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【结 构 式】 
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【分子编号】12760 【品名】tert-butyl acrylate 【CA登记号】1663-39-4 |
【 分 子 式 】C7H12O2 【 分 子 量 】128.17108 【元素组成】C 65.6% H 9.44% O 24.97% |
合成路线1
该中间体在本合成路线中的序号：(XVIII)A new asymmetric synthesis of irinotecan has been reported: The reaction of 2,6-dihydroxypyridine-4-carboxylic acid (I) with hot POCl3 and trimethylammonium chloride gives 2,6-dichloropyridine-4-carboxylic acid (II), which by a Grignard condensation with ethylmagnesium bromide in THF is converted into the propanone (III). The ketalization of (III) with ethylene glycol and trimethylsilyl chloride (TMS-Cl) affords the dioxolane (IV), which by reaction with sodium methoxide in refluxing methanol gives the monomethoxy-pyridine derivative (V). The carbonylation of (V) with butyllithium and DMF affords the pyridine-carbaldehyde (VI), which is reduced to the methanol (VII) with NaBH4. The protection of the hydroxy group of (VII) with benzyl bromide and potassium tert-butoxide in THF affords the benzyl ether (VIII), which is treated with CO, K2CO3, palladium acetate and 1,3-bis(diphenylphosphino)propane (DPPP) in propanol/DMF giving the propyl ester (IX). The treatment of (IX) with trifluoroacetic acid yields the propanone (X), which is treated with methyltriphenylphosphonium bromide and potassium bis(trimethylsilyl)amide (KHMDS) in DMF to afford the expected methylene derivative (XI). The oxidation of (XI) with OsO4 in tert-butanol gives the racemic diol (XII), which is submitted to optical resolution with PS-30 catalyst (Pseudomonas cepaica lipase over Celite 521) to give the corresponding (S)-enantiomer (XIII). The oxidation of (XIII) with NaOCl affords the 2(S)-hydroxybutyraldehyde (XIV), which is submitted to cyclization by debenzylation with H2 over Pd/C in methanol giving the cyclized diol (XV). The oxidation of (XV) with NaOCl in dichloromethane affords the hydroxylactone (XVI), which is treated with trimethylsilyl chloride and NaI to give the pyridone (XVII). A new cyclization of (XVII) with tert-butyl acrylate (XVIII) by means of Cs2CO3 in DMSO yield the tricyclic tert-butyl ester (XIX), which is decarboxylated with trifluoroacetic acid in refluxing toluene to afford the tricyclic trione (XX). The cyclization of (XX) with 2-amino-5-hydroxypropiophenone (XXI) by means of p-toluenesulfonic acid in hot toluene/acetic acid gives the camptothecin derivative (XXII), which is finally acylated with 4-(1-piperidyl)piperidine-1-carbonyl chloride (XXIII) in pyridine.
| 【1】 Ashford, S.W.; Sih, J.C.; Gu, R.L.; Henegar, K.E.; Baughman, T.A.; Practical asymmetric synthesis of (S)-4-ethyl-7,8-dihydro-4-hydroxy-1H-pyrano[3,4-f]indolizine-3,6,10(4H)-trione, a key intermediate for the synthesis of irinotecan and other camptothecin analogs. J Org Chem 1997, 62, 19, 6588. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 11295 | Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol | 107-21-1 | C2H6O2 | 详情 | 详情 | |
| (I) | 10822 | 2,6-Dihydroxyisonicotinic acid; Citrazinic acid | 99-11-6 | C6H5NO4 | 详情 | 详情 |
| (II) | 10823 | 2,6-Dichloroisonicotinic acid | 5398-44-7 | C6H3Cl2NO2 | 详情 | 详情 |
| (III) | 10824 | 1-(2,6-Dichloro-4-pyridinyl)-1-propanone | C8H7Cl2NO | 详情 | 详情 | |
| (IV) | 10825 | 2,6-Dichloro-4-(2-ethyl-1,3-dioxolan-2-yl)pyridine | C10H11Cl2NO2 | 详情 | 详情 | |
| (V) | 10826 | 2-Chloro-4-(2-ethyl-1,3-dioxolan-2-yl)-6-methoxypyridine; 6-Chloro-4-(2-ethyl-1,3-dioxolan-2-yl)-2-pyridinyl methyl ether | C11H14ClNO3 | 详情 | 详情 | |
| (VI) | 10827 | 6-Chloro-4-(2-ethyl-1,3-dioxolan-2-yl)-2-methoxynicotinaldehyde | C12H14ClNO4 | 详情 | 详情 | |
