|
【结 构 式】 
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【分子编号】19139 【品名】acrylic acid 【CA登记号】79-10-7 |
【 分 子 式 】C3H4O2 【 分 子 量 】72.06356 【元素组成】C 50% H 5.59% O 44.4% |
合成路线1
该中间体在本合成路线中的序号：(IX)The Diels-Alder reaction of butadiene (VIII) with acrylic acid (IX) gives cyclohexene-4-carboxylic acid (X), which by treatment with I2 and KI in water followed by a treatment with 1,5-diazabicyclo[4.3.0]non-5-ene (XI) in benzene is converted to 3-hydroxycyclohexene-5-carboxylic acid lactone (XII). The opening of (XII) with NaOMe in MeOH yields methyl 3-hydroxycyclohexene-5-carboxylate (XIII) as a mixture of isomers, which by treatment with phenylacetyl chloride (A) affords the corresponding phenylacetate (XIV), which by optical resolution and successive racemization of the residue with mercuric trifluoroacetate yields the active methyl 3-hydroxycyclohexene-5-carboxylate (XIIIa). The treatment of (XIIIa) with biphenylyl-4-carbonyl chloride gives the corresponding ester (XV), which is submitted to hydroxylation with OsO4-sodium chlorate yielding the glycol (XVI). Ring opening of (XVI) with sodium periodate in THF-water affords the dialdehyde (XVII), which is cyclized by treatment with pyrrolidine acetate (B) in benzene giving 5-methoxycarbonyl-3-(biphenylylcarbonyloxy)cyclopentene-1-carboxaldehyde (XVIII). The conjugate addition of (XVIII) with the vinyl cuprate (XIX) in HMPT-THF-ether at -78 C gives rise to 2-[3-(1-ethoxyethoxy)-1-octen-1-yl]-3-(4-biphenylylcarbonyloxy)-5-methyloxycarbonylcyclopentane-1-carboxaldehyde (XX), which is converted into the corresponding ethylene ketal (XXI) in the usual way (C).
| 【1】 Trost, B.M.; et al.; An enantioconvergent approach to prostanoids. J Chem Soc Chem Commun 1978, 10, 436-438. |
| 【2】 Castaner, J.; Owen, R.T.; U-46619. Drugs Fut 1980, 5, 9, 453. |
| 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) | 28439 | [1,1'-biphenyl]-4-carbonyl chloride | 14002-51-8 | C13H9ClO | 详情 | 详情 |
| (B) | 39152 | C6H12NO2 | 详情 | 详情 | ||
| (VIII) | 11579 | 1,3-Butadiene; Butadiene | 106-99-0 | C4H6 | 详情 | 详情 |
| (IX) | 19139 | acrylic acid | 79-10-7 | C3H4O2 | 详情 | 详情 |
| (X) | 39146 | 3-cyclohexene-1-carboxylic acid；Cyclohex-3-ene-1-carboxylic acid | 4771-80-6 | C7H10O2 | 详情 | 详情 |
| (XI) | 39147 | 2,3,4,6,7,8-hexahydropyrrolo[1,2-a]pyrimidine | 3001-72-7 | C7H12N2 | 详情 | 详情 |
| (XII) | 11583 | (1R,5R)-6-Oxabicyclo[3.2.1]oct-3-en-7-one | C7H8O2 | 详情 | 详情 | |
| (XIII) | 11584 | methyl (1R,5R)-5-hydroxy-3-cyclohexene-1-carboxylate | C8H12O3 | 详情 | 详情 | |
| (XIV) | 39148 | methyl (1R,5R)-5-[(2-phenylacetyl)oxy]-3-cyclohexene-1-carboxylate | C16H18O4 | 详情 | 详情 | |
| (XV) | 39149 | (1R,5R)-5-(methoxycarbonyl)-2-cyclohexen-1-yl [1,1'-biphenyl]-4-carboxylate | C21H20O4 | 详情 | 详情 | |
| (XVI) | 39150 | (1R,2R,3R,5R)-2,3-dihydroxy-5-(methoxycarbonyl)cyclohexyl [1,1'-biphenyl]-4-carboxylate | C21H22O6 | 详情 | 详情 | |
| (XVII) | 39151 | (1R,3S)-1-formyl-3-(methoxycarbonyl)-5-oxopentyl [1,1'-biphenyl]-4-carboxylate | C21H20O6 | 详情 | 详情 | |
| (XVIII) | 39153 | (1R,4S)-3-formyl-4-(methoxycarbonyl)-2-cyclopenten-1-yl [1,1'-biphenyl]-4-carboxylate | C21H18O5 | 详情 | 详情 | |
| (XIX) | 39154 | C17H30CuO2 | 详情 | 详情 | ||
| (XX) | 39155 | (1R,2R,3R,4S)-2-[(E,3S)-3-(1-ethoxyethoxy)-1-octenyl]-3-formyl-4-(methoxycarbonyl)cyclopentyl [1,1'-biphenyl]-4-carboxylate | C33H42O7 | 详情 | 详情 | |
| (XXI) | 39157 | (1R,2R,3R,4S)-3-(1,3-dioxolan-2-yl)-2-[(E,3S)-3-(1-ethoxyethoxy)-1-octenyl]-4-(methoxycarbonyl)cyclopentyl [1,1'-biphenyl]-4-carboxylate | C35H46O8 | 详情 | 详情 | |
| (C) | 39156 | 2,2-dimethyl-1,3-dioxolane | 2916-31-6 | C5H10O2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(III)The reaction of cyclohexane-1,3-dione (I) with ammonia gives 3-amino-2-cyclohexen-1-one (II), which is cyclized with acrylic acid (III) by heating at 140 C yielding 1,2,3,4,5,6,7,8-octahydroquinoline-2,5-dione (IV). The dehydrogenation of (IV) by means of Pd/C in refluxing decaline affords 5-hydroxy-1,2,3,4-tetrahydroquinolin-2-one (V), which is condensed with epichlorohydrin (VI) by means of NaOMe or NaOH in methanol giving 5-(2,3-epoxypropoxy)-1,2,3,4-tetrahydroquinolin-2-one (VII). Finally, this compound is treated with tert-butylamine in methanol.
