|
【结 构 式】 
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【分子编号】15216 【品名】N-(3-Bromopropyl)phthalimide; 2-(3-bromopropyl)-1H-isoindole-1,3(2H)-dione 【CA登记号】5460-29-7 |
【 分 子 式 】C11H10BrNO2 【 分 子 量 】268.10994 【元素组成】C 49.28% H 3.76% Br 29.8% N 5.22% O 11.93% |
合成路线1
该中间体在本合成路线中的序号：(IV)The reductocondensation of piperidine (I) with 3-hydroxybenzaldehyde (II) by means of sodium borohydride in ethanol gives 3-(1-piperidylmethyl)phenol (III), which is then condensed with N-(3-bromopropyl)phthalimide (IV) by means of NaH in DMF yielding N-[3-[3-(1-piperidylmethyl)phenoxy]propyl]phthalimide (V). The hydrolysis of (V) with hydrazine in ethanol affords 3-[3-(1-piperidylmethyl)phenoxy]propylamine (VI), which is acylated with hydroxyacetic acid (VII) at 200 C giving N-[3-[3-(1-piperidylmethyl)phenoxy]propyl]hydroxyacetamide (VIII). Finally, this compound is acetylated with acetic anhydride at 100 C.
| 【1】 Shibata, K.; et al. (Teikoku Hormone Manufacturing Co., Ltd.); Antiulcer phenoxypropylamine derivatives. EP 0024510; JP 81115750; US 4293557 . |
| 【2】 Castaner, J.; Serradell, M.N.; TZU-0460. Drugs Fut 1985, 10, 12, 995. |
| 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) | 10158 | Piperidine | 110-89-4 | C5H11N | 详情 | 详情 |
| (II) | 28537 | 3-hydroxybenzaldehyde | 100-83-4 | C7H6O2 | 详情 | 详情 |
| (III) | 29854 | 3-(1-piperidinylmethyl)phenol | C12H17NO | 详情 | 详情 | |
| (IV) | 15216 | N-(3-Bromopropyl)phthalimide; 2-(3-bromopropyl)-1H-isoindole-1,3(2H)-dione | 5460-29-7 | C11H10BrNO2 | 详情 | 详情 |
| (V) | 29855 | 2-[2-[3-(1-piperidinylmethyl)phenoxy]ethyl]-1H-isoindole-1,3(2H)-dione | C22H24N2O3 | 详情 | 详情 | |
| (VI) | 16105 | 3-[3-(piperidinomethyl)phenoxy]-1-propanamine; 3-[3-(piperidinomethyl)phenoxy]propylamine | C15H24N2O | 详情 | 详情 | |
| (VII) | 29856 | 2-hydroxyacetic acid;glycolic acid | 79-14-1 | C2H4O3 | 详情 | 详情 |
| (VIII) | 29857 | 2-hydroxy-N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]acetamide | C17H26N2O3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(X)A new synthesis of MKC-242 has been described: The tosylation of 2,2-dimethyl-1,3-dioxolane-4(R)-methanol (I) with tosyl chloride in pyridine gives the expected tosylate (II), which is condensed with pyrocatechol monobenzyl ether (III) by means of NaH in N-methylpyrrolidone (NMP) yielding 4(S)-(2-benzyloxyphenoxymethyl)-2,2-dimethyl-1,3-dioxolane (IV). The hydrolysis of the dioxolane ring with hot acetic acid affords the diol (V), which is tosylated with tosyl chloride, triethylamine and dimethylaminopyridine (DMAP) in dichloromethane to give the ditosylate (VI). The debenzylation of (VI) with H2 over Pd/C in methanol/ethyl acetate yields the phenol (VII), which is cyclized by means of K2CO3 in NMP affording 2(R)-(tosyloxymethyl)-1,4-benzodioxane (VIII). Finally, this compound is condensed with 3-(1,3-benzodioxol-5-yloxy)propylamine (IX) by means of ethyl diisopropylamine in NMP. The amine (IX) used as second starting compound has been obtained as follows: The condensation of N-(3-bromopropyl)phthalimide (X) with 5-hydroxy-1,3-benzodioxole (XI) by means of NaH in hot NMP gives N-[3-(1,3-benzodioxol-5-yloxy)propyl]phthalimide (XII), which is then treated with hydrazine in refluxing methanol to obtain amine (IX).
