII) | 68803 | (1R,3R)-tert-butyl 3-(1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxamido)-8-azabicyclo[3.2.1]octane-8-carboxylate | C25H33N3O4 | 详情 | 详情 | |
| (VIII) | 68804 | N-((1R,3R)-8-azabicyclo[3.2.1]octan-3-yl)-1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxamide 2,2,2-trifluoroacetate | C20H25N3O2.C2HF3O2 | 详情 | 详情 | |
| (IX) | 68807 | 1-chloro-3-(N-Boc-N-methylamino)propan-2(S)-ol;(S)-tert-butyl (3-chloro-2-hydroxypropyl)(methyl)carbamate | C9H18ClNO3 | 详情 | 详情 | |
| (X) | 13917 | (S)-Epichlorohydrin; (2S)-2-(Chloromethyl)oxirane;(S)-(+)-epichlorohydrin | 67843-74-7 | C3H5ClO | 详情 | 详情 |
| (XI) | 68808 | (S)-1-(benzyl(methyl)amino)-3-chloropropan-2-ol | C11H16ClNO | 详情 | 详情 | |
| (XII) | 68805 | tert-butyl ((S)-2-hydroxy-3-((1R,3R,5S)-3-(1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxamido)-8-azabicyclo[3.2.1]octan-8-yl)propyl)(methyl)carbamate | C29H42N4O5 | 详情 | 详情 | |
| (XIII) | 68806 | N-((1R,3R,5S)-8-((R)-2-hydroxy-3-(methylamino)propyl)-8-azabicyclo[3.2.1]octan-3-yl)-1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxamide 2,2,2-trifluoroacetate | C24H34N4O3.C2HF3O2 | 详情 | 详情 | |
| (XIV) | 13467 | Methanesulfonyl chloride;Mesyl chloride;Methylsulfonyl chloride;Methanesulfonic acid chloride;Methanesulfonyl chloride;Methanesulphonyl chloride | 124-63-0 | CH3ClO2S | 详情 | 详情 |
| (XV) | 68802 | N-[(S)-glycidyl]-N-methylmethanesulfonamide;(S)-N-methyl-N-(oxiran-2-ylmethyl)methanesulfonamide | C5H11NO3S | 详情 | 详情 | |
| (XVI) | 67859 | N-methylmethanesulfonamide | 1184-85-6 | C2H7NO2S | 详情 | 详情 |
| (XVII) | 13917 | (S)-Epichlorohydrin; (2S)-2-(Chloromethyl)oxirane;(S)-(+)-epichlorohydrin | 67843-74-7 | C3H5ClO | 详情 | 详情 |
| (XVIII) | 12132 | 2,5-Dimethoxytetrahydrofuran; 5-Methoxytetrahydro-2-furanyl methyl ether | 696-59-3 | C6H12O3 | 详情 | 详情 |
| (XIX) | 15530 | 1,3-Acetonedicarboxylic Acid; 3-Oxopentanedioic acid；3-oxoglutaric acid | 542-05-2 | C5H6O5 | 详情 | 详情 |
| (XX) | 68801 | (1R,5R)-8-benzyl-8-azabicyclo[3.2.1]octan-3-one;N-benzyl-8-azabicyclo[3.2.1]octan-3-one | C14H17NO | 详情 | 详情 | |
| (XXI) | 68800 | N-Boc-8-azabicyclo[3.2.1]octan-3-one | C12H19NO3 | 详情 | 详情 |