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【结 构 式】 
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【分子编号】17986 【品名】7-oxabicyclo[4.1.0]heptane; cyclohexene oxide 【CA登记号】286-20-4 |
【 分 子 式 】C6H10O 【 分 子 量 】98.1448 【元素组成】C 73.43% H 10.27% O 16.3% |
合成路线1
该中间体在本合成路线中的序号：(XI)The hydrolysis of 1-benzyl-4-(methylamino)piperidine-4-carboxamide (I) with refluxing concentrated aqueous HCl gives the corresponding free acid (II), which is debenzylated with H2 over Pd/C in basic medium yielding 4-(methylamino)piperidine-4-carboxylic acid sodium salt (III). The protection of (III) with benzyl chloroformate (IV) in basic THF - water affords 1-(benzyloxycarbonyl)-4-(methylamino)piperidine 4 carboxylic acid (V), which by cyclization with phosgene in dioxane is converted to benzyl 1-methyl-2,4-dioxo 3-oxa-1,8-diazaspiro[4.5]decane-8 carboxylate (VI). The reaction of (VI) with 2,6-dimethylaniline (II) by heating at 160 C gives benzyl 4-(2,6-dimethylphenylaminocarbonyl)-4-(methylamino)piperidine-1-carboxylate (VIII), which is methylated with refluxing methyl iodide to the corresponding dimethylamino compound (IX). The deprotection of (IX) with H2 over Pd/C in methanol yields 4-(dimethylamino)-N-(2,6-dimethylphenyl)piperidine-4-carboxamide (X), which is finally condensed with 1,2-epoxycyclohexane (XI) in refluxing ethanol.
| 【1】 De Bruyn, M.F.L.; Van Daele, G.H.P.; Verdonck, M.G.C. (Janssen Pharmaceutica NV); N-Aryl-alpha-aminocarboxamide derivs.. EP 0121972; ES 8506615 . |
| 【2】 Castaner, J.; Prous, J.; Transcainidine. Drugs Fut 1988, 13, 3, 239. |
| 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) | 22019 | 1-benzyl-4-(methylamino)-4-piperidinecarboxamide | 1024-11-9 | C14H21N3O | 详情 | 详情 |
| (II) | 22020 | 1-benzyl-4-(methylamino)-4-piperidinecarboxylic acid | C14H20N2O2 | 详情 | 详情 | |
| (III) | 22021 | sodium 4-(methylamino)-4-piperidinecarboxylate | C7H13N2NaO2 | 详情 | 详情 | |
| (IV) | 10101 | Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene | 501-53-1 | C8H7ClO2 | 详情 | 详情 |
| (V) | 22023 | 1-[(benzyloxy)carbonyl]-4-(methylamino)-4-piperidinecarboxylic acid | C15H20N2O4 | 详情 | 详情 | |
| (VI) | 22024 | benzyl 1-methyl-2,4-dioxo-3-oxa-1,8-diazaspiro[4.5]decane-8-carboxylate | C16H18N2O5 | 详情 | 详情 | |
| (VII) | 17527 | 2,6-Xylidine; 2,6-Dimethylaniline; 2,6-Dimethylphenylamine | 87-62-7 | C8H11N | 详情 | 详情 |
| (VIII) | 22026 | benzyl 4-[(2,6-dimethylanilino)carbonyl]-4-(methylamino)-1-piperidinecarboxylate | C23H29N3O3 | 详情 | 详情 | |
| (IX) | 22027 | benzyl 4-(dimethylamino)-4-[(2,6-dimethylanilino)carbonyl]-1-piperidinecarboxylate | C24H31N3O3 | 详情 | 详情 | |
| (X) | 22028 | 4-(dimethylamino)-N-(2,6-dimethylphenyl)-4-piperidinecarboxamide | C16H25N3O | 详情 | 详情 | |
