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【结 构 式】 
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【分子编号】18922 【品名】4-formylbenzoic acid 【CA登记号】619-66-9 |
【 分 子 式 】C8H6O3 【 分 子 量 】150.13384 【元素组成】C 64% H 4.03% O 31.97% |
合成路线1
该中间体在本合成路线中的序号：(XI)In a different synthetic strategy, 4-formylbenzoic acid (XI) was first coupled to diethylamine by means of EDC to yield N,N-diethyl 4-formylbenzamide (XII). The intermediate iminium salt produced by condensation between aldehyde (XII) and the chiral piperazine (IX) was then isolated as the benzotriazole adduct (XIII). Displacement of the benzotriazolyl group by the Grignard reagent (XIV) produced the title diastereoisomer as the major product, which was further enriched by recrystallization from acetonitrile/water.
| 【1】 Report from ASCO 2002 - Docetaxel improves survival in node-positive early-stage breast cancer patients. Oncology (USA) 2002, 16, 8, 1054. |
| 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) | 20690 | (2R,5S)-1-allyl-2,5-dimethylpiperazine | C9H18N2 | 详情 | 详情 | |
| (XI) | 18922 | 4-formylbenzoic acid | 619-66-9 | C8H6O3 | 详情 | 详情 |
| (XII) | 45932 | N,N-diethyl-4-formylbenzamide | C12H15NO2 | 详情 | 详情 | |
| (XIII) | 56251 | 4-[[(2S,5R)-4-allyl-2,5-dimethylpiperazinyl](1H-1,2,3-benzotriazol-1-yl)methyl]-N,N-diethylbenzamide | C27H36N6O | 详情 | 详情 | |
| (XIV) | 35984 | bromo(3-methoxyphenyl)magnesium | 36282-40-3 | C7H7BrMgO | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)The target FR-165649 has been obtained by condensation of cinnamic acid (V) with amine (XIII) using EDC and HOBt as coupling agents. The two intermediates (V) and (XIII) have been obtained as follows: 1) Wittig reaction of 4-formylbenzoic acid (I) and methyl (triphenylphosphoranylidene)acetate (II) in THF gave methyl 4-carboxycinnamate (III), which was converted into amide (IV) by reaction with methylamine hydrochloride in the presence of EDC and HOBt. Further hydrolysis of the ester group with NaOH provided 4-(methylcarbamoyl)cinnamic acid (V). 2) The alkylation of 8-hydroxy-2-methylquinoline (VI) with benzylic chloride (VII) in the presence of NaH and a catalytic amount of tetrabutylammonium iodide in DMF afforded ether (VIII). Subsequent reduction of the nitro group with iron powder and HCl in refluxing aqueous methanol gave amine (IX), which was coupled with phthalimidoacetyl chloride (X) in the presence of DMAP in a mixture of N-methylpyrrolidone and pyridine to yield amide (XI). Then, alkylation at the amide N with CH3I and NaH provided (XII), and further hydrazinolysis of the phthalimido group yielded the primary amine (XIII). Finally, the target amide was obtained by condensation of cinnamic acid (V) with amine (XIII) using EDC and HOBt as the coupling reagents.
