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【结 构 式】 
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【分子编号】28379 【品名】(2R,3R)-2,3-dihydroxybutanedioic acid; L-Tartaric acid; (2R,3R)-2,3-dihydroxysuccinic acid 【CA登记号】87-69-4 |
【 分 子 式 】C4H6O6 【 分 子 量 】150.08804 【元素组成】C 32.01% H 4.03% O 63.96% |
合成路线1
该中间体在本合成路线中的序号：(VIII)The synthesis of pipethiadene (VII) is carried out by four steps from phthalide (I) and 2-thio-phenethiol (II). A solution of the sodium salt of (II) in ethanol, prepared by dissolving (II) in ethanolic sodium ethoxide, is refluxed with (I) to give 2-(2-thienylthiomethyl)benzoic acid (III). A modified procedure for preparing (III) consists of using the crude products of reactions of 2-thienylmagnesium bromide or 2-thienylmagnesium iodide sulfur instead of the Na salt of (II).The acid (III) is then cyclized either with polyphosphoric acid in the presence of boiling toluene, with phosphorus pentoxide in boiling toluene or with phosphoric ethyl ester in toluene at 100 C. The ketone (IV) is then treated with 1-methyl-4-piperidylmagnesium chloride (A) in tetrahydrofuran and the resulting amino alcohol (V) is dehydrated with boiling dilute sulfuric acid to give the desired (VII). More recently it has been established that the expected formation of (V) is accompanied by a 1,6-addition with the subsequent air-oxidation producing the byproduct (VI). This compound melts precisely at the same temperature as compound (V), and it is necessary to separate it on the basis of its good solubility in ethanol, in which (V) is almost insoluble in the cold. Neutralization of the base (VII) with (+)-tartaric acid in ethanol affords pipethiadene (+)-tartrate.
| 【1】 Protiva, M.; Rajsner, M.; US 3519649 . |
| 【2】 Rajsner, M.; Vejdelek, Z.J.; Protiva, M.; Seidlova,V.; Adlerova, E.; Some new types of 6,11-dihydrodibenzo[b,e]thiepin derivatives and their analogues. Coll Czech Chem Commun 1964, 29, 2161. |
| 【3】 Metys, J.; Rajsner, M.; Svatek, E.; Protiva, M.; Geometric isomerism of 4-(3-dimethylaminopropylidene)-9H-thieno[2,3-b]benzo[e]thiepin. Coll Czech Chem Commun 1974, 39, 1366. |
| 【4】 Metys, J.; Protiva, M.; Svatek, E.; Rajsner, M.; 4,9-Dihyfrothieno[2,3-b]benzo[3]thiepin derivatives. Coll Czech Chem Commun 1967, 32, 2854. |
| 【5】 Rajsner, M.; Protiva, M.; Metys, J.; Holubek, J.; Ryska, M.; Polívka, Z.; Svátek, E.; Antiaminic agents derived from thieno[2,3-c][2]benzothiepin: 4-(1-methyl-4-piperidylidene)-4,9-dihydroyhieno[2,3-c][2]benzothiepin and some related compounds. Coll Czech Chem Commun 1983, 48, 623. |
| 【6】 Protiva, M.; Pipethiadene tartrate. Drugs Fut 1983, 8, 4, 334. |
| 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) | 36058 | chloro[(1-methyl-4-piperidinyl)methyl]magnesium | C7H14ClMgN | 详情 | 详情 | |
| (I) | 12576 | 2-Benzofuran-1(3H)-one; Phthalide; Benzo[b]furan-1(3H)-one; 1(3H)-Isobenzofuranoneisobenzofuran-1-one | 87-41-2 | C8H6O2 | 详情 | 详情 |
| (II) | 16019 | 2-Thienylhydrosulfide; 2-Thiophenethiol | 7774-74-5 | C4H4S2 | 详情 | 详情 |
| (III) | 36056 | 2-[(2-thienylsulfanyl)methyl]benzoic acid | C12H10O2S2 | 详情 | 详情 | |
| (IV) | 36057 | thieno[2,3-c][2]benzothiepin-4(9H)-one | C12H8OS2 | 详情 | 详情 | |
| (V) | 36059 | 4-(1-methyl-4-piperidinyl)-4,9-dihydrothieno[2,3-c][2]benzothiepin-4-ol | C18H21NOS2 | 详情 | 详情 | |
| (VI) | 36060 | 7-(1-methyl-4-piperidinyl)thieno[2,3-c][2]benzothiepin-4(9H)-one | C18H19NOS2 | 详情 | 详情 | |