| (XI) | 17986 | 7-oxabicyclo[4.1.0]heptane; cyclohexene oxide | 286-20-4 | C6H10O | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XXI)Addition of phenylmagnesium bromide to cyclohexene oxide (XXI) in the presence of CuCl gave trans-2-phenylcyclohexanol (XXII), which was further esterified with chloroacetyl chloride to afford 2-phenylcyclohexyl chloroacetate (XXIII). Enantioselective hydrolysis of the racemic ester (XXIII) by means of Pseudomonas fluorescens lipase provided pure (1R,2S)-2-phenylcyclohexanol (XXIV), which was again esterified with chloroacetyl chloride, yielding the chiral ester (XXVI). Darzen's condensation of chloro ester (XXVI) with anisaldehyde (X) led to the chiral glycidic ester (XXVII). Epoxide ring opening in (XXVII) with 2-aminothiophenol (VII) furnished amino ester (XXVIII). Intermediate thiazepinone (VIII) was then obtained by cyclization of (XXVIII) using p-toluenesulfonic acid in refluxing xylene. Alternatively, amino ester (XXVIII) was first hydrolyzed to amino acid (XXIX), which was subsequently cyclized with p-toluenesulfonic acid as above (11). The final cyclization of amino acid (XXIX) to the intermediate thiazepinone (VIII) has also been carried out in the presence of trichloroacetic acid
| 【1】 Plaum, M.J.M.; Boesten, W.H.J.; Process for the preparation of a benzothiazepine. EP 0796853; JP 1998007667; US 5859241 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (+/-)-(XXII) | 51208 | (1R,2S)-2-phenylcyclohexanol | C12H16O | 详情 | 详情 | |
| (+/-)-(XXIII) | 62445 | (1S,2R)-2-phenylcyclohexyl 2-chloroacetate | C14H17ClO2 | 详情 | 详情 | |
| (VII) | 25182 | 2-aminobenzenethiol | 137-07-5 | C6H7NS | 详情 | 详情 |
| (VIII) | 62436 | (2S,3S)-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one | C16H15NO3S | 详情 | 详情 | |
| (X) | 27251 | 4-methoxybenzaldehyde; Anisicaldehyde; p-anisaldehyde | 123-11-5 | C8H8O2 | 详情 | 详情 |
| (XXI) | 17986 | 7-oxabicyclo[4.1.0]heptane; cyclohexene oxide | 286-20-4 | C6H10O | 详情 | 详情 |
| (XXIV) | 10492 | (1S,2R)-(+)-trans-2-Phenyl-1-cyclohexanol; (1S,2R)-2-Phenylcyclohexanol | 2362-61-0 | C12H16O | 详情 | 详情 |
| (XXV) | 62445 | (1S,2R)-2-phenylcyclohexyl 2-chloroacetate | C14H17ClO2 | 详情 | 详情 | |
| (XXVI) | 62445 | (1S,2R)-2-phenylcyclohexyl 2-chloroacetate | C14H17ClO2 | 详情 | 详情 | |
| (XXVII) | 62446 | (1R,2S)-2-phenylcyclohexyl (2R,3S)-3-(4-methoxyphenyl)-2-oxiranecarboxylate | C22H24O4 | 详情 | 详情 | |
| (XXVIII) | 62447 | (1R,2S)-2-phenylcyclohexyl (2S,3S)-3-[(2-aminophenyl)sulfanyl]-2-hydroxy-3-(4-methoxyphenyl)propanoate | C28H31NO4S | 详情 | 详情 | |
| (XXIX) | 62448 | (2S,3S)-3-[(2-aminophenyl)sulfanyl]-2-hydroxy-3-(4-methoxyphenyl)propanoic acid | C16H17NO4S | 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 condensation of cyclohexene-epoxide (I) with pyrrolidine (II) gives trans-2-(1-pyrrolidinyl)cyclohexanol (III), which by reaction with NaH and methanesulfonyl chloride, and then with benzylamine is converted into trans-2-(1-pyrrolidinyl)-N-benzylcyclohexylamine (IV). The debenzylation of (IV) by hydrogenolysis with H2 over Pd/C affords trans-2-(1-pyrrolidinyl)cyclohexylamine (V), which is formylated with ethyl formate to the corresponding N-formyl-trans-2-(1-pyrrolidinyl)cyclohexylamine (VI). The reduction of (VI) with LiAlH4 in refluxing ether gives trans-N-methyl-2-(1-pyrrolidinyl)cyclohexylamine (VII), which is finally condensed with 3,4-dichlorophenylacetic acid (VIII) by means of carbonyl diimidazole (IX) in THF.
