|
【结 构 式】 
|
【分子编号】11376 【品名】Pyrrolidine 【CA登记号】123-75-1 |
【 分 子 式 】C4H9N 【 分 子 量 】71.1222 【元素组成】C 67.55% H 12.75% N 19.69% |
合成路线1
该中间体在本合成路线中的序号：(IV)The reaction of aniline (I) with 4-hydroxybenzoic acid (II) by means of P2O5 in refluxing toluene gives N-(4-hydroxybenzoyl)aniline (III), which is then condensed with pyrrolidine (IV) and formaldehyde (V) in refluxing ethanol.
| 【1】 Stout, D.M.; et al.; Synthesis and antiarrhythmic and parasympatholytic properties of substituted phenols. 3. Modifications to the linkage region (Region 3(. J Med Chem 1985, 28, 3, 295-298. |
| 【2】 Serradell, M.N.; Castaner, J.; ACC-9358. Drugs Fut 1986, 11, 3, 169. |
| 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) | 12294 | Aniline; Phenylamine | 62-53-3 | C6H7N | 详情 | 详情 |
| (II) | 28208 | 3-thioxo-2,3-dihydro-1H-2H-thieno[3,4-d]isothiazole-1,1-dione | C5H3NO2S3 | 详情 | 详情 | |
| (III) | 28206 | 4-hydroxy-N-phenylbenzamide | C13H11NO2 | 详情 | 详情 | |
| (IV) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 |
| (V) | 22075 | Formaldehyde; Paraformaldehyde | 1118-66-7 | CH2O | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(A)The reaction of beta-tetralone (I) with pyrrolidine (A) yields enamine (II), which is condensed with phenacyl bromide (B) in DMF to give the 1-phenacyl-2-tetralone (III). Finally, this diketone is cyclized with 5-aminosalycilic acid (C) in refluxing acetic acid.
| 【1】 Anderson, V.B.; et al.; Carboxyarylindoles as non steroidal anti-inflammatory agents. J Med Chem 1976, 1, 7, 320. |
| 【2】 Castaner, J.; Arrigoni-Martelli, E.; Fendosal. Drugs Fut 1976, 1, 7, 320. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (B) | 10315 | 2-Bromo-1-phenyl-ethanone; 2-Bromo-1-phenyl-1-ethanone | 70-11-1 | C8H7BrO | 详情 | 详情 |
| (A) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 |
| (I) | 39106 | 3,4-Dihydro-2(1H)-naphthalenone; beta-Tetralone | 530-93-8 | C10H10O | 详情 | 详情 |
| (II) | 20382 | 1-(3,4-dihydro-2-naphthalenyl)pyrrolidine | 21403-95-2 | C14H17N | 详情 | 详情 |
| (III) | 40460 | 1-(2-oxo-2-phenylethyl)-3,4-dihydro-2(1H)-naphthalenone | C18H16O2 | 详情 | 详情 | |
| (C) | 29932 | 5-amino-2-hydroxybenzoic acid | 89-57-6 | C7H7NO3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(III)The oxidation of 7-chloro-5-hydroxy-2,3-dihydro-1-benzothiepin (I) with H2O2 in acetic acid - water gives 7-chloro-5-hydroxy-2,3-dihydro-1-benzothiepin-1,1-dioxide (II), which by reaction with pyrrolidine (III) and p-toluenesulfonic acid in refluxing benzene is converted into 7-chloro-5-pyrrolidino-2,3-dihydro-1-benzothiepin-1,1-dioxide (IV). The condensation of (IV) with 3,4-dichlorophenyl isocyanate (V) in hot THF yields N-(3,4-dichlorophenyl)-7-chloro-5-pyrrolidino-2,3-dihydro-1-benzothiepin-4-carboxamide-1,1-dioxide (VI), which is finally hydrolyzed with HCl in refluxing ethanol - water.
| 【1】 Rosen, M.H.; 1-Benzothiepin-4-carboxamides. BE 0833787; CA 1066279; CH 617433; DE 2542329; FR 2285872; US 4185109 . |
| 【2】 Serradell, M.N.; Castaner, J.; Enolicam sodium. Drugs Fut 1984, 9, 7, 508. |
| 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) | 34279 | 7-chloro-2,3-dihydro-1-benzothiepin-5-ol | C10H9ClOS | 详情 | 详情 | |
| (II) | 34280 | 7-chloro-5-hydroxy-2,3-dihydro-1H-2H-benzothiepine-1,1-dione | C10H9ClO3S | 详情 | 详情 | |
| (III) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 |
| (IV) | 34281 | 7-chloro-5-(1-pyrrolidinyl)-2,3-dihydro-1H-2H-benzothiepine-1,1-dione | C14H16ClNO2S | 详情 | 详情 | |
| (V) | 34282 | 1,2-dichloro-4-isocyanatobenzene; 3,4-dichlorophenyl isocyanate | 102-36-3 | C7H3Cl2NO | 详情 | 详情 |
| (VI) | 34283 | 7-chloro-N-(3,4-dichlorophenyl)-1,1-dioxo-5-(1-pyrrolidinyl)-2,3-dihydro-1H-2H-benzothiepine-4-carboxamide | C21H19Cl3N2O3S | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(C)The ketalization of 11alpha-hydroxy-18-methyl-DELTA4-estrene-3,17-dione (I) with ethylene glycol (A) by means of ethyl orthoformate and p-toluene sulfonic acid gives the diketal (II), which is oxidized with CrO3 in acetone yielding the ketone (III). The Wittig reaction of (III) with triphenylmethyl-phosphonium bromide (B) by means of NaH in benzene-DMSO affords 11-methylene-18-methyl-DELTA4-estren-3,17-dione diethyleneketal (IV), which is hydrolyzed with HCl in acetone to the diketone (V). The reaction of (V) with pyrrolidine (C) in methanol gives the N-pyrrolidinyl derivative (VI), which is condensed with potassium acetylide (D) in THF yielding 17alpha-ethynyl derivative (VII). Finally, this compound is hydrolyzed with acetic acid in methanol - water.
| 【1】 Van den Broek, A.J.; Novel 11,11-alkylidene steroids. DE 2361120; ES 421253; FR 2209577; GB 1455270; JP 50029548; US 3927046 . |
| 【2】 Hillier, K.; Castaner, J.; ORG-3236. Drugs Fut 1978, 3, 9, 664. |
| 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) | 11295 | Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol | 107-21-1 | C2H6O2 | 详情 | 详情 |
| (B) | 30484 | Methyl(triphenyl)phosphonium bromide | 1779-49-3 | C19H18BrP | 详情 | 详情 |
| (D) | 33587 | Potassium acetylide | C2HK | 详情 | 详情 | |
| (I) | 33580 | (8S,9S,10R,11R,13S,14S)-13-ethyl-11-hydroxy-7,8,9,10,11,12,13,14,15,16-decahydro-1H-cyclopenta[a]phenanthrene-3,17(2H,6H)-dione; 11alpha-Hydroxy-18-methyl-delta4-estrene-3,17-dione | C19H26O3 | 详情 | 详情 | |
| (II) | 33581 | 11alpha-Hydroxy-18-methylestr-4-ene-3,17-dione bis(ethyleneketal) | C23H34O5 | 详情 | 详情 | |
| (III) | 33582 | 18-Methylestr-4-ene-3,11,17-trione 3,17-bis(ethyleneketal) | C23H32O5 | 详情 | 详情 | |
| (IV) | 33583 | 11-Methylene-18-methyl-delta4-estren-3,17-dione diethyleneketal; 18-Methyl-11,11-methyleneestr-4-ene-3,17-dione bis(ethyleneketal) | C24H34O4 | 详情 | 详情 | |
| (V) | 33584 | (8R,9S,10R,13S,14S)-13-ethyl-11-methylene-7,8,9,10,11,12,13,14,15,16-decahydro-1H-cyclopenta[a]phenanthrene-3,17(2H,6H)-dione | C20H26O2 | 详情 | 详情 | |
| (VI) | 33585 | (8R,9S,10R,13S,14S)-13-ethyl-11-methylene-3-(1-pyrrolidinyl)-1,2,7,8,9,10,11,12,13,14,15,16-dodecahydro-17H-cyclopenta[a]phenanthren-17-one | C24H33NO | 详情 | 详情 | |
| (VII) | 33586 | (8R,9S,10R,13S,14S,17R)-13-ethyl-17-ethynyl-11-methylene-3-(1-pyrrolidinyl)-2,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-ol | C26H35NO | 详情 | 详情 | |
| (C) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(V)Dehydroepiandrosterone acetate (I) is converted to the lactam (II), which is hydrolyzed to the alcohol (III). Oppenauer oxidation of (III) gives the a,3-unsaturated ketone (IV). The intermediate (IV) is treated with pyrrolidine in methanol to give the enamine (V) in excellent yield. The latter, on sodium borohydride reduction affords (VI), the 3beta- configuration being assigned on the basis of similar reductions reported elsewhere. Sodium and n-pentanol reduction of (VI) leads to the diamine (VII), the methyl derivative (VIII) of which is prepared and converted into the dimethiodide (HS-310).
