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【结 构 式】 
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【分子编号】65272 【品名】3,4-dimethoxyphenethyl trichloroacetimidate 【CA登记号】 |
【 分 子 式 】C12H14Cl3NO3 【 分 子 量 】326.6062 【元素组成】C 44.13% H 4.32% Cl 32.56% N 4.29% O 14.7% |
合成路线1
该中间体在本合成路线中的序号：(X)Condensation of (1S,2R)-2-[2-(3,4-dimethoxyphenyl)ethoxy]cyclohexyl tosylate (I) with 3(R)-benzyloxypyrrolidine (II) provides vernakalant benzyl ether (III), which is then debenzylated by catalytic hydrogenolysis over Pd/C (1). In a more direct approach, tosylate (I) is condensed with 3(R)-hydroxypyrrolidine (IV) to provide vernakalant (1, 2). An alternative strategy consists of the cyclization of (1R,2R)-2-[2-(3,4-dimethoxyphenyl)ethoxy]cyclohexylamine (V) with (R )-2-acetoxysuccinic anhydride (VI) by means of acetyl chloride or with ethyl 4-chloro-3(R )-hydroxybutyrate (VII) to give, respectively, the cyclic imide (VIIIa) or the pyrrolidinone (VIIIb), which is subsequently reduced and deprotected by means of Red-Al to yield the title hydroxypyrrolidine derivative (2). The O-benzyl precursor of vernakalant (III) can alternatively be obtained by condensation of 2(R )-[3(R )-benzyloxy-1-pyrrolidinyl]cyclohexan-1(R )-ol (IX) with 3,4-dimethoxyphenethyl trichloroacetimidate (X) (prepared from dimethoxyphenethyl alcohol [XI] and trichloroacetonitrile) in the presence of trifluoromethanesulfonic acid (2, 3). A related strategy for preparing the succinimide precursor of vernakalant (VIIIa) consists of the condensation of 2(R)-acetoxy-N-[2(R)-hydroxy-1(R)-cyclohexyl]succinimide (XII) with imidate (X) in the presence of boron trifluoride etherate (4). Scheme 1.
| 【1】 Beatch, G.N., Choi, L.S.L., Jung, G. et al. (Cardiome Pharma Corp.). Aminocyclohexyl ether compounds and uses thereof. EP 1560812, EP1666459, JP 2006525227, WO 2004099137. |
| 【2】 Plouvier, B.M.C., Chou, D.T.H., Jung, G. et al. (Cardiome Pharma Corp.). Synthetic process for aminocyclohexyl ether compounds. WO 2006088525. |
| 【3】 Machiya, K., Ike, K., Watanabe, M., Yoshino, T., Okamoto, T., Morinaga, Y., Mizobata, S. (Astellas Pharma, Inc.). Production method of optically active cyclohexane ether compounds. WO 2006075778. |
| 【4】 Roth, C.J., Jung, G., Plouvier, B.M.C., Chou, D.T.H., Yee, J.G.K. (Cardiome Pharma Corp.). Synthetic processes for the preparation of aminocyclohexyl ether compounds. WO 2006138673. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIIIa) | 65269 | C22H29NO7 | 详情 | 详情 | ||
| (VIIIb) | 65270 | C20H29NO5 | 详情 | 详情 | ||
| (I) | 65263 | (1S,2R)-2-[2-(3,4-dimethoxyphenyl)ethoxy]cyclohexyl tosylate | C23H30O6S | 详情 | 详情 | |
| (II) | 65264 | (3R)-benzyloxypyrrolidine | C11H15NO | 详情 | 详情 | |
| (III) | 65265 | vernakalant benzyl ether | C27H37NO4 | 详情 | 详情 | |
| (IV) | 14490 | (3R)tetrahydro-1H-pyrrol-3-ol; R-3-hydroxypyrrolidine | 2799-21-5 | C4H9NO | 详情 | 详情 |
| (V) | 65266 | (1R,2R)-2-[2-(3,4-dimethoxyphenyl)ethoxy]cyclohexylamine | C16H25NO3 | 详情 | 详情 | |
| (VI) | 65267 | (2R)-acetoxysuccinic anhydride | 79814-40-7 | C6H6O5 | 详情 | 详情 |
