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【结 构 式】 
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【分子编号】28721 【品名】1-bromobutane 【CA登记号】109-65-9 |
【 分 子 式 】C4H9Br 【 分 子 量 】137.01946 【元素组成】C 35.06% H 6.62% Br 58.32% |
合成路线1
该中间体在本合成路线中的序号：(A)The reaction of N-benzltoxycarbonyl-L-alanine succinimidyl ester (I) with o-glutamine (II) by means of triethylamine in THF water gives benzyloxycarbonyl-L-alanyl-o-glutamine (III), which is esterified with bromobutane and Cs2CO3 in DMF yielding the corresponding butyl ester (IV). Deprotection of (IV) by hydrogenation with H2 over Pd/C in acetic acid affords L-alanyl-D-glutamine n-butyl ester (V), which is condensed with 1-O-benzyl-4,6-O-benzylidene-N-acetylmuramic acid (VI) bv the mixed anhydride method affording 1-O-benzyl-4,6-O-benzylidene-N-acetylmuramyl-L-alanyl-o-glutamine n-butyl ester (VII). Finally, this compound is deprotected by hydrogenation with H2 over Pd/C as before.
| 【1】 Florvall, L.; Ogren, S.O.; Potential neuroleptic agents. 2,6-dialkoxybenzamide derivatives with potent dopamine receptor blocking activities. J Med Chem 1982, 25, 11, 1280. |
| 【2】 Lefrancier, P.; Parant, M.; Audibert, F.; Chedid, L.; Choay, J.; Lederer, E. (ANVAR (Agence Natl. Valor. Rech.)); Novel compounds of the muramyl peptide. DD 145274; EP 0006068; ES 481785; FR 2428051; JP 55000392; US 4693998 . |
| 【3】 Castaner, J.; Prous, J.; Murabutide. Drugs Fut 1986, 11, 9, 750. |
| 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) | 28721 | 1-bromobutane | 109-65-9 | C4H9Br | 详情 | 详情 |
| (I) | 24665 | phenethyl 2-[(2,5-dioxo-1-pyrrolidinyl)oxy]-1-methyl-2-oxoethylcarbamate | C16H18N2O6 | 详情 | 详情 | |
| (II) | 24666 | glutamine；2,5-diamino-5-oxopentanoic acid | C5H10N2O3 | 详情 | 详情 | |
| (III) | 24667 | N(2)-(2-[[(phenethyloxy)carbonyl]amino]propanoyl)glutamine | C17H23N3O6 | 详情 | 详情 | |
| (IV) | 24668 | butyl 5-amino-5-oxo-2-[(2-[[(phenethyloxy)carbonyl]amino]propanoyl)amino]pentanoate | C21H31N3O6 | 详情 | 详情 | |
| (V) | 24669 | butyl 5-amino-2-[(2-aminopropanoyl)amino]-5-oxopentanoate | C12H23N3O4 | 详情 | 详情 | |
| (VI) | 24670 | 2-[[(8R)-7-(acetamido)-6-(benzyloxy)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-8-yl]oxy]propionic acid | 74842-55-0 | C25H29NO8 | 详情 | 详情 |
| (VII) | 24671 | butyl 2-([2-[(2-[[(8R)-7-(acetamido)-6-(benzyloxy)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-8-yl]oxy]propanoyl)amino]propanoyl]amino)-5-amino-5-oxopentanoate | C37H50N4O11 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(V)This compound has been obtained by two different ways: 1) The reaction of dipropylcarbinol (I) with HBr gives 4-bromoheptane (II), which is treated with KCN to yield 2-propylpentanenitrile (III). Finally, this compound is hydrolyzed to the target compound with NaOH or with H2SO4. 2) The condensation of cyanacetic acid ethyl ester (IV) with propyl bromide (V) by means of sodium propoxide in propanol gives crude dipropylcyanaacetic acid ethyl ester, which, without isolation, is hydrolyzed with NaOH in hot water yielding dipropylcyanacetic acid (VI). The decarboxylation of (VI) at 140-190 C affords the previously reported 2-propylpentanenitrile (III).
