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【结 构 式】 
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【分子编号】20589 【品名】3-methoxybenzaldehyde; m-Anisaldehyde 【CA登记号】591-31-1 |
【 分 子 式 】C8H8O2 【 分 子 量 】136.15032 【元素组成】C 70.57% H 5.92% O 23.5% |
合成路线1
该中间体在本合成路线中的序号：(I)The condensation of m-methoxybenzaldehyde (I) with cyclohexanone (II) by means of KOH in refluxing water gives m-methoxybenzalcyclohexanone (III), which by reaction first with dimethylamine (A) in ether and then reduction with LiAlH4 in the same solvent affords cis-2-(alpha-dimethylamino-m-methoxybenzyl)cyclohexanol (IV). The hydrolysis of (IV) with HCl in isopropanol yields the racemic product, which is finally resolved into the corresponding optical isomers with tartaric acid.
| 【1】 Yardley, J.P.; Russell, P.B.; US 3928626 . |
| 【2】 Paton, D.M.; Castaner, J.; Ciramadol. Drugs Fut 1980, 5, 6, 283. |
| 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) | 20589 | 3-methoxybenzaldehyde; m-Anisaldehyde | 591-31-1 | C8H8O2 | 详情 | 详情 |
| (II) | 11059 | Cyclohexanone | 108-94-1 | C6H10O | 详情 | 详情 |
| (III) | 39125 | 2-[(E)-(3-methoxyphenyl)methylidene]cyclohexanone | C14H16O2 | 详情 | 详情 | |
| (IV) | 19943 | 5-(benzyloxy)-5-oxopentanoic acid | C12H14O4 | 详情 | 详情 | |
| (V) | 39126 | (1R,2R)-2-[(R)-(dimethylamino)(3-methoxyphenyl)methyl]cyclohexanol | C16H25NO2 | 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 condensation of 3-methoxybenzaldehyde (I) with acetone (II) by means of NaOH gives 1-(3-methoxyphenyl)-1-buten-3-one (III), which is hydrogenated with H2 over Pd/C in methanol yielding 1-(3-methoxyphenyl)-3-butanone (IV). The iodination of (IV) with I2-silver acetate in acetic acid affords 1-(2-iodo-5-methoxyphenyl)-3-butanone (V), which is reductocondensed with methylamine and sodium cyanoborohydride in methanol giving 2-iodo-5-methoxy-N,alpha-dimethylphenylpropanamine (VI). The acylation of (VI) with 3,4-dimethoxyphenylacetyl chloride (VII) by means of triethylamine in dichloromethane yields the corresponding acetamide (VIII), which is reduced with borane-THF complex affording the corresponding tertiary amine (IX), which is finally condensed with phenylacetylene (X) by means of butyllithium in THF.
| 【1】 Carson, J.R. (McNeilab, Inc.); Aralkyl(arylethynyl)aralkyl amines for use as vasodilators and antihypertensives. EP 0146271; ES 8604488; US 4661635 . |
| 【2】 Prous, J.; Castaner, J.; McN-5691. Drugs Fut 1989, 14, 4, 322. |
| 【3】 Carson, J.R.; Almond, H.R.; Brannan, M.D.; et al.; 2-Ethynylbenzenealkanamines. A new class of calcium entry blockers. J Med Chem 1988, 31, 3, 630-6. |
| 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) | 20589 | 3-methoxybenzaldehyde; m-Anisaldehyde | 591-31-1 | C8H8O2 | 详情 | 详情 |
| (II) | 23199 | 2-Propanone; Acetone; beta-ketopropane; chevron acetone;propan-2-one； Dimethyl formaldehyde; Dimethyl ketone; dimethylketal; Ketone propane; Methyl ketone; Propanone; Pyroacetic acid; Pyroacetic ether | 67-64-1 | C3H6O | 详情 | 详情 |
| (III) | 20590 | (E)-4-(3-methoxyphenyl)-3-buten-2-one | C11H12O2 | 详情 | 详情 | |
| (IV) | 20591 | 4-(3-methoxyphenyl)-2-butanone | C11H14O2 | 详情 | 详情 | |
| (V) | 20592 | 4-(2-iodo-5-methoxyphenyl)-2-butanone | C11H13IO2 | 详情 | 详情 | |
