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【结 构 式】 
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【分子编号】11791 【品名】methyl 3-oxobutanoate; Methyl acetoacetate 【CA登记号】105-45-3 |
【 分 子 式 】C5H8O3 【 分 子 量 】116.11672 【元素组成】C 51.72% H 6.94% O 41.34% |
合成路线1
该中间体在本合成路线中的序号：(III)By cyclization of 2,3-dichlorobenzaldehyde (I) with 3-aminocrotonic acid ethyl ester (II) and acetylacetic acid methyl ester (III) in refluxing ethanol.
| 【1】 Bernston, P.B.; Carlsson, S.A.I.; Gaarder, J.O.; Ljung, B.R. (AstraZeneca AB); 2,6-Dimethyl-4-2,3-disubstituted phenyl-1,4-dihydro-pyridine-3,5-dicarboxylic acid-3,5-asymmetric diesters having hypotensive properties, as well as method for treating hypertensive conditions and pharmaceutical preparations containing same. CA 1117530; EP 0007293; JP 55009083; US 4264611 . |
合成路线2
该中间体在本合成路线中的序号：(II)By cyclization of 2-(difluoromethoxy)benzaldehyde (I) with methyl acetoacetate (II) and refluxing aqueous concentrated ammonia.
| 【1】 Dubur, G.Y.; 2,6-Dimethyl-3,5-dimethoxycarbonyl-4-(o-difluoromethoxyphenyl)1,4-dihydropyridine. DE 2900537; FR 2414501; GB 2013186; JP 79122280; US 4219653 . |
| 【2】 Serradell, M.N.; Castaner, J.; Riodipine. Drugs Fut 1985, 10, 11, 922. |
合成路线3
该中间体在本合成路线中的序号：(IX)The esterification of penicillanic acid (I) with chloromethyl chlorosulfate by means of KHCO3 and tetrabutylammonium hydrogen sulfate in CH2Cl2 - water gives chloromethyl penicillanate (II), which is oxidized to chloromethyl penicillanate 1,1-dioxide (III) by means of H2O2 and sodium tungstate in isopropanol. The reaction of (III) with Na in acetone affords iodomethyl penicillanate 1,1-dioxide (IV), which is condensed with potassium 6-[N-(1-methoxycarbonylpropen-2-yl)-D-alpha-amino-alpha-phenylacetamido]penicillanate (V) in DMF yielding 1,1-dioxopenicillanoyloxymethyl-6-[N-1-methoxycarbonylpropen-2-yl)-D-alpha-amino-alpha-phenylacetamido penicillanate (VI). Finally, this compound is deprotected by treatment with 4N HCl. Compound (III) can also be obtained by direct esterification of penicillanic acid 1,1-dioxide (VII) with chloromethyl chlorosulfate as before. Compound (V) is obtained bv reaction of ampicillin (VIII) with methyl acetoacetate (IX) by means of K2CO3 in DMF.
| 【1】 Baltzer, B.; et al.; Mutual pro-drugs of beta-lactam antibiotics and beta-lactamase inhibitors. J Antibiot 1980, 33, 10, 1183-92. |
| 【2】 Von Daehne, W.; Godtfresen, W.O. (Leo Pharmaceutical Products Ltd. A/S); beta-Lactam compounds, antibacterial compositions thereof and method of use. DE 3005164; FR 2449089; GB 2044255; GB 2108107; US 4342772; US 4840944 . |
| 【3】 Castaner, J.; Serradell, M.N.; Sweetman, A.J.; Blancafort, P.; VD-1825 and VD-1827. Drugs Fut 1981, 6, 8, 496. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 40923 | chloromethanesulfonyl chloride | 3518-65-8 | CH2Cl2O2S | 详情 | 详情 | |
| (I) | 32276 | Penicillanic acid; (5R)-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid | C8H11NO3S | 详情 | 详情 | |
| (II) | 32269 | chloromethyl (5R)-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate | C9H12ClNO3S | 详情 | 详情 | |
| (III) | 32270 | chloromethyl (5R)-3,3-dimethyl-4,4,7-trioxo-4lambda(6)-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate | C9H12ClNO5S | 详情 | 详情 | |
| (IV) | 32271 | iodomethyl (5R)-3,3-dimethyl-4,4,7-trioxo-4lambda(6)-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate | C9H12INO5S | 详情 | 详情 | |
| (V) | 32275 | potassium (2S,5R,6R)-6-[((2R)-2-[[(Z)-3-methoxy-1-methyl-3-oxo-1-propenyl]amino]-2-phenylethanoyl)amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate | C21H24KN3O6S | 详情 | 详情 | |
| (VI) | 32272 | [([(2S,5R,6R)-6-[((2R)-2-[[(Z)-3-methoxy-1-methyl-3-oxo-1-propenyl]amino]-2-phenylethanoyl)amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-yl]carbonyl)oxy]methyl (2S,5R)-3,3-dimethyl-4,4,7-trioxo-4lambda(6)-thia-1-azabicyclo[3.2.0]heptane | C30H36N4O11S2 | 详情 | 详情 | |
| (VII) | 32273 | (5R)-4,4,7-trioxo-4lambda(6)-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid | C6H7NO5S | 详情 | 详情 | |
| (VIII) | 32274 | potassium (2S,5R,6R)-6-[[(2R)-2-amino-2-phenylethanoyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate | C16H18KN3O4S | 详情 | 详情 | |
| (IX) | 11791 | methyl 3-oxobutanoate; Methyl acetoacetate | 105-45-3 | C5H8O3 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(X)An enantioselective total synthesis of chloride (MOM-Cl) and NaH in THF gives the methoxymethyl ether (II), which is methylated with n-BuLi and methyl iodide in THF yielding the 6-methyl derivative (III). The condensation of (III) with 3-methyl-2-butenyl bromide (IV) by means of s-BuLi in THF affords compound (V), which is deprotected with LiBF4 and TMSCl in acetonitrile to give the phenol (VI). Methylation of (VI) with dimethyl sulfate and K2CO3 in refluxing acetone provides the ether (VII), which is hydroxylated at the terminal methyl group with SeO2 and tert-butyl hydroperoxide (TBHP) in dichloromethane giving alcohol (VIII). The reaction of (VIII) with methanesulfonyl chloride and then with LiBr affords the corresponding alkenyl bromide (IX), which is condensed with methyl acetoacetate (X) by means of NaH and n-BuLi in THF providing the ketoester (XI).
| 【1】 Ye, X.-Y.; Yang, D.; Xu, M.; Enantioselective total synthesis of (-)-triptolide, (-)-triptonide, (+)-triptophenolide, and (+)-triptoquinomide. J Org Chem 2000, 65, 7, 2208. |
| 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) | 37653 | 2-isopropylphenol | 88-69-7 | C9H12O | 详情 | 详情 |
| (II) | 37654 | 1-isopropyl-2-(methoxymethoxy)benzene; (2-isopropylphenoxy)methyl methyl ether | C11H16O2 | 详情 | 详情 | |
| (III) | 37655 | 1-isopropyl-2-(methoxymethoxy)-3-methylbenzene; (2-isopropyl-6-methylphenoxy)methyl methyl ether | C12H18O2 | 详情 | 详情 | |
| (IV) | 12989 | 4-Bromo-2-methyl-2-butene; 1-Bromo-3-methyl-2-butene | 870-63-3 | C5H9Br | 详情 | 详情 |
| (V) | 37656 | 1-isopropyl-2-(methoxymethoxy)-3-(4-methyl-3-pentenyl)benzene; [2-isopropyl-6-(4-methyl-3-pentenyl)phenoxy]methyl methyl ether | C17H26O2 | 详情 | 详情 | |
| (VI) | 37657 | 2-isopropyl-6-(4-methyl-3-pentenyl)phenol | C15H22O | 详情 | 详情 | |
| (VII) | 37658 | 1-isopropyl-2-methoxy-3-(4-methyl-3-pentenyl)benzene; 2-isopropyl-6-(4-methyl-3-pentenyl)phenyl methyl ether | C16H24O | 详情 | 详情 | |
| (VIII) | 37659 | (E)-5-(3-isopropyl-2-methoxyphenyl)-2-methyl-2-penten-1-ol | C16H24O2 | 详情 | 详情 | |
| (IX) | 37660 | 2-[(E)-5-bromo-4-methyl-3-pentenyl]-6-isopropylphenyl methyl ether; 1-[(E)-5-bromo-4-methyl-3-pentenyl]-3-isopropyl-2-methoxybenzene | C16H23BrO | 详情 | 详情 | |
| (X) | 11791 | methyl 3-oxobutanoate; Methyl acetoacetate | 105-45-3 | C5H8O3 | 详情 | 详情 |
| (XI) | 35414 | methyl (E)-9-(3-isopropyl-2-methoxyphenyl)-6-methyl-3-oxo-6-nonenoate | C21H30O4 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(IV)Compound can be prepared in two different ways: 1) By heating at 100 C a mixture of m-nitrobenzaldehyde (I), methyl beta-aminocrotonate (II) and N-benzyl-N-methylaminoethyl acetoacetate (III). 2) By cyclization of a mixture of m-nitrobenzaldehyde (I), methyl acetoacetate (IV) and N-benzyl-N-methylaminoethyl beta + aminocrotonate (V) in refluxing isopropanol.
| 【1】 Murakami, M.; et al.; BE 0811324 . |
| 【2】 Roberts, P.J.; Castaner, J.; YC-93. Drugs Fut 1977, 2, 6, 409. |
| 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) | 12646 | 3-Nitrobenzaldehyde | 99-61-6 | C7H5NO3 | 详情 | 详情 |
| (II) | 11372 | Methyl (E)-3-amino-2-butenoate; Methyl 3-aminocrotonate | C5H9NO2 | 详情 | 详情 | |
| (III) | 33898 | 2-[benzyl(methyl)amino]ethyl 3-oxobutanoate | C14H19NO3 | 详情 | 详情 | |
| (IV) | 11791 | methyl 3-oxobutanoate; Methyl acetoacetate | 105-45-3 | C5H8O3 | 详情 | 详情 |
| (V) | 33899 | 2-[benzyl(methyl)amino]ethyl (E)-3-amino-2-butenoate | C14H20N2O2 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(V)1) The condensation of ethyl acetoacetate (I) with 3-nitrobenzaldehyde (II) in toluene gives ethyl 2-(3-nitrobenzylidene)acetoacetate (III), which is then cyclized with methyl 3-aminocrotonate (IV) [prepared from methyl acetoacetate (V) with NH3 and p-toluenesulfonic acid]; the reaction is carried out in refluxing ethanol.
