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【结 构 式】 
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【分子编号】19331 【品名】3-aminopropylamine; 1,3-propanediamine 【CA登记号】109-76-2 |
【 分 子 式 】C3H10N2 【 分 子 量 】74.12588 【元素组成】C 48.61% H 13.6% N 37.79% |
合成路线1
该中间体在本合成路线中的序号：(VI)1,3-Diaminopropane (VI) was protected as the bis-sulfonamide (VIII) by acylation with mesitylenesulfonyl chloride (VII). The sodium salt of sulfonamide (VIII) was then alkylated with mesylate (V) in cold DMF/toluene to provide the fully protected tetraamine (IX). The sulfonyl and carbamate protecting groups of (IX) were finally removed by treatment with HCl in the presence of phenol at 80 C.
| 【1】 Mignonac, S.; Guy, A.; De Lamer, V. (Sanofi-Synthelabo); Preparation of polyamine(s), substd. on terminal nitrogen atoms. FR 2714052 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (V) | 59218 | 3-[[(benzyloxy)carbonyl](ethyl)amino]propyl methanesulfonate | C14H21NO5S | 详情 | 详情 | |
| (VI) | 19331 | 3-aminopropylamine; 1,3-propanediamine | 109-76-2 | C3H10N2 | 详情 | 详情 |
| (VII) | 41158 | 2,4,6-trimethylbenzenesulfonyl chloride | 773-64-8 | C9H11ClO2S | 详情 | 详情 |
| (VIII) | 59219 | N-{3-[(mesitylsulfonyl)amino]propyl}-2,4,6-trimethylbenzenesulfonamide | C21H30N2O4S2 | 详情 | 详情 | |
| (IX) | 59220 | benzyl ethyl[12-ethyl-4,8-bis(mesitylsulfonyl)-13-oxo-15-phenyl-14-oxa-4,8,12-triazapentadec-1-yl]carbamate | C47H64N4O8S2 | 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 monoprotection of propane-1,3-diamine (I) with Boc2O in dichloromethane gives the N-(3-aminopropyl)carbamic acid tert-butyl ester (II), which is condensed with vinylphosphonic acid diethyl ester (III) to yield the aminoethylphosphonic ester derivative (IV). The condensation of (IV) with 3,4-diethoxycyclobutene-1,2-dione (V) in ethanol affords the disubstituted 2-aminoethylphosphonic ester derivative (VI), which is cyclized by means of trifluoroacetic acid in dichloromethane to provide the bicyclic phosphonic ester (VII). Finally, the phosphonic ester group of (VII) is hydrolyzed by means of trimethylsilyl bromide in dichloromethane to furnish the target phosphonic acid.
| 【1】 Kinney, W.A.; Schmid, J.; Asselin, A.A. (Wyeth); Process for the preparation of [2-((8.9)-dioxo-2,6-diazabicyclo[5.2.0]-non-1(7)-en-2-yl)ethyl]phosphonic acid. US 5990307 . |
| 【2】 Kinney, W.A.; Schmid, J.; Asselin, A.A. (Wyeth); Process for the preparation of [2-((8,9)-dioxo-2,6-diazabicyclo[5.2.0]-non-1(7)-en-2-yl)-ethyl]phosphonic acid. WO 9906417 . |
| 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) | 19331 | 3-aminopropylamine; 1,3-propanediamine | 109-76-2 | C3H10N2 | 详情 | 详情 |
| (II) | 52474 | 1,1-dimethylethyl 3-aminopropylcarbamate | C8H18N2O2 | 详情 | 详情 | |
| (III) | 54644 | diethyl vinylphosphonate | C6H13O3P | 详情 | 详情 | |
| (IV) | 54645 | diethyl 2-({3-[(tert-butoxycarbonyl)amino]propyl}amino)ethylphosphonate | C14H31N2O5P | 详情 | 详情 | |
| (V) | 30975 | 3,4-diethoxy-3-cyclobutene-1,2-dione | 5231-87-8 | C8H10O4 | 详情 | 详情 |
| (VI) | 54646 | diethyl 2-[{3-[(tert-butoxycarbonyl)amino]propyl}(2-ethoxy-3,4-dioxo-1-cyclobuten-1-yl)amino]ethylphosphonate | C20H35N2O8P | 详情 | 详情 | |
| (VII) | 54142 | diethyl 2-[8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl]ethylphosphonate | n/a | C13H21N2O5P | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(CXXIV)In a further synthetic strategy, an azido precursor of spermidine (CXXX) was used in the reductive amination step. Condensation between 1,3-diaminopropane (CXXIV) and 4-chloro-1-butanol (CXXV) provided the diamino alcohol (CXXVI). Protection of the amino groups of (CXXVI) with di-tert-butyl dicarbonate yielded alcohol (CXXVII), which was converted to mesylate (CXXVIII) by treatment with methanesulfonyl chloride and triethylamine. Subsequent mesylate displacement in (CXXVIII) with NaN3 in DMF furnished the di-Boc-protected azide (CXXIX). The Boc protecting groups of (CXXIX) were then removed by treatment with HCl to give the desired diamino azide (CXXX). Reductive amination of the 3-keto steroid (CXXI) with amine (CXXX) yielded the 3-beta amino steroid (CXXXI). The azido group of (CXXXI) was finally reduced to the title triamino compound by catalytic hydrogenation over Raney-Ni.
