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【结 构 式】 
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【分子编号】22075 【品名】Formaldehyde; Paraformaldehyde 【CA登记号】1118-66-7 |
【 分 子 式 】CH2O 【 分 子 量 】30.02628 【元素组成】C 40% H 6.71% O 53.28% |
合成路线1
该中间体在本合成路线中的序号：The formylation of 6-bromo-1,3-benzodioxole-5-carbaldehyde dimethyl acetal (I) with BuLi and DMF gives the 6-formyl derivative (II), which is reduced with NaBH4 in ethanol to yield the corresponding carbinol (III). The cyclization of (III) with dimethyl acetylenedicarboxylate (V) in hot acetic acid (through the nonisolated intermediate (IV)) affords dimethyl 1,4-epoxy-6,7-(methylenedioxy)naphthalene-2,3-dicarboxylate (VI), which is hydrogenated with H2 over Pd/C in ethyl acetate to give the (1R*,2S*,3R*,4S*)-tetrahydro derivative (VII). The reduction of (VII) with LiAlH4 in refluxing ethyl ether affords the corresponding bis carbinol (VIII), which is treated with acetic anhydride to afford the diacetate (IX). The enzymatic monodeacetylation of (VIII) with PPL enzyme in DMSO/buffer gives (1R,2R,3S,4S)-2-(acetoxymethyl)-1,4-epoxy-3-(hydroxymethyl)-6,7-(methylenedioxy)-1,2,3,4-tetrahydronaphthalene (X), which is silylated with TBDMS-Cl and imidazole in DMF yielding the silyl ether (XI). The hydrolysis of the acetoxy group of (XI) with K2CO3 in methanol affords the carbinol (XII), which is oxidized with oxalyl chloride in dichloromethane affording the carbaldehyde (XIII). The exchange of the silyl protecting group of (XIII) (for stability problems) provided the triisopropylsilyl ether (XIV), which is treated with sodium methoxide in methanol to open the epoxide ring yielding the hydroxy aldehyde (XV). The protection of the hydroxy group of (XV) with 2-(trimethylsilyl)ethoxymethyl chloride and DIEA in dichloromethane provides the corresponding ether (XVI). The carbinol (III) can also be obtained directly from 6-bromo-1,3-benzodioxole-5-carbaldehyde dimethyl acetal (I) by reaction with formaldehyde and BuLi in THF.
| 【1】 Berkowitz, D.B.; et al.; Enzyme-assisted asymmetric total synthesis of (-)-podophyllotoxin and (-)-picropodophyllin. J Org Chem 2000, 65, 3, 847. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 22075 | Formaldehyde; Paraformaldehyde | 1118-66-7 | CH2O | 详情 | 详情 | |
| 33491 | Dimethylformamide | 68-12-2 | C3H7NO | 详情 | 详情 | |
| (I) | 32361 | 6-Bromo-1,3-benzodioxole-5-carbaldehyde dimethyl acetal; 5-Bromo-6-(dimethoxymethyl)-1,3-benzodioxole; (6-Bromo-1,3-benzodioxol-5-yl)(methoxy)methyl methyl ether | C10H11BrO4 | 详情 | 详情 | |
