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【结 构 式】 
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【分子编号】31767 【品名】1-(bromomethyl)cyclohexane 【CA登记号】2550-36-9 |
【 分 子 式 】C7H13Br 【 分 子 量 】177.08422 【元素组成】C 47.48% H 7.4% Br 45.12% |
合成路线1
该中间体在本合成路线中的序号：(V)The required chiral auxiliary hydroxyketone (II) was prepared from (S)-alpha-pinene (I) either by dihydroxylation with K2OsO4 and NMO, followed by Swern oxidation of the secondary alcohol, or by direct oxidation using KMnO4 under phase-transfer conditions. Condensation of (II) with 2-(aminomethyl)pyridine (III) in the presence of titanium isopropoxide or thionyl chloride as the dehydrating reagents provided the chiral imine (IV), which was estereoselectively alkylated with cyclohexylmethyl bromide (V) and n-BuLi, yielding (VI). Cleavage of the chiral auxiliary of (VI) was carried out by treatment with hydroxylamine hydrochloride. Enantiomeric enrichment of the resulting (S)-pyridylamine was achieved by recrystallization of the corresponding L-tartrate salt (VII). Finally, the amine was condensed with chlorobenzoxazole (VIII) in the presence of NaOAc and Na2CO3 in refluxing methylcyclohexane.
| 【1】 Roth, G.P.; et al.; Optimization and scale-up of an asymetric route to the LTB4 inhibitor ontazolast. Org Process Res Dev 1997, 1, 5, 331. |
| 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) | 16643 | Poly-alpha-pinene; (1S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-2-ene | 7785-26-4 | C10H16 | 详情 | 详情 |
| (II) | 31762 | (1S,2R,5S)-2-hydroxy-2,6,6-trimethylbicyclo[3.1.1]heptan-3-one | C10H16O2 | 详情 | 详情 | |
| (III) | 13582 | 2-Pyridinylmethanamine; 2-Pyridinylmethylamine; 2-(Aminomethyl)pyridine | 3731-51-9 | C6H8N2 | 详情 | 详情 |
| (IV) | 31763 | (1S,2R,5S)-2,6,6-trimethyl-3-[(2-pyridinylmethyl)imino]bicyclo[3.1.1]heptan-2-ol | C16H22N2O | 详情 | 详情 | |
| (V) | 31767 | 1-(bromomethyl)cyclohexane | 2550-36-9 | C7H13Br | 详情 | 详情 |
| (VI) | 31764 | (1S,2R,5S)-3-[[(1S)-2-cyclohexyl-1-(2-pyridinyl)ethyl]imino]-2,6,6-trimethylbicyclo[3.1.1]heptan-2-ol | C23H34N2O | 详情 | 详情 | |
| (VII) | 31765 | (1S)-2-cyclohexyl-1-(2-pyridinyl)ethylamine; (1S)-2-cyclohexyl-1-(2-pyridinyl)-1-ethanamine | C13H20N2 | 详情 | 详情 | |
| (VIII) | 31766 | 2-chloro-5-methyl-1,3-benzoxazole | C8H6ClNO | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IV)L-Histidine methyl ester (I) was protected as the bis(tritylated) derivative (II) upon treatment with triphenylmethyl chloride and Et3N. Reduction of the ester function of (III) with LiAlH4 afforded alcohol (III), which was coupled with cyclohexylmethyl bromide (IV) in the presence of NaH in DMF, yielding the cyclohexylmethyl ether (V). Finally, cleavage of the trityl protecting groups of (V) with HCl in THF provided the title compound as the dihydrochloride salt.