| 【1】 Castaner, J.; Sungurbey, K.; Carteolol. Drugs Fut 1977, 2, 5, 288. |
| 【2】 Shono, T.; et al.; A new practical synthesis of 5-hydroxy-3,4-dihydrocarbostyril and 5-hydroxycarbostyril. J Org Chem 1981, 46, 3719. |
| 【3】 Von Winkler, W.; Chemical and analytical data for the pharmaceutically active substance carteolol hydrochloride. Arzneim-Forsch Drug Res 1983, 33, 2a, 279. |
| 【4】 Mori, H.; Tamura, Y,.; Tominaga, M.; Yoshiaki, S.; Nakagawa, K.; Murakami, N. (Otsuka Pharmaceutical Co., Ltd.); 3,4-Dihydrocarbostyril derivs., their preparation, and pharmaceutical compsns. thereof. DE 2302027; GB 1424571 . |
| 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) | 11244 | 1,3-Cyclohexanedione | 504-02-9 | C6H8O2 | 详情 | 详情 |
| (II) | 31475 | 3-amino-2-cyclohexen-1-one | 5220-49-5 | C6H9NO | 详情 | 详情 |
| (III) | 19139 | acrylic acid | 79-10-7 | C3H4O2 | 详情 | 详情 |
| (IV) | 31476 | 4,6,7,8-tetrahydro-2,5(1H,3H)-quinolinedione | C9H11NO2 | 详情 | 详情 | |
| (V) | 31477 | 5-hydroxy-3,4-dihydro-2(1H)-quinolinone | C9H9NO2 | 详情 | 详情 | |
| (VI) | 29648 | 2-oxiranylmethanol | 556-52-5 | C3H6O2 | 详情 | 详情 |
| (VII) | 31478 | 5-(2-oxiranylmethoxy)-3,4-dihydro-2(1H)-quinolinone | C12H13NO3 | 详情 | 详情 | |
| (VIII) | 17895 | 2-Amino-2-methylpropane; tert-butylamine; 2-methyl-2-propanamine | 75-64-9 | C4H11N | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(IX)The intermediate 5-fluoro-3-[3-(1-piperazinyl)propyl]-1H-indole (V) has been obtained as follows: a) The condensation of 5-fluoro-1H-indole (VIII) with acrylic acid (IX) by means of acetic anhydride gives 3-(1H-indol-5-yl)propionic acid (X), which is reduced with LiAlH4 to 3-(1H-indol-5-yl)-1-propanol (XI). The tosylation of (XI) with tosyl chloride yields the tosylate (XII), which is condensed with 1-benzylpiperazine (XIII) in refluxing butyl acetate affording 3-[3-(4-benzylpiperazin-1-yl)propyl]-5-fluoro-1H-indole (XIV). Finally, this compound is debenzylated by hydrogenation with H2 over Pd/C yielding the target intermediate (V). b) The tosylate intermediate (XII) can also be condensed with ethyl piperazine-1-carboxylate (XVII) in refluxing butyl acetate giving 4-[3-(5-fluoro-1H-indol-3-yl)propyl]piperazine-1-carboxylic acid ethyl ester (XVIII), which is then decarboxylated with NaOH to the target intermediate (V). The intermediate 3-(1H-indol-5-yl)-1-propanol (XI) can also be obtained by direct cyclization of 4-fluorophenylhydrazine (XV) with dihydropyran (XVI) in hot propyleneglycol.
