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【结 构 式】 
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【分子编号】24014 【品名】Phenyllithium 【CA登记号】591-51-5 |
【 分 子 式 】C6H5Li 【 分 子 量 】84.0467 【元素组成】C 85.75% H 6% Li 8.26% |
合成路线1
该中间体在本合成路线中的序号：(II)Reaction of 1-methyl-4-piperidone (I) with phenyllithium (II) gives 1-methyl-4-phenyl-4-piperidinol (III), which is alkylated with (IV) in NaH/DMF to yield (V), followed by reduction with hydrazine/Raney-Ni.
| 【1】 Eistetter, K.; Kley, H.-P.; Menge, H.G.; Schaefer, H. (Byk Gulden Lomberg Chemische Fabrik GmbH); Anti-depressant and analgesic 4-phenoxypiperidines. US 4333942 . |
| 【2】 Menge, H.G.; Eistetter, K.; Schaefer, H.; Kley, H.-P.; B-777-81. Drugs Fut 1983, 8, 5, 387. |
| 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) | 10919 | 1-Methyl-4-piperidone; 1-Methyltetrahydro-4(1H)-pyridinone; N-Methyl-4-piperidone;1-methylpiperidin-4-one | 1445-73-4 | C6H11NO | 详情 | 详情 |
| (II) | 24014 | Phenyllithium | 591-51-5 | C6H5Li | 详情 | 详情 |
| (III) | 24016 | 1-methyl-4-phenyl-4-piperidinol | C12H17NO | 详情 | 详情 | |
| (IV) | 14153 | 4-Fluoronitrobenzene; 1-Fluoro-4-nitrobenzene | 350-46-9 | C6H4FNO2 | 详情 | 详情 |
| (V) | 36052 | 1-methyl-4-phenyl-4-piperidinyl 4-nitrophenyl ether; 1-methyl-4-(4-nitrophenoxy)-4-phenylpiperidine | C18H20N2O3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VII)The reaction of 2-bromo-4-fluorophenylacetic acid (I) with 4-isopropytthiophenol (II) by means of Cu and K2CO3 in DMF at 100 C gives 4-fluoro-2-(4-isopropylphenylthio)phenylacetic acid (III), which is cyclized by treatment with polyphosphoric acid at 1 500 yielding 3-fluoro-8-isopropyldibenzo[b,f]-thiepin-10(11H) one (IV). The reduction of (IV) with NaBH4 in ethanol affords 3-fluoro-10-hydroxy-8-isopropyl-10,11-dihydrodibenzo[b,f]thiepin (V), which is treated with SOCl2 refluxing benzene to give 10-chloro-3-fluoro-8-isopropyl-10,11-dihydro-dibenzo[b,f]thiepin (VI). Finally, this compound is condensed with 1-(2-hydroxyethyl)piperazine (VII) in refluxing CHCl3.