| 【1】 Gynther, J.; Laitinen, J.T.; Kotisaari, S.; Tuomisto, L.; Mannistö, P.T.; Kovalainen, J.T.; Christiaans, A.M.; Synthesis and in vitro pharmacology of a series of new chiral histamine H3-receptor ligands: 2-(R and S)-amino-3-(1H-imidazol-4(5)-yl)propyl ether derivatives. J Med Chem 1999, 42, 7, 1193. |
| 【2】 Kovalainen, J.T.; et al.; Investigation of the stereospecificity of the histamine H3-receptor with a series of new enantiomeric ligands. 15th European Federation for Medicinal Chemistry International Symposium on Medicinal Chemistry (Sept 6 1998, Edinburgh) 1998, Abst P.34. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 28630 | Triphenylchloromethane; 1-[Chloro(diphenyl)methyl]benzene; Trityl chloride | 76-83-5 | C19H15Cl | 详情 | 详情 | |
| (I) | 23048 | methyl (2S)-2-amino-3-(1H-imidazol-4-yl)propanoate | C7H11N3O2 | 详情 | 详情 | |
| (II) | 34449 | methyl (2S)-2-(tritylamino)-3-(1-trityl-1H-imidazol-4-yl)propanoate | C45H39N3O2 | 详情 | 详情 | |
| (III) | 34450 | (2S)-2-(tritylamino)-3-(1-trityl-1H-imidazol-4-yl)-1-propanol | C44H39N3O | 详情 | 详情 | |
| (IV) | 31767 | 1-(bromomethyl)cyclohexane | 2550-36-9 | C7H13Br | 详情 | 详情 |
| (V) | 34451 | N-[(1S)-2-(cyclohexylmethoxy)-1-[(1-trityl-1H-imidazol-4-yl)methyl]ethyl]-N-tritylamine; (2S)-1-(cyclohexylmethoxy)-N-trityl-3-(1-trityl-1H-imidazol-4-yl)-2-propanamine | C51H51N3O | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)Treatment of 6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ol (I) with (bromomethyl)cyclohexane (II) in the presence of Cs2CO3 provided the cyclohexylmethyl ether (III). Regioselective oxidation of (III) by means potassium persulfate gave ketone (IV), which was reduced to alcohol (V) with NaBH4. Azide (VI) was obtained by treatment of alcohol (V) with diphenylphosphoryl azide. Catalytic hydrogenation of azide (VI) in the presence of Boc2O furnished the tert-butyl carbamate (VII). Aromatic bromination of (VII) with N-bromosuccinimide provided bromide (VIII) which, upon lithiation and subsequent quenching with CO2, gave rise to carboxylic acid (IX). Amide (X) was prepared by treatment of acid (IX) with ammonium hydroxide in the presence of EDC and HOBt. The Boc protecting group of (X) was then removed using trifluoroacetic acid to give (XI).
| 【1】 Bohacek, R.; Sawyer, T.K.; Yang, M.G.; Eyermann, C.J.; Sundaramoorthi, R.; Shakespeare, W.C. (Ariad Pharmaceuticals Inc.); Bicyclic signal transduction inhibitors, compsns. containing them & uses thereof. WO 0027802 . |
| 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) | 43269 | 6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-2-ol | C11H14O | 详情 | 详情 | |
| (II) | 31767 | 1-(bromomethyl)cyclohexane | 2550-36-9 | C7H13Br | 详情 | 详情 |
| (III) | 43270 | 2-(cyclohexylmethoxy)-6,7,8,9-tetrahydro-5H-benzo[a]cycloheptene; cyclohexylmethyl 6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-2-yl ether | C18H26O | 详情 | 详情 | |
| (IV) | 43271 | 2-(cyclohexylmethoxy)-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-one | C18H24O2 | 详情 | 详情 | |
| (V) | 43272 | 2-(cyclohexylmethoxy)-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-ol | C18H26O2 | 详情 | 详情 | |
| (VI) | 43273 | 5-azido-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-2-yl cyclohexylmethyl ether; 5-azido-2-(cyclohexylmethoxy)-6,7,8,9-tetrahydro-5H-benzo[a]cycloheptene | C18H25N3O | 详情 | 详情 | |
| (VII) | 43274 | tert-butyl 2-(cyclohexylmethoxy)-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-ylcarbamate | C23H35NO3 | 详情 | 详情 | |
| (VIII) | 43275 | tert-butyl 3-bromo-2-(cyclohexylmethoxy)-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-ylcarbamate | C23H34BrNO3 | 详情 | 详情 | |
| (IX) | 43276 | 9-[(tert-butoxycarbonyl)amino]-3-(cyclohexylmethoxy)-6,7,8,9-tetrahydro-5H-benzo[a]cycloheptene-2-carboxylic acid | C24H35NO5 | 详情 | 详情 | |
| (X) | 43277 | tert-butyl 3-(aminocarbonyl)-2-(cyclohexylmethoxy)-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-ylcarbamate | C24H36N2O4 | 详情 | 详情 | |
| (XI) | 43278 | 9-amino-3-(cyclohexylmethoxy)-6,7,8,9-tetrahydro-5H-benzo[a]cycloheptene-2-carboxamide | C19H28N2O2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(VII)Condensation of 6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ol (VI) with (bromomethyl)cyclohexane (VII) in the presence of Cs2CO3 gave ether (VIII). Benzylic oxidation of (VIII) to provide ketone (IX) was effected by treatment with potassium persulfate in the presence of cupric sulfate. Subsequent reduction of (IX) with NaBH4 yielded alcohol (X), which was converted to azide (XI) using diphenylphosphoryl azide and DBU. Catalytic hydrogenation of the azido group of (XI) in the presence of Boc2O produced carbamate (XII). Bromination of (XII) at position 3 was carried out by means of N-bromosuccinimide in acetonitrile. The resulting aryl bromide (XIII) was lithiated with butyllithium in cold THF and subsequently converted to carboxylic acid (XIV) by quenching with CO2 gas. Coupling of acid (XIV) with ammonia by means of EDC and HOBt afforded amide (XV). The Boc group of (XV) was then removed by treatment with trifluoroacetic acid to furnish the racemic amine (XVI).