| (VII) | 10828 | [6-Chloro-4-(2-ethyl-1,3-dioxolan-2-yl)-2-methoxy-3-pyridinyl]methanol | C12H16ClNO4 | 详情 | 详情 | |
| (VIII) | 10829 | 3-[(Benzyloxy)methyl]-6-chloro-4-(2-ethyl-1,3-dioxolan-2-yl)-2-methoxypyridine; Benzyl [6-chloro-4-(2-ethyl-1,3-dioxolan-2-yl)-2-methoxy-3-pyridinyl]methyl ether | C19H22ClNO4 | 详情 | 详情 | |
| (IX) | 10830 | propyl 5-[(benzyloxy)methyl]-4-(2-ethyl-1,3-dioxolan-2-yl)-6-methoxy-2-pyridinecarboxylate | C23H29NO6 | 详情 | 详情 | |
| (X) | 10831 | propyl 5-[(benzyloxy)methyl]-6-methoxy-4-propionyl-2-pyridinecarboxylate | C21H25NO5 | 详情 | 详情 | |
| (XI) | 10832 | propyl 5-[(benzyloxy)methyl]-4-(1-ethylvinyl)-6-methoxy-2-pyridinecarboxylate | C22H27NO4 | 详情 | 详情 | |
| (XII) | 10833 | propyl 5-[(benzyloxy)methyl]-4-[1-hydroxy-1-(hydroxymethyl)propyl]-6-methoxy-2-pyridinecarboxylate | C22H29NO6 | 详情 | 详情 | |
| (XIII) | 10834 | propyl 5-[(benzyloxy)methyl]-4-[(1S)-1-hydroxy-1-(hydroxymethyl)propyl]-6-methoxy-2-pyridinecarboxylate | C22H29NO6 | 详情 | 详情 | |
| (XIV) | 10835 | propyl 5-[(benzyloxy)methyl]-4-[(1S)-1-formyl-1-hydroxypropyl]-6-methoxy-2-pyridinecarboxylate | C22H27NO6 | 详情 | 详情 | |
| (XV) | 10836 | propyl (4S)-4-ethyl-3,4-dihydroxy-8-methoxy-3,4-dihydro-1H-pyrano[3,4-c]pyridine-6-carboxylate | C15H21NO6 | 详情 | 详情 | |
| (XVI) | 10837 | propyl (4S)-4-ethyl-4-hydroxy-8-methoxy-3-oxo-3,4-dihydro-1H-pyrano[3,4-c]pyridine-6-carboxylate | C15H19NO6 | 详情 | 详情 | |
| (XVII) | 10838 | propyl (4S)-4-ethyl-4-hydroxy-3,8-dioxo-3,4,7,8-tetrahydro-1H-pyrano[3,4-c]pyridine-6-carboxylate | C14H17NO6 | 详情 | 详情 | |
| (XVIII) | 12760 | tert-butyl acrylate | 1663-39-4 | C7H12O2 | 详情 | 详情 |
| (XIX) | 10840 | tert-butyl (4S)-4-ethyl-4,6-dihydroxy-3,10-dioxo-3,4,8,10-tetrahydro-1H-pyrano[3,4-f]indolizine-7-carboxylate | C18H21NO7 | 详情 | 详情 | |
| (XX) | 10841 | (4S)-4-Ethyl-4-hydroxy-7,8-dihydro-1H-pyrano[3,4-f]indolizine-3,6,10(4H)-trione | C13H13NO5 | 详情 | 详情 | |
| (XXI) | 10842 | 1-(2-Amino-5-hydroxyphenyl)-1-propanone | C9H11NO2 | 详情 | 详情 | |
| (XXII) | 10819 | (4S)-4,11-Diethyl-4,9-dihydroxy-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione; 7-Ethyl-10-hydroxycamptothecin | C22H20N2O5 | 详情 | 详情 | |
| (XXIII) | 63047 | C11H19ClN2O | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(III)A new synthesis for L-659989 has been reported: The alkylation of 4-hydroxy-3-iodo-5-methoxybenzaldehyde (I) with propyl bromide in hot DMF gives 3-iodo-5-methoxy-4-propoxybenzaldehyde (II), which is condensed with tert-butyl acrylate (III) by means of NaCN in DMF to yield 3-(3-iodo-5-methoxy-4-propoxybenzoyl)propionic acid tert-butyl ester (IV). The stereoselective reduction of (IV) with chlorodiisopinocampheylborane (V) in THF affords 4(S)-hydroxy-4-(3-iodo-5-methoxy-4-propoxyphenyl)butyric acid tert-butyl ester (VI), which is hydrolyzed with KOH in methanol-water to the corresponding free acid (VII). The cyclization of (VII) with pyridinium p-toluenesulfonate in toluene gives 5(S)-(3-iodo-5-methoxy-4-propoxyphenyl)tetrahydrofuran-2-one (VIII), which is treated with dimethyl disulfide and copper in refluxing pyridine to yield 5(S)-[3-methoxy-5-(methylthio)-4-propoxyphenyl]tetrahydrofuran-2-one (IX). The oxidation of (IX) with magnesium monoperoxyphthalate in acetonitrile-water affords the corresponding sulfone (X), which is reduced with diisobutylaluminum hydride in toluene giving 5(S)-[3-methoxy-5-(methylsulfonyl)-4-propoxyphenyl]tetrahydrofuran-2-ol (XI). Finally, this compound is treated first with bromotrimethylsilane and then with 3,4,5-trimethoxyphenylmagnesium bromide, yielding the final product with a trans/cis ratio of 15/1 and a yield of 55%.
