|
【结 构 式】 
|
【分子编号】32112 【品名】3-iodo-1-propene;3-iodo-propen;allyl iodide 【CA登记号】556-56-9 |
【 分 子 式 】C3H5I 【 分 子 量 】167.97717 【元素组成】C 21.45% H 3% I 75.55% |
合成路线1
该中间体在本合成路线中的序号：A total synthesis of (+)-sinefungin has been reported: The reaction of D-ribose (I) with acetone and methanol by means of CuSO4 and a catalytic amount of H2SO4 gives methyl 2,3-O-isopropylidene-beta-D-ribofuranoside (II), which is oxidized to the aldehyde (III) with oxalyl chloride in DMSO/dichloromethane. The Wittig condensation of (III) with triethyl phosphonoacetate (IV) by means of NaH in THF affords the unsaturated ester (V), which is hydrogenated with H2 over Pd/C in ethyl acetate and saponified with LiOH in methanol/water to give the propionic acid (VI). The condensation of (VI) with the chiral oxazolidone (VII) by means of pivaloyl chloride and triethylamine in THF yields the oxalidone (VIII). The stereoselective alkylation of (VIII) with allyl bromide by means of lithium hexamethyldisylazide in THF affords the 2(S)-allyl derivative (IX), which is hydrolyzed with LiOH in THF/water to the corresponding free acid (X). The Curtius degradation of the acid (X) by means of diphenyl phosphorazidate and benzyl alcohol gives the corresponding benzyloxycarbonylamino derivative (XI), which is benzylated with benzyl bromide to the fully protected compound (XII). The ozonolysis of the allyl double bond of (XII) with O3 in methanol/dichloromethane yields the aldehyde (XIII).
| 【1】 Ghosh, A.K.; Liu, W.M.; Total synthesis of (+)-sinefungin. J Org Chem 1996, 61, 18, 6175. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 32112 | 3-iodo-1-propene;3-iodo-propen;allyl iodide | 556-56-9 | C3H5I | 详情 | 详情 | |
| (I) | 10016 | D-Ribose; (3R,4S,5R)-5-(Hydroxymethyl)tetrahydro-2,3,4-furantriol; (2R,3R,4R)-2,3,4,5-Tetrahydroxypentanal | 50-69-1 | C5H10O5 | 详情 | 详情 |
| (II) | 10017 | [(3aR,4R,6R,6aR)-6-Methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methanol | 4099-85-8 | C9H16O5 | 详情 | 详情 |
| (III) | 10018 | (3aR,4S,6R,6aR)-6-Methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbaldehyde | C9H14O5 | 详情 | 详情 | |
| (IV) | 10019 | Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate | 867-13-0 | C8H17O5P | 详情 | 详情 |
| (V) | 10020 | Ethyl (E)-3-[(3aR,4R,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-2-propenoate | C13H20O6 | 详情 | 详情 | |
| (VI) | 10021 | 3-[(3aR,4R,6R,6aR)-6-Methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]propionic acid | C11H18O6 | 详情 | 详情 | |
| (VII) | 10022 | [(3aS,8aR)-2-Oxo-8,8a-dihydro-2H-indeno[1,2-d][1,3]oxazol-3(3aH)-yl]lithium | C10H8LiNO2 | 详情 | 详情 | |
| (VIII) | 10023 | (3aS,8aR)-3-[3-[(3aR,4R,6R,6aR)-6-Methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]propanoyl]-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d][1,3]oxazol-2-one | C21H25NO7 | 详情 | 详情 | |
| (IX) | 10024 | (3aS,8aR)-3-((2S)-2-[[(3aR,4R,6R,6aR)-6-Methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methyl]-4-pentenoyl)-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d][1,3]oxazol-2-one | C24H29NO7 | 详情 | 详情 | |
