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【结 构 式】 
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【分子编号】25449 【品名】3-bromo-1-propanamine; 3-bromopropylamine 【CA登记号】18370-81-5 |
【 分 子 式 】C3H8BrN 【 分 子 量 】138.00726 【元素组成】C 26.11% H 5.84% Br 57.9% N 10.15% |
合成路线1
该中间体在本合成路线中的序号：(VIII)The Knoevenagel condensation between methyl acetoacetate (I) and 3,4-difluorobenzaldehyde (II) afforded the benzylidene derivative (III), which was cyclized with O-methylisourea hemisulfate (IV), yielding the dihydropyrimidine (V). This compound, upon reaction with 4-nitrophenyl chloroformate, regioselectively produced the carbamate ester (VI) (1,2). Treatment of (VI) with aqueous HCl gave the dihydropyrimidinone (VII), which was subsequently coupled with 3-bromopropylamine·HBr (VIII) to give the bromopropyl amide (IX) (1). The intermediate N-(2-carboxamidophenyl)piperazine (XIII) was obtained by condensation of 2-bromobenzonitrile (X) with piperazine (XI), followed by partial hydrolysis of the nitrile group with H2SO4. The title compound was finally obtained by condensation between piperazine (XIII) and bromide (IX) in the presence of KI and K2CO3 in refluxing acetone.
| 【1】 Lagu, B.; Nagarathnam, D.; Miao, S.W.; et al.; Design and synthesis of novel alpha1a adrenoceptor-selective antagonists. 1. Structure-activity relationship in dihydropyrimidinones. J Med Chem 1999, 42, 23, 4764. |
| 【2】 Marzabadi, M.R.; Murali Dhar, T.G.; Nagarathnam, D.; et al.; Design and synthesis of novel alpha1a adrenoceptor-selective antagonists. 2. Approaches to eliminate opioid agonist metabolites via modification of linker and 4-methoxycarbonyl-4-phenylpiperidine moiety. J Med Chem 1999, 42, 23, 4778. |
| 【3】 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) | 11791 | methyl 3-oxobutanoate; Methyl acetoacetate | 105-45-3 | C5H8O3 | 详情 | 详情 |
| (II) | 26654 | 3,4-difluorobenzaldehyde | 34036-07-2 | C7H4F2O | 详情 | 详情 |
| (III) | 38075 | methyl (Z)-2-acetyl-3-(3,4-difluorophenyl)-2-propenoate | C12H10F2O3 | 详情 | 详情 | |
| (IV) | 26657 | O-methyl isourea; [Amino(imino)methoxy]methane | 52328-05-9 | C2H6N2O | 详情 | 详情 |
| (V) | 38076 | methyl 6-(3,4-difluorophenyl)-2-methoxy-4-methyl-1,6-dihydro-5-pyrimidinecarboxylate | C14H14F2N2O3 | 详情 | 详情 | |
| (VI) | 43072 | 5-benzyl 1-(4-nitrophenyl) 6-(3,4-difluorophenyl)-2-methoxy-4-methyl-1,5(6H)-pyrimidinedicarboxylate | C27H21F2N3O7 | 详情 | 详情 | |
| (VII) | 43073 | 5-benzyl 1-(4-nitrophenyl) 6-(3,4-difluorophenyl)-4-methyl-2-oxo-3,6-dihydro-1,5(2H)-pyrimidinedicarboxylate | C26H19F2N3O7 | 详情 | 详情 | |
| (VIII) | 25449 | 3-bromo-1-propanamine; 3-bromopropylamine | 18370-81-5 | C3H8BrN | 详情 | 详情 |
| (IX) | 43074 | benzyl 3-[[(3-bromopropyl)amino]carbonyl]-4-(3,4-difluorophenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate | C23H22BrF2N3O4 | 详情 | 详情 | |
| (X) | 15541 | o-bromobenzonitrile; 2-bromobenzonitrile | 2042-37-7 | C7H4BrN | 详情 | 详情 |
| (XI) | 10355 | Diethylenediamine; Piperazine | 110-85-0 | C4H10N2 | 详情 | 详情 |
| (XII) | 43075 | 2-(1-piperazinyl)benzonitrile | C11H13N3 | 详情 | 详情 | |
| (XIII) | 43076 | 2-(1-piperazinyl)benzamide | C11H15N3O | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IX)Condensation of 4-nitrobenzaldehyde (I) with N-methyl acetoacetamide (II) in the presence of piperidine acetate gave benzylideneacetoacetamide (III). This was further condensed with 2-cyanoethyl 3-amino-2-butenoate (IV) to provide dihydropyridine (V), which was resolved into the enantiomers using chiral HPLC. Then, basic hydrolysis of the cyanoethyl ester from the appropriate enantiomer of (V) yielded carboxylic acid (VI). The aminopropyl piperidine (X) was obtained by esterification of 4-phenyl-4-piperidinecarboxylic acid (VII) with MeOH and H2SO4, followed by alkylation of piperidine (VIII) with 3-bromopropylamine (IX). Finally, amine (X) was coupled to acid (VI) by means of EDC and DMAP to furnish the target compound.