| 【1】 Tschaen, D.M.; Russ, W.; Thompson, A.S.; Simpson, P.; McSwine, D.; Conversion of a silylated hemiacetal into an alpha-bromoether using trimethylsilylbromide - Synthesis of platelet activating factor antagonist. Tetrahedron Lett 1990, 31, 48, 6953. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 32378 | bromo(3,4,5-trimethoxyphenyl)magnesium | C9H11BrMgO3 | 详情 | 详情 | ||
| 63472 | methyl 8-oxo-8-({3-[(phenylmethyl)oxy]phenyl}amino)octanoate | C22H27NO4 | 详情 | 详情 | ||
| (I) | 12758 | 4-Hydroxy-3-iodo-5-methoxybenzaldehyde; 5-Iodovanillin | 5438-36-8 | C8H7IO3 | 详情 | 详情 |
| (II) | 12759 | 3-Iodo-5-methoxy-4-propoxybenzaldehyde | C11H13IO3 | 详情 | 详情 | |
| (III) | 12760 | tert-butyl acrylate | 1663-39-4 | C7H12O2 | 详情 | 详情 |
| (IV) | 12761 | tert-butyl 4-(3-iodo-5-methoxy-4-propoxyphenyl)-4-oxobutanoate | C18H25IO5 | 详情 | 详情 | |
| (V) | 12762 | Chlorodiisopinocampheylborane | C22H40 | 详情 | 详情 | |
| (VI) | 12763 | tert-butyl (4S)-4-hydroxy-4-(3-iodo-5-methoxy-4-propoxyphenyl)butanoate | C18H27IO5 | 详情 | 详情 | |
| (VII) | 12764 | (4S)-4-Hydroxy-4-(3-iodo-5-methoxy-4-propoxyphenyl)butyric acid | C14H19IO5 | 详情 | 详情 | |
| (VIII) | 12765 | (5S)-5-(3-Iodo-5-methoxy-4-propoxyphenyl)dihydro-2(3H)-furanone | C14H17IO4 | 详情 | 详情 | |
| (IX) | 12766 | (5S)-5-[3-Methoxy-5-(methylsulfanyl)-4-propoxyphenyl]dihydro-2(3H)-furanone | C15H20O4S | 详情 | 详情 | |
| (X) | 12767 | (5S)-5-[3-Methoxy-5-(methylsulfonyl)-4-propoxyphenyl]dihydro-2(3H)-furanone | C15H20O6S | 详情 | 详情 | |
| (XI) | 12768 | (5S)-5-[3-Methoxy-5-(methylsulfonyl)-4-propoxyphenyl]tetrahydro-2-furanol | C15H22O6S | 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 intermediate amine (V) was prepared via a Heck reaction between p-bromophenylacetonitrile (I) and tert-butyl acrylate (II) to afford the p-(cyanomethyl)cinnamate (III) . Catalytic double bond hydrogenation in (III) provided the saturated cyano ester (IV), which was then reduced to amine (V) by using NaBH4 in the presence of CoCl2. Alternatively, simultaneous double bond and cyano group reduction was accomplished by hydrogenation of (III) in the presence of Pd/C and HCl.
| 【1】 Hutchison, A.J.; Williams, M.; de Jesus, R.; Yokoyama, R.; Oei, H.H.; Ghai, G.R.; Webb, R.L.; Zoganas, H.C.; Stone, G.A.; Jarvis, M.F.; 2-(Arylalkylamino)adenosin-5'-uronamides: A new class of highly selective adenosine A2 receptor ligands. J Med Chem 1990, 33, 7, 1919. |
| 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) | 45829 | 2-(4-bromophenyl)acetonitrile; 4-Bromobenzyl cyanide | 16532-79-9 | C8H6BrN | 详情 | 详情 |
| (II) | 12760 | tert-butyl acrylate | 1663-39-4 | C7H12O2 | 详情 | 详情 |
| (III) | 62371 | tert-butyl (E)-3-[4-(2-nitriloethyl)phenyl]-2-propenoate | C15H17NO2 | 详情 | 详情 | |
| (IV) | 62372 | tert-butyl 3-[4-(2-nitriloethyl)phenyl]propanoate | C15H19NO2 | 详情 | 详情 | |
| (V) | 62373 | tert-butyl 3-[4-(2-aminoethyl)phenyl]propanoate | C15H23NO2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XVI)Pyridone (XII) was converted to its dianion with LDA and then alkylated with propyl bromide to give the butyl pyridone (XIII). This was converted into bromopyridine (XIV) by subsequent treatment with PBr3. The nitrile group of (XIV) was then reduced to aldehyde (XV) using diisobutylaluminum hydride. The aldehye (XV) underwent a Heck reaction with tert-butyl acrylate (XVI) using tri-o-tolylphosphine and a palladium catalyst to provide unsaturated ester (XVII). Further condensation of the aldehyde group of (XVII) with (S,S)-pseudoephedrine (XVIII) produced the chiral oxazolidine (XIX). Alcohol (XI) was then protected as the silyl ether (XXI) using tert-butyldimethylsilyl chloride. After its conversion to the organolithium reagent with tert-butyllithium, addition to pyridyl acrylate (XIX) gave intermediate (XXII), and further acidic work-up removed the chiral auxiliary to afford aldehyde (XXIII).
