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【结 构 式】 
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【分子编号】14376 【品名】(2R)-2-amino-2-phenyl-1-ethanol; (R)-(-)-2-phenylglycinol; (R)-2-amino-2-phenyl-1-ethanol 【CA登记号】56613-80-0 |
【 分 子 式 】C8H11NO 【 分 子 量 】137.18148 【元素组成】C 70.04% H 8.08% N 10.21% O 11.66% |
合成路线1
该中间体在本合成路线中的序号：(V)1) The cyclization of ketene diethylketal (I) with diethyl fumarate (II) in hot tert-butanol gives trans-3,3-diethoxycyclobutane-1,2-dicarboxylic acid diethyl ester (III), which is saponified with KOH in hot methanol to the corresponding racemic diacid (IV). The condensation of (IV) with (R)-(-)-2-phenylglycinol (V) by means of dicyclohexylcarbodiimide (DCC) in dichloromethane followed by fractionated crystallization of the resulting diastereomeric mixture yields the diamide (VI). The hydrolytic reduction of (VI) by sequential treatments with trimethylsilyl chloride and imidazole, dinitrogen tetraoxide and finally with LiBH4 affords (S,S)-trans-3,3-diethoxycyclobutane-1,2-dimethanol (VII), which is benzoylated with benzoyl chloride in pyridine to the dibenzoate (VIII). The cleavage of the ketal group of (VIII) with H2SO4 in acetonitrile gives the cyclobutanone (IX), which is reduced with LS-Selectride in THF yielding [1S-(1alpha,2beta,3beta)]-3-hydroxycyclobutane-1,2-dimethanol 1,2-dibenzoate (X). The reaction of (X) with p-toluenesulfonyl chloride affords the corresponding tosylate (XI), which is condensed with 6-O-benzylguanidine (XII) by means of K2CO3 and 18-crown-6 in hot DMF giving [1R-(1alpha,2beta,3alpha)]-6-O-benzyl-9-[2,3-di(benzoyloxymethyl) cyclobutyl]guanine (XIII). Finally, this compound is treated with sodium methoxide in hot methanol. 2) The reaction of 6-chloropurine-2-amine (XIV) with 47% HI gives 6-iodopurine-2-amine (XV), which is condensed with [1S-(1alpha,2beta,3beta)]-3-(trifluoromethylsulfonyloxy)cyclobutane-1,2-dimethanol 1,2-dibenzoate (XVI) (obtained by treatment of the previously described cyclobutanol [X] with trifluromethanesulfonyl anhydride [Tf2O]) by means of benzyltriethylammonium hydroxide and pyridine in dichloromethane to afford the condensed iodopurine (XVII). The reaction of (XVII) with sodium methoxide hydrolyzes the benzoyl groups affording the 6-O-methylguanine derivative (XVIII), which is finally treated with aqueous HCl at 95 C.
| 【1】 Ireland, C.; Leeson, P.A.; Castaner, J.; Lobucavir. Drugs Fut 1997, 22, 4, 359. |
| 【2】 Bisacchi, G.S.; Singh, J.; Godfrey, J.D. Jr.; Kissick, T.P.; Mitt, T.; Malley, M.F.; Di Marco, J.D.; Gougoutas, J.Z.; Mueller, R.H.; Zahler, R.; Regioselective coupling of tetraalkylammonium salts of 6-iodo-2-aminopurine to a cyclobutyl triflate: Efficient preparation of homochiral BMS-180,194, a potent antiviral carbocyclic nucleoside. J Org Chem 1995, 60, 9, 2902-5. |
| 【3】 Singh, J.; Bisacchi, G.S.; Godfrey, J.D. Jr.; Mitt, T.; Mueller, R.H.; Zahler, R.; Kissick, T.P. (Bristol-Myers Squibb Co.); Process for preparing guanine-containing antiviral agents and purinyl salts useful in such process. EP 0579421 . |
| 【4】 Bisacchi, G.S.; Mitt, T. (Bristol-Myers Squibb Co.); Intermediates for an optically active cyclobutane nucleoside. US 5306837 . |
| 【5】 Bisacchi, G.S.; Braitman, A.; Cianci, C.W.; et al.; Synthesis and antiviral activity of enantiomeric forms of cyclobutyl nucleoside analogues. J Med Chem 1991, 34, 4, 1415-21. |
| 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) | 14372 | Ethene, 1,1-diethoxy-; 1-ethoxyvinyl ethyl ether; 1,1-diethoxyethylene | 2678-54-8 | C6H12O2 | 详情 | 详情 |
| (II) | 14373 | diethyl (E)-2-butenedioate; Diethyl Fumarate | 1520-50-9 | C8H12O4 | 详情 | 详情 |
