|
【结 构 式】 
|
【分子编号】10384 【品名】2-Chloro-1-ethanol; Ethylene chlorohydrin 【CA登记号】107-07-3 |
【 分 子 式 】C2H5ClO 【 分 子 量 】80.5138 【元素组成】C 29.84% H 6.26% Cl 44.03% O 19.87% |
合成路线1
该中间体在本合成路线中的序号：(VI)Delmopinol can be obtained by three different ways: 1) The reaction of 2-(benzylamino)-6-propylnonan-1-ol (I) with ethylene oxide (II) in ethanol at 100 C yields the corresponding N-(2-hydroxyethyl)derivative (III), which is cyclized with H2SO4 at 140-150 C to 4-benzyl-3-(4-propylheptyl)morpholine (IV). The debenzylation of (IV) by hydrogenolysis with H2 over Pd/C affords the free morpholine (V), which is finally condensed with 2-chloroethanol (VI) by means of KI and KOH in refluxing ethanol. 2) The Grignard condensation of 4-heptanone (VII) with allyl bromide (VIII) in ethyl ether gives 4-propyl-1-hepten-4-ol (IX), which is cyclocondensed with morpholine (X) by means of H2O2 and Na2WO4 in methanol to yield 4-(perhydroisoxazol[3,2-c][1,4]oxazin-2-ylmethyl)-4-heptanol (XI). Reductive ring opening of (XI) by hydrogenation with H2 over Pd/C and p-toluenesulfonic acid in isopropanol affords a mixture of the morpholine (V) and the hydroxymorpholine (XII). This mixture, without separation, is treated first with SOCl2 in chloroform to perform Cl-OH interchange, then with NaOH to obtain the corresponding double bond, and finally, the mixture is hydrogenated with H2 over Ra-nickel and triethylamine in dioxane in order to obtain pure (V), already obtained. 3) The acylation of the alkylmorpholine (V) with oxalic acid monomethyl ester (XIII) by means of triethylamine in refluxing benzene gives the corresponding condensation compound (XIV), which is then reduced with LiAlH4 in refluxing ethyl ester.
| 【1】 Mealy, N.; Ngo, J.; Castaner, J.; Delmopinol Hydrochloride. Drugs Fut 1996, 21, 8, 787. |
| 【2】 (Ferrosan AB); New morpholino cpds. their process of preparation and medicines containing them. BE 0888052; BE 0901496 . |
| 【3】 Hernestam, S.; Thelin, B.; Seifert, E.; Nilsson, A. (Pharmacia & Upjohn AB); Substd. isoxazolidines and isoxazolines. WO 9014342 . |
| 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) | 10380 | 2-(Benzylamino)-6-propyl-1-nonanol | C19H33NO | 详情 | 详情 | |
| (II) | 10393 | Oxirane; Ethylene oxide | 75-21-8 | C2H4O | 详情 | 详情 |
| (III) | 10381 | 2-[Benzyl(2-hydroxyethyl)amino]-6-propyl-1-nonanol | C21H37NO2 | 详情 | 详情 | |
| (IV) | 10382 | 4-Benzyl-3-(4-propylheptyl)morpholine | C21H35NO | 详情 | 详情 | |
| (V) | 10383 | 3-(4-Propylheptyl)morpholine | C14H29NO | 详情 | 详情 | |
| (VI) | 10384 | 2-Chloro-1-ethanol; Ethylene chlorohydrin | 107-07-3 | C2H5ClO | 详情 | 详情 |
| (VII) | 10385 | 4-Heptanone; Dipropyl ketone | 123-19-3 | C7H14O | 详情 | 详情 |
| (VIII) | 10386 | Allyl(bromo)magnesium | 1730-25-2 | C3H5BrMg | 详情 | 详情 |
| (IX) | 10387 | 4-Propyl-1-hepten-4-ol | C10H20O | 详情 | 详情 | |
| (X) | 10388 | Morpholine | 110-91-8 | C4H9NO | 详情 | 详情 |
| (XI) | 10389 | 4-(Hexahydroisoxazolo[3,2-c][1,4]oxazin-2-ylmethyl)-4-heptanol | C14H27NO3 | 详情 | 详情 | |
| (XII) | 10390 | 1-(1,4-Oxazinan-3-yl)-4-propyl-2-heptanol | C14H29NO2 | 详情 | 详情 | |
| (XIII) | 10391 | 2-Methoxy-2-oxoacetic acid | C3H4O4 | 详情 | 详情 | |
| (XIV) | 10392 | 2-Oxo-2-[3-(4-propylheptyl)morpholino]acetic acid | C16H29NO4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(V)1-(3-Phenylpropyl)piperazine (III) has been obtained by condensation of 3-phenylpropyl bromide (I) with piperazine (II) in refluxing acetonitrile. The condensation of bis(4-fluorophenyl)methanol (IV) with 2-chloroethanol (V) by means of sulfuric acid gives the 2-chloroethyl bis(4-fluorophenyl)methyl ether (VI), which si treated with NaI to yield the corresponding iodo derivative (VII). Finally this compound is condensed with the intermediate piperazine (III) by means of aq. Na2CO3 to afford the target disubstituted piperazine.