| 【1】 Blancafort, P.; Castaner, J.; Serradell, M.N.; U-50488. Drugs Fut 1982, 7, 6, 416. |
| 【2】 Szmuszkovicz, J.; 2-Aminocycloaliphatic amide compounds. DE 2749950; ES 463876; FR 2370723; GB 1569225; JP 53063351; JP 61233654; US 4145435 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 |
| (B) | 16602 | ethyl formate | 109-94-4 | C3H6O2 | 详情 | 详情 |
| (I) | 17986 | 7-oxabicyclo[4.1.0]heptane; cyclohexene oxide | 286-20-4 | C6H10O | 详情 | 详情 |
| (II) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 |
| (III) | 14637 | (1R,2R)-2-(1-pyrrolidinyl)cyclohexanol | C10H19NO | 详情 | 详情 | |
| (IV) | 37038 | N-phenyl-N-[(1R,2R)-2-(1-pyrrolidinyl)cyclohexyl]amine; N-[(1R,2R)-2-(1-pyrrolidinyl)cyclohexyl]aniline | C16H24N2 | 详情 | 详情 | |
| (V) | 37040 | (1R,2R)-2-(1-pyrrolidinyl)cyclohexylamine; (1R,2R)-2-(1-pyrrolidinyl)cyclohexanamine | C10H20N2 | 详情 | 详情 | |
| (VI) | 37011 | 1-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-quinoxalinyl)-2-propen-1-one | C15H20N2O | 详情 | 详情 | |
| (VII) | 31357 | N-methyl-N-[(1R,2R)-2-(1-pyrrolidinyl)cyclohexyl]amine; (1R,2R)-N-methyl-2-(1-pyrrolidinyl)cyclohexanamine | C11H22N2 | 详情 | 详情 | |
| (VIII) | 30414 | 2-(3,4-dichlorophenyl)acetic acid；2-(3,4-Dichlorophenyl)acetic acid | 5807-30-7 | C8H6Cl2O2 | 详情 | 详情 |
| (IX) | 11353 | 1,1'-Carbonyldiimidazole; Di(1H-imidazol-1-yl)methanone; N,N-Carbonyldiimidazole; 1,1'-Carbonylbis(1H-imidazole) | 530-62-1 | C7H6N4O | 详情 | 详情 |
| (X) | 37039 | 7-azabicyclo[4.1.0]heptane | C6H11N | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(III)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5
该中间体在本合成路线中的序号：(I)Ring opening of cyclohexene oxide (I) with aqueous methylamine gave trans 2-(methylamino)cyclohexanol (II), which was further cyclized to the aziridine (III) upon treatment with chlorosulfonic acid and then with NaOH. Subsequent condensation of (III) with pyrrolidine (IV) yielded the racemic trans diamine (V). Resolution was achieved by fractional crystallization of the 2,3-di-p-toluoyl-D-tartaric acid salt in MeOH. The required (-)-(R,R) enantiomer was finally coupled with 4-benzothiopheneacetyl chloride (VI) to provide the corresponding amide.
| 【1】 MacLeod, B.A.; Walker, M.J.A.; Wall, R.A. (University of British Columbia); Aminocyclohexylamides for antiarrhythmic and anaesthetic uses. EP 0632806; JP 1995505151; US 5506257; WO 9319056 . |
| 【2】 Bain, A.I. (Nortran Pharmaceuticals Inc.); Mixtures of enantiomers of aminocyclohexylamides to produce simultaneous analgesia with local anaesthesia or antiarrhythmia. WO 9916431 . |
| 【3】 Halfpenny, P.R.; Schofield, D.; Hughes, J.; Rees, D.C.; Jarvis, T.C.; Hill, R.G.; Horwell, D.C.; Clark, C.R.; Highly selective kappa opioid analgesics. Synthesis and structure-activity relationships of novel N-[(2-aminocyclohexyl)aryl]acetamide and N-[(2-aminocyclohexyl)aryloxy]acetamide derivatives. J Med Chem 1988, 31, 4, 831. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 11021 | Methanamine; Methylamine | 74-89-5 | CH5N | 详情 | 详情 | |
| (+)-(V) | 11051 | (1S,2S)-N-Methyl-2-(1-pyrrolidinyl)cyclohexanamine; N-Methyl-N-[(1S,2S)-2-(1-pyrrolidinyl)cyclohexyl]amine | C11H22N2 | 详情 | 详情 | |
| (-)-(V) | 31357 | N-methyl-N-[(1R,2R)-2-(1-pyrrolidinyl)cyclohexyl]amine; (1R,2R)-N-methyl-2-(1-pyrrolidinyl)cyclohexanamine | C11H22N2 | 详情 | 详情 | |
| (I) | 17986 | 7-oxabicyclo[4.1.0]heptane; cyclohexene oxide | 286-20-4 | C6H10O | 详情 | 详情 |