| 【1】 Sugano, M.; Saito, K.; Yamabe, H.; Chaki, H.; Abe, M.; Tabata, R.; Synthesis and 5-HT1A affinity of an optically active benzodioxane derivative MKC-242; a novel anxiolytic and antidepressant agent. 214th ACS Natl Meet (Sept. 7-11, Las Vegas) 1997, Abst MEDI 019. |
| 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) | 12698 | [(4R)-2,2-Dimethyl-1,3-dioxolan-4-yl]methanol | 14347-78-5 | C6H12O3 | 详情 | 详情 |
| (II) | 15208 | (S)-(+)-2,2-Dimethyl-4-(hydroxymethyl)-1,3-dioxolane-p-toluenesulfonate; [(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl 4-methylbenzenesulfonate | 23735-43-5 | C13H18O5S | 详情 | 详情 |
| (III) | 15209 | Phenol, 2-(phenylmethoxy)-; 2-(benzyloxy)phenol | 6272-38-4 | C13H12O2 | 详情 | 详情 |
| (IV) | 15210 | benzyl 2-[[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy]phenyl ether; (4R)-4-[[2-(benzyloxy)phenoxy]methyl]-2,2-dimethyl-1,3-dioxolane | C19H22O4 | 详情 | 详情 | |
| (V) | 15211 | (2S)-3-[2-(benzyloxy)phenoxy]-1,2-propanediol | C16H18O4 | 详情 | 详情 | |
| (VI) | 15212 | (1S)-2-[2-(benzyloxy)phenoxy]-1-[(4-methylphenoxy)methyl]ethyl 4-methylbenzenesulfonate | C30H30O6S | 详情 | 详情 | |
| (VII) | 15213 | (1S)-2-(2-hydroxyphenoxy)-1-[(4-methylphenoxy)methyl]ethyl 4-methylbenzenesulfonate | C23H24O6S | 详情 | 详情 | |
| (VIII) | 15214 | (2S)-2-[(4-methylphenoxy)methyl]-2,3-dihydro-1,4-benzodioxine; (2S)-2,3-dihydro-1,4-benzodioxin-2-ylmethyl 4-methylphenyl ether | C16H16O3 | 详情 | 详情 | |
| (IX) | 15206 | 3-(1,3-benzodioxol-5-yloxy)-1-propanamine; 3-(1,3-benzodioxol-5-yloxy)propylamine | C10H13NO3 | 详情 | 详情 | |
| (X) | 15216 | N-(3-Bromopropyl)phthalimide; 2-(3-bromopropyl)-1H-isoindole-1,3(2H)-dione | 5460-29-7 | C11H10BrNO2 | 详情 | 详情 |
| (XI) | 10985 | 1,3-Benzodioxol-5-ol; Sesamol | 533-31-3 | C7H6O3 | 详情 | 详情 |
| (XII) | 15218 | 2-[3-(1,3-benzodioxol-5-yloxy)propyl]-1H-isoindole-1,3(2H)-dione | C18H15NO5 | 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 condensation of 2-nitroimidazole (I) with N-(3-bromopropyl)phthalimide (II) by means of NaH in DMSO gives N-[3-(2-nitroimidazol-1-yl)propyl]phthalimide (III), which is treated with hydrazine in ethanol/water to yield 3-(2-nitroimidazol-1-yl)propylamine (IV). Finally this amine is condensed with 9-chloroacridine by means of TEA.