| (VII) | 65268 | ethyl 4-chloro-(3R)-hydroxybutyrate; | 90866-33-4 | C6H11ClO3 | 详情 | 详情 |
| (IX) | 65271 | (2R)-[(3R)-benzyloxy-1-pyrrolidinyl]cyclohexan-(1R)-ol | C16H25NO2 | 详情 | 详情 | |
| (X) | 65272 | 3,4-dimethoxyphenethyl trichloroacetimidate | C12H14Cl3NO3 | 详情 | 详情 | |
| (XI) | 38711 | 2-(3,4-dimethoxyphenyl)-1-ethanol | 7417-21-2 | C10H14O3 | 详情 | 详情 |
| (XII) | 65273 | (2R)-acetoxy-N-[(2R)-hydroxy-(1R)-cyclohexyl]succinimide | C12H17O5 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(X)The tosylate precursor (I) can be prepared by a number of different methods. Microbial dihydroxylation of chlorobenzene (XIII) gives (1S,2S)-3-chlorocyclohexa-3,5-diene-1,2-diol (XIV), which is further hydrogenated to (XV) in the presence of Rh/Al 2O3. Regioselective tosylation of (XV), followed by hydrogenation of the resulting monotosylate (XVI) over Pd/C, leads to (1S,2R)-2-hydroxycyclohexyl tosylate (XVII). Subsequent coupling of (XVII) with imidate (X) provides the target intermediate (I) (1). In a different method, ketalization of (S,S)-1,2-cyclohexanediol (XVIII) with 2,2-dimethoxypropane provides the acetonide (XIX), which is oxidized to 2(S)-hydroxycyclohexanone (XX) by treatment with bis(trifluoromethyl)-dioxirane (BTDO). Subsequent tosylation of (XX) furnishes 2(S)-tosyloxycyclohexanone (XXI). Alternatively, the chiral tosyl ketone (XXI) can be obtained by monotosylation of diol (XVIII) in the presence of Bu2SnO to afford the hydroxy tosylate (XXII), which is subjected to Jones oxidation, giving ketone (XXI). The diastereoselective reduction of ketone (XXI) then provides an alternative route to 2(R)-hydroxy tosylate (XVII). Alternatively, the chiral tosyl ketone (XXI) is condensed with the sodium alkoxide of 3,4-dimethoxyphenethyl alcohol (XI) to yield the 2(R)-ether (XXIIIa). Stereoselective reduction of ketone (XXIIIa) utilizing bulky reducing agents such as L-Selectride, LS-Selectride or alpine boranes gives the (S)-cyclohexanol (XXIV), which can be further converted to tosylate (I) under the usual conditions. Similarly, the phenethyl alcohol (XI) can be reacted with 2-chlorocyclohexanone (XXV) by means of NaH to yield the racemic ketone ether (XXIIIb), which is enantioselectively reduced to the (1S,2R)-phenethoxycyclohexanol (XXIV) under Noyori’s asymmetric hydrogenation conditions. A further route to the phenethoxy ketone (XXIIIa) consists of the enantioselective α-oxyamination of cyclohexanone (XXVI) with nitrosobenzene in the presence of L-proline to produce the chiral hydroxylamine derivative (XXVII), which is subsequently cleaved to 2(R)-hydroxycyclohexanone (XXVIII) by treatment with CuSO4, and then coupled with imidate (X) in the presence of boron trifluoride etherate. Optionally, 2(R)-hydroxycyclohexanone (XXVIII) can be obtained by oxidation of the (1R,2R)-cyclohexanediol acetonide (XXIX) with BTDO. Another method for obtaining the (1S,2R)-phenethoxy cyclohexanol (XXIV) is based on the asymmetric reduction of (3,4-dimethoxyphenyl)acetaldehyde cyclohexanediol acetal (XXX) by means of triethylsilane in the presence of chiral Lewis acids (2). Scheme 2.
