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【结 构 式】 
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【分子编号】13241 【品名】N-Boc-ethylenediamine;tert-butyl (2-aminoethyl)carbamate；tert-butyl 2-aminoethylcarbamate; tert-Butyl n-(2-aminoethyl)carbamate 【CA登记号】57260-73-8 |
【 分 子 式 】C7H16N2O2 【 分 子 量 】160.21632 【元素组成】C 52.48% H 10.07% N 17.48% O 19.97% |
合成路线1
该中间体在本合成路线中的序号：(II)The reaction of 5-chloropyridine-2-carboxylic acid (I) with N-(2-aminoethyl)carbamic acid tert-butyl ester (II) by means of carbonyl-dimidazole (CDI) in refluxing THF gives N-[2-(tert-butoxycarbonylamino)ethyl]-5-chloropyridine-2-carboxamide (III), which is then hydrolyzed with trifluoroacetic acid in refluxing dichloromethane and treated with ethanolic HCl to obtain the hydrochloride.
| 【1】 Imhof, R.; Kyburz, E. (F. Hoffmann-La Roche AG); Ethylenediaminemonoamide derivs., pharmaceutical compsns. containing them and use of these cpds. As antidepressants or antiparkinsonians. AU 8546636; CH 661043; CH 664755; DE 3530046; ES 8705407; ES 8800158; FR 2569694; JP 1986060657; JP 1995300417; US 4764522 . |
| 【2】 Prous, J.; Castaner, J.; Lazabemide Hydrochloride. Drugs Fut 1993, 18, 2, 113. |
| 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) | 13240 | 5-Chloro-2-pyridinecarboxylic acid | C6H4ClNO2 | 详情 | 详情 | |
| (II) | 13241 | N-Boc-ethylenediamine;tert-butyl (2-aminoethyl)carbamate；tert-butyl 2-aminoethylcarbamate; tert-Butyl n-(2-aminoethyl)carbamate | 57260-73-8 | C7H16N2O2 | 详情 | 详情 |
| (III) | 13242 | tert-butyl 2-[[(5-chloro-2-pyridinyl)carbonyl]amino]ethylcarbamate | C13H18ClN3O3 | 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 syntheses of the metabolites of grepafloxacin, 7-(2-aminoethylamino)-1-cyclopropyl-6-fluoro-5-methyl-4-oxo-1,4-dihydro quinoline-3-carboxylic acid (III), 7-(2-aminopropylamino)-1-cyclopropyl-6-fluoro-5-methyl-4-oxo-1,4-dihydr oquinoline-3-carboxylic acid (V), 7-amino-1-cyclopropyl-6-fluoro-5-methyl-4-oxo-1,4-dihydroquinoline-3-ca rboxylic acid (VIII), 7-(carboxymethylamino)-1-cyclopropyl-6-fluoro-5-methyl-4-oxo-1,4-dihydr oquinoline-3-carboxylic acid (XI), 1-cyclopropyl-6-fluoro-5-(hydroxymethyl)-7-(3-methylpiperazin-1-yl)-4-o xo-1,4-dihydroquinoline-3-carboxylic acid (XVIII) and 7-amino-1-cyclopropyl-6-fluoro-5-(hydroxymethyl)-4-oxo-1,4-dihydroquino line-3-carboxylic acid (XX) have been reported: 1) Compound (III): By condensation of 7-bromo-1-cyclopropyl-6-fluoro-5-methyl-4-oxo-1,4-dihydroquinoline-3-ca rboxylic acid diacetoxyborane ester (I) with 2-(tert-butoxycarbonylamino)ethylamine (II) by heating at 110 C followed by a treatment with HCl in ethanol/water. 2) Compound (V): By condensation of quinolone (I) with 2-(tert-butoxycarbonylamino)ethylamine (IV) by heating at 110 C, followed by hydrolysis with HCl as before. 3) Compound (VIII): The condensation of quinolone (I) with 4-methoxybenzylamine (VII) by heating at 110 C gives 1-cyclopropyl-6-fluoro-7-(4-methoxybenzylamino)-5-methyl-4-oxo-1,4-dihy droquinoline-3-carboxylic acid (VII), which is then debenzylated by treatment with a mixture of trifluoroacetic acid and concentrated sulfuric acid. 4) Compound (XI): The condensation of quinolone (I) with glycine ethyl ester (IX) by heating at 110 C gives 1-cyclopropyl-7-(ethoxycarbonylmethylamino)-6-fluoro-5-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (X), which is then saponified with NaOH in refluxing ethanol.