| (III) | 14374 | diethyl (1S,2R)-3,3-diethoxy-1,2-cyclobutanedicarboxylate | C14H24O6 | 详情 | 详情 | |
| (IV) | 14375 | (1S,2R)-3,3-diethoxy-1,2-cyclobutanedicarboxylic acid | C10H16O6 | 详情 | 详情 | |
| (V) | 14376 | (2R)-2-amino-2-phenyl-1-ethanol; (R)-(-)-2-phenylglycinol; (R)-2-amino-2-phenyl-1-ethanol | 56613-80-0 | C8H11NO | 详情 | 详情 |
| (VI) | 14377 | (1S,2R)-3,3-diethoxy-N(2)-[(1R)-2-hydroxy-1-phenylethyl]-N(1)-[(1R)-2-methoxy-1-phenylethyl]-1,2-cyclobutanedicarboxamide | C27H36N2O6 | 详情 | 详情 | |
| (VII) | 14378 | [(1S,4S)-2,2-diethoxy-4-(hydroxymethyl)cyclobutyl]methanol | C10H20O4 | 详情 | 详情 | |
| (VIII) | 14379 | [(1S,4S)-4-[(benzoyloxy)methyl]-2,2-diethoxycyclobutyl]methyl benzoate | C24H28O6 | 详情 | 详情 | |
| (IX) | 14380 | [(1S,2S)-2-[(benzoyloxy)methyl]-4-oxocyclobutyl]methyl benzoate | C20H18O5 | 详情 | 详情 | |
| (X) | 14381 | [(1S,2S,4S)-2-[(benzoyloxy)methyl]-4-hydroxycyclobutyl]methyl benzoate | C20H20O5 | 详情 | 详情 | |
| (XI) | 14382 | ((1S,2S,3S)-2-[(benzoyloxy)methyl]-3-[[(4-methylphenyl)sulfonyl]oxy]cyclobutyl)methyl benzoate | C27H26O7S | 详情 | 详情 | |
| (XII) | 14383 | 6-(benzyloxy)-9H-purin-2-ylamine; 6-(benzyloxy)-9H-purin-2-amine | 19916-73-5 | C12H11N5O | 详情 | 详情 |
| (XIII) | 14384 | [(1S,2R,3R)-3-[2-amino-6-(benzyloxy)-9H-purin-9-yl]-2-[(benzoyloxy)methyl]cyclobutyl]methyl benzoate | C32H29N5O5 | 详情 | 详情 | |
| (XIV) | 11644 | 6-Chloro-9H-purin-2-amine; 6-Chloro-9H-purin-2-ylamine; 2-Amino-6-chloropurine | 10310-21-1 | C5H4ClN5 | 详情 | 详情 |
| (XV) | 14386 | 6-iodo-9H-purin-2-ylamine; 6-iodo-9H-purin-2-amine | C5H4IN5 | 详情 | 详情 | |
| (XVI) | 14387 | ((1S,2S,4S)-2-[(benzoyloxy)methyl]-4-[[(trifluoromethyl)sulfonyl]oxy]cyclobutyl)methyl benzoate | C21H19F3O7S | 详情 | 详情 | |
| (XVII) | 14388 | [(1R,2R,4S)-2-(2-amino-6-iodo-9H-purin-9-yl)-4-[(benzoyloxy)methyl]cyclobutyl]methyl benzoate | C25H22IN5O4 | 详情 | 详情 | |
| (XVIII) | 14389 | [(1R,2S,4R)-2-(hydroxymethyl)-4-(6-methoxy-9H-purin-9-yl)cyclobutyl]methanol | C12H16N4O3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：Terikalant, the (S)-enantiomer of RP 58866, was synthesized as follows: After hydrolysis of the ethyl ester (III) with NaOH in refluxing methanol, the corresponding acid (VIII) is converted into the acid chloride by refluxing in thionyl chloride. After removal of excess thionyl chloride, the residue is distilled off under reduced pressure to yield the carboxylic acid chloride (IX). Subsequent reaction of (IX) with (R)-(-)-phenylglycinol yields a mixture of the (SR)-3,4-dihydro-N-(2-hydroxy-1-phenethyl)-2H-1-benzopyran-4-acetamide (Xa) [m.p. 143 C; alpha(D) -43 (c 1.5, EtOH)] and (RR)-3,4-dihydro-N-(2-hydroxy-1-phenethyl)-2H-1-benzopyran-4-acetamide (Xb) [m.p. 140 C; alpha(D) -6.5 (c 1.5, EtOH)] diastereoisomers, which are separated by silica gel column chromatography using methylene chloride/ethanol (95/5) as eluent and subsequently hydrolyzed to give the two pure enatiomeric carboxylic acids: (S)-(XIa) [alpha(D) -18.5 (c 1.1, EtOH)], e.e. 99.3% determined by analytical HPLC on the amide derived from (R)-(-)-phenylglycinol, and (R)-(XIb) [alpha(D) +17.4 (c 1, EtOH)]; m.p. 77-8 C. Reduction of (XIa) with lithium aluminum hydride in tetrahydrofuran gives the alcohol (XII), which is converted into the bromide (XIII) and, subsequently, to (S)-1-[2-(3,4-dihydro-2H-1-benzopyran-4-yl)ethyl]-4-(3,4-dimethoxyphenyl)piperidine (E)-2-butenedioate (1:1) , analogously with the racemic compound described in scheme 16777901a. RP 62719 is recrystallized from isopropanol and the absolute configuration is obtained through single crystal x-ray analysis of the bromhydrate. The pure (R)-isomer, RP 62718, is obtained according to the same reaction scheme as that described for (XIa), but starting with (XIb).
