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【结 构 式】 
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【分子编号】13183 【品名】2-Bromo-1,1-dimethoxyethane; 2-Bromo-1-methoxyethyl methyl ether; Bromoacetaldehyde dimethyl acetal 【CA登记号】7252-83-7 |
【 分 子 式 】C4H9BrO2 【 分 子 量 】169.01826 【元素组成】C 28.43% H 5.37% Br 47.28% O 18.93% |
合成路线1
该中间体在本合成路线中的序号：(XXV)The bromination of tetraline (XIX) with Br2 in hexane gives trans-1,2-dibromotetraline (XX), which by treatment with H2O and NaHCO3 yields trans-2-bromotetralin-1-ol (XXI) [also obtained by reaction of 1,2-dihydronaphthalene (XXII) with 1,3-dibromo-5,5-dimethylhydantoin (DBDH) and perchloric acid]. The reaction of (XXI) with methylamine affords the intermediate epoxide (XXIII), which without isolation with more methylamine gives trans 1-(methylamino) tetralin-2-ol as a racemic mixture rac-(XXIV). The optical resolution of this mixture with (+)-L-tartaric acid yields the desired enantiomer (R,R)(XXIV), which is condensed with 2-bromoacetaldehyde dimethyl acetal (XXV) by means of K2CO3 in acetonitrile furnishing the chiral tertiary amine (XXVI). The cyclization of (XXVI) with BuLi and TsCl provides the intermediate aziridinium salt (XXVII), which without isolation, is condensed with 4-chloro-3-methoxyphenyl-magnesium bromide (X) in THF to give the chiral tertiary amine (XXVIII). The cyclization of (XXVIII) by means of methanesulfonic acid yields the chiral tetracyclic compound (XXIX), which is hydrogenated by means of BH3/t-Bu-NH2 to afford (6aS,13bR)(VIII). Finally, this compound is demethylated with 48% HBr in acetic acid. The chiral secondary amine (XXVI) can also be obtained as follows: The enantioselective epoxidation of 1,2-dihydronaphthalene (XXII) by means of a chiral manganese catalyst and sodium hypochlorite gives the chiral epoxide (1S,2R)(XXIII), which is cleaved with 2-(methylamino)acetaldehyde dimethylacetal (XXX) at 95 C in a pressure vessel to yield the desired chiral secondary amine (XXVI).
| 【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 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 11021 | Methanamine; Methylamine | 74-89-5 | CH5N | 详情 | 详情 | |
| (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 | |
| (X) | 36324 | methyl 2-chloro-3-[4-[4-(2-chloro-3-methoxy-3-oxopropyl)benzyl]phenyl]propanoate | C21H22Cl2O4 | 详情 | 详情 | |
| (XIX) | 36632 | 1,2,3,4-tetrahydronaphthalene | 119-64-2 | C10H12 | 详情 | 详情 |
| (XX) | 36633 | (1S,2S)-1,2-dibromo-1,2,3,4-tetrahydronaphthalene | C10H10Br2 | 详情 | 详情 | |