| 【1】 Weis, A.L.; et al.; Synthesis of an azido spermidine equivalent. Tetrahedron Lett 1999, 40, 26, 4863. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (CXXIV) | 19331 | 3-aminopropylamine; 1,3-propanediamine | 109-76-2 | C3H10N2 | 详情 | 详情 |
| (CXXV) | 19490 | 3-chloro-1-propanol | 627-30-5 | C3H7ClO | 详情 | 详情 |
| (CXXI) | 53799 | (1R,4R)-4-[(5S,7R,8R,9S,10S,13R,14S,17R)-7-hydroxy-10,13-dimethyl-3-oxohexadecahydro-1H-cyclopenta[a]phenanthren-17-yl]-1-isopropylpentyl hydrogen sulfate | n/a | C27H46O6S | 详情 | 详情 |
| (CXXVI) | 53802 | 3-[(3-aminopropyl)amino]-1-propanol | n/a | C6H16N2O | 详情 | 详情 |
| (CXXVII) | 53803 | tert-butyl 3-[(tert-butoxycarbonyl)amino]propyl(3-hydroxypropyl)carbamate | n/a | C16H32N2O5 | 详情 | 详情 |
| (CXXVIII) | 53804 | 3-((tert-butoxycarbonyl){3-[(tert-butoxycarbonyl)amino]propyl}amino)propyl methanesulfonate | n/a | C17H34N2O7S | 详情 | 详情 |
| (CXXIX) | 53805 | tert-butyl 3-azidopropyl{3-[(tert-butoxycarbonyl)amino]propyl}carbamate | n/a | C16H31N5O4 | 详情 | 详情 |
| (CXXX) | 53806 | N-(3-aminopropyl)-N-(3-azidopropyl)amine; N1-(3-azidopropyl)-1,3-propanediamine | n/a | C6H15N5 | 详情 | 详情 |
| (CXXXII) | 53807 | (1R,4R)-4-[(3S,5R,7R,8R,9S,10S,13R,14S,17R)-3-({3-[(3-azidopropyl)amino]propyl}amino)-7-hydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl]-1-isopropylpentyl hydrogen sulfate | n/a | C33H61N5O5S | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XVI)Displacement of the benzylic bromide (XIII) with concomitant hydrolysis of the phenolic acetate with ethanolamine (XIV) gave amine (XV). A further aromatic bromide of (XV) was displaced with hot 1,3-propanediamine (XVI), yielding adduct (XVII). Hydrogenolysis of the remaining bromide of (XVII) using Pd/C furnished (XVIII). Finally, methyl ether cleavage in (XVIII) with hot HCl provided the title compound
| 【1】 Mimura, T.; Kato, N.; Sugaya, T.; Ikuta, M.; Kato, S.; Kuge, Y.; Tomioka, S.; Kasai, M.; An efficient synthesis of a new class of DNA intercalating antitumor 7,10-dihydroxy-6H-pyrazolo[4,5,1-de]acridin-6-ones. Synthesis (Stuttgart) 1999, 6, 947. |
| 【2】 Mimura, Y.; Shida, Y.; Kasai, M.; Ashizawa, T.; Gomi, K. (Kyowa Hakko Kogyo Co., Ltd.); Pyrazoloacridone derivs.. EP 0487097; JP 1993001064; US 5220026 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIII) | 60010 | 5,8-dibromo-2-(bromomethyl)-7-methoxy-6-oxo-6H-pyrazolo[4,5,1-de]acridin-10-yl acetate | C18H11Br3N2O4 | 详情 | 详情 | |
| (XIV) | 10259 | Ethanol amine;Ethanolamine;2-Aminoethanol; 2-Amino-1-ethanol；2-Aminoethyl alcohol | 141-43-5 | C2H7NO | 详情 | 详情 |
| (XV) | 60011 | 5,8-dibromo-10-hydroxy-2-{[(2-hydroxyethyl)amino]methyl}-7-methoxy-6H-pyrazolo[4,5,1-de]acridin-6-one | C18H15Br2N3O4 | 详情 | 详情 | |
| (XVI) | 19331 | 3-aminopropylamine; 1,3-propanediamine | 109-76-2 | C3H10N2 | 详情 | 详情 |
| (XVII) | 60012 | 5-[(3-aminopropyl)amino]-8-bromo-10-hydroxy-2-{[(2-hydroxyethyl)amino]methyl}-7-methoxy-6H-pyrazolo[4,5,1-de]acridin-6-one | C21H24BrN5O4 | 详情 | 详情 | |