| 【1】 Frey, L.F.; Devine, P.N.; Tschaen, D.M.; Dolling, U.H.; Tillyer, R.D.; Kato, Y. (Banyu Pharmaceutical Co., Ltd.; Merck & Co., Inc.); Stereoselective deoxygenation reaction. EP 0923557; JP 1999514676; WO 9806700 . |
| 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) | 27558 | (2S)-3-(2-bromo-5-methoxyphenyl)-2-methyl-1-propanol | C11H15BrO2 | 详情 | 详情 | |
| (XII) | 27560 | 6-methyl-2-oxo-1,2-dihydro-3-pyridinecarbonitrile | 4241-27-4 | C7H6N2O | 详情 | 详情 |
| (XIII) | 27561 | 6-butyl-2-oxo-1,2-dihydro-3-pyridinecarbonitrile | C10H12N2O | 详情 | 详情 | |
| (XIV) | 27562 | 2-bromo-6-butylnicotinonitrile | C10H11BrN2 | 详情 | 详情 | |
| (XV) | 27563 | 2-bromo-6-butylnicotinaldehyde | C10H12BrNO | 详情 | 详情 | |
| (XVI) | 12760 | tert-butyl acrylate | 1663-39-4 | C7H12O2 | 详情 | 详情 |
| (XVII) | 27564 | tert-butyl (E)-3-(6-butyl-3-formyl-2-pyridinyl)-2-propenoate | C17H23NO3 | 详情 | 详情 | |
| (XVIII) | 27565 | (1S,2S)-2-amino-1-phenyl-1-propanol | C9H13NO | 详情 | 详情 | |
| (XIX) | 27566 | tert-butyl (E)-3-[6-butyl-3-[(4S,5S)-3,4-dimethyl-5-phenyl-1,3-oxazolidin-2-yl]-2-pyridinyl]-2-propenoate | C27H36N2O3 | 详情 | 详情 | |
| (XX) | 10255 | Imidazole; 1H-Imidazole | 288-32-4 | C3H4N2 | 详情 | 详情 |
| (XXI) | 27567 | 4-bromo-3-((2S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methylpropyl)phenyl methyl ether | C17H29BrO2Si | 详情 | 详情 | |
| (XXII) | 27568 | tert-butyl (3R)-3-[6-butyl-3-[(4S,5S)-3,4-dimethyl-5-phenyl-1,3-oxazolidin-2-yl]-2-pyridinyl]-3-[2-((2S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methylpropyl)-4-methoxyphenyl]propanoate | C44H66N2O5Si | 详情 | 详情 | |
| (XXIII) | 27569 | tert-butyl (3R)-3-[2-((2S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methylpropyl)-4-methoxyphenyl]-3-(6-butyl-3-formyl-2-pyridinyl)propanoate | C34H53NO5Si | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(V)The intermediate 3-(6-butyl-3-formylpyridin-2-yl)-2(E)-propenoic acid tert-butyl ester (VI) has been obtained as follows: the alhylation of 2-hydroxy-6-methylpyridine-3-carbonitrile (I) with propyl bromide and LDA gives 6-butyl-2-hydroxypyridine-3-carbonitrile (II), which is brominated with tetrabutylammonium bromide and P2O5 yielding the 2-bromo-6-butylpyridine-3-carbonitrile (III). The reduction of (III) with DIBAL affords the corresponding aldehyde (IV), which is finally condensed with tert-butyl acrylate (V) by means of allyl palladium chloride dimer to furnich the target intermediate (VI).
| 【1】 Song, Z.J.; et al.; Practical asymetric synthesis of an endothelin receptor antagonist. J Org Chem 1999, 64, 26, 9658. |
| 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) | 38551 | 2-hydroxy-6-methylnicotinonitrile | C7H6N2O | 详情 | 详情 | |
| (II) | 38552 | 6-butyl-2-hydroxynicotinonitrile | C10H12N2O | 详情 | 详情 | |
| (III) | 27562 | 2-bromo-6-butylnicotinonitrile | C10H11BrN2 | 详情 | 详情 | |
| (IV) | 27563 | 2-bromo-6-butylnicotinaldehyde | C10H12BrNO | 详情 | 详情 | |
| (V) | 12760 | tert-butyl acrylate | 1663-39-4 | C7H12O2 | 详情 | 详情 |
| (VI) | 27564 | tert-butyl (E)-3-(6-butyl-3-formyl-2-pyridinyl)-2-propenoate | C17H23NO3 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(II)Coupling of tert-butyl acrylate (II) with 4,4'-dibromobenzyl (I) using palladium diacetate and tri-o-tolyl phosphine produced diester (III). Subsequent condensation of (III) with 4-(diethylamino)benzaldehyde (IV) in the presence of ammonium acetate generated the required imidazole system (V). Finally, deprotection of the tert-butyl esters of (V) by treatment with trifluoroacetic acid afforded the title dicarboxylic acid.
| 【1】 Mjalli, A.; Sarshar, S.; Cao, X.; Bakir, F. (Ontogen Corp.); Modulators of proteins with phosphotyrosine recognition units. US 5753687; US 5770620 . |
| 【2】 Mjalli, A.; Sarshar, S.; Bakir, F.; Cao, X. (Ontogen Corp.); Modulators of proteins with phosphotyrosine recognition units. WO 9827065 . |
| 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) | 38940 | 1,2-bis(4-bromophenyl)-1,2-ethanedione | 35578-47-3 | C14H8Br2O2 | 详情 | 详情 |
| (II) | 12760 | tert-butyl acrylate | 1663-39-4 | C7H12O2 | 详情 | 详情 |
| (III) | 38941 | tert-butyl (E)-3-[4-(2-[4-[(E)-3-(tert-butoxy)-3-oxo-1-propenyl]phenyl]-2-oxoacetyl)phenyl]-2-propenoate | C28H30O6 | 详情 | 详情 | |
| (IV) | 38942 | N,N-Diethyl-p-aminobenzaldehyde; 4-(diethylamino)benzaldehyde | 120-21-8 | C11H15NO | 详情 | 详情 |
| (V) | 38943 | tert-butyl (E)-3-(4-[4-[4-[(E)-3-(tert-butoxy)-3-oxo-1-propenyl]phenyl]-2-[4-(diethylamino)phenyl]-1H-imidazol-5-yl]phenyl)-2-propenoate | C39H45N3O4 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(X)The iodination of trichloroaniline (VIII) via diazotization produced iodide (IX). Subsequent Heck reaction of iodide (IX) with tert-butyl acrylate (X) furnished tert-butyl trichlorocinnamate (XI), which was condensed with the sodium salt of methyl mercaptoacetate (XII), yielding thioether (XIII). After acid cleavage of the tert-butyl ester of (XIII), the resulting carboxylic acid (XIV) was coupled with glycine tert-butyl ester via activation as the corresponding N-hydroxysuccinimidyl ester. Then, saponification of the methyl ester group of (XV) afforded the intermediate acid (XVI).