| (II) | 31355 | (1R,2R)-2-(methylamino)cyclohexanol | C7H15NO | 详情 | 详情 | |
| (III) | 31356 | 7-methyl-7-azabicyclo[4.1.0]heptane | C7H13N | 详情 | 详情 | |
| (IV) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 |
| (VI) | 11050 | 2-(1-Benzothiophen-4-yl)acetyl chloride | C10H7ClOS | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(VII)OP C-33509 has been obtained by coupling imidazolecarboxamide (VI) with amine (IX) in refluxing CHCl3. The intermediates (VI) and (IX) have been obtained as follows: 1) Alkylation of 6-hydroxycarbostyril (I) with N-(3-bromopropyl)- phthalimide (II) in the presence of K2CO3 in DMF furnished the phthalimidopropyl ether (III). Subsequent hydrazinolysis of the phthalimide in refluxing EtOH provided the primary amine (IV). Then, the imidazolecarboxamide (VI) was obtained by treating amine (IV) with 1,1'-carbonyldiimidazole (V) and two equivalents of imidazole in DMSO. 2) Ring opening of 1,2 epoxycyclohexane (VII) with cyclopropylamine (VIII) gave the racemic trans aminoalcohol. Resolution of enantiomers (IX) and (X) was accomplished by esterification with (S)-mandelic acid (XI), followed by chromatographic separation of the diastereomeric esters. Hydrolysis of the desired ester (XII) then provided optically pure aminoalcohol (IX). Finally, the target urea derivative was obtained by coupling imidazolyl urea (VI) with amine (IX) in refluxing chloroform.
| 【1】 Koga, Y.; Kihara, Y.; Okada, M.; Inoue, Y.; Tochizawa, S.; Toga, K.; Tachibana, K.; Kimura, Y.; Nishi, T.; Hidaka, H.; 2(1H)- Quinoline derivatives as novel anti-arteriostenotic agents showing anti-thrombotic and anti-hyperplastic activities. Bioorg Med Chem Lett 1998, 8, 12, 1471. |
| 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) | 13913 | 6-Hydroxy-2(1H)-quinolinone | C9H7NO2 | 详情 | 详情 | |
| (II) | 15216 | N-(3-Bromopropyl)phthalimide; 2-(3-bromopropyl)-1H-isoindole-1,3(2H)-dione | 5460-29-7 | C11H10BrNO2 | 详情 | 详情 |
| (III) | 18912 | 2-[3-[(2-oxo-1,2-dihydro-6-quinolinyl)oxy]propyl]-1H-isoindole-1,3(2H)-dione | C20H16N2O4 | 详情 | 详情 | |
| (IV) | 18913 | 6-(3-aminopropoxy)-2(1H)-quinolinone | C12H14N2O2 | 详情 | 详情 | |
| (V) | 11353 | 1,1'-Carbonyldiimidazole; Di(1H-imidazol-1-yl)methanone; N,N-Carbonyldiimidazole; 1,1'-Carbonylbis(1H-imidazole) | 530-62-1 | C7H6N4O | 详情 | 详情 |
| (VI) | 18915 | N-[3-[(2-oxo-1,2-dihydro-6-quinolinyl)oxy]propyl]-1H-imidazole-1-carboxamide | C16H16N4O3 | 详情 | 详情 | |
| (VII) | 17986 | 7-oxabicyclo[4.1.0]heptane; cyclohexene oxide | 286-20-4 | C6H10O | 详情 | 详情 |
| (VIII) | 12263 | Cyclopropylamine; Cyclopropanamine | 765-30-0 | C3H7N | 详情 | 详情 |
| (IX) | 18918 | (1R,2R)-2-(cyclopropylamino)cyclohexanol | C9H17NO | 详情 | 详情 | |
| (X) | 18919 | (1S,2S)-2-(cyclopropylamino)cyclohexanol | C9H17NO | 详情 | 详情 | |
| (XI) | 12563 | (2S)-2-Hydroxy-2-phenylethanoic acid; S-(+)-Mandelic acid | 17199-29-0 | C8H8O3 | 详情 | 详情 |
| (XII) | 18921 | (1R,2R)-2-(cyclopropylamino)cyclohexyl (2S)-2-hydroxy-2-phenylethanoate | C17H23NO3 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(I)Opening of cyclohexene oxide (I) with pyrrolidine (II) in aqueous K2CO3 yielded the racemic trans-2-(1-pyrrolidinyl)cyclohexanol (III). Subsequent Mitsunobu coupling of (III) with phenol (IV) in the presence of DEAD and PPh3 produced ether (V). The intermediate acid chloride (VI) was then prepared by ester hydrolysis, followed by treatment with SOCl2.