| (VI) | 20593 | N-[3-(2-iodo-5-methoxyphenyl)-1-methylpropyl]-N-methylamine; 4-(2-iodo-5-methoxyphenyl)-N-methyl-2-butanamine | C12H18INO | 详情 | 详情 | |
| (VII) | 20594 | 2-(3,4-dimethoxyphenyl)acetyl chloride | C10H11ClO3 | 详情 | 详情 | |
| (VIII) | 20595 | 2-(3,4-dimethoxyphenyl)-N-[3-(2-iodo-5-methoxyphenyl)-1-methylpropyl]-N-methylacetamide | C22H28INO4 | 详情 | 详情 | |
| (IX) | 20596 | N-(3,4-dimethoxyphenethyl)-N-[3-(2-iodo-5-methoxyphenyl)-1-methylpropyl]-N-methylamine; N-(3,4-dimethoxyphenethyl)-4-(2-iodo-5-methoxyphenyl)-N-methyl-2-butanamine | C22H30INO3 | 详情 | 详情 | |
| (X) | 20597 | 1-ethynylbenzene | 536-74-3 | C8H6 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VIII)A new procedure for the asymmetric synthesis of amine (III) was reported. Mitsunobu coupling of N-hydroxyphthalimide (V) with the chiral auxiliary (R)-phenylglycol (IV) yielded the (S)-alkoxyphthalimide (VI). Hydrazinolysis of (VI) provided the free alkoxyamine (VII), which was condensed with 3-methoxybenzaldehyde (VIII) to afford oxime (IX). Diastereoselective addition of methyllithium to the oxime ether (IX) led to the methyl adduct (X) as the major isomer. Then, reductive N-O bond cleavage to furnish amine (III) was carried out by using zinc-acetic acid or, with an improved yield, using molybdenum hexacarbonyl.
| 【1】 Yamazaki, N.; et al.; Nucleophilic addition of methyllithium to chiral oxime ethers: Asymmetric preparation of 1-(aryl)ethylamines and application to a synthesis of calcimimetics (+)-NPS R-568 and its thio analogue. Tetrahedron Lett 2001, 42, 30, 5029. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (III) | 56140 | (R)-1-(3-Methoxyphenyl)ethylamine; (R)-3-Methoxy-alpha-methylbenzylamine; (R)-m-Methoxy-alpha-methylbenzylamine | 88196-70-7 | C9H13NO | 详情 | 详情 |
| (IV) | 56141 | (R)-(-)-1-Phenyl-1,2-ethanediol; (R)-(-)-alpha,beta-Dihydroxyethylbenzene; (R)-(-)-Phenyl-1,2-ethanediol; (R)-(-)-Styrene glycol; (-)-Styrene glycol | 16355-00-3 | C8H10O2 | 详情 | 详情 |
| (V) | 13505 | N-Hydroxyphthalimide; 2-Hydroxy-1H-isoindole-1,3(2H)-dione | 524-38-9 | C8H5NO3 | 详情 | 详情 |
| (VI) | 56142 | 2-{[(1S)-2-hydroxy-1-phenylethyl]oxy}-1H-isoindole-1,3(2H)-dione | C16H13NO4 | 详情 | 详情 | |
| (VII) | 56143 | (2S)-2-(aminooxy)-2-phenyl-1-ethanol | C8H11NO2 | 详情 | 详情 | |
| (VIII) | 20589 | 3-methoxybenzaldehyde; m-Anisaldehyde | 591-31-1 | C8H8O2 | 详情 | 详情 |
| (IX) | 56144 | 3-methoxybenzaldehyde O-[(1S)-2-hydroxy-1-phenylethyl]oxime | C16H17NO3 | 详情 | 详情 | |
| (X) | 56145 | (2S)-2-({[(1R)-1-(3-methoxyphenyl)ethyl]amino}oxy)-2-phenyl-1-ethanol | C17H21NO3 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(VI)Synthesis of intermediate (VIII): Condensation of salicyl alcohol (I) with benzyl bromide (II) by means of KOtBu in DMF gives 2-benzyloxybenzyl alcohol (III), which is converted into chloride (IV) by reaction with SOCl2 in THF. Treatment of derivative (IV) with PPh3 in refluxing toluene furnishes triphenylphosphonium chloride (V), which is condensed with aldehyde (VI) by means of DBU in acetonitrile to afford benzyloxystilbene derivative (VII). Finally, intermediate (VIII) is obtained by hydrogenation of (VII) over Pd/C in EtOH.