| 【1】 Protiva, M.; et al.; Fluorinated tricyclic neuroleptics with prolonged action: 7-Fluoro-11-[4-(2-hydroxyethyl)piperazino]-2-isopropyl-10,11-dihydrodibenzo[b,f]thiepin. M Coll Czech Chem Commun 1986, 51, Suppl. 2, 698. |
| 【2】 Jilek, J.; et al.; M Coll Czech Chem Commun 1984, 49, 2, 638. |
| 【3】 Dlabac, A.; Miksik, F.; Pomykacek, J.; Jilek, J.; Sindelar, K.; Rajsner, M.; Langsadl, L.; Metysova, J.; Bartl, V.; Protiva, M. (SPOFA - United Pharmaceutical Works); 3-Fluoro-10-piperazino-8-substituted 10,11-dihydrodibenzo(bf) thiepins and method for the preparation thereof. BE 0872496; DE 2855703; FR 2412312; GB 2010843; JP 7992979; US 4243805 . |
| 【4】 Castaner, J.; Prous, J.; Isofloxythepin. Drugs Fut 1986, 11, 7, 567. |
| 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) | 23996 | 2-(2-bromo-4-fluorophenyl)acetic acid | C8H6BrFO2 | 详情 | 详情 | |
| (II) | 23997 | 4-isopropylbenzenethiol | 4946-14-9 | C9H12S | 详情 | 详情 |
| (III) | 23998 | 2-[4-fluoro-2-[(4-isopropylphenyl)sulfanyl]phenyl]acetic acid | C17H17FO2S | 详情 | 详情 | |
| (IV) | 23999 | 3-fluoro-8-isopropyldibenzo[b,f]thiepin-10(11H)-one | C17H15FOS | 详情 | 详情 | |
| (V) | 24000 | 3-fluoro-8-isopropyl-10,11-dihydrodibenzo[b,f]thiepin-10-ol | C17H17FOS | 详情 | 详情 | |
| (VI) | 24001 | 11-chloro-7-fluoro-2-isopropyl-10,11-dihydrodibenzo[b,f]thiepine | C17H16ClFS | 详情 | 详情 | |
| (VII) | 24014 | Phenyllithium | 591-51-5 | C6H5Li | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VI)1) The cyclization of 2,3-dimethylaniline (I) with diethyl acetylmalonate (II) in 1-chloronaphthalene at 240 C gives 3-acetyl-4-hydroxy-7,8-dimethylquinolin-2(1H)-one (III), which by reaction with diethyl oxalate (IV) by means of sodium ethoxide in refluxing benzene yields ethyl-4-(4-hydroxy-7,8-dimethyl-2-oxo-1,2-dihydroquinolin-3yl)-2,4-dioxo-butanoate (V). The cyclization of (V) in acetic acid concentrated HCl at 100 C affords 5,6-dihydro-7,8 dimethyl-4,5-dioxo-4H-pyrano[3,2-c]quinoline-2-carboxylic acid (VI), which is converted into the corresponding acyl chloride (VII) by reaction with refluxing SOCl2. Finally, this compound is treated with hot 3-methylbutanol (VIII).
| 【1】 Takahashi, K.; Hata, S.; Morinaka, Y.; Yamada, S.; Antiallergic agents I. Pyranoquinoline derivatives. Eur J Med Chem - Chim Ther 1981, 16, 3, 251. |
| 【2】 Castaner, J.; Prous, J.; Repirinast. Drugs Fut 1987, 12, 1, 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) | 23025 | 2,3-Dimethylphenylamine; 2,3-Dimethylaniline; 2,3-Xylidine | 87-59-2 | C8H11N | 详情 | 详情 |
| (II) | 23026 | diethyl 2-acetylmalonate | 570-08-1 | C9H14O5 | 详情 | 详情 |
| (III) | 23027 | 3-acetyl-4-hydroxy-7,8-dimethyl-2(1H)-quinolinone | C13H13NO3 | 详情 | 详情 | |
| (IV) | 17571 | Diethyl oxalate; Ethyl 2-ethoxy-2-oxoacetate | 95-92-1 | C6H10O4 | 详情 | 详情 |
| (V) | 23029 | ethyl 4-(4-hydroxy-7,8-dimethyl-2-oxo-1,2-dihydro-3-quinolinyl)-2,4-dioxobutanoate | C17H17NO6 | 详情 | 详情 | |
| (VI) | 24014 | Phenyllithium | 591-51-5 | C6H5Li | 详情 | 详情 |
| (VII) | 23031 | 7,8-dimethyl-4,5-dioxo-5,6-dihydro-4H-pyrano[3,2-c]quinoline-2-carbonyl chloride | C15H10ClNO4 | 详情 | 详情 | |
| (VIII) | 23032 | 3-methyl-1-butanol | 123-51-3 | C5H12O | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XVII)The protection of the NH group of trans-4-hydroxy-L-proline (XII) with tert-butoxycarbonyl anhydride and NaOH in tert-butanol/water gives the N-protected proline (XIII), which is esterified with benzyl alcohol and triethylamine to the benzyl ester (XIV). The tosylation of (XIV) with tosyl chloride and pyridine affords the tosylate (XV), which is debenzylated with H2 over Pd/C yielding the tosylated proline (XVI). The arylation of (XVI) with phenyllithium (XVII) and CuBr in ether/THF affords 1-(tert-butoxycarbonyl)-4(S)-phenyl)-L-proline (XVIII), which is deprotected with TFA in chloroform giving 4(S)-phenyl-L-proline (XIX). Finally, this compound is reduced with H2 over PtO2 in ethanol providing the desired intermediate trans-4-cyclohexyl-L-proline (XI).
