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【结 构 式】 
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【分子编号】18887 【品名】3-Fluorobenzaldehyde 【CA登记号】456-48-4 |
【 分 子 式 】C7H5FO 【 分 子 量 】124.1145032 【元素组成】C 67.74% H 4.06% F 15.31% O 12.89% |
合成路线1
该中间体在本合成路线中的序号：(VII)Alkylation of N-Boc-piperazine (I) with bromoacetal (II) provided piperazine acetal (III). This was submitted to Fisher cyclization with 4-(1,2,4-triazol-4-yl)phenyl hydrazine (IV) in aqueous H2SO4 to afford the deprotected indole (V). Wittig reaction of 3-fluorobenzaldehyde (VII) with phosphorane prepared from (methoxymethyl)phosphonium salt (VI) and PhLi furnished the methoxyvinyl compound (VIII) as an E:Z mixture. Subsequent acid hydrolysis of the enol ether function of (VIII) yielded aldehyde (IX). The target compound was then obtained by reductive alkylation of piperazine (V) with aldehyde (IX) in the presence of NaBH3CN.
| 【1】 Chambers, M.S.; Goodacre, S.; Street, L.J.; et al.; 3-(Piperazinylpropyl)indoles: Selective, orally bioavailable h5-HT1D receptor agonists as potential antimigraine agents. J Med Chem 1999, 42, 4, 691. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIIIa) | 25650 | 1-fluoro-3-[(E)-2-methoxyethenyl]benzene; (E)-2-(3-fluorophenyl)ethenyl methyl ether | C9H9FO | 详情 | 详情 | |
| (VIIIb) | 53875 | (Z)-2-(3-fluorophenyl)ethenyl methyl ether; 1-fluoro-3-[(Z)-2-methoxyethenyl]benzene | n/a | C9H9FO | 详情 | 详情 |
| (I) | 13225 | N-tert-Butoxycarbonyl piperazine; tert-butyl 1-piperazinecarboxylate;tert-butyl piperazine-1-carboxylate | 143238-38-4 | C9H18N2O2 | 详情 | 详情 |
| (II) | 25645 | 5-bromo-1-methoxypentyl methyl ether; 5-bromo-1,1-dimethoxypentane | C7H15BrO2 | 详情 | 详情 | |
| (III) | 25646 | tert-butyl 4-(5,5-dimethoxypentyl)-1-piperazinecarboxylate | C16H32N2O4 | 详情 | 详情 | |
| (IV) | 25647 | 4-(4-hydrazinophenyl)-4H-1,2,4-triazole | C8H9N5 | 详情 | 详情 | |
| (V) | 25648 | 3-[3-(1-piperazinyl)propyl]-5-(4H-1,2,4-triazol-4-yl)-1H-indole | C17H22N6 | 详情 | 详情 | |
| (VI) | 25649 | (methoxymethyl)(triphenyl)phosphonium bromide | C20H20BrOP | 详情 | 详情 | |
| (VII) | 18887 | 3-Fluorobenzaldehyde | 456-48-4 | C7H5FO | 详情 | 详情 |
| (IX) | 25651 | 3-(3-fluorophenyl)propanal | C9H9FO | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)The compound was prepared by condensation of acetophenone (I) with 3-flourobenzaldehyde (II) in refluxing ethanolic NaOH, followed by cyclization of the intermediate chalcone in diphenyl ether at 180 C.
| 【1】 Xia, Y.; et al.; Antitumor agents. 181. Synthesis and biological evaluation of 6,7,2',3',4'-substituted-1,2,3, 4-tetrahydro-2-phenyl-4-quinolones as a new class of antimitotic antitumor agents. J Med Chem 1998, 41, 7, 1155. |
合成路线3
该中间体在本合成路线中的序号：(II)Reaction of 4-methylphenol (I) with NaH in DMF and 3-fluorobenzaldehyde (II) yields aldehyde (III), which will be converted into secondary amine (V) via a reductive amination with amine (IV) in presence of NaBH3CN in MeOH and catalytic HOAc. Amine (V) couples with dianhydride (VI) in THF in presence of NMM or alternatively in toluene and Et3N. Final treatment with Na2CO3 in THF yields the desired product.