| 【1】 Fujimoto, K.; Tanaka, N.; Asai, F.; Ito, T.; Koike, H. (Sankyo Co., Ltd.); Phenoxyalkylamines, -pyrrolidines and -piperidines for the treatment and prevention of circulatory diseases and psychosis. EP 0600717; JP 1994234736; JP 1994306025; US 5556864 . |
| 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) | 42341 | 2-(hydroxymethyl)phenol | 90-01-7 | C7H8O2 | 详情 | 详情 |
| (II) | 12912 | 1-(Bromomethyl)benzene; Alpha-bromotoluene | 100-39-0 | C7H7Br | 详情 | 详情 |
| (III) | 42342 | [2-(benzyloxy)phenyl]methanol | C14H14O2 | 详情 | 详情 | |
| (IV) | 42343 | benzyl 2-(chloromethyl)phenyl ether; 1-(benzyloxy)-2-(chloromethyl)benzene | C14H13ClO | 详情 | 详情 | |
| (V) | 42344 | [2-(benzyloxy)benzyl](triphenyl)phosphonium chloride | C32H28ClOP | 详情 | 详情 | |
| (VI) | 20589 | 3-methoxybenzaldehyde; m-Anisaldehyde | 591-31-1 | C8H8O2 | 详情 | 详情 |
| (VII) | 42345 | 1-(benzyloxy)-2-[(E)-2-(3-methoxyphenyl)ethenyl]benzene; benzyl 2-[(E)-2-(3-methoxyphenyl)ethenyl]phenyl ether | C22H20O2 | 详情 | 详情 | |
| (VIII) | 13604 | 2-(3-Methoxyphenethyl)phenol | C15H16O2 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(XVIII)The target compound has been obtained as follows: The condensation of 3-furoic acid (XV) with ethyl 3-iodopropionate (XVI) by means of Zn-Cu and Pd(PPh3)4 in hot benzene, followed by hydrolysis with NaOH in methanol/THF/water gives 4-(3-furyl)-4-oxobutyric acid (XVII), which is condensed with 3-methoxybenzaldehyde (XVIII) by means of NaOAc in hot Ac2O yielding the lactone (XIX). The cyclization of (XIX) by means of H2SO4 in methanol or HCl/methanol/AcOH affords 4-(3-furyl)-7-methoxynaphthalene-2-carboxylic acid methyl ester (XX), which is converted into the 7-hydroxy-4-(3-furyl)naphthalene-2-carbonitrile (XXI) by reaction with (Me)2Al-NH2 in refluxing toluene, followed by demethylation with pyridine and TFAA or HCl in dioxane. Finally, the condensation of naphthol (XXI) with benzyl alcohol derivative (XXII) by means of triphenylphosphine and diethyl azodicarboxylate (DEAD) or di-tert-butyl azodicarboxylate (DBAD) in THF affords the target product. The benzyl alcohol derivative (XXII) has been obtained as follows: The condensation of the bicyclic ketone intermediate (IV) with the 3-(tert-butyldiphenylsilyloxymethyl)phenyllithium (XXIII) gives the silylated benzyl alcohol (XXIV), which is finally deprotected with TBAF to afford the intermediate (XXII).