| 【1】 Moniot, J.L.; Thottathil, J.K.; Littium diphenylcuprate reactions with 4-tosyloxy-L-prolines; An interesting stereochemical outcome. A synthesis of trans-4-phenyl-L-proline. Tetrahedron Lett 1986, 27, 2, 151. |
| 【2】 Floyd, D.; Thottathil, J.K.; Brandt, S.; Moniot, J.L. (Bristol-Myers Squibb Co.); Method for making substd. prolines. DE 3434121; US 4501901 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 12912 | 1-(Bromomethyl)benzene; Alpha-bromotoluene | 100-39-0 | C7H7Br | 详情 | 详情 | |
| (XI) | 38567 | (2S,4S)-4-cyclohexyl-2-pyrrolidinecarboxylic acid | C11H19NO2 | 详情 | 详情 | |
| (XII) | 14489 | (2S,4R)-4-hydroxytetrahydro-1H-pyrrole-2-carboxylic acid; L-Hydroxyproline | 51-35-4 | C5H9NO3 | 详情 | 详情 |
| (XIII) | 16094 | (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid;1-(tert-butoxycarbonyl)-4®-hydroxy-L-proline;(2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxytetrahydro-1H-pyrrole-2-carboxylic acid | 16094 | C10H17NO5 | 详情 | 详情 |
| (XIV) | 38568 | 2-benzyl 1-(tert-butyl) (2S,4R)-4-hydroxy-1,2-pyrrolidinedicarboxylate | C17H23NO5 | 详情 | 详情 | |
| (XV) | 38569 | 2-benzyl 1-(tert-butyl) (2S,4R)-4-[[(4-methylphenyl)sulfonyl]oxy]-1,2-pyrrolidinedicarboxylate | C24H29NO7S | 详情 | 详情 | |
| (XVI) | 38570 | (2S,4R)-1-(tert-butoxycarbonyl)-4-[[(4-methylphenyl)sulfonyl]oxy]-2-pyrrolidinecarboxylic acid | C17H23NO7S | 详情 | 详情 | |
| (XVII) | 24014 | Phenyllithium | 591-51-5 | C6H5Li | 详情 | 详情 |
| (XVIII) | 38571 | (2S,4S)-1-(tert-butoxycarbonyl)-4-phenyl-2-pyrrolidinecarboxylic acid | C16H21NO4 | 详情 | 详情 | |
| (XIX) | 38572 | (2S,4S)-4-phenyl-2-pyrrolidinecarboxylic acid | C11H13NO2 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(I)The reaction of N-methyl-4-piperidone (II) with phenyllithium (I) in benzene-ethyl ether below 10 C gives 4-hydroxy-1-methyl-4.phenypiperidine (III), which is dehydrated by treating with refuxing concentrated HCl.
| 【1】 Frank, M.; Clarke, H.Jr. (Novartis Corp.); Nouveaux benzomorphanes et leur preparation. DE 1445845; DE 1795599; FR 1440638; FR 4024M; GB 1050227; US 3320265 . |
| 【2】 Block, F.B.; et al. (Novartis Corp.); Certain 2,6-methano-3-benzazocines. US 3341538 . |
| 【3】 Castaner, J.; Prous, J.; MPTP. Drugs Fut 1986, 11, 5, 384. |
合成路线6
该中间体在本合成路线中的序号：(IV)Condensation of 1-benzyl-4-piperidone (I) with 2-fluoroaniline (II) affords imine (III). Addition of phenyllithium (IV) to imine (III) gives amine (V), which is acylated with propionyl chloride and the resultant amide (VI) is debenzylated via 1-chloroethyl chloroformate in refluxing 1,2-dichloroethane followed by methanolysis to give (VII). Amine (VII)) is alkylated with 1-(2-bromoethyl)-4-ethyl-4,5-dihydro-1H-tetrazol-5-one(VIII) to yield A-3665. A-3665 hydrochloride is precipitated with dry HCl gas in ethyl ether.