| 【1】 Cavero, I.; Renault, C.; Hardy, J.-C.; Barreau, M.; Bouquerel, J.; Mestre, M.; Synthesis and biological evaluation of RP 62719, the active enantiomer of RP 58866, a pure class III antiarrhythmic agent. 11th Int Symp Med Chem (Sept 2-7, Jerusalem) 1990, 37. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 14376 | (2R)-2-amino-2-phenyl-1-ethanol; (R)-(-)-2-phenylglycinol; (R)-2-amino-2-phenyl-1-ethanol | 56613-80-0 | C8H11NO | 详情 | 详情 | |
| 23808 | Fumaric acid; (E)-2-butenedioic acid | 110-17-8 | C4H4O4 | 详情 | 详情 | |
| (Xb) | 14469 | 2-[(4S)-3,4-dihydro-2H-chromen-4-yl]-N-[(1R)-2-hydroxy-1-phenylethyl]acetamide | C19H21NO3 | 详情 | 详情 | |
| (Xa) | 14470 | 2-[(4R)-3,4-dihydro-2H-chromen-4-yl]-N-[(1R)-2-hydroxy-1-phenylethyl]acetamide | C19H21NO3 | 详情 | 详情 | |
| (XIb) | 14471 | 2-[(4S)-3,4-dihydro-2H-chromen-4-yl]acetic acid | C11H12O3 | 详情 | 详情 | |
| (XIa) | 14472 | 2-[(4R)-3,4-dihydro-2H-chromen-4-yl]acetic acid | C11H12O3 | 详情 | 详情 | |
| (III) | 14463 | ethyl 2-(3,4-dihydro-2H-chromen-4-yl)acetate | C13H16O3 | 详情 | 详情 | |
| (VI) | 14466 | 4-(3,4-dimethoxyphenyl)piperidine; 2-methoxy-4-(4-piperidinyl)phenyl methyl ether | C13H19NO2 | 详情 | 详情 | |
| (VIII) | 14467 | 2-(3,4-dihydro-2H-chromen-4-yl)acetic acid | C11H12O3 | 详情 | 详情 | |
| (IX) | 14468 | 2-(3,4-dihydro-2H-chromen-4-yl)acetyl chloride | C11H11ClO2 | 详情 | 详情 | |
| (XII) | 14473 | 2-[(4S)-3,4-dihydro-2H-chromen-4-yl]-1-ethanol | C11H14O2 | 详情 | 详情 | |
| (XIII) | 14474 | (4R)-4-(2-bromoethyl)-3,4-dihydro-2H-chromene | C11H13BrO | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)The reaction of 6-(4-phenylbutoxy)hexanol methanesulfonate (I) with (R)-phenylglycinol (II) by means of DIEA and NaI in hot acetonitrile gives the secondary amine (III), which is condensed with 2-(benzyloxy)-5-(2-bromoacetyl)benzoic acid methyl ester (IV) by means of DIEA in refluxing 1,2-dimethoxyethane to yield the tertiary amine (V). The enantioselective reduction of (V) with LiBH4 in refluxing dimethoxyethane affords the tetrahydroxy derivative (VI), which is finally debenzylated by hydrogenation with H2 over Pd/C in ethanol to provide the target aminoethanol derivative.