| 【1】 Zhang, J.; Ironside, M.D.; Sugathapala, P.M.; Robertson, J.; Darey, M.C.P.; Scale-up synthesis of the dopamine uptake inhibitor GBR-12909. Org Process Res Dev 2002, 6, 5, 621. |
| 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) | 20884 | 1-(3-bromopropyl)benzene | 637-59-2 | C9H11Br | 详情 | 详情 |
| (II) | 10355 | Diethylenediamine; Piperazine | 110-85-0 | C4H10N2 | 详情 | 详情 |
| (III) | 38636 | 1-(3-phenylpropyl)piperazine | C13H20N2 | 详情 | 详情 | |
| (IV) | 41974 | 4,4'-Difluorobenzhydrol; bis(4-Fluorophenyl)methanol; alpha-(4-fluorophenyl)benzenemethanol; 4-fluoro-alpha-(4-fluorophenyl)benzenemethanol | 365-24-2 | C13H10F2O | 详情 | 详情 |
| (V) | 10384 | 2-Chloro-1-ethanol; Ethylene chlorohydrin | 107-07-3 | C2H5ClO | 详情 | 详情 |
| (VI) | 54931 | 1-[(2-chloroethoxy)(4-fluorophenyl)methyl]-4-fluorobenzene; bis(4-fluorophenyl)methyl 2-chloroethyl ether | C15H13ClF2O | 详情 | 详情 | |
| (VII) | 56868 | bis(4-fluorophenyl)methyl 2-iodoethyl ether; 1-fluoro-4-[(4-fluorophenyl)(2-iodoethoxy)methyl]benzene | C15H13F2IO | 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 reaction of ethyl 4-bromoacetoacetate (I) with 2-chloroethanol (II) by means of NaH in THF gives ethyl 4-(2-chloroethoxy)acetoacetate (III), which is treated with NaI in refluxing acetone to yield the corresponding 2-iodoethoxy derivative (IV). The condensation of (IV) with 2-chlorobenzaldehyde (V) by means of piperidine acetate in isopropanol affords ethyl 2-(2-chlorobenzylidene)-4-(2-iodoethoxy)acetoacetate (VI), which is cyclized with methyl 3-aminocrotonate (VII) in refluxing isopropanol to provide the dihydropyridine (VIII). The reaction of (VIII) with hexamethylenetetramine (IX) in hot acetonitrile gives the aminium salt (X), which is finally treated with benzenesulfonic acid in refluxing butanol (methanol)/water. Alternatively, the intermediate dihydropyridine (VIII) can be obtained as follows: The condensation of ethyl 4-(2-chloroethoxy)acetoacetate (III) with the aldehyde (V) by means of piperidine acetate in isopropanol gives ethyl 2-(2-chlorobenzylidene)-4-(2-chloroethoxy)acetoacetate (XI), which is cyclized with methyl 3-aminocrotonate (VII) in refluxing isopropanol to yield the corresponding dihydropyridine (XII). Finally, this compound is treated with NaI in refluxing isopropanol to afford the target intermediate dihydropyridine (VIII).