| (VII) | 36061 | 1-methyl-4-thieno[2,3-c][2]benzothiepin-4(9H)-ylidenepiperidine | C18H19NS2 | 详情 | 详情 | |
| (VIII) | 28379 | (2R,3R)-2,3-dihydroxybutanedioic acid; L-Tartaric acid; (2R,3R)-2,3-dihydroxysuccinic acid | 87-69-4 | C4H6O6 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XII)The reaction of 3-chloroaniline (I) with ethanolamine (II) by means of 47% HBr by heating at 170 C gives N-(3-chlorophenyl)ethylenediamine (III), which is condensed with ethyl 2-bromopropionate (IV) by means of triethylamine in refluxing toluene yielding the alanine derivative (V). The cyclization of (V) with refluxing 2N HCl affords the piperazinone (VI), which is reduced with LiAlH4 in ethyl ether providing 1-(3-chlorophenyl)-3-methylpiperazine (VII). The alkylation of (VII) with 1-bromo-3-chloropropane (VIII) by means of NaOH in acetone/water gives 4-(3-chlorophenyl)-1-(3-chloropropyl)-2-methylpiperazine (IX), which is condensed with the sodium salt of 1,2,4-triazolo[4,3-a]pyridin-3(2H)-one (X) in refluxing xylene/isobutanol yielding the target compound as a racemic mixture (XI). Finally, this compound is submitted to optical resolution with L-(+)-tartaric acid (XII).
| 【1】 Giannangeli, M.; Gazzolla, N.; Luparini, M.R.; Magnani, M.; Mabilia, M.; Picconi, G.; Tomaselli, M.; Baiocchi, L.; Effect of modifications of the alkylpiperazine moiety of trazodone on 5HT2A and alpha1 receptor binding affinity. J Med Chem 1999, 42, 3, 336. |
| 【2】 Baiocchi, L.; Cioli, V. (Angelini Group); Pharmacologically active enantiomers. EP 0707587; JP 1996512036; WO 9501354 . |
| 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) | 25239 | 3-chloroaniline; 3-chlorophenylamine | 108-42-9 | C6H6ClN | 详情 | 详情 |
| (II) | 10259 | Ethanol amine;Ethanolamine;2-Aminoethanol; 2-Amino-1-ethanol；2-Aminoethyl alcohol | 141-43-5 | C2H7NO | 详情 | 详情 |
| (III) | 34091 | N(1)-(3-chlorophenyl)-1,2-ethanediamine; N-(2-aminoethyl)-N-(3-chlorophenyl)amine | C8H11ClN2 | 详情 | 详情 | |
| (IV) | 19460 | ethyl 2-bromopropanoate; 2-Bromopropionic acid ethyl ester | 535-11-5 | C5H9BrO2 | 详情 | 详情 |
| (V) | 28373 | ethyl 2-[[2-(3-chloroanilino)ethyl]amino]propanoate | C13H19ClN2O2 | 详情 | 详情 | |
| (VI) | 28374 | 1-(3-chlorophenyl)-3-methyl-2-piperazinone | C11H13ClN2O | 详情 | 详情 | |
| (VII) | 28375 | 1-(3-chlorophenyl)-3-methylpiperazine | C11H15ClN2 | 详情 | 详情 | |
| (VIII) | 10358 | 1-Bromo-3-chloropropane | 109-70-6 | C3H6BrCl | 详情 | 详情 |
| (IX) | 28376 | 4-(3-chlorophenyl)-1-(3-chloropropyl)-2-methylpiperazine | C14H20Cl2N2 | 详情 | 详情 | |
| (X) | 28377 | [3-oxo[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl]sodium | C6H4N3NaO | 详情 | 详情 | |
| (XI) | 28378 | 2-[3-[4-(3-chlorophenyl)-2-methyl-1-piperazinyl]propyl][1,2,4]triazolo[4,3-a]pyridin-3(2H)-one | C20H24ClN5O | 详情 | 详情 | |
| (XII) | 28379 | (2R,3R)-2,3-dihydroxybutanedioic acid; L-Tartaric acid; (2R,3R)-2,3-dihydroxysuccinic acid | 87-69-4 | C4H6O6 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VII)Reduction of oxcarbazepine (I) using NaBH4 in ethanol/water yields the racemic alcohol (II), which is resolved into its enantiomers by means of fractional crystallization of the diastereomeric esters obtained from alcohol (II) and menthoxyacetyl chloride (III). Alkaline hydrolysis of the desired diastereoisomer (IV) provides the (S)-alcohol (V) , which is finally acylated with acetyl chloride and DMAP in pyridine/CH2Cl2 .