| 【1】 Bloomer, W.D.; Papadopoulou, M.V.; Nitroheterocyclic-linked acridines as DNA-targeting bioreductive agents. Drugs Fut 1993, 18, 3, 231. |
| 【2】 DeCarneri, I.; Giraldi, P.N.; Mariotti, V.; Studies on antiprotozoans. Synthesis and biological activity of some styrylimidazole derivatives. J Med Chem 1968, 11, 60-70. |
| 【3】 Adams, G.E.; Ahmed, I.; Stratford, I.J. (Gerald Edward Adams; Ian James Stratford; Israr Ahmed); Bis(nitro-1-imidazolyl alkylamine) platinum complexes useful in radiotheraphy or chemotherapy. GB 2131020 . |
| 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) | 10145 | 2-Nitro-1H-imidazole; 2-Nitroimidazole | 527-73-1 | C3H3N3O2 | 详情 | 详情 |
| (II) | 15216 | N-(3-Bromopropyl)phthalimide; 2-(3-bromopropyl)-1H-isoindole-1,3(2H)-dione | 5460-29-7 | C11H10BrNO2 | 详情 | 详情 |
| (III) | 41281 | 2-[3-(2-nitro-1H-imidazol-1-yl)propyl]-1H-isoindole-1,3(2H)-dione | C14H12N4O4 | 详情 | 详情 | |
| (IV) | 41282 | 3-(2-nitro-1H-imidazol-1-yl)-1-propanamine; 3-(2-nitro-1H-imidazol-1-yl)propylamine | C6H10N4O2 | 详情 | 详情 | |
| (V) | 32672 | 9-chloroacridine | 1207-69-8 | C13H8ClN | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(II)The alkylation of 3-hydroxybenzaldehyde (I) with N-(3-bromopropyl)phthalimide (II) in the presence of NaOMe leads to 3-(phthalimidopropoxy)benzaldehyde (III). The reductive alkylation of piperidine with aldehyde (III) in the presence of formic acid gives N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]phthalimide (IV), which is converted to N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]amine (V) by treatment with 6N HCl. Condensation of (V) with glycolic acid in boiling xylene provides N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]-2-hydroxyacetamide (VI), which is complexed with bismuth (+3) citrate (VII) in boiling water.
| 【1】 Petkov, O.; Lytakov, G.; Taskov, M.; Savov, E.; Kostev, V.; Tsvetkova, E.; Nikolov, G.; Atanassova, R.; Ivanov, C.; Synthesis, gastroprotective, antisecretory and anti-Helicobacter effect of +[3(3-(1-piperidinylmethyl)phenoxy)propyl]hydroxyacetamide-2-hydroxypropane-1,2,3-tricarboxylate-bismuth(3+) complex (MX1). J Pharm Pharmacol 1996, 3, 3, 297-301. |
| 【2】 N-(3-(3-(1-Piperidinylmethyl)phenoxy)propyl)propenetricarboxylate bismuth (3+) complex and the method for preparation. WO 9509162 . |
| 【3】 Mondeshka, D.; Spassov, G.; Krushkov, I.; Ivanov, C.; Marazova, K.; Roxatidine Bismuth Citrate. Drugs Fut 2000, 25, 5, 462. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 10158 | Piperidine | 110-89-4 | C5H11N | 详情 | 详情 | |
| (I) | 28537 | 3-hydroxybenzaldehyde | 100-83-4 | C7H6O2 | 详情 | 详情 |
| (II) | 15216 | N-(3-Bromopropyl)phthalimide; 2-(3-bromopropyl)-1H-isoindole-1,3(2H)-dione | 5460-29-7 | C11H10BrNO2 | 详情 | 详情 |
| (III) | 35289 | 3-[3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propoxy]benzaldehyde | C18H15NO4 | 详情 | 详情 | |
| (IV) | 35290 | 2-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]-1H-isoindole-1,3(2H)-dione | C23H26N2O3 | 详情 | 详情 | |
| (V) | 16105 | 3-[3-(piperidinomethyl)phenoxy]-1-propanamine; 3-[3-(piperidinomethyl)phenoxy]propylamine | C15H24N2O | 详情 | 详情 | |
| (VI) | 29857 | 2-hydroxy-N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]acetamide | C17H26N2O3 | 详情 | 详情 | |
| (VII) | 13855 | bismuth(3+) 2-hydroxy-1,2,3-propanetricarboxylate; Bismuth Citrate | 813-93-4 | C6H5BiO7 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(II)OP C-33509 has been obtained by coupling imidazolecarboxamide (VI) with amine (IX) in refluxing CHCl3. The intermediates (VI) and (IX) have been obtained as follows: 1) Alkylation of 6-hydroxycarbostyril (I) with N-(3-bromopropyl)- phthalimide (II) in the presence of K2CO3 in DMF furnished the phthalimidopropyl ether (III). Subsequent hydrazinolysis of the phthalimide in refluxing EtOH provided the primary amine (IV). Then, the imidazolecarboxamide (VI) was obtained by treating amine (IV) with 1,1'-carbonyldiimidazole (V) and two equivalents of imidazole in DMSO. 2) Ring opening of 1,2 epoxycyclohexane (VII) with cyclopropylamine (VIII) gave the racemic trans aminoalcohol. Resolution of enantiomers (IX) and (X) was accomplished by esterification with (S)-mandelic acid (XI), followed by chromatographic separation of the diastereomeric esters. Hydrolysis of the desired ester (XII) then provided optically pure aminoalcohol (IX). Finally, the target urea derivative was obtained by coupling imidazolyl urea (VI) with amine (IX) in refluxing chloroform.