| 【1】 Beatch, G.N., Choi, L.S.L., Jung, G. et al. (Cardiome Pharma Corp.). Aminocyclohexyl ether compounds and uses thereof. EP 1560812, EP1666459, JP 2006525227, WO 2004099137. |
| 【2】 Plouvier, B.M.C., Chou, D.T.H., Jung, G. et al. (Cardiome Pharma Corp.). Synthetic process for aminocyclohexyl ether compounds. WO 2006088525. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXIIIa) | 65283 | C16H22O4 | 详情 | 详情 | ||
| (XXIIIb) | 65284 | C16H22O4 | 详情 | 详情 | ||
| (I) | 65263 | (1S,2R)-2-[2-(3,4-dimethoxyphenyl)ethoxy]cyclohexyl tosylate | C23H30O6S | 详情 | 详情 | |
| (X) | 65272 | 3,4-dimethoxyphenethyl trichloroacetimidate | C12H14Cl3NO3 | 详情 | 详情 | |
| (XIII) | 10190 | 1-Chlorobenzene | 108-90-7 | C6H5Cl | 详情 | 详情 |
| (XIV) | 65274 | (1S,2S)-3-chlorocyclohexa-3,5-diene-1,2-diol | C6H7ClO2 | 详情 | 详情 | |
| (XV) | 65275 | (1S,2S)-3-chlorocyclohexa-3-ene-1,2-diol | C6H9ClO2 | 详情 | 详情 | |
| (XVI) | 65276 | (1S,2S)-3-chloro-2-hydroxycyclohexa-3-ene-1-yl tosylate | C13H15ClO4S | 详情 | 详情 | |
| (XVII) | 65277 | (1S,2R)-2-hydroxycyclohexyl tosylate | C13H18O4S | 详情 | 详情 | |
| (XVIII) | 65278 | (1R,2R)-1,2-Cyclohexanediol | 1072-86-2 | C6H12O2 | 详情 | 详情 |
| (XIX) | 65279 | (1S,2S)-cyclohexanediol acetonide | C9H16O2 | 详情 | 详情 | |
| (XX) | 65280 | (2S)-hydroxycyclohexanone | C6H10O2 | 详情 | 详情 | |
| (XXI) | 65281 | (2S)-tosyloxycyclohexanone | C13H16O4S | 详情 | 详情 | |
| (XXII) | 65282 | (1S,2S)-2-hydroxycyclohexyl tosylate | C13H18O4S | 详情 | 详情 | |
| (XXIV) | 65285 | (1S,2R)-phenethoxycyclohexanol | C16H24O4 | 详情 | 详情 | |
| (XXV) | 17985 | 2-Chlorocyclohexanone | 822-87-7 | C6H9ClO | 详情 | 详情 |
| (XXVI) | 11059 | Cyclohexanone | 108-94-1 | C6H10O | 详情 | 详情 |
| (XXVII) | 65286 | C12H15NO2 | 详情 | 详情 | ||
| (XXVIII) | 65287 | (2R)-hydroxycyclohexanone | C6H10O2 | 详情 | 详情 | |
| (XXIX) | 65288 | (1R,2R)-cyclohexanediol acetonide | C9H16O2 | 详情 | 详情 | |
| (XXX) | 65289 | (3,4-dimethoxyphenyl)acetaldehyde cyclohexanediol acetal | C16H21O4 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(X)The precursor (1R,2R)-2-[2-(3,4-dimethoxyphenyl)ethoxy]cyclohexylamine (V) can be prepared as follows. Ring opening of cyclohexene oxide (XXXI) with benzylamine affords racemic trans-2-benzylaminocyclohexanol (XXXII) which, after resolution with L-(–)-di-p-toluoyltartaric acid, is treated with benzyl chloroformate to produce the chiral carbamate (XXXIII). Subsequent condensation of the cyclohexanol derivative (XXXIII) with imidate (X) yields the dimethoxyphenethyl ether (XXXIV), from which the N-benzyl and carbobenzoxy protecting groups are removed by hydrogenolysis over Pd/C to furnish the target intermediate (V). Similarly, ring opening of epoxide (XXXI) with trimethylsilyl azide utilizing either Jacobsen’s (salen)Cr(III) catalyst or Nugent’s Zr C3-symmetrical complex, followed by acidic