|
【结 构 式】 
|
【分子编号】67911 【品名】(S)-1-((5,5-dimethyltetrahydrofuran-2-yl)methyl)cyclopropane-1-sulfonyl chloride 【CA登记号】 |
【 分 子 式 】C10H17ClO3S 【 分 子 量 】252.762 【元素组成】C 47.52% H 6.78% Cl 14.03% O 18.99% S 12.69% |
合成路线1
该中间体在本合成路线中的序号：(VIII)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 |
合成路线2
该中间体在本合成路线中的序号：(VIII)Chiral cyclopropanesulfonyl chloride intermediate (VIII) can be prepared as follows. Lithiation of (trimethylsilyl)acetylene (XVII) with t-BuLi in THF at –78 °C, and subsequent coupling with TBDMS-protected (S)-glycidol (XVIII) in the presence of BF3·Et2O at –78 °C affords the (S)-pentynol derivative (XIX). Then, the TMS-protecting group of intermediate (XIX) is selectively removed by means of K2CO3 in MeOH to give alkyne (XX). Iodoboration of alkyne (XX) with B-I-9-BBN in CH2Cl2 at 0 °C followed by deborination with AcOH yields 4-iodo-4-pentene-1,2(S)-diol (XXI). O-Protection of diol (XXI) with TBDMSOTf and pyridine in THF provides the bis-silyl ether (XXII), which is then submitted to Simmons-Smith cyclopropanation with CH2I2 in the presence of Et2Zn and TFA in DCE to produce 1,2-O-bis-TBDMS-3-(1-iodocyclopropyl)propane-1,2(S)-diol (XXIII). Desilylation of compound (XXIII) using HCl in THF gives 3-(1-iodocyclopropyl)propane-1,2(S)-diol (XXIV), which by trans-ketalization with 2,2-dimethoxypropane (XXV) by means of PPTS in CH2Cl2 gives 4(S)-(1-iodocyclopropylmethyl)-2,2-dimethyl-1,3-dioxolane (XXVI). Finally, alkyl iodide (XXVI) is treated with t-BuLi in Et2O at –78 °C, followed by chlorosulfonation with SO2Cl2 in Et2O (3).
Alternatively, deprotonation of dicyclopropyl disulfide (XXVII) with BuLi in THF, followed by alkylation with 4(R)-(bromomethyl)-2,2-dimethyl-1,3-dioxolane (XXVIII) at –78 °C affords the dimeric bis-acetonide (XXIX), which is reductively cleaved to the corresponding thiol monomer (XXX) by treatment with PPh3 and HCl in dioxane/H2O. Air oxidation of cyclopropanethiol derivative (XXX) in the presence of NaOH in DMF gives sodium cyclopropanesulfonate derivative (XXXI), which can also be obtained by direct oxidation of disulfide (XXIX) with H2O2 and NaOAc in AcOH at 80 °C. Finally, sulfonate (XXXI) is chlorinated using POCl3 at 80 °C. Alternatively, sulfonyl chloride (VIII) can be directly obtained from disulfide (XXIX) by oxidative cleavage with NCS in the presence of HCl in MeCN .
| 【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. |
| 【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 |
| 【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. |
| 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) | 67911 | (S)-1-((5,5-dimethyltetrahydrofuran-2-yl)methyl)cyclopropane-1-sulfonyl chloride | C10H17ClO3S | 详情 | 详情 | |
| (XVII) | 23897 | ethynyl(trimethyl)silane；trimethylsilyl acetylene | 1066-54-2 | C5H10Si | 详情 | 详情 |
| (XVIII) | 42416 | tert-butyl(dimethyl)[(2S)oxiranylmethoxy]silane; tert-butyl(dimethyl)silyl (2S)oxiranylmethyl ether | 123237-62-7 | C9H20O2Si | 详情 | 详情 |
| (XIX) | 67918 | (S)-1-((tert-butyldimethylsilyl)oxy)-5-(trimethylsilyl)pent-4-yn-2-ol | C14H30O2Si2 | 详情 | 详情 | |
| (XX) | 67919 | (S)-1-((tert-butyldimethylsilyl)oxy)pent-4-yn-2-ol | C11H22O2Si | 详情 | 详情 | |
| (XXI) | 67920 | (S)-4-iodopent-4-ene-1,2-diol | C5H9IO2 | 详情 | 详情 | |
| (XXII) | 67922 | (S)-5-(2-iodoallyl)-2,2,3,3,8,8,9,9-octamethyl-4,7-dioxa-3,8-disiladecane | C17H37IO2Si2 | 详情 | 详情 | |
| (XXIII) | 67921 | 1,2-O-bis-TBDMS-3-(1-iodocyclopropyl) propane-1,2(S)-diol;(S)-5-((1-iodocyclopropyl)methyl)-2,2,3,3,8,8,9,9-octamethyl-4,7-dioxa-3,8-disiladecane | C18H39IO2Si2 | 详情 | 详情 | |
| (XXIV) | 67923 | 3-(1-iodocyclopropyl)propane-1,2(S)-diol | C6H11O2I | 详情 | 详情 | |
| (XXV) | 10722 | 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane | 77-76-9 | C5H12O2 | 详情 | 详情 |
| (XXVI) | 67924 | 4(S)-(1-iodocyclopropylmethyl)-2,2-dimethyl- 1,3-dioxolane | C9H15IO2 | 详情 | 详情 | |
| (XXVII) | 67925 | dicyclopropyl disulfide;Dicyclopropyldisulfide | 68846-57-1 | C6H10S2 | 详情 | 详情 |
| (XXVIII) | 67926 | 4(R)-(bromomethyl)-2,2-dimethyl-1,3- dioxolane | 14437-87-7 | C6H11BrO2 | 详情 | 详情 |
| (XXIX) | 67927 | 1,2-bis(1-(((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)cyclopropyl)disulfane | C18H30O4S2 | 详情 | 详情 | |
| (XXX) | 67929 | (R)-1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)cyclopropanethiol | C9H16O2S | 详情 | 详情 | |
| (XXXI) | 67928 | sodium (R)-1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)cyclopropane-1-sulfonate | C9H15NaO5S | 详情 | 详情 |