| 【1】 Evans, B. (GlaxoSmithKline plc); Phenethanolamine cpds.. AU 9163901; EP 0422889; JP 1991133946 . |
| 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) | 52354 | 6-[(4-phenylbutyl)oxy]hexyl methanesulfonate | C17H28O4S | 详情 | 详情 | |
| (II) | 14376 | (2R)-2-amino-2-phenyl-1-ethanol; (R)-(-)-2-phenylglycinol; (R)-2-amino-2-phenyl-1-ethanol | 56613-80-0 | C8H11NO | 详情 | 详情 |
| (III) | 52355 | 2-phenyl-2-({6-[(4-phenylbutyl)oxy]hexyl}amino)-1-ethanol | C24H35NO2 | 详情 | 详情 | |
| (IV) | 52356 | methyl 5-(2-bromoacetyl)-2-[(phenylmethyl)oxy]benzoate | C17H15BrO4 | 详情 | 详情 | |
| (V) | 52357 | methyl 5-[2-((2-hydroxy-1-phenylethyl){6-[(4-phenylbutyl)oxy]hexyl}amino)acetyl]-2-[(phenylmethyl)oxy]benzoate | C41H49NO6 | 详情 | 详情 | |
| (VI) | 52358 | (1R)-1-[4-(benzyloxy)-3-(hydroxymethyl)phenyl]-2-{[(1R)-2-hydroxy-1-phenylethyl][6-(4-phenylbutoxy)hexyl]amino}-1-ethanol | C40H51NO5 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XXIV)Preparation of the intermediate chiral amine (XVII) was reported by a number of synthetic strategies. Piperonal (X) was condensed with D-phenylglycinol (XXIV) to give imine (XXV). Diastereoselective addition of allylmagnesium chloride (XXVI) to imine (XXV) afforded amine (XXVII). Simultaneous hydrogenation of the double bond and hydrogenolysis of the chiral auxiliary of (XXVII) furnished the desired amine (XVII).
| 【1】 Storace, L.; et al.; An efficient large-scale process for the human leukocyte elastase inhibitor, DMP 777. Org Process Res Dev 2002, 6, 1, 54. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (X) | 10127 | 1,3-Benzodioxole-5-carbaldehyde; Heliotropine | 120-57-0 | C8H6O3 | 详情 | 详情 |
| (XVII) | 53631 | (1R)-1-(1,3-benzodioxol-5-yl)-1-butanamine; (1R)-1-(1,3-benzodioxol-5-yl)butylamine | n/a | C11H15NO2 | 详情 | 详情 |
| (XXIV) | 14376 | (2R)-2-amino-2-phenyl-1-ethanol; (R)-(-)-2-phenylglycinol; (R)-2-amino-2-phenyl-1-ethanol | 56613-80-0 | C8H11NO | 详情 | 详情 |
| (XXV) | 53637 | (2R)-2-{[(E)-1,3-benzodioxol-5-ylmethylidene]amino}-2-phenyl-1-ethanol | n/a | C16H15NO3 | 详情 | 详情 |
| (XXVI) | 53638 | allyl(chloro)magnesium | 2622-05-1 | C3H5ClMg | 详情 | 详情 |
| (XXVII) | 53639 | (2R)-2-{[(1R)-1-(1,3-benzodioxol-5-yl)-3-butenyl]amino}-2-phenyl-1-ethanol | n/a | C19H21NO3 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(X)Reaction of 4,6-dimethylpyridin-2-amine (I) with isoamyl nitrite and HCl gives 2-chloro-4,6-dimethylpyridine (II), which is treated with hydrazine in diethylene glycol at 140 C yielding 2-hydrazino-4,6-dimethylpyridine (III). Cyclization of (III) with cyclohexanone (IV) in refluxing diethylene glycol affords the tetrahydro-alpha-carboline (V), which is dehydrogenated with Pd in refluxing diethylene glycol, giving the alpha-carboline (VI). The alkylation of (VI) with the benzyl bromide (VII) by means of potassium tert-butoxide in DMF yields the adduct (VIII), which is hydrolyzed with concentrated H2SO4 to provide the carboxylic acid (IX). Finally, this acid is condensed with (R)-2-hydroxy-1-phenylethylamine (X) by means of HOBT and EDC in CH2Cl2, giving a diastereomeric mixture of the corresponding amides that is resolved by column chromatography. The benzyl bromide intermediate (VII) has been obtained as follows: Esterification of 2-(4-methylphenyl)acetic acid (XI) with tert-butanol and DCC and DMAP in CH2Cl2 gives the corresponding tert-butyl ester (XII), which is condensed with cyclopentyl bromide (XIII) by means of t-BuOK in DMF to yield racemic 2-cyclopentyl-2-(4-methylphenyl)acetic acid tert-butyl ester (XIV). Finally, this compound is brominated with NBS and AIBN in refluxing CCl4.
