【结 构 式】 |
【分子编号】33492 【品名】N,N-dibutylamine; N-butyl-1-butanamine 【CA登记号】111-92-2 |
【 分 子 式 】C8H19N 【 分 子 量 】129.2456 【元素组成】C 74.35% H 14.82% N 10.84% |
合成路线1
该中间体在本合成路线中的序号:(E)By condensation of 5-(4-methoxy-2,3,6-trimethylphenyl)-3-methylpenta-2,4-diene-1-triphenylphosphonium bromide (I) with 3-formylcrotonic acid butyl ester (II) by means of NaH in DMF to yield 9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethylnona-2,4,6,8-tetraen-1-oic acid butyl ester (III), which is then hydrolyzed with KOH in refluxing ethanol - water. The starting products (I) and (II) are obtained as follows: 1) The methylation of 2,3,5-trimethylphenol (IV) with KOH and methyl iodide in refluxing aqueous ethanol gives 2,3,5-trimethylanisole (V), which is then carbonylated with POCl3 and DMF (A) to afford 4-methoxy-2,3,6-trimethylbenzaldehyde (VI). The condensation of (VI) with acetone (B) by means of NaOH gives 4-(4-methoxy-2,3,6-trimethylphenyl)-3-buten-2-one (VII), which by a Grignard reaction with ethynylmagnesium bromide (C) in THF is converted into 5-(4-methoxy-2,3,6-trimethylphenyl)-3-methyl-3-hydroxy-4-penten-1-yne (VIII). The controlled hydrogenation of (VIII) with H2 over a Pd catalyst in hexane yields 5-(4-methoxy-2,3,6-trimethylphenyl)-3-methyl-3-hydroxy-1,4-pentadiene (IX), which is finally treated with triphenylphosphonium bromide in benzene at 60 C to give the phosphonium salt (I). 2) The oxidation of dibutyl L-(+)-tartrate (X) with lead tetraacetate in benzene gives butyl glyoxalate (XI), which is then condensed with propionic aldehyde (D) by means of dibutylamine (E) to afford ester (II).
【1】 Bollag, W.; et al.; Polyene derivatives. BE 0813002; DE 2414619; FR 2223037; GB 1468401; GB 1468402; JP 49126637 . |
【2】 Castaner, J.; Hillier, K.; RO 10-1670. Drugs Fut 1977, 2, 11, 763. |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(D) | 15966 | propionaldehyde | 123-38-6 | C3H6O | 详情 | 详情 |
(B) | 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 |
(A) | 33491 | Dimethylformamide | 68-12-2 | C3H7NO | 详情 | 详情 |
(E) | 33492 | N,N-dibutylamine; N-butyl-1-butanamine | 111-92-2 | C8H19N | 详情 | 详情 |
(I) | 33485 | [(2E,4E)-5-(4-methoxy-2,3,6-trimethylphenyl)-3-methyl-2,4-pentadienyl](triphenyl)phosphonium bromide | C34H36BrOP | 详情 | 详情 | |
(II) | 33486 | butyl (E)-3-methyl-4-oxo-2-butenoate | C9H14O3 | 详情 | 详情 | |
(III) | 33487 | butyl (2E,4E,6E,8E)-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenoate | C25H34O3 | 详情 | 详情 | |
(IV) | 33479 | 2,3,5-trimethylphenol | 697-82-5 | C9H12O | 详情 | 详情 |
(V) | 33480 | 1-methoxy-2,3,5-trimethylbenzene; methyl 2,3,5-trimethylphenyl ether | 20469-61-8 | C10H14O | 详情 | 详情 |
(VI) | 33481 | 4-methoxy-2,3,6-trimethylbenzaldehyde | C11H14O2 | 详情 | 详情 | |
(VII) | 33482 | (E)-4-(4-methoxy-2,3,6-trimethylphenyl)-3-buten-2-one | 54757-47-0 | C14H18O2 | 详情 | 详情 |
(VIII) | 33483 | (E)-1-(4-methoxy-2,3,6-trimethylphenyl)-3-methyl-1-penten-4-yn-3-ol | C16H20O2 | 详情 | 详情 | |
(IX) | 33484 | (1E)-1-(4-methoxy-2,3,6-trimethylphenyl)-3-methyl-1,4-pentadien-3-ol | C16H22O2 | 详情 | 详情 | |
(X) | 33490 | Dibutyl tartrate | 87-92-3 | C12H22O6 | 详情 | 详情 |
(XI) | 30937 | butyl 2-oxoacetate | C6H10O3 | 详情 | 详情 | |
(C) | 17778 | ETHYNYLMAGNESIUM BROMIDE; bromo(ethynyl)magnesium | 4301-14-8 | C2HBrMg | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号:(D)The methylation of 2,3,5-trimethylphenol (I) with MeI and KOH in 10% aqueous ethanol gives 2,3,5-trimethylanisole (II), which is formylated with DMF and POCl3 yielding 2,3,6-trimethyl-p-anisylaldehyde (III). The condensation of (III) with acetone (B) by means of NaOH affords 4-(4-methoxy-2,3,6-trimethylphenyl)but-3-en-2-one (IV), which by a Grignard reaction with ethynylmagnesium bromide (C) in THF is converted into the acetylenic alcohol (V). Partial hydrogenation of (V) with H2 over Pd/C in hexane gives dienic alcohol (VI), which is condensed with triphenylphosphine hydrobromide in benzene affording 5-(4-methoxy-2,3,6 trimethylphenyl)-3-methylpenta-2,4-diene-1-triphenylphosphonium bromide (VII). A Wittig condensation of (VII) with butyl 3-formylcrotonate (VIII) by means of NaH in DMF gives butyl 9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethylnona-2,4,6,8-tetraenoate (IX), which is hydrolyzed with KOH in refluxing ethanol-water yielding the corresponding free acid (X). This acid is converted into the acyl chloride (XI) by treatment with PCl3 in refluxing benzene. Finally, this compound is treated with ethylamine (E) in ether. The butyl 3-formylcrotonate (VIII) is obtained as follows: The oxidation of dibutyl tartrate (XII) with lead tetraacetate in benzene gives butyl glyoxalate (XIII), which is then condensed with propionaldehyde (XIV) by heating at 110 C with dibutyl-amine (D).
