【结 构 式】 |
【分子编号】21059 【品名】N-[di(tert-butoxy)methyl]-N,N-dimethylamine; di(tert-butoxy)-N,N-dimethylmethanamine 【CA登记号】36805-97-7 |
【 分 子 式 】C11H25NO2 【 分 子 量 】203.32504 【元素组成】C 64.98% H 12.39% N 6.89% O 15.74% |
合成路线1
该中间体在本合成路线中的序号:GV217828 was prepared following the synthetic route shown in Scheme 22578902a. In this event, due to the lability of the cyclic imide in basic medium, indole aldehyde (I) was transformed into the corresponding tert-butyl ester derivative (XI). Wittig reaction with phosphorane (XII) gave the olefinic intermediate (XIII) as a single E regioisomer. The removal of the tert-butyl protecting group afforded the desired compound G-217828 in high yield.
【1】 Hedaya, E.; Theodoropulos, S.; Preparation and reactions of stable phosphorus ylides derived from malic anhydrides. Tetrahedron 1968, 24, 2241. |
【2】 Di Fabio, R.; Corsi, M.; Ugolini, A.R.; Gaviraghi, G.; Giacobbe, S.; Gastaldi, P.; Pentassuglia, G.; Quartaroli, M.; Conti, N.; Donati, D.; Trist, D.G.; Ratti, E.; GV196771. Drugs Fut 2000, 25, 2, 137. |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
21059 | N-[di(tert-butoxy)methyl]-N,N-dimethylamine; di(tert-butoxy)-N,N-dimethylmethanamine | 36805-97-7 | C11H25NO2 | 详情 | 详情 | |
(I) | 32144 | ethyl 4,6-dichloro-3-formyl-1H-indole-2-carboxylate | C12H9Cl2NO3 | 详情 | 详情 | |
(IX) | 32906 | 4,6-dichloro-3-formyl-1H-indole-2-carboxylic acid | C10H5Cl2NO3 | 详情 | 详情 | |
(X) | 32909 | tert-butyl 4,6-dichloro-3-formyl-1H-indole-2-carboxylate | C14H13Cl2NO3 | 详情 | 详情 | |
(XI) | 32910 | di(tert-butyl) 4,6-dichloro-3-formyl-1H-indole-1,2-dicarboxylate | C19H21Cl2NO5 | 详情 | 详情 | |
(XII) | 32907 | 5-oxo-1-phenyl-4-(triphenylphosphonio)-4,5-dihydro-1H-pyrrol-2-olate | C28H22NO2P | 详情 | 详情 | |
(XIII) | 32908 | di(tert-butyl) 4,6-dichloro-3-[(2,5-dioxo-1-phenyl-3-pyrrolidinylidene)methyl]-1H-indole-1,2-dicarboxylate | C29H28Cl2N2O6 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号:(XVII)The condensation of 4-methoxypyridine-3-carbaldehyde (I) with 2-azidoacetic acid ethyl ester (II) by means of NaOMe in ethanol gives 2-azido-3-(4-methoxypyridin-3-yl)acrylic acid ethyl ester (III), which is cyclized in refluxing o-xylene to yield the pyrrolopyridine (IV). The reaction of the NH group of (IV) with Sem-Cl and NaH in DMF affords the N-protected compound (V), whose ester group is reduced with LiAlH4 in refluxing THF to provide the carbinol (VI). The oxidation of (VI) with MnO2 in dichloromethane gives the corresponding carbaldehyde (VII), which is condensed with 2-azidoacetic acid ethyl ester (II) as before to yield the azido acrylic ester (VIII). The condensation of (VIII) with triphenylphosphine (IX) in dichloromethane affords the iminophosphorane (X), which is N-deprotected by means of TBAF in THF to provide the deprotected iminophosphorane (XI). The cyclization of (XI) with alpha-methylbenzyl isocyanate (XII) in THF gives the tricyclic pyrimidopyrrolopyridine (XIII), which is brominated with Br2 in pyridine to yield intermediate (XIV). The reaction of (XIV) with 1-ethoxyvinyl trimethyl tin (XV) by means of PdCl2(PPh3)2 in DMF affords the acetyl derivative (XVI), which is condensed with dimethylformamide di-tert-butyl acetal (XVII) in hot DMF to provide the dimethyl enaminone (XVIII). The cyclization of (XVIII) with guanidine (XIX) by means of K2CO3 in refluxing 2-methoxyethanol gives the 2-aminopyrimidine derivative (XX), with simultaneous hydrolysis of the ester group. The decarboxylation of (XX), with simultaneous demethylation, by heating at 260 C in diphenyl ether yields the N-protected precursor (XXI), which is finally treated with triflic acid to afford the target variolin B.