| (XXI) | 36634 | (1S,2S)-2-bromo-1,2,3,4-tetrahydro-1-naphthalenol | C10H11BrO | 详情 | 详情 | |
| (XXII) | 36635 | 1,2-dihydronaphthalene | 447-53-0 | C10H10 | 详情 | 详情 |
| (XXIII) | 36636 | (1aR,7bS)-1a,2,3,7b-tetrahydronaphtho[1,2-b]oxirene | C10H10O | 详情 | 详情 | |
| (XXIV) | 36637 | (1R,2R)-1-(methylamino)-1,2,3,4-tetrahydro-2-naphthalenol | C11H15NO | 详情 | 详情 | |
| (XXV) | 13183 | 2-Bromo-1,1-dimethoxyethane; 2-Bromo-1-methoxyethyl methyl ether; Bromoacetaldehyde dimethyl acetal | 7252-83-7 | C4H9BrO2 | 详情 | 详情 |
| (XXVI) | 36638 | (1R,2R)-1-[(2,2-dimethoxyethyl)(methyl)amino]-1,2,3,4-tetrahydro-2-naphthalenol | C15H23NO3 | 详情 | 详情 | |
| (XXVII) | 36639 | n/a | AB | 详情 | 详情 | |
| (XXVIII) | 36640 | N-[(1S,2S)-1-(4-chloro-3-methoxyphenyl)-1,2,3,4-tetrahydro-2-naphthalenyl]-N-(2,2-dimethoxyethyl)-N-methylamine; (1S,2S)-1-(4-chloro-3-methoxyphenyl)-N-(2,2-dimethoxyethyl)-N-methyl-1,2,3,4-tetrahydro-2-naphthalenamine | C22H28ClNO3 | 详情 | 详情 | |
| (XXIX) | 36641 | (3aS,9bR)-12-chloro-3-methyl-3a,4,5,9b-tetrahydro-3H-naphtho[1,2-a][3]benzazepin-11-yl methyl ether; (3aS,9bR)-12-chloro-11-methoxy-3-methyl-3a,4,5,9b-tetrahydro-3H-naphtho[1,2-a][3]benzazepine | C20H20ClNO | 详情 | 详情 | |
| (XXX) | 36650 | 2,2-dimethoxy-N-methyl-1-ethanamine;1,1-Dimethoxy-2-(methylamino)-ethane;Methylaminoacetaldehyde dimethyl acetal;N-(2,2-dimethoxyethyl)-N-methylamine | 122-07-6 | C5H13NO2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XXV)The reaction of L-homophenylalanine (XXXIX) with methyl chloroformate, NaHCO3 and NaOH gives N-(methoxycarbonyl)-L-homophenylalanine (XXXI), which is treated with SOCl2 yielding the acyl chloride (XXXII). The cyclization of (XXXII) by means of AlCl3 in dichloromethane affords the chiral tetralone (XXXIII), which is condensed with the aryllithium (or arylmagnesium bromide) (XXXIV) to give the intermediate alcohol (XXXV). Elimination of the OH group of (XXXV) by means of Et3SiH and TFA yields the carbamate (XXXVI) as a 3.6:1 mixture of cis- and trans-isomers, which is reduced with LiAlH4 in refluxing THF providing the secondary amine (XXXVII). The alkylation of (XXXVII) with 2-bromoacetaldehyde dimethylacetal (XXV) by means of KF/Al2O3 in refluxing acetonitrile affords the tertiary amine (XXXVIII), also as a mixture of cis- and trans-isomers. The 1:3 trans/cis ratio of isomers in (XXXVIII) is improved up to 50:1 by treatment with t-BuOK in DMSO/DMF providing the desired trans(1R,2S)-isomer (XXVIII) already reported.