【1】 Bollag, W.; et al.; Polyene derivatives. BE 0813002; FR 2223037; GB 1468401; GB 1468402 . |
【2】 Bollag, W.; et al.; Antidandruff compositions containing 9-(4-lower alkoxy-2,3,6-trilower-alkylphenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oic acid lower alkyl amides. DE 2542366; ES 441173; FR 2330381; GB 1504350; JP 51057840; US 4021574 . |
【3】 Castaner, J.; Hillier, K.; Motretinide. Drugs Fut 1978, 3, 2, 126. |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(E) | 10928 | Ethanamine | 75-04-7 | C2H7N | 详情 | 详情 |
(B) | 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 |
(A) | 33491 | Dimethylformamide | 68-12-2 | C3H7NO | 详情 | 详情 |
(D) | 33492 | N,N-dibutylamine; N-butyl-1-butanamine | 111-92-2 | C8H19N | 详情 | 详情 |
(I) | 33479 | 2,3,5-trimethylphenol | 697-82-5 | C9H12O | 详情 | 详情 |
(II) | 33480 | 1-methoxy-2,3,5-trimethylbenzene; methyl 2,3,5-trimethylphenyl ether | 20469-61-8 | C10H14O | 详情 | 详情 |
(III) | 33481 | 4-methoxy-2,3,6-trimethylbenzaldehyde | C11H14O2 | 详情 | 详情 | |
(IV) | 33482 | (E)-4-(4-methoxy-2,3,6-trimethylphenyl)-3-buten-2-one | 54757-47-0 | C14H18O2 | 详情 | 详情 |
(V) | 33483 | (E)-1-(4-methoxy-2,3,6-trimethylphenyl)-3-methyl-1-penten-4-yn-3-ol | C16H20O2 | 详情 | 详情 | |
(VI) | 33484 | (1E)-1-(4-methoxy-2,3,6-trimethylphenyl)-3-methyl-1,4-pentadien-3-ol | C16H22O2 | 详情 | 详情 | |
(VII) | 33485 | [(2E,4E)-5-(4-methoxy-2,3,6-trimethylphenyl)-3-methyl-2,4-pentadienyl](triphenyl)phosphonium bromide | C34H36BrOP | 详情 | 详情 | |
(VIII) | 33486 | butyl (E)-3-methyl-4-oxo-2-butenoate | C9H14O3 | 详情 | 详情 | |
(IX) | 33487 | butyl (2E,4E,6E,8E)-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenoate | C25H34O3 | 详情 | 详情 | |
(X) | 33488 | (2E,4E,6E,8E)-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenoic acid | C21H26O3 | 详情 | 详情 | |
(XI) | 33489 | (2E,4E,6E,8E)-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenoyl chloride | C21H25ClO2 | 详情 | 详情 | |
(XII) | 33490 | Dibutyl tartrate | 87-92-3 | C12H22O6 | 详情 | 详情 |
(XIII) | 30937 | butyl 2-oxoacetate | C6H10O3 | 详情 | 详情 | |
(XIV) | 15966 | propionaldehyde | 123-38-6 | C3H6O | 详情 | 详情 |
(C) | 17778 | ETHYNYLMAGNESIUM BROMIDE; bromo(ethynyl)magnesium | 4301-14-8 | C2HBrMg | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号:(XIX)Condensation of 1,3-benzodioxole-5-carbaldehyde (XV) with nitromethane by means of ammonium acetate in HOAc gives the nitrostyrene (I), which is condensed with ethyl 2-(4-methoxybenzoyl)acetate (II) [obtained by reaction of acetophenone (XVI), diethyl carbonate and potassium tert-amyloxide] by means of NaOEt in THF to yield the 4-nitrobutyrate (III). Reductive cyclization of (III) with H2 over Raney-Ni in THF affords the (cis, cis)-pyrrolidine (VI), which is isomerized to the (trans,trans)-isomer (V) by means of NaOEt in refluxing ethanol. This racemic ester (V) is submitted to optical resolution with (S)-(+)-mandelic acid to provide the pure chiral ester (XVII). This compound is condensed with 2-bromo-N,N-dibutylacetamide (XIII) [obtained by reaction of 2-bromoacetyl bromide (XVIII) with dibutylamine (XIX) in toluene] by means of DIEA in acetonitrile to give the ethyl ester (XX), which is finally hydrolyzed with NaOH in hot ethanol.