| (X) | 10025 | (2S)-2-[[(3aR,4R,6R,6aR)-6-Methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methyl]-4-pentenoic acid | C14H22O6 | 详情 | 详情 | |
| (XI) | 10026 | Benzyl N-((1S)-1-[[(3aR,4R,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methyl]-3-butenyl)carbamate | 180776-29-8 | C21H29NO6 | 详情 | 详情 |
| (XII) | 10027 | Benzyl (1S)-1-[[(3aR,4R,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methyl]-3-butenyl(benzyl)carbamate | C28H35NO6 | 详情 | 详情 | |
| (XIII) | 10028 | Benzyl (1R)-1-[[(3aR,4R,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methyl]-3-oxopropyl(benzyl)carbamate | C27H33NO7 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XVII)In a different procedure, 3,4-dichlorophenylacetic acid (XIV) was condensed with the lithiated chiral oxazolidinone (XV), via activation as the mixed anhydride with pivaloyl chloride, to afford the N-acyl oxazolidinone (XVI). Diastereoselective alkylation of the sodium enolate of (XVI) with allyl iodide (XVII) afforded the (S)-pentenyl oxazolidinone (XVIII), which was further hydrolyzed to the chiral acid (XIX) by means of lithium peroxide. Alternatively, acid (XIX) was obtained by alkylation of the lithium dianion of 3,4-dichlorophenylacetic acid (XIV) with allyl bromide (XX), followed by resolution of the resultant racemic acid (XXI) with (S)-1-phenylethylamine. Acid (XIX) was converted to the amide (XXII) via the corresponding acid chloride. Reduction of amide (XXII) with DIBAL gave the secondary amine (XXIII), which was subsequently acylated with benzoyl chloride, yielding benzamide (XXIV). Dihydroxylation of the olefin double bond with N-methylmorpholine-N-oxide in the presence of OsO4, followed by oxidative cleavage of the resultant diol (XXV) with sodium periodate furnished aldehyde (XXVI). Finally, reductive amination of aldehyde (XXVI) with piperidine (III) in the presence of NaBH3CN provided the title compound
| 【1】 Hale, J.J.; Finke, P.E.; MacCross, M.; A facile synthesis of the novel neurokinin A antagonist SR 48968. Bioorg Med Chem Lett 1993, 3, 2, 319. |
| 【2】 Finke, P.E.; Mills, S.G.; Hale, J.J.; MacCoss, M. (Merck & Co., Inc.); Process of making chiral 2-aryl-1,4-butanediamine derivs.. WO 9407839 . |
| 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) | 59283 | N-(4-phenyl-4-piperidinyl)acetamide | C13H18N2O | 详情 | 详情 | |
| (XIV) | 30414 | 2-(3,4-dichlorophenyl)acetic acid；2-(3,4-Dichlorophenyl)acetic acid | 5807-30-7 | C8H6Cl2O2 | 详情 | 详情 |
| (XV) | 58942 | C10H10LiNO2 | 详情 | 详情 | ||
| (XVI) | 62381 | (4S)-4-benzyl-3-[2-(3,4-dichlorophenyl)acetyl]-1,3-oxazolidin-2-one | C18H15Cl2NO3 | 详情 | 详情 | |
| (XVII) | 32112 | 3-iodo-1-propene;3-iodo-propen;allyl iodide | 556-56-9 | C3H5I | 详情 | 详情 |
| (XVIII) | 62382 | (4S)-4-benzyl-3-[(2S)-2-(3,4-dichlorophenyl)-4-pentenoyl]-1,3-oxazolidin-2-one | C21H19Cl2NO3 | 详情 | 详情 | |
| (XIX) | 62383 | (2S)-2-(3,4-dichlorophenyl)-4-pentenoic acid | C11H10Cl2O2 | 详情 | 详情 | |
| (XX) | 11463 | 3-Bromo-1-propene; 3-Bromopropene；allyl bromide | 106-95-6 | C3H5Br | 详情 | 详情 |