| 【1】 Singh, H.; Paul, D.; Steroids and related studies. Part XXV. Chandonium iodide (17alpha-Methyl-3beta-pyrrolidino-17alpha-aza-D-homoandrost-5-ene-Dimethyliodide) and other quaternary ammonium steroid analogues. J Chem Soc - Perkins Trans I 1974, 1476. |
| 【2】 Schmitt, J.; et al.; Recherches sur les amino-stéroïdes. VI. Stéroïdes à restes aminés fixés en C3. Préparation par réduction au borohydrurre de sodium et au diborane des "énamines" derivées de céto-3. Bull Soc Chim France 1963, 807-815. |
| 【3】 Marshall, J.A.; Johnson, W.S.; Reduction od steroidal enamines. J Org Chem 1963, 28, 421-423. |
| 【4】 Arya. V.P.; Chandonium iodide. Drugs Fut 1978, 3, 11, 807. |
| 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) | 20083 | Prasterone acetate;3b-Hydroxy-5-androstene-17-one acetate；Dehydroisoandrosterone acetate;Dehydroepiandrosterone 3-acetate;Dehydroepiandrosterone acetate;(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-oxo-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl acetate | 853-23-6 | C21H30O3 | 详情 | 详情 |
| (II) | 39912 | (4aS,4bR,8S,10aR,10bS,12aS)-10a,12a-dimethyl-2-oxo-1,2,3,4,4a,4b,5,7,8,9,10,10a,10b,11,12,12a-hexadecahydronaphtho[2,1-f]quinolin-8-yl acetate | C21H31NO3 | 详情 | 详情 | |
| (III) | 39913 | (4aS,4bR,8S,10aR,10bS,12aS)-8-hydroxy-10a,12a-dimethyl-3,4,4a,4b,5,7,8,9,10,10a,10b,11,12,12a-tetradecahydronaphtho[2,1-f]quinolin-2(1H)-one | C19H29NO2 | 详情 | 详情 | |
| (IV) | 39914 | (4aS,4bR,10aR,10bS,12aS)-10a,12a-dimethyl-1,3,4,4a,4b,5,6,9,10,10a,10b,11,12,12a-tetradecahydronaphtho[2,1-f]quinoline-2,8-dione | C19H27NO2 | 详情 | 详情 | |
| (V) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 |
| (VI) | 39915 | (4aS,4bR,10aR,10bS,12aS)-10a,12a-dimethyl-8-(1-pyrrolidinyl)-3,4,4a,4b,5,9,10,10a,10b,11,12,12a-dodecahydronaphtho[2,1-f]quinolin-2(1H)-one | C23H34N2O | 详情 | 详情 | |
| (VII) | 39916 | (4aS,4bR,10aR,10bS,12aS)-10a,12a-dimethyl-8-(1-pyrrolidinyl)-3,4,4a,4b,5,7,8,9,10,10a,10b,11,12,12a-tetradecahydronaphtho[2,1-f]quinolin-2(1H)-one | C23H36N2O | 详情 | 详情 | |
| (VIII) | 39917 | (4aS,4bR,10aR,10bS,12aS)-10a,12a-dimethyl-8-(1-pyrrolidinyl)-1,2,3,4,4a,4b,5,7,8,9,10,10a,10b,11,12,12a-hexadecahydronaphtho[2,1-f]quinoline | C23H38N2 | 详情 | 详情 | |
| (IX) | 39918 | (4aS,4bR,10aR,10bS,12aS)-1,10a,12a-trimethyl-8-(1-pyrrolidinyl)-1,2,3,4,4a,4b,5,7,8,9,10,10a,10b,11,12,12a-hexadecahydronaphtho[2,1-f]quinoline | C24H40N2 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(A)4-(4-isopropylpiperazinocarbonyl)phenol (IV) is obtained by reaction of 1-isopropylpiperazine (I) and 4-ethoxycarbonyloxybenzoylchloride (II) in CHCl3 using triethylamine (Et3N) as a proton scavenger, followed by removing its ethoxycarbonyl group using pyrrolidine in ethylacetate. Also, the reaction in CHCl3 of 1,2,3,4-tetrahydro-1-naphtoyl chloride (III) and (IV) using Et3N, followed by neutralization of the medium using NaOH and by salt formation using CH3SO3H in ethanol, yields FK-448.
| 【1】 Fujii, S.; Hattori, E.; Hirata, M.; Watanabe, K.; Onogi, K.; Nagakura, M. (Kowa Co., Ltd.); Benzoylpiperazine esters and a process for their production. EP 0098713; JP 83225080; US 4898876 . |
| 【2】 Prous, J.; Castaner, J.; FK-448. Drugs Fut 1986, 11, 3, 185. |
| 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) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 |
| (I) | 27370 | 1-isopropylpiperazine | C7H16N2 | 详情 | 详情 | |
| (II) | 27371 | 4-(chlorocarbonyl)phenyl ethyl carbonate | C10H9ClO4 | 详情 | 详情 | |
| (III) | 27373 | 1,2,3,4-tetrahydro-1-naphthalenecarbonyl chloride | C11H11ClO | 详情 | 详情 | |
| (IV) | 27372 | (4-hydroxyphenyl)(4-isopropyl-1-piperazinyl)methanone | C14H20N2O2 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(II)The reaction of 4-benzoyloxycyclohexanone (I) with pyrrolidine (II) by means of p-toluenesulfonic acid in refluxing benzene gives the corresponding enamine (III), which is cyclized with acrylamide (IV) in refluxing dioxane yielding the mixture of hexahydroquinolones (V) and (VI). Benzylation of this mixture with benzylbromide (A) and NaH in THF affords the mixture of N-benzylquinolones (VII) and (VIII), which is reduced with LiAlH4 to the mixture of N-benzylhexahydroquinolines (IX) and (X). The reduction of this mixture with sodium cyanoborohydride in THF affords trans-1-benzyl-6-hydroxydecahydro quinoline (XI), which by reaction with BN in CH2Cl2 is converted to trans-1-cyano-6-hydroxydecahydro quinoline (XII). Oxidation of (XII) with CrO3/pyridine in CH2Cl2 gives the corresponding quinolone (XIII), which by reaction with dimethylformamide dimethyl acetal (XIV) in refluxing benzene is converted to 1-cyano-6-oxo-7-(dimethylaminomethylene)decahydroquinoline (XV). The cyclization of (XV) with hydrazine in refluxing methanol affords 5-cyano-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]quinoline (XVI), which by a reductive cleavage with Zn and acetic acid gives 4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]quinoline (XVII). Finally, this compound is alkylated with propionaldehyde (B) and sodium cyanoborohydride in methanol.
| 【1】 Bach, N.; Kornfeld, E.C. (Eli Lilly and Company); Prolactin inhibiting octahydropyrazolo[3,4-g]quinolines. DD 148517; EP 0013787; ES 482087; FR 2446820; FR 2446821; FR 2446822; GB 2040915; GB 2092579; US 4198415 . |
| 【2】 Serradell, M.N.; Castaner, J.; Castaner, R.M.; Mannhold, R.; Quinpirole Hydrochloride. Drugs Fut 1987, 12, 6, 558. |
| 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) | 12912 | 1-(Bromomethyl)benzene; Alpha-bromotoluene | 100-39-0 | C7H7Br | 详情 | 详情 |
| (B) | 15966 | propionaldehyde | 123-38-6 | C3H6O | 详情 | 详情 |
| (I) | 16967 | N-(tert-butyl)-5-propyl-2-thiophenecarboxamide | C12H19NOS | 详情 | 详情 | |
| (II) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 |
| (III) | 28829 | 4-(1-pyrrolidinyl)-3-cyclohexen-1-yl benzoate | C17H21NO2 | 详情 | 详情 | |
| (IV) | 10851 | Acrylamide | 79-06-1 | C3H5NO | 详情 | 详情 |
| (V) | 28830 | 2-oxo-1,2,3,4,5,6,7,8-octahydro-6-quinolinyl benzoate | C16H17NO3 | 详情 | 详情 | |
| (VI) | 28831 | 2-oxo-1,2,3,4,4a,5,6,7-octahydro-6-quinolinyl benzoate | C16H17NO3 | 详情 | 详情 | |
| (VII) | 28832 | 1-benzyl-2-oxo-1,2,3,4,5,6,7,8-octahydro-6-quinolinyl benzoate | C23H23NO3 | 详情 | 详情 | |
| (VIII) | 28833 | 1-benzyl-2-oxo-1,2,3,4,4a,5,6,7-octahydro-6-quinolinyl benzoate | C23H23NO3 | 详情 | 详情 | |
| (IX) | 28834 | 1-benzyl-6-hydroxy-3,4,5,6,7,8-hexahydro-2(1H)-quinolinone | C16H19NO2 | 详情 | 详情 | |
| (X) | 28835 | 1-benzyl-6-hydroxy-3,4,4a,5,6,7-hexahydro-2(1H)-quinolinone | C16H19NO2 | 详情 | 详情 | |
| (XI) | 28836 | (4aR,8aR)-1-benzyldecahydro-6-quinolinol | C16H23NO | 详情 | 详情 | |
| (XII) | 28837 | (4aR,8aR)-1-cyanodecahydro-6-quinolinol | C10H16N2O | 详情 | 详情 | |
| (XIII) | 28838 | (4aR,8aR)-1-cyanooctahydro-6(2H)-quinolinone | C10H14N2O | 详情 | 详情 | |
| (XIV) | 11984 | N-(Dimethoxymethyl)-N,N-dimethylamine;dimethylformamide dimethylacetal;1,1-dimethoxy-N,N-dimethylmethanamine； Dimethoxy-N,N-dimethylmethanamine; N,N-Dimethylformamide dimethyl acetal | 4637-24-5 | C5H13NO2 | 详情 | 详情 |
| (XV) | 28839 | (4aR,8aR)-1-cyano-7-[(Z)-(dimethylamino)methylidene]octahydro-6-quinolinone | C13H19N3O | 详情 | 详情 | |
| (XVI) | 28840 | (4aR,8aR)-5-cyano-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]quinoline | C11H14N4 | 详情 | 详情 | |
| (XVII) | 28841 | (4aR,8aR)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]quinoline | C10H15N3 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(I)By condensation of pyrrolidine (I) with paraformaldehyde (II) and 4-ethylpropiophenone (III) by means of dry HCl in refluxing ethyl acetate.