| 【1】 Koga, Y.; Kihara, Y.; Okada, M.; Inoue, Y.; Tochizawa, S.; Toga, K.; Tachibana, K.; Kimura, Y.; Nishi, T.; Hidaka, H.; 2(1H)- Quinoline derivatives as novel anti-arteriostenotic agents showing anti-thrombotic and anti-hyperplastic activities. Bioorg Med Chem Lett 1998, 8, 12, 1471. |
| 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) | 13913 | 6-Hydroxy-2(1H)-quinolinone | C9H7NO2 | 详情 | 详情 | |
| (II) | 15216 | N-(3-Bromopropyl)phthalimide; 2-(3-bromopropyl)-1H-isoindole-1,3(2H)-dione | 5460-29-7 | C11H10BrNO2 | 详情 | 详情 |
| (III) | 18912 | 2-[3-[(2-oxo-1,2-dihydro-6-quinolinyl)oxy]propyl]-1H-isoindole-1,3(2H)-dione | C20H16N2O4 | 详情 | 详情 | |
| (IV) | 18913 | 6-(3-aminopropoxy)-2(1H)-quinolinone | C12H14N2O2 | 详情 | 详情 | |
| (V) | 11353 | 1,1'-Carbonyldiimidazole; Di(1H-imidazol-1-yl)methanone; N,N-Carbonyldiimidazole; 1,1'-Carbonylbis(1H-imidazole) | 530-62-1 | C7H6N4O | 详情 | 详情 |
| (VI) | 18915 | N-[3-[(2-oxo-1,2-dihydro-6-quinolinyl)oxy]propyl]-1H-imidazole-1-carboxamide | C16H16N4O3 | 详情 | 详情 | |
| (VII) | 17986 | 7-oxabicyclo[4.1.0]heptane; cyclohexene oxide | 286-20-4 | C6H10O | 详情 | 详情 |
| (VIII) | 12263 | Cyclopropylamine; Cyclopropanamine | 765-30-0 | C3H7N | 详情 | 详情 |
| (IX) | 18918 | (1R,2R)-2-(cyclopropylamino)cyclohexanol | C9H17NO | 详情 | 详情 | |
| (X) | 18919 | (1S,2S)-2-(cyclopropylamino)cyclohexanol | C9H17NO | 详情 | 详情 | |
| (XI) | 12563 | (2S)-2-Hydroxy-2-phenylethanoic acid; S-(+)-Mandelic acid | 17199-29-0 | C8H8O3 | 详情 | 详情 |
| (XII) | 18921 | (1R,2R)-2-(cyclopropylamino)cyclohexyl (2S)-2-hydroxy-2-phenylethanoate | 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)The intermediate amine (IV) was prepared by alkylation of 4-cyano-4-phenylpiperidine (I) with N-(3-bromopropyl)phthalimide (II), followed by hydrazinolysis of the substituted phthalimide (III).
| 【1】 Wong, W.C.; Lagu, B.; Nagarathnam, D.; Marzabadi, M.R.; Gluchowski, C. (Synaptic Pharmaceutical Corp.); Dihydropyrimidines and uses thereof. EP 1021185; JP 2000506904; WO 9742956 . |
| 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) | 43077 | 4-phenyl-4-piperidinecarbonitrile | 40481-13-8 | C12H14N2 | 详情 | 详情 |
| (II) | 15216 | N-(3-Bromopropyl)phthalimide; 2-(3-bromopropyl)-1H-isoindole-1,3(2H)-dione | 5460-29-7 | C11H10BrNO2 | 详情 | 详情 |
| (III) | 43078 | 1-[3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propyl]-4-phenyl-4-piperidinecarbonitrile | C23H23N3O2 | 详情 | 详情 | |
| (IV) | 43079 | 1-(3-aminopropyl)-4-phenyl-4-piperidinecarbonitrile | C15H21N3 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(III)Catalytic hydrogenation of tetrahydropyridine (I) produced piperidine (II). Alkylation of (II) with N-(3-bromopropyl)phthalimide (III) gave (IV). Subsequent hydrazinolysis of the phthalimido group of (IV) yielded amine (V). In a related procedure, piperidine (II) was alkylated with N-Boc-3-bromopropylamine (VI) to give (VII), which was deprotected with HCl in EtOAc to give the diamino precursor (V).