| 【1】 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): 2. L-homophenylalanine-based syntheses. Org Process Res Dev 1998, 2, 3, 186. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 16993 | methyl chlorocarbonate;Carbonochloridic acid methyl ester；[(chlorocarbonyl)oxy]methane；methyl chloroformate | 79-22-1 | C2H3ClO2 | 详情 | 详情 | |
| (XXXIVb) | 36624 | bromo(4-chloro-3-methoxyphenyl)magnesium | C7H6BrClMgO | 详情 | 详情 | |
| (XXXIVa) | 36646 | (4-chloro-3-methoxyphenyl)lithium | C7H6ClLiO | 详情 | 详情 | |
| (XXV) | 13183 | 2-Bromo-1,1-dimethoxyethane; 2-Bromo-1-methoxyethyl methyl ether; Bromoacetaldehyde dimethyl acetal | 7252-83-7 | C4H9BrO2 | 详情 | 详情 |
| (XXVIII) | 63422 | (2S)-1-(4-chloro-3-methoxyphenyl)-N-(2,2-dimethoxyethyl)-N-methyl-1,2,3,4-tetrahydro-2-naphthalenamine; N-[(2S)-1-(4-chloro-3-methoxyphenyl)-1,2,3,4-tetrahydro-2-naphthalenyl]-N-(2,2-dimethoxyethyl)-N-methylamine | C22H28ClNO3 | 详情 | 详情 | |
| (XXXI) | 36643 | (2S)-2-[(methoxycarbonyl)amino]-4-phenylbutyric acid | C12H15NO4 | 详情 | 详情 | |
| (XXXII) | 36644 | methyl (1S)-1-(chlorocarbonyl)-3-phenylpropylcarbamate | C12H14ClNO3 | 详情 | 详情 | |
| (XXXIII) | 36645 | methyl (2S)-1-oxo-1,2,3,4-tetrahydro-2-naphthalenylcarbamate | C12H13NO3 | 详情 | 详情 | |
| (XXXV) | 36647 | methyl (1R,2S)-1-(4-chloro-3-methoxyphenyl)-1-hydroxy-1,2,3,4-tetrahydro-2-naphthalenylcarbamate | C19H20ClNO4 | 详情 | 详情 | |
| (XXXVI) | 36648 | methyl (2S)-1-(4-chloro-3-methoxyphenyl)-1,2,3,4-tetrahydro-2-naphthalenylcarbamate | C19H20ClNO3 | 详情 | 详情 | |
| (XXXVII) | 36649 | (2S)-1-(4-chloro-3-methoxyphenyl)-N-methyl-1,2,3,4-tetrahydro-2-naphthalenamine; N-[(2S)-1-(4-chloro-3-methoxyphenyl)-1,2,3,4-tetrahydro-2-naphthalenyl]-N-methylamine | C18H20ClNO | 详情 | 详情 | |
| (XXXVIII) | 36640 | N-[(1S,2S)-1-(4-chloro-3-methoxyphenyl)-1,2,3,4-tetrahydro-2-naphthalenyl]-N-(2,2-dimethoxyethyl)-N-methylamine; (1S,2S)-1-(4-chloro-3-methoxyphenyl)-N-(2,2-dimethoxyethyl)-N-methyl-1,2,3,4-tetrahydro-2-naphthalenamine | C22H28ClNO3 | 详情 | 详情 | |
| (XXXIX) | 36642 | (2S)-2-amino-4-phenylbutyric acid | 943-73-7 | C10H13NO2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)The condensation of 2-methoxyphenol (I) with 2-bromoethanal dimethylacetal (II) by means of K2CO3 in hot DMF gives 2-(2-methoxyphenoxy)ethanal dimethylacetal (III), which is hydrolyzed to the corresponding free aldehyde (IV) with 2N H2SO4 in methanol. The cyclization of (IV) with cysteamine (V) by means of potassium acetate in water affords 2-(2-methoxyphenoxymethyl)thiazolidine (VI), which is finally condensed with ethoxymalonyl chloride (VII) by means of KHCO3 in ethyl acetate.
