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【结 构 式】 
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【分子编号】27347 【品名】N,N-dicyclohexylamine 【CA登记号】101-83-7 |
【 分 子 式 】C12H23N 【 分 子 量 】181.32136 【元素组成】C 79.49% H 12.79% N 7.72% |
合成路线1
该中间体在本合成路线中的序号：(A)Elimoclavine (I) obtained by fermentation is first O-mesylated and then the mesyl group in the product (II) displaced by 2-aminoethanol to give the hydroxyethylamino derivative (III). Repeated acylation of (III) with mesyl chloride affords the N,O-dimesylate (IV), which exchanges the O-mesyl group for an azido group on treatment with sodium azide to give the base (VI). Salt formation with maleic acid gives RGH-7825 (1,2).
| 【1】 Mago, N.K.E.; et al. (Gedeon Richter Ltd.); Novel ergol-8-ene and ergolin compounds and process for preparing same. DE 3026271; HU 180467 . |
| 【2】 Nogradi, M.; RGH-7825. Drugs Fut 1985, 10, 9, 753. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (B) | 10259 | Ethanol amine;Ethanolamine;2-Aminoethanol; 2-Amino-1-ethanol；2-Aminoethyl alcohol | 141-43-5 | C2H7NO | 详情 | 详情 |
| (A) | 27347 | N,N-dicyclohexylamine | 101-83-7 | C12H23N | 详情 | 详情 |
| (I) | 27346 | [(6aR,10aR)-7-methyl-4,6,6a,7,8,10a-hexahydroindolo[4,3-fg]quinolin-9-yl]methanol | C16H18N2O | 详情 | 详情 | |
| (II) | 27348 | [(6aR,10aR)-7-methyl-4,6,6a,7,8,10a-hexahydroindolo[4,3-fg]quinolin-9-yl]methyl methanesulfonate | C17H20N2O3S | 详情 | 详情 | |
| (III) | 27349 | 2-([[(6aR,10aR)-7-methyl-4,6,6a,7,8,10a-hexahydroindolo[4,3-fg]quinolin-9-yl]methyl]amino)-1-ethanol | C18H23N3O | 详情 | 详情 | |
| (IV) | 27350 | 2-[[[(6aR,10aR)-7-methyl-4,6,6a,7,8,10a-hexahydroindolo[4,3-fg]quinolin-9-yl]methyl](methylsulfonyl)amino]ethyl methanesulfonate | C20H27N3O5S2 | 详情 | 详情 | |
| (V) | 27351 | N-[[(6aR,10aR)-7-methyl-4,6,6a,7,8,10a-hexahydroindolo[4,3-fg]quinolin-9-yl]methyl]-N-(2-azidoethyl)methanesulfonamide | C19H24N6O2S | 详情 | 详情 | |
| (VI) | 23808 | Fumaric acid; (E)-2-butenedioic acid | 110-17-8 | C4H4O4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：1) The methanolysis of 3-(acetoxymethyl)-7-[4-chloro-3-oxo-2(Z)-(methoxyimino)butyrylamidol-3-cephem-4-carboxylic acid (I) with methanol and NaHCO3 gives the corresponding 3-(methoxymethyl) derivative (II), which is esterified with 1-iodoethylisopropyl carbonate (III) by means of dicyclohexylamine in DMA to afford the corresponding ester (IV). Finally, this compound is cyclized with thiourea (V) and methyl iodide in a phosphate buffer.
| 【1】 Fujimoto, K.; Nakayama, E.; Nakao, H. (Sankyo Co., Ltd.); Process for preparing 3-alkoxymethylcephalosporin derivatives. DE 3244457 . |
| 【2】 Fujimoto, K.; Ishihara, S.; Yanagisawa, H.; Ide, J.; Nakayama, E.; Nakao, H.; Sugawara, S.; Iwata, M.; Studies on orally active cephalosporin esters. J Antibiot 1987, 40, 3, 370. |
| 【3】 Castaner, J.; Serradell, M.N.; Cefpodoxime Proxetil. Drugs Fut 1988, 13, 1, 16. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 27347 | N,N-dicyclohexylamine | 101-83-7 | C12H23N | 详情 | 详情 | |
| (I) | 21554 | (6R,7R)-3-[(acetoxy)methyl]-7-[[4-chloro-2-(methoxyimino)-3-oxobutanoyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | C15H16ClN3O8S | 详情 | 详情 | |
| (II) | 21555 | (6R,7R)-7-[[4-chloro-2-(methoxyimino)-3-oxobutanoyl]amino]-3-(methoxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | C14H16ClN3O7S | 详情 | 详情 | |
| (III) | 15685 | 1-iodoethyl isopropyl carbonate | C6H11IO3 | 详情 | 详情 | |
| (V) | 10180 | Thiourea | 62-56-6 | CH4N2S | 详情 | 详情 |
