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【结 构 式】 
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【分子编号】19502 【品名】Propyl bromide; 1-Bromopropane 【CA登记号】106-94-5 |
【 分 子 式 】C3H7Br 【 分 子 量 】122.99258 【元素组成】C 29.3% H 5.74% Br 64.97% |
合成路线1
该中间体在本合成路线中的序号：(A)The reaction of methyl dihydro-lysergate (I) with cyanogen bromide in methylene chloride gives 6-cyano-8beta-methoxycarbonylergoline (II), which is treated with Zn dust and acetic acid - water to afford 8beta-methoxycarbonylergoline (III). The alkylation of (III) with propyl bromide (A) and potassium carbonate in DMF yields 6-n-propyl-8beta-methoxycarbonylergoline (IV), which is reduced with NaBH4 in dioxane - methanol to 6-n-propyl-8beta-hydroxymethylergoline (V). The mesylation of (V) with mesyl chloride in pyridine gives 6-n-propyl-8beta-mesyloxymethylergoline (VI), which is finally treated with sodium methylmercaptide in dimethylacetamide and with methanesulfonic acid.
| 【1】 Kornfeld, E.C.; Bach, N.J. (Eli Lilly and Company); 6-N-Propyl-8-methoxymethyl or methylmercaptomethylergolines and related compounds. AT 371817B; DD 141928; EP 0003667; FR 2416891; GB 2014140; US 4166182 . |
| 【2】 Serradell, M.N.; Castaner, J.; Blancafort, P.; Owen, R.T.; Pergolide mesylate. Drugs Fut 1981, 6, 4, 231. |
| 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) | 19502 | Propyl bromide; 1-Bromopropane | 106-94-5 | C3H7Br | 详情 | 详情 |
| (I) | 32239 | Methyl dihydro-lysergate; Methyl (6aR,9R,10aR)-7-methyl-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinoline-9-carboxylate | C17H20N2O2 | 详情 | 详情 | |
| (II) | 32240 | 6-Cyano-8beta-methoxycarbonylergoline; Methyl (6aR,9R,10aR)-7-cyano-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinoline-9-carboxylate | C17H17N3O2 | 详情 | 详情 | |
| (III) | 11273 | 8beta-Methoxycarbonylergoline; Methyl (6aR,9R,10aR)-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinoline-9-carboxylate | C16H18N2O2 | 详情 | 详情 | |
| (IV) | 32241 | 6-n-Propyl-8beta-methoxycarbonylergoline; Methyl (6aR,9R,10aR)-7-propyl-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinoline-9-carboxylate | C19H24N2O2 | 详情 | 详情 | |
| (V) | 32242 | [(6aR,9R,10aR)-7-propyl-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinolin-9-yl]methanol; 6-n-Propyl-8beta-hydroxymethylergoline | C18H24N2O | 详情 | 详情 | |
| (VI) | 32243 | 6-n-Propyl-8beta-mesyloxymethylergoline; (6aR,9R,10aR)-9-([[Methyl(dimethylene)-lambda(6)-sulfanyl]oxy]methyl)-7-propyl-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinoline | C21H30N2OS | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(A)The reaction of 3-bromoanisole (I) with magnesium in THF gives 3-methoxyphenylmagnesium bromide (II), which is condensed with 3-bromopyridine (III) in THF by means of dichlorobis(triphenylphosphine)nickel yielding 3-(3-pyridinyl)anisole (IV). The alkylation of (IV) with propylbromide (A) in acetone at 110 C (under pressure) affords N-propyl-3-(3-methoxyphenyl)pyridinium bromide (V), which is reduced with H2 over Pt in methanol to give 1-propyl-3-(3-methoxyphenyl)piperidine (VI). Finally, this compound is demethylated by treatment with refluxing aqueous 48% HBr. The reduction of (IV) with H2 over Pt in methanol gives 3-(3-methoxyphenyl)piperidine (VII), which is acylated and reduced simultaneously with propionic acid (B) and NaBH4 in refluxing benzene to yield (VI), already obtained.