【1】 Leeson, P.; Castañer, R.M.; Sorbera, L.A.; Castañer, J.; Atrasentan. Drugs Fut 2001, 26, 10, 939. |
【2】 Winn, M.; Boyd, S.A.; Hutchins, C.W.; Tasker, A.S.; Von Geldern, T.W.; Kester, J.A.; Sorensen, B.K.; Szczepankiewicz, B.G.; Henry, K.J. Jr.; Liu, G.; Wittenberger, S.J.; King, S.A. (Abbott Laboratories Inc.); Novel benzo-1,3-dioxolyl- and benzofuranyl substd. pyrrolidine derivs. as endothelin antagonists. EP 0885215; WO 9730045 . |
【3】 Jae, H.-S.; Hutchins, C.W.; Szczepankiewicz, B.G.; King, S.A.; Winn, M.; Boyd, S.A.; Henry, K.J.; Geldern, T.W.; Wittenberger, S.J.; Tasker, A.S.; Sorensen, B.K.; Kester, J.A. (Abbott Laboratories Inc.); Endothelin antagonists. WO 9906397 . |
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) | 20675 | 5-[(E)-2-nitroethenyl]-1,3-benzodioxole | 1485-00-3 | C9H7NO4 | 详情 | 详情 |
(II) | 20676 | ethyl 3-(4-methoxyphenyl)-3-oxopropanoate | C12H14O4 | 详情 | 详情 | |
(III) | 20677 | ethyl 3-(1,3-benzodioxol-5-yl)-2-(4-methoxybenzoyl)-4-nitrobutanoate | C21H21NO8 | 详情 | 详情 | |
(VI) | 20679 | ethyl (2S,3R,4R)-4-(1,3-benzodioxol-5-yl)-2-(4-methoxyphenyl)-3-pyrrolidinecarboxylate | C21H23NO5 | 详情 | 详情 | |
(XIII) | 20685 | 2-Bromo-N,N-dibutylacetamide; N,N-Dibutylbromoacetamide | C10H20BrNO | 详情 | 详情 | |
(XV) | 10127 | 1,3-Benzodioxole-5-carbaldehyde; Heliotropine | 120-57-0 | C8H6O3 | 详情 | 详情 |
(XVI) | 11041 | 4-Methoxyacetophenone; 1-(4-Methoxyphenyl)-1-ethanone | 100-06-1 | C9H10O2 | 详情 | 详情 |
(XVII) | 20680 | ethyl (2S,3S,4R)-4-(1,3-benzodioxol-5-yl)-2-(4-methoxyphenyl)-3-pyrrolidinecarboxylate | C21H23NO5 | 详情 | 详情 | |
(XVIII) | 14005 | 2-Bromoacetyl bromide; Bromoacetyl bromide | 598-21-0 | C2H2Br2O | 详情 | 详情 |
(XIX) | 33492 | N,N-dibutylamine; N-butyl-1-butanamine | 111-92-2 | C8H19N | 详情 | 详情 |
(XX) | 48687 | ethyl (2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)-3-pyrrolidinecarboxylate | C31H42N2O6 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号:(V)
【1】 Murugesan B, Rafe M, Sathyananarayana S(Ranbaxy Laboratories Limited, India). 2007. A process for the preparation of dichlorofluorene as a key intermediate to lumefantrine. Indian Pat Appl, IN 2007DE00012. |
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) | 67236 | Fluorene;Diphenylenemethane;2,2'-Methylenebiphenyl;2,3-Benzindene;o-Biphenylenemethane;alpha-Diphenylenemethane-9H-fluorene | 86-73-7 | C13H10 | 详情 | 详情 |
(III) | 67237 | 2,7-dichloro-9H-fluorene | 7012-16-0 | C13H8Cl2 | 详情 | 详情 |
(IV) | 67240 | 2-(2,7-dichloro-9H-fluoren-4-yl)oxirane | 53221-14-0 | C15H10Cl2O | 详情 | 详情 |
(V) | 33492 | N,N-dibutylamine; N-butyl-1-butanamine | 111-92-2 | C8H19N | 详情 | 详情 |
(VI) | 67241 | 2-(dibutylamino)-1-(2,7-dichloro-9H-fluoren-4-yl)ethanol | 69759-61-1 | C23H29Cl2NO | 详情 | 详情 |
(VII) | 29029 | 4-chlorobenzaldehyde | 104-88-1 | C7H5ClO | 详情 | 详情 |
(IX) | 67246 | sulfuryl dichloride | 7791-25-5 | Cl2O2S | 详情 | 详情 |