| 【1】 Nagarathnam, D.; Wetzel, J.M.; Miao, S.W.; Marzabadi, M.R.; Chiu, G.; Wong, W.C.; Hong, X.; Fang, J.; Forray, C.; Branchek, T.A.; Heydorn, W.E.; Chang, R.S.; Broten, T.; Schorn, T.W.; Gluchowski, C.; Design and synthesis of novel alpha1a adrenoceptor-selective dihydropyridine antagonists for the treatment of benign prostatic hyperplasia. J Med Chem 1998, 41, 26, 5320. |
| 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) | 18184 | 4-Nitrobenzaldehyde | 555-16-8 | C7H5NO3 | 详情 | 详情 |
| (II) | 25443 | N-methyl-3-oxobutanamide | 20306-75-6 | C5H9NO2 | 详情 | 详情 |
| (III) | 25444 | (Z)-2-acetyl-N-methyl-3-(4-nitrophenyl)-2-propenamide | C12H12N2O4 | 详情 | 详情 | |
| (IV) | 13987 | 2-cyanoethyl (E)-3-amino-2-butenoate | C7H10N2O2 | 详情 | 详情 | |
| (V) | 25445 | 2-cyanoethyl 2,6-dimethyl-5-[(methylamino)carbonyl]-4-(4-nitrophenyl)-1,4-dihydro-3-pyridinecarboxylate | C19H20N4O5 | 详情 | 详情 | |
| (VI) | 25446 | 2,6-dimethyl-5-[(methylamino)carbonyl]-4-(4-nitrophenyl)-1,4-dihydro-3-pyridinecarboxylic acid | C16H17N3O5 | 详情 | 详情 | |
| (VII) | 25447 | 4-phenyl-4-piperidinecarboxylic acid | 3627-45-0 | C12H15NO2 | 详情 | 详情 |
| (VIII) | 25448 | methyl 4-phenyl-4-piperidinecarboxylate | C13H17NO2 | 详情 | 详情 | |
| (IX) | 25449 | 3-bromo-1-propanamine; 3-bromopropylamine | 18370-81-5 | C3H8BrN | 详情 | 详情 |
| (X) | 25450 | methyl 1-(3-aminopropyl)-4-phenyl-4-piperidinecarboxylate | C16H24N2O2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VII)Condensation of 2-pyridylacetonitrile (I) with N,N-bis-(2-chloroethyl)benzylamine (II) under phase-transfer conditions produced the pyridylpiperidine (III). The cyano group of (III) was hydrolyzed to carboxamide (IV) with concentrated sulfuric acid and then decarboxylated to (V) by treatment with methanolic HCl. Subsequent hydrogenolysis of the N-benzyl group of (V) afforded piperidine (VI). N-Boc-3-bromopropylamine (VIII) was prepared by treatment of 3-bromopropylamine (VII) with di-tert-butyl dicarbonate. Alkylation of piperidine (VI) with bromide (VIII) gave adduct (IX). The N-Boc protecting group of (IX) was then removed by treatment with trifluoroacetic acid to yield intermediate aine (X).
| 【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 . |
| 【2】 Lagu, B.; Nagarathnam, D.; Marzabadi, M.R.; Wong, W.C.; Gluchowski, C. (Synaptic Pharmaceutical Corp.); Dihydropyrimidines and uses thereof. WO 9851311 . |
| 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) | 36179 | 2-(2-pyridinyl)acetonitrile | C7H6N2 | 详情 | 详情 | |
| (II) | 23122 | N-benzyl-2-chloro-N-(2-chloroethyl)-1-ethanamine; N-Benzylbis(2-chloroethyl)amine | 10429-82-0 | C11H15Cl2N | 详情 | 详情 |
| (III) | 48382 | 1-benzyl-4-(2-pyridinyl)-4-piperidinecarbonitrile | C18H19N3 | 详情 | 详情 | |
| (IV) | 48383 | 1-benzyl-4-(2-pyridinyl)-4-piperidinecarboxamide | C18H21N3O | 详情 | 详情 | |
| (V) | 48384 | 1-benzyl-4-(2-pyridinyl)piperidine | C17H20N2 | 详情 | 详情 | |
| (VI) | 48385 | 2-(4-piperidinyl)pyridine | C10H14N2 | 详情 | 详情 | |
| (VII) | 25449 | 3-bromo-1-propanamine; 3-bromopropylamine | 18370-81-5 | C3H8BrN | 详情 | 详情 |
| (VIII) | 37752 | tert-butyl 3-bromopropylcarbamate | C8H16BrNO2 | 详情 | 详情 | |
| (IX) | 48386 | tert-butyl 3-[4-(2-pyridinyl)-1-piperidinyl]propylcarbamate | C18H29N3O2 | 详情 | 详情 | |
| (X) | 48387 | 3-[4-(2-pyridinyl)-1-piperidinyl]propylamine; 3-[4-(2-pyridinyl)-1-piperidinyl]-1-propanamine | C13H21N3 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XII)In an alternative method, 2,4'-dipyridyl (XI) was alkylated with 3-bromopropylamine hydrobromide (VII) in hot DMF to provide the pyridinium salt (XII). Reduction of (XII) with NaBH4 gave the tetrahydropyridine (XIII), which was further hydrogenated in the presence of Pearlman's catalyst to yield the intermediate pyridylpiperidine (X).