| 【1】 Sullivan, G.M.; Rosenberg, S.H.; Prasad, R.N.; O'Connor, S.J.; Donner, B.G.; Fakhoury, S.A.; Fung, K.L.; Stout, D.M.; Rockway, T.W.; Baker, W.R.; Shen, W.; Garvey, D.S. (Abbott Laboratories Inc.); Benzene, pyridine, naphthalene or benzophenone derivs. as inhibitors of squalene synthetase and protein farnesyltransferase. WO 9634851 . |
| 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) | 37678 | p-cresol | 106-44-5 | C7H8O | 详情 | 详情 |
| (II) | 18887 | 3-Fluorobenzaldehyde | 456-48-4 | C7H5FO | 详情 | 详情 |
| (III) | 41482 | 3-(4-methylphenoxy)benzaldehyde | 79124-75-7 | C14H12O2 | 详情 | 详情 |
| (IV) | 38253 | 2-ethoxybenzylamine; (2-ethoxyphenyl)methanamine | C9H13NO | 详情 | 详情 | |
| (V) | 41483 | N-(2-ethoxybenzyl)[3-(4-methylphenoxy)phenyl]methanamine; N-(2-ethoxybenzyl)-N-[3-(4-methylphenoxy)benzyl]amine | n/a | C23H25NO2 | 详情 | 详情 |
| (VI) | 41484 | 1H,3H-furo[3,4-f][2]benzofuran-1,3,5,7-tetrone | 89-32-7 | C10H2O6 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(V)The title compound is also prepared by a related method. Indanone (I) is fluorinated by means of N-fluorobenzenesulfonimide in the presence of lithium hexamethyldisilazide, to afford the corresponding fluoro ketone (II). Subsequent dealkylation of the N-benzyl group of (II) is accomplished by treatment with 1-chloroethyl chloroformate, to produce the intermediate carbamate (III), which is then decarboxylated to the secondary amine (IV) in boiling MeOH. Finally, piperidine (IV) is reductively alkylated with 3-fluorobenzaldehyde (V) in the presence of NaBH(OAc)3.
| 【1】 Takeuchi, Y.; Yamanishi, Y.; Sugimoto, H.; Suzuki, N.; Iimura, Y.; Kawakami, Y.; Inoue, A.; Kuriya, Y.; Kosasa, T.; Recent advances in the study of acetylcholinesterase inhibitor "donepezil" (1): Synthesis and structure-activity relationships of fluorine-introduced donepezil and related compounds. 221st ACS Natl Meet (April 1 2001, San Diego) 2001, Abst MEDI 67. |
| 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) | 57510 | 2-[(1-benzyl-4-piperidinyl)methyl]-5,6-dimethoxy-1-indanone | C24H29NO3 | 详情 | 详情 | |
| (II) | 57511 | 2-[(1-benzyl-4-piperidinyl)methyl]-2-fluoro-5,6-dimethoxy-1-indanone | C24H28FNO3 | 详情 | 详情 | |
| (III) | 57512 | 1-chloroethyl 4-[(2-fluoro-5,6-dimethoxy-1-oxo-2,3-dihydro-1H-inden-2-yl)methyl]-1-piperidinecarboxylate | C20H25ClFNO5 | 详情 | 详情 | |
| (IV) | 57513 | 2-fluoro-5,6-dimethoxy-2-(4-piperidinylmethyl)-1-indanone | C17H22FNO3 | 详情 | 详情 | |
| (V) | 18887 | 3-Fluorobenzaldehyde | 456-48-4 | C7H5FO | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(IV)Treatment of substituted pyrimidine (I) with an aqueous solution of methylamine in HOAc/THF provides monomethylamino derivative (II), whose nitro group is hydrogenated over Ni-Raney in MeOH/HOAc to afford 5-amino compound (III). Condensation of (III) with aldehyde (IV) in HOAc/MeOH forms the Schiff base (V), which is converted into substituted purine (VI) by oxidative ring closure with FeCl3 in refluxing EtOH and posterior treatment with HCl in refluxing H2O/THF. Diazotization-substitution reaction of (VI) with diiodomethane, CuI and isoamyl nitrite in THF furnishes 2-iodo compound (VII), which is subjected to a cross-coupling reaction with alkyne (VIII) by means of bistriphenylphosphine palladium dichloride, cuprous iodide and Et3N in THF to afford 2-alkynyl compound (IX). Finally, the desired product is obtained by amination of (IX) with ammonia either in EtOH or in H2O/1,2-dimethoxyethane.