【1】 Molina, P.; et al.; Synthesis of the potent antitumoral marine alkaloid variolin B. Tetrahedron Lett 2002, 43, 6, 1005. |
【2】 Fresneda, P.M.; et al.; Synthetic studies towards the 2-aminopyrimidine alkaloids variolins and meridianins from marine origin. Tetrahedron Lett 2000, 41, 24, 4777. |
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) | 55718 | 4-methoxynicotinaldehyde | C7H7NO2 | 详情 | 详情 | |
(II) | 32916 | ethyl 2-azidoacetate | 637-81-0 | C4H7N3O2 | 详情 | 详情 |
(III) | 55719 | ethyl (Z)-2-azido-3-(4-methoxy-3-pyridinyl)-2-propenoate | C11H12N4O3 | 详情 | 详情 | |
(IV) | 55720 | ethyl 4-methoxy-1H-pyrrolo[2,3-b]pyridine-2-carboxylate | C11H12N2O3 | 详情 | 详情 | |
(V) | 55721 | ethyl 4-methoxy-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-2-carboxylate | C17H26N2O4Si | 详情 | 详情 | |
(VI) | 55722 | (4-methoxy-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-2-yl)methanol | C15H24N2O3Si | 详情 | 详情 | |
(VII) | 55723 | 4-methoxy-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-2-carbaldehyde | C15H22N2O3Si | 详情 | 详情 | |
(VIII) | 55724 | ethyl (Z)-2-azido-3-(4-methoxy-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-propenoate | C19H27N5O4Si | 详情 | 详情 | |
(IX) | 12437 | Triphenylphosphine; Triphenyl phosphine | 603-35-0 | C18H15P | 详情 | 详情 |
(X) | 55725 | ethyl (Z)-3-(4-methoxy-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-[(triphenylphosphoranylidene)amino]-2-propenoate | C37H42N3O4PSi | 详情 | 详情 | |
(XI) | 55726 | ethyl (Z)-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-[(triphenylphosphoranylidene)amino]-2-propenoate | C31H28N3O3P | 详情 | 详情 | |
(XII) | 55734 | (S)-(-)-1-Phenylethyl isocyanate; (S)-(-)-Phenylethyl Isocyanate; Isocyanic acid (S)-(-)-alpha-phenylethyl ester; S-(-)-alpha-Methylbenzyl isocyanate | 14649-03-7 | C9H9NO | 详情 | 详情 |
(XIII) | 55727 | ethyl 4-methoxy-9-{[(1S)-1-phenylethyl]amino}pyrido[3',2':4,5]pyrrolo[1,2-c]pyrimidine-7-carboxylate | C22H22N4O3 | 详情 | 详情 | |
(XIV) | 55728 | ethyl 5-bromo-4-methoxy-9-{[(1S)-1-phenylethyl]amino}pyrido[3',2':4,5]pyrrolo[1,2-c]pyrimidine-7-carboxylate | C22H21BrN4O3 | 详情 | 详情 | |
(XV) | 55729 | ethyl 1-(trimethylstannyl)vinyl ether; (1-ethoxyvinyl)(trimethyl)stannane | C7H16OSn | 详情 | 详情 | |
(XVI) | 55730 | ethyl 5-acetyl-4-methoxy-9-{[(1S)-1-phenylethyl]amino}pyrido[3',2':4,5]pyrrolo[1,2-c]pyrimidine-7-carboxylate | C24H24N4O4 | 详情 | 详情 | |
(XVII) | 21059 | N-[di(tert-butoxy)methyl]-N,N-dimethylamine; di(tert-butoxy)-N,N-dimethylmethanamine | 36805-97-7 | C11H25NO2 | 详情 | 详情 |
(XVIII) | 55731 | ethyl 5-[(E)-3-(dimethylamino)-2-propenoyl]-4-methoxy-9-{[(1S)-1-phenylethyl]amino}pyrido[3',2':4,5]pyrrolo[1,2-c]pyrimidine-7-carboxylate | C27H29N5O4 | 详情 | 详情 | |
(XIX) | 14790 | Guanidine | 113-00-8 | CH5N3 | 详情 | 详情 |
(XX) | 55732 | 5-(2-amino-4-pyrimidinyl)-4-methoxy-9-{[(1S)-1-phenylethyl]amino}pyrido[3',2':4,5]pyrrolo[1,2-c]pyrimidine-7-carboxylic acid | C24H21N7O3 | 详情 | 详情 | |