Condensation of racemic alcohol (II) with di-O-acetyl-L-tartaric acid anhydride (VI) – obtained by treatment of L-tartaric (VII) acid with hot AcO2 and trace H2SO4 – gives a disastereomeric mixture of tartrate monoesters (VIII), which is separated into diastereomeric alcohol esters by fractional crystallization in water and then the desired (S)-diastereomer hydrolyzed under alkaline conditions to afford alcohol (V) .
| 【1】 Benes, J., Vieira Araujo Soares da Silva, P.M. (Bial – Portela & Ca., SA). Substituted dihydrodibenzo[b,f]azepines, method of their preparation, their use in the treatment of some central nervous system disorders, and pharmaceutical compositions containing them. CA 2180301, EP 0751129, JP 1997110836, JP 2004256516, US 5753646, WO 199700250. |
| 【2】 Benes, J., Parada, A., Figueiredo, A. et al. Anticonvulsant and sodium channel-blocking properties of novel 10,11-dihydro-5H-dibenz[b,f]azepine-5-carboxamide derivatives. J Med Chem 1999, 42(14): 2582-7. |
| 【3】 Learmonth, D.A. (Portela & Ca., SA). Method for preparation of (S)-(+)-and (R)-(-)-10,11-dihydro-10-hydroxy-5H, dibenz[b,f]azepine-5-carboxamide. CA 2447980, EP 1385826, GB 2377440, JP 2004534753, US 2004162280, US 2007073057, US 7119197, WO 2002092572. |
| 【4】 Learmonth, D.A., Grasa, G.A., Zanotti-Gerosa, A. (Bial – Portela & Ca.,SA). Asymmetric catalytic reduction of oxcarbazepine. CA 2616984, EP 1915346, JP 2009502893, WO 2007012793. |
| 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) | 33774 | 10-oxo-10,11-dihydro-5H-dibenzo[b,f]azepine-5-carboxamide | 28721-07-5 | C15H12N2O2 | 详情 | 详情 |
| (II) | 58231 | 10-hydroxy-10,11-dihydro-5H-dibenzo[b,f]azepine-5-carboxamide | C15H14N2O2 | 详情 | 详情 | |
| (III) | 33776 | 2-[[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]oxy]acetyl chloride | 15356-62-4 | C12H21ClO2 | 详情 | 详情 |
| (IV) | 33777 | (10S)-5-(aminocarbonyl)-10,11-dihydro-5H-dibenzo[b,f]azepin-10-yl 2-[[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]oxy]acetate | C27H34N2O4 | 详情 | 详情 | |
| (V) | 33775 | (10S)-10-hydroxy-10,11-dihydro-5H-dibenzo[b,f]azepine-5-carboxamide | C15H14N2O2 | 详情 | 详情 | |
| (VI) | 69302 | di-O-acetyl-L-tartaric acid anhydride;(3R,4R)-2,5-dioxotetrahydrofuran-3,4-diyl diacetate | C8H8O7 | 详情 | 详情 | |
| (VII) | 28379 | (2R,3R)-2,3-dihydroxybutanedioic acid; L-Tartaric acid; (2R,3R)-2,3-dihydroxysuccinic acid | 87-69-4 | C4H6O6 | 详情 | 详情 |
| (VIII) | 69303 | (2S,3S)-4-((5-carbamoyl-10,11-dihydro-5H-dibenzo[b,f]azepin-10-yl)oxy)-2,3-dihydroxy-4-oxobutanoic acid | C19H18N2O7 | 详情 | 详情 |