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【结 构 式】 
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【分子编号】12435 【品名】Acetylcyclopropane; 1-Cyclopropyl-1-ethanone; Cyclopropylmethylketone 【CA登记号】765-43-5 |
【 分 子 式 】C5H8O 【 分 子 量 】84.11792 【元素组成】C 71.39% H 9.59% O 19.02% |
合成路线1
该中间体在本合成路线中的序号：(I)This compound can be obtained in two different ways: 1) The reaction of cyclopropylmethyl ketone oxime (II) with epibromohydrin (A) in THF containing NaH gives O-[2,3-epoxypropyl]cyclopropylmethyl ketone oxime (III), which is treated with excess tert-butylamine (C) in ethanol yielding the final compound. 2) By condensation of cyclopropylmethyl ketone (I) with 3-(aminooxy)-N-tert-butyl-2-hydroxypropanamine (B) in ethanol.
| 【1】 Leclerc, G.; Bouzoubaa, M.; Andermann, G.; Ethers and oxime ethers of alkylamino alcohols as medicaments and novel products, and processes for their preparation. AU 1167283; EP 0087378; FR 2521856; JP 58154538; US 4766151 . |
| 【2】 Schwartz, J.; Bieth, N.; Leclerc, G.; Synthesis and beta-adrenergic blocking activity of a new aliphatic oxime ethers. J Med Chem 1980, 23, 6, 620. |
| 【3】 Castaner, J.; Serradell, M.N.; Falintolol oxalate. Drugs Fut 1984, 9, 7, 510. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 29679 | 2-(bromomethyl)oxirane | 3132-64-7 | C3H5BrO | 详情 | 详情 |
| (B) | 34255 | 1-(aminooxy)-3-(tert-butylamino)-2-propanol | C7H18N2O2 | 详情 | 详情 | |
| (I) | 12435 | Acetylcyclopropane; 1-Cyclopropyl-1-ethanone; Cyclopropylmethylketone | 765-43-5 | C5H8O | 详情 | 详情 |
| (II) | 34253 | 1-cyclopropyl-1-ethanone oxime | C5H9NO | 详情 | 详情 | |
| (III) | 34254 | 1-cyclopropyl-1-ethanone O-(2-oxiranylmethyl)oxime | C8H13NO2 | 详情 | 详情 | |
| (C) | 17895 | 2-Amino-2-methylpropane; tert-butylamine; 2-methyl-2-propanamine | 75-64-9 | C4H11N | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XI)The treatment with NaHCO3 of the corresponding mixture of the 6(R)- and 6(S)-SO2-aldehydic adducts (VIII) gives a mixture of the 20(R) and 20(S) epimeric aldehydes (IX). The Wittig condensation of the aldehyde mixture (IX) with cyclopropylcarbonylmethylenetriphenylphosphorane (X) [prepared from acetylcyclopropane (XI) by bromination to bromoacetylcyclopropane (XII), reaction with triphenylphosphine (XIII) to the phosphonium salt (XIV) and treatment with NaOH] in DMSO at 105 C, followed by chromatographic separation yields the epimeric 20(R)-enone (XV). The reduction of (XV) with NaBH4 and CeCl3 in THF-methanol, followed by chromatographic purification affords the epimeric 3'(R)-allylic alcohol (XVI), which is isomerized by irradiation with UV-light from a TQ 718Z2 Hanau lamp in toluene in the presence of anthracene to give the corresponding 5(Z)-derivative (XVII). Finally, this compound is deprotected by a treatment with tetrabutylammonium fluoride in THF at 60 C.