| 【1】 Singh, J.; et al.; A practical synthesis of an anti-methicillin resistant Staphylococcus aureus cephalosporin BMS-247243. Org Process Res Dev 2000, 4, 6, 488. |
| 【2】 Springer, D.M.; Luh, B.Y.; D'Andrea, S.V.; Hudyma, T.W.; Kim, O.K. (Bristol-Myers Squibb Co.); Cephalosporin derivs.. EP 0966472; WO 9823621 . |
| 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) | 46013 | 2,4,5-trichlorophenylamine; 2,4,5-trichloroaniline | 636-30-6 | C6H4Cl3N | 详情 | 详情 |
| (IX) | 46014 | 1-Iodo-2,4,5-trichlorobenzene; 2,4,5-Trichloroiodobenzene; 1,2,4-trichloro-5-iodobenzene | 7145-82-6 | C6H2Cl3I | 详情 | 详情 |
| (X) | 12760 | tert-butyl acrylate | 1663-39-4 | C7H12O2 | 详情 | 详情 |
| (XI) | 46015 | tert-butyl (E)-3-(2,4,5-trichlorophenyl)-2-propenoate | C13H13Cl3O2 | 详情 | 详情 | |
| (XII) | 46016 | sodium 2-methoxy-2-oxo-1-ethanethiolate | C3H5NaO2S | 详情 | 详情 | |
| (XIII) | 46017 | tert-butyl (E)-3-[2,5-dichloro-4-[(2-methoxy-2-oxoethyl)sulfanyl]phenyl]-2-propenoate | C16H18Cl2O4S | 详情 | 详情 | |
| (XIV) | 46018 | (E)-3-[2,5-dichloro-4-[(2-methoxy-2-oxoethyl)sulfanyl]phenyl]-2-propenoic acid | C12H10Cl2O4S | 详情 | 详情 | |
| (XV) | 46019 | methyl 2-[[4-((E)-3-[[2-(tert-butoxy)-2-oxoethyl]amino]-3-oxo-1-propenyl)-2,5-dichlorophenyl]sulfanyl]acetate | C18H21Cl2NO5S | 详情 | 详情 | |
| (XVI) | 46020 | 2-[[4-((E)-3-[[2-(tert-butoxy)-2-oxoethyl]amino]-3-oxo-1-propenyl)-2,5-dichlorophenyl]sulfanyl]acetic acid | C17H19Cl2NO5S | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(III)Terephthaldehyde mono-diethyl acetal (I) was treated with hydroxylamine.HCl and Et3N to give the corresponding oxime (II). The nitrile oxide resulting from the treatment of oxime (II) with sodium hypochlorite was subjected to a dipolar cycloaddition with tert-butyl acrylate (III), yielding the isoxazoline (IV). Subsequent hydrolysis of acetal (IV) employing an acidic ion-exchange resin provided the intermediate isoxazoline aldehyde (V).
| 【1】 Slee, D.H.; et al.; Development of potent non-carbohydrate imidazole-based small molecule selectin inhibitors antiinflammatory activity. J Med Chem 2001, 44, 13, 2094. |
| 【2】 Kondo, H.; Inoue, Y.; Jones, T.K.; Ripka, W.C.; Yu, J.; Raheja, R.K.; Nguyen, T.N.; Slee, D.H. (NV Organon; Ontogen Corp.); Substd. thiazoles for treatment of human diseases involving modulators of P-, L- and E-selectin. WO 0033836; WO 0034255 . |
| 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) | 45671 | Terephthaldehyde mono(diethyl acetal); Terephthalaldehyde mono(diethyl acetal); 4-(Diethoxymethyl)benzaldehyde | 81172-89-6 | C12H16O3 | 详情 | 详情 |
| (II) | 45672 | 4-(diethoxymethyl)benzaldehyde oxime | C12H17NO3 | 详情 | 详情 | |
| (III) | 12760 | tert-butyl acrylate | 1663-39-4 | C7H12O2 | 详情 | 详情 |
| (IV) | 45673 | tert-butyl 3-[4-(diethoxymethyl)phenyl]-4,5-dihydro-5-isoxazolecarboxylate | C19H27NO5 | 详情 | 详情 | |
| (V) | 45674 | tert-butyl 3-(4-formylphenyl)-4,5-dihydro-5-isoxazolecarboxylate | C15H17NO4 | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(III)Heck reaction of 4,4'-dibromobenzil (VI) with tert-butyl acrylate (III) in the presence of palladium diacetate and tri(o-tolyl)phosphine afforded the arylacrylate ester (VII), which was subsequently condensed with the acrylamide (X) (prepared from acryloyl chloride (VIII) and hexadecylamine (IX)), to furnish adduct (XI). The condensation of diketone (XI) with aldehyde (V) in the presence of ammonium acetate in HOAc produced imidazole (XII). The tert-butyl ester groups of (XII) were finally cleaved by treatment with trifluoroacetic acid.