| 【1】 Oku, T.; Kayakiri, H.; Satoh, S.; Abe, Y.; Sawada, Y.; Inoue, T.; Tanaka, H. (Fujisawa Pharmaceutical Co., Ltd.); Pyridopyrimidones, quinolines and fused N-heterocycles as bradykinin antagonists. EP 0807105; JP 1998507764; WO 9613485 . |
| 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) | 18922 | 4-formylbenzoic acid | 619-66-9 | C8H6O3 | 详情 | 详情 |
| (II) | 14689 | Methyl (triphenylphosphoranylidene)acetate; (methoxycarbonylmethylene)triphenylphosphorane；Methyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate | 2605-67-6 | C21H19O2P | 详情 | 详情 |
| (III) | 18924 | 4-[(E)-3-methoxy-3-oxo-1-propenyl]benzoic acid | C11H10O4 | 详情 | 详情 | |
| (IV) | 18925 | methyl (E)-3-[4-[(methylamino)carbonyl]phenyl]-2-propenoate | C12H13NO3 | 详情 | 详情 | |
| (V) | 18926 | (E)-3-[4-[(methylamino)carbonyl]phenyl]-2-propenoic acid | C11H11NO3 | 详情 | 详情 | |
| (VI) | 18598 | 2-methyl-8-quinolinol | 826-81-3 | C10H9NO | 详情 | 详情 |
| (VII) | 18928 | 1,3-dichloro-2-(chloromethyl)-4-nitrobenzene | C7H4Cl3NO2 | 详情 | 详情 | |
| (VIII) | 18929 | 2,6-dichloro-3-nitrobenzyl 2-methyl-8-quinolinyl ether; 8-[(2,6-dichloro-3-nitrobenzyl)oxy]-2-methylquinoline | C17H12Cl2N2O3 | 详情 | 详情 | |
| (IX) | 18930 | 2,4-dichloro-3-[[(2-methyl-8-quinolinyl)oxy]methyl]phenylamine; 2,4-dichloro-3-[[(2-methyl-8-quinolinyl)oxy]methyl]aniline | C17H14Cl2N2O | 详情 | 详情 | |
| (X) | 10278 | 2-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)acetyl chloride | 6780-38-7 | C10H6ClNO3 | 详情 | 详情 |
| (XI) | 18932 | N-(2,4-dichloro-3-[[(2-methyl-8-quinolinyl)oxy]methyl]phenyl)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)acetamide | C27H19Cl2N3O4 | 详情 | 详情 | |
| (XII) | 18599 | N-(2,4-dichloro-3-[[(2-methyl-8-quinolinyl)oxy]methyl]phenyl)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-N-methylacetamide | C28H21Cl2N3O4 | 详情 | 详情 | |
| (XIII) | 18600 | 2-amino-N-(2,4-dichloro-3-[[(2-methyl-8-quinolinyl)oxy]methyl]phenyl)-N-methylacetamide | C20H19Cl2N3O2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)The common intermediate (IV) was obtained by coupling of 4-formylbenzoic acid (I) with methyl 2-L-amino-5-phthalimidopentanoate.HCl (III) via the mixed anhydride (II).
| 【1】 Rosowsky, A.; Vaidya, C.M.; Wright, J.E.; Forsch, R.A.; Bader, H.; Analogues of the potent nonpolyglutamatable antifolate Nalpha-(4-amino-4-deoxypteroyl)-Ndelta-hemiphthaloyl-L-ornithine (PT523) with modifications in the side chain, p-aminobenzoyl moiety, or 9,10-bridge: Synthesis and in vitro antitumor activity. J Med Chem 2000, 43, 8, 1620. |
| 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) | 18922 | 4-formylbenzoic acid | 619-66-9 | C8H6O3 | 详情 | 详情 |
| (II) | 42874 | C13H14O5 | 详情 | 详情 | ||
| (III) | 42875 | methyl (2S)-2-amino-5-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)pentanoate | C14H16N2O4 | 详情 | 详情 | |
| (IV) | 42876 | methyl (2S)-5-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-2-[(4-formylbenzoyl)amino]pentanoate | C22H20N2O6 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XIV)Conversion of 4-hydroxy-L-proline (I) into the corresponding cis-N-Boc-4-hydroxy-L-proline methyl ester (II) is performed as follows: Treatment of (I) with SOCl2 in MeOH followed by reaction with Boc2O and Et3N in EtOAc affords the corresponding protected acid chloride; then the methyl ester moiety is formed under Mitsunobu conditions with formic acid, DIAD and PPh3 in THF followed by treatment with NaOH in MeOH. The OH group of (II) is converted into thioether (IV) by first mesylation with MsCl and Et3N in toluene followed by reaction with triphenylmethanethiol (III) in THF in the presence of NaH. Reduction of the methyl ester of (IV) with LiBH4 in THF provides alcohol (V), which is mesylated with MsCl and Et3N in THF and then treated with NaN3 and HMPA to furnish azide (VI). Boc removal in (VI) is performed by treatment with HCl in EtOAc to give derivative (VII), which is then converted into compound (VIII) by condensation with 2-(2,4-difluorobenzoyl)benzoic acid (XI) by means of water-soluble carbodiimide (WSC) and HOBt in DMF (compound (XI) can be obtained by Friedel-Crafts reaction between phthalic anhydride (IX) and 1,3-difluorobenzene (X) in the presence of AlCl3). Reduction of the azido moiety of (VIII) by means of SnCl2 and NaOH in EtOH furnishes amine (XII), which is finally converted into the desired product by condensation with carboxylic acid (XIII) by means of WSC and HOBt (derivative (XIII) can be obtained by Knoevenagel reaction between 4-formyl-benzoic acid (XIV) and 2,4-thiazolidinedione (XV) in refluxing 2-methoxyethanol in the presence of piperidine).