| 【1】 Arvidsson, F.L.E.; et al.; EP 0030526 . |
| 【2】 Sanchez, D.; Nilsson, J.L.G.; Hacksell, U.; Lindberg, P.; Carlsson, A.; Arvidsson, L.E.; Svensson, U.; Hjorth, S.; Wikstroem, H.; 3-Phenylpiperidines. Central dopamine-autoreceptor stimulating activity. J Med Chem 1981, 24, 12, 1475-82. |
| 【3】 Serradell, M.N.; Nohria, V.; Castaner, J.; Blancafort, P.; 3-PPP. Drugs Fut 1983, 8, 1, 27. |
| 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) | 19502 | Propyl bromide; 1-Bromopropane | 106-94-5 | C3H7Br | 详情 | 详情 |
| (B) | 20178 | propionic acid | 79-09-4 | C3H6O2 | 详情 | 详情 |
| (I) | 35983 | m-bromoanisole; 1-Bromo-3-methoxybenzene; 3-Bromoanisole; 3-Bromophenyl methyl ether | 2398-37-0 | C7H7BrO | 详情 | 详情 |
| (II) | 35984 | bromo(3-methoxyphenyl)magnesium | 36282-40-3 | C7H7BrMgO | 详情 | 详情 |
| (III) | 13265 | 3-Bromopyridine | 626-55-1 | C5H4BrN | 详情 | 详情 |
| (IV) | 35985 | 3-(3-methoxyphenyl)pyridine; methyl 3-(3-pyridinyl)phenyl ether | C12H11NO | 详情 | 详情 | |
| (V) | 35986 | 3-(3-methoxyphenyl)-1-propylpyridinium bromide | C15H18BrNO | 详情 | 详情 | |
| (VI) | 35987 | 3-(3-methoxyphenyl)-1-propylpiperidine; methyl 3-(1-propyl-3-piperidinyl)phenyl ether | C15H23NO | 详情 | 详情 | |
| (VII) | 35988 | 3-(3-methoxyphenyl)piperidine; methyl 3-(3-piperidinyl)phenyl ether | C12H17NO | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VI)Optical resolution of DL-pipecolinic acid (I) with (+)-tartaric acid gives L-pipecolinic acid (II), which is treated with PCl5 to obtain acil chloride (III). This compound is condensed with 2,5-dimethylaniline (IV) by means N-methylpirrolidine (NMP) to afford amide (V). Finally, amide (V) is alkylated with 1-bromopropane by means potassium carbonate (K2CO3) to yield Ropivacaine.
| 【1】 Sandeberg, R.V. (AstraZeneca plc); S-(-)-1-propyl-2',6'-pipecoloxylidide hydrochloride monohydrate, process for its preparation and pharmaceutical preparation containing it. EP 0239710; US 4870086 . |
| 【2】 T. af Ekenstam, B.; Bovin, C. (Alpharma Inc.); L-N-n-Propylpipecolic acid-2,6-xylidide and method for preparing the same. JP 1985502054; WO 8500599 . |
| 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) | 17532 | 2-piperidinecarboxylic acid; pipecolic acid | 535-75-1 | C6H11NO2 | 详情 | 详情 |
| (II) | 17380 | (2S)hexahydro-2-pyridinecarboxylic acid; (S)-pipecolic acid | 3105-95-1 | C6H11NO2 | 详情 | 详情 |
| (III) | 19499 | (2S)-2-piperidinecarbonyl chloride | C6H10ClNO | 详情 | 详情 | |
| (IV) | 17527 | 2,6-Xylidine; 2,6-Dimethylaniline; 2,6-Dimethylphenylamine | 87-62-7 | C8H11N | 详情 | 详情 |
| (V) | 17531 | (2S)-N-(2,6-dimethylphenyl)-2-piperidinecarboxamide | C14H20N2O | 详情 | 详情 | |
| (VI) | 19502 | Propyl bromide; 1-Bromopropane | 106-94-5 | C3H7Br | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(II)The alkylation of 4-hydroxy-3-iodo-5-methoxybenzaldehyde (I) with propyl bromide (II) by means of K2CO3 in hot DMF gives the propyl ether (III), which is condensed with 3-(dimethylamino)-1-(3,4,5-trimethoxyphenyl)-1-propanone (IV) (obtained by reaction of 3,4,5-trimethoxyacetophenone (V) with dimethylamine and formaldehyde), yielding the asymmetric butanedione (VI). The reaction of (VI) with dimethyl disulfide by means of Cu at 160 C affords the methylsulfanyl compound (VII), which is oxidized with MCPBA in dichloromethane to provide the sulfone derivative (VIII). The reduction of the butanedione (VIII) with NaBH4 in hot ethanol gives the (RS,RS)-diol (IX), which is finally cyclized by means of TFA in chloroform.