| 【1】 Calverley, M.J.; Synthesis of MC 903, a biologically active vitamin D metabolite analogue. Tetrahedron 1987, 43, 20, 4609-19. |
| 【2】 Binderup, E.; CALCIPOTRIOL. Drugs Fut 1990, 15, 1, 15. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIII) | 12432 | (2S)-2-[(1R,3aR,7aR)-4-[(E)-((4S,6R)-4,6-bis[[tert-Butyl(dimethyl)silyl]oxy]-2,2-dioxooctahydro-1H-2-benzothiophen-1-yl)methylidene]-7a-methyloctahydro-1H-inden-1-yl]propanal | C34H62O5SSi2 | 详情 | 详情 | |
| (IX) | 12433 | 2-[(1R,3aS,7aR)-4-[(E)-2-((3S,5R)-3,5-bis[[tert-Butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)ethylidene]-7a-methyloctahydro-1H-inden-1-yl]propanal | C34H60O3Si2 | 详情 | 详情 | |
| (X) | 12434 | 1-cyclopropyl-2-(triphenylphosphoranylidene)-1-ethanone | C23H21OP | 详情 | 详情 | |
| (XI) | 12435 | Acetylcyclopropane; 1-Cyclopropyl-1-ethanone; Cyclopropylmethylketone | 765-43-5 | C5H8O | 详情 | 详情 |
| (XII) | 12436 | 2-Bromo-1-cyclopropyl-1-ethanone | 69267-75-0 | C5H7BrO | 详情 | 详情 |
| (XIII) | 12437 | Triphenylphosphine; Triphenyl phosphine | 603-35-0 | C18H15P | 详情 | 详情 |
| (XIV) | 12438 | (2-Cyclopropyl-2-oxoethyl)(triphenyl)phosphonium bromide | 112849-15-7 | C23H22BrOP | 详情 | 详情 |
| (XV) | 12439 | (E,4R)-4-[(1R,3aR,7aR)-4-[(E)-2-((3S,5R)-3,5-Bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)ethylidene]-7a-methyloctahydro-1H-inden-1-yl]-1-cyclopropyl-2-penten-1-one | C39H66O3Si2 | 详情 | 详情 | |
| (XVI) | 12440 | (1S,2E,4R)-4-[(1R,3aR,7aR)-4-[(E)-2-((3S,5R)-3,5-Bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)ethylidene]-7a-methyloctahydro-1H-inden-1-yl]-1-cyclopropyl-2-penten-1-ol | C39H68O3Si2 | 详情 | 详情 | |
| (XVII) | 12441 | (1S,2E,4R)-4-[(1R,3aR,7aR)-4-[(E)-2-((3S,5R)-3,5-Bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)ethylidene]-7a-methyloctahydro-1H-inden-1-yl]-1-cyclopropyl-2-penten-1-ol | C39H68O3Si2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(LVI)6) Synthesis of the quinoline (XXI): Anthranilic acid (LI) is tolylated with tosyl chloride and treated with PCl5 in 1,2-dichloroethane to give the corresponding acyl chloride (LII), which is submitted to a Friedel Crafts condensation with fluorobenzene (LIII)/AlCl3 yielding 2-amino-4'-fluorobenzophenone (LIV). The cyclization of (LIV) with ethyl 2-(cyclopropylcarbonyl)acetate (LV) [obtained by condensation of cyclopropyl methyl ketone (LVI) and diethyl carbonate (LVII) with H2SO4] by means of p-toluenesulfonic acid yields 2-cyclopropyl-4-(4-fluorophenyl)-quinoline-3-carboxylic acid ethyl ester (LVIII), which is submitted to a decarboxylative iodination with I2 and acetyl peroxide to afford 2-cyclopropyl-4-(4-fluorophenyl)-3-iodoquinoline (XXI). 7) Synthesis of the quinoline (XXXVII): The reduction of the quinolinecarboxylate (LVIII) with LiAlH4 in THF gives the corresponding methanol derivative (LIX), which is then treated with diphenyl disulfide (LX) and tri-butylphosphine in pyridine to afford 2-cyclopropyl-4-(4-fluorophenyl)-3-(phenylsulfanylmethyl)quinoline (XXXVII).