| 【1】 Hoshino, Y.; Harada, H.; Asano, O.; et al.; 2-Alkynyl-8-aryl-9-ethyladenines as novel adenosine receptor antagonists: Their synthesis and structure-activity relationships toward hepatic glucose production induced via agonism of the A2B receptor. J Med Chem 2001, 44, 2, 170. |
| 【2】 Asano, O.; Hoshino, Y.; Kobayashi, S.; Nagata, K.; Harada, H.; Yoshikawa, S.; Nagaoka, J.; Inoue, T.; Horizoe, T.; Yasuda, N.; Murakami, M. (Eisai Co., Ltd.); Purine derivs. and adenosine A2 receptor antagonists serving as preventives/remedies for diabetes. EP 1054012; JP 1999263789; WO 9935147 . |
| 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) | 48994 | N-(4,6-dichloro-5-nitro-2-pyrimidinyl)acetamide | C6H4Cl2N4O3 | 详情 | 详情 | |
| (II) | 48995 | N-[4-chloro-6-(methylamino)-5-nitro-2-pyrimidinyl]acetamide | C7H8ClN5O3 | 详情 | 详情 | |
| (III) | 48996 | N-[5-amino-4-chloro-6-(methylamino)-2-pyrimidinyl]acetamide | C7H10ClN5O | 详情 | 详情 | |
| (IV) | 18887 | 3-Fluorobenzaldehyde | 456-48-4 | C7H5FO | 详情 | 详情 |
| (V) | 48997 | N-[4-chloro-5-[[(E)-(3-fluorophenyl)methylidene]amino]-6-(methylamino)-2-pyrimidinyl]acetamide | C14H13ClFN5O | 详情 | 详情 | |
| (VI) | 48998 | 6-chloro-8-(3-fluorophenyl)-9-methyl-9H-purin-2-amine; 6-chloro-8-(3-fluorophenyl)-9-methyl-9H-purin-2-ylamine | C12H9ClFN5 | 详情 | 详情 | |
| (VII) | 48999 | 6-chloro-8-(3-fluorophenyl)-2-iodo-9-methyl-9H-purine | C12H7ClFIN4 | 详情 | 详情 | |
| (VIII) | 49000 | 1-Ethynyl-1-cyclopentanol; 1-Ethynylcyclopentanol; Cyclopentyl ethynyl carbinol | 17356-19-3 | C7H10O | 详情 | 详情 |
| (IX) | 49001 | 1-[2-[6-chloro-8-(3-fluorophenyl)-9-methyl-9H-purin-2-yl]ethynyl]cyclopentanol | C19H16ClFN4O | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(VI)Condensation of chloropyrimidinone (I) with 3-aminobenzonitrile (II) produces the anilino pyrimidinone (III). This is subsequently chlorinated to chloropyrimidine (IV) by using phosphoryl chloride in the presence of N,N-dimethylaniline and tetraethylammonium chloride. Reduction of the nitro group of (IV) to amine (V) is performed by means of stannous chloride and sodium borohydride. Condensation of diaminopyrimidine (V) with 3-fluorobenzaldehyde (VI), followed by oxidative treatment with ferric chloride, furnishes the purine derivative (VII). Conversion of aminopurine (VII) to the iodo analogue (VIII) is achieved by diazotization with isoamyl nitrite in the presence of cuprous iodide and diiodomethane. Iodopurine (VIII) is then coupled to 1-ethynylcyclohexanol (IX) in the presence of palladium catalyst to give the disubstituted alkyne (X).
| 【1】 Asano, O.; Kawata, T.; Inoue, T.; Horizoe, T.; Yasuda, N.; Nagata, K.; Nagaoka, J.; Kobayashi, S.; Tanaka, I.; Abe, S.; Harada, H.; Murakami, M.; 2-Alkynyl-8-aryladenines possessing an amide moiety: Their synthesis and structure-activity relationships of effects on hepatic glucose production induced via agonism of the A2B adenosine receptor. Bioorg Med Chem 2001, 9, 10, 2709. |
| 【2】 Asano, O.; Hoshino, Y.; Kobayashi, S.; Nagata, K.; Harada, H.; Yoshikawa, S.; Nagaoka, J.; Inoue, T.; Horizoe, T.; Yasuda, N.; Murakami, M. (Eisai Co., Ltd.); Purine derivs. and adenosine A2 receptor antagonists serving as preventives/remedies for diabetes. EP 1054012; JP 1999263789; WO 9935147 . |