| (II) | 32362 | 6-(dimethoxymethyl)-1,3-benzodioxole-5-carbaldehyde | C11H12O5 | 详情 | 详情 | |
| (III) | 32363 | [6-(dimethoxymethyl)-1,3-benzodioxol-5-yl]methanol | C11H14O5 | 详情 | 详情 | |
| (IV) | 32364 | furo[3,4-f][1,3]benzodioxole | C9H6O3 | 详情 | 详情 | |
| (V) | 24551 | Dimethyl acetylenedicarboxylate; Dimethyl 2-butynedioate;Acetylenedicarboxylic acid dimethyl ester | 762-42-5 | C6H6O4 | 详情 | 详情 |
| (VI) | 32365 | dimethyl (1R,11S)-5,7,14-trioxatetracyclo[9.2.1.0(2,10).0(4,8)]tetradeca-2(10),3,8,12-tetraene-12,13-dicarboxylate | C15H12O7 | 详情 | 详情 | |
| (VII) | 32366 | dimethyl (1R,11S,12S,13R)-5,7,14-trioxatetracyclo[9.2.1.0(2,10).0(4,8)]tetradeca-2(10),3,8-triene-12,13-dicarboxylate | C15H14O7 | 详情 | 详情 | |
| (VIII) | 32367 | [(1S,11R,12S,13R)-13-(hydroxymethyl)-5,7,14-trioxatetracyclo[9.2.1.0(2,10).0(4,8)]tetradeca-2(10),3,8-trien-12-yl]methanol | C13H14O5 | 详情 | 详情 | |
| (IX) | 32368 | [(1R,11S,12S,13R)-13-[(acetoxy)methyl]-5,7,14-trioxatetracyclo[9.2.1.0(2,10).0(4,8)]tetradeca-2(10),3,8-trien-12-yl]methyl acetate | C17H18O7 | 详情 | 详情 | |
| (X) | 32369 | [(1S,11R,12S,13R)-13-(hydroxymethyl)-5,7,14-trioxatetracyclo[9.2.1.0(2,10).0(4,8)]tetradeca-2(10),3,8-trien-12-yl]methyl acetate | C15H16O6 | 详情 | 详情 | |
| (XI) | 32370 | [(1S,11R,12S,13R)-13-([[tert-butyl(dimethyl)silyl]oxy]methyl)-5,7,14-trioxatetracyclo[9.2.1.0(2,10).0(4,8)]tetradeca-2(10),3,8-trien-12-yl]methyl acetate | C21H30O6Si | 详情 | 详情 | |
| (XII) | 32371 | [(1S,11R,12S,13R)-13-([[tert-butyl(dimethyl)silyl]oxy]methyl)-5,7,14-trioxatetracyclo[9.2.1.0(2,10).0(4,8)]tetradeca-2(10),3,8-trien-12-yl]methanol | C19H28O5Si | 详情 | 详情 | |
| (XIII) | 32372 | (1S,11R,12R,13R)-13-([[tert-butyl(dimethyl)silyl]oxy]methyl)-5,7,14-trioxatetracyclo[9.2.1.0(2,10).0(4,8)]tetradeca-2(10),3,8-triene-12-carbaldehyde | C19H26O5Si | 详情 | 详情 | |
| (XIV) | 32373 | (1S,11R,12R,13R)-13-[[(triisopropylsilyl)oxy]methyl]-5,7,14-trioxatetracyclo[9.2.1.0(2,10).0(4,8)]tetradeca-2(10),3,8-triene-12-carbaldehyde | C22H32O5Si | 详情 | 详情 | |
| (XV) | 32374 | (7R,8R)-8-hydroxy-7-[[(triisopropylsilyl)oxy]methyl]-7,8-dihydronaphtho[2,3-d][1,3]dioxole-6-carbaldehyde | C22H32O5Si | 详情 | 详情 | |
| (XVI) | 32375 | (7R,8R)-7-[[(triisopropylsilyl)oxy]methyl]-8-[[2-(trimethylsilyl)ethoxy]methoxy]-7,8-dihydronaphtho[2,3-d][1,3]dioxole-6-carbaldehyde | C28H46O6Si2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(V)The reaction of aniline (I) with 4-hydroxybenzoic acid (II) by means of P2O5 in refluxing toluene gives N-(4-hydroxybenzoyl)aniline (III), which is then condensed with pyrrolidine (IV) and formaldehyde (V) in refluxing ethanol.