| 【1】 Bohacek, R.; Sawyer, T.K.; Yang, M.G.; Eyermann, C.J.; Sundaramoorthi, R.; Shakespeare, W.C. (Ariad Pharmaceuticals Inc.); Bicyclic signal transduction inhibitors, compsns. containing them & uses thereof. WO 0027802 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VI) | 43269 | 6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-2-ol | C11H14O | 详情 | 详情 | |
| (VII) | 31767 | 1-(bromomethyl)cyclohexane | 2550-36-9 | C7H13Br | 详情 | 详情 |
| (VIII) | 43270 | 2-(cyclohexylmethoxy)-6,7,8,9-tetrahydro-5H-benzo[a]cycloheptene; cyclohexylmethyl 6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-2-yl ether | C18H26O | 详情 | 详情 | |
| (IX) | 43271 | 2-(cyclohexylmethoxy)-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-one | C18H24O2 | 详情 | 详情 | |
| (X) | 43272 | 2-(cyclohexylmethoxy)-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-ol | C18H26O2 | 详情 | 详情 | |
| (XI) | 43273 | 5-azido-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-2-yl cyclohexylmethyl ether; 5-azido-2-(cyclohexylmethoxy)-6,7,8,9-tetrahydro-5H-benzo[a]cycloheptene | C18H25N3O | 详情 | 详情 | |
| (XII) | 43274 | tert-butyl 2-(cyclohexylmethoxy)-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-ylcarbamate | C23H35NO3 | 详情 | 详情 | |
| (XIII) | 43275 | tert-butyl 3-bromo-2-(cyclohexylmethoxy)-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-ylcarbamate | C23H34BrNO3 | 详情 | 详情 | |
| (XIV) | 43276 | 9-[(tert-butoxycarbonyl)amino]-3-(cyclohexylmethoxy)-6,7,8,9-tetrahydro-5H-benzo[a]cycloheptene-2-carboxylic acid | C24H35NO5 | 详情 | 详情 | |
| (XV) | 43277 | tert-butyl 3-(aminocarbonyl)-2-(cyclohexylmethoxy)-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-ylcarbamate | C24H36N2O4 | 详情 | 详情 | |
| (XVI) | 43278 | 9-amino-3-(cyclohexylmethoxy)-6,7,8,9-tetrahydro-5H-benzo[a]cycloheptene-2-carboxamide | C19H28N2O2 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(IX)Reaction of 3-(tetrahydropyranyloxy)benzaldehyde (I) with acetonitrile (II) in the presence of t-BuOK in THF gives the b-hydroxypropionitrile (III), which by reduction with LiAlH4 in THF/Et2O yields the primary amine (IV). N-Protection of amine (IV) with ethyl trifluoroacetate (V) in THF affords the carbamate (VI), whose secondary hydroxyl group is oxidized with MnO2 in CH2Cl2 to yield the ketone (VII). Enantioselective reduction of ketone (VII) with (–)-DIP-Cl and DIEA in THF provides the (R)-alcohol (VIII), which is O-alkylated at its phenolic hydroxyl group with cyclohexylmethyl bromide (IX) and K2CO3 in DMF to give ether (X). Finally, compound (X) is N-deprotected by means of K2CO3 in MeOH/H2O and treated with HCl in i-PrOH .