| (XVIII) | 60013 | 5-[(3-aminopropyl)amino]-10-hydroxy-2-{[(2-hydroxyethyl)amino]methyl}-7-methoxy-6H-pyrazolo[4,5,1-de]acridin-6-one | C21H25N5O4 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(XVI)An improved synthesis of the title compound has been developed. Methyl ester (XX) was prepared from the known indazolylbenzoate sodium salt (XIX) by alkylation with iodomethane and K2CO3. Benzylic bromination of (XX) using NBS in the presence of AIBN as the radical initiator furnished the bromomethyl derivative (XXI). The brominated ester (XXI) was cyclized with trifluoromethanesulfonic acid at 100 C to provide the pyrazoloacridone (XXII) along with some phenol analogue (XXIII). Complete cleavage of the methyl ether of (XXII) was then accomplished with HBr in AcOH at 70 C. Further bromination of (XXIII) with elemental bromine in dichloroethane gave the ortho-bromophenol (XXIV). Introduction of the hydroxy group at C-10 was carried out by a two step sequence involving oxidation of (XXIV) to quinone (XXV) with (diacetoxy)iodobenzene, followed by its reduction to the corresponding hydroquinone (XXVI) with tetrabutylammonium triacetoxyborohydride. Condensation of (XXVI) with N-benzylethanolamine (XXVII) yielded the tertiary amine (XXVIII). Further bromine displacement in (XXVIII) with 1,3-propanediamine (XVI) provided (XXIX). The remaining bromine and the N-benzyl protecting groups of (XXIX) were finally subjected to hydrogenolysis in the presence of Pd/C
| 【1】 Mimura, T.; Kato, N.; Sugaya, T.; Ikuta, M.; Kato, S.; Kuge, Y.; Tomioka, S.; Kasai, M.; An efficient synthesis of a new class of DNA intercalating antitumor 7,10-dihydroxy-6H-pyrazolo[4,5,1-de]acridin-6-ones. Synthesis (Stuttgart) 1999, 6, 947. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XVI) | 19331 | 3-aminopropylamine; 1,3-propanediamine | 109-76-2 | C3H10N2 | 详情 | 详情 |
| (XIX) | 60014 | 2-(6-bromo-3-methyl-1H-indazol-1-yl)-6-methoxybenzoate | C16H12BrN2O3 | 详情 | 详情 | |
| (XX) | 60015 | methyl 2-(6-bromo-3-methyl-1H-indazol-1-yl)-6-methoxybenzoate | C17H15BrN2O3 | 详情 | 详情 | |
| (XXI) | 60016 | methyl 2-[6-bromo-3-(bromomethyl)-1H-indazol-1-yl]-6-methoxybenzoate | C17H14Br2N2O3 | 详情 | 详情 | |
| (XXII) | 60017 | 5-bromo-2-(bromomethyl)-7-methoxy-6H-pyrazolo[4,5,1-de]acridin-6-one | C16H10Br2N2O2 | 详情 | 详情 | |
| (XXIII) | 60018 | 5-bromo-2-(bromomethyl)-7-hydroxy-6H-pyrazolo[4,5,1-de]acridin-6-one | C15H8Br2N2O2 | 详情 | 详情 | |
| (XXIV) | 60019 | 5,8-dibromo-2-(bromomethyl)-7-hydroxy-6H-pyrazolo[4,5,1-de]acridin-6-one | C15H7Br3N2O2 | 详情 | 详情 | |
| (XXV) | 60005 | 5,8-dibromo-7-hydroxy-2-methyl-6H-pyrazolo[4,5,1-de]acridin-6-one | C15H8Br2N2O2 | 详情 | 详情 | |
| (XXVI) | 60007 | 5,8-dibromo-7,10-dihydroxy-2-methyl-6H-pyrazolo[4,5,1-de]acridin-6-one | C15H8Br2N2O3 | 详情 | 详情 | |
| (XXVII) | 25630 | 2-(benzylamino)-1-ethanol | 104-63-2 | C9H13NO | 详情 | 详情 |
| (XXVIII) | 60020 | 2-{[benzyl(butyl)amino]methyl}-5,8-dibromo-7,10-dihydroxy-6H-pyrazolo[4,5,1-de]acridin-6-one | C26H23Br2N3O3 | 详情 | 详情 | |