| 【1】 Stout, D.M.; et al.; Synthesis and antiarrhythmic and parasympatholytic properties of substituted phenols. 3. Modifications to the linkage region (Region 3(. J Med Chem 1985, 28, 3, 295-298. |
| 【2】 Serradell, M.N.; Castaner, J.; ACC-9358. Drugs Fut 1986, 11, 3, 169. |
| 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) | 12294 | Aniline; Phenylamine | 62-53-3 | C6H7N | 详情 | 详情 |
| (II) | 28208 | 3-thioxo-2,3-dihydro-1H-2H-thieno[3,4-d]isothiazole-1,1-dione | C5H3NO2S3 | 详情 | 详情 | |
| (III) | 28206 | 4-hydroxy-N-phenylbenzamide | C13H11NO2 | 详情 | 详情 | |
| (IV) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 |
| (V) | 22075 | Formaldehyde; Paraformaldehyde | 1118-66-7 | CH2O | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)This compound can be obtained by several different ways: 1) By condensation of 4-ethylpropiophenone (I), formaldehyde (II) and piperidine (III) in refluxing isopropanol. 2) By reaction of 4-ethyl-alpha-methyl-beta-chloropropiophenone (IV) with (III) in refluxing ethanol. 3) By cyclization of 4-ethyl-alpha-methyl-beta-amino-propiophenone (V) with 1,5-dibromopentane (VI) in hot ethanol. 4) By a Friedel-Kraft's reaction of ethylbenzene (VII) with 3-piperidinoisobutyryl chloride (VIII) by means of AlCl3 at reflux temperature. 5) By condensation of 4-ethyl-alpha-methylenepropiophenone (IX) with (III) in ethanol.
| 【1】 Murakami, M.; Sone, T.; Sako, K.; Wakabayashi, M.; Kodaira, R.; JP 7925571 . |
| 【2】 Murakami, M.; Sone, T.; Sako, K.; Wakabayashi, M.; Kodaira, R.; Preparation of propiophenone derivative. JP 54036274 . |
| 【3】 Murakami, M.; Sone, T.; Sako, K.; Wakabayashi, M.; Kodaira, R.; Novel preparation of piperidine derivatives. JP 54032480 . |
| 【4】 Murakami, M.; Sone, T.; Sako, K.; Wakabayashi, M.; Kodaira, R; Preparation of propiophenone derivative. JP 54030178 . |
| 【5】 Morita, E.; Kanai, T.; Amino-substituted propiophenone derivatives and medicaments containing same. JP 52085175 . |
| 【6】 Morita, E.; Kanai, T. (Eisai Co., Ltd.); Propiophenone derivatives in the treatment of pathological muscular conditions. US 3995047; US 4181803 . |
| 【7】 Castaner, J.; Blancafort, P.; Serradell, M.N.; EMPP. Drugs Fut 1982, 7, 2, 105. |
| 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) | 22076 | 1-(4-ethylphenyl)-1-propanone | 27465-51-6 | C11H14O | 详情 | 详情 |
| (II) | 22075 | Formaldehyde; Paraformaldehyde | 1118-66-7 | CH2O | 详情 | 详情 |
| (III) | 10158 | Piperidine | 110-89-4 | C5H11N | 详情 | 详情 |
| (IV) | 31975 | 3-chloro-1-(4-ethylphenyl)-2-methyl-1-propanone | C12H15ClO | 详情 | 详情 | |
| (V) | 31976 | 3-amino-1-(4-ethylphenyl)-2-methyl-1-propanone | C12H17NO | 详情 | 详情 | |
| (VI) | 30560 | 1,5-dibromopentane | 111-24-0 | C5H10Br2 | 详情 | 详情 |
| (VII) | 31977 | 1-ethylbenzene | 100-41-4 | C8H10 | 详情 | 详情 |
| (VIII) | 31978 | 2-methyl-3-(1-piperidinyl)propanoyl chloride | C9H16ClNO | 详情 | 详情 | |
| (IX) | 31979 | 1-(4-ethylphenyl)-2-methyl-2-propen-1-one | C12H14O | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(II)By condensation of pyrrolidine (I) with paraformaldehyde (II) and 4-ethylpropiophenone (III) by means of dry HCl in refluxing ethyl acetate.