| 【1】 Kudzma, L.V.; Spencer, H.K.; Severnak, S.A. (BOC Health Care, Inc.); 4-Phenyl-4-[N-(phenyl)amido]piperidine derivs. and methods employing such cpds. AU 8824558; EP 0315405; JP 1990015061; JP 1990152963; US 4791121; US 4921864 . |
| 【2】 Kudzma, L.V.; Ossipov, M.H.; Benvenga, M.J.; Spaulding, T.C.; Rudo, F.G.; A-3665. Drugs Fut 1990, 15, 6, 559. |
| 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) | 15750 | (6R,7R)-3-[(acetoacetoxy)methyl]-7-[[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(methoxyimino)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | C17H18N6O8S2 | 详情 | 详情 | |
| (II) | 22296 | 2-fluorophenylamine; 2-fluoroaniline | 348-54-9 | C6H6FN | 详情 | 详情 |
| (III) | 13865 | N-(1-Benzyl-4-piperidinylidene)-N-(2-fluorophenyl)amine; N-(1-Benzyl-4-piperidinylidene)-2-fluoroaniline | C18H19FN2 | 详情 | 详情 | |
| (IV) | 24014 | Phenyllithium | 591-51-5 | C6H5Li | 详情 | 详情 |
| (V) | 13866 | N-(1-Benzyl-4-phenyl-4-piperidinyl)-N-(2-fluorophenyl)amine; 1-Benzyl-N-(2-fluorophenyl)-4-phenyl-4-piperidinamine | C24H25FN2 | 详情 | 详情 | |
| (VI) | 13867 | N-(1-Benzyl-4-phenyl-4-piperidinyl)-N-(2-fluorophenyl)propanamide | C27H29FN2O | 详情 | 详情 | |
| (VII) | 13868 | N-(2-Fluorophenyl)-N-(4-phenyl-4-piperidinyl)propanamide | C20H23FN2O | 详情 | 详情 | |
| (VIII) | 14721 | 1-(2-bromoethyl)-4-ethyl-1,4-dihydro-5H-1,2,3,4-tetraazol-5-one | C5H9BrN4O | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(XVII)The protection of 3-bromo-1-propanol (I) with dihydropyran (DHP) and p-toluenesulfonic acid gives the tetrahydropyranyl ether (II), which is condensed with 3,4-dichlorophenylacetonitrile (III) by means of NaH in THF yielding the pentanenitrile (IV). The condensation of (IV) with ethyl 3-bromopropionate (V) by means of potassium hexamethyldisylazide (KHMDS) in THF affords the heptanoate (VI), which is reductocyclized with H2 over RaNi in ethanol/aq. NH4OH affording the piperidone (VII). The reduction of (VII) by means of LiAlH4 in THF gives the piperidine (VIII), which is deprotected with HCl in ethyl ether yielding the racemic propanol (IX). The optical resolution of (IX) by means of (+)-camphorsulfonic acid in isopropanol affords the desired enantiomer (X), which is acylated with benzoyl chloride (XI) and DIEA in dichloromethane providing the benzoylpiperidine (XII). The reaction of (XII) with methanesulfonyl chloride and triethylamine gives the mesylate (XIII), which is treated with KI in refluxing acetone to yield the 3-iodopropyl derivative (XIV). Finally, (XIV) is condensed with 4-hydroxy-4-phenylpiperidine (XV) by means of KHCO3 in hot acetonitrile. The intermediate 4-hydroxy-4-phenylpiperidine (XV) has been obtained as follows: The reaction of 1-benzyl-4-piperidone (XVI) with phenyllithium in THF gives 1-benzyl-4-hydroxy-4-phenylpiperidine (XVII), which is then debenzy-lated by hydrogenation with H2.