| 【1】 Slee, D.H.; et al.; Development of potent non-carbohydrate imidazole-based small molecule selectin inhibitors antiinflammatory activity. J Med Chem 2001, 44, 13, 2094. |
| 【2】 Kondo, H.; Inoue, Y.; Jones, T.K.; Ripka, W.C.; Yu, J.; Raheja, R.K.; Nguyen, T.N.; Slee, D.H. (NV Organon; Ontogen Corp.); Substd. thiazoles for treatment of human diseases involving modulators of P-, L- and E-selectin. WO 0033836; WO 0034255 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (III) | 12760 | tert-butyl acrylate | 1663-39-4 | C7H12O2 | 详情 | 详情 |
| (V) | 45678 | tert-butyl (E)-3-[4-(2-[4-[(E)-3-(hexadecylamino)-3-oxo-1-propenyl]phenyl]-2-oxoacetyl)phenyl]-2-propenoate | C40H55NO5 | 详情 | 详情 | |
| (VI) | 38940 | 1,2-bis(4-bromophenyl)-1,2-ethanedione | 35578-47-3 | C14H8Br2O2 | 详情 | 详情 |
| (VII) | 45675 | tert-butyl (E)-3-[4-[2-(4-bromophenyl)-2-oxoacetyl]phenyl]-2-propenoate | C21H19BrO4 | 详情 | 详情 | |
| (VIII) | 11577 | Acryloyl chloride; Acrylyl chloride;2-Propenoyl chloride | 814-68-6 | C3H3ClO | 详情 | 详情 |
| (IX) | 45676 | 1-Aminohexadecane; n-Hexadecylamine; Palmitylamine; Cetylamine; hexadecylamine; 1-hexadecanamine | 143-27-1 | C16H35N | 详情 | 详情 |
| (X) | 45677 | N-hexadecylacrylamide | C19H37NO | 详情 | 详情 | |
| (XI) | 45674 | tert-butyl 3-(4-formylphenyl)-4,5-dihydro-5-isoxazolecarboxylate | C15H17NO4 | 详情 | 详情 | |
| (XII) | 45679 | tert-butyl 3-[4-(4-[4-[(E)-3-(tert-butoxy)-3-oxo-1-propenyl]phenyl]-5-[4-[(E)-3-(hexadecylamino)-3-oxo-1-propenyl]phenyl]-1H-imidazol-2-yl)phenyl]-4,5-dihydro-5-isoxazolecarboxylate | C55H72N4O6 | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(II)Condensation between benzyl N-Cbz-alpha-glutamate (I) and tert-butyl acrylate (II) in THF in the presence of tert-BuOK followed by treatment with ammonium acetate in refluxing methanol provides pyrroline acetic acid (III), which is converted into the corresponding benzyl ester (IV) by reaction with benzyl bromide and DIEA in refluxing CH2Cl2. Protection of (IV) with Boc2O and DMAP in CH2Cl2 yields the bis-Boc derivative (V), which is subjected to hydrogenation over Pd/C in HOAc to afford a mixture diastereomers (VI) and (VI’) which are inseparable chromatographically. The mixture of (VI)/(VI') is subjected to reaction with carbamoyl chloride (VII) in CH2Cl2 in the presence of DIEA or pyridine to give the corresponding N-ethyl-N-isopropylureas from which diastereomer (2S,3R,4R)-(VIII) is chromatographically isolated. Derivative (2S,3R,4R)-(VIII) is subjected to Curtius rearrangement using diphenylphosphoryl azide (DPPA) and Et3N in toluene in the presence of benzyl alcohol to give the Cbz-protected amine (IX), which is then deprotected by hydrogenation over Pd in formic acid/MeOH to yield free amine (X). Coupling of (X) with trifluoroacetic acid (XI) by means of EDCI and HOBt in CH2Cl2 furnishes acetamide (XII), which is finally converted into the desired product by removal of the corresponding protecting groups with TFA in CH2Cl2.