| 【1】 O'Malley, S.S.; Chen, T.-B.; Chang, R.S.L.; et al.; In vitro studies on L-771,688 (SNAP 6383), a new potent and selective alpha1A-adrenoceptor antagonist. Eur J Pharmacol 2000, 409, 3, 301. |
| 【2】 Ikemoto, N.; Taylor, C.S.; Sidler, D.R.; Chartrain, M.; Bills, G.F.; Roberge, C.M.; Li, W.; Larsen, R.D. (Merck & Co., Inc.); alpha 1a Adrenergic receptor antagonist. WO 9907695 . |
| 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) | 48387 | 3-[4-(2-pyridinyl)-1-piperidinyl]propylamine; 3-[4-(2-pyridinyl)-1-piperidinyl]-1-propanamine | C13H21N3 | 详情 | 详情 | |
| (XI) | 36311 | 2,4'-Dipyridyl | 581-47-5 | C10H8N2 | 详情 | 详情 |
| (XII) | 25449 | 3-bromo-1-propanamine; 3-bromopropylamine | 18370-81-5 | C3H8BrN | 详情 | 详情 |
| (XIII) | 48388 | 1-(3-aminopropyl)-4-(2-pyridinyl)pyridinium bromide | C13H16BrN3 | 详情 | 详情 | |
| (XIV) | 48389 | 3-[4-(2-pyridinyl)-3,6-dihydro-1(2H)-pyridinyl]-1-propanamine; 3-[4-(2-pyridinyl)-3,6-dihydro-1(2H)-pyridinyl]propylamine | C13H19N3 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(IX)Di-tolylacetic acid (V) was converted into the benzyl ester (VI) using benzyl bromide and K2CO3 in DMF. Subsequent alpha-alkylation of ester (VI) with ethyl bromoacetate provided diester (VII). The benzyl ester group of (VII) was then removed by hydrogenolysis over Pd/C. Condensation of the resulting mono-acid (VIII) with 3-bromopropylamine (IX) in the presence of EDC and HOBt furnished the N-(bromopropyl)succinimide (X). This was finally condensed with piperidine (IV) to provide the title compound.
| 【1】 Newton, R.C.; Freidinger, R.M.; Price, R.A.; Chang, R.S.L.; Patane, M.A.; DiPardo, R.M.; Di Salvo, J.; Broten, T.P.; Ransom, R.W.; Bock, M.G.; Cyclic imides as potent and selective alpha-1A adrenergic receptor antagonists. Bioorg Med Chem Lett 2001, 11, 14, 1959. |
| 【2】 Bell, M.G.; DiPardo, R.M.; Crowell, T.A.; et al.; Cyclic imides as potent and selective alpha-1A adrenergic receptor antagonists. 220th ACS Natl Meet (Aug 20 2000, Washington DC) 2000, Abst MEDI 298. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IV) | 43941 | 4-(2-methylphenyl)-4-piperidinecarbonitrile | C13H16N2 | 详情 | 详情 | |
| (V) | 43942 | 2,2-bis(4-methylphenyl)acetic acid | C16H16O2 | 详情 | 详情 | |
| (VI) | 43943 | benzyl 2,2-bis(4-methylphenyl)acetate | C23H22O2 | 详情 | 详情 | |
| (VII) | 43944 | 1-benzyl 4-ethyl 2,2-bis(4-methylphenyl)succinate | C27H28O4 | 详情 | 详情 | |
| (VIII) | 43945 | 4-ethoxy-2,2-bis(4-methylphenyl)-4-oxobutyric acid | C20H22O4 | 详情 | 详情 | |
| (IX) | 25449 | 3-bromo-1-propanamine; 3-bromopropylamine | 18370-81-5 | C3H8BrN | 详情 | 详情 |
| (X) | 43946 | 1-(3-bromopropyl)-3,3-bis(4-methylphenyl)-2,5-pyrrolidinedione | C21H22BrNO2 | 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 on N-Boc-L-valine (I) with 3-bromopropylamine (II) by means of HBTU afforded amide (III). After Boc group cleavage in (III) using trifluoroacetic acid, the resultant amine (IV) was coupled with N-Boc-L-tyrosine (V) to yield the dipeptide amide (VI). Intramolecular cyclization of (VI) to produce the macrocycle (VII) was achieved by treatment with cesium carbonate in the presence of tetrabutylammonium iodide. Subsequent acid cleavage of the Boc protecting group of (VII) furnished the intermediate amine (VIII).