| 【1】 Kuo, B.-S.; Lee, H.T.; Roth, B.D.; Chung, F.-Z.; Atherton, J.; Chen, M.H.; Syntheses and biological activities of chiral piperidines-tachykinin NK3 antagonists. Acta Pharm Sin 1999, 20, 3, 283. |
| 【2】 Chen, M.H.G.; Lee, H.T.; Chung, F.-Z. (Pfizer Inc.); 3-Alkyl-3-phenyl-piperidines. WO 9811090 . |
| 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) | 12573 | 3-Bromo-1-propanol; 3-Bromopropanol | 627-18-9 | C3H7BrO | 详情 | 详情 |
| (II) | 29460 | 2-(4-bromobutoxy)tetrahydro-2H-pyran; 4-bromobutyl tetrahydro-2H-pyran-2-yl ether | C9H17BrO2 | 详情 | 详情 | |
| (III) | 26935 | 2-(3,4-dichlorophenyl)acetonitrile | 3218-49-3 | C8H5Cl2N | 详情 | 详情 |
| (IV) | 29461 | 2-(3,4-dichlorophenyl)-6-(tetrahydro-2H-pyran-2-yloxy)hexanenitrile | C17H21Cl2NO2 | 详情 | 详情 | |
| (V) | 29132 | ethyl 3-bromopropanoate | 539-74-2 | C5H9BrO2 | 详情 | 详情 |
| (VI) | 29462 | ethyl 4-cyano-4-(3,4-dichlorophenyl)-8-(tetrahydro-2H-pyran-2-yloxy)octanoate | C22H29Cl2NO4 | 详情 | 详情 | |
| (VII) | 29463 | 5-(3,4-dichlorophenyl)-5-[4-(tetrahydro-2H-pyran-2-yloxy)butyl]-2-piperidinone | C20H27Cl2NO3 | 详情 | 详情 | |
| (VIII) | 29464 | 3-(3,4-dichlorophenyl)-3-[4-(tetrahydro-2H-pyran-2-yloxy)butyl]piperidine; 4-[3-(3,4-dichlorophenyl)-3-piperidinyl]butyl tetrahydro-2H-pyran-2-yl ether | C20H29Cl2NO2 | 详情 | 详情 | |
| (IX) | 29465 | 3-[3-(3,4-dichlorophenyl)-3-piperidinyl]-1-propanol | C14H19Cl2NO | 详情 | 详情 | |
| (X) | 29466 | 3-[(3S)-3-(3,4-dichlorophenyl)piperidinyl]-1-propanol | C14H19Cl2NO | 详情 | 详情 | |
| (XI) | 10463 | Benzoyl chloride | 98-88-4 | C7H5ClO | 详情 | 详情 |
| (XII) | 29467 | [(3S)-3-(3,4-dichlorophenyl)-3-(3-hydroxypropyl)piperidinyl](phenyl)methanone | C21H23Cl2NO2 | 详情 | 详情 | |
| (XIII) | 29468 | 3-[(3S)-1-benzoyl-3-(3,4-dichlorophenyl)piperidinyl]propyl methanesulfonate | C22H25Cl2NO4S | 详情 | 详情 | |
| (XIV) | 29469 | [(3S)-3-(3,4-dichlorophenyl)-3-(3-iodopropyl)piperidinyl](phenyl)methanone | C21H22Cl2INO | 详情 | 详情 | |
| (XV) | 28021 | 4-phenyl-4-piperidinol; 4-Hydroxy-4-phenylpiperidine; 4-(4-Phenyl)-4-hydroxypiperidine | 40807-61-2 | C11H15NO | 详情 | 详情 |
| (XVI) | 15720 | 1-benzyltetrahydro-4(1H)-pyridinone; 1-Benzyl-4-piperidone; N-Benzyl-4-piperidone; 1-(benzyl)-4-piperidinone; 1-benzylpiperidin-4-one; 1-(benzyl)piperidin-4-one | 3612-20-2 | C12H15NO | 详情 | 详情 |
| (XVII) | 24014 | Phenyllithium | 591-51-5 | C6H5Li | 详情 | 详情 |