| 【1】 Németh, N.; Vereczkey, G.D.; Krasznai, G.; Koványi, G.; Német, G.; Blask, G.; Tömpe, P.; Nagy, K.; Bozsing, D.; Simig, G. (Egis Pharmaceuticals Ltd.); A process and intermediate cpds. for the preparation of amlodipine benzene sulphonate. EP 0902016 . |
| 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) | 36651 | Ethyl (bromoacetyl)acetate;ethyl 4-bromo-3-oxobutanoate | 13176-46-0 | C6H9BrO3 | 详情 | 详情 |
| (II) | 10384 | 2-Chloro-1-ethanol; Ethylene chlorohydrin | 107-07-3 | C2H5ClO | 详情 | 详情 |
| (III) | 48269 | ethyl 4-(2-chloroethoxy)-3-oxobutanoate | C8H13ClO4 | 详情 | 详情 | |
| (IV) | 48270 | ethyl 4-(2-iodoethoxy)-3-oxobutanoate | C8H13IO4 | 详情 | 详情 | |
| (V) | 24114 | 2-chlorobenzaldehyde | 89-98-5 | C7H5ClO | 详情 | 详情 |
| (VI) | 48271 | ethyl (Z)-3-(2-chlorophenyl)-2-[2-(2-iodoethoxy)acetyl]-2-propenoate | C15H16ClIO4 | 详情 | 详情 | |
| (VII) | 11372 | Methyl (E)-3-amino-2-butenoate; Methyl 3-aminocrotonate | C5H9NO2 | 详情 | 详情 | |
| (VIII) | 48272 | 3-ethyl 5-methyl 4-(2-chlorophenyl)-2-[(2-iodoethoxy)methyl]-6-methyl-1,4-dihydro-3,5-pyridinedicarboxylate | C20H23ClINO5 | 详情 | 详情 | |
| (IX) | 34873 | 1,3,5,7-tetraazatricyclo[3.3.1.1(3,7)]decane | 100-97-0 | C6H12N4 | 详情 | 详情 |
| (X) | 48273 | 1-(2-[[4-(2-chlorophenyl)-3-(ethoxycarbonyl)-5-(methoxycarbonyl)-6-methyl-1,4-dihydro-2-pyridinyl]methoxy]ethyl)-3,5,7-triaza-1-azoniatricyclo[3.3.1.1(3,7)]decane iodide | C26H35ClIN5O5 | 详情 | 详情 | |
| (XI) | 48274 | ethyl (Z)-2-[2-(2-chloroethoxy)acetyl]-3-(2-chlorophenyl)-2-propenoate | C15H16Cl2O4 | 详情 | 详情 | |
| (XII) | 48275 | 3-ethyl 5-methyl 2-[(2-chloroethoxy)methyl]-4-(2-chlorophenyl)-6-methyl-1,4-dihydro-3,5-pyridinedicarboxylate | C20H23Cl2NO5 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(X)Chlorination of 5-amino-2,4,6-triiodoisophthalic acid (I) with SOCl2 in EtOAc or toluene affords acid chloride (II). Yields have been improved with the addition of benzyltriethylammonium chloride as a catalyst. Acid chloride (II) is then condensed with 3-amino-1,2-propanediol (III) to produce diamide (IV). Compound (IV) is converted to the tetraacetate ester (V) employing acetic anhydride in pyridine. Subsequent acylation of the amino group of (V) with acetoxyacetyl chloride (VI) gives amide (VII). After saponification of the ester groups of (VII), the resultant hydroxy acetamide (VIII) is alkylated by 2-chloroethanol (IX) to furnish the title compound. Alternatively, amide (VIII) is alkylated by bromoethyl acetate (X), producing (XI). Hexa-ester (XI) is finally hydrolyzed with aqueous sulfuric acid. An improved procedure for this final hydrolysis step uses 1,1,2-trichloroethane as co-solvent.