| 【1】 Anderson, N.G.; et al.; Process development of 5-fluoro-3[3-[4-(5-methoxy-4-pyrimidinyl)-1-piperazinyl]propyl]-1H-indole dihydrochloride. Org Process Res Dev 1997, 1, 4, 300. |
| 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) | 32385 | 5-fluoro-3-[3-(1-piperazinyl)propyl]-1H-indole | C15H20FN3 | 详情 | 详情 | |
| (VIII) | 32388 | 5-Fluoroindole; 5-Fluoro-1H-indole | 399-52-0 | C8H6FN | 详情 | 详情 |
| (IX) | 19139 | acrylic acid | 79-10-7 | C3H4O2 | 详情 | 详情 |
| (X) | 32389 | 3-(5-fluoro-1H-indol-3-yl)propionic acid | C11H10FNO2 | 详情 | 详情 | |
| (XI) | 32390 | 3-(5-fluoro-1H-indol-3-yl)-1-propanol | C11H12FNO | 详情 | 详情 | |
| (XII) | 32391 | 3-(5-fluoro-1H-indol-3-yl)propyl 4-methylbenzenesulfonate | C18H18FNO3S | 详情 | 详情 | |
| (XIII) | 28542 | N-Benzylpiperazine; 1-Benzylpiperazine | 2759-28-6 | C11H16N2 | 详情 | 详情 |
| (XIV) | 32392 | 3-[3-(4-benzyl-1-piperazinyl)propyl]-5-fluoro-1H-indole | C22H26FN3 | 详情 | 详情 | |
| (XV) | 22135 | 1-(4-fluorophenyl)hydrazine | 371-14-2 | C6H7FN2 | 详情 | 详情 |
| (XVI) | 13684 | 3,4-Dihydro-2H-pyran;2,3-Dihydro-4H-pyran; 5,6-Dihydro-4H-pyran;Dihydropyran | 110-87-2 | C5H8O | 详情 | 详情 |
| (XVII) | 24694 | N-ethoxycarbonylpiperidine; Ethyl 1-piperazinecarboxylate; N-Ethoxycarbonyl piperazine; N-Carbethoxy piperazine | 120-43-4 | C7H14N2O2 | 详情 | 详情 |
| (XVIII) | 32393 | ethyl 4-[3-(5-fluoro-1H-indol-3-yl)propyl]-1-piperazinecarboxylate | C18H24FN3O2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(V)Coupling of chloroquinazoline (I) with 3-bromoaniline (II) in refluxing isopropanol yielded anilinoquinazoline (III). The nitro group was then reduced with Fe dust and AcOH in aqueous ethanol to give amine (IV). Finally, condensation with acrylic acid (V) using 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide.HCl (EDC) in DMF provided the target acrylamide.
| 【1】 Rewcastle, G.W.; et al.; Tyrosine kinase inhibitors. 5. Synthesis and structure-activity relationships for 4-[(phenylmethyl)amino]- and 4-(phenylamino)quinazolines as potent adenosine 5'-triphosphate binding site inhibitors of the tyrosine kinase domain of the epidermal growth f. J Med Chem 1995, 38, 18, 3482. |
| 【2】 Dobrusin, E.M.; Bridges, A.J.; Zhou, H.; Smaill, J.B.; Doherty, A.M.; Denny, W.A.; McNamara, D.J.; Showalter, H.D. (Pfizer Inc.); Irreversible inhibitors of tyrosine kinases. JP 2000508657; WO 9738983 . |
| 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) | 19135 | 4-chloro-7-nitroquinazoline | C8H4ClN3O2 | 详情 | 详情 | |
| (II) | 19136 | 3-bromoaniline; 3-bromophenylamine; 3-bromobenzenamine | 591-19-5 | C6H6BrN | 详情 | 详情 |
| (III) | 19137 | N-(3-bromophenyl)-N-(7-nitro-4-quinazolinyl)amine; N-(3-bromophenyl)-7-nitro-4-quinazolinamine | C14H9BrN4O2 | 详情 | 详情 | |
| (IV) | 19138 | N(4)-(3-bromophenyl)-4,7-quinazolinediamine; N-(7-amino-4-quinazolinyl)-N-(3-bromophenyl)amine | C14H11BrN4 | 详情 | 详情 | |
| (V) | 19139 | acrylic acid | 79-10-7 | C3H4O2 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(IX)Nitration of quinazolinone (I) with fuming HNO3 in H2SO4 at 100 C gave a mixture of 6-nitro and 8-nitroquinazolines, from which the desired 6-isomer was isolated by recrystallization from AcOH. Subsequent treatment with refluxing SOCl2 and a catalytic amount of DMF gave chloride (III), which was condensed with 3-bromoaniline (IV) in isopropanol to afford anilinoquinazoline (V). Reaction with sodium alkoxide (VI) in refluxing THF provided ether (VII). Then, the nitro group was reduced with Fe dust and AcOH in aqueous ethanol to give amine (VIII). Finally, condensation with acrylic acid (X) using 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide.HCl (EDC) in DMF yielded the target acrylamide.