| (XVIII) | 29470 | 1-benzyl-4-phenyl-4-piperidinol | C18H21NO | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(VI)Swern oxidation of N-Boc-S-valinol (I) provided aldehyde (II). After conversion of (II) to the corresponding oxime (III) upon treatment with hydroxylamine, chlorination with N-chlorosuccinimide gave the hydroximinoyl chloride (IV). Reaction of ethyl 2-(bromomethyl)acrylate (V) with phenyllithium (VI) in the presence of CuCN produced ethyl 2-benzylacrylate (VII). The dipolar cycloaddition of the nitrile oxide generated from (IV) to acrylate (VII) furnished the isoxazoline (VIII) as a diastereomeric mixture. The N-Boc protecting group of (VIII) was then cleaved with trifluoroacetic acid to give amine (IX), which was coupled with 2-naphthoic acid (X), yielding amide (XI). The carboxylic acid (XII), resulting from the basic hydrolysis of ethyl ester (XI), was then coupled with the glutamate ester (XIII) to give (XIV).
| 【1】 Chung, H.-H.; Park, M.-J.; Min, C.-H.; Kang, C.-Y.; Park, T.-K.; Chang, H.-K.; Lee, T.-H.; Moon, K.-Y.; Kim, E.E.-K.; Oh, Y.-L.; Kim, Y.-M. (LG Chem Ltd.); Caspase inhibitor. WO 0121599; WO 0121600 . |
| 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) | 48024 | tert-butyl (1S)-1-(hydroxymethyl)-2-methylpropylcarbamate | C10H21NO3 | 详情 | 详情 | |
| (II) | 47805 | tert-butyl (1S)-1-formyl-2-methylpropylcarbamate | C10H19NO3 | 详情 | 详情 | |
| (III) | 48025 | tert-butyl (1S)-1-[(hydroxyimino)methyl]-2-methylpropylcarbamate | C10H20N2O3 | 详情 | 详情 | |
| (IV) | 48026 | tert-butyl (1S)-1-[chloro(hydroxyimino)methyl]-2-methylpropylcarbamate | C10H19ClN2O3 | 详情 | 详情 | |
| (V) | 11328 | ethyl 2-(bromomethyl)acrylate | 17435-72-2 | C6H9BrO2 | 详情 | 详情 |
| (VI) | 24014 | Phenyllithium | 591-51-5 | C6H5Li | 详情 | 详情 |
| (VII) | 48027 | ethyl 2-benzylacrylate | C12H14O2 | 详情 | 详情 | |
| (VIII) | 48028 | ethyl 5-benzyl-3-[(1S)-1-[(tert-butoxycarbonyl)amino]-2-methylpropyl]-4,5-dihydro-5-isoxazolecarboxylate | C22H32N2O5 | 详情 | 详情 | |
| (IX) | 48029 | ethyl 3-[(1S)-1-amino-2-methylpropyl]-5-benzyl-4,5-dihydro-5-isoxazolecarboxylate | C17H24N2O3 | 详情 | 详情 | |
| (X) | 10106 | 1-Naphthoic acid | 86-55-5 | C11H8O2 | 详情 | 详情 |
| (XI) | 48030 | ethyl 5-benzyl-3-[(1S)-2-methyl-1-(1-naphthoylamino)propyl]-4,5-dihydro-5-isoxazolecarboxylate | C28H30N2O4 | 详情 | 详情 | |
| (XII) | 48031 | 5-benzyl-3-[(1S)-2-methyl-1-(1-naphthoylamino)propyl]-4,5-dihydro-5-isoxazolecarboxylic acid | C26H26N2O4 | 详情 | 详情 | |
| (XIII) | 48032 | 4-(tert-butyl) 1-methyl (2S)-2-aminobutanedioate | C9H17NO4 | 详情 | 详情 | |