| 【1】 McCowan, J.R.; Sall, D.J.; Gifford-Moore, D.S.; Takeuchi, K.; Denney, M.L.; Kohn, T.J.; Smith, G.F.; Dibasic benzo[b]thiophene derivatives as a novel class of active site directed thrombin inhibitors: 4. SAR studies on the conformationally restricted C3-side chain of hydroxybenzo[b]thiophenes. Bioorg Med Chem Lett 1999, 9, 5, 759. |
| 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) | 17986 | 7-oxabicyclo[4.1.0]heptane; cyclohexene oxide | 286-20-4 | C6H10O | 详情 | 详情 |
| (II) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 |
| (III) | 14637 | (1R,2R)-2-(1-pyrrolidinyl)cyclohexanol | C10H19NO | 详情 | 详情 | |
| (IV) | 29176 | methyl 4-hydroxy-3-methoxybenzoate | 3943-74-6 | C9H10O4 | 详情 | 详情 |
| (V) | 29177 | methyl 3-methoxy-4-[[(1R,2R)-2-(1-pyrrolidinyl)cyclohexyl]oxy]benzoate | C19H27NO4 | 详情 | 详情 | |
| (VI) | 29178 | 3-methoxy-4-[[(1R,2R)-2-(1-pyrrolidinyl)cyclohexyl]oxy]benzoyl chloride | C18H24ClNO3 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(I)Ring opening of cyclohexene oxide (I) with phenylmagnesium bromide in the presence of CuI, followed by acetylation of the resulting alcohol (II) gave the racemic trans-2-phenylcyclohexyl acetate (III). Enzymatic resolution of (III) using porcine liver acetone powder yielded the desired (-)-alcohol (II) along with unreacted (+)-acetate (III). Condensation of the sodium alkoxide of benzyl alcohol with bromoacetic acid (IV) afforded benzyloxyacetic acid (V), which was then coupled with the chiral alcohol (-)-(II) to give ester (VI). Hydrogenolysis of the O-benzyl group of (VI), followed by silylation of the resulting hydroxyacetate ester (VII) with triisopropylsilyl chloride, furnished (VIII). Imine (XI) was prepared by condensation of 3-methyl-2-butenal (IX) with p-anisidine (X). The asymmetric cyclocondensation reaction of the lithium enolate derived from ester (VIII) with imine (XI) yielded the chiral beta-lactam (XII). Oxidative removal of the p-methoxyphenyl protecting group of (XII) and then reprotection of the lactam N atom with Boc2O furnished the intermediate N-Boc lactam (XIII).