| 【1】 Gandolfi, C.A.; Spinelli, S.; Tofanetti, O.; Russo, R.; Tognella, S. (Boehringer Ingelheim Italia SpA); Antitussive and mucus regulating 2-substituted thiazolidines. AU 8545242; EP 0169581; ES 8605249; GB 2164333; GB 2177690; JP 1986063669; US 4857643 . |
| 【2】 Gandolfi, C.A.; Di Domenico, R.; Spinelli, S.; Lumachi, B.; Gallico, L.; Tognella, S. (Boehringer Ingelheim Italia SpA); Beta-carbonyl-carboxyamides of 1,3-thiazolidines. EP 0333080; JP 1991504123; US 5206254 . |
| 【3】 De Angelis, L.; Moguisteine. Drugs Fut 1991, 16, 7, 618. |
| 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) | 13182 | Guaiacol; 2-Methoxyphenol | 90-05-1 | C7H8O2 | 详情 | 详情 |
| (II) | 13183 | 2-Bromo-1,1-dimethoxyethane; 2-Bromo-1-methoxyethyl methyl ether; Bromoacetaldehyde dimethyl acetal | 7252-83-7 | C4H9BrO2 | 详情 | 详情 |
| (III) | 13184 | 1-(2,2-Dimethoxyethoxy)-2-methoxybenzene; 2-(2,2-Dimethoxyethoxy)phenyl methyl ether | C11H16O4 | 详情 | 详情 | |
| (IV) | 13185 | 2-(2-Methoxyphenoxy)acetaldehyde | C9H10O3 | 详情 | 详情 | |
| (V) | 13186 | 2-Aminoethanethiol; 2-Amino-1-ethanethiol; 2-Aminoethylhydrosulfide; Cysteamine | 60-23-1 | C2H7NS | 详情 | 详情 |
| (VI) | 13187 | 2-[(2-Methoxyphenoxy)methyl]-1,3-thiazolidine; 2-Methoxyphenyl 1,3-thiazolidin-2-ylmethyl ether | C11H15NO2S | 详情 | 详情 | |
| (VII) | 13188 | ethyl 3-chloro-3-oxopropanoate; 2-Ethoxycarbonylacetyl chloride; Ethyl malonyl chloride | 36239-09-5 | C5H7ClO3 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)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5
该中间体在本合成路线中的序号：(XIV)2. In an alternative synthesis, 5-bromosalicylaldehyde (XIII) was alkylated with bromoacetaldehyde dimethyl acetal (XIV) to afford ether (XV). Further Baeyer-Villiger reaction with (XV) produced phenol (XVI), which was cyclized to the benzodioxine (XVII) with p-TsOH. Lithiation of (XVII), followed by reaction with triisopropyl borate and hydrolytic work-up, gave boronic acid (XVIII). Aldehyde (II) was treated with MCPBA yielding phenol (XIII), which was iodinated in the presence of tert-butylamine to give the bromo iodo derivative (XIV). Sequential Suzuki coupling of bromo iodo compound (XIV) with boronic acid (XVIII) yielding (XIX), and then with boronic acid (I) provided terphenyl (XX). Hydrolysis of the methyl acetal of (XX) using p-TsOH gave cyclic hemiacetal (XXI). Finally, Wittig reaction of (XXI) with the phosphorane prepared from isopropyl triphenylphosphonium iodide and n-BuLi provided the title compound.
| 【1】 Yonezawa, S.; et al.; Total synthesis of terprenin, a novel immunosuppressive p-terphenyl derivative. J Org Chem 1998, 63, 17, 5831. |
| 【2】 Nagashima, K.; Kamigauchi, T.; Sakazaki, R.; et al.; Terprenins, novel immunosuppressants produced by Aspergillus candidus. J Antibiot 1998, 51, 4, 445. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIIIa) | 25618 | 3-bromo-2,5-dimethoxyphenol | C8H9BrO3 | 详情 | 详情 | |
| (XIVb) | 25619 | 3-bromo-6-iodo-2,5-dimethoxyphenol | C8H8BrIO3 | 详情 | 详情 | |
| (I) | 25602 | 4-[[tert-butyl(dimethyl)silyl]oxy]phenylboronic acid | C12H21BO3Si | 详情 | 详情 | |
| (II) | 25603 | 3-bromo-2,5-dimethoxybenzaldehyde | C9H9BrO3 | 详情 | 详情 | |
| (XIII) | 25613 | 5-bromo-2-hydroxybenzaldehyde; 5-Bromosalicylaldehyde | 1761-61-1 | C7H5BrO2 | 详情 | 详情 |