(XXI) | 55733 | 5-(2-amino-4-pyrimidinyl)-9-{[(1S)-1-phenylethyl]amino}pyrido[3',2':4,5]pyrrolo[1,2-c]pyrimidin-4-ol | C22H19N7O | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号:(IV)Condensation of D-isoleucine (I) with 4-methoxy-benzenesulfonyl chloride (II) in the presence of Et3N afforded sulfonyl derivative (III), which was subsequently converted to tert-butyl ester (V) upon treatment with dimethylformamide di-tert-butyl acetal (IV). Alkylation of (V) with benzyl bromide and K2CO3 in DMF provided the N-benzyl compound (VI). Then, the tert-butyl ester of (VI) was deprotected with HCl in CH2Cl2, and the resulting carboxylic acid (VII) was condensed with O-tert-butyl hydroxylamine using N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide-HCl (EDC) and 1-hydroxybenzotriazole (HOBt) to give the tert-butyl hydroxamate (VIII). The target hydroxamic acid was then obtained by deprotection of (VIII) with HCl in dichloroethane containing one equivalent of EtOH.
【1】 MacPherson, L.J.; et al.; Discovery of CGS 27023A, a non-peptidic, potent, and orally active stromelysin inhibitor that blocks cartilage degradation in rabbits. J Med Chem 1997, 40, 16, 2525. |
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) | 21073 | (2R,3S)-2-amino-3-methylpentanoic acid | C6H13NO2 | 详情 | 详情 | |
(II) | 15719 | 4-methoxybenzenesulfonyl chloride | 98-68-0 | C7H7ClO3S | 详情 | 详情 |
(III) | 21075 | (2R,3S)-2-[[(4-methoxyphenyl)sulfonyl]amino]-3-methylpentanoic acid | C13H19NO5S | 详情 | 详情 | |
(IV) | 21059 | N-[di(tert-butoxy)methyl]-N,N-dimethylamine; di(tert-butoxy)-N,N-dimethylmethanamine | 36805-97-7 | C11H25NO2 | 详情 | 详情 |
(V) | 21077 | tert-butyl (2R,3S)-2-[[(4-methoxyphenyl)sulfonyl]amino]-3-methylpentanoate | C17H27NO5S | 详情 | 详情 | |
(VI) | 21078 | tert-butyl (2R,3S)-2-[benzyl[(4-methoxyphenyl)sulfonyl]amino]-3-methylpentanoate | C24H33NO5S | 详情 | 详情 | |
(VII) | 21079 | (2R,3S)-2-[benzyl[(4-methoxyphenyl)sulfonyl]amino]-3-methylpentanoic acid | C20H25NO5S | 详情 | 详情 | |
(VIII) | 21080 | (2R,3S)-2-[benzyl[(4-methoxyphenyl)sulfonyl]amino]-N-(tert-butoxy)-3-methylpentanamide | C24H34N2O5S | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号:(IV)Condensation of D-valine (I) with 4-methoxybenzenesulfonyl chloride (II) in the presence of Et3N afforded sulfonyl derivative (III), which was subsequently converted to tert-butyl ester (V) upon treatment with dimethylformamide di-tert-butyl acetal (IV). Alkylation of (V) with 2-picolyl chloride-HCl (VI) and K2CO3 in DMF provided the N-(2-picolyl) compound (VII). Then, the tert-butyl ester of (VII) was deprotected with HCl in CH2Cl2, and the resulting carboxylic acid (VIII) was condensed with O-tert-butyl hydroxylamine using N-(3-dimethylaminopropyl)-N'-ethylcarbo-diimide-HCl (EDC) and 1-hydroxybenzotriazole (HOBt) to give the tert-butyl hydroxamate (IX). The target hydroxamic acid was then obtained by deprotection of (IX) with HCl in dichloroethane containing one equivalent of EtOH.