| 【1】 Ponpipom, M.M.; Hwang, S.B.; Doebber, T.W.; Acton, J.J.; Alberts, A.W.; Biftu, T.; Brooker, D.R.; Bugianesi, R.L.; Chabala, J.C.; Gamble, N.L.; et al.; (±)-trans-2-(3-Methoxy-5-methylsulfonyl-4-propoxyphenyl)-5-(3,4,5-trimethoxyphenyl)tetrahydrofuran (L-659,989), a novel, potent PAF receptor antagonist. Biochem Biophys Res Commun 1988, 150, 3, 1213. |
| 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) | 12758 | 4-Hydroxy-3-iodo-5-methoxybenzaldehyde; 5-Iodovanillin | 5438-36-8 | C8H7IO3 | 详情 | 详情 |
| (II) | 19502 | Propyl bromide; 1-Bromopropane | 106-94-5 | C3H7Br | 详情 | 详情 |
| (III) | 12759 | 3-Iodo-5-methoxy-4-propoxybenzaldehyde | C11H13IO3 | 详情 | 详情 | |
| (IV) | 44362 | 1-(3,4,5-trimethoxyphenyl)-1-ethanone | 1136-86-3 | C11H14O4 | 详情 | 详情 |
| (V) | 44363 | 3-(dimethylamino)-1-(3,4,5-trimethoxyphenyl)-1-propanone | C14H21NO4 | 详情 | 详情 | |
| (VI) | 44369 | 1-(3-iodo-5-methoxy-4-propoxyphenyl)-4-(3,4,5-trimethoxyphenyl)-1,4-butanedione | C23H27IO7 | 详情 | 详情 | |
| (VII) | 44370 | 1-[3-methoxy-5-(methylsulfanyl)-4-propoxyphenyl]-4-(3,4,5-trimethoxyphenyl)-1,4-butanedione | C24H30O7S | 详情 | 详情 | |
| (VIII) | 44366 | 1-[3-methoxy-5-(methylsulfonyl)-4-propoxyphenyl]-4-(3,4,5-trimethoxyphenyl)-1,4-butanedione | C24H30O9S | 详情 | 详情 | |
| (IX) | 44368 | (1R,4R)-1-[3-methoxy-5-(methylsulfonyl)-4-propoxyphenyl]-4-(3,4,5-trimethoxyphenyl)-1,4-butanediol | C24H34O9S | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(VI)1) The optical resolution of pipecolic acid (I) with (+)-tartaric acid in water-ethanol gives L-pipecolic acid (II), which by reaction with Cl5P in acetyl chloride is converted to the acyl chloride (III). The condensation of (III) with 2,6-xylidine (IV) by means of N-methylpyrrolidone (NMP) in acetone affords L-pipecolic acid 2,6-xylidide (V), which is finally alkylated with propyl bromide (VI) and K2CO3 in hot isopropanol.