| 【1】 Rewcastle, G.W.; et al.; Tyrosine kinase inhibitors. 9. Synthesis and evaluation of fused tricyclic quinazoline analogues as ATP site inhibitors of the tyrosine kinase activity of the epidermal growth factor receptor. J Med Chem 1996, 39, 4, 918. |
| 【2】 Dobrusin, E.M.; Bridges, A.J.; Zhou, H.; Smaill, J.B.; Doherty, A.M.; Denny, W.A.; McNamara, D.J.; Showalter, H.D. (Pfizer Inc.); Irreversible inhibitors of tyrosine kinases. JP 2000508657; WO 9738983 . |
| 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) | 19140 | 7-fluoro-4(3H)-quinazolinone | C8H5FN2O | 详情 | 详情 | |
| (II) | 19141 | 7-fluoro-6-nitro-4(3H)-quinazolinone | C8H4FN3O3 | 详情 | 详情 | |
| (III) | 19142 | 4-chloro-7-fluoro-6-nitroquinazoline | C8H3ClFN3O2 | 详情 | 详情 | |
| (IV) | 19136 | 3-bromoaniline; 3-bromophenylamine; 3-bromobenzenamine | 591-19-5 | C6H6BrN | 详情 | 详情 |
| (V) | 19144 | N-(3-bromophenyl)-N-(7-fluoro-6-nitro-4-quinazolinyl)amine; N-(3-bromophenyl)-7-fluoro-6-nitro-4-quinazolinamine | C14H8BrFN4O2 | 详情 | 详情 | |
| (VI) | 19145 | 3-(4-Morpholinyl)-1-propanol sodium salt | C7H14NNaO2 | 详情 | 详情 | |
| (VII) | 19146 | N-(3-bromophenyl)-7-[3-(4-morpholinyl)propoxy]-6-nitro-4-quinazolinamine; N-(3-bromophenyl)-N-[7-[3-(4-morpholinyl)propoxy]-6-nitro-4-quinazolinyl]amine | C21H22BrN5O4 | 详情 | 详情 | |
| (VIII) | 19147 | N(4)-(3-bromophenyl)-7-[3-(4-morpholinyl)propoxy]-4,6-quinazolinediamine; N-[6-amino-7-[3-(4-morpholinyl)propoxy]-4-quinazolinyl]-N-(3-bromophenyl)amine | C21H24BrN5O2 | 详情 | 详情 | |
| (IX) | 19139 | acrylic acid | 79-10-7 | C3H4O2 | 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 intermediate 4-ethyltetrahydroquinoline (VII) has been prepared by two procedures: 1.- Conjugate addition of acrylic acid (II) to aniline (I) gave 3-(phenylamino)propionic acid (III), which was cyclized with PPA at 100 C to afford quinolinone (IV). After protection of (IV) as the tert-butyl carbamate (V), addition of ethylmagnesium bromide provided carbinol (VI). Hydrogenolysis of the hydroxyl group of (VI), followed by deprotection with trifluoroacetic acid then furnished tetrahydroquinoline (VII). 2.- In an alternative procedure, side-chain alkylation of lepidine (VIII) with CH3I and LDA provided 4-ethylquinoline (IX). This was then reduced to the desired tetrahydroquinoline (VII) using NaBH4 and NiCl2. 3.- After nitration of (VII) with HNO3 and H2SO4, the resulting 7-nitroquinoline (X) was reduced to diamine (XI) by catalytic hydrogenation over Pd/C. Finally, Knorr cyclization of (XI) with ethyl 4,4,4-trifluoroacetylacetate (XII) and ZnCl2 produced the target pyridoquinoline.