| 【1】 Castañer, J.; Silvestre, J.S.; Sorbera, L.A.; Martín, L.; Implitapide. Drugs Fut 2000, 25, 11, 1138. |
| 【2】 Muller, U.; Connell, R.; Goldmann, S.; Grutzmann, R.; Beuck, M.; Bischoff, H.; Denzer, D.; Domdey-Bette, A.; Wohlfeil, S. (Bayer AG); Cycloalkano-indole- and -azaindole derivs.. CA 2159546; DE 4435477; EP 0705831; JP 1996225526; US 5684014 . |
| 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) | 41793 | 4,6-dimethyl-2-pyridinamine; 4,6-dimethyl-2-pyridinylamine | 5407-87-4 | C7H10N2 | 详情 | 详情 |
| (II) | 41794 | 2-chloro-4,6-dimethylpyridine | 30838-93-8 | C7H8ClN | 详情 | 详情 |
| (III) | 41795 | 2-hydrazino-4,6-dimethylpyridine | C7H11N3 | 详情 | 详情 | |
| (IV) | 11059 | Cyclohexanone | 108-94-1 | C6H10O | 详情 | 详情 |
| (V) | 41796 | 2,4-dimethyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole | C13H16N2 | 详情 | 详情 | |
| (VI) | 41797 | 2,4-dimethyl-9H-pyrido[2,3-b]indole | C13H12N2 | 详情 | 详情 | |
| (VII) | 41798 | tert-butyl 2-[4-(bromomethyl)phenyl]-2-cyclopentylacetate | C18H25BrO2 | 详情 | 详情 | |
| (VIII) | 41799 | tert-butyl 2-cyclopentyl-2-[4-[(2,4-dimethyl-9H-pyrido[2,3-b]indol-9-yl)methyl]phenyl]acetate | C31H36N2O2 | 详情 | 详情 | |
| (IX) | 41800 | 2-cyclopentyl-2-[4-[(2,4-dimethyl-9H-pyrido[2,3-b]indol-9-yl)methyl]phenyl]acetic acid | C27H28N2O2 | 详情 | 详情 | |
| (X) | 14376 | (2R)-2-amino-2-phenyl-1-ethanol; (R)-(-)-2-phenylglycinol; (R)-2-amino-2-phenyl-1-ethanol | 56613-80-0 | C8H11NO | 详情 | 详情 |
| (XI) | 28316 | 2-(4-methylphenyl)acetic acid | 622-47-9 | C9H10O2 | 详情 | 详情 |
| (XII) | 41801 | tert-butyl 2-(4-methylphenyl)acetate | C13H18O2 | 详情 | 详情 | |
| (XIII) | 10792 | Butanoyl chloride; Butyryl chloride | 141-75-3 | C4H7ClO | 详情 | 详情 |
| (XIV) | 41802 | tert-butyl 2-cyclopentyl-2-(4-methylphenyl)acetate | C18H26O2 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(X)Esterification of 2-(4-methylphenyl)acetic acid (XI) with L-menthol (XV) by means of MsOH in refluxing toluene gives the ester (XVI), which is diastereoselectively condensed with cyclopentyl bromide (XIII) by means of t-BuOK in DMF, affording 2(S)-cyclopentyl-2-(4-methylphenyl)acetic acid L-menthyl ester (XVII). Bromination of (XVII) with 1,3-dibromo-5,5-dimethylhydantoin (DBMH) in hot chlorobenzene gives the chiral benzyl bromide (XVIII), which is condensed with the already described alpha-carboline (VI) by means of t-BuOK in DMF to yield the adduct (XIX). Hydrolysis of (XIX) with HBr in formic acid affords the chiral cyclopentylacetic acid (XX), which is treated with SOCl2 in refluxing CH2Cl2 to provide the corresponding acyl chloride (XXI). Finally, this compound is condensed with (R)-2-hydroxy-1-phenylethylamine (X) by means of TEA in hot toluene.
| 【1】 Castañer, J.; Silvestre, J.S.; Sorbera, L.A.; Martín, L.; Implitapide. Drugs Fut 2000, 25, 11, 1138. |
| 【2】 Fey, P.; Naab, P.; Lenfers, J.-B.; Van Laak, K. (Bayer AG); Process for the preparation of enantiomerically pure cycloalkano-indol -and azaindol -and pyrimido[1,2a]indolcarboxycyclic acids and their activated derivs.. CA 2201435; DE 19613549; EP 0799829; JP 1998045759; US 5952498 . |
| 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) | 41797 | 2,4-dimethyl-9H-pyrido[2,3-b]indole | C13H12N2 | 详情 | 详情 | |
| (X) | 14376 | (2R)-2-amino-2-phenyl-1-ethanol; (R)-(-)-2-phenylglycinol; (R)-2-amino-2-phenyl-1-ethanol | 56613-80-0 | C8H11NO | 详情 | 详情 |
| (XI) | 28316 | 2-(4-methylphenyl)acetic acid | 622-47-9 | C9H10O2 | 详情 | 详情 |
| (XIII) | 10792 | Butanoyl chloride; Butyryl chloride | 141-75-3 | C4H7ClO | 详情 | 详情 |
| (XV) | 41803 | (1R,2S,5R)-2-isopropyl-5-methylcyclohexanol; L-menthol | 2216-51-5 | C10H20O | 详情 | 详情 |
| (XVI) | 41804 | (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl 2-(4-methylphenyl)acetate | C19H28O2 | 详情 | 详情 | |