| 【1】 Otsubo, K.; Kawano, Y.; Ohguro, K.; Uchida, M.; Ohtani, T.; Ohmori, K.; Matsubara, J.; Morita, S.; Synthesis of possible metabolites of 1-cyclopropyl-1,4-dihydro-6-fluoro-5-methyl-7-(3-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid (grepafloxacin, OPC-17116). Chem Pharm Bull 1995, 43, 12, 2246. |
| 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) | 15093 | diacetyl (7-bromo-1-cyclopropyl-6-fluoro-5-methyl-4-oxo-1,4-dihydro-3-quinolinyl)carbonyl borate | C18H16BBrFNO7 | 详情 | 详情 | |
| (II) | 13241 | N-Boc-ethylenediamine;tert-butyl (2-aminoethyl)carbamate；tert-butyl 2-aminoethylcarbamate; tert-Butyl n-(2-aminoethyl)carbamate | 57260-73-8 | C7H16N2O2 | 详情 | 详情 |
| (III) | 15095 | 7-[(2-aminoethyl)amino]-1-cyclopropyl-6-fluoro-5-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid | C16H18FN3O3 | 详情 | 详情 | |
| (IV) | 15096 | tert-butyl N-(2-amino-1-methylethyl)carbamate | C8H18N2O2 | 详情 | 详情 | |
| (V) | 15097 | 7-[(2-aminopropyl)amino]-1-cyclopropyl-6-fluoro-5-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid | C17H20FN3O3 | 详情 | 详情 | |
| (VI) | 15098 | 4-Methoxybenzylamine; (4-Methoxyphenyl)methanamine | 2393-23-9 | C8H11NO | 详情 | 详情 |
| (VII) | 15099 | 1-cyclopropyl-6-fluoro-7-[(4-methoxybenzyl)amino]-5-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid | C22H21FN2O4 | 详情 | 详情 | |
| (VIII) | 15100 | 7-amino-1-cyclopropyl-6-fluoro-5-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid | C14H13FN2O3 | 详情 | 详情 | |
| (IX) | 10309 | ethyl 2-aminoacetate; Glycine ethyl ester | 459-73-4 | C4H9NO2 | 详情 | 详情 |
| (X) | 15102 | 1-cyclopropyl-7-[(2-ethoxy-2-oxoethyl)amino]-6-fluoro-5-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid | C18H19FN2O5 | 详情 | 详情 | |
| (XI) | 15103 | 7-[(carboxymethyl)amino]-1-cyclopropyl-6-fluoro-5-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid | C16H15FN2O5 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VIII)3,4-Pyridinedicarboxylic acid (I) was converted to the cyclic anhydride (II) upon heating with acetic anhydride. Friedel-Crafts condensation of anhydride (II) with p-difluorobenzene (III) in the presence of AlCl3 gave rise to a mixture of two regioisomeric keto acids, (IV) and (V). Cyclization of this mixture in fuming sulfuric acid at 140 C generated the benzoisoquinoline (VI) (1,2). Subsequent displacement of the fluorine atoms of (VI) with ethylenediamine (VII) in pyridine provided the target bis(2-aminoethylamino) derivative, which was finally converted to the stable dimaleate salt. Alternatively, ethylenediamine (VII) was protected as the mono-N-Boc derivative (VIII) by treatment with Boc2O. Condensation of the difluoro compound (VI) with the protected ethylenediamine (VIII) furnished (IX). The Boc groups of (IX) were then removed by treatment with trifluoroacetic acid. After adjustment of the pH to 4.2 with KOH, treatment with maleic acid provided BBR-2778.
| 【1】 Spinelli, S.; DiDomenico, R. (Roche Diagnostics GmbH); 6,9-Bis[(2-aminoethyl)amino]benzo[g]isoquinoline-5, 10-dione and its dimaleate salt. JP 1997507674; JP 2001089454; US 5506232; WO 9526189 . |
| 【2】 Krapcho, P.A. (University of Vermont); 6,9-Bis(substd.-amino)benzo-[g]isoquinoline-5,10-diones. EP 0503537; EP 0575526; JP 1994511230; WO 9215300 . |
| 【3】 Krapcho, A.P.; et al.; 6,9-Bis[(aminoalkyl)amino]benzo[g]isoquinoline-5, 10-diones. A novel class of chromophore-modified antitumor anthracene-9,10-diones: Synthesis and antitumor evaluations. J Med Chem 1994, 37, 6, 828. |
| 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) | 52805 | 3,4-Pyridinedicarboxylic acid; Cinchomeronic acid; Pyridin-3,4-dicarboxylic acid; Pyridine-3,4-dicarboxylic acid | 490-11-9 | C7H5NO4 | 详情 | 详情 |
| (II) | 52806 | 3,4-Pyridine dicarboxylic anhydride; Pyridine-3,4-dicarboxylic anhydride | 4664-08-8 | C7H3NO3 | 详情 | 详情 |
| (III) | 52807 | 1,4-Difluorobenzene; p-Difluorobenzene | 540-36-3 | C6H4F2 | 详情 | 详情 |
| (IV) | 52808 | 4-(2,5-difluorobenzoyl)nicotinic acid | C13H7F2NO3 | 详情 | 详情 | |
| (V) | 52809 | 3-(2,5-difluorobenzoyl)isonicotinic acid | C13H7F2NO3 | 详情 | 详情 | |
| (VI) | 52810 | 6,9-difluorobenzo[g]isoquinoline-5,10-dione | C13H5F2NO2 | 详情 | 详情 | |
| (VII) | 14754 | ethylenediamine;1,2-Diaminoethane;ethane-1,2-diamine；1,2-Ethanediamine | 107-15-3 | C2H8N2 | 详情 | 详情 |
| (VIII) | 13241 | N-Boc-ethylenediamine;tert-butyl (2-aminoethyl)carbamate；tert-butyl 2-aminoethylcarbamate; tert-Butyl n-(2-aminoethyl)carbamate | 57260-73-8 | C7H16N2O2 | 详情 | 详情 |
| (IX) | 52811 | tert-butyl 2-{[6-({2-[(tert-butoxycarbonyl)amino]ethyl}amino)-5,10-dioxo-5,10-dihydrobenzo[g]isoquinolin-9-yl]amino}ethylcarbamate | C27H35N5O6 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(VII)Friedel-Crafts bis-acylation of p-dimethoxybenzene (X) with anhydride (II) in molten aluminum chloride/sodium chloride afforded the benzoisoquinoline (XI). This compound was reduced with sodium dithionite to generate an intermediate leuco form (XII). Subsequent addition of Boc-ethylenediamine (VIII) to (XII) produced, after air oxidation during the work-up, the protected tetraamino compound (IX). Alternatively, addition of ethylenediamine (VII) to the intermediate (XII) led to the free base of BBR-2778, which was converted to the maleate.