| 【1】 Susumu, O.; Masaru, S.; Tomio, Y.; Yutaka, N.; Masatoshi, H. (Nippon Chemiphar Co., Ltd.); Benzimidazole derivs. and antiulcer agents contain. AU 8546409; BE 0903128; CH 665417; DE 3531487; ES 8703142; FR 2569691; GB 2163747; JP 1986060660; JP 1986221175; JP 1986221176; JP 1991223260; JP 1991223261; JP 1991223262; JP 1991227927 . |
| 【2】 Itho, Y.; Kato, H.; Koshinaka, E.; Nishino, H.; Ogawa, N. (Hokuriku Seiyaku Co., Ltd.); Derivs. of 3-pyrrolidinopropiophenone and a proces. FR 2559771 . |
| 【3】 Itho, Y.; Kato, H.; Koshinaka, E.; Nishino, H.; Ogawa, N. (Hokuriku Seiyaku Co., Ltd.); Derivs. of 3-pyrrolidinopropiophenone and a proces. EP 0150235 . |
| 【4】 Prous, J.; Castaner, J.; HSR-770. Drugs Fut 1988, 13, 4, 310. |
合成路线9
该中间体在本合成路线中的序号：(I)The first total synthesis of hyperzine A as racemic is carried out as follows: The reaction of pyrrolidine (I) with cyclohexane-1,4-dione monoethyleneketal (II) by means of p-toluenesulfonic acid in refluxing benzene gives the enamine (III), which is cyclized with acrylamide (IV) in refluxing dioxane affording the bicyclic pyridone (V). The benzylation of (V) with benzyl chloride and KH in THF yields the N-benzyl derivative (VI), which is dehydrogenated by means of phenylselenium chloride in THF, followed by a treatment with NaIO4 in refluxing methanol to give the protected pyridone (VII). The debenzylation of (VII) with Pd(OH)2 in acetic acid yields the free pyridone (VIII), which is aromatized with methyl iodide and silver carbonate to the 2-methoxypyridine (IX). Elimination of the ketal group of (IX) with HCl in refluxing acetone affords the tetrahydroquinolone (X), which is carboxylated by means of dimethyl carbonate and KH to give 2-methoxy-6-oxo-5,6,7,8-tetrahydroquinoline-5-carboxylic acid methyl ester (XI). The cyclization of (XI) with 2-methylacrolein (XII) by means of sodium methoxide in methanol or tetramethylguanidine in dichloromethane yields the tricyclic compound (XIII), which is mesylated with mesyl chloride to the mesylate (XIV). Elimination of the mesyl group of (XIV) with refluxing acetic acid - sodium acetate affords the olefinic compound (XV), which is submitted to a Wittig condensation with ethylidenetriphenylphosphorane in ether giving the diolefinic compound (XVI) as a mixture of the E- and Z-isomers. Selective hydrolysis of (XVI) with NaOH in THF - methanol yields acid (XVII) as the E-isomer, which is treated with SOCl2 and sodium azide in a modified Curtius reaction to obtain the urethane (XVIII). Lastly trimethylsilyl iodide is used to effect both N- and O-deprotection.
| 【1】 Xia, Y.; Kozikowski, A.P.; A practical synthesis of the Chinese "nootropic" agent huperzine A: A possible lead in the treatment of Alzheimer's disease. J Am Chem Soc 1989, 111, 11, 4116. |
| 【2】 Qian, L.; Ji, R.; A total synthesis of (±)-huperzine A. Tetrahedron Lett 1989, 30, 16, 2089. |
| 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) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 |
| (II) | 11377 | 1,4-Dioxaspiro[4.5]decan-8-one | 4746-97-8 | C8H12O3 | 详情 | 详情 |
| (III) | 11378 | 1-(1,4-Dioxaspiro[4.5]dec-7-en-8-yl)pyrrolidine | C12H19NO2 | 详情 | 详情 | |
| (IV) | 11379 | 3-Butenamide | C4H7NO | 详情 | 详情 | |
| (V) | 11380 | 1',2',3',4',5',6',7',8'-Octahydrospiro[1,3-dioxlane-2,6'-quinolin]-2'-one | C11H15NO3 | 详情 | 详情 | |
| (VI) | 11381 | 1'-Benzyl-1',2',3',4',5',6',7',8'-Octahydrospiro[1,3-dioxlane-2,6'-quinolin]-2'-one | C18H21NO3 | 详情 | 详情 | |
| (VII) | 11382 | 1'-Benzyl-1',2',5',6',7',8'-Hexahydrospiro[1,3-dioxlane-2,6'-quinolin]-2'-one | C18H19NO3 | 详情 | 详情 | |
| (VIII) | 11383 | 1',2',5',6',7',8'-Hexahydrospiro[1,3-dioxlane-2,6'-quinolin]-2'-one | C11H13NO3 | 详情 | 详情 | |
| (IX) | 11384 | 2'-Methoxy-5',6',7',8'-tetrahydrospiro[1,3-dioxlane-2,6'-quinoline] | C12H15NO3 | 详情 | 详情 | |
| (X) | 11385 | 2-Methoxy-7,8-dihydro-6(5H)-quinolinone | C10H11NO2 | 详情 | 详情 | |
| (XI) | 11386 | methyl 2-methoxy-6-oxo-5,6,7,8-tetrahydro-5-quinolinecarboxylate | C12H13NO4 | 详情 | 详情 | |
| (XII) | 11387 | 2-Methylacrylaldehyde; Methacrylaldehyde | 78-85-3 | C4H6O | 详情 | 详情 |
| (XIII) | 11388 | methyl (1S)-10-hydroxy-5-methoxy-11-methyl-13-oxo-6-azatricyclo[7.3.1.0(2,7)]trideca-2,4,6-triene-1-carboxylate | C16H19NO5 | 详情 | 详情 | |
| (XIV) | 11389 | methyl (1S)-5-methoxy-11-methyl-10-[(methylsulfonyl)oxy]-13-oxo-6-azatricyclo[7.3.1.0(2,7)]trideca-2,4,6-triene-1-carboxylate | C17H21NO7S | 详情 | 详情 | |
| (XV) | 11390 | methyl (1S)-5-methoxy-11-methyl-13-oxo-6-azatricyclo[7.3.1.0(2,7)]trideca-2,4,6,10-tetraene-1-carboxylate | C16H17NO4 | 详情 | 详情 | |
| (XVI) | 11391 | methyl (1R)-13-[(E)ethylidene]-5-methoxy-11-methyl-6-azatricyclo[7.3.1.0(2,7)]trideca-2,4,6,10-tetraene-1-carboxylate | C18H21NO3 | 详情 | 详情 | |
| (XVII) | 11392 | (1R)-13-[(E)Ethylidene]-5-methoxy-11-methyl-6-azatricyclo[7.3.1.0(2,7)]trideca-2,4,6,10-tetraene-1-carboxylic acid | C17H19NO3 | 详情 | 详情 | |
| (XVIII) | 11393 | ethyl 13-[(E)ethylidene]-5-methoxy-11-methyl-6-azatricyclo[7.3.1.0(2,7)]trideca-2,4,6,10-tetraen-1-ylcarbamate | C19H24N2O3 | 详情 | 详情 | |
| (XIX) | 11394 | ethyl 13-[(E)ethylidene]-11-methyl-5-oxo-6-azatricyclo[7.3.1.0(2,7)]trideca-2(7),3,10-trien-1-ylcarbamate | C18H22N2O3 | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(VIII)The cyclization of ethyl cyanoacetate (I) with urea (II) in ethanolic NaOEt provided 6-aminouracil (III). Nitrosation of (III) with NaNO2 in aqueous AcOH, followed by reduction of the resulting nitroso compound (IV) using sodium hydrosulfite gave 5,6-diaminouracil, which was purified by conversion to its hydrochloride salt (V). Condensation of this diamine with melted oxalic acid produced tetrahydroxypteridine (VI). Subsequent reaction of (VI) with PCl5 and POCl3 afforded tetrachlorocompound (VII). The reaction of (VII) with pyrrolidine (VIII) in aqueous KHCO3/CHCl3 resulted in a mixture of 2-, 4-, 7- and 4,7-substituted compounds, from which the desired 4-pyrrolidino-2,6,7-trichloropteridine (IX) was isolated by column chromatography. Further treatment of (IX) with benzylamine (X) in dioxan at r.t. provided diamine (XI). Finally, substitution of the third chlorine atom for piperazine (XII) was accomplished in boiling dioxan.
| 【1】 Merz, K.-H.; Marko, D.; Regiert, T.; Reiss, G.; Frank, W.; Eisenbrand, G.; Synthesis of 7-benzylamino-6-chloro-2-piperazino-4-pyrrolidinopteridine and novel derivatives free of positional isomers. Potent inhibitors of cAMP-specific phosphodiesterase and of malignant tumor cell growth. J Med Chem 1998, 41, 24, 4733. |
| 【2】 Taylor, E.C. Jr.; Sherman, W.R.; Diaminouracil hydrochloride. Org Synth Coll 1957, 37, 15. |
| 【3】 Schopf, C.; Reichert, R.; Zur kenntnis des leukopterins. Liebigs Ann Chem 1941, 548, 82. |
| 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) | 11877 | Cyanoacetic acid ethyl ester; Ethyl 2-cyanoacetate; Ethyl cyanoacetate; Ethyl isocyanacetate | 105-56-6 | C5H7NO2 | 详情 | 详情 |
| (II) | 19310 | urea | 57-13-6 | CH4N2O | 详情 | 详情 |
| (III) | 19311 | 6-amino-2,4(1H,3H)-pyrimidinedione | 873-83-6 | C4H5N3O2 | 详情 | 详情 |
| (IV) | 19312 | 6-amino-5-nitroso-2,4(1H,3H)-pyrimidinedione | C4H4N4O3 | 详情 | 详情 | |
| (V) | 19313 | 5,6-diamino-2,4(1H,3H)-pyrimidinedione | 3240-72-0 | C4H6N4O2 | 详情 | 详情 |
| (VI) | 19314 | 2,4,6,7-pteridinetetrol | C6H4N4O4 | 详情 | 详情 | |
| (VII) | 19315 | 2,4,6,7-tetrachloropteridine | C6Cl4N4 | 详情 | 详情 | |
| (VIII) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 |
| (IX) | 19317 | 2,6,7-trichloro-4-(1-pyrrolidinyl)pteridine | C10H8Cl3N5 | 详情 | 详情 | |
| (X) | 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 |
| (XI) | 19319 | N-benzyl-N-[2,6-dichloro-4-(1-pyrrolidinyl)-7-pteridinyl]amine; N-benzyl-2,6-dichloro-4-(1-pyrrolidinyl)-7-pteridinamine | C17H16Cl2N6 | 详情 | 详情 | |
| (XII) | 10355 | Diethylenediamine; Piperazine | 110-85-0 | C4H10N2 | 详情 | 详情 |
合成路线11
该中间体在本合成路线中的序号：(II)N-(Methoxycarbonyl)-(S)-phenylglycine (I) was converted to amide (III) by coupling with pyrrolidine (II) by means of DCC and HOBT. Simultaneous reduction of both carbamoyl and amide functions of (III) using excess LiAlH4 in THF gave the chiral diamine (IV). Final acylation of (IV) with (3,4-dichlorophenyl)acetyl chloride (V) in CH2Cl2 yielded the target amide.