| (XVII) | 41805 | (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl (2S)-2-cyclopentyl-2-(4-methylphenyl)ethanoate | C24H36O2 | 详情 | 详情 | |
| (XVIII) | 41806 | (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl (2S)-2-[4-(bromomethyl)phenyl]-2-cyclopentylethanoate | C24H35BrO2 | 详情 | 详情 | |
| (XIX) | 41807 | (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl (2S)-2-cyclopentyl-2-[4-[(2,4-dimethyl-9H-pyrido[2,3-b]indol-9-yl)methyl]phenyl]ethanoate | C37H46N2O2 | 详情 | 详情 | |
| (XX) | 41808 | (2S)-2-cyclopentyl-2-[4-[(2,4-dimethyl-9H-pyrido[2,3-b]indol-9-yl)methyl]phenyl]ethanoic acid | C27H28N2O2 | 详情 | 详情 | |
| (XXI) | 41809 | (2S)-2-cyclopentyl-2-[4-[(2,4-dimethyl-9H-pyrido[2,3-b]indol-9-yl)methyl]phenyl]ethanoyl chloride | C27H27ClN2O | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(VI)The preparation of the precursor amino acids is shown in Schemes 1-4. Ozonolysis of (R)-citronellol (I), followed by Wittig reaction of the resulting aldehyde (II) with methylene triphenylphosphorane gave heptenol (III). Subsequent hydrogenation of (III) over Pd/C provided the saturated alcohol (IV), which was oxidized to the corresponding aldehyde (V) by treatment with Dess-Martin reagent. Asymmetric Strecker reaction in (V) utilizing (R)-phenylglycinol (VI) and trimethylsilyl cyanide afforded a diastereomeric mixture of aminonitriles (VII). After oxidative cleavage of (VII) with lead tetraacetate, the free (2S)-amine (VIII) was separated from its minor diastereomer by column chromatography. Acid hydrolysis of the nitrile group of (VIII) gave 5-propyl-L-leucine (IX), which was protected as the tert-butyl carbamate (X) with Boc2O.
| 【1】 Boger, D.L.; et al.; Total synthesis of HUN-7293. J Am Chem Soc 1999, 121, 26, 6197. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 27301 | methylene(triphenyl)phosphorane | C19H17P | 详情 | 详情 | ||
| (A) | 18845 | Dess-Martin periodinane; 1,1,1-Triacetoxy-1,2-benziodoxol-3(1H)-one | 87413-09-0 | C13H13IO8 | 详情 | 详情 |
| (I) | 26264 | (3R)-3,7-dimethyl-6-octen-1-ol | 1117-61-9 | C10H20O | 详情 | 详情 |
| (II) | 26265 | (4R)-6-hydroxy-4-methylhexanal | C7H14O2 | 详情 | 详情 | |
| (III) | 26266 | (3R)-3-methyl-6-hepten-1-ol | C8H16O | 详情 | 详情 | |
| (IV) | 26267 | (3R)-3-methyl-1-heptanol | C8H18O | 详情 | 详情 | |
| (V) | 26268 | (3R)-3-methylheptanal | C8H16O | 详情 | 详情 | |
| (VI) | 14376 | (2R)-2-amino-2-phenyl-1-ethanol; (R)-(-)-2-phenylglycinol; (R)-2-amino-2-phenyl-1-ethanol | 56613-80-0 | C8H11NO | 详情 | 详情 |
| (VII) | 26269 | (4R)-2-[[(1R)-2-hydroxy-1-phenylethyl]amino]-4-methyloctanenitrile | C17H26N2O | 详情 | 详情 | |
| (VIII) | 26270 | (2S,4R)-2-amino-4-methyloctanenitrile | C9H18N2 | 详情 | 详情 | |
| (IX) | 26271 | (2S,4R)-2-amino-4-methyloctanoic acid | C9H19NO2 | 详情 | 详情 | |
| (X) | 26272 | (2S,4R)-2-[(tert-butoxycarbonyl)amino]-4-methyloctanoic acid | C14H27NO4 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(IX)The reaction of 2-(4-hydroxyphenyl)ethyl alcohol (I) with Ms-Cl and TEA in dichloromethane gives the bis-methanesulfonate (II), which is condensed with 4-hydroxybenzaldehyde (III) by means of K2CO3 in acetonitrile to yield the substituted benzaldehyde (IV). The condensation of (IV) with phosphonium salt (V) by means of tetramethylguanidine (TMG) in chloroform affords the acrylic ester (VI), which is reduced with H2 over Pd/C in ethyl acetate to provide the propionic ester (VII). The hydrolysis of (VII) with LiOH in THF/water gives the propionic acid (VIII) as a racemic mixture, which is condensed with (R)-phenylglycinol (IX) by means of EDC, HOBt and DIEA in dichloromethane to yield the amide (X) as a diastereomeric mixture that is separated by crystallization and chromatography. The desired (S)-isomer (XI) is treated with H2SO4 in hot dioxane/water to furnish the target propionic acid.
