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【结 构 式】

【分子编号】65263

【品名】(1S,2R)-2-[2-(3,4-dimethoxyphenyl)ethoxy]cyclohexyl tosylate

【CA登记号】 

【 分 子 式 】C23H30O6S

【 分 子 量 】434.5536

【元素组成】C 63.57% H 6.96% O 22.09% S 7.38%

与该中间体有关的原料药合成路线共 3 条

合成路线1

该中间体在本合成路线中的序号:(I)

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:(I)

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:(I)

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
Extended Information