| 【1】 Girard, Y.; Dube, D.; Fortin, R.; Hamel, P.; Delorme, D.; Lepine, C. (Merck Frosst Canada Inc.); Heteroarylnaphthalenes as inhibitors of leukotriene biosynthesis. EP 0579304; JP 1994087847; US 5308852; WO 9400444 . |
| 【2】 Belyk, K.M.; et al.; Practical synthesis of 1,6-anhydro-2,4-dideoxy-beta-D-glycero-hexapyramos-3-ulose from levoglucosan. J Org Chem 2000, 65, 8, 2588. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IV) | 38608 | 6,8-dioxabicyclo[3.2.1]octan-3-one | C6H8O3 | 详情 | 详情 | |
| (XV) | 38615 | 3-furoyl chloride | C5H3ClO2 | 详情 | 详情 | |
| (XVI) | 25530 | ethyl 3-iodopropanoate | C5H9IO2 | 详情 | 详情 | |
| (XVII) | 38616 | 4-(3-furyl)-4-oxobutyric acid | C8H8O4 | 详情 | 详情 | |
| (XVIII) | 20589 | 3-methoxybenzaldehyde; m-Anisaldehyde | 591-31-1 | C8H8O2 | 详情 | 详情 |
| (XIX) | 38617 | 5-(3-furyl)-3-[(E)-(3-methoxyphenyl)methylidene]-2(3H)-furanone | C16H12O4 | 详情 | 详情 | |
| (XX) | 38618 | methyl 4-(3-furyl)-7-methoxy-2-naphthoate | C17H14O4 | 详情 | 详情 | |
| (XXI) | 38619 | 4-(3-furyl)-7-hydroxy-2-naphthonitrile | C15H9NO2 | 详情 | 详情 | |
| (XXII) | 38620 | (3S)-3-[3-(hydroxymethyl)phenyl]-6,8-dioxabicyclo[3.2.1]octan-3-ol | C13H16O4 | 详情 | 详情 | |
| (XXIII) | 38621 | [3-([[tert-butyl(diphenyl)silyl]oxy]methyl)phenyl]lithium | C23H25LiOSi | 详情 | 详情 | |
| (XXIV) | 38622 | (3S)-3-[3-([[tert-butyl(diphenyl)silyl]oxy]methyl)phenyl]-6,8-dioxabicyclo[3.2.1]octan-3-ol | C29H34O4Si | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(I)By condensation of 3-methoxybenzaldehyde (I) with ethyl cyanoacetate (II) by means of NaOH in ethanol.
| 【1】 Tiwari, S.; et al.; Synthesis and antileishmanial activity of alpha-cyano ethyl propenoates - A new class of antileishmanials. Arzneim-Forsch Drug Res 1999, 49, 2, 144. |
合成路线7
该中间体在本合成路线中的序号：(VI)Treatment of salicyl alcohol (I) with benzyl bromide (II) in DMF in the presence of KOtBu affords benzyloxybenzyl alcohol (III), which is converted into its chloride form (IV) by means of SOCl2 in THF. Reaction of (IV) with PPh3 in refluxing toluene gives triphenyl phosphonium chloride derivative (V), which is then subjected to a Wittig reaction with aldehyde (VI) to yield olefine (VII). Catalytic hydrogenolysis of (VII) over Pd/C provides phenol derivative (VIII), which is then alkylated by reaction with tosylate (XVI) and KOtBu in dimethylacetamide to yield (XVII). Finally, ethoxycarbonyl derivative (XVII) is reduced by means of LiAlH4 in THF and converted into its hydrochloride form by treatment with HCl in dioxane. Intermediate (XVI) can be prepared as follows: Protection of 2(S)-pyrrolidinemethanol (IX) by reaction with ethyl chloroformate in the presence of Et3N in dichloromethane affords carbamate (XI), which is tosylated by means of Ts2O and Et3N in dichloromethane to yield (XII). One carbon elongation of (XII) by reaction with NaCN in DMF provides (XIII), which is then converted into ester (XIV) by means of H2SO4 in EtOH. Reduction of ester (XIV) with LiAlH4 in THF gives alcohol (XV), which is finally tosylated by reaction with Ts2O and Et3N in dichloromethane.
| 【1】 Fujimoto, K.; Tanaka, N.; Asai, F.; Ito, T.; Koike, H. (Sankyo Co., Ltd.); Phenoxyalkylamines, -pyrrolidines and -piperidines for the treatment and prevention of circulatory diseases and psychosis. EP 0600717; JP 1994234736; JP 1994306025; US 5556864 . |
| 【2】 Goto, R.; Hayakawa, M.; Ito, R.; Ogawa, T.; Sugidachi, A.; Tanaka, N.; Asai, F.; Fujimoto, K.; [2-(omega-Phenylalkyl)phenoxy]alkylamines II: Synthesis and selective serotonin-2 receptor binding. Chem Pharm Bull 2000, 48, 2, 245. |