| 【1】 Mak, C.C.; Le, V.-D.; Wong, C.-H.; Elder, J.H.; Lin, Y.-C.; Design, synthesis, and biological evaluation of HIV/FIV protease inhibitors incorporating a conformationally constrained macrocycle with a small P3' residue. Bioorg Med Chem Lett 2001, 11, 2, 219. |
| 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) | 19733 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutyric acid | C10H19NO4 | 详情 | 详情 | |
| (II) | 25449 | 3-bromo-1-propanamine; 3-bromopropylamine | 18370-81-5 | C3H8BrN | 详情 | 详情 |
| (III) | 47889 | tert-butyl (1S)-1-[[(3-bromopropyl)amino]carbonyl]-2-methylpropylcarbamate | C13H25BrN2O3 | 详情 | 详情 | |
| (IV) | 47890 | (2S)-2-amino-N-(3-bromopropyl)-3-methylbutanamide | C8H17BrN2O | 详情 | 详情 | |
| (V) | 25395 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-hydroxyphenyl)propionic acid | 3978-80-1 | C14H19NO5 | 详情 | 详情 |
| (VI) | 47891 | tert-butyl (1S)-2-[((1S)-1-[[(3-bromopropyl)amino]carbonyl]-2-methylpropyl)amino]-1-(4-hydroxybenzyl)-2-oxoethylcarbamate | C22H34BrN3O5 | 详情 | 详情 | |
| (VII) | 47892 | tert-butyl (8S,11S)-8-isopropyl-7,10-dioxo-2-oxa-6,9-diazabicyclo[11.2.2]heptadeca-1(15),13,16-trien-11-ylcarbamate | C22H33N3O5 | 详情 | 详情 | |
| (VIII) | 47893 | (8S,11S)-11-amino-8-isopropyl-2-oxa-6,9-diazabicyclo[11.2.2]heptadeca-1(15),13,16-triene-7,10-dione | C17H25N3O3 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(V)3,4-Difluorobenzaldehyde (I) is condensed with methyl 4-methoxyacetoacetate (II) and urea in the presence of boron trifluoride etherate and copper (I) oxide to produce the dihydropyrimidinone adduct (III). After isolation of the desired enantiomer by means of chiral HPLC, reaction with p-nitrophenyl chloroformate leads to the nitrophenyl carbamate (IV). Then, condensation of (IV) with 3 bromoproylamine (V) furnishes the N-bromopropyl urea derivative (VI).
| 【1】 Gluchowski, C.; Chiu, G.; Marzabadi, M.R.; Nagarathnam, D.; Lagu, B.; Noble, S.; Wetzel, J.; Deleon, J.E. (Synaptic Pharmaceutical Corp.); Selective melanin concentrating hormone-1 (MCH1) receptor antagonists and uses thereof. EP 1299362; WO 0206245 . |
| 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) | 26654 | 3,4-difluorobenzaldehyde | 34036-07-2 | C7H4F2O | 详情 | 详情 |
| (II) | 26655 | methyl 4-methoxy-3-oxobutanoate;Methyl 4-methoxyacetoacetate;Methyl 4-methoxy-3-oxo-butanoate | 41051-15-4 | C6H10O4 | 详情 | 详情 |
| (III) | 39303 | methyl 4-(3,4-difluorophenyl)-6-(methoxymethyl)-2-oxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate | C14H14F2N2O4 | 详情 | 详情 | |
| (IV) | 48400 | 5-methyl 1-(4-nitrophenyl) (6S)-6-(3,4-difluorophenyl)-4-(methoxymethyl)-2-oxo-3,6-dihydro-1,5(2H)-pyrimidinedicarboxylate | C21H17F2N3O8 | 详情 | 详情 | |
| (V) | 25449 | 3-bromo-1-propanamine; 3-bromopropylamine | 18370-81-5 | C3H8BrN | 详情 | 详情 |
| (VI) | 60991 | methyl (4S)-3-{[(3-bromopropyl)amino]carbonyl}-4-(3,4-difluorophenyl)-6-(methoxymethyl)-2-oxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate | C18H20BrF2N3O5 | 详情 | 详情 |