| (XIV) | 13183 | 2-Bromo-1,1-dimethoxyethane; 2-Bromo-1-methoxyethyl methyl ether; Bromoacetaldehyde dimethyl acetal | 7252-83-7 | C4H9BrO2 | 详情 | 详情 |
| (XV) | 25614 | 5-bromo-2-(2,2-dimethoxyethoxy)benzaldehyde | C11H13BrO4 | 详情 | 详情 | |
| (XVI) | 25615 | 5-bromo-2-(2,2-dimethoxyethoxy)phenol | C10H13BrO4 | 详情 | 详情 | |
| (XVII) | 25616 | 7-bromo-2,3-dihydro-1,4-benzodioxin-2-yl methyl ether | C9H9BrO3 | 详情 | 详情 | |
| (XVIII) | 25617 | 3-methoxy-2,3-dihydro-1,4-benzodioxin-6-ylboronic acid | C9H11BO5 | 详情 | 详情 | |
| (XIX) | 25620 | 3-bromo-2,5-dimethoxy-6-(3-methoxy-2,3-dihydro-1,4-benzodioxin-6-yl)phenol | C17H17BrO6 | 详情 | 详情 | |
| (XX) | 25621 | 2,5-dimethoxy-4-(3-methoxy-2,3-dihydro-1,4-benzodioxin-6-yl)[1,1'-biphenyl]-3,4'-diol | C23H22O7 | 详情 | 详情 | |
| (XXI) | 25622 | 4-(3-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-2,5-dimethoxy[1,1'-biphenyl]-3,4'-diol | C22H20O7 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(II)The condensation of 2-hydroxy-3,6-dimethylbenzaldehyde (I) with 2-bromoacetaldehyde dimethyl acetal (II) by means of K2CO3 in DM gives the phenoxyacetaldehyde acetal (III), which is cyclized by means of acetic acid to yield 4,7-dimethylbenzofuran (IV). The condensation of (IV) with 4-acryloylbenzoic acid methyl ester (V) by means of 3-benzyl-5-(hydroxymethyl)-4-methylthiazolium chloride (BHMT) and TEA in DMF affords the butanedione derivative (VI), which is cyclized to the pyrrole derivative (VII) by means of NH4OAc in refluxing methanol. Finally, the methyl ester group of (VII) is hydrolyzed with NaOH in ethanol to afford the target carboxylic acid.
| 【1】 Yoshimura, H.; et al.; Discovery of novel and potent retinoic acid receptor alpha agonists: Syntheses and evaluation of benzofuranyl-pyrrole and benzothiophenyl-pyrrole derivatives. J Med Chem 2000, 43, 15, 2929. |
| 【2】 Tagami, K.; Yoshimura, H.; Nagai, M.; Hibi, S.; Kikuchi, K.; Sato, T.; Okita, M.; Okamoto, Y.; Nagasaka, Y.; Kobayashi, N.; Hida, T.; Tai, K.; Tokuhara, N.; Kobayashi, S. (Eisai Co., Ltd.); Fused-ring carboxylic acid derivs.. EP 0889032; US 6110959; US 6121309; WO 9734869 . |
| 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) | 50362 | 2-hydroxy-3,6-dimethylbenzaldehyde | C9H10O2 | 详情 | 详情 | |
| (II) | 13183 | 2-Bromo-1,1-dimethoxyethane; 2-Bromo-1-methoxyethyl methyl ether; Bromoacetaldehyde dimethyl acetal | 7252-83-7 | C4H9BrO2 | 详情 | 详情 |
| (III) | 50363 | 2-(2,2-dimethoxyethoxy)-3,6-dimethylbenzaldehyde | C13H18O4 | 详情 | 详情 | |
| (IV) | 35861 | 4,7-dimethyl-1-benzofuran-2-carbaldehyde | C11H10O2 | 详情 | 详情 | |
| (V) | 35857 | methyl 4-acryloylbenzoate | C11H10O3 | 详情 | 详情 | |
| (VI) | 35862 | methyl 4-[4-(4,7-dimethyl-1-benzofuran-2-yl)-4-oxobutanoyl]benzoate | C22H20O5 | 详情 | 详情 | |
| (VII) | 35863 | methyl 4-[5-(4,7-dimethyl-1-benzofuran-2-yl)-1H-pyrrol-2-yl]benzoate | C22H19NO3 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(II)Dialkylation of 2-aryl acetonitrile (I) with bromoacetaldehyde dimethyl acetal (II) by means of NaNH2 in toluene provides diacetal (III), which is cyclized to cyanopiperidine derivative (IV) by first hydrolysis of the acetal groups with HCl, followed by reductive amination with methylamine in the presence of NaBH3CN in MeOH. Finally, the target product is obtained by hydrolysis of the nitrile group of (IV) with aqueous H2SO4, followed by esterification performed by heating with EtOH.