| 【1】 Scott, I.L., Kuksa, V.A. Orme, M.W., Little, T., gall, A., Hong, f. (Acucela, Inc.). Alkoxy compounds for disease treatment. CN 103553945, EP 2091955, JP 2011512321, US 2009326074, US 7982071, US 2012122938, US 2012214852, US 2013197096, US 8829244, WO 2009045479. |
| 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) | 67832 | 3-((tetrahydro-2H-pyran-2-yl)oxy)benzaldehyde | C12H14O3 | 详情 | 详情 | |
| (II) | 37210 | acetonitrile | 75-05-8 | C2H3N | 详情 | 详情 |
| (III) | 67833 | 3-hydroxy-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)propanenitrile | C14H17NO3 | 详情 | 详情 | |
| (IV) | 67834 | 3-amino-1-(3-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)propan-1-ol | C14H21NO3 | 详情 | 详情 | |
| (V) | 14588 | Ethyl 2,2,2-trifluoroacetate; Trifluoroethyl acetate | 383-63-1 | C4H5F3O2 | 详情 | 详情 |
| (VI) | 67835 | 2,2,2-trifluoro-N-(3-hydroxy-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)propyl)acetamide | C16H20F3NO4 | 详情 | 详情 | |
| (VII) | 67836 | 2,2,2-trifluoro-N-(3-oxo-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)propyl)acetamide | C16H18F3NO4 | 详情 | 详情 | |
| (VIII) | 67837 | (R)-2,2,2-trifluoro-N-(3-hydroxy-3-(3-hydroxyphenyl)propyl)acetamide | C11H12F3NO3 | 详情 | 详情 | |
| (IX) | 31767 | 1-(bromomethyl)cyclohexane | 2550-36-9 | C7H13Br | 详情 | 详情 |
| (X) | 67838 | (R)-N-(3-(3-(cyclohexylmethoxy)phenyl)-3-hydroxypropyl)-2,2,2-trifluoroacetamide | C18H24F3NO3 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(IX)Mitsunobu reaction of 3-hydroxybenzaldehyde (XI) with cyclohexylmethanol (XII) using PPh3 and DEAD in THF or condensation of 3-hydroxybenzaldehyde (XI) with cyclohexylmethyl bromide (IX) using K2CO3 and NMP in DMF at 75 °C give ether (XIII), which by reaction with acetonitrile (II) by means of LDA in THF at –78 °C or t-BuOK in THF yields the b-hydroxynitrile (XIV). Reduction of nitrile (XIV) with LiAlH4 or BH3·Me2S in THF affords the primary amine (XV), which by N-protection with Fmoc-Cl and DIEA in CH2Cl2 provides carbamate (XVI). Oxidation of secondary alcohol (XVI) with MnO2 in CH2Cl2 leads to the ketone (XVII), which is finally submitted to enantioselective reduction using (–)-DIP-Cl (prepared in situ by treating (–)-a-pinene with chloroborane-methyl sulfide complex in hexane) and DIEA in THF, followed by deprotection of the obtained N-Fmoc protected compound with DBU in THF. Alternatively, resolution of racemic emixustat (XV) can be performed using D-mandelic acid .
| 【1】 Scott, I.L., Kuksa, V.A. Orme, M.W., Little, T., gall, A., Hong, f. (Acucela, Inc.). Alkoxy compounds for disease treatment. CN 103553945, EP 2091955, JP 2011512321, US 2009326074, US 7982071, US 2012122938, US 2012214852, US 2013197096, US 8829244, WO 2009045479. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 37210 | acetonitrile | 75-05-8 | C2H3N | 详情 | 详情 |
| (IX) | 31767 | 1-(bromomethyl)cyclohexane | 2550-36-9 | C7H13Br | 详情 | 详情 |
| (XI) | 28537 | 3-hydroxybenzaldehyde | 100-83-4 | C7H6O2 | 详情 | 详情 |
| (XII) | 28360 | cyclohexylmethanol | 100-49-2 | C7H14O | 详情 | 详情 |
| (XIII) | 67839 | 3-(cyclohexylmethoxy)benzaldehyde | C14H18O2 | 详情 | 详情 | |
| (XIV) | 67840 | 3-(3-(cyclohexylmethoxy)phenyl)-3-hydroxypropanenitrile | C16H21NO2 | 详情 | 详情 | |
| (XV) | 67841 | 3-amino-1-(3-(cyclohexylmethoxy)phenyl)propan-1-ol | C16H25NO2 | 详情 | 详情 | |
| (XVI) | 67842 | (9H-fluoren-9-yl)methyl (3-(3-(cyclohexylmethoxy)phenyl)-3-hydroxypropyl)carbamate | C31H35NO4 | 详情 | 详情 | |
| (XVII) | 67843 | (9H-fluoren-9-yl)methyl (3-(3-(cyclohexylmethoxy)phenyl)-3-oxopropyl)carbamate | C31H33NO4 | 详情 | 详情 |