| 【1】 Susumu, O.; Masaru, S.; Tomio, Y.; Yutaka, N.; Masatoshi, H. (Nippon Chemiphar Co., Ltd.); Benzimidazole derivs. and antiulcer agents contain. AU 8546409; BE 0903128; CH 665417; DE 3531487; ES 8703142; FR 2569691; GB 2163747; JP 1986060660; JP 1986221175; JP 1986221176; JP 1991223260; JP 1991223261; JP 1991223262; JP 1991227927 . |
| 【2】 Itho, Y.; Kato, H.; Koshinaka, E.; Nishino, H.; Ogawa, N. (Hokuriku Seiyaku Co., Ltd.); Derivs. of 3-pyrrolidinopropiophenone and a proces. FR 2559771 . |
| 【3】 Itho, Y.; Kato, H.; Koshinaka, E.; Nishino, H.; Ogawa, N. (Hokuriku Seiyaku Co., Ltd.); Derivs. of 3-pyrrolidinopropiophenone and a proces. EP 0150235 . |
| 【4】 Prous, J.; Castaner, J.; HSR-770. Drugs Fut 1988, 13, 4, 310. |
合成路线5
该中间体在本合成路线中的序号：(XII)Alternatively, compound (R)-(IX) can be obtained as follows: treatment of butylmalonic acid (XI) with formaldehyde (XII) in ethanol in the presence of piperidine provides 2-butyl acrylic acid (XIII), which is converted into oxazolidinone derivative (XVI) by first reaction with pivaloyl chloride (XIV) and Et3N in THF followed by treatment with derivative (XV) and BuLi in THF. Oxazolidinone (XVI) is then enantioselectively condensed with O-benzylhydroxylamine (XVII) and treated with p-TsOH to afford a single diastereoisomer (XVIII), which is then hydrolyzed with LiOH in THF to yield (XIX). Finally, hexanoic acid (XIX) is coupled to tert-Leucine-N,N-dimethylamide (VII) by means of EDC and HOBt in DMF.
| 【1】 Spavold, Z.M.; Launchbury, S.; Clements, J.M.; Hunter, M.G.; Davies, S.J.; Pratt, L.M.; Beckett, R.P.; Whittaker, M. (British Biotech Pharmaceuticals Ltd.); Antibacterial agents. WO 9939704 . |
| 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) | 45886 | (2S)-2-amino-N,N,3,3-tetramethylbutanamide | C8H18N2O | 详情 | 详情 | |
| (IX) | 45888 | (2R)-2-[[(benzyloxy)amino]methyl]-N-[(1S)-1-[(dimethylamino)carbonyl]-2,2-dimethylpropyl]hexanamide | C22H37N3O3 | 详情 | 详情 | |
| (XI) | 45891 | 2-butylmalonic acid | 534-59-8 | C7H12O4 | 详情 | 详情 |
| (XII) | 22075 | Formaldehyde; Paraformaldehyde | 1118-66-7 | CH2O | 详情 | 详情 |
| (XIII) | 45892 | 2-[(ethylsulfanyl)methyl]acrylic acid | C6H10O2S | 详情 | 详情 | |
| (XIV) | 13597 | 2,2-Dimethylpropanoyl chloride; Pivaloyl chloride | 3282-30-2 | C5H9ClO | 详情 | 详情 |
| (XV) | 45893 | (4S)-4-benzyl-5,5-dimethyl-1,3-oxazolidin-2-one | C12H15NO2 | 详情 | 详情 | |
| (XVI) | 45894 | (4S)-4-benzyl-3-[2-[(ethylsulfanyl)methyl]acryloyl]-5,5-dimethyl-1,3-oxazolidin-2-one | C18H23NO3S | 详情 | 详情 | |
| (XVII) | 14640 | O-benzylhydroxylamine; 1-[(aminooxy)methyl]benzene | 622-33-3 | C7H9NO | 详情 | 详情 |
| (XVIII) | 45895 | (4S)-4-benzyl-3-[(2R)-3-[(benzyloxy)amino]-2-[(ethylsulfanyl)methyl]propanoyl]-5,5-dimethyl-1,3-oxazolidin-2-one | C25H32N2O4S | 详情 | 详情 | |
| (XIX) | 45897 | 3-[4-[2-(benzyloxy)ethoxy]phenyl]-2-ethoxypropanamide | C20H25NO4 | 详情 | 详情 |