| 【1】 Krapcho, A.P.; et al.; 6,9-Bis[(aminoalkyl)amino]benzo[g]isoquinoline-5, 10-diones. A novel class of chromophore-modified antitumor anthracene-9,10-diones: Synthesis and antitumor evaluations. J Med Chem 1994, 37, 6, 828. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIIII) | 14754 | ethylenediamine;1,2-Diaminoethane;ethane-1,2-diamine；1,2-Ethanediamine | 107-15-3 | C2H8N2 | 详情 | 详情 |
| (II) | 52806 | 3,4-Pyridine dicarboxylic anhydride; Pyridine-3,4-dicarboxylic anhydride | 4664-08-8 | C7H3NO3 | 详情 | 详情 |
| (VII) | 13241 | N-Boc-ethylenediamine;tert-butyl (2-aminoethyl)carbamate；tert-butyl 2-aminoethylcarbamate; tert-Butyl n-(2-aminoethyl)carbamate | 57260-73-8 | C7H16N2O2 | 详情 | 详情 |
| (IX) | 52811 | tert-butyl 2-{[6-({2-[(tert-butoxycarbonyl)amino]ethyl}amino)-5,10-dioxo-5,10-dihydrobenzo[g]isoquinolin-9-yl]amino}ethylcarbamate | C27H35N5O6 | 详情 | 详情 | |
| (X) | 21946 | 1,4-dimethoxybenzene; 4-methoxyphenyl methyl ether | 150-78-7 | C8H10O2 | 详情 | 详情 |
| (XI) | 52812 | 6,9-dihydroxybenzo[g]isoquinoline-5,10-dione | C13H7NO4 | 详情 | 详情 | |
| (XII) | 52813 | 5,10-dihydroxy-7,8-dihydrobenzo[g]isoquinoline-6,9-dione | C13H9NO4 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(I)N-Boc-ethylenediamine (I) was treated with S-methylisothiourea (II) yielding guanidine (III). The Boc group of (III) was then cleaved by treatment with HCl.
| 【1】 Cozzi, P.; Beria, I.; Biasoli, G.; Caldarelli, M.; Capolongo, L.; Franzetti, C. (Pharmacia & Upjohn AB); Acryloyl substd. distamycin derivs., process for preparing them, and their use as antitumor and antiviral agents. WO 9804524 . |
| 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) | 13241 | N-Boc-ethylenediamine;tert-butyl (2-aminoethyl)carbamate；tert-butyl 2-aminoethylcarbamate; tert-Butyl n-(2-aminoethyl)carbamate | 57260-73-8 | C7H16N2O2 | 详情 | 详情 |
| (II) | 10272 | [[Amino(imino)methyl]sulfanyl]methane | 2986-19-8 | C2H6N2S | 详情 | 详情 |
| (III) | 41436 | tert-butyl 2-[[amino(imino)methyl]amino]ethylcarbamate | C8H18N4O2 | 详情 | 详情 | |
| (IV) | 41437 | N-(2-aminoethyl)guanidine | C3H10N4 | 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 reaction of ethylenediamine (I) with Boc2O in dioxane gives the monocarbamate (II), which is condensed with O-methylisourea (III) to yield the aminoguanidine carbamate (IV). The cleavage of the carbamate group of (IV) by means of HCl in methanol affords the aminoguanidine (V), which is condensed with 1-methyl-4-nitropyrrole-2-carbonyl chloride (VI) by means of NaHCO3 in dioxane/water to provide the amide (VII). The reduction of the nitro group of (VII) by means of H2 over Pd/C in 1N HCl affords the 4-aminopyrrole-2-carboxamide (VIII), which is condensed with the acid chloride (VI) as before to give the diamide (IX). Reduction of the nitro group of (IX) under the same conditions described above yields the amino diamide (X), which is condensed with the 14-labeled acid chloride (XI) as described above to afford the triamide (XII). Further reduction of the nitro group of (XII) gives the amino triamide (XIII), which is finally condensed with 4-(2-bromopropenamido)-1-methylpyrrole-2-carbonyl chloride (XIV) by means of NaHCO3 in dioxane/water to yield the target 14C labeled pentaamide compound.
| 【1】 Fontana, E.; Pignatti, A.; Synthesis of brostallicin (PNU-166196A) labelled with 2H and 14C. Label. Cop. & Radiopharm. 2002, 45, 11, 899. |
| 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) | 14754 | ethylenediamine;1,2-Diaminoethane;ethane-1,2-diamine；1,2-Ethanediamine | 107-15-3 | C2H8N2 | 详情 | 详情 |
| (II) | 13241 | N-Boc-ethylenediamine;tert-butyl (2-aminoethyl)carbamate；tert-butyl 2-aminoethylcarbamate; tert-Butyl n-(2-aminoethyl)carbamate | 57260-73-8 | C7H16N2O2 | 详情 | 详情 |
| (III) | 26657 | O-methyl isourea; [Amino(imino)methoxy]methane | 52328-05-9 | C2H6N2O | 详情 | 详情 |
| (IV) | 41436 | tert-butyl 2-[[amino(imino)methyl]amino]ethylcarbamate | C8H18N4O2 | 详情 | 详情 | |
| (V) | 41437 | N-(2-aminoethyl)guanidine | C3H10N4 | 详情 | 详情 | |
| (VI) | 27852 | 1-methyl-4-nitro-1H-pyrrole-2-carbonyl chloride | C6H5ClN2O3 | 详情 | 详情 | |
| (VII) | 41445 | N-(2-[[amino(imino)methyl]amino]ethyl)-1-methyl-4-nitro-1H-pyrrole-2-carboxamide | C9H14N6O3 | 详情 | 详情 | |
| (VIII) | 41446 | 4-amino-N-(2-[[amino(imino)methyl]amino]ethyl)-1-methyl-1H-pyrrole-2-carboxamide | C9H16N6O | 详情 | 详情 | |
| (IX) | 41447 | N-(2-[[amino(imino)methyl]amino]ethyl)-1-methyl-4-[[(1-methyl-4-nitro-1H-pyrrol-2-yl)carbonyl]amino]-1H-pyrrole-2-carboxamide | C15H20N8O4 | 详情 | 详情 | |
| (X) | 41448 | N-(2-[[amino(imino)methyl]amino]ethyl)-4-[[(4-amino-1-methyl-1H-pyrrol-2-yl)carbonyl]amino]-1-methyl-1H-pyrrole-2-carboxamide | C15H22N8O2 | 详情 | 详情 | |