| 【1】 Wehinger, E.; Stoepel, K.; Vater, W.; Meyer, H.; Bossert, F.; Synthesis and comparative pharmacological studies of 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylates with non-identical estes function. Arzneim-Forsch Drug Res 1981, 31, 3, 407-409. |
| 【2】 Serradell, M.N.; Castaner, J.; Grau, M.; Blancafort, P.; Nitrendipine. Drugs Fut 1983, 8, 6, 508. |
| 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) | 11819 | ethyl acetoacetate; ethyl 3-oxobutanoate；Acetoacetic ester;Ethyl beta-ketobutyrate;ethyl 3-oxobutyrate | 141-97-9 | C6H10O3 | 详情 | 详情 |
| (II) | 12646 | 3-Nitrobenzaldehyde | 99-61-6 | C7H5NO3 | 详情 | 详情 |
| (III) | 30721 | ethyl (Z)-2-acetyl-3-(3-nitrophenyl)-2-propenoate | C13H13NO5 | 详情 | 详情 | |
| (IV) | 11372 | Methyl (E)-3-amino-2-butenoate; Methyl 3-aminocrotonate | C5H9NO2 | 详情 | 详情 | |
| (V) | 11791 | methyl 3-oxobutanoate; Methyl acetoacetate | 105-45-3 | C5H8O3 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(I)1) The trans-esterification of methyl acetoacetate (I) with allyl alcohol (II) gives the allyl ester (III), which is treated with p-toluenesulfonyl azide (IV) and triethylamine in acetonitrile to yield the diazo derivative (V). The reaction of (V) with tert-butyl-dimethylsilyl triflate (VI) and triethyl amine in dichloromethane affords the enol silyl ether (VII), which is condensed with 3-[1-(tert-butyldimethyl-silyloxy)ethyl-4 acetoxyazetidin-2-one (VIII) by means of ZnCl2 in dichloromethane giving 3-[l-(tertbutyldimethylsilyloxy)ethyl]-4-(4-allyloxy-3-diazo-2,4-dioxobutyl)azetidin-2-one (IX). The cyclization of (IX) by means of rhodium acetate in refluxing benzene yields allyl 6alpha-[l(R)-hydroxyethyl]-2-oxocarbapenam-3-carboxylate (X), which is condensed with 2-(mercaptomethyl)pyridine (XI) by means of diphenyl chlorophosphate and diisopropylamine in acetonitrile affording allyl 6alpha-[l(R)-hydroxy-ethyl]-2-(2-pyridylmethylthio)carbapen-2-em-3-carboxylate (XII). The hydrolysis of (XII) with tetrakis-triphenylphosphine-palladium, triphenylphosphine and potassium 2-ethylhexanoate in dichloromethane gives the potassium salt (XIII), which is finally quaternized with methyl triflate and p-toluenesulfonic acid in acetone.
| 【1】 Kim, C.U. (Bristol-Myers Squibb Co.); Carbapenem antibiotics. DE 3334937; GB 2128187; US 4644061 . |
| 【2】 Prous, J.; Castaner, J.; BMY-25174. Drugs Fut 1988, 13, 6, 511. |
| 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) | 12234 | 2-Propen-1-ol; Allyl alcohol | 107-18-6 | C3H6O | 详情 | 详情 |
| (III) | 22675 | allyl 3-oxobutanoate | 1118-84-9 | C7H10O3 | 详情 | 详情 |
| (IV) | 22676 | p-Toluenesulfonyloxy azide | C7H7N3O3S | 详情 | 详情 | |
| (V) | 22677 | 2-Diazo-3-oxobutyric acid allyl ester | C7H8N2O3 | 详情 | 详情 | |
| (VI) | 22678 | tert-butyl(dimethyl)silyl trifluoromethanesulfonate | 69739-34-0 | C7H15F3O3SSi | 详情 | 详情 |
| (VII) | 22679 | 2-Diazo-3-(tert-butyldimethylsilyloxy)-3-butenoic acid allyl ester | C13H22N2O3Si | 详情 | 详情 | |
| (VIII) | 22680 | (3R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetidinyl acetate | C13H25NO4Si | 详情 | 详情 | |
| (IX) | 22681 | 4-[3(S)-[1(R)-(Tert-butyldimethylsilyloxy)ethyl]-4-oxoazetidin-2(R)-yl]-2-diazo-3-oxobutyric acid allyl ester | C18H29N3O5Si | 详情 | 详情 | |
| (X) | 22682 | allyl (5R,6S)-6-[(1R)-1-hydroxyethyl]-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylate | C12H15NO5 | 详情 | 详情 | |
| (XI) | 22683 | 2-pyridinylmethylhydrosulfide; 2-pyridinylmethanethiol | C6H7NS | 详情 | 详情 | |
| (XII) | 22684 | allyl (5R,6S)-6-[(1R)-1-hydroxyethyl]-7-oxo-3-[(2-pyridinylmethyl)sulfanyl]-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C18H20N2O4S | 详情 | 详情 | |
| (XIII) | 22685 | (5R,6S)-6-[(1R)-1-hydroxyethyl]-7-oxo-3-[(2-pyridinylmethyl)sulfanyl]-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C15H15KN2O4S | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(VI)The condensation of 4-fluorophenacyl chloride (I) with N-isopropylaniline gives N-(4-fluorobenzoylmethyl)-N-isopropylaniline (II), which is cyclized in a conventional way to 3-(4-fluorophenyl)-1-isopropyl-indole (III) and condensed with 3-(dimethylamino)acrolein (IV) by means of POCl3 in refluxing acetonitrile, yielding 3-[3-(4-fluorophenyl)-1-isopropyl-indol-2-yl]acrolein (V). The condensation of (V) with methylacetoacetate (VI) by means of NaH and butyl-lithium in THF affords methyl 7-[3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl]-5-hydroxy-3-oxo-6-heptenoate (VII), which is reduced with triethylborane and NaBH4 in THF, giving the dihydroxy ester (VIII). Finally, this compound is hydrolyzed with NaOH in ethanol.
| 【1】 Kathawala, F. (Novartis AG); Analogs of mevalolactone and derivs. thereof, processes for their production, pharmaceutical compsns. containing them and their use as pharmaceuticals. JP 1991047167; US 4739073; WO 8402131 . |
| 【2】 Kapa, P.K. (Novartis AG); 6-Substituted-4-hydroxy-tetrahydropyran-2-ones. US 4571428 . |
| 【3】 Chen, K.-M.; Hardtmann, G.E.; Lee, G.T.; Linder, J.; Wattanasin, S. (Novartis AG; Novartis Deutschland GmbH); Preparation of olefinic cpds. EP 0244364 . |
| 【4】 Castaner, J.; Prous, J.; Fluvastatin Sodium. Drugs Fut 1991, 16, 9, 804. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 27905 | N-isopropyl-N-phenylamine | 768-52-5 | C9H13N | 详情 | 详情 | |
| (I) | 11786 | 2-Chloro-1-(4-fluorophenyl)-1-ethanone; 2-Chloro-4'-fluoroacetophenone | 456-04-2 | C8H6ClFO | 详情 | 详情 |
| (II) | 11787 | 1-(4-Fluorophenyl)-2-(isopropylanilino)-1-ethanone | C17H18FNO | 详情 | 详情 | |
| (III) | 11788 | 3-(4-Fluorophenyl)-1-isopropyl-1H-indole | 93957-49-4 | C17H16FN | 详情 | 详情 |
| (IV) | 11789 | (E)-3-(Dimethylamino)-2-propenal | 692-32-0 | C5H9NO | 详情 | 详情 |
| (V) | 11790 | (E)-3-[3-(4-Fluorophenyl)-1-isopropyl-1H-indol-2-yl]-2-propenal | C20H18FNO | 详情 | 详情 | |
| (VI) | 11791 | methyl 3-oxobutanoate; Methyl acetoacetate | 105-45-3 | C5H8O3 | 详情 | 详情 |
| (VII) | 11792 | methyl (E)-7-[3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl]-5-hydroxy-3-oxo-6-heptenoate | C25H26FNO4 | 详情 | 详情 | |
| (VIII) | 11793 | methyl (3R,5S,6E)-7-[3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl]-3,5-dihydroxy-6-heptenoate | C25H28FNO4 | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(IV)A new synthesis for TC-81 has been described: By condensation of 2-(2-fluoro-5-nitrobenzylidene)acetoacetic acid methyl ester (I) with 3-aminocrotonic acid 3-(N-benzyl-N-methylamino)-2,2-dimethylpropyl ester (II) by means of triethylamine in refluxing isopropanol. The starting products (I) and (II) are prepared as follows: The condensation of 2-fluoro-5-nitrobenzaldehyde (III) with methylacetoacetate (IV) by means of HCl in toluene gives the benzylidene derivative (I). The condensation of 3-(N-benzyl-N-methylamino)-2,2-dimethylpropanol (V) with diketene (VI) in hot benzene gives the acetoacetic ester (VII), which is treated with gaseous ammonia in ethanol, yielding crotonate (III).
| 【1】 Okamiya, Y.; Yamaguchi, H.; Takeshita, T.; Sunakawa, K.; Kanno, H.; Synthesis and antihypertensive activity of 1,4-dihydropyridine derivatives with a 4-(disubstituted phenyl)ring and an aminoalkyl ester group: Highly potent and long-lasting calcium antagonists. Chem Pharm Bull 1992, 40, 8, 2049. |
| 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) | 12106 | methyl (Z)-2-acetyl-3-(2-fluoro-5-nitrophenyl)-2-propenoate | C12H10FNO5 | 详情 | 详情 | |
| (II) | 12107 | 3-[benzyl(methyl)amino]-2,2-dimethylpropyl (E)-3-amino-2-butenoate | C17H26N2O2 | 详情 | 详情 | |
| (III) | 12108 | 2-Fluoro-5-nitrobenzaldehyde | 27996-87-8 | C7H4FNO3 | 详情 | 详情 |
| (IV) | 11791 | methyl 3-oxobutanoate; Methyl acetoacetate | 105-45-3 | C5H8O3 | 详情 | 详情 |
| (V) | 12110 | 3-[Benzyl(methyl)amino]-2,2-dimethyl-1-propanol | C13H21NO | 详情 | 详情 | |
| (VI) | 11367 | 4-Methylene-2-oxetanone; Acetyl ketene | 674-82-8 | C4H4O2 | 详情 | 详情 |
| (VII) | 12112 | 3-[benzyl(methyl)amino]-2,2-dimethylpropyl 3-oxobutanoate | C17H25NO3 | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(XI)2) The condensation of acetoacetic ester (VI) with aldehyde (VII) gives the benzylidene derivative (X), which is then submitted to cyclization with crotonate (IX) as before. 3) Finally, the title product can also be obtained by cyclization of benzylidene derivative (X) with methyl acetoacetate (XI) and concentrated aqueous ammonia in refluxing isopropanol.