| 【1】 Lin, Y. (Mallinckrodt Medical Inc.); Cpds. suitable for X-ray visualisation methods. EP 0083964; US 4396598 . |
| 【2】 Dunn, T.J.; White, D.H.; Kneller, M.T.; Jones, M.M.; Doran, N.O. III; Bailey, A.R. (Mallinckrodt Medical Inc.); Process for producing ioversol. WO 9727172 . |
| 【3】 Kneller, M.T.; Bailey, A.R.; Sathe, S.S.; Spears, A.T.; Wisneski, R.C. (Mallinckrodt Medical Inc.); Improved synthesis of ioversol. WO 9323365 . |
| 【4】 Villa, M.; Castaldi, G.; Pozzoli, C.; Russo, L. (Zambon Group SpA); Process for the preparation of 5-amino-2,4,6-triiodoisophthalic acid dichloride by chlorination with thionyl chloride in the presence of a catalyst. WO 9636590 . |
| 【5】 Lin, Y.; Dean, R.T.; Kneller, M.; Wallace, R.A.; McCarthy, W.Z.; White, D.H. (Mallinckrodt Medical Inc.); Process for production of ioversol. WO 9111431 . |
| 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) | 22006 | 5-amino-2,4,6-triiodoisophthalic acid | 35453-19-1 | C8H4I3NO4 | 详情 | 详情 |
| (II) | 31194 | 5-amino-2,4,6-triiodoisophthaloyl dichloride | 37441-29-5 | C8H2Cl2I3NO2 | 详情 | 详情 |
| (III) | 12979 | 3-Amino-1,2-propanediol；3-aminopropane-1,2-diol | 616-30-8 | C3H9NO2 | 详情 | 详情 |
| (IV) | 59316 | 5-amino-N~1~,N~3~-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide | C14H18I3N3O6 | 详情 | 详情 | |
| (V) | 59322 | 2-(acetyloxy)-1-({[3-amino-5-({[2,3-bis(acetyloxy)propyl]amino}carbonyl)-2,4,6-triiodobenzoyl]amino}methyl)ethyl acetate | C22H26I3N3O10 | 详情 | 详情 | |
| (VI) | 10456 | Acetoxiacetil chloride; 2-chloro-2-oxoethyl acetate | 13831-31-7 | C4H5ClO3 | 详情 | 详情 |
| (VII) | 59323 | 2-(acetyloxy)-1-({[3-{[2-(acetyloxy)acetyl]amino}-5-({[2,3-bis(acetyloxy)propyl]amino}carbonyl)-2,4,6-triiodobenzoyl]amino}methyl)ethyl acetate | C26H30I3N3O13 | 详情 | 详情 | |
| (VIII) | 59324 | N~1~,N~3~-bis(2,3-dihydroxypropyl)-5-(glycoloylamino)-2,4,6-triiodoisophthalamide | C16H20I3N3O8 | 详情 | 详情 | |
| (IX) | 33463 | 2-bromoethyl acetate | 927-68-4 | C4H7BrO2 | 详情 | 详情 |
| (X) | 10384 | 2-Chloro-1-ethanol; Ethylene chlorohydrin | 107-07-3 | C2H5ClO | 详情 | 详情 |
| (XI) | 59325 | 2-[[2-(acetyloxy)acetyl]-3,5-bis({[2,3-bis(acetyloxy)propyl]amino}carbonyl)-2,4,6-triiodoanilino]ethyl acetate | C30H36I3N3O15 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(VI)In a related method, the intermediate tetrahydroxy amine (I) is acylated by chloroacetyl chloride (II) to produce the penta(chloroacetyl) derivative (III). The chloroacetate ester groups are then hydrolyzed under basic conditions to afford the tetra-hydroxy chloroacetamide (IV). Conversion of (IV) to the hydroxy acetamide (V) is accomplished by treatment with sodium acetate and NaOH. Amide (V) is finally alkylated with either chloroetanol (VI) or with ethylene oxide (VII) to furnish the title N-(hydroxyethyl) amide.