| 【1】 T. af Ekenstam, B.; Bovin, C. (Astra Lakemedel AB); L-N-n-Propylpipecolic acid 2,6-xylidide. US 4695576 . |
| 【2】 Prous, J.; Castaner, J.; ROPIVACAINE HYDROCHLORIDE < Rec INNM >. Drugs Fut 1989, 14, 8, 767. |
| 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) | 17532 | 2-piperidinecarboxylic acid; pipecolic acid | 535-75-1 | C6H11NO2 | 详情 | 详情 |
| (II) | 17380 | (2S)hexahydro-2-pyridinecarboxylic acid; (S)-pipecolic acid | 3105-95-1 | C6H11NO2 | 详情 | 详情 |
| (III) | 19499 | (2S)-2-piperidinecarbonyl chloride | C6H10ClNO | 详情 | 详情 | |
| (IV) | 17527 | 2,6-Xylidine; 2,6-Dimethylaniline; 2,6-Dimethylphenylamine | 87-62-7 | C8H11N | 详情 | 详情 |
| (V) | 17531 | (2S)-N-(2,6-dimethylphenyl)-2-piperidinecarboxamide | C14H20N2O | 详情 | 详情 | |
| (VI) | 19502 | Propyl bromide; 1-Bromopropane | 106-94-5 | C3H7Br | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(VI)2) The protection of L-pipecolic acid (II) with benzyl chloroformate (VII) gives the benzyloxycarbonyl compound (VIII), which is condensed with o-toluidine (IX) by means of SOCl2 and dimethylaminopyridine (DMAP) yielding the amide (X). The methylation of (X) with methyl iodide and palladium diacetate in acetic acid affords the 2,6-xylidide (XI), which is deprotected with HBr in acetic acid to give L-pipecolic acid 2,6-xylidide (V). Finally, this compound is alkylated with propyl iodide and K2CO3 in acetonitrile.
| 【1】 Prous, J.; Castaner, J.; ROPIVACAINE HYDROCHLORIDE < Rec INNM >. Drugs Fut 1989, 14, 8, 767. |
| 【2】 Sahlberg, C.; Synthesis of carbon-14 labelled ropivacaine, a local anaesthetic agent. J Label Compd Radiopharm 1987, 24, 5, 529. |
| 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) | 17380 | (2S)hexahydro-2-pyridinecarboxylic acid; (S)-pipecolic acid | 3105-95-1 | C6H11NO2 | 详情 | 详情 |
| (V) | 17531 | (2S)-N-(2,6-dimethylphenyl)-2-piperidinecarboxamide | C14H20N2O | 详情 | 详情 | |
| (VI) | 19502 | Propyl bromide; 1-Bromopropane | 106-94-5 | C3H7Br | 详情 | 详情 |
| (VII) | 10101 | Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene | 501-53-1 | C8H7ClO2 | 详情 | 详情 |
| (VIII) | 19504 | (2S)-1-[(benzyloxy)carbonyl]-2-piperidinecarboxylic acid | C14H17NO4 | 详情 | 详情 | |
| (IX) | 15511 | o-toluidine; 2-methylphenylamine;2-Methylaniline；2-Aminotoluene;1-Amino-2-methylbenzene;1-Methyl-2-aminobenzene; ortho-Toluidine | 95-53-4 | C7H9N | 详情 | 详情 |
| (X) | 19506 | benzyl (2S)-2-(2-toluidinocarbonyl)-1-piperidinecarboxylate | C21H24N2O3 | 详情 | 详情 | |
| (XI) | 19507 | benzyl (2S)-2-[(2,6-dimethylanilino)carbonyl]-1-piperidinecarboxylate | C22H26N2O3 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(VI)3) The protection of 1,2,3,6-tetrahydropyridine-2(S)-carboxylic acid (XII) with benzyl chloroformate (VII) gives the benzyloxycarbonyl derivative (XIII), which is condensed with 2,6-xylidine (IV) with SOCl2 and DMAP as before yielding the amide (XIV). Deprotection of (XIV) with iodotrimethylsilane in dichloromethane affords N-(2,6-dimethylphenyl)-1,2,3,6-tetrahydropyridine-2(S)-carboxamide (XV), which is reduced with H2 over Rh/Al2O3 in DMF giving the saturated amide (V). Finally, this compound is alkylated with propyl iodide and K2CO3 as before.