| 【1】 Yamaguchi, H.; Odamiya, Y.; Kanno, H.; Sunakawa, K. (Teijin Ltd.); 1,4-Dihydropyridine derivs., process for production thereof and pharmaceutical use thereof. EP 0128010; JP 1984222474; JP 1984227859; JP 1985104065; US 4578395 . |
| 【2】 Prous, J.; Castaner, J.; TC-81. Drugs Fut 1989, 14, 3, 239. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VI) | 12112 | 3-[benzyl(methyl)amino]-2,2-dimethylpropyl 3-oxobutanoate | C17H25NO3 | 详情 | 详情 | |
| (VII) | 12108 | 2-Fluoro-5-nitrobenzaldehyde | 27996-87-8 | C7H4FNO3 | 详情 | 详情 |
| (IX) | 11372 | Methyl (E)-3-amino-2-butenoate; Methyl 3-aminocrotonate | C5H9NO2 | 详情 | 详情 | |
| (X) | 20565 | 3-[benzyl(methyl)amino]-2,2-dimethylpropyl (Z)-2-acetyl-3-(2-fluoro-5-nitrophenyl)-2-propenoate | C24H27FN2O5 | 详情 | 详情 | |
| (XI) | 11791 | methyl 3-oxobutanoate; Methyl acetoacetate | 105-45-3 | C5H8O3 | 详情 | 详情 |
合成路线11
该中间体在本合成路线中的序号：(III)A synthesis of the (R)- and (S)-isomers of manidipine hydrochloride has been described: The cyclization of 3-nitrobenzaldehyde (I) with methyl 3-aminocrotonate (II) and methylacetylacetate (III) gives 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester (IV), which is alkylated with ethoxymethyl chloride and NaH yielding the 1-(ethoxymethyl) derivative (V). Selective hydrolysis of (V) with 1-(dimethylamino)-2-propanol - Na - H2O affords the monomethyl ester (VI), which is submitted to optical resolution with cinchonidine and cinchonine giving (R)-1-(ethoxymethyl-5-(methoxycarbonyl)-2,6-dimethyl-4-(3-nitrophenyl)- 1,4-dihydropyridine-3-carboxylic acid (VIII) and the corresponding (S)-isomer (IX), respectively. The cleavage of the ethoxymethyl group of (VIII) and (IX) in acidic medium affords the corresponding free (R)-5-(methoxycarbonyl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyrid ine-3-carboxylic acid (X) and the (S)-isomer (XI). Both compounds are esterified with 2-[4-(diphenylmethyl)piperazin-1-yl]ethanol (XII) by means of PCl5 and NaHCO3, finally yielding the (S)- and (R)-isomers of manidipine hydrochloride, respectively.
| 【1】 Wada, Y.; Kajino, M.; Nagai, Y.; Meguro, K.; Nagaoka, A.; Synthesis and biological activities of optical isomers of 2-(4-diphenylmethyl-1-piperazinyl)ethyl methyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate (manidipine) dihydrochloride. Chem Pharm Bull 1989, 37, 8, 2225-8. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 12646 | 3-Nitrobenzaldehyde | 99-61-6 | C7H5NO3 | 详情 | 详情 |
| (II) | 11372 | Methyl (E)-3-amino-2-butenoate; Methyl 3-aminocrotonate | C5H9NO2 | 详情 | 详情 | |
| (III) | 11791 | methyl 3-oxobutanoate; Methyl acetoacetate | 105-45-3 | C5H8O3 | 详情 | 详情 |
| (IV) | 12667 | dimethyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydro-3,5-pyridinedicarboxylate; 2,6-Dimethyl-4-(3-nitro-ph)-1,4-2h-pyridine-3,5-dicarboxylic acid dimethyl ester | 21881-77-6 | C17H18N2O6 | 详情 | 详情 |
| (V) | 12668 | dimethyl 1-(ethoxymethyl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydro-3,5-pyridinedicarboxylate | C20H24N2O7 | 详情 | 详情 | |
| (VI) | 12669 | 1-(Ethoxymethyl)-5-(methoxycarbonyl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydro-3-pyridinecarboxylic acid | C19H22N2O7 | 详情 | 详情 | |
| (VIII) | 12670 | (4R)-1-(Ethoxymethyl)-5-(methoxycarbonyl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydro-3-pyridinecarboxylic acid | C19H22N2O7 | 详情 | 详情 | |
| (IX) | 12671 | (4S)-1-(Ethoxymethyl)-5-(methoxycarbonyl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydro-3-pyridinecarboxylic acid | C19H22N2O7 | 详情 | 详情 | |
| (X) | 12672 | (4R)-5-(Methoxycarbonyl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydro-3-pyridinecarboxylic acid | C16H16N2O6 | 详情 | 详情 | |
| (XI) | 12673 | (4S)-5-(Methoxycarbonyl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydro-3-pyridinecarboxylic acid | C16H16N2O6 | 详情 | 详情 | |
| (XII) | 12674 | 2-(4-Benzhydryl-1-piperazinyl)-1-ethanol | C19H24N2O | 详情 | 详情 |
合成路线12
该中间体在本合成路线中的序号：(X)2) The reaction of 2-(4-piperazinyl)ethanol (I) with diphenylmethyl bromide (II) by means of K2CO3 in DMF gives 2-[4-(diphenylmethyl)-1-piperazinyl] ethanol (III), which is condensed with diketene (IV) at 80 C to yield 2-[4-(diphenylmethyl)-1-piperazinyl] ethyl acetoacetate (V). The reaction of acetoacetate (V) with NH3 in ethanol gives the corresponding aminocrotonate (IX), which is then cyclized with methyl (3-nitrobenzylidene)acetoacetate (VI) [prepared from methyl acetoacetate (X) and 3-nitrobenzaldehyde (VI)] in refluxing isopropanol.
| 【1】 Meguro, K.; Kawamatsu, Y.; Aizawa, M.; Nagaoka, A.; Sohda, T.; New 1,4-dihydropyridine derivatives with potent an. Chem Pharm Bull 1985, 33, 9, 3787. |
| 【2】 Meguro, K.; Nagaoka, A. (Takeda Chemical Industries, Ltd.); Dihydropyridine derivs., their production and use. EP 0138505; JP 1985084269; US 4603135 . |
| 【3】 Prous, J.; Castaner, J.; CV-4093. Drugs Fut 1988, 13, 3, 207. |
| 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) | 21893 | 2-(1-piperazinyl)-1-ethanol; 1-piperazineethanol; 1-(2-Hydroxyethyl)piperazine | 103-76-4 | C6H14N2O | 详情 | 详情 |
| (II) | 12079 | Bromodiphenylmethane; 1-[Bromo(phenyl)methyl]benzene; Benzhydrylbromide | 776-74-9 | C13H11Br | 详情 | 详情 |
| (III) | 12674 | 2-(4-Benzhydryl-1-piperazinyl)-1-ethanol | C19H24N2O | 详情 | 详情 | |
| (IV) | 21896 | 4-methyl-2H-oxet-2-one | C4H4O2 | 详情 | 详情 | |
| (V) | 21897 | 2-(4-benzhydryl-1-piperazinyl)ethyl 3-oxobutanoate | C23H28N2O3 | 详情 | 详情 | |
| (VI) | 12646 | 3-Nitrobenzaldehyde | 99-61-6 | C7H5NO3 | 详情 | 详情 |
| (IX) | 21900 | 2-(4-benzhydryl-1-piperazinyl)ethyl (E)-3-amino-2-butenoate | C23H29N3O2 | 详情 | 详情 | |
| (X) | 11791 | methyl 3-oxobutanoate; Methyl acetoacetate | 105-45-3 | C5H8O3 | 详情 | 详情 |
| (XI) | 12276 | methyl (Z)-2-acetyl-3-(3-nitrophenyl)-2-propenoate | C12H11NO5 | 详情 | 详情 |
合成路线13
该中间体在本合成路线中的序号：(X)4) By cyclization of aldehyde (VI) with aminocrotonate (IX) and methyl acetoacetate (X) in refluxing isopropanol.
| 【1】 Meguro, K.; Kawamatsu, Y.; Aizawa, M.; Nagaoka, A.; Sohda, T.; New 1,4-dihydropyridine derivatives with potent an. Chem Pharm Bull 1985, 33, 9, 3787. |
| 【2】 Meguro, K.; Nagaoka, A. (Takeda Chemical Industries, Ltd.); Dihydropyridine derivs., their production and use. EP 0138505; JP 1985084269; US 4603135 . |
| 【3】 Prous, J.; Castaner, J.; CV-4093. Drugs Fut 1988, 13, 3, 207. |
合成路线14
该中间体在本合成路线中的序号：(V)In an alternative procedure, condensation of L-valine (IV) with methyl acetoacetate (V) in the presence of NaOH produced the enamine-protected valine sodium salt (VI). Condensation of (VI) with the tosylate (VII), (prepared from acyclovir (I) and tosyl chloride) afforded ester (VIII). Then, acidic hydrolysis of the enaminoester moiety of (VIII) furnished the target valine ester. Similar procedures were also reported using omega-mesyl and omega-chloro acyclovir.
| 【1】 Montoro, M.; Pirovano, S.; Process of preparation of valacyclovir and relevant intermediates. WO 9803553 . |
| 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) | 28279 | 2-amino-9-[(2-hydroxyethoxy)methyl]-1,9-dihydro-6H-purin-6-one | 59277-89-3 | C8H11N5O3 | 详情 | 详情 |
| (IV) | 37828 | L-2-Amino-3-methylbutyric acid; L-2-Aminoisovaleric acid; 2-Aminoisovaleric acid; L-2-Amino-3-methylbutyric acid; L-alpha-Aminoisovaleric acid; L-valine; (S)-(+)-Valine; (S)-alpha-Aminoisovaleric acid | 72-18-4 | C5H11NO2 | 详情 | 详情 |
| (V) | 11791 | methyl 3-oxobutanoate; Methyl acetoacetate | 105-45-3 | C5H8O3 | 详情 | 详情 |
| (VI) | 59533 | sodium (2S)-2-{[(E)-3-methoxy-1-methyl-3-oxo-1-propenyl]amino}-3-methylbutanoate | C10H16NNaO4 | 详情 | 详情 | |
| (VII) | 59534 | 2-[(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methoxy]ethyl 4-methylbenzenesulfonate | C15H17N5O5S | 详情 | 详情 | |
| (VIII) | 59535 | methyl (E)-3-{[(1S)-1-({2-[(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methoxy]ethoxy}carbonyl)-2-methylpropyl]amino}-2-butenoate | C18H26N6O6 | 详情 | 详情 |
合成路线15
该中间体在本合成路线中的序号：(II)This compound can be obtained by three different ways: 1) The reaction of 3-nitrobenzaldehyde (I) with methyl acetoacetate (II) by means of m-toluidine in methanol gives methyl 2-(3-nitrobenzylidene)acetoacetate (III), which is then cyclized with 3-aminocrotonic acid 3-phenyl-2(E)-propenyl ester (IV) in refluxing isopropanol. 2) By cyclization of methyl 3-aminocrotonate (V) with aldehyde (I) and acetoacetic acid 3-phenyl-2(E)-propenyl ester (VI) in refluxing isopropanol. 3) By esterification of 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid monomethyl ester (VII) with 3-phenyl-2(E)-propenyl alcohol (VIII), by means of dicyclohexylcarbodiimide (DCC) in pyridine.