| (XI) | 65171 | 1-methyl-4-nitro-1H-pyrrole-2-carbonyl chloride | 28494-51-1 | C6H5ClN2O3 | 详情 | 详情 |
| (XII) | 41443 | N-(2-[[amino(imino)methyl]amino]ethyl)-1-methyl-4-[[(1-methyl-4-[[(1-methyl-4-nitro-1H-pyrrol-2-yl)carbonyl]amino]-1H-pyrrol-2-yl)carbonyl]amino]-1H-pyrrole-2-carboxamide | C21H26N10O5 | 详情 | 详情 | |
| (XIII) | 61732 | 4-amino-N-(5-{[(5-{[(2-{[amino(imino)methyl]amino}ethyl)amino]carbonyl}-1-methyl-1H-pyrrol-3-yl)amino]carbonyl}-1-methyl-1H-pyrrol-3-yl)-1-methyl-1H-pyrrole-2-carboxamide | C21H28N10O3 | 详情 | 详情 | |
| (XIV) | 41441 | 4-[(2-bromoacryloyl)amino]-1-methyl-1H-pyrrole-2-carbonyl chloride | C9H8BrClN2O2 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(II)The reaction of deuterium labeled ethylenediamine (I) with Boc2O in dioxane gives the monocarbamate (II), which is condensed with O-methylisourea (III) to yield the labeled aminoguanidine carbamate (IV). The cleavage of the carbamate group of (IV) by means of HCl in methanol affords the aminoguanidine (V), which is condensed with 1-methyl-4-nitropyrrole-2-carbonyl chloride (VI) by means of NaHCO3 in dioxane/water to provide the amide (VII). The reduction of the nitro group of (VII) by means of H2 over Pd/C in 1N HCl affords the 4-aminopyrrole-2-carboxamide (VIII), which is condensed with the acid chloride (VI) as before to give the diamide (IX). Reduction of the nitro group of (IX) under the same conditions described above yields the amino diamide (X), which is condensed with acid chloride (VI) as described above to afford the triamide (XI). Further reduction of the nitro group of (XI) gives the amino triamide (XII), which is finally condensed with 4-(2-bromopropenamido)-1-methylpyrrole-2-carbonyl chloride (XIII) by means of NaHCO3 in dioxane/water to yield the target deuterium labeled pentaamide compound.
| 【1】 Fontana, E.; Pignatti, A.; Synthesis of brostallicin (PNU-166196A) labelled with 2H and 14C. Label. Cop. & Radiopharm. 2002, 45, 11, 899. |
| 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) | 14754 | ethylenediamine;1,2-Diaminoethane;ethane-1,2-diamine；1,2-Ethanediamine | 107-15-3 | C2H8N2 | 详情 | 详情 |
| (II) | 13241 | N-Boc-ethylenediamine;tert-butyl (2-aminoethyl)carbamate；tert-butyl 2-aminoethylcarbamate; tert-Butyl n-(2-aminoethyl)carbamate | 57260-73-8 | C7H16N2O2 | 详情 | 详情 |
| (III) | 26657 | O-methyl isourea; [Amino(imino)methoxy]methane | 52328-05-9 | C2H6N2O | 详情 | 详情 |
| (IV) | 41436 | tert-butyl 2-[[amino(imino)methyl]amino]ethylcarbamate | C8H18N4O2 | 详情 | 详情 | |
| (V) | 41437 | N-(2-aminoethyl)guanidine | C3H10N4 | 详情 | 详情 | |
| (VI) | 27852 | 1-methyl-4-nitro-1H-pyrrole-2-carbonyl chloride | C6H5ClN2O3 | 详情 | 详情 | |
| (VII) | 41445 | N-(2-[[amino(imino)methyl]amino]ethyl)-1-methyl-4-nitro-1H-pyrrole-2-carboxamide | C9H14N6O3 | 详情 | 详情 | |
| (VIII) | 41446 | 4-amino-N-(2-[[amino(imino)methyl]amino]ethyl)-1-methyl-1H-pyrrole-2-carboxamide | C9H16N6O | 详情 | 详情 | |
| (IX) | 41447 | N-(2-[[amino(imino)methyl]amino]ethyl)-1-methyl-4-[[(1-methyl-4-nitro-1H-pyrrol-2-yl)carbonyl]amino]-1H-pyrrole-2-carboxamide | C15H20N8O4 | 详情 | 详情 | |
| (X) | 41448 | N-(2-[[amino(imino)methyl]amino]ethyl)-4-[[(4-amino-1-methyl-1H-pyrrol-2-yl)carbonyl]amino]-1-methyl-1H-pyrrole-2-carboxamide | C15H22N8O2 | 详情 | 详情 | |
| (XI) | 41443 | N-(2-[[amino(imino)methyl]amino]ethyl)-1-methyl-4-[[(1-methyl-4-[[(1-methyl-4-nitro-1H-pyrrol-2-yl)carbonyl]amino]-1H-pyrrol-2-yl)carbonyl]amino]-1H-pyrrole-2-carboxamide | C21H26N10O5 | 详情 | 详情 | |
| (XII) | 41444 | N-(2-[[amino(imino)methyl]amino]ethyl)-4-[[(4-[[(4-amino-1-methyl-1H-pyrrol-2-yl)carbonyl]amino]-1-methyl-1H-pyrrol-2-yl)carbonyl]amino]-1-methyl-1H-pyrrole-2-carboxamide | C21H28N10O3 | 详情 | 详情 | |
| (XIII) | 41441 | 4-[(2-bromoacryloyl)amino]-1-methyl-1H-pyrrole-2-carbonyl chloride | C9H8BrClN2O2 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(II)The reaction of 6-chloropyridine-3-carbonitrile (I) with carbamate (II) by means of KHCO3 in hot DMF gives the adduct (III), which is treated with TFA in dichloromethane to yield 6-(2-aminoethylamino)pyridine-3-carbonitrile (IV). The cyclization of (IV) with formaldehyde affords 6-(1-imidazoldinyl)pyridine-3-carbonitrile (V), which is condensed with 1-(2-bromoacetyl)piperidine-2(S)-carbonitrile (VI) by means of TEA in THF to provide the adduct (VII). Finally, the cleavage of the imidazolidine ring of (VII) by means of TFA in water, or TFA and 3-(4-(hydrazinosulfonyl)phenyl)propionyl AM resin in dichloromethane, gives rise to the target pyridine-carbonitrile derivative.