| 【1】 Walles, M.; et al.; Z Physiolog Chem 1947, 282, 2, 137. |
| 【2】 Grain, C.; Chignac, M.; Pigerol, C. (Labaz); Process for the preparation of acetonitrile deriv.. US 4155929 . |
| 【3】 Chignac, M.; Grain, C.; Pigerol, C. (Labaz); Process for preparing an acetonitrile deriv.. GB 1522450 . |
| 【4】 Pigerol, C.; Grain, C.; Chignac, M. (Labaz); Process for preparing acetic acid derivs.. GB 1529786 . |
| 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) | 34880 | 4-heptanol | 589-55-9 | C7H16O | 详情 | 详情 |
| (II) | 34881 | 4-bromoheptane | 998-93-6 | C7H15Br | 详情 | 详情 |
| (III) | 34882 | 2-propylpentanenitrile | 13310-75-3 | C8H15N | 详情 | 详情 |
| (IV) | 11877 | Cyanoacetic acid ethyl ester; Ethyl 2-cyanoacetate; Ethyl cyanoacetate; Ethyl isocyanacetate | 105-56-6 | C5H7NO2 | 详情 | 详情 |
| (V) | 28721 | 1-bromobutane | 109-65-9 | C4H9Br | 详情 | 详情 |
| (VI) | 34883 | 2-cyano-2-propylpentanoic acid | C9H15NO2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VII)The chlorination of 8-acetamido-2,3-dihydro-1,4-benzodioxin-5-carboxylic acid (I) with chlorine in acetic acid gives the 7-chloro derivative (II), which is treated with aqueous NaOH to yield 8-amino-2,3-dihydro-1,4-benzodioxin-5-carboxylic acid (III). The reaction of (III) with carbonyldiimidazole (CDI) affords the activated intermediate (IV), which is finally condensed with 1-(1-butylpiperidin-4-yl)methanol (V) by means of MeLi in THF. The intermediate 1-(1-butylpiperidin-4-yl)methanol (V) has been obtained by condensation of piperidine-4-carboxylic acid ethyl ester (VI) with 1-bromobutane (VII) by means of K2CO3 in methanol, followed by reduction of the ester group with LiAlH4 in THF.
| 【1】 Bulteau, G.; Acher, J.; Thominet, M.; Collignon, C. (Ile de France); Substituted 2,3-alkylenedioxybenzamides. DE 2734270; FR 2360305; GB 1571278; GB 1571447; JP 53018570; US 4186135; US 4248885; US 4255580 . |
| 【2】 Gaster, L.M.; Sanger, G.J.; SB-204070: 5-HT4 receptor antagonists and their potential therapeutic utility. Drugs Fut 1994, 19, 12, 1109. |
| 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) | 41270 | 8-(acetamido)-2,3-dihydro-1,4-benzodioxine-5-carboxylic acid | C11H11NO5 | 详情 | 详情 | |
| (II) | 41271 | 8-(acetamido)-7-chloro-2,3-dihydro-1,4-benzodioxine-5-carboxylic acid | C11H10ClNO5 | 详情 | 详情 | |
| (III) | 41272 | 8-amino-7-chloro-2,3-dihydro-1,4-benzodioxine-5-carboxylic acid | C9H8ClNO4 | 详情 | 详情 | |
| (IV) | 41273 | (8-amino-7-chloro-2,3-dihydro-1,4-benzodioxin-5-yl)(1H-imidazol-1-yl)methanone | C12H10ClN3O3 | 详情 | 详情 | |
| (V) | 41274 | (1-butyl-4-piperidinyl)methanol | C10H21NO | 详情 | 详情 | |
| (VI) | 17410 | Ethyl isonipecotate; ethyl 4-piperidinecarboxylate | 1126-09-6 | C8H15NO2 | 详情 | 详情 |
| (VII) | 28721 | 1-bromobutane | 109-65-9 | C4H9Br | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XXII)Calix[4]arene (XXI) was alkylated with n-butyl bromide (XXII) and NaH to produce the tetrabutyl ether (XXIII). Formylation of (XXIII) with dichloromethyl methyl ether and TiCl4 yielded the aldehyde (XXIV), which was further oxidized to the tetracarboxylic acid (XXV) using sodium chlorite. Then, treatment of (XXV) with oxalyl chloride and DMF gave the corresponding acid chloride (XXVI).