| 【1】 Prous, J.; Castaner, J.; ROPIVACAINE HYDROCHLORIDE < Rec INNM >. Drugs Fut 1989, 14, 8, 767. |
| 【2】 Gawell, L.; Synthesis of tritium labelled ropivacaine - A new potential local anaesthetic. J Label Compd Radiopharm 1987, 24, 5, 521. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IV) | 17527 | 2,6-Xylidine; 2,6-Dimethylaniline; 2,6-Dimethylphenylamine | 87-62-7 | C8H11N | 详情 | 详情 |
| (V) | 17531 | (2S)-N-(2,6-dimethylphenyl)-2-piperidinecarboxamide | C14H20N2O | 详情 | 详情 | |
| (VI) | 19502 | Propyl bromide; 1-Bromopropane | 106-94-5 | C3H7Br | 详情 | 详情 |
| (VII) | 10101 | Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene | 501-53-1 | C8H7ClO2 | 详情 | 详情 |
| (XII) | 19508 | (2S)-1,2,3,4-tetrahydro-2-pyridinecarboxylic acid | C6H9NO2 | 详情 | 详情 | |
| (XIII) | 19509 | (2S)-1-[(benzyloxy)carbonyl]-1,2,3,4-tetrahydro-2-pyridinecarboxylic acid | C14H15NO4 | 详情 | 详情 | |
| (XIV) | 19510 | benzyl (2S)-2-[(2,6-dimethylanilino)carbonyl]-3,4-dihydro-1(2H)-pyridinecarboxylate | C22H24N2O3 | 详情 | 详情 | |
| (XV) | 19511 | (2S)-N-(2,6-dimethylphenyl)-1,2,3,4-tetrahydro-2-pyridinecarboxamide | C14H18N2O | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：1) The acylation of 2-amino-7-methoxy-1-tetralone (I) with chloroacetyl chloride in ethyl acetate - water by means of NaHCO3 gives the corresponding chloroacetamido derivative (II), which is reduced with NaBH4 in ethanol - CHCl3 to trans-2-(chloroacetamido)-7-methoxy-1,2,3,4-tetrahydronaphthalen-1-ol (III). The cyclization of (III) by means of NaH in DMF yields the oxazinone (IV), which is reduced with LiAlH4 in refluxing THF to trans-9-methoxy-3,4,4a,5,6,10b-hexahydro-2H-naphth[1,2-b]-1,4-oxazine (V). The alkylation of (V) with propyl bromide by means of K2CO3 in DMF gives the N-propyl derivative (VI), which is finally demethylated by means of pyridine hydrochloride at 200 C.
| 【1】 Jones, J.H.; McClure, D.E.; Grenda, V.J. (Merck & Co., Inc.); Hexahydronaphth(1,2-b)-1,4-oxazines, process for their preparation and pharmaceutical formulation containing them. EP 0080115 . |
| 【2】 Prous, J.; Castaner, J.; NAXAGOLIDE HYDROCHLORIDE < Prop INNM; USAN >. Drugs Fut 1989, 14, 10, 951. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 11296 | 2-Chloroacetyl chloride; Chloroacetic chloride | 79-04-9 | C2H2Cl2O | 详情 | 详情 | |
| 19502 | Propyl bromide; 1-Bromopropane | 106-94-5 | C3H7Br | 详情 | 详情 | |
| (I) | 21376 | 2-amino-7-methoxy-3,4-dihydro-1(2H)-naphthalenone | C11H13NO2 | 详情 | 详情 | |
| (II) | 21377 | 2-chloro-N-(7-methoxy-1-oxo-1,2,3,4-tetrahydro-2-naphthalenyl)acetamide | C13H14ClNO3 | 详情 | 详情 | |
| (III) | 21378 | 2-chloro-N-[(1R,2R)-1-hydroxy-7-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl]acetamide | C13H16ClNO3 | 详情 | 详情 | |
| (IV) | 21379 | (4aR,10bR)-9-methoxy-4a,5,6,10b-tetrahydro-2H-naphtho[1,2-b][1,4]oxazin-3(4H)-one | C13H15NO3 | 详情 | 详情 | |
| (V) | 21380 | (4aR,10bR)-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazin-9-yl methyl ether | C13H17NO2 | 详情 | 详情 | |
| (VI) | 21381 | (4aR,10bR)-4-propyl-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazin-9-yl methyl ether | C16H23NO2 | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(II)The reaction of 2-hydroxy-4-methylbenzoic acid (I) with ethyl bromide (II) and K2CO3 in acetone at 150 C gives 2-ethoxy-4-methylbenzoic acid ethyl ester (III), which is brominated with Br2 and AIBN in CCl4 to yield the bromomethyl derivative (IV). The reaction of (IV) with NaCN and benzyl-tributylammonium chloride affords the cyanomethyl compound (V), which is hydrolyzed with HCl (g) in refluxing ethanol to provide 2-ethoxy-4-(ethoxycarbonylmethyl)benzoic acid ethyl ester (VI). Finally, this compound is selectively hydrolyzed with 2N NaOH in ethanol to furnish the target intermediate, the 2-[3-ethoxy-4-(ethoxycarbonyl)phenyl]acetic acid (VII).