| 【1】 Willand, N.; et al.; Solid and solution phase syntheses of the 2-cyanopyrrolidide DPP-IV inhihitor NVP-DPP728. Tetrahedron 2002, 58, 28, 5741. |
| 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) | 57164 | 2-Chloro-5-cyanopyridine; 6-Chloro-3-cyanopyridine; 6-Chloronicotinonitrile | 33252-28-7 | C6H3ClN2 | 详情 | 详情 |
| (II) | 13241 | N-Boc-ethylenediamine;tert-butyl (2-aminoethyl)carbamate；tert-butyl 2-aminoethylcarbamate; tert-Butyl n-(2-aminoethyl)carbamate | 57260-73-8 | C7H16N2O2 | 详情 | 详情 |
| (III) | 57165 | tert-butyl 2-[(5-cyano-2-pyridinyl)amino]ethylcarbamate | C13H18N4O2 | 详情 | 详情 | |
| (IV) | 54332 | 6-[(2-aminoethyl)amino]nicotinonitrile | n/a | C8H10N4 | 详情 | 详情 |
| (V) | 57166 | 6-(1-imidazolidinyl)nicotinonitrile | C9H10N4 | 详情 | 详情 | |
| (VI) | 54334 | (2S)-1-(2-bromoacetyl)-2-pyrrolidinecarbonitrile | n/a | C7H9BrN2O | 详情 | 详情 |
| (VII) | 57167 | 6-(3-{2-[(2S)-2-cyanopyrrolidinyl]-2-oxoethyl}-1-imidazolidinyl)nicotinonitrile | C16H18N6O | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(II)Ethylenediamine (I) was selectively monoprotected as the N-Boc derivative (II) and then coupled with sulfonyl chloride (III), yielding sulfonamide (IV). After deprotection of the Boc group of (IV) with HCl in dioxan, the resulting amine (V) was condensed with hydroxyacid (VI) by means of BOP reagent to give amide (VII). Acid deprotection of the Boc group of (VII), followed by condensation with 2,6-dichlorobenzoyl chloride (IX), provided (X). Finally, the hydroxyl group of (X) was oxidized to the title ketone employing the Dess-Martin periodinane reagent in CH2Cl2.
| 【1】 Ator, M.A.; Mallamo, J.P.; Chatterjee, S.; Tao, M.; Wells, G.; Dunn, D.; Bihovsky, R.; Siman, R.; Gu, Z.-Q; P2-Achiral, P'-extended alpha-ketoamide inhibitors of calpain I. Bioorg Med Chem Lett 1999, 9, 16, 2371. |
| 【2】 Wells, G.J.; Mallamo, J.P.; Chatterjee, S.; Bihovsky, R. (Cephalon, Inc.); Peptidyl-containing alpha-ketoamide cysteine and serine protease inhibitors. US 6150378 . |
| 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) | 14574 | 3-methoxy-3-oxo-2-(2-thienylmethyl)propionic acid | C9H10O4S | 详情 | 详情 | |
| (II) | 13241 | N-Boc-ethylenediamine;tert-butyl (2-aminoethyl)carbamate；tert-butyl 2-aminoethylcarbamate; tert-Butyl n-(2-aminoethyl)carbamate | 57260-73-8 | C7H16N2O2 | 详情 | 详情 |
| (III) | 43065 | 5-(3-cyanophenyl)-2-thiophenesulfonyl chloride | C11H6ClNO2S2 | 详情 | 详情 | |
| (IV) | 43066 | tert-butyl 2-([[5-(3-cyanophenyl)-2-thienyl]sulfonyl]amino)ethylcarbamate | C18H21N3O4S2 | 详情 | 详情 | |
| (V) | 43067 | N-(2-aminoethyl)-5-(3-cyanophenyl)-2-thiophenesulfonamide | C13H13N3O2S2 | 详情 | 详情 | |
| (VI) | 43071 | (3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-4-phenylbutyric acid | C15H21NO5 | 详情 | 详情 | |
| (VII) | 43068 | tert-butyl (1S)-1-benzyl-3-[[2-([[5-(3-cyanophenyl)-2-thienyl]sulfonyl]amino)ethyl]amino]-2-hydroxy-3-oxopropylcarbamate | C28H32N4O6S2 | 详情 | 详情 | |
| (VIII) | 43069 | (3S)-3-amino-N-[2-([[5-(3-cyanophenyl)-2-thienyl]sulfonyl]amino)ethyl]-2-hydroxy-4-phenylbutanamide | C23H24N4O4S2 | 详情 | 详情 | |
| (IX) | 25087 | 2,6-dichlorobenzoyl chloride | 4659-45-4 | C7H3Cl3O | 详情 | 详情 |
| (X) | 43070 | N-((1S)-1-benzyl-3-[[2-([[5-(3-cyanophenyl)-2-thienyl]sulfonyl]amino)ethyl]amino]-2-hydroxy-3-oxopropyl)-2,6-dichlorobenzamide | C30H26Cl2N4O5S2 | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(V)Boc-Nitroarginine (I) was activated as the mixed anhydride (II), which was further converted to the Weinreb amide (III) upon treatment with N,O-dimethylhydroxylamine. Reduction of (III) with LiAlH4 furnished N-Boc-nitroargininal (IV). This was reductively condensed with the mono-Boc-protected ethylenediamine (V) in the presence of sodium triacetoxyborohydride, yielding amine (VI). The Boc protecting groups of (VI) were finally removed by treatment with trifluoroacetic acid to provide the title compound.