| 【1】 katz, J.L.; Trudell, M.L.; Lomenzo, S.A.; Kopajtic, T.; Gerdes, R.M.; Izenwasser, S.; Synthesis, dopamine and serotonin transporter binding affinities of novel analogues of meperidine. Bioorg Med Chem Lett 1999, 9, 23, 3273. |
| 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) | 26935 | 2-(3,4-dichlorophenyl)acetonitrile | 3218-49-3 | C8H5Cl2N | 详情 | 详情 |
| (II) | 13183 | 2-Bromo-1,1-dimethoxyethane; 2-Bromo-1-methoxyethyl methyl ether; Bromoacetaldehyde dimethyl acetal | 7252-83-7 | C4H9BrO2 | 详情 | 详情 |
| (III) | 47009 | 2-(3,4-dichlorophenyl)-2-(2,2-dimethoxyethyl)-4,4-dimethoxybutanenitrile | C16H21Cl2NO4 | 详情 | 详情 | |
| (IV) | 47010 | 4-(3,4-dichlorophenyl)-1-methyl-4-piperidinecarbonitrile | C13H14Cl2N2 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(XXIII)Condensation of ethyl 3-(dimethylamino)acrylate (XVIII) with (benzyloxy)acetyl chloride (XIX) by means of pyridine in CH2Cl2 gives ethyl 2-[(benzyloxy)acetyl]-3-(dimethylamino)-2-propenoate (XX), which by cyclocondensation with ethyl oxalyl chloride (XXI) in the presence of LiHMDS in THF at –78 °C followed by heating with NH4OAc and AcOH affords pyridone derivative (XXII). Alkylation of pyridone (XXII) with bromoacetaldehyde dimethyl acetal (XXIII) and Cs2CO3 in DMF yields diethyl 1-(2,2-dimethoxyethyl)-3-(benzyloxy)-1,4-dihydropyridine-2,5-dicarboxylate (XXIV), which can also be obtained by condensation of diethyl 3-(benzyloxy)-4-oxo-4H-pyran-2,5-dicarboxylate (XXV) with 2,2-dimethoxyethylamine (XXVI) in EtOH. Hydrolysis of acetal (XXIV) with H2SO4 and HCOOH in CH2Cl2 yields aldehyde (XXVII), which upon cyclocondensation with 3(R)-amino-1-butanol (XI) by means of AcOH in refluxing MeOH/toluene provides the hexahydropyrido[1’,2’:4,5]pyrazino[2,1-b][1,3]oxazine derivative (XXVIII). Hydrolysis of ester (XXVIII) with NaOH in THF/MeOH/H2O gives the corresponding free acid (XXIX), which is finally condensed with 2,4-difluorobenzylamine (XIV) in the presence of HATU and NMM in DMF .