| 【1】 Salman, M.; et al.; An efficient and cost-effective synthesis of 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid: A key acid synthon of repaglinide. Org Process Res Dev 2002, 6, 2, 184. |
| 【2】 Grell, W.; Hurnaus, R.; Griss, G.; Sauter, R.; Rupprecht, E.; Mark, M.; Luger, P.; Nar, H.; Wittneben, H.; Muller, P.; Repaglinide and related hypoglycemic benzoic acid derivatives. J Med Chem 1998, 41, 26, 5219. |
| 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) | 53446 | 2-Hydroxy-4-methylbenzoic acid; 2-Hydroxy-p-toluic Acid; 4-Methylsalicylic acid; m-Cresotinic acid | 50-85-1 | C8H8O3 | 详情 | 详情 |
| (II) | 19502 | Propyl bromide; 1-Bromopropane | 106-94-5 | C3H7Br | 详情 | 详情 |
| (III) | 53447 | ethyl 2-ethoxy-4-methylbenzoate | 88709-17-5 | C12H16O3 | 详情 | 详情 |
| (IV) | 53448 | ethyl 4-(bromomethyl)-2-ethoxybenzoate | n/a | C12H15BrO3 | 详情 | 详情 |
| (V) | 53449 | ethyl 4-(cyanomethyl)-2-ethoxybenzoate | n/a | C13H15NO3 | 详情 | 详情 |
| (VI) | 53450 | ethyl 2-ethoxy-4-(2-ethoxy-2-oxoethyl)benzoate | n/a | C15H20O5 | 详情 | 详情 |
| (VII) | 15301 | 2-[3-ethoxy-4-(ethoxycarbonyl)phenyl]acetic acid | C13H16O5 | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(II)The reaction of 2-hydroxy-4-methylbenzoic acid (I) with ethyl bromide (II) and K2CO3 in DMSO gives 2-ethoxy-4-methylbenzoic acid ethyl ester (III), which is carboxylated by reaction with LDA and CO2 in THF/1,3-dimethylperhydropyrimidin-2-one to furnish the target intermediate the 2-[3-ethoxy-4-(ethoxycarbonyl)phenyl]acetic acid (IV).
| 【1】 Salman, M.; et al.; An efficient and cost-effective synthesis of 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid: A key acid synthon of repaglinide. Org Process Res Dev 2002, 6, 2, 184. |
| 【2】 Kumar, N.; Biswas, S.; Salman, M.; Babu, S.J.; Ray, P.C. (Ranbaxy Laboratories Ltd.); Synthesis of 3-ethoxy-4-ethoxycarbonyl phenyl acetic acid, a key acid synthon of repaglinide. WO 0135900 . |
| 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) | 53446 | 2-Hydroxy-4-methylbenzoic acid; 2-Hydroxy-p-toluic Acid; 4-Methylsalicylic acid; m-Cresotinic acid | 50-85-1 | C8H8O3 | 详情 | 详情 |
| (II) | 19502 | Propyl bromide; 1-Bromopropane | 106-94-5 | C3H7Br | 详情 | 详情 |
| (III) | 53447 | ethyl 2-ethoxy-4-methylbenzoate | 88709-17-5 | C12H16O3 | 详情 | 详情 |
| (IV) | 15301 | 2-[3-ethoxy-4-(ethoxycarbonyl)phenyl]acetic acid | C13H16O5 | 详情 | 详情 |
合成路线11
该中间体在本合成路线中的序号：(VIII)Wittig reaction between aldehyde (I) and bromo derivative (II) by means of triethyl phosphonoacetate and NaH in 1,2-dimethoxyethane (A) affords a mixture of isomeric acrylates (IIIa-b), which are hydrogenated over Pd/C in EtOH to yield derivative (IV). Hydrolysis of ethyl ester (IV) by means of KOH or NaOH provides carboxylic acid (V), which is then converted into N-protected derivative (VI) by first treatment with diphenylphosphoryl azide (DPPA) and Et3N in refluxing benzene, followed by reaction with refluxing t-butanol. Boc removal of (VI) with TFA in CH2Cl2 furnishes free amine (VII), which is finally alkylated with propyl bromide (VIII) by means of K2CO3 in DMF to yield the target product.