| 【1】 Hah, J.-M.; et al.; Reduced amide bond peptidomimetics. (4S)-N-(4-Amino-5-(aminoalkyl]aminopentyl)-N'-nitroguanidines, potent and highly selective inhibitors of neuronal nitric oxide synthase. J Med Chem 2001, 44, 16, 2667. |
| 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) | 32085 | N(G)-nitro-N2-(tert-butoxy-carbonyl)-L-arginine; Nalpha-(tert-butoxycarbonyl)-Nomega-nitro-L-arginine | C11H21N5O6 | 详情 | 详情 | |
| (II) | 53139 | n/a | C16H29N5O8 | 详情 | 详情 | |
| (III) | 53140 | n/a | C13H26N6O6 | 详情 | 详情 | |
| (IV) | 53141 | n/a | C11H21N5O5 | 详情 | 详情 | |
| (V) | 13241 | N-Boc-ethylenediamine;tert-butyl (2-aminoethyl)carbamate；tert-butyl 2-aminoethylcarbamate; tert-Butyl n-(2-aminoethyl)carbamate | 57260-73-8 | C7H16N2O2 | 详情 | 详情 |
| (VI) | 53142 | n/a | C18H37N7O6 | 详情 | 详情 |
合成路线11
该中间体在本合成路线中的序号：(V)The condensation of 4-piperidinylmethanol (I) with 4-chloropyridine (II) gives 1-(4-pyridyl)piperidin-4-ylmethanol (III), which is oxidized with (COCl)2 and TEA in DMSO to yield the carbaldehyde (IV). The reductocondensation of (IV) with N-(tert-butoxycarbonyl)ethylene-1,2-diamine (V) by means of sodium triacetoxyborohydride and acetic acid affords the corresponding adduct as the borane complex (VI), which is acylated with bromoacetyl chloride (VII) and TEA in dichloromethane, providing the bromoacetamide (VIII). The cleavage of the boron complex and the Boc protecting group of (VIII) with TFA and anisole in ethyl ether gives the precursor (IX), which is cyclized to the piperazinone (X) by means of TEA in DMF. Finally, compound (X) is condensed with 6-chloronaphthalene-2-sulfonyl chloride by means of TEA in dichloromethane to yield the target sulfonamide.
| 【1】 Nishida, H.; et al.; Synthesis and evaluation of 1-arylsulfonyl-3-piperazinone derivatives as factor Xa inhibitor. Chem Pharm Bull 2001, 49, 10, 1237. |
| 【2】 Miyazaki, Y.; Mukaihira, T.; Nishida, H.; Hosaka, Y.; Matsusue, T. (Mochida Pharmaceutical Co., Ltd.); Aromatic cpds. having cyclic amino or salts thereof. EP 1048652; WO 9933805 . |
| 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) | 32954 | 4-piperidinylmethanol | C6H13NO | 详情 | 详情 | |
| (II) | 32889 | 4-chloropyridine | 7379-35-3 | C5H4ClN | 详情 | 详情 |
| (III) | 45860 | [1-(4-pyridinyl)-4-piperidinyl]methanol | C11H16N2O | 详情 | 详情 | |
| (IV) | 52205 | 1-(4-pyridinyl)-4-piperidinecarbaldehyde | C11H14N2O | 详情 | 详情 | |
| (V) | 13241 | N-Boc-ethylenediamine;tert-butyl (2-aminoethyl)carbamate；tert-butyl 2-aminoethylcarbamate; tert-Butyl n-(2-aminoethyl)carbamate | 57260-73-8 | C7H16N2O2 | 详情 | 详情 |
| (VI) | 52206 | C22H37BN4O7 | 详情 | 详情 | ||
| (VII) | 27903 | 2-Bromoacetyl chloride | 22118-09-8 | C2H2BrClO | 详情 | 详情 |
| (VIII) | 52207 | C24H38BBrN4O8 | 详情 | 详情 | ||
| (IX) | 52208 | N-(2-aminoethyl)-2-bromo-N-{[1-(4-pyridinyl)-4-piperidinyl]methyl}acetamide | C15H23BrN4O | 详情 | 详情 | |
| (X) | 52209 | 1-{[1-(4-pyridinyl)-4-piperidinyl]methyl}-2-piperazinone | C15H22N4O | 详情 | 详情 | |
| (XI) | 45865 | 6-chloro-2-naphthalenesulfonyl chloride | C10H6Cl2O2S | 详情 | 详情 |
合成路线12
该中间体在本合成路线中的序号：(I)The synthesis of suvorexant by the medicinal route starts with conjugate addition of monoprotected diamine (I) to methyl vinyl ketone (II) in Et2O, followed by in situ trapping with benzyl chloroformate in the presence of Et3N to yield the fully protected diaminoketone (III), from which the Boc-protecting group is cleaved by means of HCl in EtOAc to provide primary amine (IV). Intramolecular reductive cyclization of amino ketone (IV) in the presence of NaBH(OAc)3 and AcOH in CH2Cl2 affords benzyl 5-methyl-1,4-diazepane-1-carboxylate (V), which is then N-protected with di-tert-butyl dicarbonate in the presence of Et3N in CH2Cl2 to give the diprotected diazepine derivative (VI). Resolution of racemic diazepine (VI) by means of chiral HPLC provides the desired (R)-enantiomer (VII), which is then N-deprotected with HCl in EtOAc to afford benzyl 5(R)-methyl-1,4-diazepane-1-carboxylate (VIII). Coupling of cyclic amine (VIII) or its hydrochloride with 5-methyl-2-(1,2,3-triazol-2-yl)benzoic acid (IX) [prepared by condensation of 2-iodo-5-methylbenzoic acid (X) with 1,2,3-triazole (XI) in the presence of Cs2CO3, CuI and t-DAMCH in DMF at 120 °C] using EDC, HOAt and NMM in DMF produces the corresponding amide (XII). N-Deprotection of N-Cbz-amine (XII) by means of H2 over Pd(OH)2/C in EtOAc/MeOH or EtOAc generates the 7(R)-methyldiazepane derivative (XIII), which is finally condensed with 2,5-dichloro-1,3-benzoxazole (XIV) [prepared by the chlorination of 5-chloro-2-mercaptobenzoxazole (XV) with POCl3 and PCl5 in CH2Cl2] in the presence of Et3N in DMF at 75 °C .