| 【1】 McIntyre, J.A.; Castaner, J.; Bayes, M.; Tesaglitazar. Drugs Fut 2003, 28, 10, 959. |
| 【2】 Andersson, K.; Boije, M.; Inghardt, T.; Lindstedt Alstermark, E.-L.; Gottfries, J.; Li, L. (AstraZeneca plc); New 3-aryl-2-aryl propionic acid derivs. and analogs. EP 1084101; EP 1084102; EP 1084103; WO 9962870; WO 9962871; WO 9962872 . |
| 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) | 47355 | 4-(2-hydroxyethyl)phenol | 501-94-0 | C8H10O2 | 详情 | 详情 |
| (II) | 50403 | 4-[2-[(methylsulfonyl)oxy]ethyl]phenyl methanesulfonate | C10H14O6S2 | 详情 | 详情 | |
| (III) | 13433 | 4-Hydroxybenzaldehyde; p-Hydroxybenzaldehyde | 123-08-0 | C7H6O2 | 详情 | 详情 |
| (IV) | 50404 | 4-[2-(4-formylphenoxy)ethyl]phenyl methanesulfonate | C16H16O5S | 详情 | 详情 | |
| (V) | 50405 | (Ethoxy(ethoxycarbonyl)methyl)triphenylphosphonium chloride | C24H26ClO3P | 详情 | 详情 | |
| (VI) | 50406 | ethyl (E)-2-ethoxy-3-[4-([4-[(methylsulfonyl)oxy]phenethyl]oxy)phenyl]-2-propenoate | C22H26O7S | 详情 | 详情 | |
| (VII) | 50407 | ethyl 2-ethoxy-3-[4-([4-[(methylsulfonyl)oxy]phenethyl]oxy)phenyl]propanoate | C22H28O7S | 详情 | 详情 | |
| (VIII) | 50408 | 2-ethoxy-3-[4-([4-[(methylsulfonyl)oxy]phenethyl]oxy)phenyl]propionic acid | C20H24O7S | 详情 | 详情 | |
| (IX) | 14376 | (2R)-2-amino-2-phenyl-1-ethanol; (R)-(-)-2-phenylglycinol; (R)-2-amino-2-phenyl-1-ethanol | 56613-80-0 | C8H11NO | 详情 | 详情 |
| (X) | 50409 | 4-[2-[4-(2-ethoxy-3-[[(1R)-2-hydroxy-1-phenylethyl]amino]-3-oxopropyl)phenoxy]ethyl]phenyl methanesulfonate | C28H33NO7S | 详情 | 详情 | |
| (XI) | 50410 | 4-[2-[4-((2S)-2-ethoxy-3-[[(1R)-2-hydroxy-1-phenylethyl]amino]-3-oxopropyl)phenoxy]ethyl]phenyl methanesulfonate | C28H33NO7S | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(IX)The condensation of 4-(benzyloxy)benzaldehyde (XII) with phosphonium salt (V) by means of TMG as before gives the acrylic ester (XIII), which is hydrogenated with H2 over Rh/C in methanol to yield the propionic ester (XIV). The hydrolysis of (XIV) with LiOH in dioxane/water affords the corresponding acid (XV) as a racemic mixture, which is condensed with (R)-phenylglycinol (IX) by means of EDC, HOBt and DIEA in dichloromethane to provide the amide (XVI) as a diastereomeric mixture that is separated by crystallization and chromatography. The desired (S)-isomer (XVII) is treated with H2SO4 in hot dioxane/water to furnish the chiral propionic acid (XVIII), which is esterified with EtOH and HCl to give the ethyl propionate (XIX). The hydrogenolysis of the benzyl ether group of (XIX) with H2 over Pd/C in ethyl acetate yields the phenolic derivative (XX), which is condensed with the bis-methanesulfonate by means of K2CO3 in acetonitrile to afford the adduct (XXI). Finally, the ester group of (XXI) is hydrolyzed with LiOH in THF/water to provide the target propionic acid.