desilylation, furnishes (R,R)-2-azidocyclohexanol (XXXV). After coupling of (XXXV) with imidate (X), catalytic hydrogenation of the resulting azido ether (XXXVI) provides amine (V). In an alternative method, aminolysis of cyclohexene oxide (XXXI) produces racemic trans-2-aminocyclohexanol (XXXVII), which, after resolution with L-tartaric acid, is reacted with benzyl chloroformate to give (R,R)-2-(benzyloxycarbonylamino)cyclohexanol (XXXVIII). Optionally, the chiral carbamate (XXXVIII) can be obtained by reaction of racemic aminocyclohexanol (XXXVII) with benzyl chloroformate, followed by enantioselective acetylation of the obtained compound (XXXIX) with vinyl acetate in the presence of lipase, to furnish the (R,R)-acetate (XL), which is then hydrolyzed to (XXXVIII) under alkaline conditions. Coupling of (R,R)-2-(benzyloxycarbonylamino)cyclohexanol (XXXVIII) with imidate (X) produces the carbobenzoxy-protected amino ether (XLI), which is then hydrolyzed to (V) in refluxing 6N HCl. A different route to the intermediate amine (V) consists of displacement of tosylate (I) with NaN3, followed by catalytic hydrogenation of the resulting alkyl azide (2). Scheme 3.
| 【2】 Plouvier, B.M.C., Chou, D.T.H., Jung, G. et al. (Cardiome Pharma Corp.). Synthetic process for aminocyclohexyl ether compounds. WO 2006088525. |
| 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) | 65263 | (1S,2R)-2-[2-(3,4-dimethoxyphenyl)ethoxy]cyclohexyl tosylate | C23H30O6S | 详情 | 详情 | |
| (V) | 65266 | (1R,2R)-2-[2-(3,4-dimethoxyphenyl)ethoxy]cyclohexylamine | C16H25NO3 | 详情 | 详情 | |
| (X) | 65272 | 3,4-dimethoxyphenethyl trichloroacetimidate | C12H14Cl3NO3 | 详情 | 详情 | |
| (XXXI) | 17986 | 7-oxabicyclo[4.1.0]heptane; cyclohexene oxide | 286-20-4 | C6H10O | 详情 | 详情 |
| (XXXII) | 65290 | racemic trans-2-benzylaminocyclohexanol | C13H18NO | 详情 | 详情 | |
| (XXXIII) | 65291 | C21H24NO3 | 详情 | 详情 | ||
| (XXXIV) | 65292 | C31H36NO5 | 详情 | 详情 | ||
| (XXXV) | 65293 | (R,R)-2-azidocyclohexanol | C6H11N3O | 详情 | 详情 | |
| (XXXVI) | 65294 | C16H22N3O3 | 详情 | 详情 | ||
| (XXXVII) | 65295 | racemic trans-2-aminocyclohexanol | 6850-38-0 | C6H13NO | 详情 | 详情 |
| (XXXVIII) | 65296 | (R,R)-2-(benzyloxycarbonylamino)cyclohexanol | C14H19NO3 | 详情 | 详情 | |
| (XXXIX) | 65297 | (RS,RS)-2-(benzyloxycarbonylamino)cyclohexanol | C14H19NO3 | 详情 | 详情 | |
| (XL) | 65298 | (R,R)-2-(benzyloxycarbonylamino)cyclohexanyl acetate | C16H21NO4 | 详情 | 详情 | |