| (VI) | 21558 | (6R,7R)-7-[[2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino]-3-(methoxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | C15H17N5O6S2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：Montelukast can be obtained by two related ways: 1) The Grignard reaction of 3-[2(E)-(7-chloroquinolin-2-yl)vinyl]benzaldehyde (I) with vinylmagnesium bromide (II) in toluene/THF gives the expected secondary alcohol (III), which is condensed with methyl 2-bromobenzoate (IV) by means of palladium acetate and lithium acetate in DMF to yield methyl 2-[3-[3-[2(E)-(7-chloroquinolin-2-yl)vinyl]phenyl]-3-oxopropyl]benzoate (V). The enantioselective reduction of the keto group of (V) with (-)-B-chlorodiisopinocampheylborane in THF affords methyl 2-[3-[3-[2(E)-(7-chloroquinolin-2-yl)vinyl]phenyl]-3(S)-hydroxypropyl] benzoate (VI), which is reacted with methylmagnesium bromide in toluene/THF or methylmagnesium chloride/CeCl3 in THF to give the expected tertiary diol (VII). The selective esterification of (VII) with mesyl chloride and diisopropylethylamine in toluene/acetonitrile yields the expected secondary mesylate (VIII), which is condensed with 2-[1-(sulfanylmethyl)cyclopropyl]acetic acid (IX) by means of butyllithium in THF to afford the corresponding condensation product as free acid that is separated by addition of dicyclohexylamine and precipitates the corresponding salt (X). Finally, this dicyclohexylamine salt (X) is treated with NaOH in toluene/water. 2) The 2-[1-(sulfanylmethyl)cyclopropyl]acetic acid (IX) has been obtained as follows: The reaction of 1,1-cyclopropanedimethanol (XI) with SOCl2 or diisopropyl sulfite in dichloromethane gives 1,1-cyclopropanedimethanol cyclic sulfite (XII), which is treated with NaCN in dichloromethane yielding 2-[1-(hydroxymethyl)cyclopropyl]acetonitrile (XIII). The reaction of (XIII) with mesyl chloride and triethylamine affords the corresponding mesylate (XIV), which is treated with potassium thioacetate in isopropyl acetate giving 2-[1-(acetylsulfanyl)cyclopropyl]acetonitrile (XV). Finally, this compound is hydrolyzed with NaOH in toluene/water to afford (IX).
| 【1】 Graul, A.; Martín, L.; Castañer, J.; Montelukast Sodium. Drugs Fut 1997, 22, 10, 1103. |
| 【2】 Belley, M.L.; Leger, S.; Roy, P.; Xiang, Y.B.; Labelle, M.; Guay, D. (Merck Frosst Canada Inc.); Unsaturated hydroxyalkylquinoline acids as leukotriene antagonists. EP 0480717; JP 1993105665 . |
| 【3】 Bhupathy, M.; McNamara, J.M.; Sidler, D.R.; Volante, R.P.; Bergan, J.J. (Merck & Co., Inc.); Process for the preparation of leukotriene antagonists. WO 9518107 . |
| 【4】 King, S.; Pipik, B.; Conlon, D.A. (Merck & Co., Inc.); Process for the preparation of 1-(thiomethyl)-cyclopropaneacetic acid. US 5523477 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 27347 | N,N-dicyclohexylamine | 101-83-7 | C12H23N | 详情 | 详情 | |
| (I) | 16523 | 3-[(E)-2-(7-chloro-2-quinolinyl)ethenyl]benzaldehyde | C18H12ClNO | 详情 | 详情 | |
| (II) | 16524 | bromo(vinyl)magnesium | 1826-67-1 | C2H3BrMg | 详情 | 详情 |
| (III) | 16525 | 1-[3-[(E)-2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-2-propen-1-ol | C20H16ClNO | 详情 | 详情 | |
| (IV) | 15938 | methyl 2-bromobenzoate | 610-94-6 | C8H7BrO2 | 详情 | 详情 |
| (V) | 16527 | methyl 2-(3-[3-[(E)-2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-oxopropyl)benzoate | C28H22ClNO3 | 详情 | 详情 | |
| (VI) | 16528 | methyl 2-((3S)-3-[3-[(E)-2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-hydroxypropyl)benzoate | C28H24ClNO3 | 详情 | 详情 | |
| (VII) | 16529 | (1S)-1-[3-[(E)-2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]-1-propanol | C29H28ClNO2 | 详情 | 详情 | |
| (VIII) | 16530 | (1S)-1-[3-[(E)-2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl methanesulfonate | C30H30ClNO4S | 详情 | 详情 | |
| (IX) | 16531 | 2-[1-(sulfanylmethyl)cyclopropyl]acetic acid; 1-(mercaptomethyl)cyclopropane acetic acid | C6H10O2S | 详情 | 详情 | |
| (X) | 16532 | 2-[1-[1(R)-[3-[2(E)-(7-Chloroquinolin-2-yl)vinyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propylsulfanylmethyl]cyclopropyl]acetic acid dicyclohexylamine salt | C47H59ClN2O3S | 详情 | 详情 | |
| (XI) | 16533 | [1-(hydroxymethyl)cyclopropyl]methanol | C5H10O2 | 详情 | 详情 | |
| (XII) | 16534 | 5,7-dioxa-6lambda(4)-thiaspiro[2.5]octan-6-one | C5H8O3S | 详情 | 详情 | |
| (XIII) | 16535 | 2-[1-(hydroxymethyl)cyclopropyl]acetonitrile | C6H9NO | 详情 | 详情 | |
| (XIV) | 16536 | [1-(cyanomethyl)cyclopropyl]methyl methanesulfonate | C7H11NO3S | 详情 | 详情 | |
| (XV) | 16537 | S-[[1-(cyanomethyl)cyclopropyl]methyl] ethanethioate | C8H11NOS | 详情 | 详情 |