| 【1】 Castaner, J.; Sorbera, L.A.; Leeson, P.A.; NK-104. Drugs Fut 1998, 23, 8, 847-859. |
| 【2】 Kamikubo, T.; Takano, S.; Sugihara, T.; Suzuki, M.; Ogasawara, K.; Enantioconvergent synthesis of a promising HMG-CoA reductase inhibitor NK-104 from both enantiomers of epichlorohydrin. Tetrahedron Asymmetry 1993, 4, 2, 201-4. |
| 【3】 Iwasaki, H.; Miyachi, N.; Yanagawa, Y.; Ohara, Y.; Hiyama, T.; A novel synthetic method of HMG-CoA reductase inhibitor NK-104 via a hydroboration-cross-coupling sequence. Tetrahedron Lett 1993, 34, 51, 8267-70. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXI) | 17435 | 2-cyclopropyl-4-(4-fluorophenyl)-3-iodoquinoline | C18H13FIN | 详情 | 详情 | |
| (XXXVII) | 17451 | [2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]methyl phenyl sulfide; 2-cyclopropyl-4-(4-fluorophenyl)-3-[(phenylsulfanyl)methyl]quinoline | C25H20FNS | 详情 | 详情 | |
| (LI) | 11661 | 2-Aminobenzoic acid;Anthranilic acid; o-Aminobenzoic acid | 118-92-3 | C7H7NO2 | 详情 | 详情 |
| (LII) | 17465 | 2-aminobenzoyl chloride | C7H6ClNO | 详情 | 详情 | |
| (LIII) | 17466 | Fluorobenzene | 462-06-6 | C6H5F | 详情 | 详情 |
| (LIV) | 17467 | (2-aminophenyl)(4-fluorophenyl)methanone | C13H10FNO | 详情 | 详情 | |
| (LV) | 15949 | 3-Cyclopropyl-3-oxo-propionic acid ethyl ester; ethyl 3-cyclopropyl-3-oxopropanoate | 24922-02-9 | C8H12O3 | 详情 | 详情 |
| (LVI) | 12435 | Acetylcyclopropane; 1-Cyclopropyl-1-ethanone; Cyclopropylmethylketone | 765-43-5 | C5H8O | 详情 | 详情 |
| (LVII) | 17470 | diethyl carbonate; diethylcarbonate | 105-58-8 | C5H10O3 | 详情 | 详情 |
| (LVIII) | 17471 | ethyl 2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinecarboxylate | C21H18FNO2 | 详情 | 详情 | |
| (LIX) | 17472 | [2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]methanol | C19H16FNO | 详情 | 详情 | |
| (LX) | 17473 | diphenyl disulfide; 1-(phenyldisulfanyl)benzene; diphenyldisulfide | 882-33-7 | C12H10S2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)The cyclization of acetyl cyclopropane (I) with 2-nitroacetamide (II) and formamide dimethylacetal (III) by means of p-tolulenesulfonic acid gives the nitro-pyridinone (IV) (1), which is reduced with H2 over Pd/C affording 3-amino-6-propylpyridin-2(1H)-one (V). The protection of the amino group of (V) with benzyl chloroformate affords the carbamate (VI), which is condensed with tert-butyl bromoacetate (VII) by means of NaH in THF giving substituted acetate ester (VIII). The deprotection of (VIII) by hydrogenolysis with H2 over Pd/C in ethyl acetate yields intermediate (IX) with a free amino group, which is treated with benzylsulfonyl chloride (X) and pyridine to afford the sulfonamide (XI). Hydrolysis of the ester group of (XI) with HCl in ethyl acetate gives the carboxylic acid (XII), which is condensed with the pyridylmethylamine (XIII) by means of EDC and HOBT to afford the carboxamide (XIV). Finally, this compound is deprotected with HCl as usual.
