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【结 构 式】 
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【分子编号】17985 【品名】2-Chlorocyclohexanone 【CA登记号】822-87-7 |
【 分 子 式 】C6H9ClO 【 分 子 量 】132.58956 【元素组成】C 54.35% H 6.84% Cl 26.74% O 12.07% |
合成路线1
该中间体在本合成路线中的序号：(II)This compound was prepared by two ways starting from 3-(3-oxo-2,3-dihydropyridazin-6-yl)-2-phenylpyrazolo[1,5-a]pyridine (I). Alkylation of (I) with 2-chlorocyclohexanone (II) in the presence of NaH in DMF gave diketone (V). Alternatively, condensation of (I) with epoxycyclohexane and NaH in DMF at 127 C yielded the ketoalcohol (IV) as a mixture of cis and trans isomers, which were separated by column chromatography. The major trans isomer was then oxidized with pyridinium dichromate to the diketone (V). Reaction of this diketone with the sodium salt of triethyl phosphonoacetate (VI) in toluene at 100 C afforded a mixture of unsaturated esters (VII) and (VIII), which were subsequently submitted to hydrolysis with NaOH. Then, column chromatography of the mixture provided the desired endocyclic unsaturated acid.
| 【1】 Tenda, Y.; Kinoshita, T.; Sakane, K.; Nishimura, S.; Akahane, A.; Durkin, K.; Kuroda, S.; Discovery of FR166124, a novel water-soluble pyrazolo-[1,5-a]pyridine adenosine A1 receptor antagonist. Bioorg Med Chem Lett 1999, 9, 14, 1979. |
| 【2】 Akahane, A.; Nishimura, S.; Itani, H.; Durkin, K.P.M. (Fujisawa Pharmaceutical Co., Ltd.); Pyrazolopyridine adenosine antagonists. EP 0737193; JP 1997507485; US 5773530; WO 9518128 . |
| 【3】 Zanka, A.; et al.; Process improvements in the production of a novel non-xanthine adenosine A1 receptopr antagonist. A "one-pot" horner-emmons isomerization reaction. Org Process Res Dev 1999, 3, 6, 394. |
| 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) | 17984 | 6-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-3(2H)-pyridazinone | C17H12N4O | 详情 | 详情 | |
| (II) | 17985 | 2-Chlorocyclohexanone | 822-87-7 | C6H9ClO | 详情 | 详情 |
| (III) | 17986 | 7-oxabicyclo[4.1.0]heptane; cyclohexene oxide | 286-20-4 | C6H10O | 详情 | 详情 |
| (IV) | 17987 | 2-(2-hydroxycyclohexyl)-6-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-3(2H)-pyridazinone | C23H22N4O2 | 详情 | 详情 | |
| (V) | 17988 | 2-(2-oxocyclohexyl)-6-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-3(2H)-pyridazinone | C23H20N4O2 | 详情 | 详情 | |
| (VI) | 10019 | Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate | 867-13-0 | C8H17O5P | 详情 | 详情 |
| (VII) | 17990 | ethyl 2-[2-[6-oxo-3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-1(6H)-pyridazinyl]cyclohexylidene]acetate | C27H26N4O3 | 详情 | 详情 | |
| (VIII) | 17991 | ethyl 2-[2-[6-oxo-3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-1(6H)-pyridazinyl]-1-cyclohexen-1-yl]acetate | C27H26N4O3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)Condensation of 7-hydroxy-5-methoxy-4-methylcoumarin (I) with 2-chlorocyclohexanone (II) by means of K2CO3 in refluxing acetone affords derivative (III), which is then cyclized by means of refluxing NaOH to provide compound (IV). Oxidation of (IV) by means of DDQ in refluxing benzene furnishes angelicine (V), whose methoxy group is then hydrolyzed with HI and acetic anhydride in refluxing HOAc to yield compound (VI). Finally, the desired product is obtained by coupling of (VI) with 3-chloro-N,N'-dimethylpropylamine (VII) by means of Williamson's reaction using NaH and NaI in refluxing DMF or using K2CO3 and HMPA in refluxing acetone.
| 【1】 Santana, L.; Gia, O.; Dalla Via, L.; Uriarte, E.; A new benzoangelicin with strong photobiological activity. Bioorg Med Chem Lett 2000, 10, 2, 135. |
| 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) | 47132 | 7-hydroxy-5-methoxy-4-methyl-2H-chromen-2-one | C11H10O4 | 详情 | 详情 | |
| (II) | 17985 | 2-Chlorocyclohexanone | 822-87-7 | C6H9ClO | 详情 | 详情 |
| (III) | 47133 | 5-methoxy-4-methyl-7-[(2-oxocyclohexyl)oxy]-2H-chromen-2-one | C17H18O5 | 详情 | 详情 | |
| (IV) | 47134 | 5-methoxy-4-methyl-8,9,10,11-tetrahydro-2H-[1]benzofuro[2,3-h]chromen-2-one | C17H16O4 | 详情 | 详情 | |
| (V) | 47135 | 5-methoxy-4-methyl-2H-[1]benzofuro[2,3-h]chromen-2-one | C17H12O4 | 详情 | 详情 | |
| (VI) | 47136 | 5-hydroxy-4-methyl-2H-[1]benzofuro[2,3-h]chromen-2-one | C16H10O4 | 详情 | 详情 | |
| (VII) | 24581 | 3-(Dimethylamino)propyl chloride; 3-Chloro-N,N-dimethyl-1-propanamine | 5407-04-5 | C5H12ClN | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XXV)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 |