| 【1】 Costello, G.F.; et al.; 2-(3, 4-Dichlorophenyl)-N-methyl-N-[2-(1-pyrrolidinyl)-1-substituted-ethyl]-acetamides: The use of conformational analysis in the development of a novel series of potent opioid kappa agonists. J Med Chem 1991, 34, 1, 181-9. |
| 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) | 26108 | (2S)-2-[(methoxycarbonyl)amino]-2-phenylethanoic acid | C10H11NO4 | 详情 | 详情 | |
| (II) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 |
| (III) | 26109 | methyl (1S)-2-oxo-1-phenyl-2-(1-pyrrolidinyl)ethylcarbamate | C14H18N2O3 | 详情 | 详情 | |
| (IV) | 26110 | N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]amine; (1S)-N-methyl-1-phenyl-2-(1-pyrrolidinyl)-1-ethanamine | C13H20N2 | 详情 | 详情 | |
| (V) | 26111 | 2-(3,4-dichlorophenyl)acetyl chloride | C8H5Cl3O | 详情 | 详情 |
合成路线12
该中间体在本合成路线中的序号：(V)Initially, a small-scale synthetic route to idoxifene had been described involving Friedel-Crafts acylation of 2-chloroethoxybenzene by 2-phenylbutyric acid followed by reaction of the resulting ketone with 4-iodophenyllithium (prepared by monolithiation of 1,4-diiodobenzene) . A mixture of E and Z isomers of the triphenylbutene was then produced by dehydration of the intermediate tertiary alcohol from which the desired E isomer (in which the unsubstituted phenyl and iodophenyl residues are in a trans relationship) was separated by crystallization. Idoxifene was then produced by final modification of the chloroethoxy side chain using pyrrolidine. Modification of the above scheme to provide an efficient, large-scale synthesis of idoxifene has now been described initially involving treatment of 2-phenoxyethanol with pyridine (in catalytic amounts) and thionyl chloride/heat to produce 2-chloroethoxybenzene.
| 【1】 Kelland, L.R.; Jarman, M.; Idoxifene. Drugs Fut 1995, 20, 7, 666. |
| 【2】 Potter, G.A.; Jarman, M.; McCague, R.; An efficient, large-scale synthesis of idoxifene ((E)-1-[4-[N-(pyrrolidino)ethoxy]phenyl]-1-(4-iodophenyl)-2-phenyl-1-butene). Org Prep Proced Int 1994, 26, 343-6. |
| 【3】 McCague, R. (National Research Development Corp.); Tamoxifen derivs. EP 0260066; GB 2196003; JP 1988077845 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (B) | 12844 | (4-Iodophenyl)lithium | C6H4ILi | 详情 | 详情 | |
| (A) | 21130 | 2-Phenylbutyric acid; alpha-Ethylbenzeneacetic acid | 90-27-7 | C10H12O2 | 详情 | 详情 |
| (I) | 12841 | 2-Phenoxyethanol; 2-Phenoxy-1-ethanol | 122-99-6 | C8H10O2 | 详情 | 详情 |
| (II) | 12842 | 2-Chloroethyl phenyl ether; b-Chlorophenetole; 1-(2-Chloroethoxy)benzene | 622-86-6 | C8H9ClO | 详情 | 详情 |
| (III) | 12843 | 1-[4-(2-Chloroethoxy)phenyl]-2-phenyl-1-butanone | C18H19ClO2 | 详情 | 详情 | |
| (IV) | 12845 | 2-Chloroethyl 4-[(E)-1-(4-iodophenyl)-2-phenyl-1-butenyl]phenyl ether; 1-[(E)-1-[4-(2-Chloroethoxy)phenyl]-2-phenyl-1-butenyl]-4-iodobenzene | C24H22ClIO | 详情 | 详情 | |
| (V) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 |
合成路线13
该中间体在本合成路线中的序号：(IV)This compound can be obtained in a simple way: Under nitrogen, borontrifluoride etherate solution is added to heated 2-methyl-1-propanol (II), and 1-chloro-2,3-epoxypropane (I) is added. When the reaction is completed, pyrrolidine (IV) is added to obtain alpha-[2-methyl-propoxymethyl]-1-pyrrolidine-ethanol (V). 1-[2-Chloro-3-(2-methylpropoxy)propyl]pyrrolidine (VI) is obtained by chlorination with thionyl chloride of the subsequent amino alcohol. The condensation of 1-propynyl-1-cyclohexanol (VII) with 1-[2-chloro-3-(2-methylpropoxy)propyl]pyrrolidine (VI) in toluene and sodium hydroxide in water affords dopropidil. Due to the pyrrolidine shift mechanism, the reaction yields the correct structure, confirmed by 1H and 13C NMR as well as by mass spectra and X-ray analysis. The pyrrolidine shift mechanism is explained by the assumption of an intermediate aziridinium ion (VIII), which is opened regiospecifically at the less hindered C-N bond by the nucleophile ion.
| 【1】 Carlier, P.; Montell, A.J.-C.; Simond, J.A.L. (Riom Laboratoires); Ethers of 1-(2-propynyloxy)-2-amino-3-propanol, their preparation and their application in therapeutic. EP 0031771; US 4430332 . |
| 【2】 Dupont, L.; Dideberg, O.; Simond, J.; X-ray analysis of CERM 4205. Acta Cryst Sect C 1986, 42, 864. |
| 【3】 Massingham, R.; Monteil, A.; DOPROPIDIL HYDROCHLORIDE. Drugs Fut 1990, 15, 5, 453. |
| 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) | 10146 | Epichlorohydrin; 2-(Chloromethyl)oxirane | 106-89-8 | C3H5ClO | 详情 | 详情 |
| (II) | 12982 | 2-Methyl-1-propanol | 78-83-1 | C4H10O | 详情 | 详情 |
| (III) | 12983 | 2-(Isobutoxymethyl)oxirane; Isobutyl 2-oxiranylmethyl ether | C7H14O2 | 详情 | 详情 | |
| (IV) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 |
| (V) | 12985 | 1-Isobutoxy-3-(1-pyrrolidinyl)-2-propanol | C11H23NO2 | 详情 | 详情 | |
| (VI) | 12986 | 2-Chloro-3-(1-pyrrolidinyl)propyl isobutyl ether; 1-(2-Chloro-3-isobutoxypropyl)pyrrolidine | C11H22ClNO | 详情 | 详情 | |
| (VII) | 12987 | 1-Propynyl-1-cyclohexanol; 1-(1-Propynyl)cyclohexanol | 697-37-0 | C9H14O | 详情 | 详情 |
| (VIII) | 12988 | 1-(Isobutoxymethyl)-3-azoniaspiro[2.4]heptane | C11H22NO | 详情 | 详情 |
合成路线14
该中间体在本合成路线中的序号：(IV)The Grignard reaction of 4-(trifluoromethyl)benzaldehyde (I) with ethylmagnesium bromide in ethyl ether gives 1-[4-(trifluoromethyl)phenyl]-1-propanol (II), which is oxidized with CrO3/H2SO4 yielding 4-(trifluoromethyl)propiophenone (III). The condensation of (III) with pyrrolidine (IV) and paraformaldehyde by means of HCl in refluxing isopropanol affords racemic 2-methyl-3-(1-pyrrolidinyl)propiophenone (V), which is finally submitted to optical resolution with N-acetyl-L-phenylglycine (VI) or D-malic acid (VII) and treated with dry HCl gas.