| 【1】 Nishitani, S.; Minamikawa, J.; Kano, M.; Otsubo, J.; Manabe, Y. (Otsuka Pharmaceutical Co., Ltd.); Process for preparing novel dihydropyridine derivs. EP 0173126 . |
| 【2】 Tamada, S.; Ei, K.; Teramoto, S.; Tanaka, T.; Nakagawa, T. (Otsuka Pharmaceutical Co., Ltd.); Dihydropyridine derivs. JP 1986140567 . |
| 【3】 Tamada, S.; Nagami, K.; Teramoto, S.; Tanaka, T.; Nakagawa, K. (Otsuka Pharmaceutical Co., Ltd.); Novel dihydropyridine derivs. and process for preparing the same. EP 0145434; ES 8604516; ES 8701726; ES 8701727; JP 1985120861; JP 1989151557; US 5034395; US 5137889 . |
| 【4】 Prous, J.; Castaner, J.; OPC-13340. Drugs Fut 1991, 16, 2, 119. |
| 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) | 12646 | 3-Nitrobenzaldehyde | 99-61-6 | C7H5NO3 | 详情 | 详情 |
| (II) | 11791 | methyl 3-oxobutanoate; Methyl acetoacetate | 105-45-3 | C5H8O3 | 详情 | 详情 |
| (III) | 12276 | methyl (Z)-2-acetyl-3-(3-nitrophenyl)-2-propenoate | C12H11NO5 | 详情 | 详情 | |
| (IV) | 13947 | (E)-3-phenyl-2-propenyl (E)-3-amino-2-butenoate | C13H15NO2 | 详情 | 详情 | |
| (V) | 11372 | Methyl (E)-3-amino-2-butenoate; Methyl 3-aminocrotonate | C5H9NO2 | 详情 | 详情 | |
| (VI) | 13949 | (E)-3-phenyl-2-propenyl 3-oxobutanoate | C13H14O3 | 详情 | 详情 | |
| (VII) | 13950 | 5-(Methoxycarbonyl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydro-3-pyridinecarboxylic acid | C16H16N2O6 | 详情 | 详情 | |
| (VIII) | 13951 | (E)-3-Phenyl-2-propen-1-ol | 104-54-1 | C9H10O | 详情 | 详情 |
合成路线16
该中间体在本合成路线中的序号：(III)Synthesis of Furaldipine (EN:163877)
| 【1】 Frank, A.; Karn, H.; Spanig, H. (Abbott GmbH & Co. KG); Production of 1-hydroxyalkyl-5-nitroimidazoles. DE 2359625; FR 2253019; GB 1481349 . |
| 【2】 Frank, A.; Dockner, T.; Karn, H. (Abbott GmbH & Co. KG); Process for the preparation of 1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole of high purity. EP 0150407 . |
| 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) | 14082 | tetrahydro-2-furanylmethyl 3-oxobutanoate | C9H14O4 | 详情 | 详情 | |
| (II) | 11370 | 2-Nitrobenzaldehyde | 552-89-6 | C7H5NO3 | 详情 | 详情 |
| (III) | 11791 | methyl 3-oxobutanoate; Methyl acetoacetate | 105-45-3 | C5H8O3 | 详情 | 详情 |
| (IV) | 14085 | tetrahydro-2-furanylmethyl (E)-3-amino-2-butenoate | C9H15NO3 | 详情 | 详情 | |
| (V) | 11375 | Methyl-2-(2-nitrobenzylidene)acetoacetate; methyl (Z)-2-acetyl-3-(2-nitrophenyl)-2-propenoate | 39562-27-1 | C12H11NO5 | 详情 | 详情 |
合成路线17
该中间体在本合成路线中的序号：(VII)The 2-chloro-4,4,6,6-tetramethylcyclohexene aldehyde (II), prepared by a Vilsmeier reaction on commercially available 3,3,5,5-tetramethylcyclohexanone (I), underwent a copper catalyzed 1,4 addition of the Grignard reagent derived from 5-bromo-2-fluorotoluene(III) to yield the 2-aryl substituted 4,4,6,6-tetramethylcyclohexene aldehyde (IV). Treatment of the aldehyde (IV) with the anion of ethylidenecyclohexylamine (V), followed by hydrolysis of the intermediate beta-hydroxyimine by silica gel chromatography, gave the extended aldehyde (VI). Addition of the dianion of methyl acetoacetate (VII) to aldehyde (VI) and stereospecific reduction of the resulting delta-hydroxy-beta-ketoester (VIII) with triethylborane and sodium borohydride yielded the erythro 3,5-dihydroxy methyl ester (IX). Hydrolysis of the methyl ester, followed by lactonization with triethylamine and methyl chloroformate produced dalvastatin).
| 【1】 Neuenschwander, K.W.; Regan, J.R.; Kosmider, B.J.; Scotese, A.C. (Aventis Pharma SA); Novel HMG-CoA reductase inhibitors. EP 0403487; JP 1991503280; US 4863957; WO 8905639 . |
| 【2】 Amin, D.; Neuenschwander, K.; Dalvastatin. Drugs Fut 1992, 17, 5, 377. |
| 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) | 14433 | 3,3,5,5-tetramethylcyclohexanone | 14376-79-5 | C10H18O | 详情 | 详情 |
| (II) | 14434 | 2-chloro-4,4,6,6-tetramethyl-1-cyclohexene-1-carbaldehyde | C11H17ClO | 详情 | 详情 | |
| (III) | 63828 | bromo(4-fluoro-3-methylphenyl)magnesium | 82297-89-0 | C7H6BrFMg | 详情 | 详情 |
| (IV) | 14435 | 2-(4-fluoro-3-methylphenyl)-4,4,6,6-tetramethyl-1-cyclohexene-1-carbaldehyde | C18H23FO | 详情 | 详情 | |
| (V) | 63829 | N-[(E)ethylidene]cyclohexanamine; N-cyclohexyl-N-[(E)ethylidene]amine | C8H15N | 详情 | 详情 | |
| (VI) | 14436 | (E)-3-[2-(4-fluoro-3-methylphenyl)-4,4,6,6-tetramethyl-1-cyclohexen-1-yl]-2-propenal | C20H25FO | 详情 | 详情 | |
| (VII) | 11791 | methyl 3-oxobutanoate; Methyl acetoacetate | 105-45-3 | C5H8O3 | 详情 | 详情 |
| (VIII) | 14437 | methyl (E)-7-[2-(4-fluoro-3-methylphenyl)-4,4,6,6-tetramethyl-1-cyclohexen-1-yl]-5-hydroxy-3-oxo-6-heptenoate | C25H33FO4 | 详情 | 详情 | |
| (IX) | 14438 | methyl (3R,5S,6E)-7-[2-(4-fluoro-3-methylphenyl)-4,4,6,6-tetramethyl-1-cyclohexen-1-yl]-3,5-dihydroxy-6-heptenoate | C25H35FO4 | 详情 | 详情 |
合成路线18
该中间体在本合成路线中的序号：(II)The condensation of indoline (I) with methyl acetoacetate (II) by means of Ts-OH in refluxing benzene gives the adduct (III), which is cyclized by means of Pd(OAc)2 in hot DMA to yield the pyrroloindole (IV). The hydrolysis of the acetate group of (IV) by means of K2CO3 in methanol affords the hydroxymethyl compound (V), which is treated with CCl4 and PPh3 to provide the chloromethyl derivative (VI). The cleavage of the benzyl protecting group of (VI) by means of HCOONH4 and Pd/C in THF gives the hydroxy derivative (VII), which is N-deprotected by means of HCl in ethyl acetate to yield the intermediate (VIII). The condensation of (VIII) with 5,6,7-trimethoxy-1H-indole-2-carboxylic acid (IX) by means of EDC in DMF affords the carboxamide (X), which is treated with DBU in acetonitrile to provide the cyclopropapyrroloindole (XI). The reaction of (XI) with HBr in acetonitrile gives the bromomethyl derivative (XII), which is treated with 4-nitrophenyl chloroformate (XIII) to yield the active carbonate ester (XIV). Finally, this compound is treated with 1-methylpiperazine (XV) to provide the target Pibrozelesin.