| (XLI) | 65299 | C24H31NO5 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(X)Several alternative routes to the intermediate amine (V) are shown in Scheme 4. The asymmetric reduction of ethyl 2-oxocyclohexanecarboxylate (XLII) gives the (1R,2S)-hydroxy ester (XLIII), which is converted to amide (XLIV) by treatment with aqueous ammonia and ammonium chloride. After activation of the hydroxyl group of (XLIV) as the corresponding mesylate (XLV), displacement with the potassium alkoxide of 3,4-dimethoxyphenethyl alcohol (XI) affords the trans-amide ether (XLVI). The target amine (V) is then obtained by Hofmann rearrangement of carboxamide (XLVI) employing NaOCl and NaOH. A different resolution method involves transesterification of ethyl 2-oxocyclohexanecarboxylate (XLII) with benzyl alcohol, followed by enzymatic reduction of the resulting benzyl keto ester (XLVII) with carbonyl reductase to provide the (1R,2R)-hydroxy ester (XLVIII). Coupling of (XLVIII) with imidate (X) furnishes the benzyl phenethoxycyclohexanecarboxylate (XLIX), which is subjected to benzyl group hydrogenolysis to provide acid (L). This compound can also be obtained by condensation of ethyl 2(R)-hydroxy-1(R)-cyclohexanecarboxylate (LI) with 3,4-dimethoxyphenethyl trichloroacetimidate (X), followed by alkaline hydrolysis of the obtained ethyl 2-phenethoxycyclohexanecarboxylate (LII). Optionally, the ethyl ester (LII) can be converted to amide (XLVI) by reaction with methanolic ammonia, or to hydrazide (LIII) by treatment with hydrazine hydrate in EtOH. Conversion of acid (L) to the target amine (V) can then be accomplished by Curtius rearrangement employing diphenylphosphoryl azide. Analogously, diazotization of hydrazide (LIII), followed by Curtius rearrangement of the intermediate acyl azide and alkaline hydrolysis results in the target amine (V) (2). Scheme 4.
| 【2】 Plouvier, B.M.C., Chou, D.T.H., Jung, G. et al. (Cardiome Pharma Corp.). Synthetic process for aminocyclohexyl ether compounds. WO 2006088525. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (V) | 65266 | (1R,2R)-2-[2-(3,4-dimethoxyphenyl)ethoxy]cyclohexylamine | C16H25NO3 | 详情 | 详情 | |
| (X) | 65272 | 3,4-dimethoxyphenethyl trichloroacetimidate | C12H14Cl3NO3 | 详情 | 详情 | |
| (XI) | 38711 | 2-(3,4-dimethoxyphenyl)-1-ethanol | 7417-21-2 | C10H14O3 | 详情 | 详情 |
| (XLII) | 11889 | ethyl 2-oxocyclohexanecarboxylate; Ethyl 2-cyclohexanonecarboxylate | 1655-07-8 | C9H14O3 | 详情 | 详情 |
| (XLIII) | 15589 | ethyl 2-hydroxycyclohexanecarboxylate; Ethyl cis-2-hydroxy-1-cyclohexanecarboxylate | 6149-52-6 | C9H16O3 | 详情 | 详情 |
| (XLIV) | 65300 | cis-2-Hydroxy-1-Cyclohexanecarboxamide; (1R,2S)-2-Hydroxy-1-Cyclohexanecarboxamide; Zinc01081409 | 73045-98-4 | C7H13NO2 | 详情 | 详情 |
| (XLV) | 65301 | C7H12NaNO2 | 详情 | 详情 | ||
| (XLVI) | 65302 | C17H25NO4 | 详情 | 详情 | ||
| (XLVII) | 65303 | C14H16O3 | 详情 | 详情 | ||
| (XLVIII) | 65304 | C14H18O3 | 详情 | 详情 | ||
| (XLIX) | 65305 | C24H30O5 | 详情 | 详情 | ||
| (L) | 65306 | C16H24O5 | 详情 | 详情 | ||
| (LI) | 65307 | Ethyl trans-2-hydroxycyclohexanecarboxylate | 3444-72-2 | C9H16O3 | 详情 | 详情 |
| (LII) | 65308 | C19H28O5 | 详情 | 详情 | ||
| (LIII) | 65309 | C17H26N2O4 | 详情 | 详情 |