| 【1】 Kurashige, S.; Izumi, G.; Shiozawa, A.; Narita, K.; Sakitama, K.; Ishikawa, M.; Synthesis and activity of 2-methyl-3-aminopropiophenones as centrally acting muscle relaxants. Eur J Med Chem 1995, 30, 1, 85-94. |
| 【2】 Wroblewskki, T.; Castaner, J.; Leeson, P.; Lanperisone Hydrochloride. Drugs Fut 1998, 23, 5, 485. |
| 【3】 Shiozawa, A.; Ishikawa, M.; Sugimura, H.; Yamamoto, H.; Sakasai, T.; Ohtsuki, K.; Kurashige, S. (Nippon Kayaku Co., Ltd.); An optically active propanone deriv. and process for producing the same and use thereof. EP 0266577; JP 1989131171 . |
| 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) | 13380 | 4-(Trifluoromethyl)benzaldehyde; alpha,alpha,alpha-Trifluoro-p-tolualdehyde | 455-19-6 | C8H5F3O | 详情 | 详情 |
| (II) | 13381 | 1-[4-(Trifluoromethyl)phenyl]-1-propanol | C10H11F3O | 详情 | 详情 | |
| (III) | 13382 | 1-[4-(Trifluoromethyl)phenyl]-1-propanone; 4-(Trifluoromethyl)propiophenone | 711-33-1 | C10H9F3O | 详情 | 详情 |
| (IV) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 |
| (V) | 13384 | 2-Methyl-3-(1-pyrrolidinyl)-1-[4-(trifluoromethyl)phenyl]-1-propanone | C15H18F3NO | 详情 | 详情 | |
| (VI) | 13385 | (2S)-2-(Acetamido)-2-phenylethanoic acid | C10H11NO3 | 详情 | 详情 |
合成路线15
该中间体在本合成路线中的序号：(II)The condensation of (2alpha,3alpha,5alpha,16alpha,17alpha)-2,3:16,17-diepoxyandrostan-17-ol acetate (I) with pyrrolidine (II) by means of NaOH in methanol, followed by reduction with NaBH4 in the same solvent gives (2alpha,3alpha,5alpha,16beta,17beta)-2,3-epoxy-16-(1-pyrrolidinyl) androstan-17-ol (III), which is further condensed with morpholine (IV) in refluxing water yielding (2beta,3alpha,5alpha,16beta,17beta)-2-(4-morpholinyl)-16-(1-pyrrolidinyl)androstane-3,17-diol (V). Partial acetylation of (V) with acetyl chloride in dichloromethane at room temperature affords the corresponding 17-acetoxy derivative (VI), which is finally quaternized with allyl bromide (VII) in dichloromethane.
| 【1】 Savage, D.S.; Sleig, T.; Carlyle, I.G. (Akzo Nobel N.V.); Novel 2beta-morpholino-androstane derivs. and process for their preparation. AU 8814570; EP 0287150; JP 1988277693; US 4894369 . |
| 【2】 Pento, J.T.; Castaner, J.; Rocuronium Bromide. Drugs Fut 1994, 19, 9, 841. |
| 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) | 13647 | (1aR,2aS,2bS,4aS,5aR,6aS,6bR,8aS,9aS)-2a,4a-dimethylhexadecahydro-4bH-oxireno[2'',3'':4',5']cyclopenta[1',2':7,8]phenanthro[2,3-b]oxiren-4-yl acetate | C21H30O4 | 详情 | 详情 | |
| (II) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 |
| (III) | 13649 | (1R,2S,3aS,3bR,5aS,6aS,7aR,8aS,8bS,10aS)-8a,10a-Dimethyl-2-(1-pyrrolidinyl)hexadecahydro-1H-cyclopenta[7,8]phenanthro[2,3-b]oxiren-1-ol | C23H37NO2 | 详情 | 详情 | |
| (IV) | 10388 | Morpholine | 110-91-8 | C4H9NO | 详情 | 详情 |
| (V) | 13651 | (2S,3S,5S,8R,9S,10S,13S,14S,16S,17R)-10,13-Dimethyl-2-(4-morpholinyl)-16-(1-pyrrolidinyl)hexadecahydro-1H-cyclopenta[a]phenanthrene-3,17-diol | C27H46N2O3 | 详情 | 详情 | |
| (VI) | 13652 | (2S,3S,5S,8R,9S,10S,13S,14S,16S,17R)-3-hydroxy-10,13-dimethyl-2-(4-morpholinyl)-16-(1-pyrrolidinyl)hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl acetate | C29H48N2O4 | 详情 | 详情 | |
| (VII) | 11463 | 3-Bromo-1-propene; 3-Bromopropene；allyl bromide | 106-95-6 | C3H5Br | 详情 | 详情 |
合成路线16
该中间体在本合成路线中的序号：(II)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17
该中间体在本合成路线中的序号：(VIII)Coupling of indanylacetic acid (IV) with L-thioproline ethyl ester (V) by means of EDC gave amide (VI). Subsequent saponification of the ethyl ester group of (VI) furnished (indanylacetyl)thioproline (VII). The title compound was finally obtained by coupling of acid (VII) with pyrrolidine (VIII).
| 【1】 Aotsuka, T.; Torizuka, M.; Soeda, M.; Ogura, K.; Tanaka, Y.; Kato, H.; Nakata, N.; Miura, N.; Morita, H. (Zeria Pharmaceutical Co., Ltd.); Condensed benzene deriv.. AU 8945914; EP 0372484; JP 1990262557; US 5028604 . |
| 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) | 21721 | 2-(2,3-dihydro-1H-inden-2-yl)acetic acid | 37868-26-1 | C11H12O2 | 详情 | 详情 |
| (V) | 12901 | ethyl (4R)-1,3-thiazolidine-4-carboxylate | C6H11NO2S | 详情 | 详情 | |
| (VI) | 55612 | ethyl (4R)-3-[2-(2,3-dihydro-1H-inden-2-yl)acetyl]-1,3-thiazolidine-4-carboxylate | C17H21NO3S | 详情 | 详情 | |
| (VII) | 55613 | (4R)-3-[2-(2,3-dihydro-1H-inden-2-yl)acetyl]-1,3-thiazolidine-4-carboxylic acid | C15H17NO3S | 详情 | 详情 | |
| (VIII) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 |
合成路线18
该中间体在本合成路线中的序号：(A)By refluxing a solution of equimolecular quantities of 3-pentyloxyphenyl isocyanate (I) and trans-2-(1-pyrrolidinyl)cyclohexanol (II) in toluene. The obtained pentacaine base is transformed to the hydrochloride by treatment of an ether solution of anhydrous hydrogen chloride (1,2). The starting amino-alcohol (II) is prepared from cyclohexanol (III), which is first dehydrated to cyclohexene (IV). The following addition of HClO gives trans-2-chlorocyclohexanol (V), which, in turn is dehydrochlorinated to 1,2-epoxycyclohexane (VI). Final addition of pyrrolidine (A) yields the required intermediate (II).
| 【1】 Castaner, J.; Pentacaine. Drugs Fut 1976, 1, 8, 379. |
| 【2】 Subert, J.; et al.; Studies on local anesthetics. XLVIII. Preliminary analytical evaluation of the substance K-1902 (pentacaine). Cesk Farm 1975, 24, 5. |
| 【3】 Benes, L.; Borovansky, A.; Kopácová, L.; Basische trans- und cis-Cyklohexylester substituierter Alkoxycarbanilsäuren. XLI. Studien über Lokalanästhetika. Arch Pharm 1972, 305, 648. |
| 【4】 Benes, L.; Borovansky, A.; Kopácová, L.; Alkoxycarbanilic acid esters with high local anaesthetic activity. Arzneim-Forsch Drug Res 1969, 19, 1902-3. |
| 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) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 |
| (I) | 14636 | 3-(pentyloxy)phenyl isocyanate; 1-isocyanato-3-(pentyloxy)benzene | C12H15NO2 | 详情 | 详情 | |
| (II) | 14637 | (1R,2R)-2-(1-pyrrolidinyl)cyclohexanol | C10H19NO | 详情 | 详情 | |
| (III) | 11306 | Cyclohexanol | 108-93-0 | C6H12O | 详情 | 详情 |
| (IV) | 40446 | 1-cyclohexene | 110-83-8 | C6H10 | 详情 | 详情 |
| (V) | 40447 | (1R,2R)-2-chlorocyclohexanol | 1561-86-0 | C6H11ClO | 详情 | 详情 |
| (VI) | 40448 | (1R,6R)-7-oxabicyclo[4.1.0]heptane | C6H10O | 详情 | 详情 |
合成路线19
该中间体在本合成路线中的序号：(VI)4) The intermediate 4-(1-pyrrolidinylsulfonylmethyl)phenylhydrazine (III) can be obtained as follows: The condensation of pyrrolidine (VI) with 1-(4-nitrobenzylsulfonyl)chloride (VII) in dichloromethane gives the expected sulfonamide (VIII), which is reduced with H2 over RaNi in DMF, yielding 4-(1-pyrrolidinylsulfonylmethyl)aniline (IX). The diazotation of (IX) with NaNO2/HCl affords the corresponding diazo compound (X), which is finally reduced to the target intermediate (III) with SnCl2/HCl.
| 【1】 Fernandez-Forner, D.; New aniline derivatives as key intermediates in th. Res Disclosure 1998, 412, 1088. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (III) | 23429 | 1-[(4-hydrazinobenzyl)sulfonyl]pyrrolidine | C11H17N3O2S | 详情 | 详情 | |
| (VI) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 |
| (VII) | 23433 | (4-nitrophenyl)methanesulfonyl chloride | C7H6ClNO4S | 详情 | 详情 | |
| (VIII) | 23434 | 1-[(4-nitrobenzyl)sulfonyl]pyrrolidine | C11H14N2O4S | 详情 | 详情 | |
| (IX) | 23435 | 4-[(1-pyrrolidinylsulfonyl)methyl]phenylamine; 4-[(1-pyrrolidinylsulfonyl)methyl]aniline | C11H16N2O2S | 详情 | 详情 | |
| (X) | 23436 | 4-[(1-pyrrolidinylsulfonyl)methyl]benzenediazonium | C11H14N3O2S | 详情 | 详情 |
合成路线20
该中间体在本合成路线中的序号：(II)N-tert-Butoxycarbonyl valine (I) was converted to amide (III) by coupling with pyrrolidine (II) by means of DCC and HOBT. Simultaneous reduction of both carbamoyl and amide functions of (III) using excess LiAlH4 in THF gave the chiral diamine (IV). Final acylation of (IV) with (3,4-dichlorophenyl)acetyl chloride (V) in CH2Cl2 yielded the target amide.