| 【1】 Fukuda, Y.; et al.; Novel syntheses of optically active CC-1065, U-73,975 (adozelesin), U-80,244 (carzelesin), U-77,779 (bizelesin), KW-2189, and DU-86. Heterocycles 1997, 45, 12, 2303. |
| 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) | 59123 | tert-butyl (3S)-3-[(acetyloxy)methyl]-5-amino-6-(benzyloxy)-2,3-dihydro-1H-indole-1-carboxylate | C23H28N2O5 | 详情 | 详情 | |
| (II) | 11791 | methyl 3-oxobutanoate; Methyl acetoacetate | 105-45-3 | C5H8O3 | 详情 | 详情 |
| (III) | 61767 | tert-butyl (3S)-3-[(acetyloxy)methyl]-6-(benzyloxy)-5-{[(E)-3-methoxy-1-methyl-3-oxo-1-propenyl]amino}-2,3-dihydro-1H-indole-1-carboxylate | C28H34N2O7 | 详情 | 详情 | |
| (IV) | 61768 | 6-(tert-butyl) 1-methyl (8S)-8-[(acetyloxy)methyl]-4-(benzyloxy)-2-methyl-7,8-dihydropyrrolo[3,2-e]indole-1,6(3H)-dicarboxylate | C28H32N2O7 | 详情 | 详情 | |
| (V) | 61769 | 6-(tert-butyl) 1-methyl (8S)-4-(benzyloxy)-8-(hydroxymethyl)-2-methyl-7,8-dihydropyrrolo[3,2-e]indole-1,6(3H)-dicarboxylate | C26H30N2O6 | 详情 | 详情 | |
| (VI) | 61770 | 6-(tert-butyl) 1-methyl (8S)-4-(benzyloxy)-8-(chloromethyl)-2-methyl-7,8-dihydropyrrolo[3,2-e]indole-1,6(3H)-dicarboxylate | C26H29ClN2O5 | 详情 | 详情 | |
| (VII) | 61771 | 6-(tert-butyl) 1-methyl (8S)-8-(chloromethyl)-4-hydroxy-2-methyl-7,8-dihydropyrrolo[3,2-e]indole-1,6(3H)-dicarboxylate | C19H23ClN2O5 | 详情 | 详情 | |
| (VIII) | 61772 | methyl (8S)-8-(chloromethyl)-4-hydroxy-2-methyl-3,6,7,8-tetrahydropyrrolo[3,2-e]indole-1-carboxylate | C14H15ClN2O3 | 详情 | 详情 | |
| (IX) | 61773 | 5,6,7-trimethoxy-1H-indole-2-carboxylic acid | C12H13NO5 | 详情 | 详情 | |
| (X) | 61774 | methyl (8S)-8-(chloromethyl)-4-hydroxy-2-methyl-6-[(5,6,7-trimethoxy-1H-indol-2-yl)carbonyl]-3,6,7,8-tetrahydropyrrolo[3,2-e]indole-1-carboxylate | C26H26ClN3O7 | 详情 | 详情 | |
| (XI) | 40881 | methyl (3bR,4aS)-2-methyl-8-oxo-6-[(5,6,7-trimethoxy-1H-indol-2-yl)carbonyl]-1,4,4a,5,6,8-hexahydrocyclopropa[c]pyrrolo[3,2-e]indole-3-carboxylate | C26H25N3O7 | 详情 | 详情 | |
| (XII) | 61775 | methyl (8S)-8-(bromomethyl)-4-hydroxy-2-methyl-6-[(5,6,7-trimethoxy-1H-indol-2-yl)carbonyl]-3,6,7,8-tetrahydropyrrolo[3,2-e]indole-1-carboxylate | C26H26BrN3O7 | 详情 | 详情 | |
| (XIII) | 16605 | 4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene | 7693-46-1 | C7H4ClNO4 | 详情 | 详情 |
| (XIV) | 61776 | methyl (8S)-8-(bromomethyl)-2-methyl-4-{[(4-nitrophenoxy)carbonyl]oxy}-6-[(5,6,7-trimethoxy-1H-indol-2-yl)carbonyl]-3,6,7,8-tetrahydropyrrolo[3,2-e]indole-1-carboxylate | C33H29BrN4O11 | 详情 | 详情 | |
| (XV) | 10061 | 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine | 109-01-3 | C5H12N2 | 详情 | 详情 |
合成路线19
该中间体在本合成路线中的序号：(XII)1) The condensation of 2-(1,3-dixolan-2-yl)ethylamine (I) with ethyl 2-bromo-2-(4-fluorophenyl)acetate (II) by means of triethylamine in acetonitrile gives ethyl 2-[2-(1,3-dioxolan-2-yl)ethylamino]-2-(4-fluorophenyl)acetate (III), which is acylated with isobutyryl chloride (IV) and triethylamine in dichloromethane yielding the corresponding amide (V). Saponification of the ester (V) with NaOH in methanol/water affords the free acid (VI), which is cyclized with N,3-diphenylpropynamide (VII) [obtained in the reaction of 3-phenylpropynoic acid (VIII) with aniline (IX) by means of dicyclohexylcarbodiimide (DCC)] by heating at 90 C in acetic anhydride giving 1-[2-(1,3-dioxolan-2-yl)ethyl]-5-(4-fluorophenyl)-2-isopropyl-N,4-diphenylpyrrole-3-carboxamide (X). The hydrolysis of the dioxolane group of (X) with HCl yields the corresponding aldehyde (XI), which is condensed with methyl acetoacetate (XII) by means of NaH in THF affording 7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(N-phenylcarbamoyl)pyrrol-1-yl]-5-hydroxy-3-oxoheptanoic acid methyl ester (XIII). The reduction of the carbonyl group of (XIII) with tributylborane and NaBH4 in THF gives the (3R*,5R*)-dihydroxy ester (XIV), which is saponified with NaOH in water yielding the corresponding free acid (XV). The lactonization of (XV) by heating in refluxing toluene affords the (R*,R*)-lactone (XVI), which is submitted to optical resolution by reaction with (R)-1-phenylethylamine (XVII) followed by fractional crystallization thus obtaining the amide (XVII) as the pure (R,R,R)-enantiomer. The hydrolysis of the amide (XVIII) with NaOH, followed by heating in refluxing toluene gives the (R,R)-lactone (XIX), which is finally treated first with NaOH in methanol/water, and then with CaCl2 or calcium acetate.
| 【1】 Graul, A.; Castaner, J.; Atorvastatin Calcium. Drugs Fut 1997, 22, 9, 956. |
| 【2】 Roth, B.D.; Blankley, C.J.; Chucholowski, A.W.; Ferguson, E.; Hoefle, M.L.; Ortwine, D.F.; Newton, R.S.; Sekerke, C.S.; Sliskovic, D.R.; Stratton, C.D.; Wilson, M.W.; Inhibitors of cholesterol biosynthesis. 3. Tetrahydro-4-hydroxy-6-[2-(1H-pyrrol-1-yl)ethyl]-2H-pyran-2-one inhibitors of HMG-CoA reductase. 2. Effects of introducing substituents at positions three and four of the pyrrole nucleus. J Med Chem 1991, 34, 1, 357-66. |
| 【3】 Roth, B.D. (Pfizer Inc.); Trans-6-[2-(3- or 4-carboxamido-substd. pyrrol-1-yl)alkyl]-4-hydroxypyran-2-one inhibitors of cholesterol synthesis. EP 0247633; US 4681893 . |
| 【4】 Roth, B.D. (Pfizer Inc.); (R-(R*R*)-2-(4-Fluorophenyl)-beta,delta-dihydroxy-5-(1-methylethyl-3 -phenyl-4-[(phenylamino)-carbonyl]-1H-pyrrole-1-heptanoic acid, its lactone form and salts thereo. EP 0409281; JP 1991058967; US 5273995 . |
| 【5】 Mills, N.; Muhammad, N.A.; Weiss, J.; Nesbitt, R.U. (Pfizer Inc.); Stable oral CI-981 formulation and process for preparing same. EP 0680320; JP 1996505640; US 5686104; WO 9416693 . |
| 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) | 15376 | 2-(1,3-dioxolan-2-yl)ethylamine; 2-(1,3-dioxolan-2-yl)-1-ethanamine | 5754-35-8 | C5H11NO2 | 详情 | 详情 |
| (II) | 15377 | ethyl 2-bromo-2-(4-fluorophenyl)acetate | 712-52-7 | C10H10BrFO2 | 详情 | 详情 |
| (III) | 15378 | ethyl 2-[[2-(1,3-dioxolan-2-yl)ethyl]amino]-2-(4-fluorophenyl)acetate | C15H20FNO4 | 详情 | 详情 | |
| (IV) | 14932 | isobutyryl chloride; 2-methylpropanoyl chloride | 79-30-1 | C4H7ClO | 详情 | 详情 |
| (V) | 15380 | ethyl 2-[[2-(1,3-dioxolan-2-yl)ethyl](isobutyryl)amino]-2-(4-fluorophenyl)acetate | C19H26FNO5 | 详情 | 详情 | |
| (VI) | 15381 | 2-[[2-(1,3-dioxolan-2-yl)ethyl](isobutyryl)amino]-2-(4-fluorophenyl)acetic acid | C17H22FNO5 | 详情 | 详情 | |
| (VII) | 15382 | N,3-diphenyl-2-propynamide | C15H11NO | 详情 | 详情 | |
| (VIII) | 15383 | 3-phenyl-2-propynoic acid; Phenylpropiolic acid | 637-44-5 | C9H6O2 | 详情 | 详情 |
| (IX) | 12294 | Aniline; Phenylamine | 62-53-3 | C6H7N | 详情 | 详情 |
| (X) | 15385 | 1-[2-(1,3-dioxolan-2-yl)ethyl]-5-(4-fluorophenyl)-2-isopropyl-N,4-diphenyl-1H-pyrrole-3-carboxamide | C31H31FN2O3 | 详情 | 详情 | |
| (XI) | 15386 | 5-(4-fluorophenyl)-2-isopropyl-1-(3-oxopropyl)-N,4-diphenyl-1H-pyrrole-3-carboxamide | C29H27FN2O2 | 详情 | 详情 | |
| (XII) | 11791 | methyl 3-oxobutanoate; Methyl acetoacetate | 105-45-3 | C5H8O3 | 详情 | 详情 |
| (XIII) | 15388 | methyl 7-[3-(anilinocarbonyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-1-yl]-5-hydroxy-3-oxoheptanoate | C34H35FN2O5 | 详情 | 详情 | |
| (XIV) | 15389 | methyl (3R,5R)-7-[3-(anilinocarbonyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-1-yl]-3,5-dihydroxyheptanoate | C34H37FN2O5 | 详情 | 详情 | |
| (XV) | 15390 | (3R,5R)-7-[3-(anilinocarbonyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-1-yl]-3,5-dihydroxyheptanoic acid | C33H35FN2O5 | 详情 | 详情 | |
| (XVI) | 15391 | 5-(4-fluorophenyl)-1-[2-[(2R,4R)-4-hydroxy-6-oxotetrahydro-2H-pyran-2-yl]ethyl]-2-isopropyl-N,4-diphenyl-1H-pyrrole-3-carboxamide | C33H33FN2O4 | 详情 | 详情 | |
| (XVII) | 10039 | (1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine | 3886-69-9 | C8H11N | 详情 | 详情 |
| (XVIII) | 15393 | 1-((3R,5R)-3,5-dihydroxy-7-oxo-7-[[(1R)-1-phenylethyl]amino]heptyl)-5-(4-fluorophenyl)-2-isopropyl-N,4-diphenyl-1H-pyrrole-3-carboxamide | C41H44FN3O4 | 详情 | 详情 | |
| (XIX) | 15391 | 5-(4-fluorophenyl)-1-[2-[(2R,4R)-4-hydroxy-6-oxotetrahydro-2H-pyran-2-yl]ethyl]-2-isopropyl-N,4-diphenyl-1H-pyrrole-3-carboxamide | C33H33FN2O4 | 详情 | 详情 |
合成路线20
该中间体在本合成路线中的序号：(VI)1NK-104 in its open and lactone forms has been synthesized by several different ways: 1) Lactone form: The reaction of 1(R),7,7-trimethylbicyclo[2.2.1]heptan-2-one (I) with 1-naphthylmagnesium bromide (II) gives the tertiary alcohol (III), which by reaction with SOCl2 and then with NaHCO3 yields 2-(1-naphthyl)-1(R),7,7-trimethylbicyclo[2.2.1]heptene (IV). Hydroboration of (IV) with BH3 followed by oxidation with H2O2 affords 4(S),7,7-trimethyl-3exo-(1-naphthyl)bicyclo[2.2.1]heptan-2exo-ol (V), which is submitted to transesterification with methyl acetoacetate (VI) and dimethyl-aminopyridine (DMAP) to give the corresponding ester (VII). The condensation of (VII) with N-methoxy-N-methyl-3-[2-cyclopropyl-4-(4-fluorophenyl) quinolin-3-yl]-2(E)-propenamide (VIII) by means of NaH yields the corresponding chiral 3,5-dioxoheptenoic acid ester (IX), which is selectively reduced first with diisobutylaluminum hy-dride acid (DIBAL) and then with diethylmethoxyborane and sodium borohydride affording the 3(R),5(S)-dihydroxyheptenoic ester (X). Finally, this compound is saponified with NaOH and treated with acetic acid/sodium acetate. The intermediate amide (VIII) is obtained by condensation of 2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-carbaldehyde (XI) with N-methoxy-N-methylacetamide (XII) by means of butyllithium to the hydroxy propionamide (XIII), which is then dehydrated with methanesulfonyl chloride and triethylamine in the usual way).