| 【1】 Rittle, K.; et al.; Dihydropyrimidinone C-5 amides as potent and selective alpha1A receptor antagonists. 219th ACS Natl Meet (March 26 2000, San Francisco) 2000, Abst MEDI 90. |
| 【2】 Selnick, H.G.; Barrow, J.C.; Nanterment, P.G.; et al.; In vitro and in vivo evaluation of dihydropyrimidinone C-5 amides as potent and selective alpha1A receptor antagonists for the treatment of benign prostatic hyperplasia. J Med Chem 2000, 43, 14, 2703. |
| 【3】 Selnick, H.G.; Nantermet, P.G.; Barrow, J.C. (Merck & Co., Inc.); alpha1a Adrenergic receptor antagonists. WO 0006565 . |
| 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) | 23465 | 4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine | 1978-59-2 | C11H12FN | 详情 | 详情 |
| (II) | 39299 | 4-(4-fluorophenyl)piperidine | 37656-48-7 | C11H14FN | 详情 | 详情 |
| (III) | 15216 | N-(3-Bromopropyl)phthalimide; 2-(3-bromopropyl)-1H-isoindole-1,3(2H)-dione | 5460-29-7 | C11H10BrNO2 | 详情 | 详情 |
| (IV) | 39300 | 2-[3-[4-(4-fluorophenyl)-1-piperidinyl]propyl]-1H-isoindole-1,3(2H)-dione | C22H23FN2O2 | 详情 | 详情 | |
| (V) | 39302 | 3-[4-(4-fluorophenyl)-1-piperidinyl]propylamine; 3-[4-(4-fluorophenyl)-1-piperidinyl]-1-propanamine | C14H21FN2 | 详情 | 详情 | |
| (VI) | 37752 | tert-butyl 3-bromopropylcarbamate | C8H16BrNO2 | 详情 | 详情 | |
| (VII) | 39301 | tert-butyl 3-[4-(4-fluorophenyl)-1-piperidinyl]propylcarbamate | C19H29FN2O2 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(XVIII)Addition of 4-fluorophenylmagnesium bromide (XIII) to 1-benzyl-4-piperidinone (XII) afforded carbinol (XIV), which was dehydrated to the tetrahydropyridine (XV) by treatment with p-toluenesulfonic acid in refluxing toluene. Hydrogenation of the olefin (XV) with concomitant benzyl group hydrogenolysis gave 4-(4-fluorophenyl)piperidine (XVI) (1). This compound was also obtained by catalytic hydrogenation of the commercially available 4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine (XVII). Alkylation of piperidine (XVI) with N-(3-bromopropyl)phthalimide (XVIII) provided adduct (XIX), which was subjected to hydrazinolysis in refluxing MeOH to furnish the primary amine (XX). Deprotonation of oxazolidine (IX) with n-butyllithium in THF at -78 C, followed by condensation with p-nitrophenyl chloroformate, gave the p-nitrophenoxycarbonyl derivative (XXI). This was finally coupled with amine (XX) to furnish the title carboxamide.