| 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) | 42341 | 2-(hydroxymethyl)phenol | 90-01-7 | C7H8O2 | 详情 | 详情 |
| (II) | 12912 | 1-(Bromomethyl)benzene; Alpha-bromotoluene | 100-39-0 | C7H7Br | 详情 | 详情 |
| (III) | 42342 | [2-(benzyloxy)phenyl]methanol | C14H14O2 | 详情 | 详情 | |
| (IV) | 42343 | benzyl 2-(chloromethyl)phenyl ether; 1-(benzyloxy)-2-(chloromethyl)benzene | C14H13ClO | 详情 | 详情 | |
| (V) | 42344 | [2-(benzyloxy)benzyl](triphenyl)phosphonium chloride | C32H28ClOP | 详情 | 详情 | |
| (VI) | 20589 | 3-methoxybenzaldehyde; m-Anisaldehyde | 591-31-1 | C8H8O2 | 详情 | 详情 |
| (VII) | 42345 | 1-(benzyloxy)-2-[(E)-2-(3-methoxyphenyl)ethenyl]benzene; benzyl 2-[(E)-2-(3-methoxyphenyl)ethenyl]phenyl ether | C22H20O2 | 详情 | 详情 | |
| (VIII) | 13604 | 2-(3-Methoxyphenethyl)phenol | C15H16O2 | 详情 | 详情 | |
| (IX) | 21347 | (2S)pyrrolidinylmethanol | 23356-96-9 | C5H11NO | 详情 | 详情 |
| (X) | 11229 | 1-[(Chlorocarbonyl)oxy]ethane;ethyl carbonochloridate; Carbonchloridic acid ethyl ester;Ethyl chloroformate;Ethyl chlorocarbonate | 541-41-3 | C3H5ClO2 | 详情 | 详情 |
| (XI) | 42346 | ethyl (2S)-2-(hydroxymethyl)-1-pyrrolidinecarboxylate | C8H15NO3 | 详情 | 详情 | |
| (XII) | 42347 | ethyl (2S)-2-([[(4-methylphenyl)sulfonyl]oxy]methyl)-1-pyrrolidinecarboxylate | C15H21NO5S | 详情 | 详情 | |
| (XIII) | 42348 | ethyl (2S)-2-(cyanomethyl)-1-pyrrolidinecarboxylate | C9H14N2O2 | 详情 | 详情 | |
| (XIV) | 42349 | ethyl (2S)-2-(2-ethoxy-2-oxoethyl)-1-pyrrolidinecarboxylate | C11H19NO4 | 详情 | 详情 | |
| (XV) | 42350 | ethyl (2S)-2-(2-hydroxyethyl)-1-pyrrolidinecarboxylate | C9H17NO3 | 详情 | 详情 | |
| (XVI) | 42351 | ethyl (2S)-2-(2-[[(4-methylphenyl)sulfonyl]oxy]ethyl)-1-pyrrolidinecarboxylate | C16H23NO5S | 详情 | 详情 | |
| (XVII) | 42352 | ethyl (2S)-2-[2-[2-(3-methoxyphenethyl)phenoxy]ethyl]-1-pyrrolidinecarboxylate | C24H31NO4 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(II)The desired 2'-amino chalcone is synthesized by a base-catalyzed condensation of 2-amino acetophenone (I) and benzaldehyde (II) by means of aqueous NaOH in EtOH.
| 【1】 Xia, Y.; et al.; Antitumor agents. 181. Synthesis and biological evaluation of 6,7,2',3',4'-substituted-1,2,3, 4-tetrahydro-2-phenyl-4-quinolones as a new class of antimitotic antitumor agents. J Med Chem 1998, 41, 7, 1155. |
| 【2】 Xia, P.; Xia, Y.; Lee, K.-H.; Bastow, K.F.; Nakanishi, Y.; Yang, Z.-Y.; Antitumor agents. Part 202: Novel 2'-amino chalcones: Design, synthesis and biological evaluation. Bioorg Med Chem Lett 2000, 10, 8, 699. |
合成路线9
该中间体在本合成路线中的序号：(I)The condensation between 3-methoxybenzaldehyde (I), S-methylisothiourea (II) and ethyl cyanoacetate (III) in the presence of K2CO3 in hot EtOH leads to pyrimidine (IV). Subsequent chlorination of (IV) by means of POCl3 and dimethylaniline furnishes the 6-chloropyrimidine (V). Reaction of (V) with ethyl mercaptoacetate (VI) and potassium tert-butoxide gives rise to the thienopyrimidine (VII). The ethyl ester group of (VII) is then hydrolyzed to the carboxylic acid (VIII) employing LiOH. Finally, coupling of acid (VIII) with tert-butylamine by means of TBTU produces the target N-tert-butyl amide
| 【1】 Adang, A.E.P.; Gerritsma, G.G.; Van Straten, N.C.R. (Akzo Nobel N.V.); Bicyclic heteroaromatic cpds. useful as LH agonists. EP 1171443; JP 2002541259; US 6569863; WO 0061586 . |
| 【2】 Timmers, C.M.; Karstens, W.F.J. (Akzo Nobel N.V.); Bicyclic heteroaromatic cpds.. WO 0224703 . |