| 【1】 Dunn, T.J.; Kneller, M.T.; White, D.H.; Jones, M.M.; Doran, N.O. (Mallinckrodt Medical Inc.); Process for producing ioversol. WO 9640286 . |
| 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) | 59316 | 5-amino-N~1~,N~3~-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide | C14H18I3N3O6 | 详情 | 详情 | |
| (II) | 11296 | 2-Chloroacetyl chloride; Chloroacetic chloride | 79-04-9 | C2H2Cl2O | 详情 | 详情 |
| (III) | 59326 | 2-({3-[({2,3-bis[(2-chloroacetyl)oxy]propyl}amino)carbonyl]-5-[(2-chloroacetyl)amino]-2,4,6-triiodobenzoyl}amino)-1-{[(2-chloroacetyl)oxy]methyl}ethyl 2-chloroacetate | C24H23Cl5I3N3O11 | 详情 | 详情 | |
| (IV) | 59327 | 5-[(2-chloroacetyl)amino]-N~1~,N~3~-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide | C16H19ClI3N3O7 | 详情 | 详情 | |
| (V) | 59324 | N~1~,N~3~-bis(2,3-dihydroxypropyl)-5-(glycoloylamino)-2,4,6-triiodoisophthalamide | C16H20I3N3O8 | 详情 | 详情 | |
| (VI) | 10384 | 2-Chloro-1-ethanol; Ethylene chlorohydrin | 107-07-3 | C2H5ClO | 详情 | 详情 |
| (VII) | 10393 | Oxirane; Ethylene oxide | 75-21-8 | C2H4O | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(III)In an improved method, the acetamido isophthalamide (I) is treated with boric acid and KOH to form the cyclic diborate tripotassium salt (II). Subsequent alkylation of (II) with 2-chloroethanol (III) yields regioselectively the N-alkylated acetamide (IV). The borate groups of (IV) are finally removed upon quenching with diluted HCl.
| 【1】 Bjoersvik, H.-R.; et al.; A selective process for N-alkylation in competition with O-alkylation: Boric acid, borax, and metaborate as a cheap and effective protecting group applicable for industrial-scale synthetic processes. Org Process Res Dev 2001, 5, 5, 472. |
| 【2】 Priebe, H. (Amersham plc); An N-alkylation. GB 2331098 . |
合成路线7
该中间体在本合成路线中的序号：(II)By reaction of diosmin (I) with 2-chloroethanol (II) in alkaline aqueous medium.
| 【1】 Mosquera, R.; Orjales, A. (FAES); Preparation of mono- and di-beta-hydroxyethyl diosmine mixture. DE 3715447; ES 554841; FR 2598415; IT 1215471 . |
| 【2】 Orjales, A.; Hidrosmin. Drugs Fut 1987, 12, 11, 1015. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IIIa) | 28154 | 5-(2-hydroxyethoxy)-2-(3-hydroxy-4-methoxyphenyl)-7-[[(2S,3R,4S,5S)-3,4,5-trihydroxy-6-([[(2R,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl]oxy]methyl)tetrahydro-2H-pyran-2-yl]oxy]-4H-chromen-4-one | C30H36O16 | 详情 | 详情 | |
| (IIIb) | 28155 | 5-(2-hydroxyethoxy)-2-[3-(2-hydroxyethoxy)-4-methoxyphenyl]-7-[[(2S,3R,4S,5S)-3,4,5-trihydroxy-6-([[(2R,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl]oxy]methyl)tetrahydro-2H-pyran-2-yl]oxy]-4H-chromen-4-one | C32H40O17 | 详情 | 详情 | |
| (I) | 23461 | 5-hydroxy-2-(3-hydroxy-4-methoxyphenyl)-7-[[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-([[(2R,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl]oxy]methyl)tetrahydro-2H-pyran-2-yl]oxy]-4H-chromen-4-one | 520-27-4 | C28H32O15 | 详情 | 详情 |
| (II) | 10384 | 2-Chloro-1-ethanol; Ethylene chlorohydrin | 107-07-3 | C2H5ClO | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(II)1) The condensation of a phenylpiperazine (I) with chloroethanol (II) gives compound (III) which, upon reaction with the acid chloride (IV), yields lobuprofen.