| (XXI) | 50421 | 2-(3,4-dichlorophenyl)-4-pentenoic acid | C11H10Cl2O2 | 详情 | 详情 | |
| (XXII) | 62384 | (2S)-2-(3,4-dichlorophenyl)-N-methyl-4-pentenamide | C12H13Cl2NO | 详情 | 详情 | |
| (XXIII) | 62385 | (2S)-2-(3,4-dichlorophenyl)-N-methyl-4-penten-1-amine; N-[(2S)-2-(3,4-dichlorophenyl)-4-pentenyl]-N-methylamine | C12H15Cl2N | 详情 | 详情 | |
| (XXIV) | 62386 | N-[(2S)-2-(3,4-dichlorophenyl)-4-pentenyl]-N-methylbenzamide | C19H19Cl2NO | 详情 | 详情 | |
| (XXV) | 62387 | N-[(2S)-2-(3,4-dichlorophenyl)-4,5-dihydroxypentyl]-N-methylbenzamide | C19H21Cl2NO3 | 详情 | 详情 | |
| (XXVI) | 26943 | N-[(2S)-2-(3,4-dichlorophenyl)-4-oxobutyl]-N-methylbenzamide | C18H17Cl2NO2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：Pyrrolidinone (XXVI): The selective hydrolysis of the known methyl ester (XIV) with NaOH in methanol/water gives the corresponding carboxylic acid (XV), which is coupled with the chiral oxazolidinone (XVI) by means of pivaloyl chloride and Et3N in THF to yield the amide (XVII). The regiocontrolled alkylation of (XVII) with allyl iodide and NaN(SiMe3)2 in THF affords the allyl derivative (XVIII), which is submitted to ozonolysis in dichloromethane to provide the aldehyde (XIX). The condensation of (XIX) with 2,4-dimethoxybenzylamine (XX) yields imine (XXI), which by a reductive cyclization with NaBH3CN in THF/EtOH affords pyrrolidinone (XXII). Cleavage of the oxazolidine ring of (XXII) with TsOH in hot methanol gives the amino alcohol (XXIII), which is oxidized with oxalyl chloride in DMSO to the aldehyde (XXIV). Finally, this compound is condensed with triethyl phosphonoacetate (XXV) by means of NaN(SiMe3)2 in THF to provide the desired pyrrolidinone (XXVI).
| 【1】 Dragovich, P.S.; Prins, T.J.; Zhou, R.; et al.; Structure-based design, synthesis, and biological evaluation of irreversible human rhinovirus 3C protease inhibitors. 4. Incorporation of P1 lactam moieties as L-glutamine replacements. J Med Chem 1999, 42, 7, 1213. |
| 【2】 Graul, A.; Castañer, J.; AG-7088. Drugs Fut 2000, 25, 1, 9. |
| 【3】 Meyer, M.D.; Daanen, J.F.; Ehrlich, P.P.; Ralston, J.W. (Abbott Laboratories Inc.); 3-Phenylpyrrole alpha-1 adrenergic cpds.. WO 9957122 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 32112 | 3-iodo-1-propene;3-iodo-propen;allyl iodide | 556-56-9 | C3H5I | 详情 | 详情 | |
| (XIV) | 32109 | tert-butyl (4S)-4-(3-methoxy-3-oxopropyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate | C14H25NO5 | 详情 | 详情 | |
| (XV) | 32110 | 3-[(4S)-3-(tert-butoxycarbonyl)-2,2-dimethyl-1,3-oxazolidin-4-yl]propionic acid | C13H23NO5 | 详情 | 详情 | |
| (XVI) | 14694 | (S)-4-Benzyl-2-oxazolidinone; (4S)-4-Benzyl-1,3-oxazolan-2-one; (S)-(-)-4-Benzyl-2-oxazolidinone | 90719-32-7 | C10H11NO2 | 详情 | 详情 |
| (XVII) | 32111 | tert-butyl (4S)-4-[3-[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-3-oxopropyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate | C23H32N2O6 | 详情 | 详情 | |
| (XVIII) | 32113 | tert-butyl (4S)-4-((2S)-2-[[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl]-4-pentenyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate | C26H36N2O6 | 详情 | 详情 | |