| 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) | 20589 | 3-methoxybenzaldehyde; m-Anisaldehyde | 591-31-1 | C8H8O2 | 详情 | 详情 |
| (II) | 10272 | [[Amino(imino)methyl]sulfanyl]methane | 2986-19-8 | C2H6N2S | 详情 | 详情 |
| (III) | 11877 | Cyanoacetic acid ethyl ester; Ethyl 2-cyanoacetate; Ethyl cyanoacetate; Ethyl isocyanacetate | 105-56-6 | C5H7NO2 | 详情 | 详情 |
| (IV) | 60410 | 4-hydroxy-6-(3-methoxyphenyl)-2-(methylsulfanyl)-5-pyrimidinecarbonitrile | C13H11N3O2S | 详情 | 详情 | |
| (V) | 60411 | 4-chloro-6-(3-methoxyphenyl)-2-(methylsulfanyl)-5-pyrimidinecarbonitrile | C13H10ClN3OS | 详情 | 详情 | |
| (VI) | 23995 | ethyl 2-sulfanylacetate | 2713-34-0 | C4H8O2S | 详情 | 详情 |
| (VII) | 60412 | ethyl 5-amino-4-(3-methoxyphenyl)-2-(methylsulfanyl)thieno[2,3-d]pyrimidine-6-carboxylate | C17H17N3O3S2 | 详情 | 详情 | |
| (VIII) | 60413 | 5-amino-4-(3-methoxyphenyl)-2-(methylsulfanyl)thieno[2,3-d]pyrimidine-6-carboxylic acid | C15H13N3O3S2 | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(VI)Synthesis of intermediate (VIII): Condensation of salicyl alcohol (I) with benzyl bromide (II) by means of KOtBu in DMF gives 2-benzyloxybenzyl alcohol (III), which is then converted into chloride (IV) by reaction with SOCl2 in THF. Treatment of derivative (IV) with PPh3 in refluxing toluene furnishes triphenylphosphonium chloride (V), which is then condensed with aldehyde (VI) by means of DBU in acetonitrile to afford benzyloxystilbene derivative (VII). Finally, intermediate (VIII) is obtained by hydrogenation of (VII) over Pd/C in EtOH.
| 【1】 Fujimoto, K.; Tanaka, N.; Asai, F.; Ito, T.; Koike, H. (Sankyo Co., Ltd.); Phenoxyalkylamines, -pyrrolidines and -piperidines for the treatment and prevention of circulatory diseases and psychosis. EP 0600717; JP 1994234736; JP 1994306025; US 5556864 . |
| 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) | 42341 | 2-(hydroxymethyl)phenol | 90-01-7 | C7H8O2 | 详情 | 详情 |
| (II) | 12912 | 1-(Bromomethyl)benzene; Alpha-bromotoluene | 100-39-0 | C7H7Br | 详情 | 详情 |
| (III) | 42342 | [2-(benzyloxy)phenyl]methanol | C14H14O2 | 详情 | 详情 | |
| (IV) | 42343 | benzyl 2-(chloromethyl)phenyl ether; 1-(benzyloxy)-2-(chloromethyl)benzene | C14H13ClO | 详情 | 详情 | |
| (V) | 42344 | [2-(benzyloxy)benzyl](triphenyl)phosphonium chloride | C32H28ClOP | 详情 | 详情 | |
| (VI) | 20589 | 3-methoxybenzaldehyde; m-Anisaldehyde | 591-31-1 | C8H8O2 | 详情 | 详情 |
| (VII) | 42345 | 1-(benzyloxy)-2-[(E)-2-(3-methoxyphenyl)ethenyl]benzene; benzyl 2-[(E)-2-(3-methoxyphenyl)ethenyl]phenyl ether | C22H20O2 | 详情 | 详情 | |
| (VIII) | 13604 | 2-(3-Methoxyphenethyl)phenol | C15H16O2 | 详情 | 详情 |
合成路线11
该中间体在本合成路线中的序号：(I)Conjugate addition of methyl acrylate (II) to 3-methoxybenzaldehyde (I) under reversion of reactivity conditions in the presence of KCN produced the keto ester (III). The Wolff-Kishner reduction of the keto group caused simultaneous ester hydrolysis, yielding acid (IV), which was further cyclized to the tetralone (V) employing hot polyphosphoric acid. Mannich reaction of ketone (V) with N-benzyl methylamine and paraformaldehyde furnished amino ketone (VI). To this was added phenylmagnesium bromide (VII), yielding amino alcohol (VIII), which was subsequently dehydrated to (IX) by means of trifluoroacetic acid. Catalytic hydrogenation of the olefin double bond of (IX) with simultaneous N-benzyl group hydrogenolysis gave the secondary amine (X). This was then alkylated with ethyl bromoacetate, producing the substituted glycine ester (XI), which was finally hydrolyzed by means of LiOH.