Propenoate (XX) can also be prepared by condensation of ethyl 4-chloroacetoacetate (XXX) with PhCH2OH in the presence of t-AmONa to give benzyl ether (XXXI), which then reacts with N,N-dimethylformamide dimethyl acetal (XXXII) in toluene .
| 【1】 Sumino, Y., Okamoto, K., Masui, M., Yamada, D., Ikarashi, F. (Shionogi & Co., Ltd.). Process for preparing compound having HIV integrase inhibitory activity. WO 2012018065. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XI) | 68577 | 3(R)-amino-1-butanol;(R)-3-aminobutan-1-ol | 61477-39-2 | C4H11NO | 详情 | 详情 |
| (XIV) | 68578 | 2,4-difluorobenzylamine | 72235-52-0 | C7H7F2N | 详情 | 详情 |
| (XV) | 68579 | (4R,12aS)-7-(benzyloxy)-N-(2,4-difluorobenzyl)-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxamide | C27H25F2N3O5 | 详情 | 详情 | |
| (XVIII) | 16000 | ethyl (E)-3-(dimethylamino)-2-propenoate; Ethyl trans-3-dimethylaminoacrylate | 1117-37-9 | C7H13NO2 | 详情 | 详情 |
| (XIX) | 10493 | 2-(Benzyloxy)acetyl chloride; Benzyloxyacetyl chloride | 19810-31-2 | C9H9ClO2 | 详情 | 详情 |
| (XX) | 68583 | (E)-ethyl 4-(benzyloxy)-2-((dimethylamino)methylene)-3-oxobutanoate | C16H21NO4 | 详情 | 详情 | |
| (XXI) | 11043 | Ethyl 2-chloro-2-oxoacetate; Ethyl oxalyl chloride | 4755-77-5 | C4H5ClO3 | 详情 | 详情 |
| (XXII) | 68584 | diethyl 3-(benzyloxy)-4-oxo-1,4-dihydropyridine-2,5-dicarboxylate | C18H19NO6 | 详情 | 详情 | |
| (XXIII) | 13183 | 2-Bromo-1,1-dimethoxyethane; 2-Bromo-1-methoxyethyl methyl ether; Bromoacetaldehyde dimethyl acetal | 7252-83-7 | C4H9BrO2 | 详情 | 详情 |
| (XXIV) | 68585 | 1-(2,2-dimethoxyethyl)-3-(benzyloxy)-1,4-dihydropyridine-2,5-dicarboxylate diethyl；diethyl 3-(benzyloxy)-1-(2,2-dimethoxyethyl)-4-oxo-1,4-dihydropyridine-2,5-dicarboxylate | C22H27NO8 | 详情 | 详情 | |
| (XXV) | 68586 | diethyl 3-(benzyloxy)-4-oxo-4H-pyran-2,5-dicarboxylate | C18H18O7 | 详情 | 详情 | |
| (XXVI) | 34158 | aminoacetaldehyde dimethylacetal; 2,2-dimethoxy-1-ethanamine; 2,2-dimethoxyethylamine | 22483-09-6 | C4H11NO2 | 详情 | 详情 |
| (XXVII) | 68587 | diethyl 3-(benzyloxy)-4-oxo-1-(2-oxoethyl)-1,4-dihydropyridine-2,5-dicarboxylate | C20H21NO7 | 详情 | 详情 | |
| (XXVIII) | 68588 | (4R,12aS)-ethyl 7-(benzyloxy)-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxylate | C22H24N2O6 | 详情 | 详情 | |
| (XXIX) | 68589 | (4R,12aS)-7-(benzyloxy)-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxylic acid | C20H20N2O6 | 详情 | 详情 | |
| (XXX) | 23541 | ethyl 4-chloro-3-oxobutanoate；Ethyl 4-chloro-3-oxobutanoate；Ethyl 4-chloroacetoacetate | 638-07-3 | C6H9ClO3 | 详情 | 详情 |
| (XXXI) | 68590 | ethyl 4-(benzyloxy)-3-oxobutanoate | C13H16O4 | 详情 | 详情 | |
| (XXXII) | 11984 | N-(Dimethoxymethyl)-N,N-dimethylamine;dimethylformamide dimethylacetal;1,1-dimethoxy-N,N-dimethylmethanamine； Dimethoxy-N,N-dimethylmethanamine; N,N-Dimethylformamide dimethyl acetal | 4637-24-5 | C5H13NO2 | 详情 | 详情 |