| 【1】 Costello, G.F.; et al.; 2-(3, 4-Dichlorophenyl)-N-methyl-N-[2-(1-pyrrolidinyl)-1-substituted-ethyl]-acetamides: The use of conformational analysis in the development of a novel series of potent opioid kappa agonists. J Med Chem 1991, 34, 1, 181-9. |
| 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) | 19733 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutyric acid | C10H19NO4 | 详情 | 详情 | |
| (II) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 |
| (III) | 26112 | tert-butyl (1S)-2-methyl-1-(1-pyrrolidinylcarbonyl)propylcarbamate | C14H26N2O3 | 详情 | 详情 | |
| (IV) | 26113 | N-methyl-N-[(1S)-2-methyl-1-(1-pyrrolidinylmethyl)propyl]amine; (2S)-N,3-dimethyl-1-(1-pyrrolidinyl)-2-butanamine | C10H22N2 | 详情 | 详情 | |
| (V) | 26111 | 2-(3,4-dichlorophenyl)acetyl chloride | C8H5Cl3O | 详情 | 详情 |
合成路线21
该中间体在本合成路线中的序号：(VI)CFC-222 has been obtained by four closely related ways: 1) The acylation of beta-alanine (I) with tosyl chloride and NaOH in water gives the corresponding tosylate (II), which is esterified with SOCl2 and ethanol as usual yielding the ethyl ester (III). The alkylation of the amido group of (III) with 2-methylallyl chloride (IV) by means of KI, K2CO3 and tetrabutylammonium iodide in acetonitrile affords the alkylated sulfonamide (V), which is condensed with pyrrolidine (VI) by means of SOCl2 in dichloromethane to give the acylated pyrrolidine (VII). The cyclization of (VII) by means of trifluoromethanesulfonic anhydride and collidine in dichloromethane yields racemic cis-1-methyl-3-(p-toluenesulfonyl)-3-azabicyclo[3.2.0]heptan-6-one (VIII), which is converted to the corresponding oxime (IX) with hydroxylamine in pyridine. The reduction of (IX) with NaBH4 and NiCl2 affords racemic cis-1-methyl-3-(p-toluenesulfonyl)-3-azabicyclo[3.2.0]heptan-6-amine (X), which is submitted to optical resolution with L-tartaric acid to give pure (1R,5S,6S)-isomer (XI). Elimination of the tosyl group of (XI) with concentrated HBr yields (1R,5S,6S)-3-azabicyclo[3.2.0]heptan-6-amine (XII), which is finally condensed with 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (XIII) by means of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and HCl in acetonitrile. 2) The cyclization of the alkylated sulfonamide (V) to the racemic bicyclic ketone (VIII) can also be performed (with better yields) by direct cyclization with SOCl2 and triethylamine. 3) The conversion of the racemic ketone (VIII) to the racemic amine (X) can also be performed by treatment of (VIII) with O-methylhydroxylamine in methanol to obtain the O-methyloxime (XIV), which is then reduced to amine (X) with NaBH4 and trifluoroacetic acid (with poorer yields). 4) The optical resolution of racemic amine (X) can also be performed with N-tosyl-L-phenylalanine.
| 【1】 Lee, J.M.; Whang, H.S.; Lee, K.H.; Song, S.B.; Yoon, Y.H.; Kim, J.W.; Cho, I.H.; Practical synthesis of CFC-222, a new fluoroquinolone. 35th Intersci Conf Antimicrob Agents Chemother (Sept 17-20, San Francisco) 1995, Abst F198. |
| 【2】 Graul, A.; Castañer, J.; Ecenofloxacin Hydrochloride. Drugs Fut 1998, 23, 4, 370. |
| 【3】 Kim, C.S.; Kim, J.W.; Lee, J.M.; Cho, I.H.; Youn, Y.S.; Shin, Y.J.; Lee, K.H.; Kim, J.H.; Jung, Y.H.; An, S.H. (Cheil Jedang Corporation); Novel pyridone carboxylic acid derivs. JP 1996505384; US 5527910; WO 9415933 . |
| 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-(VIII) | 17029 | (1R,5S)-1-methyl-3-[(4-methylphenyl)sulfonyl]-3-azabicyclo[3.2.0]heptan-6-one | C14H17NO3S | 详情 | 详情 | |
| rac-(IX) | 17030 | (1R,5S)-1-methyl-3-[(4-methylphenyl)sulfonyl]-3-azabicyclo[3.2.0]heptan-6-one oxime | C14H18N2O3S | 详情 | 详情 | |
| rac-(X) | 17031 | (rac)-(1R*,5S*,6S*)-1-methyl-3-[(4-methylphenyl)sulfonyl]-3-azabicyclo[3.2.0]hept-6-ylamine; (rac)-(1R*,5S*,6S*)-1-methyl-3-[(4-methylphenyl)sulfonyl]-3-azabicyclo[3.2.0]heptan-6-amine | C14H20N2O2S | 详情 | 详情 | |
| rac-(XIV) | 17035 | (1R,5S)-1-methyl-3-[(4-methylphenyl)sulfonyl]-3-azabicyclo[3.2.0]heptan-6-one O-methyloxime | C15H20N2O3S | 详情 | 详情 | |
| (I) | 17022 | beta-Alanine; 3-aminopropionic acid | 107-95-9 | C3H7NO2 | 详情 | 详情 |
| (II) | 17023 | 3-(Toluene-4-sulfonylamino)-propionic acid; 3-[[(4-methylphenyl)sulfonyl]amino]propionic acid | C10H13NO4S | 详情 | 详情 | |
| (III) | 17024 | ethyl 3-[[(4-methylphenyl)sulfonyl]amino]propanoate | C12H17NO4S | 详情 | 详情 | |
| (V) | 17026 | ethyl 3-[[(4-methylphenyl)sulfonyl](2-methyl-2-propenyl)amino]propanoate | C16H23NO4S | 详情 | 详情 | |
| (VI) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 |
| (VII) | 17028 | 4-methyl-N-(2-methyl-2-propenyl)-N-[3-oxo-3-(1-pyrrolidinyl)propyl]benzenesulfonamide | C18H26N2O3S | 详情 | 详情 | |
| (XI) | 65065 | (1R,5S,6S)-1-methyl-3-[(4-methylphenyl)sulfonyl]-3-azabicyclo[3.2.0]hept-6-ylamine; (1R,5S,6S)-1-methyl-3-[(4-methylphenyl)sulfonyl]-3-azabicyclo[3.2.0]heptan-6-amine | C14H20N2O2S | 详情 | 详情 | |
| (XII) | 17033 | (1R,5S,6S)-1-methyl-3-azabicyclo[3.2.0]heptan-6-amine; (1R,5S,6S)-1-methyl-3-azabicyclo[3.2.0]hept-6-ylamine | C7H14N2 | 详情 | 详情 | |
| (XIII) | 17034 | 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxylic acid | 100361-18-0 | C12H8ClFN2O3 | 详情 | 详情 |
合成路线22
该中间体在本合成路线中的序号：(II)A new synthesis of Sch-56592 has been described: The reaction of (S)-ethyl lactate (I) with pyrrolidine (II) gives 1-[(S)-lactoyl]pyrrolidine (III), which is benzylated as usual with benzyl chloride yielding the benzyl ether (IV). The reaction of (IV) with ethylmagnesium bromide in THF affords 2(S)-benzyloxy-3-pentanone (V), which is reduced with LiBH4 in dimethoxyethane giving 2(S)-benzyloxy-3(RS)-pentanol (VI). The reaction of (VI) with 4-chlorobenzenesulfonyl chloride (VII) yields the corresponding sulfonate (VIII), which is treated with hydrazine in ethanol to afford a diastereomeric mixture of hydrazines that is resolved with L-dibenzoyltartaric acid giving the (S,S)-enantiomer (IX). The formylation of (IX) with refluxing ethyl formate yields the chiral formyl hydrazide (X), which is cyclized with N-[4-[4-[4-(trimethylsilyloxy)phenyl]piperazin-1-yl]phenyl]carbamic acid phenyl ester (XI) affording the triazolone (XII). Finally, this compound is condensed with the chiral tetrahydrofuran derivative (XIII) by means of NaOH in DMSO, and debenzylated by hydrogenation with H2 over Pd/C in formic acid
| 【1】 Andrews, D.R.; Gala, D.; Gosteli, J.; Guenter, F.; Leong, W.; Mergelsberg, I.; Sudhakar, A. (Schering Corp.); Process for the preparation of triazolones. WO 9633178 . |
| 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) | 16659 | ethyl (2S)-2-hydroxypropanoate; (S)-ethyl lactate | 687-47-8 | C5H10O3 | 详情 | 详情 |
| (II) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 |
| (III) | 17099 | (2S)-2-hydroxy-1-(1-pyrrolidinyl)-1-propanone | C7H13NO2 | 详情 | 详情 | |
| (IV) | 17100 | (2S)-2-(benzyloxy)-1-(1-pyrrolidinyl)-1-propanone | 122151-32-0 | C14H19NO2 | 详情 | 详情 |
| (V) | 17101 | (2S)-2-(benzyloxy)-3-pentanone | C12H16O2 | 详情 | 详情 | |
| (VI) | 17102 | (2S)-2-(benzyloxy)-3-pentanol | C12H18O2 | 详情 | 详情 | |
| (VII) | 15787 | 4-chlorobenzenesulfonyl chloride;4-chlorobenzene-1-sulfonyl chloride | 98-60-2 | C6H4Cl2O2S | 详情 | 详情 |
| (VIII) | 17104 | (2S)-2-(benzyloxy)-1-ethylpropyl 4-chlorobenzenesulfonate | C18H21ClO4S | 详情 | 详情 | |
| (IX) | 17105 | 1-[(1S,2S)-2-(benzyloxy)-1-ethylpropyl]hydrazine; benzyl (1S,2S)-2-hydrazino-1-methylbutyl ether | C12H20N2O | 详情 | 详情 | |
| (X) | 17106 | N'-[(1S,2S)-2-(benzyloxy)-1-ethylpropyl]formic hydrazide | C13H20N2O2 | 详情 | 详情 | |
| (XI) | 17107 | phenyl 4-(4-[4-[(trimethylsilyl)methyl]phenyl]-1-piperazinyl)phenylcarbamate | C27H33N3O2Si | 详情 | 详情 | |
| (XII) | 17108 | 2-[(1S,2S)-2-(benzyloxy)-1-ethylpropyl]-4-[4-[4-(4-hydroxyphenyl)-1-piperazinyl]phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one | C30H35N5O3 | 详情 | 详情 | |
| (XIII) | 17109 | [(3S,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methyl 4-chlorobenzenesulfonate | C20H18ClF2N3O4S | 详情 | 详情 | |
| (XIV) | 17110 | 4-[4-(4-aminophenyl)piperazino]phenol; 1-(4-Aminophenyl)-4-(4-hydroxyphenyl)piperazine; 1-(4-Hydroxyphenyl)-4-(4-aminophenyl)piperazine | 74853-08-0 | C16H19N3O | 详情 | 详情 |
| (XV) | 17111 | phenyl N-[4-[4-(4-hydroxyphenyl)piperazino]phenyl]carbamate | C23H23N3O3 | 详情 | 详情 |
合成路线23
该中间体在本合成路线中的序号：(IV)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24
该中间体在本合成路线中的序号：(IV)Condensation of methyl 3-(3-hydroxyphenyl)propanoate (I) with an excess of methyl magnesium bromide in THF at low temperature afforded tertiary alcohol (II), which was brominated with N-bromosuccinimide (NBS) in DMF at 0 C to give (III). Then, a double Mannich reaction with pyrrolidine (IV) and formaldehyde provided diamine (V). To hydrogenolyze the benzylic amine groups an indirect route was required. Thus, reaction with an excess of 4-methoxybenzylmercaptan (VI) at 180 C displaced both amino groups with concomitant debromination to give thioether (VII), which was desulfurized on treatment with Raney Nickel to the dimethylphenol (VIII). The Ritter reaction with NaCN in sulfuric acid-acetic acid yielded directly the cyclized imine (IX), generated from the intermediate nitrilium ion. Reduction to amine (X) was effected by catalytic hydrogenation in the presence of Raney Nickel, and this compound was finally oxidized to N-oxide the nitrone with H2O2 and a catalytic amount of sodium tungstate.