| 【1】 Jaap, D.R.; Gilfillan, R.; Gibson, S.G.; Thorn, S.N. (Akzo Nobel N.V.); Aminomethylcarboxylic acid derivs.. EP 1100769; WO 0007978 . |
| 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) | 20589 | 3-methoxybenzaldehyde; m-Anisaldehyde | 591-31-1 | C8H8O2 | 详情 | 详情 |
| (II) | 14156 | methyl acrylate | 96-33-3 | C4H6O2 | 详情 | 详情 |
| (III) | 51352 | methyl 4-(3-methoxyphenyl)-4-oxobutanoate | C12H14O4 | 详情 | 详情 | |
| (IV) | 51353 | 4-(3-methoxyphenyl)butyric acid | C11H14O3 | 详情 | 详情 | |
| (V) | 17594 | 6-methoxy-3,4-dihydro-1(2H)-naphthalenone; 6-Methoxytetralone; 6-Methoxy-1-tetralone; 3,4-dihydro-6-methoxy-1(2H)-naphthalenone | 1078-19-9 | C11H12O2 | 详情 | 详情 |
| (VI) | 51354 | 2-[[benzyl(methyl)amino]methyl]-6-methoxy-3,4-dihydro-1(2H)-naphthalenone | C20H23NO2 | 详情 | 详情 | |
| (VII) | 17616 | bromo(phenyl)magnesium; Phenyl Magnesium Bromide | 100-58-3 | C6H5BrMg | 详情 | 详情 |
| (VIII) | 51355 | 2-[[benzyl(methyl)amino]methyl]-6-methoxy-1-phenyl-1,2,3,4-tetrahydro-1-naphthalenol | C26H29NO2 | 详情 | 详情 | |
| (IX) | 51356 | N-benzyl(6-methoxy-1-phenyl-3,4-dihydro-2-naphthalenyl)-N-methylmethanamine; N-benzyl-N-[(6-methoxy-1-phenyl-3,4-dihydro-2-naphthalenyl)methyl]-N-methylamine | C26H27NO | 详情 | 详情 | |
| (X) | 51357 | [(1S,2R)-6-methoxy-1-phenyl-1,2,3,4-tetrahydro-2-naphthalenyl]-N-methylmethanamine; N-[[(1S,2R)-6-methoxy-1-phenyl-1,2,3,4-tetrahydro-2-naphthalenyl]methyl]-N-methylamine | C19H23NO | 详情 | 详情 | |
| (XI) | 51358 | ethyl 2-[[[(1S,2R)-6-methoxy-1-phenyl-1,2,3,4-tetrahydro-2-naphthalenyl]methyl](methyl)amino]acetate | C23H29NO3 | 详情 | 详情 |
合成路线12
该中间体在本合成路线中的序号：(VII)The esterification of 4(R)-hydroxypyrrolidine-2(S)-carboxylic acid (I) gives the methyl ester (II), which is N-protected to yield 1-Boc-4(R)-hydroxypyrrolidine-2(S)-carboxylic acid methyl ester (III). Compound (III) which is mesylated to afford 1-Boc-4(R)-(mesyloxy)pyrrolidine-2(S)-carboxylic acid methyl ester (IV). The reaction of (IV) with sodium azide affords (V), which is reduced with H2 over Pd/C in ethanol to provide 4(S)-amino-1-Boc-pyrrolidine-2(S)-carboxylic acid methyl ester (VI). The reductocondensation of (VI) with 3-methoxybenzaldehyde (VII) by means of NaBH(OAc)3 provides the secondary amine (VIII), which is acylated with 3,3-dimethylbutyryl chloride (IX) and TEA in dichloromethane to give the amide (X). The deprotection of the pyrrolidine NH of (X) by means of TFA yields the pyrrolidine (XI), which is reductocondensed with piperonal (XII) by means of NaBH3CN to afford the N-substituted pyrrolidine (XIII). The hydrolysis of the ester group of (XIII) with LiOH in methanol/water provides the carboxylic acid (XIV), which is condensed with N-Boc-piperazine (XV) by means of TBTU and DIEA in DMF to give the protected intermediate (XVI). Finally, this compound is deprotected by means of TFA in dichloromethane to furnish the target carboxamide.