【1】 MacPherson, L.J.; et al.; Discovery of CGS 27023A, a non-peptidic, potent, and orally active stromelysin inhibitor that blocks cartilage degradation in rabbits. J Med Chem 1997, 40, 16, 2525. |
【2】 MacPherson, L.J.; Parker, D.T.; Jeng, A.Y. (Novartis Corp.); Arylsulfonamido-substd. hydroxamic acids. US 5506242; US 5552419 . |
【3】 MacPherson, L.J.; Parker, D.T. (Novartis Corp.); Arylsulfonamido-substd. hydroxamic acids. US 5646167 . |
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) | 21056 | (R)-(-)-Valine; D-Valine; (R)-alpha-Aminoisovaleric acid | 640-68-6 | C5H11NO2 | 详情 | 详情 |
(II) | 15719 | 4-methoxybenzenesulfonyl chloride | 98-68-0 | C7H7ClO3S | 详情 | 详情 |
(III) | 21058 | (2R)-2-[[(4-methoxyphenyl)sulfonyl]amino]-3-methylbutyric acid | C12H17NO5S | 详情 | 详情 | |
(IV) | 21059 | N-[di(tert-butoxy)methyl]-N,N-dimethylamine; di(tert-butoxy)-N,N-dimethylmethanamine | 36805-97-7 | C11H25NO2 | 详情 | 详情 |
(V) | 21060 | tert-butyl (2R)-2-[[(4-methoxyphenyl)sulfonyl]amino]-3-methylbutanoate | C16H25NO5S | 详情 | 详情 | |
(VI) | 21061 | 2-(chloromethyl)pyridine hydrochloride | 6959-47-3 | C6H7Cl2N | 详情 | 详情 |
(VII) | 21062 | tert-butyl (2R)-2-[[(4-methoxyphenyl)sulfonyl](2-pyridinylmethyl)amino]-3-methylbutanoate | C22H30N2O5S | 详情 | 详情 | |
(VIII) | 21063 | (2R)-2-[[(4-methoxyphenyl)sulfonyl](2-pyridinylmethyl)amino]-3-methylbutyric acid hydrochloride | C18H23ClN2O5S | 详情 | 详情 | |
(IX) | 21064 | (2R)-N-(tert-butoxy)-2-[[(4-methoxyphenyl)sulfonyl](2-pyridinylmethyl)amino]-3-methylbutanamide | C22H31N3O5S | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号:(V)Isoxazolin-5-one (III) was synthesized from ethyl propiolate (I) via ethyl malonaldehyde oxime (II) by a known method. Treatment of N-Boc-L-serine (IV) with N,N-dimethylformamide di-tert-butylacetal (V) in refluxing benzene produced Boc-serine tert-butyl ester (VI) along with a small amount of O-formyl derivative, which was separated by column chromatography. Mitsunobu coupling of isoxazolinone (III) with serine derivative (VI) employing diisopropyl azodicarboxylate (DIAD) and triphenylphosphine afforded the protected O-isoxazolyl serine (VII). The protecting groups of (VII) were finally removed by treatment with trifluoroacetic acid.
【1】 Ikegami, F.; et al.; Synthesis and pharmacological activity of O-(5-isoxazolyl)-L-serine. Chem Pharm Bull 2000, 48, 2, 278. |
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) | 35333 | ethyl propiolate | 623-47-2 | C5H6O2 | 详情 | 详情 |
(II) | 40205 | ethyl 3-(hydroxyimino)propanoate | C5H9NO3 | 详情 | 详情 | |
(III) | 40206 | 5(4H)-isoxazolone | C3H3NO2 | 详情 | 详情 | |
(IV) | 20126 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-hydroxypropionic acid | C8H15NO5 | 详情 | 详情 | |
(V) | 21059 | N-[di(tert-butoxy)methyl]-N,N-dimethylamine; di(tert-butoxy)-N,N-dimethylmethanamine | 36805-97-7 | C11H25NO2 | 详情 | 详情 |
(VI) | 40207 | tert-butyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-hydroxypropanoate | C12H23NO5 | 详情 | 详情 | |
(VII) | 40208 | tert-butyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(5-isoxazolyloxy)propanoate | C15H24N2O6 | 详情 | 详情 |