| 【1】 Strum, M.; Tynebor, R.; Pera, P.; Bernacki, R.J.; Ojima, I.; Synthesis and SAR of advanced second generation taxoids. 221st ACS Natl Meet (April 1 2001, San Diego) 2001, Abst MEDI 132. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (rac)-(III) | 51206 | (1R,2S)-2-phenylcyclohexyl acetate | C14H18O2 | 详情 | 详情 | |
| (rac)-(II) | 51208 | (1R,2S)-2-phenylcyclohexanol | C12H16O | 详情 | 详情 | |
| (-)-(II) | 51209 | (-)-(1R,2S)-2-phenylcyclohexanol | C12H16O | 详情 | 详情 | |
| (+)-(III) | 51210 | (1S,2R)-2-phenylcyclohexyl acetate | C14H18O2 | 详情 | 详情 | |
| (I) | 17986 | 7-oxabicyclo[4.1.0]heptane; cyclohexene oxide | 286-20-4 | C6H10O | 详情 | 详情 |
| (IV) | 23660 | 2-Bromoacetic acid | 79-08-3 | C2H3BrO2 | 详情 | 详情 |
| (V) | 51207 | 2-(benzyloxy)acetic acid | C9H10O3 | 详情 | 详情 | |
| (VI) | 51211 | (1R,2S)-2-phenylcyclohexyl 2-(benzyloxy)acetate | C21H24O3 | 详情 | 详情 | |
| (VII) | 51212 | (1R,2S)-2-phenylcyclohexyl 2-hydroxyacetate | C14H18O3 | 详情 | 详情 | |
| (VIII) | 19151 | (1R,2S)-2-phenylcyclohexyl 2-[(triisopropylsilyl)oxy]acetate | C23H38O3Si | 详情 | 详情 | |
| (IX) | 19152 | 3-methyl-2-butenal | 107-86-8 | C5H8O | 详情 | 详情 |
| (X) | 10478 | p-Anisidine; 4-Methoxyaniline; 4-Methoxyphenylamine | 104-94-9 | C7H9NO | 详情 | 详情 |
| (XI) | 19154 | 4-methoxy-N-[(E)-3-methyl-2-butenylidene]aniline; N-(4-methoxyphenyl)-N-[(E)-3-methyl-2-butenylidene]amine | C12H15NO | 详情 | 详情 | |
| (XII) | 19155 | (3R,4S)-1-(4-methoxyphenyl)-4-(2-methyl-1-propenyl)-3-[(triisopropylsilyl)oxy]-2-azetidinone | C23H37NO3Si | 详情 | 详情 | |
| (XIII) | 19157 | tert-butyl (2S,3R)-2-(2-methyl-1-propenyl)-4-oxo-3-[(triisopropylsilyl)oxy]-1-azetidinecarboxylate | C21H39NO4Si | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(XXXI)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10
该中间体在本合成路线中的序号：(XXXI)The pyrrolidine building blocks are in turn synthesized as shown in Scheme 5. 3(R)-Hydroxypyrrolidine (IV) is protected as the N-Boc derivative (LIV), followed by O-alkylation with benzyl bromide and acidic deprotection of the resulting benzyl ether (LV) to furnish 3(R)-benzyloxypyrrolidine (II). Condensation of pyrrolidine (II) with cyclohexene oxide (XXXI) gives the trans-pyrrolidinocyclohexanol (LVI) as a diastereomeric mixture, which is separated either by crystallization with di-p-toluoyl-L-tartaric acid (DTTA) or by diastereoselective N-oxidation of the undesired diastereoisomer to furnish the target isomer (IX). Alternatively, intermediate (IX) can be obtained by ring opening of epoxide (XXXI) with pyrrolidine (II) in the presence of chiral catalysts. In a different strategy, enantioselective ring opening of cyclohexene oxide (XXXI) with B-bromodiisopinocamphenylborane provides the optically enriched trans-bromohydrin (LVII), which is then condensed with benzyloxypyrrolidine (II) to yield the (1S,2R)-pyrrolidinocyclohexanol (LVIII). Inversion of the configuration of alcohol (LVIII) to produce (IX) is then accomplished by Mitsunobu coupling with formic acid, followed by acidic hydrolysis of the resulting (1R,2R)-formate ester (LIX). Further synthetic strategies leading to the pyrrolidinocyclohexanol (IX) involve cyclization of (R,R)-2-aminocyclohexanol (LX) with 2(R)-benzyloxy-1,4-butanediol ditosylate (LXI), and condensation of (LX) with cyclohexanone (XXVI), followed by asymmetric hydroboration and oxidative work-up of the resulting enamine (LXII) (2). Alternatively, (R,R)-2-aminocyclohexanol (LX) can be converted to the intermediate acetoxysuccinimide (XII) by condensation with 2(R)-acetoxysuccinic anhydride (VI) (prepared from L-malic acid [LXIII] and acetyl chloride) to produce a regioisomeric mixture of succinamic acids (LXIVa) and (LXIVb), which undergoes cyclization to imide (XII) upon heating with acetyl chloride (4). Similarly, racemic trans-2-benzyloxycyclohexylamine (LXV) is resolved by enantioselective N-acylation with isopropyl methoxyacetate in the presence of lipase, followed by hydrolysis of the resulting (R,R)-methoxyacetamide (LXVI) to provide (LXVII) (5). Acylation of (R,R)-2-benzyloxycyclohexylamine (LXVII) with O-acetylmalic anhydride (VI), followed by cyclization with acetyl chloride, yields the N-(2-benzyloxycyclohexyl)succinimide (LXVIII), which is then debenzylated to (XII) by catalytic hydrogenation over Pd/C (4). Scheme 5.