| 【1】 Bergman, J.M., Breslin, M.J., Coleman, P.J., Cox, C.D., Mercer, S.P.,Roecker, A.J. (Merck & Co., Inc.) Substituted diazepan compounds as orexin receptor antagonists. CN 101880276, EP 2089382, EP 2392572, JP 201051121, JP 2011068665, JP 2011079848, US 2008132490, US 7951797, US 2011195957, WO 2008069997. |
| 【2】 Cox, C.D., Breslin, M.J., Whitman, D.B. et al. Discovery of the dual orexin receptor antagonist [(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone (MK-4305) for the treatment of insomnia. J Med Chem 2010, 53(14): 5320-32. |
| 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) | 13241 | N-Boc-ethylenediamine;tert-butyl (2-aminoethyl)carbamate；tert-butyl 2-aminoethylcarbamate; tert-Butyl n-(2-aminoethyl)carbamate | 57260-73-8 | C7H16N2O2 | 详情 | 详情 |
| (II) | 30324 | 3-buten-2-one; methyl vinyl ketone | 78-94-4 | C4H6O | 详情 | 详情 |
| (III) | 67930 | benzyl (2-((tert-butoxycarbonyl)amino)ethyl)(3-oxobutyl)carbamate | C19H28N2O5 | 详情 | 详情 | |
| (IV) | 67931 | benzyl (2-aminoethyl)(3-oxobutyl)carbamate | C14H20N2O3 | 详情 | 详情 | |
| (V) | 67932 | benzyl 5-methyl-1,4-diazepane-1-carboxylate | C14H20N2O2 | 详情 | 详情 | |
| (VI) | 67933 | 1-benzyl 4-tert-butyl 5-methyl-1,4-diazepane-1,4-dicarboxylate | C19H28N2O4 | 详情 | 详情 | |
| (VII) | 67934 | (R)-1-benzyl 4-tert-butyl 5-methyl-1,4-diazepane-1,4-dicarboxylate | C19H28N2O4 | 详情 | 详情 | |
| (VIII) | 67935 | benzyl 5(R)-methyl-1,4-diazepane-1-carboxylate | C14H20N2O2 | 详情 | 详情 | |
| (IX) | 67936 | 5-methyl-2-(1,2,3-triazol-2-yl)benzoic acid | C10H9N3O2 | 详情 | 详情 | |
| (X) | 34151 | 2-iodo-5-methylbenzoic acid | 52548-14-8 | C8H7IO2 | 详情 | 详情 |
| (XI) | 67937 | 2H-1,2,3-triazole | C2H3N3 | 详情 | 详情 | |
| (XII) | 67938 | (R)-benzyl 5-methyl-4-(5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl)-1,4-diazepane-1-carboxylate | C24H27N5O3 | 详情 | 详情 | |
| (XIII) | 67939 | (R)-(7-methyl-1,4-diazepan-1-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone | C16H21N5O | 详情 | 详情 | |
| (XIV) | 67940 | 2,5-dichloro-1,3-benzoxazole；2,5-Dichlorobenzoxazole | 3621-81-6 | C7H3Cl2NO | 详情 | 详情 |
| (XV) | 67941 | 5-chloro-2-mercaptobenzoxazole | 22876-19-3 | C7H4ClNOS | 详情 | 详情 |
合成路线13
该中间体在本合成路线中的序号：(I)Process route to suvorexant starts with treatment of dichlorobenzoxazole (XIV) with N-Boc-ethylenediamine (I) in the presence of Et3N to provide 82% yield of 2-aminobenzoxazole (XXV), which by reaction with methyl vinyl ketone (II) in the presence of DBU in acetonitrile provides intermediate (XXVI) in a high yield. Clean deprotection of (XXVI) is achieved with methanesulfonic acid in THF to give 94% of aminoketone in the form of salt (XXVII). Reductive cyclization of this salt by means of Na(OAc)3BH in the presence of NaOAc in CH2Cl2 provides 98% yield of racemic diazepane (XXVIII). An extensive screening of classical resolution methods for racemate (XXVIII) led to optimal conditions based on resolution with dibenzoyl-L-tartaric acid in THF/CH2Cl2, giving 39% yield (74% ee). Recrystallization of this salt in a 4:1 mixture of i-PrAc/MeOH then provided a 70% yield (96% ee). Treatment of the tartrate salt with NaOH provided the free base (XXIX), which is finally condensed with acid chloride (XXIV) in the presence of Et3N, giving a 95% yield of suvorexant .