| 【1】 Hamann, L.G.; Mani, N.S.; Davis, R.L.; Marschke, K.B.; Wang, X.-N.; Jones, T.K.; Discovery of a potent, orally active, nonsteroidal androgen receptor agonist: 4-Ethyl-1,2,3,4-tetrahydro-6-(trifluoromethyl)-8-pyridono[5,6-g]quinoline (LG121071). J Med Chem 1999, 42, 2, 210. |
| 【2】 Jones, T.K.; Goldman, M.E.; Pooley, C.L.F.; Winn, D.T.; Edwards, J.E.; West, S.J.; Tegley, C.M.; Zhi, L.; Hamann, L.G.; Farmer, L.J.; Davis, R.J. (Ligand Pharmaceuticals, Inc.); Steroid receptor modulator cpds. and methods. EP 0800519; JP 1998510840; US 5688808; US 5688810; US 5693646; US 5693647; US 5696127; US 5696130; US 5696133; WO 9619458 . |
| 【3】 Edwards, J.P.; Higuchi, R.; Jones, T. (Ligand Pharmaceuticals, Inc.); Androgen receptor modulator cpds. and methods. EP 0918774; US 6017924; WO 9749709 . |
| 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) | 12294 | Aniline; Phenylamine | 62-53-3 | C6H7N | 详情 | 详情 |
| (II) | 19139 | acrylic acid | 79-10-7 | C3H4O2 | 详情 | 详情 |
| (III) | 25423 | 3-anilinopropionic acid | 5652-38-0 | C9H11NO2 | 详情 | 详情 |
| (IV) | 25424 | 2,3-dihydro-4(1H)-quinolinone | 4295-36-7 | C9H9NO | 详情 | 详情 |
| (V) | 25425 | tert-butyl 4-oxo-3,4-dihydro-1(2H)-quinolinecarboxylate | C14H17NO3 | 详情 | 详情 | |
| (VI) | 25426 | tert-butyl 4-ethyl-4-hydroxy-3,4-dihydro-1(2H)-quinolinecarboxylate | C16H23NO3 | 详情 | 详情 | |
| (VII) | 25427 | 4-ethyl-1,2,3,4-tetrahydroquinoline | C11H15N | 详情 | 详情 | |
| (VIII) | 25428 | 4-methylquinoline | 491-35-0 | C10H9N | 详情 | 详情 |
| (IX) | 25429 | 4-ethylquinoline | C11H11N | 详情 | 详情 | |
| (X) | 25430 | 4-ethyl-7-nitro-1,2,3,4-tetrahydroquinoline | C11H14N2O2 | 详情 | 详情 | |
| (XI) | 25431 | 4-ethyl-1,2,3,4-tetrahydro-7-quinolinamine; 4-ethyl-1,2,3,4-tetrahydro-7-quinolinylamine | C11H16N2 | 详情 | 详情 | |
| (XII) | 25432 | ethyl 4,4,4-trifluoro-3-oxobutanoate | 372-31-6 | C6H7F3O3 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(VII)4-Chloro-7-fluoro-6-nitroquinazoline (I) was condensed with 3-chloro-4-fluoroaniline (II) to afford the 4-anilino quinazoline (III). Displacement of the activated fluorine of (III) with the potassium alkoxide of morpholinopropanol (IV) gave the morpholinopropyl ether (V). Subsequent reduction of the nitro group of (V), either using iron dust and acetic acid or catalytic hydrogenation over Raney-Ni, furnished aminoquinazoline (VI). This was finally condensed with acrylic acid (VII), via activation as the mixed anhydride with isobutyl chloroformate or using EDC as the coupling reagent, to provide the title acrylamide.
| 【1】 Loo, J.A.; Rewcastle, G.W.; Smaill, J.B.; et al.; Tyrosine kinase inhibitors.17. Irreversible inhibitors of the epidermal growth factor receptor: 4-(Phenylamino)quinazoline- and 4-(phenylamino)pyrido[3,2-d]pyrimidine-6-acrylamides baring additional solubilizing functions. J Med Chem 2000, 43, 7, 1380. |
| 【2】 Bridges, A.J.; Klohs, W.D.; Driscoll, D. (Pfizer Inc.); N-[4-(3-Chloro-4-fluoro-phenylamino)-7-(3-morpholin-4-yl-propoxy)-quinazolin-6-yl]-acrylamide, an irreversible inhibitor of tyrosine kinases. EP 1131304; US 6344455; WO 0031048 . |
| 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) | 19142 | 4-chloro-7-fluoro-6-nitroquinazoline | C8H3ClFN3O2 | 详情 | 详情 | |
| (II) | 18688 | 3-Chloro-4-fluorophenylamine; 3-Chloro-4-fluoroaniline | 367-21-5 | C6H5ClFN | 详情 | 详情 |
| (III) | 54956 | N-(3-chloro-4-fluorophenyl)-7-fluoro-6-nitro-4-quinazolinamine; N-(3-chloro-4-fluorophenyl)-N-(7-fluoro-6-nitro-4-quinazolinyl)amine | 162012-67-1 | C14H7ClF2N4O2 | 详情 | 详情 |
| (IV) | 54957 | 3-(4-morpholinyl)-1-propanol | C7H15NO2 | 详情 | 详情 | |
| (V) | 54958 | N-(3-chloro-4-fluorophenyl)-7-[3-(4-morpholinyl)propoxy]-6-nitro-4-quinazolinamine; N-(3-chloro-4-fluorophenyl)-N-{7-[3-(4-morpholinyl)propoxy]-6-nitro-4-quinazolinyl}amine | C21H21ClFN5O4 | 详情 | 详情 | |
| (VI) | 54959 | N-{6-amino-7-[3-(4-morpholinyl)propoxy]-4-quinazolinyl}-N-(3-chloro-4-fluorophenyl)amine; N~4~-(3-chloro-4-fluorophenyl)-7-[3-(4-morpholinyl)propoxy]-4,6-quinazolinediamine | C21H23ClFN5O2 | 详情 | 详情 | |
| (VII) | 19139 | acrylic acid | 79-10-7 | C3H4O2 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(XII)Treatment of Wang resin with acryloyl chloride (XI) in the presence of diisopropyl ethylamine produced the acrylate bound resin (XII). Conjugate addition of 3,4-dimethoxybenzylamine (XIII) to the acrylate (XII) afforded the beta-amino ester resin (XIV). This was coupled with the intermediate carboxylic acid (X) employing O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) to furnish (XV). The title compound was finally liberated from the resin (XV) by cleavage with trifluoroacetic acid.
