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【结 构 式】 
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【分子编号】10190 【品名】1-Chlorobenzene 【CA登记号】108-90-7 |
【 分 子 式 】C6H5Cl 【 分 子 量 】112.5584 【元素组成】C 64.03% H 4.48% Cl 31.5% |
合成路线1
该中间体在本合成路线中的序号：(III)A more complete synthesis for LF-1695 has been reported: The reaction of 2-chloro-5-nitrobenzoic acid (I) with PCl5 in hot chlorobenzene gives the corresponding acyl chloride (II), which is condensed with chlorobenzene (III) by means of AlCl3, yielding 2,4'-dichloro-5-nitrobenzophenone (IV). The condensation of (IV) with 4-methylpiperidine (V) by means of K2CO3 at 150 C affords 4'-chloro-2-(4-methylpiperidin-1-yl)-5-nitrobenzophenone (VI), which is finally reduced with Fe or SnCl2 and HCl.
| 【1】 Ou, K.; Robin, J.; Bellamy, F.D.; Dodey, P.; Chazan, J.B.; Pascal, M.; Dutartre, P.; (Benzoylphenyl)piperidines: A new class of immunomodulators. J Med Chem 1991, 34, 5, 1545-52. |
| 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) | 10188 | 2-Chloro-5-nitrobenzoic acid | 2516-96-3 | C7H4ClNO4 | 详情 | 详情 |
| (II) | 10189 | 2-Chloro-5-nitrobenzoyl chloride | 25784-91-2 | C7H3Cl2NO3 | 详情 | 详情 |
| (III) | 10190 | 1-Chlorobenzene | 108-90-7 | C6H5Cl | 详情 | 详情 |
| (IV) | 10191 | (2-Chloro-5-nitrophenyl)(4-chlorophenyl)methanone | C13H7Cl2NO3 | 详情 | 详情 | |
| (V) | 10192 | 4-Methylpiperidine; gamma-Pipecoline | 626-58-4 | C6H13N | 详情 | 详情 |
| (VI) | 10193 | (4-Chlorophenyl)[2-(4-methylpiperidino)-5-nitrophenyl]methanone | C19H19ClN2O3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XVII)Alternatively, the target compound can be obtained as follows: Condensation between 2,6-dichloro-4-methylbenzonitrile (X) and 4-chloroiodobenzene (XI) by means of Mg in refluxing ether gives methyleneimine derivative (XII), which is then converted into 4-(4-chlorobenzoyl)-3,5-dichlorotoluene (XIII) by refluxing in dioxane-aqueous phosphate buffer. (Alternatively, compound (XIII) can also be obtained either by condensation of 3,5-dichlorotoluene (XIV) with p-chlorobenzoyl chloride (IV) by means of BuLi in THF or by treatment of 2,6-dichloro-4-methylbenzoic acid (XV) with thionyl chloride (SOCl2) in refluxing DMF to give (XVI), which then reacts with chlorobenzene (XVII) by means of AlCl3 in refluxing CCl4). Bromination of (XIII) is then performed by reaction with N-bromosuccinimide and dibenzoyl peroxide in refluxing benzene to give 4-(4-chlorobenzoyl)-3,5-dichlorobenzyl bromide (XVIII). (Alternatively, (XVIII) can also be synthesized by treatment of the already reported benzophenone derivative (V) with HOAc in THF/H2O followed by reaction with phosphorus tribromide in diethyl ether.) Finally, (XVIII) is converted into the desired compound either by treatment with 5-amino-1,2,3-triazole-4-carboxamide (XIX) by means of NaH in refluxing EtOH or by first reaction of (XVIII) with KN3 in refluxing EtOH to furnish benzyl azide (VIII), followed by reaction with cyanoacetamide (IX) and NaOMe in refluxing EtOH.
| 【1】 Bochis, R.J.; Chabala, J.C.; Fisher, M.H. (Merck & Co., Inc.); 5-(Amino or substd.amino)-1,2,3-triazoles. EP 0151529; JP 1985188376; US 4590201 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IV) | 10295 | p-Chlorobenzoyl chloride; 4-Chlorobenzoyl chloride | 122-01-0 | C7H4Cl2O | 详情 | 详情 |
| (V) | 49484 | [4-([[tert-butyl(dimethyl)silyl]oxy]methyl)-2,6-dichlorophenyl](4-chlorophenyl)methanone | C20H23Cl3O2Si | 详情 | 详情 | |
| (VIII) | 49487 | [4-(azidomethyl)-2,6-dichlorophenyl](4-chlorophenyl)methanone | C14H8Cl3N3O | 详情 | 详情 | |
| (IX) | 12122 | Cyanoacetamide; 2-Cyanoacetamide | 107-91-5 | C3H4N2O | 详情 | 详情 |
| (X) | 49488 | 2,6-dichloro-4-methylbenzonitrile | C8H5Cl2N | 详情 | 详情 | |
| (XI) | 19395 | 1-chloro-4-iodobenzene | 637-87-6 | C6H4ClI | 详情 | 详情 |
| (XII) | 49489 | (4-chlorophenyl)(2,6-dichloro-4-methylphenyl)methanimine | C14H10Cl3N | 详情 | 详情 | |
| (XIII) | 49490 | (4-chlorophenyl)(2,6-dichloro-4-methylphenyl)methanone | C14H9Cl3O | 详情 | 详情 | |
| (XIV) | 49491 | 1,3-dichloro-5-methylbenzene | C7H6Cl2 | 详情 | 详情 | |
| (XV) | 49492 | 2,6-dichloro-4-methylbenzoic acid | C8H6Cl2O2 | 详情 | 详情 | |
| (XVI) | 49493 | 2,6-dichloro-4-methylbenzoyl chloride | C8H5Cl3O | 详情 | 详情 | |
| (XVII) | 10190 | 1-Chlorobenzene | 108-90-7 | C6H5Cl | 详情 | 详情 |
| (XVIII) | 49494 | [4-(bromomethyl)-2,6-dichlorophenyl](4-chlorophenyl)methanone | C14H8BrCl3O | 详情 | 详情 | |
| (XIX) | 49495 | 5-amino-1H-1,2,3-triazole-4-carboxamide | C3H5N5O | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(V)4-Chloro-alpha-methylbenzhydrol (I) is alkylated with N-(2-chloroethyl)hexamethyleneimine (II) in benzene in the presence of sodium amide to give setastine. The starting products are obtained as follows; Caprolactame (III) is O-alkylated with dimethyl sulfate to yield the lactimether (IV), which is reduced with sodium borohydride to hexamethyleneimine (II). Friedel Cratts acylation of chlorobenzene (V) with benzoyl chloride (VI) affords the benzophenone (VII), to which methylmagnesium bromide is added to give the carbinol (I).