| (XIX) | 32114 | tert-butyl (4S)-4-((2R)-2-[[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl]-4-oxobutyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate | C25H34N2O7 | 详情 | 详情 | |
| (XX) | 32115 | (2,4-dimethoxyphenyl)methanamine; 2,4-dimethoxybenzylamine | 20781-21-9 | C9H13NO2 | 详情 | 详情 |
| (XXI) | 32116 | tert-butyl (4S)-4-[(2R)-2-[[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl]-4-[(2,4-dimethoxybenzyl)imino]butyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate | C34H45N3O8 | 详情 | 详情 | |
| (XXII) | 32117 | tert-butyl (4S)-4-[[(3S)-1-(2,4-dimethoxybenzyl)-2-oxopyrrolidinyl]methyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate | C24H36N2O6 | 详情 | 详情 | |
| (XXIII) | 32118 | tert-butyl (1S)-2-[(3S)-1-(2,4-dimethoxybenzyl)-2-oxopyrrolidinyl]-1-(hydroxymethyl)ethylcarbamate | C21H32N2O6 | 详情 | 详情 | |
| (XXIV) | 32119 | tert-butyl (1S)-2-[(3S)-1-(2,4-dimethoxybenzyl)-2-oxopyrrolidinyl]-1-formylethylcarbamate | C21H30N2O6 | 详情 | 详情 | |
| (XXV) | 10019 | Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate | 867-13-0 | C8H17O5P | 详情 | 详情 |
| (XXVI) | 32105 | ethyl (E,4S)-4-[(tert-butoxycarbonyl)amino]-5-[(3S)-1-(2,4-dimethoxybenzyl)-2-oxopyrrolidinyl]-2-pentenoate | C25H36N2O7 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XIV)Condensation of 1,2,3,5-tetrafluoro-4-nitrobenzene (I) with 2-fluoro-4-iodoaniline (II) by means of LiHMDS in THF gives diaryl amine (III),which undergoes selective fluoride substitution with NaOMe in THF to yield 5-methoxy-6-nitroaniline derivative (IV). Nitro group reduction in intermediate (IV) by means of Fe and NH4Cl in refluxing EtOH provides the corresponding diamine (V), which is then condensed with 1-allylcyclopropanesulfonyl chloride (VI) in the presence of pyridine at 40 °C to produce the sulfonamide (VII). Dihydroxylation of the allyl group of compound (VII) with OsO4 and NMMO in THF affords racemic refametinib, which is finally resolved using chiral HPLC .
In an alternative method, coupling of the primary amine (V) with the chiral sulfonyl chloride (VIII) in the presence of pyridine yields the corresponding sulfonamide (IX), which is finally hydrolyzed at the acetonide moiety with HCl in THF .
1-Allylcyclopropanesulfonyl chloride intermediate (VI) is prepared as follows. Treatment of 3-chloro-1-propanesulfonyl chloride (X) with BuOH affords butyl 3-chloro-1-propanesulfonate (XI), which cyclizes in the presence of BuLi to yield butyl cyclopropanesulfonate (XII),which can also be obtained by treatment of cyclopropanesulfonyl chloride (XIII) with BuOH in the presence of pyridine. Alkylation of butyl cyclopropanesulfonate (XII) with allyl iodide (XIV) using BuLi in THF at –78 °C yields butyl 1-allylcyclopropanesulfonate (XV), which is hydrolyzed by treatment with KSCN in DME/H2O at reflux producing potassium 1-allylcyclopropanesulfonate (XVI). Finally, the potassium sulfonate (XVI) is chlorinated with refluxing SOCl2 in the presence of a catalytic amount of DMF .