| 【1】 Castaner, J.; Sorbera, L.A.; Leeson, P.A.; NK-104. Drugs Fut 1998, 23, 8, 847-859. |
| 【2】 Guntor, B.; Kaiyama, T.; Arai, K.; Minami, T.; Suzuki, M.; Kobara, Y.; Sakota, R. (Nissan Chemical Industry, Ltd.; Sagami Chemical Research Center); Optically active ß,*-diketo acid esters and their reduced forms. JP 1994025092 . |
| 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) | 17415 | (1R,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-one | 464-49-3 | C10H16O | 详情 | 详情 |
| (II) | 17416 | bromo(1-naphthyl)magnesium | C10H7BrMg | 详情 | 详情 | |
| (III) | 17417 | (1R,2S,4R)-1,7,7-trimethyl-2-(1-naphthyl)bicyclo[2.2.1]heptan-2-ol | C20H24O | 详情 | 详情 | |
| (IV) | 17418 | 1-[(1R,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-en-2-yl]naphthalene | C20H22 | 详情 | 详情 | |
| (V) | 17419 | (1S,2R,3R,4S)-4,7,7-trimethyl-3-(1-naphthyl)bicyclo[2.2.1]heptan-2-ol | C20H24O | 详情 | 详情 | |
| (VI) | 11791 | methyl 3-oxobutanoate; Methyl acetoacetate | 105-45-3 | C5H8O3 | 详情 | 详情 |
| (VII) | 17421 | (1S,2R,3R,4S)-4,7,7-trimethyl-3-(1-naphthyl)bicyclo[2.2.1]hept-2-yl 3-oxobutanoate | C24H28O3 | 详情 | 详情 | |
| (VIII) | 17422 | (E)-3-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]-N-methoxy-N-methyl-2-propenamide | C23H21FN2O2 | 详情 | 详情 | |
| (IX) | 17423 | (1S,2R,3R,4S)-4,7,7-trimethyl-3-(1-naphthyl)bicyclo[2.2.1]hept-2-yl (E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]-3,5-dioxo-6-heptenoate | C45H42FNO4 | 详情 | 详情 | |
| (X) | 17424 | (1S,2R,3R,4S)-4,7,7-trimethyl-3-(1-naphthyl)bicyclo[2.2.1]hept-2-yl (3R,5S,6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]-3,5-dihydroxy-6-heptenoate | C45H46FNO4 | 详情 | 详情 | |
| (XI) | 17425 | 2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinecarbaldehyde | 121660-37-5 | C19H14FNO | 详情 | 详情 |
| (XII) | 17426 | N-methoxy-N-methylacetamide | 78191-00-1 | C4H9NO2 | 详情 | 详情 |
| (XIII) | 17427 | 3-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]-3-hydroxy-N-methoxy-N-methylpropanamide | C23H23FN2O3 | 详情 | 详情 | |
| (XLVI) | 64696 | (4R,6S)-6-{(E)-2-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]ethenyl}-4-hydroxytetrahydro-2H-pyran-2-one | C25H22FNO3 | 详情 | 详情 |
合成路线21
该中间体在本合成路线中的序号：(II)A new synthesis of PNU-140690 has been developed: The condensation of 1-phenyl-3-hexanone (I) with methyl acetoacetate (II) by means of NaH in THF, followed by cyclization gives the hydroxypyrone (III), which by condensation with 3-nitrobenzaldehyde (IV) by means of AlCl3 in THF yields the benzylidene-pyrone (V). The alkylation of (V) with Et3Al, CuBr-Me2S in THF affords intermediate (VI), which is reduced at the nitro group with H2 over Pd/C in methanol giving the racemic amine (VII). The optical resolution of the N-benzyloxycarbonyl derivative of (VII) with chiral HPLC yielded the desired (R,R)-enantiomer (VIII), which was finally sulfonated with 5-(trifluoromethyl)pyridine-2-sulfonyl chloride (IX) in pyridine/dichloromethane.
| 【1】 Turner, S.R.; Strohbach, J.W.; Tommasi, R.A.; Aristoff, P.A.; Johnson, P.D.; Skulnick, H.I.; Dolak, L.A.; Seest, E.P.; Tomich, P.K.; Bohanon, M.J.; Horng, M.M.; Lynn, J.C.; Chong, K.T.; Hinshaw, R.R.; Watenpaugh, K.D.; Janakiraman, M.N.; Thaisrivongs, S.; Tipranavir (PNU-140690): A potent, orally bioavailable nonpeptidic HIV protease inhibitor of the 5,6-dihydro-4-hydroxy-2-pyrone sulfonamide class. J Med Chem 1998, 41, 18, 3467. |
| 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) | 17233 | 1-phenyl-3-hexanone | C12H16O | 详情 | 详情 | |
| (II) | 11791 | methyl 3-oxobutanoate; Methyl acetoacetate | 105-45-3 | C5H8O3 | 详情 | 详情 |
| (III) | 32879 | 4-hydroxy-6-phenethyl-6-propyl-5,6-dihydro-2H-pyran-2-one | C16H20O3 | 详情 | 详情 | |
| (IV) | 12646 | 3-Nitrobenzaldehyde | 99-61-6 | C7H5NO3 | 详情 | 详情 |
| (V) | 32880 | 3-[(Z)-(3-nitrophenyl)methylidene]-6-phenethyl-6-propyldihydro-2H-pyran-2,4-dione | C23H23NO5 | 详情 | 详情 | |
| (VI) | 32881 | 4-hydroxy-3-[1-(3-nitrophenyl)propyl]-6-phenethyl-6-propyl-5,6-dihydro-2H-pyran-2-one | C25H29NO5 | 详情 | 详情 | |
| (VII) | 32882 | 3-[1-(3-aminophenyl)propyl]-4-hydroxy-6-phenethyl-6-propyl-5,6-dihydro-2H-pyran-2-one | C25H31NO3 | 详情 | 详情 | |
| (VIII) | 17236 | (6R)-3-[(1R)-1-(3-aminophenyl)propyl]-4-hydroxy-6-phenethyl-6-propyl-5,6-dihydro-2H-pyran-2-one | C25H31NO3 | 详情 | 详情 | |
| (IX) | 17237 | 5-(trifluoromethyl)-2-pyridinesulfonyl chloride | C6H3ClF3NO2S | 详情 | 详情 |
合成路线22
该中间体在本合成路线中的序号：(II)The Hantzsch cyclization of 3-nitrobenzaldehyde (I), methyl acetoacetate (II) and NH4OAc in refluxing ethanol or isopropanol gives 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester (III), which is reduced with H2 over sulfided carbon in ethanol or with Fe/NH4Cl in methanol/water to yield the corresponding amino derivative (IV). The reaction of (IV) with methyl chloroformate and pyridine in acetonitrile/dichloromethane affords the carbamate (V), which is treated with B-chlorocatecholborane in refluxing THF to provide the corresponding isocyanate (VI). Finally, this compound is condensed with 3-[4-(3-methoxyphenyl)piperidin-1-yl]propylamine (VII) in dichloromethane to furnish the target urea. The intermediate 3-[4-(3-methoxyphenyl)piperidin-1-yl]propylamine (VII) is obtained by condensation of 4-(3-methoxyphenyl)piperidine (VIII) with acrylonitrile (IX) in refluxing acetonitrile to give 3-[4-(3-methoxyphenyl)piperidin-1-yl]propionitrile (X), which is reduced with H2 over Raney-Ni in methanol/aq. NH3.
| 【1】 Poindexter, G.S.; et al.; Dihydropyridine neuropeptide Y Y1 receptor antagonists. Bioorg Med Chem Lett 2002, 12, 3, 379. |
| 【2】 Poindexter, G.S.; Bruce, M.; Johnson, G.; leBoulluec, K.; Sloan, C.P. (Bristol-Myers Squibb Co.); Dihydropyridine NPY antagonists: Piperidine derivs.. CA 2177110; EP 0747357; JP 1997003045; US 5668151 . |
| 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) | 12646 | 3-Nitrobenzaldehyde | 99-61-6 | C7H5NO3 | 详情 | 详情 |
| (II) | 11791 | methyl 3-oxobutanoate; Methyl acetoacetate | 105-45-3 | C5H8O3 | 详情 | 详情 |
| (III) | 12667 | dimethyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydro-3,5-pyridinedicarboxylate; 2,6-Dimethyl-4-(3-nitro-ph)-1,4-2h-pyridine-3,5-dicarboxylic acid dimethyl ester | 21881-77-6 | C17H18N2O6 | 详情 | 详情 |
| (IV) | 55440 | dimethyl 4-(3-aminophenyl)-2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylate | C17H20N2O4 | 详情 | 详情 | |
| (V) | 55441 | dimethyl 4-{3-[(methoxycarbonyl)amino]phenyl}-2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylate | C19H22N2O6 | 详情 | 详情 | |
| (VI) | 55442 | dimethyl 4-(3-isocyanatophenyl)-2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylate | C18H18N2O5 | 详情 | 详情 | |
| (VII) | 55443 | 3-[4-(3-methoxyphenyl)-1-piperidinyl]-1-propanamine; 3-[4-(3-methoxyphenyl)-1-piperidinyl]propylamine | C15H24N2O | 详情 | 详情 | |
| (VIII) | 47138 | 4-(3-methoxyphenyl)piperidine; methyl 3-(4-piperidinyl)phenyl ether | C12H17NO | 详情 | 详情 | |
| (IX) | 10847 | Acrylonitrile | 107-13-1 | C3H3N | 详情 | 详情 |
| (X) | 55444 | 3-[4-(3-methoxyphenyl)-1-piperidinyl]propanenitrile | C15H20N2O | 详情 | 详情 |
合成路线23
该中间体在本合成路线中的序号：(I)The reaction of methyl acetoacetate (I) with 3,4-difluorobenzaldehyde (II) in hot benzene gives the corresponding benzylidene derivative (III), which is cyclized with O-methylisourea (IV) by means of NaHCO3 in hot DMF yielding the dihydropyrimidine (V). The condensation of (V) with 4-nitrophenyl chloroformate (VI) by means of DMAP in dichloromethane affords the 4-nitrophenyl ester (VII), which is brominated with Br2 in chloroform to the bromomethyl compound (VIII). The cyclization of (VIII) by heating at 130 C affords the furopyrimidine (X), which is treated with propylamine derivative (X) in THF or dichloromethane to furnish the target amide.