| (XXIX) | 60021 | 5-[(3-aminopropyl)amino]-2-{[benzyl(butyl)amino]methyl}-8-bromo-7,10-dihydroxy-6H-pyrazolo[4,5,1-de]acridin-6-one | C29H32BrN5O3 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(I)Monoalkylation of 1,3-propanediamine (I) with 4-chlorobutanol (II) in refluxing n-BuOH afforded diaminoalcohol (III), which was protected as the bis-carbamate (IV) upon treatment with Boc2O. Subsequent reaction of (IV) with methanesulfonyl chloride and Et3N provided mesylate (V), and this was further treated with ethanolic ammonia to yield primary amine (VI). Condensation of amine (VI) with (methoxycarbonylmethyl) phenyl carbonate (VII) in refluxing toluene gave carbamate (VIII). Saponification of the methyl ester function of (VIII) then furnished carboxylic acid (IX). 1,6-Hexanediamine (X) was condensed with N,N'-bis(tert-butoxycarbonyl)-S-methylisothiourea (XI) to produce the (6-aminohexyl)guanidine derivative (XII). This was then coupled with carboxylic acid (IX) using DCC and HOBt. Finally, the N-Boc groups were deprotected with trifluoroacetic acid in CH2Cl2.
| 【1】 Lebreton, L.; Annat, J.; Derrepas, P.; Dutartre, P.; Renaut, P.; Structure-immunosuppressive activity relationships of new analogues of 15-deoxyspergualin. 1. Structural modifications of the hydroxyglycine moiety. J Med Chem 1999, 42, 2, 277. |
| 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) | 19331 | 3-aminopropylamine; 1,3-propanediamine | 109-76-2 | C3H10N2 | 详情 | 详情 |
| (II) | 22336 | 4-chloro-1-butanol | 928-51-8 | C4H9ClO | 详情 | 详情 |
| (III) | 22337 | 4-[(3-aminopropyl)amino]-1-butanol | C7H18N2O | 详情 | 详情 | |
| (IV) | 22338 | tert-butyl 3-[(tert-butoxycarbonyl)amino]propyl(4-hydroxybutyl)carbamate | C17H34N2O5 | 详情 | 详情 | |
| (V) | 22339 | 4-((tert-butoxycarbonyl)[3-[(tert-butoxycarbonyl)amino]propyl]amino)butyl methanesulfonate | C18H36N2O7S | 详情 | 详情 | |
| (VI) | 22340 | tert-butyl 4-aminobutyl[3-[(tert-butoxycarbonyl)amino]propyl]carbamate | C17H35N3O4 | 详情 | 详情 | |
| (VII) | 22341 | methyl 2-[(phenoxycarbonyl)oxy]acetate | C10H10O5 | 详情 | 详情 | |
| (VIII) | 22342 | methyl 9-(tert-butoxycarbonyl)-2,2-dimethyl-4,15-dioxo-3,16-dioxa-5,9,14-triazaoctadecan-18-oate | C21H39N3O8 | 详情 | 详情 | |
| (IX) | 22343 | 9-(tert-butoxycarbonyl)-2,2-dimethyl-4,15-dioxo-3,16-dioxa-5,9,14-triazaoctadecan-18-oic acid | C20H37N3O8 | 详情 | 详情 | |
| (X) | 22344 | 1,6-hexanediamine; 6-aminohexylamine | 124-09-4 | C6H16N2 | 详情 | 详情 |
| (XI) | 22345 | tert-butyl (E)-[(tert-butoxycarbonyl)amino](methylsulfanyl)methylidenecarbamate | C12H22N2O4S | 详情 | 详情 | |
| (XII) | 22346 | tert-butyl (Z)-[(6-aminohexyl)amino][(tert-butoxycarbonyl)amino]methylidenecarbamate | C17H34N4O4 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(XVII)The trifluoroacetylated intermediate (XIII) has been obtained as follows: The reductocondensation of 1-(benzyloxycarbonyl)-4-piperidone (XVI) with propylene-1,3-diamine (XVII) by means of NaBH3CN in methanol/acetic acid gives 4-(3-aminopropylamino)-1-(benzyloxycarbonyl)piperidine (XVIII), which is acylated with trifluoroacetyl anhydride and triethylamine in chloroform yielding the protected diacylated piperidine (XIX). Finally, this compound is deprotected by hydrogenation with H2 over Pd/C in ethanol to afford the target intermediate (XIII).