| 【1】 Rakoczi, J.; Bolla, K.; Beck, I.; Porszasz, K. (Egis Pharmaceuticals Ltd.); New benzhydryloxy-alkylamine derivs. and process f. DE 2528194; GB 1463038 . |
| 【2】 Nogradi, M.; Setastine hydrochloride. Drugs Fut 1987, 12, 4, 357. |
| 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) | 22917 | 1-(4-chlorophenyl)-1-phenyl-1-ethanol | C14H13ClO | 详情 | 详情 | |
| (II) | 22918 | 1-(2-chloroethyl)azepane | C8H16ClN | 详情 | 详情 | |
| (III) | 22919 | 2-azepanone | 105-60-2 | C6H11NO | 详情 | 详情 |
| (IV) | 22920 | 7-methoxy-3,4,5,6-tetrahydro-2H-azepine; methyl 3,4,5,6-tetrahydro-2H-azepin-7-yl ether | 2525-16-8 | C7H13NO | 详情 | 详情 |
| (V) | 10190 | 1-Chlorobenzene | 108-90-7 | C6H5Cl | 详情 | 详情 |
| (VI) | 10463 | Benzoyl chloride | 98-88-4 | C7H5ClO | 详情 | 详情 |
| (VII) | 22923 | (4-chlorophenyl)(phenyl)methanone; 4-Chlorobenzophenone | 134-85-0 | C13H9ClO | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)Friedel-Crafts acylation of chlorobenzene (I) with levulinic acid chloride (II) afforded diketone (III), which was converted to pyrrole (V) by condensation with 4-chloroaniline (IV) in the presence of a catalytic amount of HBr. Mannich reaction of (V) with formaldehyde and N-methylpiperazine (VI) then provided the target aminomethyl pyrrole.
| 【1】 Retico, A.; Cerreto, F.; Scalzo, M.; Villa, A.; Studies on anti-Candida agents with a pyrrole moiety. Synthesis and microbiological activity of some 3-aminomethyl-1,5-diaryl-2-methyl-pyrrole derivatives. Eur J Med Chem 1992, 27, 7, 701. |
| 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) | 10190 | 1-Chlorobenzene | 108-90-7 | C6H5Cl | 详情 | 详情 |
| (II) | 28526 | 4-oxopentanoyl chloride | C5H7ClO2 | 详情 | 详情 | |
| (III) | 28527 | 1-(4-chlorophenyl)-1,4-pentanedione | C11H11ClO2 | 详情 | 详情 | |
| (IV) | 12034 | 4-Chlorophenylamine; 4-Chloroaniline; p-Chloroaniline | 106-47-8 | C6H6ClN | 详情 | 详情 |
| (V) | 28528 | 1,2-bis(4-chlorophenyl)-5-methyl-1H-pyrrole | C17H13Cl2N | 详情 | 详情 | |
| (VI) | 10061 | 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine | 109-01-3 | C5H12N2 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(VIII)Friedel-Crafts acylation of chlorobenzene (VIII) with 8-bromooctanoyl chloride (IX) in the presence of AlCl3 gave rise to bromo ketone (X). Finally, alkylation of thiouracil (VII) with bromoketone (X) generated the title compound.
| 【1】 Hickey, D.M.B.; Boyd, H.F.; Flynn, S.T.; et al.; 2-(Alkylthio)pyrimidin-4-ones as novel, reversible inhibitors of lipoprotein-associated phospholipase A2. Bioorg Med Chem Lett 2000, 10, 4, 395. |
| 【2】 Pinto, I.L.; Ife, R.J.; Hickey, D.M.B.; Smith, S.A.; Leach, C.A.; Porter, R.A. (SmithKline Beecham plc); Pyrimidinone cpds. and pharmaceutical compsns. containing them. EP 1028955; WO 9924420 . |
合成路线6
该中间体在本合成路线中的序号：(XIII)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 |