| 【1】 Fevig, T.L.; et al.; Design, synthesis, and in vitro evaluation of cyclic nitrones as free radical traps for the treatment of stroke. J Med Chem 1996, 39, 25, 4988. |
| 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) | 18437 | methyl 3-(3-hydroxyphenyl)propanoate | C10H12O3 | 详情 | 详情 | |
| (II) | 18438 | 3-(3-hydroxy-3-methylbutyl)phenol | C11H16O2 | 详情 | 详情 | |
| (III) | 18439 | 4-bromo-3-(3-hydroxy-3-methylbutyl)phenol | C11H15BrO2 | 详情 | 详情 | |
| (IV) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 |
| (V) | 18441 | 4-bromo-3-(3-hydroxy-3-methylbutyl)-2,6-bis(1-pyrrolidinylmethyl)phenol | C21H33BrN2O2 | 详情 | 详情 | |
| (VI) | 13220 | 4-Methoxybenzylhydrosulfide; (4-Methoxyphenyl)methanethiol; 4-Methoxy-alpha-toluenethiol | 6258-60-2 | C8H10OS | 详情 | 详情 |
| (VII) | 18443 | 3-(3-hydroxy-3-methylbutyl)-2,6-bis[[(4-methoxybenzyl)sulfanyl]methyl]phenol | C29H36O4S2 | 详情 | 详情 | |
| (VIII) | 18444 | 3-(3-hydroxy-3-methylbutyl)-2,6-dimethylphenol | C13H20O2 | 详情 | 详情 | |
| (IX) | 18445 | 3,3,6,8-tetramethyl-4,5-dihydro-3H-2-benzazepin-7-ol | C14H19NO | 详情 | 详情 | |
| (X) | 18446 | 3,3,6,8-tetramethyl-2,3,4,5-tetrahydro-1H-2-benzazepin-7-ol | C14H21NO | 详情 | 详情 |
合成路线25
该中间体在本合成路线中的序号：(VIII)Ethyl isonipecotate (I) was protected as the N-trityl derivative (II) using triphenylmethyl chloride and triethylamine. Addition of Grignard reagent (IV) (prepared from 1-bromo-4-fluorobenzene (III) and magnesium in Et2O) to (II) produced the diaryl carbinol (V). Alcohol dehydration with simultaneous trityl group cleavage under acidic conditions yielded 4-[bis(4-fluorophenyl)methylene]piperidine (VI). 4-Chlorobutyrylpyrrolidine (IX), prepared by coupling of 4-chlorobutyryl chloride (VII) and pyrrolidine (VIII), was then condensed with piperidine (VI) to yield the target compound.
| 【1】 Rae, D.R.; Jaap, D.R. (Akzo Nobel N.V.); Diphenylmethylene piperidine derivs.. EP 0842170; JP 1999508907; US 5935974; WO 9703065 . |
| 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) | 33780 | ethyl 1-trityl-4-piperidinecarboxylate | C27H29NO2 | 详情 | 详情 | |
| (III) | 29012 | 1-bromo-4-fluorobenzene | 460-00-4 | C6H4BrF | 详情 | 详情 |
| (IV) | 13643 | 4-fluorophenyl magnesium bromide;Bromo(4-fluorophenyl)magnesium;bromo(p-fluorophenyl)Magnesium;p-Fluorophenylmagnesium bromide | 352-13-6 | C6H4BrFMg | 详情 | 详情 |
| (V) | 33781 | bis(4-fluorophenyl)(1-trityl-4-piperidinyl)methanol | C37H33F2NO | 详情 | 详情 | |
| (VI) | 24706 | 4-[bis(4-fluorophenyl)methylene]piperidine | C18H17F2N | 详情 | 详情 | |
| (VII) | 11265 | 4-Chlorobutanoyl chloride; 4-Chlorobutyric acid chloride | 4635-59-0 | C4H6Cl2O | 详情 | 详情 |
| (VIII) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 |
| (IX) | 33782 | 4-chloro-1-(1-pyrrolidinyl)-1-butanone | C8H14ClNO | 详情 | 详情 |
合成路线26
该中间体在本合成路线中的序号：(VI)Mannich reaction of 6,7-dimethyltetralone (I) with dimethylamine and formaldehyde provided amino ketone (II). Subsequent quaternization of (II) with MeI in acetone gave ammonium salt (III), that was further displaced by KCN yielding nitrile (IV). Acidic hydrolysis of the cyano group of (IV) produced carboxylic acid (V). This was then coupled with pyrrolidine (VI) employing BOP reagent to furnish amide (VII). Reduction of the ketone and amide functions of (VII) by means of vitride?in toluene afforded amino alcohol (VIII). After alcohol (VIII) dehydration with ethanolic HCl, the title compound was isolated as the fumarate salt.
| 【1】 Kai, N.; Kanehira, A.; Morie, T.; Hino, K.; Kawashima, K.; Shimizu, I.; Akiyama, K. (Dainippon Pharmaceutical Co., Ltd.); 1-[omega-(3,4-Dihydro-2-naphthalenyl)alkyl]cyclic amine derivs., process for producing the same, and medicinal compsn. containing the same. EP 0825180; US 5847159; WO 9633169 . |
| 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) | 41589 | 6,7-dimethyl-3,4-dihydro-1(2H)-naphthalenone | C12H14O | 详情 | 详情 | |
| (II) | 41590 | 2-[(dimethylamino)methyl]-6,7-dimethyl-3,4-dihydro-1(2H)-naphthalenone | C15H21NO | 详情 | 详情 | |
| (III) | 41591 | (6,7-dimethyl-1-oxo-1,2,3,4-tetrahydro-2-naphthalenyl)-N,N,N-trimethylmethanaminium iodide | C16H24INO | 详情 | 详情 | |
| (IV) | 41592 | 2-(6,7-dimethyl-1-oxo-1,2,3,4-tetrahydro-2-naphthalenyl)acetonitrile | C14H15NO | 详情 | 详情 | |
| (V) | 41593 | 2-(6,7-dimethyl-1-oxo-1,2,3,4-tetrahydro-2-naphthalenyl)acetic acid | C14H16O3 | 详情 | 详情 | |
| (VI) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 |
| (VII) | 41594 | 6,7-dimethyl-2-[2-oxo-2-(1-pyrrolidinyl)ethyl]-3,4-dihydro-1(2H)-naphthalenone | C18H23NO2 | 详情 | 详情 | |
| (VIII) | 41595 | 6,7-dimethyl-2-[2-(1-pyrrolidinyl)ethyl]-1,2,3,4-tetrahydro-1-naphthalenol | C18H27NO | 详情 | 详情 |
合成路线27
该中间体在本合成路线中的序号：(XIX)In an alternative synthesis, phenylacetaldehyde (XVIII) was condensed with pyrrolidine (XIX) to give enamine (XX). Nitrosation of malononitrile (XXI), followed by treatment with tosyl chloride, produced the O-tosyl oxime (XXII). This was condensed with enamine (XX), and to the intermediate adduct (XXIII) was added thiophenol producing the phenylthiopyrazine (XXIV). Subsequent oxidation of the sulfide group of (XXIV) to sulfone (XXV), followed by condensation with methyl thioglycolate, gave the desired thienopyrazine (XIII).