| 【1】 Miller, S.C. (AstraZeneca plc); Therapeutic heterocycles which antagonize neurokinin receptors. JP 1997501439; US 5567700; US 5990130; US 6124279; WO 9505377 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIII) | 26944 | 2,2,2-trifluoro-N-(4-piperidinyl)-N-[3-[(2,2,2-trifluoroacetyl)amino]propyl]acetamide | C12H17F6N3O2 | 详情 | 详情 | |
| (XVI) | 26947 | benzyl 4-oxo-1-piperidinecarboxylate; N-Benzyloxycarbonyl-4-piperidone | 19099-93-5 | C13H15NO3 | 详情 | 详情 |
| (XVII) | 19331 | 3-aminopropylamine; 1,3-propanediamine | 109-76-2 | C3H10N2 | 详情 | 详情 |
| (XVIII) | 26948 | benzyl 4-[(3-aminopropyl)amino]-1-piperidinecarboxylate | C16H25N3O2 | 详情 | 详情 | |
| (XIX) | 26949 | benzyl 4-((2,2,2-trifluoroacetyl)[3-[(2,2,2-trifluoroacetyl)amino]propyl]amino)-1-piperidinecarboxylate | C20H23F6N3O4 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(II)Pyrroline (III) was prepared by Favorskii rearrangement of 3,5-dibromo-2,2,6,6-tetramethylpiperidinone (I) in the presence of 1,3-diaminopropane (II). Acylation at the primary amino group of (III) with phthalic anhydride (IV) gave the 2-carboxybenzamide (VI), which was cyclized to the target phthalimide (VII) by refluxing in toluene in the presence of Et3N. Alternatively, the phthalimido derivative (VII) was obtained by condensation of amine (III) with phthalimide (V) at 150 C. The target compound was then isolated as the hydrochloride salt upon treatment with HCl in EtOH-Et2O.
| 【1】 Bodi, I.; Csak, J.; Frank, L.; Hankovszky, O.H.; Hideg, K. (Alkaloida Chemical Co. Ltd.); New alkyl diamine derivatives. EP 0134225; JP 1985500669; US 4703056; US 5028609; US 5032600; WO 8402907 . |
| 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) | 25327 | 3,5-dibromo-2,2,6,6-tetramethyl-4-piperidinone | 57167-75-6 | C9H15Br2NO | 详情 | 详情 |
| (II) | 19331 | 3-aminopropylamine; 1,3-propanediamine | 109-76-2 | C3H10N2 | 详情 | 详情 |
| (III) | 25328 | N-(3-aminopropyl)-2,2,5,5-tetramethyl-2,5-dihydro-1H-pyrrole-3-carboxamide | C12H23N3O | 详情 | 详情 | |
| (IV) | 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 |
| (V) | 12376 | Phthalimide; 1H-Isoindole-1,3(2H)-dione; Isoindole-1,3-dione;Phthalic dicarboximide;Phenylimide;Isoindole-1,3-dione | 85-41-6 | C8H5NO2 | 详情 | 详情 |
| (VI) | 25329 | 2-[[(3-[[(2,2,5,5-tetramethyl-2,5-dihydro-1H-pyrrol-3-yl)carbonyl]amino]propyl)amino]carbonyl]benzoic acid | C20H27N3O4 | 详情 | 详情 | |
| (VII) | 25330 | N-[3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propyl]-2,2,5,5-tetramethyl-2,5-dihydro-1H-pyrrole-3-carboxamide | C20H25N3O3 | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(II)Reaction of 2,5-dibromopyridine (I) with an excess of 1,3-diaminopropane (II) in refluxing pyridine provided N-1-(2-pyridyl)propanediamine (III). This compound was further alkylated at the 1N with 3,4-dichlorobenzyl chloride (IV) in DMSO using NaH as the base to afford (V). From this, isothiocyanate (VI) was prepared by reaction with CS2 and DCC in THF. Subsequent coupling with trityl-protected amine (VII) yielded the thiourea (VIII). Finally, the trityl protecting group was removed by refluxing in 1 N HCl.