| 【1】 Wang, G.T.; Chen, Y.; Wang, S.; et al.; Design, synthesis, and structural analysis of influenza neuraminidase inhibitors containing pyrrolidine cores. J Med Chem 2001, 44, 8, 1192. |
| 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') | 49806 | 2-[(2R,3R,4R)-3-[bis(tert-butoxycarbonyl)amino]-4-(tert-butoxycarbonyl)pyrrolidinyl]acetic acid | C21H36N2O8 | 详情 | 详情 | |
| (I) | 43458 | (3S)-4-(benzyloxy)-3-[[(benzyloxy)carbonyl]amino]-4-oxobutyric acid | 4779-31-1 | C19H19NO6 | 详情 | 详情 |
| (II) | 12760 | tert-butyl acrylate | 1663-39-4 | C7H12O2 | 详情 | 详情 |
| (III) | 49802 | 2-[3-amino-1-[(benzyloxy)carbonyl]-4-(tert-butoxycarbonyl)-2,5-dihydro-1H-pyrrol-2-yl]acetic acid | C19H24N2O6 | 详情 | 详情 | |
| (IV) | 49803 | 1-benzyl 3-(tert-butyl) 4-amino-5-[2-(benzyloxy)-2-oxoethyl]-2,5-dihydro-1H-pyrrole-1,3-dicarboxylate | C26H30N2O6 | 详情 | 详情 | |
| (V) | 49804 | 1-benzyl 3-(tert-butyl) 5-[2-(benzyloxy)-2-oxoethyl]-4-[bis(tert-butoxycarbonyl)amino]-2,5-dihydro-1H-pyrrole-1,3-dicarboxylate | C36H46N2O10 | 详情 | 详情 | |
| (V) | 49805 | 2-[(2S,3R,4R)-3-[bis(tert-butoxycarbonyl)amino]-4-(tert-butoxycarbonyl)pyrrolidinyl]acetic acid | C21H36N2O8 | 详情 | 详情 | |
| (VII) | 49807 | 2-[(chlorocarbonyl)(ethyl)amino]propane | C6H12ClNO | 详情 | 详情 | |
| (VIII) | 49808 | 2-((2S,3R,4R)-3-[bis(tert-butoxycarbonyl)amino]-4-(tert-butoxycarbonyl)-1-[[ethyl(isopropyl)amino]carbonyl]pyrrolidinyl)acetic acid | C27H47N3O9 | 详情 | 详情 | |
| (IX) | 49809 | tert-butyl (3R,4R,5S)-5-([[(benzyloxy)carbonyl]amino]methyl)-4-[bis(tert-butoxycarbonyl)amino]-1-[[ethyl(isopropyl)amino]carbonyl]-3-pyrrolidinecarboxylate | C34H54N4O9 | 详情 | 详情 | |
| (X) | 49810 | tert-butyl (3R,4R,5S)-5-(aminomethyl)-4-[bis(tert-butoxycarbonyl)amino]-1-[[ethyl(isopropyl)amino]carbonyl]-3-pyrrolidinecarboxylate | C26H48N4O7 | 详情 | 详情 | |
| (XI) | 49811 | trifluoro-lambda(5)-azanecarboxylic acid | CH2F3NO2 | 详情 | 详情 | |
| (XII) | 49812 | tert-butyl (3R,4R,5S)-4-[bis(tert-butoxycarbonyl)amino]-1-[[ethyl(isopropyl)amino]carbonyl]-5-([[(trifluoro-lambda(5)-azanyl)carbonyl]amino]methyl)-3-pyrrolidinecarboxylate | C27H48F3N5O8 | 详情 | 详情 |
合成路线11
该中间体在本合成路线中的序号：(XI)The title compound was obtained from the bromo naphthyridinone (X) by two related methods. Palladium-catalyzed Heck coupling of bromide (X) with acrylamide (IV) yielded directly the desired naphthyridinyl acrylamide. Alternatively, bromo naphthyridinone (X) was subjected to Heck coupling with tert-butyl acrylate (XI) to give adduct (XII). After acidic cleavage of the tert-butyl ester group of (XII), the resultant naphthyridinyl acrylic acid (XIII) was coupled to the indolylmethyl amine (II) to furnish the desired amide.
| 【1】 Seefeled, M.A.; et al.; Discovery and characterization of highly potent naphthyridine-based FabI inhibitors with in vivo activity. 41st Intersci Conf Antimicrob Agents Chemother (Dec 16 2001, Chicago) 2001, Abst F-1690. |
| 【2】 Uzinskas, I.N.; Miller, W.H.; Newlander, K.A.; Jakas, D.R.; Seefeld, M.A.; DeWolf, W.E. Jr. (GlaxoSmithKline Inc.); Fab I inhibitors. EP 1226138; WO 0127103 . |
| 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) | 56110 | N-methyl-N-[(2-methyl-1H-indol-3-yl)methyl]amine; N-methyl(2-methyl-1H-indol-3-yl)methanamine | C11H14N2 | 详情 | 详情 | |
| (IV) | 56111 | N-methyl-N-[(2-methyl-1H-indol-3-yl)methyl]acrylamide | C14H16N2O | 详情 | 详情 | |
| (X) | 56116 | 6-bromo-3,4-dihydro[1,8]naphthyridin-2(1H)-one | C8H7BrN2O | 详情 | 详情 | |
| (XI) | 12760 | tert-butyl acrylate | 1663-39-4 | C7H12O2 | 详情 | 详情 |
| (XII) | 56117 | tert-butyl (E)-3-(7-oxo-5,6,7,8-tetrahydro[1,8]naphthyridin-3-yl)-2-propenoate | C15H18N2O3 | 详情 | 详情 | |
| (XIII) | 56118 | (E)-3-(7-oxo-5,6,7,8-tetrahydro[1,8]naphthyridin-3-yl)-2-propenoic acid | C11H10N2O3 | 详情 | 详情 |
合成路线12
该中间体在本合成路线中的序号：(VIII)Reduction of 2-aminonicotinic acid (I) with LiAlH4 in THF gives (2-amino-3-pyridinyl)methanol (II), which by bromination with Br2 in AcOH yields (2-amino-5-bromo-3-pyridinyl)methanol hydrobromide (III). Substitution of alcohol (III) with aqueous HBr at reflux provides the corresponding bromide (IV), which by cyclocondensation with dimethyl malonate (V) in the presence of NaH in DMF/THF provides methyl 6-bromo-2-oxo-1,2,3,4-tetrahydro-1,8-naphthyridine-3-carboxylate (VI). Hydrolysis of ester (VI) with NaOH in refluxing MeOH, followed by decarboxylation in refluxing HCl leads to 6-bromo-3,4-dihydro-1,8-naphthyridin-2-one (VII) . Heck coupling of aryl bromide (VII) with t-butyl acrylate (VIII) in the presence of Pd(OAc)2, DIEA and P(o-tol)3 in propionitrile/DMF or acetonitrile/DMF affords the naphthyridinyl-acrylate (IX) , whose t-butyl ester group is then cleaved using TFA in CH2Cl2 to afford, after treatment with HCl in dioxane, (E)-3-(7-oxo-6,8-dihydro-5H-1,8-naphthyridin-3-yl)acrylic acid hydrochloride (Xa) . Similarly, hydrolysis of t-butyl ester (IX) using HBr in AcOH yields 3-(7-oxo-6,8-dihydro-5H-1,8-naphthyridin-3-yl)acrylic acid hydrobromide (Xb) . Finally, acrylic acids (Xa) or (Xb) are condensed with N-methyl-N-(3-methylbenzofuran-2-ylmethyl)-amine (XI) using EDC, HOBt and DIEA in DMF .