| 【1】 Baxter, C.A., Cleator, E., Brands, K.M.J. et al. The first large-scale synthesis of MK-4305: A dual orexin receptor antagonist for the treatment of sleep disorder. Org Proc Res Dev 2011, 15(2): 367-75. |
| 【2】 Wallace, D.J. Development of the manufacturing route for suvorexant - A dual orexin antagonist for sleep disorder. 244th ACS Natl Meet Exp (Aug 19-23, Philadelphia) 2012, Abst ORGN-271. |
| 【3】 Baxter, C.A. Development of the manufacturing route for suvorexant - A dual orexin antagonist for sleep disorder. Balticum Organicum Syntheticum Intl Conf Org Synth (July 1-4, Tallinn) 2012, p 16. |
| 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) | 13241 | N-Boc-ethylenediamine;tert-butyl (2-aminoethyl)carbamate；tert-butyl 2-aminoethylcarbamate; tert-Butyl n-(2-aminoethyl)carbamate | 57260-73-8 | C7H16N2O2 | 详情 | 详情 |
| (II) | 30324 | 3-buten-2-one; methyl vinyl ketone | 78-94-4 | C4H6O | 详情 | 详情 |
| (XIV) | 67940 | 2,5-dichloro-1,3-benzoxazole；2,5-Dichlorobenzoxazole | 3621-81-6 | C7H3Cl2NO | 详情 | 详情 |
| (XXIV) | 67949 | 5-methyl-2-(1,2,3-triazol-2-yl)benzoyl chloride | C10H8ClN3O | 详情 | 详情 | |
| (XXV) | 67950 | tert-butyl (2-((5-chlorobenzo[d]oxazol-2-yl)amino)ethyl)carbamate | C14H18ClN3O3 | 详情 | 详情 | |
| (XXVI) | 67951 | tert-butyl (2-((5-chlorobenzo[d]oxazol-2-yl)(3-oxobutyl)amino)ethyl)carbamate | C18H24ClN3O4 | 详情 | 详情 | |
| (XXVII) | 67952 | 4-((2-aminoethyl)(5-chlorobenzo[d]oxazol-2-yl)amino)butan-2-one dimethanesulfonate | C13H16ClN3O3.2CH4O3S | 详情 | 详情 | |
| (XXVIII) | 67953 | 5-chloro-2-(5-methyl-1,4-diazepan-1-yl)benzo[d]oxazole | C13H16ClN3O | 详情 | 详情 | |
| (XXIX) | 67954 | (R)-5-chloro-2-(5-methyl-1,4-diazepan-1-yl)benzo[d]oxazole | C13H16ClN3O | 详情 | 详情 |
合成路线14
该中间体在本合成路线中的序号：(XI)The pyrazolyl urea intermediate (IV) is prepared as follows. Treatment of 5-amino-1-methylpyrazole (VI) with NaNO2/HCl in water at 5 oC gives the 4-nitrosopyrazole derivative (VII), which is reduced to the diaminopyrazole (VIII) by catalytic hydrogenation over Pd/C in the presence of H2SO4. Selective acylation of the 4-amino group of compound (VIII) with phenyl chloroformate in the presence of NaOH in H2O/dioxane at 10 oC then yields the phenyl carbamate (IX). After protection of the free amine group of carbamate (IX) with chlorotriphenylmethane in the presence of Et3N in THF, the resulting N-trityl derivative (X) is coupled with N-Boc-ethylenediamine (XI) in the presence of Et3N in DMF to afford pyrazolyl urea (IV) .
| 【1】 Ohki, H., Yamanaka, T., Toda, A. et al. (Astellas Pharma, Inc.; Wakunaga Pharmaceutical Co., Ltd.). Cephem compounds. EP 1556389, JP 2006506459, US 7129232, US 2007037786, WO 2004039814. |
| 【2】 Toda, A., Ohki, H., Yamanaka, T. et al. Synthesis and SAR of novel parenteral anti-pseudomonal cephalosporins: Discovery of FR264205. Bioorg Med Chem Lett 2008, 18(17): 4849-52. |
| 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) | 69139 | 4-[(N-Boc-aminoethyl)carbamoylamino]-1-methyl-5-tritylaminopyrazole;tert-butyl (2-(3-(1-methyl-5-(tritylamino)-1H-pyrazol-4-yl)ureido)ethyl)carbamate | C31H36N6O3 | 详情 | 详情 | |
| (VI) | 69140 | 1-methyl-1H-pyrazol-5-amine；1-Methyl-1H-pyrazol-5-ylamine | 1192-21-8 | C4H7N3 | 详情 | 详情 |
| (VII) | 69141 | 1-methyl-4-nitro-1H-pyrazol-5-amine；5-Amino-1-methyl-4-nitropyrazole | 19868-85-0 | C4H6N4O2 | 详情 | 详情 |
| (VIII) | 69142 | 1-methyl-1H-pyrazole-4,5-diamine | C4H8N4 | 详情 | 详情 | |
| (IX) | 69143 | phenyl (5-amino-1-methyl-1H-pyrazol-4-yl)carbamate | C11H12N4O2 | 详情 | 详情 | |
| (X) | 69144 | phenyl (1-methyl-5-(tritylamino)-1H-pyrazol-4-yl)carbamate | C30H26N4O2 | 详情 | 详情 | |
| (XI) | 13241 | N-Boc-ethylenediamine;tert-butyl (2-aminoethyl)carbamate；tert-butyl 2-aminoethylcarbamate; tert-Butyl n-(2-aminoethyl)carbamate | 57260-73-8 | C7H16N2O2 | 详情 | 详情 |