| 【1】 Liu, S.; Tang, C.; Ho, B.; Ankersen, M.; Stidsen, C.E.; Crider, A.M.; Nonpeptide somatostatin agonists with sst4 selectivity: Synthesis and structure-activity relationships of thioureas. J Med Chem 1998, 41, 24, 4693. |
| 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) | 19330 | 2,5-dibromopyridine | 624-28-2 | C5H3Br2N | 详情 | 详情 |
| (II) | 19331 | 3-aminopropylamine; 1,3-propanediamine | 109-76-2 | C3H10N2 | 详情 | 详情 |
| (III) | 19332 | N-(3-aminopropyl)-N-(5-bromo-2-pyridinyl)amine; N(1)-(5-bromo-2-pyridinyl)-1,3-propanediamine | C8H12BrN3 | 详情 | 详情 | |
| (IV) | 19333 | 1,2-dichloro-4-(chloromethyl)benzene | 102-47-6 | C7H5Cl3 | 详情 | 详情 |
| (V) | 19334 | N(1)-(5-bromo-2-pyridinyl)-N(1)-(3,4-dichlorobenzyl)-1,3-propanediamine; N-(3-aminopropyl)-N-(5-bromo-2-pyridinyl)-N-(3,4-dichlorobenzyl)amine | C15H16BrCl2N3 | 详情 | 详情 | |
| (VI) | 19335 | N-(5-bromo-2-pyridinyl)-N-(3,4-dichlorobenzyl)-N-(3-isothiocyanatopropyl)amine; 5-bromo-N-(3,4-dichlorobenzyl)-N-(3-isothiocyanatopropyl)-2-pyridinamine | C16H14BrCl2N3S | 详情 | 详情 | |
| (VII) | 19336 | 3-(1-trityl-1H-imidazol-4-yl)-1-propanamine; 3-(1-trityl-1H-imidazol-4-yl)propylamine | C25H25N3 | 详情 | 详情 | |
| (VIII) | 19337 | N-[3-[(5-bromo-2-pyridinyl)(3,4-dichlorobenzyl)amino]propyl]-N'-[3-(1-trityl-1H-imidazol-4-yl)propyl]thiourea | C41H39BrCl2N6S | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(VII)Displacement of 2-chloro-4-ethoxyquinoline (VI) with 1,3-propanediamine (VII) affords the aminoquinoline (VIII). Subsequent acidic hydrolysis of (VIII) provides quinolinone (IX). Finally, reductive condensation between amine (IX) and ketone (V) in the presence of NaBH3CN leads to the target disubstituted propanediamine
| 【1】 Jarvest, R.L.; Berge, J.M.; Berry, V.; et al.; Nanomolar inhibitors of Staphylococcus aureus methionyl tRNA synthetase with potent antibacterial activity against Gram-positive pathogens. J Med Chem 2002, 45, 10, 1959. |
| 【2】 Berge, J.M.; Forrest, A.K.; Elder, J.S.; Jarvest, R.L. (GlaxoSmithKline plc); Quinolones as t-RNA synthetase inhibitors and antibacterial agents. WO 0021949 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (V) | 60626 | 6-ethyl-8-iodo-2,3-dihydro-4(1H)-quinolinone | C11H12INO | 详情 | 详情 | |
| (VI) | 60627 | 2-chloro-4-ethoxyquinoline; 2-chloro-4-quinolinyl ethyl ether | C11H10ClNO | 详情 | 详情 | |
| (VII) | 19331 | 3-aminopropylamine; 1,3-propanediamine | 109-76-2 | C3H10N2 | 详情 | 详情 |
| (VIII) | 60628 | N-(3-aminopropyl)-N-(4-ethoxy-2-quinolinyl)amine; N~1~-(4-ethoxy-2-quinolinyl)-1,3-propanediamine | C14H19N3O | 详情 | 详情 | |
| (IX) | 60629 | 2-[(3-aminopropyl)amino]-4(1H)-quinolinone | C12H15N3O | 详情 | 详情 |
合成路线11
该中间体在本合成路线中的序号：(IV)Alkylation of sodium cyanide with 4-tert-butyl-2,6-dimethylbenzyl chloride (I) afforded nitrile (II). Imidate (III) was then prepared by Pinner reaction of nitrile (II) with ethanolic HCl. Cyclization of (III) with 1,3-diaminopropane (IV) in ethanol furnished the desired cyclic amidine. In an alternative procedure, the target amidine was directly obtained by melting at 200 C nitrile (II) with the mono-tosylate salt of 1,3-diaminopropane.