| 【1】 McIntyre, J.A.; Castaner, J.; Bayes, M.; Tesaglitazar. Drugs Fut 2003, 28, 10, 959. |
| 【2】 Andersson, K.; Boije, M.; Inghardt, T.; Lindstedt Alstermark, E.-L.; Gottfries, J.; Li, L. (AstraZeneca plc); New 3-aryl-2-aryl propionic acid derivs. and analogs. EP 1084101; EP 1084102; EP 1084103; WO 9962870; WO 9962871; WO 9962872 . |
| 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) | 50403 | 4-[2-[(methylsulfonyl)oxy]ethyl]phenyl methanesulfonate | C10H14O6S2 | 详情 | 详情 | |
| (V) | 50405 | (Ethoxy(ethoxycarbonyl)methyl)triphenylphosphonium chloride | C24H26ClO3P | 详情 | 详情 | |
| (IX) | 14376 | (2R)-2-amino-2-phenyl-1-ethanol; (R)-(-)-2-phenylglycinol; (R)-2-amino-2-phenyl-1-ethanol | 56613-80-0 | C8H11NO | 详情 | 详情 |
| (XII) | 29179 | 4-(Benzyloxy)benzaldehyde | 4397-53-9 | C14H12O2 | 详情 | 详情 |
| (XIII) | 50411 | ethyl (E)-3-[4-(benzyloxy)phenyl]-2-ethoxy-2-propenoate | C20H22O4 | 详情 | 详情 | |
| (XIV) | 50412 | ethyl 3-[4-(benzyloxy)phenyl]-2-ethoxypropanoate | C20H24O4 | 详情 | 详情 | |
| (XV) | 50413 | 3-[4-(benzyloxy)phenyl]-2-ethoxypropionic acid | C18H20O4 | 详情 | 详情 | |
| (XVI) | 50414 | 3-[4-(benzyloxy)phenyl]-2-ethoxy-N-[(1R)-2-hydroxy-1-phenylethyl]propanamide | C26H29NO4 | 详情 | 详情 | |
| (XVII) | 50415 | (2S)-3-[4-(benzyloxy)phenyl]-2-ethoxy-N-[(1R)-2-hydroxy-1-phenylethyl]propanamide | C26H29NO4 | 详情 | 详情 | |
| (XVIII) | 40516 | methyl (1R,5R)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene-2-carboxylate | C10H15NO2 | 详情 | 详情 | |
| (XIX) | 50417 | ethyl (2S)-3-[4-(benzyloxy)phenyl]-2-ethoxypropanoate | C20H24O4 | 详情 | 详情 | |
| (XX) | 50418 | ethyl (2S)-2-ethoxy-3-(4-hydroxyphenyl)propanoate | C13H18O4 | 详情 | 详情 | |
| (XXI) | 50419 | ethyl (2S)-2-ethoxy-3-[4-([4-[(methylsulfonyl)oxy]phenethyl]oxy)phenyl]propanoate | C22H28O7S | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(XIX)The intermediate (S)-adamantylglycine (I) can be prepared as follows. Reduction of adamantane-1-carboxylic acid (XVI) using LiAlH4 in THF gives the primary alcohol (XVII), which is oxidized to aldehyde (XVIII) under Swern conditions. Adamantane-1-carbaldehyde (XVIII) is then condensed with (R)-phenylglycinol (XIX) and KCN in the presence of NaHSO3 to yield the chiral aminonitrile (XX). After acidic hydrolysis of nitrile (XX) to the corresponding amino acid (XXI), the chiral auxiliary group is removed by hydrogenolysis over Pearlman’s catalyst to furnish intermediate (I) (1, 6). Scheme 2.
| 【1】 Robl, J.A., Sulsky, R.B., Betebenner, D.A., Magnin, D.R., Hamann, L.G., Augeri, D.J. (Bristol-Myers Squibb Co.). Cyclopropyl-fused pyrrolidine-based inhibitors of dipeptidyl peptidase IV and method. EP 1261586, JP 2003531118, US 6395767, WO 0168603. |
| 【6】 Augeri, D.J., Robl, J.A., Betebenner, D.A. et al. Discovery and preclinical profile of saxagliptin (BMS-477118): A highly potent, long-acting, orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. J Med Chem 2005, 48(15): 5025-37. |
| 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) | 65644 | C35H41INOPSSi | 详情 | 详情 | ||
| (XVI) | 65693 | 1-Adamantanecarboxylic acid; Adamantane-1-carboxylic acid; Tricyclo[3.3.1.1(3,7)]decan-1-Carboxylic acid | 828-51-3 | C11H16O2 | 详情 | 详情 |
| (XVII) | 65694 | 1-Adamantanemethanol; 1-(Hydroxymethyl)adamantane; 1-Tricyclo[3.3.1.1(3,7)]decanemethanol | 770-71-8 | C11H18O | 详情 | 详情 |
| (XVIII) | 65695 | 1-Adamantylcarboxaldehyde; Tricyclo[3.3.1.1(3,7)]decane-1-carboxaldehyde; 1-Formyladamantane | 2094-74-8 | C11H16O | 详情 | 详情 |
| (XIX) | 14376 | (2R)-2-amino-2-phenyl-1-ethanol; (R)-(-)-2-phenylglycinol; (R)-2-amino-2-phenyl-1-ethanol | 56613-80-0 | C8H11NO | 详情 | 详情 |
| (XX) | 65696 | (alphaS)-alpha-[[(1R)-2-Hydroxy-1-phenylethyl]amino]-tricyclo[3.3.1.1(3,7)]decane-1-acetonitrile | 361441-95-4 | C20H26N2O | 详情 | 详情 |
| (XXI) | 65697 | C20H27NO3 | 详情 | 详情 |