| (XIV) | 48033 | 4-(tert-butyl) 1-methyl (2S)-2-[([5-benzyl-3-[(1S)-2-methyl-1-(1-naphthoylamino)propyl]-4,5-dihydro-5-isoxazolyl]carbonyl)amino]butanedioate | C35H41N3O7 | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(VIII)Alkylation of ethyl isonipecotate (I) with 1-bromo-2-chloroethane (II) in the presence of K2CO3 in acetone yields ethyl 1-(2-chloro-ethyl)piperidine-4-carboxylate (III), which by treatment with LDA in THF cyclizes to the quinuclidine derivative (IV) . Alternatively, quinuclidine (IV) can be prepared by alkylation of Boc-protected ethyl nipecotate (V) with 1-bromo-2-chloroethane (II) using LiHMDS in toluene to yield the 4-(2-chloroethyl)piperidine derivative (VI), which is then N-deprotected with HCl in water/dioxane, followed by cyclization of the resulting chloro amine (VII) by means of K2CO3 in refluxing toluene . Addition of phenyl lithium (VIII) to ester (IV) in THF affords 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (IX), which finally undergoes quaternization with benzyl 2-bromoethyl ether (X) in acetonitrile/chloroform .
| 【1】 Lainé, D.I., McCleland, B., Thomas, S. et al. Discovery of novel 1-azoniabicyclo[2.2.2]octane muscarinic acetylcholine receptor antagonists. J Med Chem 2009, 52(8): 2493-505. |
| 【2】 Lainé, D.I., Palovich, M.R., McCleland, B.W., Neipp, C.E., Thomas, S.M.(GlaxoSmithKline plc). Muscarinic acetylcholine receptor antagonists. CA 2564742, CN 102040602, EP 1740177, JP 2007534769, KR 2011010841, US 200785155, US 7498440, US 8183257, US 2012157491, US 8309572, US 2013030015, WO 2005104745. |
| 【3】 Carangio, A., Cheung, I., D’Souza, E.C.F., Leahy, J.H., Strachan, J.B. (GlaxoSmithKline plc). Methods of preparation of muscarinic acetylcholine receptor antagonists. WO 2011029896. |
| 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) | 17410 | Ethyl isonipecotate; ethyl 4-piperidinecarboxylate | 1126-09-6 | C8H15NO2 | 详情 | 详情 |
| (II) | 24271 | 1-bromo-2-chloroethane | 107-04-0 | C2H4BrCl | 详情 | 详情 |
| (III) | 67994 | ethyl 1-(2-chloroethyl)piperidine-4-carboxylate | C10H18ClNO2 | 详情 | 详情 | |
| (IV) | 67995 | ethyl quinuclidine-4-carboxylate | C10H17NO2 | 详情 | 详情 | |
| (V) | 49847 | 1-(tert-butyl) 4-ethyl-1,4-piperidinedicarboxylate; N-Boc-4-Carbethoxypiperidine | 142851-03-4 | C13H23NO4 | 详情 | 详情 |
| (VI) | 67996 | 1-tert-butyl 4-ethyl 4-(2-chloroethyl)piperidine-1,4-dicarboxylate | C15H26ClNO4 | 详情 | 详情 | |
| (VII) | 67997 | ethyl 4-(2-chloroethyl)piperidine-4-carboxylate hydrochloride | C10H18ClNO2.HCl | 详情 | 详情 | |
| (VIII) | 24014 | Phenyllithium | 591-51-5 | C6H5Li | 详情 | 详情 |
| (IX) | 67998 | diphenyl(quinuclidin-4-yl)methanol;1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol | C20H23NO | 详情 | 详情 | |
| (X) | 35528 | 1-[(2-bromoethoxy)methyl]benzene; benzyl 2-bromoethyl ether | 1462-37-9 | C9H11BrO | 详情 | 详情 |