Chlorination of 3-methylbenzofuran-2-carboxylic acid (XII) with (COCl)2 and catalytic DMF, followed by condensation with CH3NH2 in CH2Cl2 yields the corresponding benzofuran-2-carboxamide (XIII), which is finally reduced with LiAlH4 in THF .Alternatively, 3-methylbenzofuran-2-carbaldehyde (XIV) is condensed with CH3NH2 in MeOH and subsequently reduced with NaBH4 in EtOH .
| 【1】 Burgess, W.J., Huffman, W.F., Miller, W.H., Uzinskas, I.N., Jakas, D., Newlander, K.A., Seefeld, M.A. (Affinium Pharmaceuticals, Inc.). CA 2447597, EP 1560584, JP 2005519984, US 2004147580, US 7049310, US 8153652, WO 2003088897. |
| 【2】 Schmid, M.B., Mendlein, J.D., Berman, J.M., Kaplan, N. (Affinium Pharmaceuticals, Inc.). EP 1608377, JP 2006523207, US 2006142265, US 7879872, US 2012010127, WO 2004082586. |
| 【3】 Pauls, H., Ramnauth, J. (Affinium Pharmaceuticals, Inc.). EP 2125802, US 8263613, US 2013150400, WO 2008098374. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (Xa) | 67798 | (E)-3-(7-oxo-6,8-dihydro-5H-1,8-naphthyridin-3-yl)acrylic acid hydrochloride | C11H10N2O3.HCl | 详情 | 详情 | |
| (Xb) | 67799 | 3-(7-oxo-6,8-dihydro-5H-1,8-naphthyridin-3-yl)acrylic acid hydrobromide | C11H10N2O3.HBr | 详情 | 详情 | |
| (I) | 55933 | 2-Aminonicotinic acid; 2-Aminopyridine-3-carboxylic acid | 5345-47-1 | C6H6N2O2 | 详情 | 详情 |
| (II) | 56112 | (2-amino-3-pyridinyl)methanol | 23612-57-9 | C6H8N2O | 详情 | 详情 |
| (III) | 67797 | (2-amino-5-bromo-3-pyridinyl)methanol hydrobromide | 443956-55-6 | C6H72N2O.HBr | 详情 | 详情 |
| (IV) | 56114 | 5-bromo-3-(bromomethyl)-2-pyridinamine; 5-bromo-3-(bromomethyl)-2-pyridinylamine | 335033-38-0 | C6H6Br2N2.HBr | 详情 | 详情 |
| (V) | 19373 | dimethyl malonate；Methyl malonate;Propanedioic acid dimethyl ester | 108-59-8 | C5H8O4 | 详情 | 详情 |
| (VI) | 56115 | methyl 6-bromo-2-oxo-1,2,3,4-tetrahydro[1,8]naphthyridine-3-carboxylate | 335031-10-2 | C10H9BrN2O3 | 详情 | 详情 |
| (VII) | 56116 | 6-bromo-3,4-dihydro[1,8]naphthyridin-2(1H)-one | C8H7BrN2O | 详情 | 详情 | |
| (VIII) | 12760 | tert-butyl acrylate | 1663-39-4 | C7H12O2 | 详情 | 详情 |
| (IX) | 56117 | tert-butyl (E)-3-(7-oxo-5,6,7,8-tetrahydro[1,8]naphthyridin-3-yl)-2-propenoate | C15H18N2O3 | 详情 | 详情 | |
| (XI) | 67800 | N-methyl-N-(3-methylbenzofuran-2-ylmethyl)-amine | C11H13NO | 详情 | 详情 | |
| (XII) | 67801 | 3-methylbenzofuran-2-carboxylic acid | C10H8O3 | 详情 | 详情 | |
| (XIII) | 67802 | N,3-dimethylbenzofuran-2-carboxamide | C11H11NO2 | 详情 | 详情 | |
| (XIV) | 67803 | 3-methylbenzofuran-2-carbaldehyde | C10H8O2 | 详情 | 详情 |