| 【1】 Morley, A.D.; Harris, N.V.; Astles, P.C. (Rhone-Poulenc Rorer Ltd.); Substd. beta-alanines. WO 9933789 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (X) | 39720 | 2-[(2-[3-methoxy-4-[(2-toluidinocarbonyl)amino]phenyl]acetyl)amino]acetic acid | C19H21N3O5 | 详情 | 详情 | |
| (XI) | 11577 | Acryloyl chloride; Acrylyl chloride;2-Propenoyl chloride | 814-68-6 | C3H3ClO | 详情 | 详情 |
| (XII) | 19139 | acrylic acid | 79-10-7 | C3H4O2 | 详情 | 详情 |
| (XIII) | 13920 | (3,4-Dimethoxyphenyl)methanamine; 3,4-Dimethoxybenzylamine; Veratrylamine | 5763-61-1 | C9H13NO2 | 详情 | 详情 |
| (XIV) | 39721 | N-(3,4-dimethoxybenzyl)-beta-alanine | C12H17NO4 | 详情 | 详情 | |
| (XV) | 39722 | N-(3,4-dimethoxybenzyl)-N-[2-[(2-[3-methoxy-4-[(2-toluidinocarbonyl)amino]phenyl]acetyl)amino]acetyl]-beta-alanine | C31H36N4O8 | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(XVII)An improved procedure for the synthesis of intermediate (XVI) was further developed. Heck coupling of iodide (IX) with acrylic acid formed cinnamic acid (XVIII). This was converted to the corresponding acid chloride upon treatment with Vilsmeier reagent, and subsequent coupling with glycine tert-butyl ester gave amide (XIX). Selective chlorine displacement in (XIX) by means of the lithium salt of methyl mercaptoacetate, followed by in situ hydrolysis with LiOH, afforded 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. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (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 |
| (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 | |
| (XVII) | 19139 | acrylic acid | 79-10-7 | C3H4O2 | 详情 | 详情 |
| (XVIII) | 46021 | (E)-3-(2,4,5-trichlorophenyl)-2-propenoic acid | C9H5Cl3O2 | 详情 | 详情 | |
| (XIX) | 46022 | tert-butyl 2-[[(E)-3-(2,4,5-trichlorophenyl)-2-propenoyl]amino]acetate | C15H16Cl3NO3 | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(II)Heck coupling of 2-bromophenylacetic acid (I) with acrylic acid (II) produces the dicarboxylic acid adduct (III). Subsequent catalytic hydrogenation of the olefinic double bond of (III) gives rise to the saturated diacid (IV). Then, Friedel-Crafts intramolecular cyclization of (IV) in hot H2SO4 affords indanone (V). Bromination of (V) in AcOH yields 2-bromo-1-oxoindan-4-ylacetic acid (VI). Esterification of (VI) is carried out via conversion to the corresponding acid chloride, followed by quenching with EtOH to provide the ethyl ester (VII). Condensation of bromo indanone (VII) with diethyl imidazole-2,4-dicarboxylate (VIII) furnishes the imidazolyl indanone (IX). Ring closure of keto ester (IX) with ammonium acetate in refluxing AcOH produces the tetracyclic compound (X). The ethyl ester groups of (X) are finally hydrolyzed under basic conditions to yield the title dicarboxylic acid.
| 【2】 Aloup, J.-C.; Bouquerel, J.; Damour, D.; Hardy, J.-C.; Jimonet, P.; Manfre, M.; Mignani, S.; Nemecek, P. (Aventis Pharma SA); 5H,10H-Imidazo[1,2-a]indeno[1,2-e]pyrazine-4-one derivs., preparation thereof, intermediates thereof and drugs containing same. EP 0880522; FR 2743366; JP 2000505073; US 5990108; WO 9725328 . |
| 【1】 Mignani, S.; et al.; 9-Carboxymethyl-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one-2-carbocylic acid (RPR117824): Selective anticonvulsive and neuroprotective AMPA antagonist. Bioorg Med Chem 2002, 10, 5, 1627. |
| 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) | 62312 | 2-Bromophenylacetic acid; O-Bromophenylacetic Acid; o-BROMOPHENYLACETIC ACID; OBPAA | 18698-97-0 | C8H7BrO2 | 详情 | 详情 |
| (II) | 19139 | acrylic acid | 79-10-7 | C3H4O2 | 详情 | 详情 |
| (III) | 62313 | (Z)-3-[2-(2-hydroxy-2-oxoethyl)phenyl]-2-propenoic acid | C11H10O4 | 详情 | 详情 | |
| (IV) | 53198 | 3-[2-(carboxymethyl)phenyl]propanoic acid | n/a | C11H12O4 | 详情 | 详情 |