| 【1】 Maderna, A., Vernier, J., Barawkar, D., Chamakura, V., El Abdellaoui, H., Hong, Z. (Ardea Biosciences, Inc.). Derivatives of N-(arylamino)sulfonamides as inhibitors of MEK. US 2008058340, US 8101799. |
| 【3】 Maderna, A., Vernier, J.-M. (Ardea Biosciences, Inc.). Preparation of (R)-and (S)-N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2, 3-dihydroxypropyl)cyclopropane-1-sulfonamide and protected derivatives thereof. EP 2462111, JP 2013500242, KR 2012032536, WO 2011009541. |
| 【2】 Maderna, A., Vernier, J.-M., Barawkar, D., Chamakura, V., Abdellaoui, H.E., Hong, Z. (Ardea Biosciences, Inc.). N-(Arylamino)-sulfonamide inhibitors of MEK. EP 1912636, US 2012022076, WO 2007014011 |
| 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) | 67905 | 1,2,3,5-tetrafluoro-4-nitrobenzene | 314-41-0 | C6HF4NO2 | 详情 | 详情 |
| (II) | 63342 | 2-fluoro-4-iodoaniline; 2-fluoro-4-iodophenylamine | 29632-74-4 | C6H5FIN | 详情 | 详情 |
| (III) | 67906 | 2,3,5-trifluoro-N-(2-fluoro-4-iodophenyl)-6-nitroaniline | C12H5F4IN2O2 | 详情 | 详情 | |
| (IV) | 67907 | 2,3-difluoro-N-(2-fluoro-4-iodophenyl)-5-methoxy-6-nitroaniline | C13H8F3IN2O3 | 详情 | 详情 | |
| (V) | 67908 | 5,6-difluoro-N1-(2-fluoro-4-iodophenyl)-3-methoxybenzene-1,2-diamine | C13H10F3IN2O | 详情 | 详情 | |
| (VI) | 67909 | 1-allylcyclopropanesulfonyl chloride | 923032-59-1 | C6H9ClO2S | 详情 | 详情 |
| (VII) | 67910 | 1-allyl-N-(3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-6-methoxyphenyl)cyclopropane-1-sulfonamide | C19H18F3IN2O3S | 详情 | 详情 | |
| (VIII) | 67911 | (S)-1-((5,5-dimethyltetrahydrofuran-2-yl)methyl)cyclopropane-1-sulfonyl chloride | C10H17ClO3S | 详情 | 详情 | |
| (IX) | 67912 | (S)-N-(3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-6-methoxyphenyl)-1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)cyclopropane-1-sulfonamide | C22H24F3IN2O5S | 详情 | 详情 | |
| (X) | 39225 | g-Chloropropanesulfonyl chloride;3-Chloropropansulfonyl chloride;1-Chloro-3-propanesulfonylchloride;3-Chloropropanesulfonyl chloride;3-chloro-1-propanesulfonyl chloride;3-chloropropane-1-sulfonyl chloride | 1633-82-5 | C3H6Cl2O2S | 详情 | 详情 |
| (XI) | 67913 | butyl 3-chloro-1-propanesulfonate;3-Chloro-propane-1-sulfonic acid butyl ester | 146475-47-0 | C7H15ClO3S | 详情 | 详情 |
| (XII) | 67914 | butyl cyclopropanesulfonate | 83635-12-5 | C7H14O3S | 详情 | 详情 |
| (XIII) | 67915 | cyclopropanesulfonyl chloride;Cyclopropylsulfonylchloride;Cyclopropylsulphonyl chloride | 139631-62-2 | C3H5ClO2S | 详情 | 详情 |
| (XIV) | 32112 | 3-iodo-1-propene;3-iodo-propen;allyl iodide | 556-56-9 | C3H5I | 详情 | 详情 |
| (XV) | 67917 | butyl 1-allylcyclopropane-1-sulfonate | C10H18O3S | 详情 | 详情 | |
| (XVI) | 67916 | potassium 1-allylcyclopropanesulfonate | 923032-57-9 | C6H9KO3S | 详情 | 详情 |