| 【1】 Lin, Q.; et al.; Protein surface recognition by synthetic receptors. NATO ASI Series. Series C: Mathematical and Physical Sciences 1999, 527, 197. |
| 【2】 Park, H.S.; et al.; Protein surface recognition by synthetic receptors: A route to novel submicromolar inhibitors for alpha-chymotrypsin. J Am Chem Soc 1999, 121, 1, 8. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXI) | 47349 | pentacyclo[19.3.1.1(3,7).1(9,13).1(15,19)]octacosa-1(25),3(28),4,6,9(27),10,12,15(26),16,18,21,23-dodecaene-25,26,27,28-tetrol | 74568-07-3 | C28H24O4 | 详情 | 详情 |
| (XXII) | 28721 | 1-bromobutane | 109-65-9 | C4H9Br | 详情 | 详情 |
| (XXIII) | 47350 | butyl 26,27,28-tributoxypentacyclo[19.3.1.1(3,7).1(9,13).1(15,19)]octacosa-1(25),3(28),4,6,9(27),10,12,15(26),16,18,21,23-dodecaen-25-yl ether; 25,26,27,28-tetrabutoxypentacyclo[19.3.1.1(3,7).1(9,13).1(15,19)]octacosa-1(25),3(28),4,6,9(27),10,12,15(26),16,18,21,23-dodecaene | C44H56O4 | 详情 | 详情 | |
| (XXIV) | 47351 | 25,26,27,28-tetrabutoxypentacyclo[19.3.1.1(3,7).1(9,13).1(15,19)]octacosa-1(25),3(28),4,6,9(27),10,12,15(26),16,18,21,23-dodecaene-5,11,17,23-tetracarbaldehyde | C48H56O8 | 详情 | 详情 | |
| (XXV) | 47352 | 25,26,27,28-tetrabutoxypentacyclo[19.3.1.1(3,7).1(9,13).1(15,19)]octacosa-1(25),3(28),4,6,9(27),10,12,15(26),16,18,21,23-dodecaene-5,11,17,23-tetracarboxylic acid | C48H56O12 | 详情 | 详情 | |
| (XXVI) | 47353 | 25,26,27,28-tetrabutoxypentacyclo[19.3.1.1(3,7).1(9,13).1(15,19)]octacosa-1(25),3(28),4,6,9(27),10,12,15(26),16,18,21,23-dodecaene-5,11,17,23-tetracarbonyl tetrachloride | C48H52Cl4O8 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(IV)The reaction of 3,5-dihydroxybenzoic acid (I) with N,O-dimethylhydroxylamine (II) by means of EDC and NMM in dichloromethane gives the N,O-dimethylbenzamide (III), which is alkylated with butyl bromide (IV) and K2CO3 in hot DMF to yield the dibutoxybenzamide (V). The condensation of (V) with 4-methylpyridine (VI) by means of LDA in THF affords 1-(2,4-dibutoxyphenyl)-2-(4-pyridyl)ethanone (VII), which is oxidized with SeO2 in hot acetic acid to provide the dione (VIII). Finally, this compound is cyclized with 4-chlorobenzaldehyde (IX) and ammonium acetate in refluxing acetic acid to furnish the target imidazole.
| 【1】 Chang, L.L.; et al.; Substituted imidazoles as gluagon receptor antagonists. Bioorg Med Chem Lett 2001, 11, 18, 2549. |
| 【2】 de Laszlo, S.; O'Keefe, S.; Li, B.; MacCoss, M.; Rolando, A.; mantlo, N.; Koch, G.; Cascieri, M.A.; Hagmann, W.K.; Chang, L.L.; Pang, M.; Sidler, K.L.; Selective, non-peptide antagonists for the glucagon receptor: Substituted imidazoles. 221st ACS Natl Meet (April 1 2001, San Diego) 2001, Abst MEDI 237. |
| 【3】 Chang, L.L. (Merck & Co., Inc.); Triaryl substd. imidazoles as glucagon antagonists. EP 0959886; JP 2000514088; US 5880139; WO 9822109 . |
| 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) | 48820 | 2,4-Dihydroxybenzenecarboxylic acid; 2,4-Dihydroxybenzoic acid; beta-Resorcylic acid; Resorcinol-4-carboxylic acid | 89-86-1 | C7H6O4 | 详情 | 详情 |
| (II) | 13361 | (Methoxyamino)methane; N,O-Dimethylhydroxylamine | 1117-97-1 | C2H7NO | 详情 | 详情 |
| (III) | 48821 | 2,4-dihydroxy-N-methoxy-N-methylbenzamide | C9H11NO4 | 详情 | 详情 | |
| (IV) | 28721 | 1-bromobutane | 109-65-9 | C4H9Br | 详情 | 详情 |
| (V) | 48822 | 2,4-dibutoxy-N-methoxy-N-methylbenzamide | C17H27NO4 | 详情 | 详情 | |
| (VI) | 31150 | 4-methylpyridine | 108-89-4 | C6H7N | 详情 | 详情 |
| (VII) | 48823 | 1-(2,4-dibutoxyphenyl)-2-(4-pyridinyl)-1-ethanone | C21H27NO3 | 详情 | 详情 | |
| (VIII) | 48824 | 1-(2,4-dibutoxyphenyl)-2-(4-pyridinyl)-1,2-ethanedione | C21H25NO4 | 详情 | 详情 | |
| (IX) | 29029 | 4-chlorobenzaldehyde | 104-88-1 | C7H5ClO | 详情 | 详情 |