| (V) | 53199 | 2-(1-oxo-2,3-dihydro-1H-inden-4-yl)acetic acid | n/a | C11H10O3 | 详情 | 详情 |
| (VI) | 62314 | 2-(2-bromo-1-oxo-2,3-dihydro-1H-inden-4-yl)acetic acid | C11H9BrO3 | 详情 | 详情 | |
| (VII) | 53201 | ethyl 2-(2-bromo-1-oxo-2,3-dihydro-1H-inden-4-yl)acetate | n/a | C13H13BrO3 | 详情 | 详情 |
| (VIII) | 62315 | diethyl 1H-imidazole-2,4-dicarboxylate | C9H12N2O4 | 详情 | 详情 | |
| (IX) | 62316 | diethyl 1-[4-(2-ethoxy-2-oxoethyl)-1-oxo-2,3-dihydro-1H-inden-2-yl]-1H-imidazole-2,4-dicarboxylate | C22H24N2O7 | 详情 | 详情 | |
| (X) | 62317 | ethyl 9-(2-ethoxy-2-oxoethyl)-4-oxo-5,10-dihydro-4H-imidazo[1,2-a]indeno[1,2-e]pyrazine-2-carboxylate | C20H19N3O5 | 详情 | 详情 |
合成路线11
该中间体在本合成路线中的序号：(II)Condensation of substituted aniline (I) with acrylic acid (II) in toluene affords bicyclic derivative (III), whose carbonyl is reduced by means of Red-Al in toluene to yield compound (IV). Conversion of (IV) into bicyclic hydrazine (V) is then performed by treatment with NaNO2 and HOAc followed by reduction of the resulting diazo derivative with LiAlH4 in THF. Derivative (V) is then subjected to a Fisher indole cyclization process by reaction with ketone (VI) and HCl in iPrOH to provide compound (VII), which is then regioselectively reduced with NaCNBH3 in TFA to give tetracyclic indoline (VIII). N-Protection of (VIII) with Boc2O and NaOH affords Boc protected derivative (IX), which is then selectively brominated by means of NBS in DMF to yield bromo derivative (X). Finally, the desired compound is obtained by a Suzuki cross-coupling reaction between (X) and boronic acid (XI) catalyzed by Pd(PPh3)4, followed by Boc removal with TFA in CH2Cl2.
| 【1】 Robichaud, A.J.; Chen, W.; McClung, C.; et al.; Synthesis and biological evaluation of novel, selective 5-HT2C receptor agonists for the treatment of obesity. 221st ACS Natl Meet (April 1 2001, San Diego) 2001, Abst MEDI 105. |
| 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) | 25182 | 2-aminobenzenethiol | 137-07-5 | C6H7NS | 详情 | 详情 |
| (II) | 19139 | acrylic acid | 79-10-7 | C3H4O2 | 详情 | 详情 |
| (III) | 48910 | 2,3,4,5-Tetrahydro-1,5-benzothiazepin-4-one | C9H9NOS | 详情 | 详情 | |
| (IV) | 22617 | 2,3,4,5-tetrahydro-1,5-benzothiazepine | C9H11NS | 详情 | 详情 | |
| (V) | 48146 | 3,4-dihydro-1,5-benzothiazepin-5(2H)-amine; 3,4-dihydro-1,5-benzothiazepin-5(2H)-ylamine | C9H12N2S | 详情 | 详情 | |
| (VI) | 27115 | 4-piperidinone | 40064-34-4 | C5H9NO | 详情 | 详情 |
| (VII) | 48147 | 6,7,9,10,11,12-hexahydro-5H-pyrido[4,3-b][1,4]thiazepino[2,3,4-hi]indole | C14H16N2S | 详情 | 详情 | |
| (VIII) | 48150 | (8aS,12aR)-6,7,8a,9,10,11,12,12a-octahydro-5H-pyrido[4,3-b][1,4]thiazepino[2,3,4-hi]indole | C14H18N2S | 详情 | 详情 | |
| (IX) | 48149 | tert-butyl (8aS,12aR)-6,7,9,10,12,12a-hexahydro-5H-pyrido[4,3-b][1,4]thiazepino[2,3,4-hi]indole-11(8aH)-carboxylate | C19H26N2O2S | 详情 | 详情 | |
| (X) | 48911 | tert-butyl (8aS,12aR)-2-bromo-6,7,9,10,12,12a-hexahydro-5H-pyrido[4,3-b][1,4]thiazepino[2,3,4-hi]indole-11(8aH)-carboxylate | C19H25BrN2O2S | 详情 | 详情 | |
| (XI) | 48912 | 2,4-Dichlorophenylboronic acid; 2,4-Dichlorobenzeneboronic acid | 68716-47-2 | C6H5BCl2O2 | 详情 | 详情 |
合成路线12
该中间体在本合成路线中的序号：(IV)Acylation of 4-iodoaniline (I) with 3,4-dimethoxybenzenesulfonyl chloride (II), followed by basic methanolysis leads to sulfonamide (III). Heck coupling of aryl iodide (III) with acrylic acid (IV) in the presence of tris(dibenzylideneacetone)dipalladium and tri(o-tolyl)phosphine gives the cinnamic acid derivative (V). This is then coupled to the tetrahydropyranyl-protected hydroxylamine (VI) by means of EDC/HOBt to furnish (VII). The tetrahydropyranyl hydroxamate (VII) is finally deprotected under acidic conditions to produce the title compound.