| 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) | 57619 | N-(4-chloro-5-nitro-6-oxo-1,6-dihydro-2-pyrimidinyl)acetamide | C6H5ClN4O4 | 详情 | 详情 | |
| (II) | 28662 | 3-aminobenzonitrile | 2237-30-1 | C7H6N2 | 详情 | 详情 |
| (III) | 57620 | N-[4-(3-cyanoanilino)-5-nitro-6-oxo-1,6-dihydro-2-pyrimidinyl]acetamide | C13H10N6O4 | 详情 | 详情 | |
| (IV) | 57621 | N-[4-chloro-6-(3-cyanoanilino)-5-nitro-2-pyrimidinyl]acetamide | C13H9ClN6O3 | 详情 | 详情 | |
| (V) | 57622 | 3-[(2,5-diamino-6-chloro-4-pyrimidinyl)amino]benzonitrile | C11H9ClN6 | 详情 | 详情 | |
| (VI) | 18887 | 3-Fluorobenzaldehyde | 456-48-4 | C7H5FO | 详情 | 详情 |
| (VII) | 57623 | 3-[2-amino-6-chloro-8-(3-fluorophenyl)-9H-purin-9-yl]benzonitrile | C18H10ClFN6 | 详情 | 详情 | |
| (VIII) | 57624 | 3-[6-chloro-8-(3-fluorophenyl)-2-iodo-9H-purin-9-yl]benzonitrile | C18H8ClFIN5 | 详情 | 详情 | |
| (IX) | 57625 | 1-ethynylcyclohexanol | C8H12O | 详情 | 详情 | |
| (X) | 57626 | 3-{6-chloro-8-(3-fluorophenyl)-2-[2-(1-hydroxycyclohexyl)ethynyl]-9H-purin-9-yl}benzonitrile | C26H19ClFN5O | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(XII)The condensation of 3-fluoroaniline (I) with 4-fluorobenzonitrile (II) by means of BCl3 and AlCl3 in xylene at 120 C gives the benzophenone (III), which is reduced with hydrazine and KOH in ethyleneglycol at 200 C to yield the diphenylmethane (IV). The acylation of the NH2 group of (IV) with refluxing formic acid affords the formamide (V), which is cyclized by means of PPA and POCl3 in xylene at 100 C to provide the dibenzazepine (VI). The reduction of (VI) with H2 over Pd/C in THF/methanol gives the corresponding dihydro compound (VII), which is oxidized with 3-phenyl-2-(phenylsulfonyl)oxaziridine (VIII) in dichloromethane to yield the N-oxide (IX). Finally, this compound is cyclized with N-allyl-N,N-dimethylamine (X) by heating in toluene at 100 C to afford the target oxazolidine derivative. Alternatively, the cyclization of 5-fluoro-2-hydroxyaniline (XI) with 3-fluorobenzaldehyde (XII) by means of chloroacetic acid at 100 C in methanol or isopropanol gives 7-fluoro-2-(4-fluorophenyl)-2,4-dihydro-1H-3,1-benzoxazine (XIII), which is reduced with NaBH4 in refluxing ethanol to yield N-(3-fluorobenzyl)-N-[2-(hydroxymethyl)-5-fluorophenyl]amine (XIV). Finally, this compound is cyclized by means of H2SO4 in dichloromethane to afford the previously described dihydro-benzodiazepine (VII), which is worked up as before.
| 【1】 Alonso, J.M.; Alcázar, J.; Andrés, J.I.; et al.; Synthesis and structure-activity relationship of 2-(aminoalkyl)-2,3,3a,8-tetrahydrodibenzo[c,f]isoxazolo[2,3-a]azepine derivatives: A novel series of 5-HT2A/2C receptor antagonists. Part 2. Bioorg Med Chem Lett 2002, 12, 2, 249. |
| 【2】 Sipido, V.K.; Fernandez-Gadea, F.J.; Andres-Gil, J.I.; Meert, T.F.; Gil-Lopetegui, P. (Janssen Pharmaceutica NV); Substd. tetracyclic azepine derivs. which have affinity for 5-HT2 receptors. EP 0789701; JP 1998508308; US 5552399; WO 9614320 . |
| 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) | 20697 | 3-fluoroaniline; 3-fluorophenylamine | 372-19-0 | C6H6FN | 详情 | 详情 |
| (II) | 14144 | 4-Fluorobenzonitrile | 1194-02-1 | C7H4FN | 详情 | 详情 |
| (III) | 54726 | (2-amino-4-fluorophenyl)(4-fluorophenyl)methanone | C13H9F2NO | 详情 | 详情 | |