| 【1】 Alamo Gonzalez, C.; Carretero Colon, J.M.; Martin Jimenez, J.L. (Juste, SA Quimico-Farmaceutica); Novel phenylpiperazine derivs., process for prepar. EP 0141884 . |
| 【2】 Carretero, J.M.; Alamo, C.; Martin, J.L.; Lobuprofen hydrochloride. Drugs Fut 1988, 13, 4, 314. |
| 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) | 22114 | 1-(3-chlorophenyl)piperazine | 6640-24-0 | C10H13ClN2 | 详情 | 详情 |
| (II) | 10384 | 2-Chloro-1-ethanol; Ethylene chlorohydrin | 107-07-3 | C2H5ClO | 详情 | 详情 |
| (III) | 22116 | 2-[4-(3-chlorophenyl)-1-piperazinyl]-1-ethanol | C12H17ClN2O | 详情 | 详情 | |
| (IV) | 22117 | 2-(4-isobutylphenyl)propanoyl chloride | C13H17ClO | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(II)2) The acid chloride (IV) is reacted with chloroethanol to give compound (V), which, upon condensation with a piperazine (I), yields lobuprofen.
| 【1】 Alamo Gonzalez, C.; Carretero Colon, J.M.; Martin Jimenez, J.L. (Juste, SA Quimico-Farmaceutica); Novel phenylpiperazine derivs., process for prepar. EP 0141884 . |
| 【2】 Prous, J.; Castaner, J.; ONO-RS-411. Drugs Fut 1988, 13, 4, 317. |
| 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) | 22114 | 1-(3-chlorophenyl)piperazine | 6640-24-0 | C10H13ClN2 | 详情 | 详情 |
| (II) | 10384 | 2-Chloro-1-ethanol; Ethylene chlorohydrin | 107-07-3 | C2H5ClO | 详情 | 详情 |
| (IV) | 22117 | 2-(4-isobutylphenyl)propanoyl chloride | C13H17ClO | 详情 | 详情 | |
| (V) | 22118 | 2-chloroethyl 2-(4-isobutylphenyl)propanoate | C15H21ClO2 | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(VIII)The reduction of diethyl 3-(methoxymethoxy)glutarate (I) with LiAlH4 in THF gives 3-(methoxymethoxy)pentane-1,5-diol (II), which is treated with Ts-OH and TEA in THF to yield the disulfonate (III). The condensation of (III) with 5-ethoxyindolin-2-one (IV) by means of tBu-OK in THF affords the spiro compound (V), which is deprotected with HCl in methanol to afford the spiranic alcohol (VI). The oxidation of (VI) with pyridinium chlorochromate (PCC) over Al2O3 provides the spiranic cyclohexanone (VII), which is treated with 2-chloroethanol (VIII) and Ms-OH in toluene to give the ketal (IX). The reaction of (IX) with zinc borohydride and trimethylsilyl chloride in ethyl ether/dichloromethane yields the 2-chloroethoxy derivative (X), which is condensed with 4-(N-tert-butylcarbamoyl)-2-methoxybenzenesulfonyl chloride (XI) by means of tBu-OK in THF to afford the adduct (XII). Finally, the target compound is obtained by condensation of (XII) with morpholine (XIII) by means of NaI in DMF, followed by treatment with fumaric acid.