| 【1】 Bouchain, G.; Leit, S.; Frechette, S.; et al.; Development of potential antitumor agents. Synthesis and biological evaluation of a new set of sulfonamide derivatives as histone deacetylase inhibitors. J Med Chem 2003, 46, 5, 820. |
| 【2】 Lavoie, R.; Bouchain, G.; Frechette, S.; et al.; Design and synthesis of a novel class of histone deacetylase inhibitors. Bioorg Med Chem Lett 2001, 11, 21, 2847. |
| 【3】 Delorme, D.; Ruel, R.; Lavoie, R.; Thibault, C.; Abou-Khalil, E. (MethylGene Inc.); Inhibitors of histone deacetylase. EP 1233958; JP 2003514904; WO 0138322 . |
| 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) | 26393 | 4-iodoaniline; 4-iodophenylamine | 540-37-4 | C6H6IN | 详情 | 详情 |
| (II) | 47469 | 3,4-dimethoxybenzenesulfonyl chloride | 23095-31-0 | C8H9ClO4S | 详情 | 详情 |
| (III) | 63287 | N-(4-iodophenyl)-3,4-dimethoxybenzenesulfonamide | C14H14INO4S | 详情 | 详情 | |
| (IV) | 19139 | acrylic acid | 79-10-7 | C3H4O2 | 详情 | 详情 |
| (V) | 63288 | (E)-3-(4-{[(3,4-dimethoxyphenyl)sulfonyl]amino}phenyl)-2-propenoic acid | C17H17NO6S | 详情 | 详情 | |
| (VI) | 52106 | 2-(aminooxy)tetrahydro-2H-pyran; O-tetrahydro-2H-pyran-2-ylhydroxylamine | C5H11NO2 | 详情 | 详情 | |
| (VII) | 63289 | (E)-3-(4-{[(3,4-dimethoxyphenyl)sulfonyl]amino}phenyl)-N-(tetrahydro-2H-pyran-2-yloxy)-2-propenamide | C22H26N2O7S | 详情 | 详情 |
合成路线13
该中间体在本合成路线中的序号：(IV)Jones oxidation of 4-bromothiophene-2-carbaldehyde (I) leads to acid (II), which is further esterified with H2SO4/MeOH to furnish methyl 4-bromothiophene-2-carboxylate (III). Subsequent Heck coupling of aryl bromide (III) with cyclohexylammonium acrylate (IV) gives rise to the thienylacrylic acid (V). Cyclization of (V) with SOCl2 in the presence of pyridine produces the thienothiophene derivative (VI). Acid chloride (VI) is then coupled to N-(dimethylaminopropyl)aniline (VII) under Schotten-Baumann conditions, yielding amide (VIII). Finally, photochemical cyclization of (VIII) affords the target tetracyclic compound.
| 【1】 DoganKoruznjak, J.; Slade, N.; Zamola, B.; Pavelic, K.; Karminski-Zamola, G.; Synthesis, photochemical synthesis and antitumor evaluation of novel derivatives of thieno[3',2':4,5]thieno[2,3-c]quinolones. Chem Pharm Bull 2002, 50, 5, 656. |
| 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) | 24142 | 4-bromo-2-thiophenecarbaldehyde | 18791-75-8 | C5H3BrOS | 详情 | 详情 |
| (II) | 64296 | 4-bromo-2-thiophenecarboxylic acid | C5H3BrO2S | 详情 | 详情 | |
| (III) | 64297 | methyl 4-bromo-2-thiophenecarboxylate | C6H5BrO2S | 详情 | 详情 | |
| (IV) | 19139 | acrylic acid | 79-10-7 | C3H4O2 | 详情 | 详情 |
| (V) | 64298 | (E)-3-[5-(methoxycarbonyl)-3-thienyl]-2-propenoic acid | C9H8O4S | 详情 | 详情 | |
| (VI) | 64299 | methyl 4-chloro-5-(chlorocarbonyl)thieno[2,3-b]thiophene-2-carboxylate | C9H4Cl2O3S2 | 详情 | 详情 | |
| (VII) | 64300 | N-(3-anilinopropyl)-N,N-dimethylamine; N~1~,N~1~-dimethyl-N~3~-phenyl-1,3-propanediamine | C11H18N2 | 详情 | 详情 | |
| (VIII) | 64301 | methyl 4-chloro-5-({[3-(dimethylamino)propyl]anilino}carbonyl)thieno[2,3-b]thiophene-2-carboxylate | C20H21ClN2O3S2 | 详情 | 详情 |