| 【2】 Plouvier, B.M.C., Chou, D.T.H., Jung, G. et al. (Cardiome Pharma Corp.). Synthetic process for aminocyclohexyl ether compounds. WO 2006088525. |
| 【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. |
| 【5】 Balkenhohl, F., Ditrich, K., Nübling, C. (BASF AG). Racemate separation of primary and secondary heteroatom-substituted amine by enzyme-catalysed acylation. WO 9623894. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (LXIVa) | 65319 | C12H19NO6 | 详情 | 详情 | ||
| (LXIVb) | 65320 | C12H19NO6 | 详情 | 详情 | ||
| (II) | 65264 | (3R)-benzyloxypyrrolidine | C11H15NO | 详情 | 详情 | |
| (IV) | 14490 | (3R)tetrahydro-1H-pyrrol-3-ol; R-3-hydroxypyrrolidine | 2799-21-5 | C4H9NO | 详情 | 详情 |
| (VI) | 65267 | (2R)-acetoxysuccinic anhydride | 79814-40-7 | C6H6O5 | 详情 | 详情 |
| (VI) | 51236 | 2,4-Dimethylpyrrole | 625-82-1 | C6H9N | 详情 | 详情 |
| (IX) | 65271 | (2R)-[(3R)-benzyloxy-1-pyrrolidinyl]cyclohexan-(1R)-ol | C16H25NO2 | 详情 | 详情 | |
| (XII) | 65273 | (2R)-acetoxy-N-[(2R)-hydroxy-(1R)-cyclohexyl]succinimide | C12H17O5 | 详情 | 详情 | |
| (XXVI) | 11059 | Cyclohexanone | 108-94-1 | C6H10O | 详情 | 详情 |
| (XXXI) | 17986 | 7-oxabicyclo[4.1.0]heptane; cyclohexene oxide | 286-20-4 | C6H10O | 详情 | 详情 |
| (LIV) | 65310 | (R )-1-Boc-3-hydroxypyrrolidine; (R )-N-(tert-Butoxycarbonyl)-3-hydroxypyrrolidine; (R )-3-Hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester | 103057-44-9 | C9H17O3N | 详情 | 详情 |
| (LV) | 65311 | C16H23O3N | 详情 | 详情 | ||
| (LVI) | 65312 | C17H25NO2 | 详情 | 详情 | ||
| (LVII) | 65313 | trans-2-bromocyclohexanol | C6H11BrO | 详情 | 详情 | |
| (LVIII) | 65314 | C17H24NO2 | 详情 | 详情 | ||
| (LIX) | 65315 | C18H25NO3 | 详情 | 详情 | ||
| (LX) | 65316 | (1R,2R)-2-aminocyclohexanol | C6H13NO | 详情 | 详情 | |
| (LXI) | 65317 | C25H28O7S2 | 详情 | 详情 | ||
| (LXII) | 65318 | C17H23NO | 详情 | 详情 | ||
| (LXIII) | 11058 | (S)-(+)-Hydroxysuccinic acid; (S)-(+)-Malic acid; (S)-(+)-2-Hydroxybutanedioic acid; L-(-)-Apple acid | 97-67-6 | C4H6O5 | 详情 | 详情 |
| (LXV) | 65321 | racemic trans-2-benzyloxycyclohexylamine | C13H17NO | 详情 | 详情 | |
| (LXVI) | 65322 | C16H23NO3 | 详情 | 详情 | ||
| (LXVII) | 65323 | C13H19NO | 详情 | 详情 | ||
| (LXVIII) | 65324 | C19H23NO5 | 详情 | 详情 |