| 【1】 Di Malta, A.; Foulon, L.; Garcia, G.; Nisato, D.; Roux, R.; Serradeil-Legal, C.; Valette, G.; Wagnon, J. (Sanofi-Synthélabo); Derivs. of 1-benzenesulfonyl-1,3-dihydro-indol-2-one, their preparation and pharmaceutical compsns. containing them. CA 2129215; EP 0636608; FR 2708605; JP 1995247269 . |
| 【2】 Foulon, L.; Garcia, G.; Serradeil-Le Gal, C.; Valette, G. (Sanofi-Synthelabo); 3-Spiro-indolin-2-one derivs. as vasopressin and/or oxytocin receptor ligands. EP 0873309; FR 2740136; JP 1999509232; JP 2001302631; US 5994350; WO 9715556 . |
| 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) | 50294 | diethyl 3-(methoxymethoxy)pentanedioate | C11H20O6 | 详情 | 详情 | |
| (II) | 50295 | 3-(methoxymethoxy)-1,5-pentanediol | C7H16O4 | 详情 | 详情 | |
| (III) | 50296 | 3-(methoxymethoxy)-5-[[(4-methylphenyl)sulfonyl]oxy]pentyl 4-methylbenzenesulfonate | C21H28O8S2 | 详情 | 详情 | |
| (IV) | 50297 | 5-ethoxy-1,3-dihydro-2H-indol-2-one | C10H11NO2 | 详情 | 详情 | |
| (V) | 50298 | C17H23NO4 | 详情 | 详情 | ||
| (VI) | 50299 | C15H19NO3 | 详情 | 详情 | ||
| (VII) | 50300 | C15H17NO3 | 详情 | 详情 | ||
| (VIII) | 10384 | 2-Chloro-1-ethanol; Ethylene chlorohydrin | 107-07-3 | C2H5ClO | 详情 | 详情 |
| (IX) | 50301 | C19H25Cl2NO4 | 详情 | 详情 | ||
| (X) | 50302 | C17H22ClNO3 | 详情 | 详情 | ||
| (XI) | 50284 | 4-[(tert-butylamino)carbonyl]-2-methoxybenzenesulfonyl chloride | C12H16ClNO4S | 详情 | 详情 | |
| (XII) | 50303 | C29H37ClN2O7S | 详情 | 详情 | ||
| (XIII) | 10388 | Morpholine | 110-91-8 | C4H9NO | 详情 | 详情 |
合成路线11
该中间体在本合成路线中的序号：(VII)The intermediate dimesylate (VI) can be obtained as follows: The condensation of 2,3-dihydro-1,4-benzodioxin-5-amine (I) with ethyl bromoacetate (II) by means of Hunig's base and NaI in refluxing toluene gives the tertiary amine (III), which is reduced by means of LiAlH4 in THF to yield the diethanolamine (IV). Finally, this compound is esterified by means of mesyl chloride (V) to provide the desired dimesylate intermediate (VI). Alternatively, the diethanolamine (IV) can be obtained by direct condensation of 2,3-dihydro-1,4-benzodioxin-5-amine (I) with 2-chloroethanol (VII) by means of Hunig's base.
| 【1】 Jirkovsky, I.; Zeldis, J.; Chan, A.W.-Y.; Fiegelson, G.B. (Wyeth); Preparation of N1-(2'-pyridyl)-1,2-propanediamine sulfamic acid and its use in the synthesis of biologically active piperazines. WO 0378396 . |
| 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) | 22000 | 2,3-dihydro-1,4-benzodioxin-5-amine; 2,3-dihydro-1,4-benzodioxin-5-ylamine; 5-Amino-1,4-benzodioxane | 16081-46-2 | C8H9NO2 | 详情 | 详情 |
| (II) | 16640 | Ethyl 2-bromoacetate; Ethyl bromoacetate | 105-36-2 | C4H7BrO2 | 详情 | 详情 |
| (III) | 64784 | ethyl 2-[2,3-dihydro-1,4-benzodioxin-5-yl(2-ethoxy-2-oxoethyl)amino]acetate | C16H21NO6 | 详情 | 详情 | |
| (IV) | 64785 | 2-[2,3-dihydro-1,4-benzodioxin-5-yl(2-hydroxyethyl)amino]-1-ethanol | C12H17NO4 | 详情 | 详情 | |
| (V) | 13467 | Methanesulfonyl chloride;Mesyl chloride;Methylsulfonyl chloride;Methanesulfonic acid chloride;Methanesulfonyl chloride;Methanesulphonyl chloride | 124-63-0 | CH3ClO2S | 详情 | 详情 |
| (VI) | 64786 | 2-(2,3-dihydro-1,4-benzodioxin-5-yl{2-[(methylsulfonyl)oxy]ethyl}amino)ethyl methanesulfonate | C14H21NO8S2 | 详情 | 详情 | |
| (VII) | 10384 | 2-Chloro-1-ethanol; Ethylene chlorohydrin | 107-07-3 | C2H5ClO | 详情 | 详情 |