| (IV) | 54727 | 5-fluoro-2-(4-fluorobenzyl)aniline; 5-fluoro-2-(4-fluorobenzyl)phenylamine | C13H11F2N | 详情 | 详情 | |
| (V) | 54728 | 5-fluoro-2-(4-fluorobenzyl)phenylformamide | C14H11F2NO | 详情 | 详情 | |
| (VI) | 54729 | 3,8-difluoro-11H-dibenzo[b,e]azepine | C14H9F2N | 详情 | 详情 | |
| (VII) | 54730 | 3,8-difluoro-6,11-dihydro-5H-dibenzo[b,e]azepine | C14H11F2N | 详情 | 详情 | |
| (VIII) | 31834 | 3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine;2-(Phenylsulfonyl)-3-phenyloxaziridine;2-Benzenesulfonyl-3-phenyloxaziridine;3-Phenyl-2-phenylsulfonyloxaziridine;3-Phenyl-N-phenylsulfonyloxaziridine;N-(Phenylsulfonyl)phenyloxaziridine;N-Benzenesulfonyl-3-phenyloxaziridine | 63160-13-4 | C13H11NO3S | 详情 | 详情 |
| (IX) | 54731 | 3,8-difluoro-11H-dibenzo[b,e]azepinium-5-olate | C14H9F2NO | 详情 | 详情 | |
| (X) | 54732 | 1-Dimethylamino-2-propene; Allyldimethylamine; N,N-Dimethylallylamine; N-Allyl-N,N-dimethylamine | 2155-94-4 | C5H11N | 详情 | 详情 |
| (XI) | 54733 | 2-amino-4-fluorophenol | C6H6FNO | 详情 | 详情 | |
| (XII) | 18887 | 3-Fluorobenzaldehyde | 456-48-4 | C7H5FO | 详情 | 详情 |
| (XIII) | 54734 | 7-fluoro-2-(3-fluorophenyl)-1,4-dihydro-2H-3,1-benzoxazine | C14H11F2NO | 详情 | 详情 | |
| (XIV) | 54735 | {4-fluoro-2-[(3-fluorobenzyl)amino]phenyl}methanol | C14H13F2NO | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(I)Ethyl 3-fluorocinnamate (III) was prepared by Wittig condensation of 3-fluorobenzaldehyde (I) with phosphorane (II). Conjugate addition of (R)-N-benzyl-alpha-methylbenzylamine (IV) to the unsaturated ester (III) furnished the chiral amino ester (V). The primary amine (VI) was then obtained by hydrogenolysis of the N-benzyl groups in the presence of palladium hydroxyde. Coupling of the known pyrrolidinoneacetic acid (VII) to the amino ester (VI) by means of EDC/HOBt afforded amide (VIII). Finally, saponification of the ethyl ester group of (VIII) led to the corresponding carboxylic acid.
| 【1】 Brashear, K.M.; Hunt, C.A.; Coleman, P.J.; et al.; Non-peptide alphavbeta3 antagonists. Part 3: Identification of potent RGD mimetics incorporating novel beta-amino acids as aspartic acid replacements. Bioorg Med Chem Lett 2002, 12, 1, 31. |
| 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) | 18887 | 3-Fluorobenzaldehyde | 456-48-4 | C7H5FO | 详情 | 详情 |
| (II) | 14182 | ethyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate; (Carbethoxymethylene)triphenylphosphorane | 1099-45-2 | C22H21O2P | 详情 | 详情 |
| (III) | 59701 | Ethyl (E)-3-(3-fluorophenyl)-2-propenoate; Ethyl 3-fluorocinnamate | C11H11FO2 | 详情 | 详情 | |
| (IV) | 47881 | (1R)-N-benzyl-1-phenyl-1-ethanamine; N-benzyl-N-[(1R)-1-phenylethyl]amine | C15H17N | 详情 | 详情 | |
| (V) | 59702 | ethyl (3S)-3-{benzyl[(1R)-1-phenylethyl]amino}-3-(3-fluorophenyl)propanoate | C26H28FNO2 | 详情 | 详情 | |
| (VI) | 59703 | ethyl (3S)-3-amino-3-(3-fluorophenyl)propanoate | C11H14FNO2 | 详情 | 详情 | |
| (VII) | 59704 | 2-{(3S)-2-oxo-3-[2-(5,6,7,8-tetrahydro[1,8]naphthyridin-2-yl)ethyl]pyrrolidinyl}acetic acid | C16H21N3O3 | 详情 | 详情 | |
| (VIII) | 59705 | ethyl (3S)-3-(3-fluorophenyl)-3-[(2-{(3S)-2-oxo-3-[2-(5,6,7,8-tetrahydro[1,8]naphthyridin-2-yl)ethyl]pyrrolidinyl}acetyl)amino]propanoate | C27H33FN4O4 | 详情 | 详情 |