| 【1】 Chiu, G.; Tian, D.; Lagu, B.; et al.; Synthesis and evaluation of furo[3,4-d]pyrimidinones as selective alpha1a-adrenergic receptor antagonists. Bioorg Med Chem Lett 2000, 10, 2, 175. |
| 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) | 16605 | 4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene | 7693-46-1 | C7H4ClNO4 | 详情 | 详情 |
| (VII) | 38077 | 5-methyl 1-(4-nitrophenyl) 6-(3,4-difluorophenyl)-2-methoxy-4-methyl-1,5(6H)-pyrimidinedicarboxylate | C21H17F2N3O7 | 详情 | 详情 | |
| (VIII) | 38078 | 5-methyl 1-(4-nitrophenyl) 4-(bromomethyl)-6-(3,4-difluorophenyl)-2-methoxy-1,5(6H)-pyrimidinedicarboxylate | C21H16BrF2N3O7 | 详情 | 详情 | |
| (IX) | 38079 | 4-nitrophenyl 4-(3,4-difluorophenyl)-2-methoxy-5-oxo-5,6-dihydrofuro[2,3-d]pyrimidine-3(4H)-carboxylate | C20H13F2N3O7 | 详情 | 详情 | |
| (X) | 25450 | methyl 1-(3-aminopropyl)-4-phenyl-4-piperidinecarboxylate | C16H24N2O2 | 详情 | 详情 |
合成路线24
该中间体在本合成路线中的序号：(I)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25
该中间体在本合成路线中的序号：(I)Title compound has been prepared by several related ways. Alkylation of methyl acetoacetate (I) with n-heptyl bromide (II) in the presence of NaOMe in refluxing MeOH yielded (III), which was brominated in CHCl3 at 0 C to give (IV). Subsequent reaction with triphenylmethyl mercaptan (V) and tetrabutyl ammonium hydroxide in toluene at r.t. provided (XI). Alternatively, beta-ketoester (XI) was prepared from a-mercaptoacetic acid (VI). Thus, protection as the S-trityl compound (VIII) by treatment with triphenylcarbinol (VII) and TFA, followed by condensation with N,O-dimethyl hydroxylamine in the presence of EDC and HOBt afforded N-methoxyamide (IX). Then, Claisen condensation with methyl nonanoate (X) using LDA as the base in THF at -78 C provided ketoester (XI). In order to avoid b-ketoacid decarboxylation, ketone (XI) was reduced to alcohol (XV) with NaBH4 in MeOH at 0 C. This hydroxyester was also prepared by a related route, consisting of protection of methyl mercaptoacetate (XII) as the S-trityl compound (XIII), followed by reduction to aldehyde (XIV) with DIBAL-H and condensation with methyl nonanoate (X). Saponification of methyl ester (XV) with KOH yielded hydroxyacid (XVI). Subsequent coupling with tert-butylglycine amide (XVII) using EDC and HOBt as the condensing agents produced amide (XVIII). Ketoamide (XX) was then obtained by oxidation with Dess-Martin periodinane (XIX). Finally, deprotection of the S-trityl group was effected by trifluoroacetic acid treatment under reducing conditions with triethyl silane to provide the target compound.
| 【1】 Campbell, D.A.; Xiao, X.Y.; Harris, D.; Ida, S.; Mortezaei, R.; Ngu, K.; Shi, L.; Tien, D.; Wang, Y.; Navre, M.; Patel, D.V.; Sharr, M.A.; DiJoseph, J.F.; Killar, L.M.; Leone, C.L.; Levin, J.I.; Skotnicki, J.S.; Malonyl alpha-mercaptoketones and alpha-mercaptoalcohols, a new class of matrix metalloproteinase inhibitors. Bioorg Med Chem Lett 1998, 8, 10, 1157. |
| 【2】 Campbell, D.A.; Patel, D.V.; Xiao, X.Y. (Affymax Technologies, NV); Novel inhibitors of collagenase-1 and stromelysin-I metalloproteases, pharmaceutical compsns. comprising same and methods of their use. WO 9640204 . |
| 【3】 Campbell, D.A.; Patel, D.V.; Xiao, X.Y. (Affymax Technologies, NV); Novel inhibitors of metalloproteases, pharmaceutical compsns. comprising same and methods of their use. WO 9640738 . |
| 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) | 18828 | 1-bromoheptane | 629-04-9 | C7H15Br | 详情 | 详情 |
| (III) | 18829 | methyl 2-acetylnonanoate | C12H22O3 | 详情 | 详情 | |
| (IV) | 18830 | methyl 2-(2-bromoacetyl)nonanoate | C12H21BrO3 | 详情 | 详情 | |
| (V) | 18831 | tritylhydrosulfide; triphenylmethanethiol | 3695-77-0 | C19H16S | 详情 | 详情 |
| (VI) | 18524 | 2-sulfanylacetic acid | 68-11-1 | C2H4O2S | 详情 | 详情 |
| (VII) | 18833 | Trityl alcohol; triphenylmethanol | 76-84-6 | C19H16O | 详情 | 详情 |
| (VIII) | 18834 | 2-(tritylsulfanyl)acetic acid | C21H18O2S | 详情 | 详情 | |
| (IX) | 18835 | N-methoxy-N-methyl-2-(tritylsulfanyl)acetamide | C23H23NO2S | 详情 | 详情 | |
| (X) | 18836 | methyl nonanoate | 1731-84-6 | C10H20O2 | 详情 | 详情 |
| (XI) | 18837 | methyl 2-[2-(tritylsulfanyl)acetyl]nonanoate | C31H36O3S | 详情 | 详情 | |
| (XII) | 18838 | methyl 2-sulfanylacetate | 2365-48-2 | C3H6O2S | 详情 | 详情 |
| (XIII) | 18839 | methyl 2-(tritylsulfanyl)acetate | C22H20O2S | 详情 | 详情 | |
| (XIV) | 18840 | 2-(tritylsulfanyl)acetaldehyde | C21H18OS | 详情 | 详情 | |
| (XV) | 18841 | methyl 2-[1-hydroxy-2-(tritylsulfanyl)ethyl]nonanoate | C31H38O3S | 详情 | 详情 | |
| (XVI) | 18842 | 2-[1-hydroxy-2-(tritylsulfanyl)ethyl]nonanoic acid | C30H36O3S | 详情 | 详情 | |
| (XVII) | 18843 | (2S)-2-amino-N,3,3-trimethylbutanamide | 89226-12-0 | C7H16N2O | 详情 | 详情 |
| (XVIII) | 18844 | N-[(1S)-2,2-dimethyl-1-[(methylamino)carbonyl]propyl]-2-[1-hydroxy-2-(tritylsulfanyl)ethyl]nonanamide | C37H50N2O3S | 详情 | 详情 | |
| (XIX) | 18845 | Dess-Martin periodinane; 1,1,1-Triacetoxy-1,2-benziodoxol-3(1H)-one | 87413-09-0 | C13H13IO8 | 详情 | 详情 |
| (XX) | 18846 | N-[(1S)-2,2-dimethyl-1-[(methylamino)carbonyl]propyl]-2-[2-(tritylsulfanyl)acetyl]nonanamide | C37H48N2O3S | 详情 | 详情 |
合成路线26
该中间体在本合成路线中的序号：(I)The cyclization of methyl acetoacetate (I), 2-methoxybenzaldehyde (II) and thiourea (III) by means of HCl in refluxing ethanol gives the tetrahydropyrimidine (IV), which is finally cyclized with chloroacetic acid (V) and benzaldehyde (VI) by means of sodium acetate in a refluxing mixture of acetic acid and acetic anhydride.
| 【1】 Kelicen, P.; Ertan, M.; Demirdamar, R.; Krebs, B.; Tozkoparan, B.; Lage, M.; Condensed heterocyclic compounds: Synthesis and antiinflammatory activity of novel thiazolo[3,2-a]pyrimidines. Arch Pharm 1998, 331, 6, 201. |
| 【2】 Assandri, A.; et al.; Pharmacokinetics of a new antihypertensive pyrrolyl pyridazinamine (MDL-899) in the rat and the dog. Arzneim-Forsch Drug Res 1985, 35, 2, 508. |
| 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) | 12568 | 2-Methoxybenzaldehyde; o-Methoxybenzaldehyde | 135-02-4 | C8H8O2 | 详情 | 详情 |
| (III) | 10180 | Thiourea | 62-56-6 | CH4N2S | 详情 | 详情 |
| (IV) | 27432 | methyl 4-(2-methoxyphenyl)-6-methyl-2-thioxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate | C14H16N2O3S | 详情 | 详情 | |
| (V) | 11847 | 2-Chloroacetic acid; Chloroacetic Acid | 79-11-8 | C2H3ClO2 | 详情 | 详情 |
| (VI) | 10498 | Benzaldehyde;Benzoic aldehyde;Phenylmethanal | 100-52-7 | C7H6O | 详情 | 详情 |
合成路线27
该中间体在本合成路线中的序号：(XIV)2) Alternatively, aldehyde (VII) was condensed with the dianion of methyl acetoacetate (XIV) to give hydroxyketone (XV), which was converted to the cyanohydrin (XVI) using KCN and KH2PO4. Basic hydrolysis of (XV) then provided a mixture of the (3R*,5S*)- (XIII) and (3R*,5R*)- (XVII) diastereoisomers.
| 【1】 Gribble, A.D.; Ife, R.J.; Shaw, A.; McNair, D.; Novelli, C.E.; Bakewell, S.; Shah, V.P.; Dolle, R.E.; Groot, P.H.; Pearce, N.; Yates, J.; Tew, D.; Boyd, H.; Ashman, S.; Eggleston, D.S.; Haltiwanger, R.C.; Okafo, G.; ATP-citrate lyase as a target for hypolipidemic intervention. 2. Synthesis and evaluation of (3R*,5S*)-omega-substituted-3-carboxy-3,5-dihydroxyalkanoic acids and their gamma-lactone prodrugs as inhibitors of the enzyme in vitro and in vivo. J Med Chem 1998, 41, 19, 3582. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (rac-XIII) | 22208 | 2-[8-(2,4-Dichlorophenyl)-2(R)-hydroxyoctyl]-2-hydroxysuccinic acid disodium salt | C20H28Cl2O4 | 详情 | 详情 | |
| (rac-XVII) | 22227 | (2S)-2-[(2R)-8-(2,4-dichlorophenyl)-2-hydroxyoctyl]-2-hydroxybutanedioic acid | C18H24Cl2O6 | 详情 | 详情 | |
| (VII) | 22202 | 7-(2,4-dichlorophenyl)heptanal | C13H16Cl2O | 详情 | 详情 | |
| (XIV) | 11791 | methyl 3-oxobutanoate; Methyl acetoacetate | 105-45-3 | C5H8O3 | 详情 | 详情 |
| (XV) | 22225 | methyl 11-(2,4-dichlorophenyl)-5-hydroxy-3-oxoundecanoate | C18H24Cl2O4 | 详情 | 详情 | |
| (XVI) | 22226 | methyl 3-cyano-11-(2,4-dichlorophenyl)-3,5-dihydroxyundecanoate | C19H25Cl2NO4 | 详情 | 详情 |
合成路线28
该中间体在本合成路线中的序号：(VI)The condensation of vanillin (I) with epichlorohydrin (II) in ethanolic NaOH produced the glycidyl ether (III). Epoxide ring opening in (III) by means of tert-butylamine (IV) in EtOH furnished amino alcohol (V). The title dihydropyridine derivative was then obtained by reaction between aldehyde (V), methyl acetoacetate (VI), ammonia under Hantzsch condensation conditions, and was isolated after conversion to the hydrochloride salt.