| 【1】 Prisinzano, T.; et al.; Imidazoline-modified benzylimidazolines as h5-HT1D/1B serotonergic ligands. Bioorg Med Chem 2001, 9, 3, 613. |
| 【2】 Glennon, R.A.; Law, H. (NPS Allelix Corp.; Virginia Commonwealth University); Imidazoles with serotonin receptor binding activity. US 5969137; WO 9812183 . |
| 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) | 49759 | 5-(tert-butyl)-2-(chloromethyl)-1,3-dimethylbenzene | C13H19Cl | 详情 | 详情 | |
| (II) | 49760 | 2-[4-(tert-butyl)-2,6-dimethylphenyl]acetonitrile | C14H19N | 详情 | 详情 | |
| (III) | 49761 | ethyl 2-[4-(tert-butyl)-2,6-dimethylphenyl]ethanimidoate | C16H25NO | 详情 | 详情 | |
| (IV) | 19331 | 3-aminopropylamine; 1,3-propanediamine | 109-76-2 | C3H10N2 | 详情 | 详情 |
合成路线12
该中间体在本合成路线中的序号：(VI)The hydrolysis of the 1-isopentyl-4-nitro-1H-pyrrole-2-carboxylic acid ethyl ester (I) with NaOH in hot ethanol gives the carboxylic acid (II), which is treated with refluxing SOCl2 to yield the acyl chloride (III). The reaction of (III) with 3-aminopropionitrile (IV) in toluene affords the carboxamide (V), which is treated with propane-1,3-diamine (VI) and HCl in ethanol to provide the tetrahydropyrimidine derivative (VII). The reduction of the nitro group of (VII) with H2 over Pd/C in methanol gives the aminopyrrole (VIII), which is finally condensed with bis pentafluorophenyl terephthalate (XI) to afford the target terephthalamide. The activated ester bis pentafluorophenyl terephthalate (XI) has been obtained by esterification of terephthalic acid (IX) with pentafluorophenyl trifluoroacetate (X) by means of DIEA in DMF.
| 【1】 Roberts, C.D.; Keicher, J.D.; Dyatkina, N.B.; et al.; Minor groove DNA binders as antimicrobial agents. 1. Pyrrole tetraamides are potent antibacterials against vancomycin resistant Enteroccoci and methicillin resistant Staphylococcus aureus. J Med Chem 2002, 45, 4, 805. |
| 【2】 Nelson, P.H.; Muchowski, J.M.; Dyatkina, N.B.; Shi, D.-F.; Zhang, W.; Liehr, S.J.R.; Velligan, M.D.; Botyanszki, J.; Roberts, C.D.; Khorlin, A. (Genelabs Technologies, Inc.); Novel cpds. possessing antibacterial, antifungal or antitumor activity. WO 0200650 . |
| 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) | 54019 | ethyl 1-isopentyl-4-nitro-1H-pyrrole-2-carboxylate | C12H18N2O4 | 详情 | 详情 | |
| (II) | 54020 | 1-isopentyl-4-nitro-1H-pyrrole-2-carboxylic acid | C10H14N2O4 | 详情 | 详情 | |
| (III) | 54021 | 1-isopentyl-4-nitro-1H-pyrrole-2-carbonyl chloride | C10H13ClN2O3 | 详情 | 详情 | |
| (IV) | 38094 | 3-aminopropanenitrile | 151-18-8 | C3H6N2 | 详情 | 详情 |
| (V) | 54022 | N-(2-cyanoethyl)-1-isopentyl-4-nitro-1H-pyrrole-2-carboxamide | C13H18N4O3 | 详情 | 详情 | |