| 【1】 Tomisawa, K.; Ohta, K.; Nakazato, A.; Kumagai, T.; Chaki, S.; Okuyama, S.; Synthesis and SAR of 1-alkyl-2-phenylethylamine derivatives designed from N,N-dipropyl-4-methoxy-3-(2-phenylethoxy)phenylethylamine to discover sigma1 ligands. J Med Chem 1999, 42, 19, 3965. |
| 【2】 Nakazato, A.; Kumagai, T.; Miyazawa, T.; Ohta, K.; Kawashima, Y.; Hatayama, K. (Taisho Pharmaceutical Co., Ltd.); Optically active substd. phenylalkylamine derivs.. EP 0870758; JP 1997059230; US 5990151; WO 9700238 . |
| 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) | 10019 | Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate | 867-13-0 | C8H17O5P | 详情 | 详情 |
| (IIIa) | 46235 | ethyl (Z)-2-isopentyl-3-[4-methoxy-3-(phenethyloxy)phenyl]-2-propenoate | C25H32O4 | 详情 | 详情 | |
| (IIIb) | 46236 | ethyl (E)-2-isopentyl-3-[4-methoxy-3-(phenethyloxy)phenyl]-2-propenoate | C25H32O4 | 详情 | 详情 | |
| (I) | 23679 | 4-methoxy-3-(phenethyloxy)benzaldehyde | C16H16O3 | 详情 | 详情 | |
| (II) | 46234 | 1-bromo-3-methylbutane | C5H11Br | 详情 | 详情 | |
| (IV) | 46237 | ethyl 2-[4-methoxy-3-(phenethyloxy)benzyl]-5-methylhexanoate | C25H34O4 | 详情 | 详情 | |
| (V) | 46238 | 2-[4-methoxy-3-(phenethyloxy)benzyl]-5-methylhexanoic acid | C23H30O4 | 详情 | 详情 | |
| (VI) | 46239 | tert-butyl 1-[4-methoxy-3-(phenethyloxy)benzyl]-4-methylpentylcarbamate | C27H39NO4 | 详情 | 详情 | |
| (VII) | 46240 | 1-[4-methoxy-3-(phenethyloxy)benzyl]-4-methylpentylamine; 1-[4-methoxy-3-(phenethyloxy)phenyl]-5-methyl-2-hexanamine | C22H31NO2 | 详情 | 详情 | |
| (VIII) | 19502 | Propyl bromide; 1-Bromopropane | 106-94-5 | C3H7Br | 详情 | 详情 |
合成路线12
该中间体在本合成路线中的序号：(A)By treating 3-methylxanthine (I) with sodium hydroxide and 1-bromo-5-hexanone (II) to give 3-methyl-7-(5-oxohexyl)xanthine (III), which is reacted to (IV) with 1-bromopropane (A) in the same way. Compound (IV) is reduced to the title compound with sodium borohydride.
| 【1】 Unterhalt, B.; HWA-153. Drugs Fut 1980, 5, 2, 77. |
| 【2】 Stefanovich, V.; Private Communication 2002, 10, 9, 3001. |
| 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) | 19502 | Propyl bromide; 1-Bromopropane | 106-94-5 | C3H7Br | 详情 | 详情 |
| (I) | 39122 | 3-methyl-3,7-dihydro-1H-purine-2,6-dione | 1076-22-8 | C6H6N4O2 | 详情 | 详情 |
| (II) | 37057 | 6-bromo-2-hexanone | C6H11BrO | 详情 | 详情 | |
| (III) | 39123 | 3-methyl-7-(5-oxohexyl)-3,7-dihydro-1H-purine-2,6-dione | C12H16N4O3 | 详情 | 详情 | |
| (IV) | 39124 | 3-methyl-7-(5-oxohexyl)-1-propyl-3,7-dihydro-1H-purine-2,6-dione | C15H22N4O3 | 详情 | 详情 |