| 【1】 Liang, J.-C.; Chen, I.-J.; Tsai, C.-H.; Liou, S.-F.; Wang, C.-S.; Yeh, J.-L.; The new generation dihydropyridine type calcium blockers, bearing 4-phenyl oxypropanolamine, display alpha-/beta-adrenoceptor antagonist and long-acting antihypertensive activities. Bioorg Med Chem 2002, 10, 3, 719. |
| 【2】 Donovan, S. (Allergan, Inc.); Method for treating a neoplasm. WO 0209743 . |
| 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) | 22701 | 4-hydroxy-3-methoxybenzaldehyde | 121-33-5 | C8H8O3 | 详情 | 详情 |
| (II) | 10146 | Epichlorohydrin; 2-(Chloromethyl)oxirane | 106-89-8 | C3H5ClO | 详情 | 详情 |
| (III) | 59599 | 3-methoxy-4-(2-oxiranylmethoxy)benzaldehyde | C11H12O4 | 详情 | 详情 | |
| (IV) | 17895 | 2-Amino-2-methylpropane; tert-butylamine; 2-methyl-2-propanamine | 75-64-9 | C4H11N | 详情 | 详情 |
| (V) | 59600 | 4-[3-(tert-butylamino)-2-hydroxypropoxy]-3-methoxybenzaldehyde | C15H23NO4 | 详情 | 详情 | |
| (VI) | 11791 | methyl 3-oxobutanoate; Methyl acetoacetate | 105-45-3 | C5H8O3 | 详情 | 详情 |
合成路线29
该中间体在本合成路线中的序号：(IX)Knoevenagel condensation of 2-chloro-4-fluorobenzaldehyde (VIII) with methyl acetoacetate (IX) in the presence of piperidine acetate afforded the benzylidene compound (X). Cyclocondensation of (X) with amidine (VII) provided the racemic dihydropyrimidine (XI). Resolution of (XI) was accomplished either by chiral HPLC or via conversion to the diastereoisomeric salts with (-)-camphanic acid.
| 【2】 Paessens, A.; Stoltefuss, J.; Goldmann, S.; Niewohner, U.; Kramer, T.; Schlemmer, K.-H.; Weber, O.; Graef, E.; Lottmann, S.; Stolting, J.; Deres, K. (Bayer AG); Dihydropyrimidines and their use in the treatment of hepatitis B. WO 0058302 . |
| 【1】 Goldmann, S.; et al.; BAY 41-4109: A novel non-nucleosidic and highly potent inhibitor of human hepatitis B virus. Part 1: Synthesis and structure activity relationship (SAR). 41st Intersci Conf Antimicrob Agents Chemother (Dec 16 2001, Chicago) 2001, Abst F-1664. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VII) | 55047 | 3,5-difluoro-N'-hydroxy-2-pyridinecarboximidamide | C6H5F2N3O | 详情 | 详情 | |
| (VIII) | 55048 | 2-Chloro-4-fluorobenzaldehyde; 4-Fluoro-2-chlorobenzaldehyde | 84194-36-5 | C7H4ClFO | 详情 | 详情 |
| (IX) | 11791 | methyl 3-oxobutanoate; Methyl acetoacetate | 105-45-3 | C5H8O3 | 详情 | 详情 |
| (X) | 55049 | methyl (Z)-2-acetyl-3-(2-chloro-4-fluorophenyl)-2-propenoate | C12H10ClFO3 | 详情 | 详情 | |
| (XI) | 55050 | methyl 4-(2-chloro-4-fluorophenyl)-2-(3,5-difluoro-2-pyridinyl)-6-methyl-1,4-dihydro-5-pyrimidinecarboxylate | C18H13ClF3N3O2 | 详情 | 详情 |
合成路线30
该中间体在本合成路线中的序号：(VII)Bromination of methyl toluate (I) with N-bromosuccinimide and benzoyl peroxide (Bz2O2) in refluxing CCl4 gives alpha-bromo-o-toluate (II), which is coupled with phenolic derivative (III) by means of K2CO3 in DMF to provide phenoxy derivative (IV). Saponification of the methyl ester group of (IV) by treatment with KOH in refluxing EtOH affords carboxylic acid (V), which is then converted into the desired compound via the corresponding acid chloride obtained by reaction with oxalyl chloride in CHCl3, followed by coupling with 4,6-diamino-2-methylquinoline (XII) by means of pyridine. Quinoline (XII) can be obtained as follows: Condensation of 4-aminoacetanilide (VII) with methyl acetoacetate (VIII) by heating in MeOH affords crotonate (IX), which is then subjected to cyclization in refluxing Dowtherm A to provide hydroxy quinoline (X). Methylation of (X) with dimethyl sulfate in refluxing toluene gives methoxy quinoline (XI), whose methoxy group is converted into an amino group with ammonium acetate and whose acetyl group is finally removed by hydrolysis with HCl.
| 【1】 Kitao, Y.; Shinkai, H.; Ito, T.; Uchida, I.; Yamada, H.; Iida, T.; 4-Aminoquinolones: Novel nociceptin antagonists with analgesics activity. J Med Chem 2000, 43, 24, 4667. |
| 【2】 Shinkai, H.; Yamada, H.; to, T. (Japan Tobacco Inc.); Amide derivs. and nociceptin antagonists. EP 1072263; JP 1999335355; WO 9948492 . |
| 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) | 49024 | 2-Methyl Methylbenzoate; 2-Methylbenzoic acid methyl ester; Methyl o-toluate; o-Toluic acid methyl ester | 89-71-4 | C9H10O2 | 详情 | 详情 |
| (II) | 28575 | methyl 2-(bromomethyl)benzoate | C9H9BrO2 | 详情 | 详情 | |
| (III) | 49025 | p-Ethylphenol; 4-Ethylphenol | 123-07-9 | C8H10O | 详情 | 详情 |
| (IV) | 49026 | methyl 2-[(4-ethylphenoxy)methyl]benzoate | C17H18O3 | 详情 | 详情 | |
| (V) | 49027 | 2-[(4-ethylphenoxy)methyl]benzoic acid | C16H16O3 | 详情 | 详情 | |
| (VI) | 29016 | N-(4-aminophenyl)acetamide | 122-80-5 | C8H10N2O | 详情 | 详情 |
| (VII) | 11791 | methyl 3-oxobutanoate; Methyl acetoacetate | 105-45-3 | C5H8O3 | 详情 | 详情 |
| (VIII) | 49028 | methyl (Z)-3-[4-(acetamido)anilino]-2-butenoate | C13H16N2O3 | 详情 | 详情 | |
| (IX) | 49029 | N-(4-hydroxy-2-methyl-6-quinolinyl)acetamide | C12H12N2O2 | 详情 | 详情 | |
| (X) | 49030 | N-(4-methoxy-2-methyl-6-quinolinyl)acetamide | C13H14N2O2 | 详情 | 详情 | |
| (XI) | 49031 | 4-amino-2-methyl-6-quinolinylamine; 2-methyl-4,6-quinolinediamine | C10H11N3 | 详情 | 详情 |
合成路线31
该中间体在本合成路线中的序号：(XI)The condensation of vanillin (VII) with epichlorohydrin (VIII) in ethanolic NaOH produced the glycidyl ether (IX). Epoxide ring opening in (IX) by means of amine (VI) in EtOH furnished amino alcohol (X). The title dihydropyridine derivative was then obtained by reaction between aldehyde (X), methyl acetoacetate (XI), and ammonia under Hantzsch condensation conditions.
| 【1】 Liang, J.-C.; Chen, I.-J.; Tsai, C.-H.; Liou, S.-F.; Wang, C.-S.; Yeh, J.-L.; The new generation dihydropyridine type calcium blockers, bearing 4-phenyl oxypropanolamine, display alpha-/beta-adrenoceptor antagonist and long-acting antihypertensive activities. Bioorg Med Chem 2002, 10, 3, 719. |
| 【2】 Lin, T.-H.; Chen, I.-J.; Guaiacoxypropanolamines with alpha/beta-adrenergic blocking activity. EP 1108710; WO 0005209 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VI) | 31105 | 2-(2-methoxyphenoxy)ethylamine; 2-(2-methoxyphenoxy)-1-ethanamine | 1836-62-0 | C9H13NO2 | 详情 | 详情 |
| (VII) | 22701 | 4-hydroxy-3-methoxybenzaldehyde | 121-33-5 | C8H8O3 | 详情 | 详情 |
| (VIII) | 10146 | Epichlorohydrin; 2-(Chloromethyl)oxirane | 106-89-8 | C3H5ClO | 详情 | 详情 |
| (IX) | 59599 | 3-methoxy-4-(2-oxiranylmethoxy)benzaldehyde | C11H12O4 | 详情 | 详情 | |
| (X) | 59618 | 4-(2-hydroxy-3-{[2-(2-methoxyphenoxy)ethyl]amino}propoxy)-3-methoxybenzaldehyde | C20H25NO6 | 详情 | 详情 | |
| (XI) | 11791 | methyl 3-oxobutanoate; Methyl acetoacetate | 105-45-3 | C5H8O3 | 详情 | 详情 |
合成路线32
该中间体在本合成路线中的序号：(IX)Condensation between 3-nitrobenzaldehyde (VIII) and methyl acetoacetate (IX) in the presence of ammonium acetate under Hantzsch reaction conditions leads to dihydropyridine (X). The nitro group of (X) is then reduced by catalytic hydrogenation to the corresponding aniline (XI). Finally, condensation of aniline (XI) with the cyanoisothiourea (VII) employing HgCl2 furnishes the target N-cyanoguanidine.
| 【1】 Poindexter, G.S.; Sit, S.-Y.; Swann, R.T.; Bruce, M.A.; Morton, M.A.; Huang, Y.; Breitenbucher, J.G. (Bristol-Myers Squibb Co.); Dihydropyridine NPY antagonists: Cyanoguanidine derivs.. US 6001836; WO 9854136 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VII) | 58483 | sodium 1-(3-{[(cyanoimino)(sulfido)methyl]amino}propyl)-4-phenylpiperidine | C16H21N4NaS | 详情 | 详情 | |
| (VIII) | 12646 | 3-Nitrobenzaldehyde | 99-61-6 | C7H5NO3 | 详情 | 详情 |
| (IX) | 11791 | methyl 3-oxobutanoate; Methyl acetoacetate | 105-45-3 | C5H8O3 | 详情 | 详情 |
| (X) | 12667 | dimethyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydro-3,5-pyridinedicarboxylate; 2,6-Dimethyl-4-(3-nitro-ph)-1,4-2h-pyridine-3,5-dicarboxylic acid dimethyl ester | 21881-77-6 | C17H18N2O6 | 详情 | 详情 |
| (XI) | 55440 | dimethyl 4-(3-aminophenyl)-2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylate | C17H20N2O4 | 详情 | 详情 |