| 【1】 Baxter, A.D.; Boyd, E.A.; Price, S.; Guicherit, O.M.; Rubin, L. (Curis, Inc.); Mediators of hedgehog signaling pathways, compsns. and uses related thereto. WO 0126644 . |
| 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) | 14489 | (2S,4R)-4-hydroxytetrahydro-1H-pyrrole-2-carboxylic acid; L-Hydroxyproline | 51-35-4 | C5H9NO3 | 详情 | 详情 |
| (II) | 15796 | methyl (2S,4R)-4-hydroxytetrahydro-1H-pyrrole-2-carboxylate | C6H11NO3 | 详情 | 详情 | |
| (III) | 15780 | 1-(tert-butyl) 2-methyl (2S,4S)-4-hydroxytetrahydro-1H-pyrrole-1,2-dicarboxylate;(2S,4S)-1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate | C11H19NO5 | 详情 | 详情 | |
| (IV) | 15781 | 1-(tert-butyl) 2-methyl (2S,4R)-4-[(methylsulfonyl)oxy]tetrahydro-1H-pyrrole-1,2-dicarboxylate | C12H21NO7S | 详情 | 详情 | |
| (V) | 43411 | 1-(tert-butyl) 2-methyl (2S,4S)-4-azido-1,2-pyrrolidinedicarboxylate | C11H18N4O4 | 详情 | 详情 | |
| (VI) | 55407 | 1-(tert-butyl) 2-methyl (2S,4S)-4-amino-1,2-pyrrolidinedicarboxylate | C11H20N2O4 | 详情 | 详情 | |
| (VII) | 20589 | 3-methoxybenzaldehyde; m-Anisaldehyde | 591-31-1 | C8H8O2 | 详情 | 详情 |
| (VIII) | 55407 | 1-(tert-butyl) 2-methyl (2S,4S)-4-amino-1,2-pyrrolidinedicarboxylate | C11H20N2O4 | 详情 | 详情 | |
| (IX) | 21738 | 3,3-dimethylbutanoyl chloride | 7065-46-5 | C6H11ClO | 详情 | 详情 |
| (X) | 55409 | 1-(tert-butyl) 2-methyl (2S,4S)-4-[(3,3-dimethylbutanoyl)(3-methoxybenzyl)amino]-1,2-pyrrolidinedicarboxylate | C25H38N2O6 | 详情 | 详情 | |
| (XI) | 55410 | methyl (2S,4S)-4-[(3,3-dimethylbutanoyl)(3-methoxybenzyl)amino]-2-pyrrolidinecarboxylate | C20H30N2O4 | 详情 | 详情 | |
| (XII) | 10127 | 1,3-Benzodioxole-5-carbaldehyde; Heliotropine | 120-57-0 | C8H6O3 | 详情 | 详情 |
| (XIII) | 55411 | methyl (2S,4S)-1-(1,3-benzodioxol-5-ylmethyl)-4-[(3,3-dimethylbutanoyl)(3-methoxybenzyl)amino]-2-pyrrolidinecarboxylate | C28H36N2O6 | 详情 | 详情 | |
| (XIV) | 55412 | (2S,4S)-1-(1,3-benzodioxol-5-ylmethyl)-4-[(3,3-dimethylbutanoyl)(3-methoxybenzyl)amino]-2-pyrrolidinecarboxylic acid | C27H34N2O6 | 详情 | 详情 | |
| (XV) | 13225 | N-tert-Butoxycarbonyl piperazine; tert-butyl 1-piperazinecarboxylate;tert-butyl piperazine-1-carboxylate | 143238-38-4 | C9H18N2O2 | 详情 | 详情 |
| (XVI) | 55413 | tert-butyl 4-({(2S,4S)-1-(1,3-benzodioxol-5-ylmethyl)-4-[(3,3-dimethylbutanoyl)(3-methoxybenzyl)amino]pyrrolidinyl}carbonyl)-1-piperazinecarboxylate | C36H50N4O7 | 详情 | 详情 |