| 【1】 C6 modification of the pyridinone core of thrombin inhibitor L-374,087 as a means of enhancing its oral absorption. Bioorg Med Chem Lett 1998, 8, 13, 1719. |
| 【2】 Sanderson, P.E.; Naylor-Olsen, A.M.; Dyer, D.L.; Vacca, J.P.; Isaacs, R.C.A.; Dorsey, B.D.; Fraley, M.E. (Merck & Co., Inc.); Pyridinone-thrombin inhibitors. EP 0835109; JP 1999508558; WO 9701338 . |
| 【3】 Dorsey, B.D.; Isaacs, R.C.A.; Sanderson, P.E.; Dyer, D.L.; Naylor-Olsen, A.M.; Fraley, M.E.; Vacca, J.P. (Merck & Co., Inc.); Pyridinone thrombin inhibitors. US 5668289 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 10101 | Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene | 501-53-1 | C8H7ClO2 | 详情 | 详情 | |
| (I) | 12435 | Acetylcyclopropane; 1-Cyclopropyl-1-ethanone; Cyclopropylmethylketone | 765-43-5 | C5H8O | 详情 | 详情 |
| (II) | 27209 | 2-nitroacetamide | C2H4N2O3 | 详情 | 详情 | |
| (III) | 11984 | N-(Dimethoxymethyl)-N,N-dimethylamine;dimethylformamide dimethylacetal;1,1-dimethoxy-N,N-dimethylmethanamine； Dimethoxy-N,N-dimethylmethanamine; N,N-Dimethylformamide dimethyl acetal | 4637-24-5 | C5H13NO2 | 详情 | 详情 |
| (IV) | 27210 | 6-cyclopropyl-3-nitro-2(1H)-pyridinone | C8H8N2O3 | 详情 | 详情 | |
| (V) | 27211 | 3-amino-6-propyl-2(1H)-pyridinone | C8H12N2O | 详情 | 详情 | |
| (VI) | 27212 | benzyl 2-oxo-6-propyl-1,2-dihydro-3-pyridinylcarbamate | C16H18N2O3 | 详情 | 详情 | |
| (VII) | 17430 | 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate | 5292-43-3 | C6H11BrO2 | 详情 | 详情 |
| (VIII) | 27213 | tert-butyl 2-[3-[[(benzyloxy)carbonyl]amino]-2-oxo-6-propyl-1(2H)-pyridinyl]acetate | C22H28N2O5 | 详情 | 详情 | |
| (IX) | 27214 | tert-butyl 2-[3-amino-2-oxo-6-propyl-1(2H)-pyridinyl]acetate | C14H22N2O3 | 详情 | 详情 | |
| (X) | 27215 | phenylmethanesulfenyl chloride | C7H7ClS | 详情 | 详情 | |
| (XI) | 27216 | tert-butyl 2-[3-[(benzylsulfonyl)amino]-2-oxo-6-propyl-1(2H)-pyridinyl]acetate | C21H28N2O5S | 详情 | 详情 | |
| (XII) | 27217 | 2-[3-[(benzylsulfonyl)amino]-2-oxo-6-propyl-1(2H)-pyridinyl]acetic acid | C17H20N2O5S | 详情 | 详情 | |
| (XIII) | 27218 | tert-butyl 5-(aminomethyl)-6-methyl-2-pyridinylcarbamate | C12H19N3O2 | 详情 | 详情 | |
| (XIV) | 27219 | tert-butyl 5-[([2-[3-[(benzylsulfonyl)amino]-2-oxo-6-propyl-1(2H)-pyridinyl]acetyl]amino)methyl]-6-methyl-2-pyridinylcarbamate | C29H37N5O6S | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(V)The reaction of aniline (I) with di(2-pyridyl)thione (DPT) gives the corresponding isothiocyanate (II), which is condensed with cyanamide (III) and 2-bromo-1-cyclopropylethanone (IV) (obtained by bromination of acetylcyclopropane (V)) by means of NaOMe to yield the adduct (VI). This compound, without isolation, cyclizes to the target thiazole.
| 【1】 Sorensen, A.R.; Engelhardt, S.; Kurtzhals, P.; Urso, B.; Bowler, A.N.; 2,4-Diaminothiazoles: A novel class of glycogen synthase kinase-3 (GSK-3) inhibitors. 11th RSC-SCI Med Chem Symp (Sept 9 2001, Cambridge) 2001, Abst P20. |
| 【2】 Olesen, P.H.; Kurtzhals, P.; Bowler, A.N.; Soerensen, A.R.; Worsaae, H.; Hansen, B.F. (Novo Nordisk A/S); 2,4-Diaminothiazole derivs.. WO 0156567 . |
| 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) | 22146 | 1-isothiocyanatobenzene; phenyl isothiocyanate | 103-72-0 | C7H5NS | 详情 | 详情 |
| (III) | 19648 | Cyanamide | 420-04-2 | CH2N2 | 详情 | 详情 |
| (IV) | 12436 | 2-Bromo-1-cyclopropyl-1-ethanone | 69267-75-0 | C5H7BrO | 详情 | 详情 |
| (V) | 12435 | Acetylcyclopropane; 1-Cyclopropyl-1-ethanone; Cyclopropylmethylketone | 765-43-5 | C5H8O | 详情 | 详情 |
| (VI) | 53529 | (Z)-3-anilino-3-[(2-cyclopropyl-2-oxoethyl)sulfanyl]-2-propenenitrile | n/a | C14H14N2OS | 详情 | 详情 |