| (VI) | 19331 | 3-aminopropylamine; 1,3-propanediamine | 109-76-2 | C3H10N2 | 详情 | 详情 |
| (VII) | 54023 | 1-isopentyl-4-nitro-N-[2-(1,4,5,6-tetrahydro-2-pyrimidinyl)ethyl]-1H-pyrrole-2-carboxamide | C16H25N5O3 | 详情 | 详情 | |
| (VIII) | 54024 | 4-amino-1-isopentyl-N-[2-(1,4,5,6-tetrahydro-2-pyrimidinyl)ethyl]-1H-pyrrole-2-carboxamide | C16H27N5O | 详情 | 详情 | |
| (IX) | 54025 | 1,4-Benzenedicarboxylic acid; Benzene-1,4-dicarboxylic acid; p-Benzenedicarboxylic acid; p-Phthalic acid; Terephthalic acid | 100-21-0 | C8H6O4 | 详情 | 详情 |
| (X) | 54026 | Trifluoroacetic acid pentafluorophenylester | 14533-84-7 | C8F8O2 | 详情 | 详情 |
| (XI) | 54027 | bis(2,3,4,5,6-pentafluorophenyl) terephthalate | C20H4F10O4 | 详情 | 详情 |
合成路线13
该中间体在本合成路线中的序号：(II)Condensation of 3-chloro-thiosalicylic acid (I) with 1,3-propanediamine (II) in boiling ortho-dichlorobenzene leads to the cyclic amidine (III). Subsequent alkylation of the thiol group of (III) with 5-bromo-2-methoxybenzyl chloride (IV) furnishes the target thioether
| 【1】 Maguire, M.P.; Dai, M.; Vos, T.J. (Millennium Pharmaceuticals, Inc.); Melanocortin-4 receptor binding cpds. and methods of use thereof. WO 0110842 . |
| 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) | 62066 | 3-chloro-2-sulfanylbenzoic acid | C7H5ClO2S | 详情 | 详情 | |
| (II) | 19331 | 3-aminopropylamine; 1,3-propanediamine | 109-76-2 | C3H10N2 | 详情 | 详情 |
| (III) | 62067 | 2-chloro-6-(1,4,5,6-tetrahydro-2-pyrimidinyl)benzenethiol; 2-chloro-6-(1,4,5,6-tetrahydro-2-pyrimidinyl)phenylhydrosulfide | C10H11ClN2S | 详情 | 详情 | |
| (IV) | 62068 | 4-bromo-2-(chloromethyl)-1-methoxybenzene; 4-bromo-2-(chloromethyl)phenyl methyl ether | C8H8BrClO | 详情 | 详情 |
合成路线14
该中间体在本合成路线中的序号：(I)1,3-Diaminopropane (I) is mono-protected with benzyl chloroformate, producing carbamate (II). Coupling of (II) with N,N'-bis-Boc-S-methylisothiourea (III) yields the Boc-protected guanidine (IV). The benzyloxycarbonyl group of (IV) is then removed by catalytic hydrogenolysis to furnish the noragmatine derivative (V)
| 【1】 Szelke, M.; Evans, D.M.; Jones, D.M. (Ferring AB); Kininogen inhibitors. WO 9507291 . |
| 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) | 19331 | 3-aminopropylamine; 1,3-propanediamine | 109-76-2 | C3H10N2 | 详情 | 详情 |
| (II) | 62059 | benzyl 3-aminopropylcarbamate | C11H16N2O2 | 详情 | 详情 | |
| (III) | 22345 | tert-butyl (E)-[(tert-butoxycarbonyl)amino](methylsulfanyl)methylidenecarbamate | C12H22N2O4S | 详情 | 详情 | |
| (IV) | 62060 | benzyl 3-({[(tert-butoxycarbonyl)amino][(tert-butoxycarbonyl)imino]methyl}amino)propylcarbamate | C22H34N4O6 | 详情 | 详情 | |
| (V) | 26836 | tert-butyl (Z)-[(3-aminopropyl)amino][(tert-butoxycarbonyl)amino]methylidenecarbamate | C14H28N4O4 | 详情 | 详情 |