| 【1】 Nishi, K.; Seno, K.; Ono, T.; Yamada, K.; Murakami, Y.; Nakamoto, S.; Okuno, T.; Pyrrolidine inhibitors of human cytosolic phospholipase A2. Part 2: Synthesis of potent and crystallized 4-triphenylmethylthio derivative "pyrrophenone". Bioorg Med Chem Lett 2001, 11, 4, 587. |
| 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) | 14489 | (2S,4R)-4-hydroxytetrahydro-1H-pyrrole-2-carboxylic acid; L-Hydroxyproline | 51-35-4 | C5H9NO3 | 详情 | 详情 |
| (II) | 15783 | 1-(tert-butyl) 2-methyl (2S,4S)-4-hydroxytetrahydro-1H-pyrrole-1,2-dicarboxylate | C11H19NO5 | 详情 | 详情 | |
| (III) | 18831 | tritylhydrosulfide; triphenylmethanethiol | 3695-77-0 | C19H16S | 详情 | 详情 |
| (IV) | 50070 | 1-(tert-butyl) 2-methyl (2S,4R)-4-(tritylsulfanyl)-1,2-pyrrolidinedicarboxylate | C30H33NO4S | 详情 | 详情 | |
| (V) | 50071 | tert-butyl (2S,4R)-2-(hydroxymethyl)-4-(tritylsulfanyl)-1-pyrrolidinecarboxylate | C29H33NO3S | 详情 | 详情 | |
| (VI) | 50072 | tert-butyl (2S,4R)-2-(azidomethyl)-4-(tritylsulfanyl)-1-pyrrolidinecarboxylate | C29H32N4O2S | 详情 | 详情 | |
| (VII) | 50073 | (2S,4R)-2-(azidomethyl)-4-(tritylsulfanyl)pyrrolidine; (3R,5S)-5-(azidomethyl)pyrrolidinyl trityl sulfide | C24H24N4S | 详情 | 详情 | |
| (VIII) | 50074 | [(2S,4R)-2-(azidomethyl)-4-(tritylsulfanyl)pyrrolidinyl][2-(2,4-difluorobenzoyl)phenyl]methanone | C38H30F2N4O2S | 详情 | 详情 | |
| (IX) | 11900 | 2-Benzofuran-1,3-dione;1,2-Benzenedicarboxylic Anhydride;1,2-BENZENE DICARBOXYLIC ACID ANHYDRIDE;1,2-BENZENEDICARBONIC ACID, ANHYDRIDE;1,3-DIOXOPHTHALAN;1,3-ISOBENZOFURANDIONE;o-phthalic anhydride; Phthalic anhydride | 85-44-9 | C8H4O3 | 详情 | 详情 |
| (X) | 13095 | m-Difluorobenzene; 1,3-Difluorobenzene | 372-18-9 | C6H4F2 | 详情 | 详情 |
| (XI) | 41002 | 2-(2,4-difluorobenzoyl)benzoic acid | C14H8F2O3 | 详情 | 详情 | |
| (XII) | 50075 | [(2S,4R)-2-(aminomethyl)-4-(tritylsulfanyl)pyrrolidinyl][2-(2,4-difluorobenzoyl)phenyl]methanone | C38H32F2N2O2S | 详情 | 详情 | |
| (XIII) | 50076 | 4-[(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]benzoic acid | C11H7NO4S | 详情 | 详情 | |
| (XIV) | 18922 | 4-formylbenzoic acid | 619-66-9 | C8H6O3 | 详情 | 详情 |
| (XV) | 10883 | 1,3-Thiazolane-2,4-dione; 2,4-Thiazolidinedione | 2295-31-0 | C3H3NO2S | 详情 | 详情 |