| 【1】 Tian, D.; Jeon, Y.; Lagu, B.; et al.; De novo design of a novel oxazolidinone analogue as a potent and selective alpha1A adrenergic receptor antagonist with high oral bioavailability. J Med Chem 2000, 43, 15, 2775. |
| 【2】 Broten, T.P.; Nichtberger, S.A.; Siegl, P.K.S. (Merck & Co., Inc.); Combination therapy for the treatment of benign prostatic hyperplasia. WO 9948530 . |
| 【3】 Marzabadi, M.R.; Wong, W.C.; Gluchowski, C.; Tian, D.; Nagarathnam, D.; Lagu, B.; Dhar, T.G.M.; Jeon, Y.T. (Synaptic Pharmaceutical Corp.); Heterocyclic substd. piperidines and uses thereof. EP 0988295; WO 9857940 . |
| 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) | 43324 | (4S,5S)-4-(3,4-difluorophenyl)-5-methyl-1,3-oxazolidin-2-one | C10H9F2NO2 | 详情 | 详情 | |
| (XII) | 15720 | 1-benzyltetrahydro-4(1H)-pyridinone; 1-Benzyl-4-piperidone; N-Benzyl-4-piperidone; 1-(benzyl)-4-piperidinone; 1-benzylpiperidin-4-one; 1-(benzyl)piperidin-4-one | 3612-20-2 | C12H15NO | 详情 | 详情 |
| (XIII) | 13643 | 4-fluorophenyl magnesium bromide;Bromo(4-fluorophenyl)magnesium;bromo(p-fluorophenyl)Magnesium;p-Fluorophenylmagnesium bromide | 352-13-6 | C6H4BrFMg | 详情 | 详情 |
| (XIV) | 15722 | 1-benzyl-4-(4-fluorophenyl)-4-piperidinol | C18H20FNO | 详情 | 详情 | |
| (XV) | 43327 | 1-benzyl-4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine | C18H18FN | 详情 | 详情 | |
| (XVI) | 39299 | 4-(4-fluorophenyl)piperidine | 37656-48-7 | C11H14FN | 详情 | 详情 |
| (XVII) | 23465 | 4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine | 1978-59-2 | C11H12FN | 详情 | 详情 |
| (XVIII) | 15216 | N-(3-Bromopropyl)phthalimide; 2-(3-bromopropyl)-1H-isoindole-1,3(2H)-dione | 5460-29-7 | C11H10BrNO2 | 详情 | 详情 |
| (XIX) | 39300 | 2-[3-[4-(4-fluorophenyl)-1-piperidinyl]propyl]-1H-isoindole-1,3(2H)-dione | C22H23FN2O2 | 详情 | 详情 | |
| (XX) | 39302 | 3-[4-(4-fluorophenyl)-1-piperidinyl]propylamine; 3-[4-(4-fluorophenyl)-1-piperidinyl]-1-propanamine | C14H21FN2 | 详情 | 详情 | |
| (XXI) | 43328 | 4-nitrophenyl (4S,5S)-4-(3,4-difluorophenyl)-5-methyl-2-oxo-1,3-oxazolidine-3-carboxylate | C17H12F2N2O6 | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(II)The alkylation of 4-methylimidazole (I) with N-(3-bromopropyl)phthalimide (II) produced a mixture of N-alkylated regioisomers (III) and (IV). After selective derivatization of the undesired 5-methyl isomer (III) with trityl chloride, the 4-methyl derivative was isolated by flash chromatography and subsequently subjected to phthaloyl group hydrazinolysis to yield amine (V). Reductive condensation of amine (V) with benzaldehyde (VI) in the presence of NaBH4 afforded the N-benzyl amine (VII).
| 【1】 Guzi, T.; Taveras, A.G.; Ferreira, J.A.; Desai, J.A.; Wang, J.J.S.; Lalwani, T.; Alvarez, C.; Afonso, A.; Girijavallabhan, V.M.; Mallams, A.K.; Doll, R.J.; Weinstein, J.; Cooper, A.B.; Chao, J.; Rane, D.F.; Aki, C.J.; Kelly, J.M. (Schering Corp.); Tricyclic farnesyl protein transferase inhibitors. EP 1140902; WO 0037459 . |
| 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) | 51586 | 4-Methylimidazole; 4-Methyl-1H-imidazole; 4-Methyl Imidazole | 822-36-6 | C4H6N2 | 详情 | 详情 |
| (II) | 15216 | N-(3-Bromopropyl)phthalimide; 2-(3-bromopropyl)-1H-isoindole-1,3(2H)-dione | 5460-29-7 | C11H10BrNO2 | 详情 | 详情 |
| (III) | 51587 | 2-[3-(5-methyl-1H-imidazol-1-yl)propyl]-1H-isoindole-1,3(2H)-dione | C15H15N3O2 | 详情 | 详情 | |
| (IV) | 51588 | 2-[3-(4-methyl-1H-imidazol-1-yl)propyl]-1H-isoindole-1,3(2H)-dione | C15H15N3O2 | 详情 | 详情 | |
| (V) | 51589 | 3-(4-methyl-1H-imidazol-1-yl)-1-propanamine; 3-(4-methyl-1H-imidazol-1-yl)propylamine | C7H13N3 | 详情 | 详情 | |
| (VI) | 10498 | Benzaldehyde;Benzoic aldehyde;Phenylmethanal | 100-52-7 | C7H6O | 详情 | 详情 |
| (VII) | 51590 | N-benzyl-3-(4-methyl-1H-imidazol-1-yl)-1-propanamine; N-benzyl-N-[3-(4-methyl-1H-imidazol-1-yl)propyl]amine | C14H19N3 | 详情 | 详情 |