| 【1】 Meyer, M.D.; Altenbach, R.J.; Basha, F.; Carroll, W.A.; Drizin, I.; Kerwin, J.F.; Wendt, M.D.; Haight, A.R.; Zhang, W. (Abbott Laboratories Inc.); Benzopyranopyrrole and benzopyranopyridine alpha-1 adrenergic cpds.. EP 0942911; US 5891882; US 6046207; WO 9824791 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIII) | 46503 | methyl 7-amino-2-phenylthieno[2,3-b]pyrazine-6-carboxylate | C14H11N3O2S | 详情 | 详情 | |
| (XVIII) | 18456 | 2-phenylacetaldehyde | 122-78-1 | C8H8O | 详情 | 详情 |
| (XIX) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 |
| (XX) | 46508 | 1-[(E)-2-phenylethenyl]pyrrolidine | C12H15N | 详情 | 详情 | |
| (XXI) | 12061 | Malononitrile | 109-77-3 | C3H2N2 | 详情 | 详情 |
| (XXII) | 46509 | 2-([[(4-methylphenyl)sulfonyl]oxy]imino)malononitrile | C10H7N3O3S | 详情 | 详情 | |
| (XXIII) | 46510 | 2-[[(E)-1-phenyl-2-(1-pyrrolidinyl)ethenyl]imino]malononitrile | C15H14N4 | 详情 | 详情 | |
| (XXIV) | 46511 | 6-phenyl-3-(phenylsulfanyl)-2-pyrazinecarbonitrile | C17H11N3S | 详情 | 详情 | |
| (XXV) | 46512 | 6-phenyl-3-(phenylsulfonyl)-2-pyrazinecarbonitrile | C17H11N3O2S | 详情 | 详情 |
合成路线28
该中间体在本合成路线中的序号：(III)(1R,2R)-2-Benzyloxycarbonylamino-1-phenyl-1,3-propanediol (I) was converted to mesylate (II) upon treatment with methanesulfonyl chloride in pyridine. Reaction of this mesylate with pyrrolidine (III) provided pyrrolidino compound (IV). The N-benzyloxycarbonyl group of (IV) was then eliminated by hydrogenolysis over Pd/C to yield the vicinal hydroxyamine (V), which was finally condensed with decanoyl chloride (VI) to furnish the target decanoyl amide.
| 【1】 Oyamada, H.; Inokuchi, J.; Jinbo, M. (Seikagaku Corp.); Amino alcohol deriv. and method for preparing the . EP 0782992 . |
| 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) | 22793 | phenyl (1R,2R)-2-hydroxy-1-(hydroxymethyl)-2-phenylethylcarbamate | C16H17NO4 | 详情 | 详情 | |
| (II) | 22794 | (2R,3R)-3-hydroxy-2-[(phenoxycarbonyl)amino]-3-phenylpropyl methanesulfonate | C17H19NO6S | 详情 | 详情 | |
| (III) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 |
| (IV) | 22796 | phenyl (1R,2R)-2-hydroxy-2-phenyl-1-(1-pyrrolidinylmethyl)ethylcarbamate | C20H24N2O3 | 详情 | 详情 | |
| (V) | 22797 | (1R,2R)-2-amino-1-phenyl-3-(1-pyrrolidinyl)-1-propanol | C13H20N2O | 详情 | 详情 | |
| (VI) | 22798 | 1-chloro-2-undecanone | C11H21ClO | 详情 | 详情 |
合成路线29
该中间体在本合成路线中的序号：(II)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30
该中间体在本合成路线中的序号：(A)Radical bromination of methyl 3-methoxy-4-methylbenzoate (I) using N-bromosuccinimide and azobisisobutyronitrile gave benzyl bromide (II), which was treated with pyrrolidine to afford the tertiary amine (III). Hydrolysis of the methyl ester group of (III) with LiOH provided carboxylic acid (IV), which was converted to acid chloride (V) upon treatment with SOCl2.
| 【1】 Antithrombotic diamines. EP 0863755; US 6025382; WO 9725033 . |
| 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) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 |
| (I) | 11919 | methyl 3-methoxy-4-methylbenzoate | 3556-83-0 | C10H12O3 | 详情 | 详情 |
| (II) | 11920 | methyl 4-(bromomethyl)-3-methoxybenzoate; 4-(Bromomethyl)-3-methoxy benzoic acid methyl ester | C10H11BrO3 | 详情 | 详情 | |
| (III) | 31412 | methyl 3-methoxy-4-(1-pyrrolidinylmethyl)benzoate | C14H19NO3 | 详情 | 详情 | |
| (IV) | 31413 | 3-methoxy-4-(1-pyrrolidinylmethyl)benzoic acid | C13H17NO3 | 详情 | 详情 | |
| (V) | 31414 | 3-methoxy-4-(1-pyrrolidinylmethyl)benzoyl chloride | C13H16ClNO2 | 详情 | 详情 |
合成路线31
该中间体在本合成路线中的序号：(XX)4-Methoxyphenylacetic acid (XI) was esterified using EtOH and p-toluenesulfonic acid, and then brominated with NBS to give bromoester (XII). Coupling of (XII) with 4-nitroimidazole (XIII) afforded adduct (XIV), which was alkylated using iodomethane and NaH to yield (XVa-b). Hydrolysis of the ester group of (XVa-b) with LiOH gave the corresponding carboxylic acid, which was converted to acid chloride (XVIa-b) by means of treatment with oxalyl chloride. Reaction of (XVI) with the lithium salt of the chiral oxazolidinone (XVII) provided a diastereomeric mixture of N-acyloxazolidinones, which were separated by silica gel chromatography. Removal of the chiral auxiliary from the desired isomer (XVIII) under basic conditions, followed by treatment with oxalyl chloride provided acid chloride (XIX). Further reaction of (XIX) with pyrrolidine (XX) produced amide (XXI). Reduction of the nitro group of (XXI) using hydrogen and Pd/C generated the aminoimidazole derivative (XXII). This was coupled with the N-Boc-dipeptide (X) affording amide (XXIII). The Boc protecting group of (XXIII) was then cleaved by treatment with trifluoroacetic acid, and the title compound was finally isolated as the dihydrochloride salt.
| 【1】 Growth hormone secretagogues. EP 0933365; WO 9908699 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XVa) | 35766 | ethyl (2R)-2-(4-methoxyphenyl)-2-(4-nitro-1H-imidazol-1-yl)propanoate | C15H17N3O5 | 详情 | 详情 | |
| (XVIa) | 35767 | (2R)-2-(4-methoxyphenyl)-2-(4-nitro-1H-imidazol-1-yl)propanoyl chloride | C13H12ClN3O4 | 详情 | 详情 | |
| (XVIb) | 35768 | (2S)-2-(4-methoxyphenyl)-2-(4-nitro-1H-imidazol-1-yl)propanoyl chloride | C13H12ClN3O4 | 详情 | 详情 | |
| (XVb) | 35769 | ethyl (2R)-2-(4-methoxyphenyl)-2-(4-nitro-1H-imidazol-1-yl)propanoate | C15H17N3O5 | 详情 | 详情 | |
| (X) | 18473 | (2R)-2-([2-[(tert-butoxycarbonyl)amino]-2-methylpropanoyl]amino)-5-phenylpentanoic acid | C20H30N2O5 | 详情 | 详情 | |
| (XI) | 34793 | 2-(4-methoxyphenyl)acetic acid; p-Methoxyphenyl formate; Homoanisic acid; p-Methyl benzyl formate; 4-methoxyphenylacetic acid; 4-methoxybenzeneacetic acid; p-methoxyphenylacetic acid | 104-01-8 | C9H10O3 | 详情 | 详情 |
| (XII) | 35763 | ethyl 2-bromo-2-(4-methoxyphenyl)acetate | 77053-56-6 | C11H13BrO3 | 详情 | 详情 |
| (XIII) | 35764 | 4-nitro-1H-imidazole | 3034-38-6 | C3H3N3O2 | 详情 | 详情 |
| (XIV) | 35765 | ethyl 2-(4-methoxyphenyl)-2-(4-nitro-1H-imidazol-1-yl)acetate | C14H15N3O5 | 详情 | 详情 | |
| (XVII) | 35770 | C10H10LiNO2 | 详情 | 详情 | ||
| (XVIII) | 35771 | (4R,5S)-3-[(2R)-2-(4-methoxyphenyl)-2-(4-nitro-1H-imidazol-1-yl)propanoyl]-4-methyl-5-phenyl-1,3-oxazolidin-2-one | C23H22N4O6 | 详情 | 详情 | |
| (XIX) | 35767 | (2R)-2-(4-methoxyphenyl)-2-(4-nitro-1H-imidazol-1-yl)propanoyl chloride | C13H12ClN3O4 | 详情 | 详情 | |
| (XX) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 |
| (XXI) | 35772 | (2R)-2-(4-methoxyphenyl)-2-(4-nitro-1H-imidazol-1-yl)-1-(1-pyrrolidinyl)-1-propanone | C17H20N4O4 | 详情 | 详情 | |
| (XXII) | 35773 | (2R)-2-(4-amino-1H-imidazol-1-yl)-2-(4-methoxyphenyl)-1-(1-pyrrolidinyl)-1-propanone | C17H22N4O2 | 详情 | 详情 | |
| (XXIII) | 35774 | tert-butyl 2-([(1R)-1-[([1-[(1R)-1-(4-methoxyphenyl)-1-methyl-2-oxo-2-(1-pyrrolidinyl)ethyl]-1H-imidazol-4-yl]amino)carbonyl]-4-phenylbutyl]amino)-1,1-dimethyl-2-oxoethylcarbamate | C37H50N6O6 | 详情 | 详情 |
合成路线32
该中间体在本合成路线中的序号：(I)Exposure of pyrrolidine (I) to NO in acetonitrile/ether in the presence of NaOMe in MeOH provides sodium 1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate (II), which is converted into the desired product by reaction with bromomethyl acetate (III) in DMSO in the presence of Na2CO3 and silver acetate (HgOAc).
| 【1】 Saavedra, J.E.; et al.; Targeting nitric oxide (NO) delivery in vivo. Design of a liver-selective NO donor prodrug that blocks tumor necrosis factor-alpha-induced apoptosis and toxicity in the liver. J Med Chem 1997, 40, 13, 1947. |
| 【2】 Booth, M.N.; Keefer, L.K.; Shami, P.J.; Wang, L.Y.; Saavedra, J.E.; Davies, K.M.; Citro, M.L.; Esterase-sensitive nitric oxide donors of the diazeniumdiolate family: In vitro antileukemic activity. J Med Chem 2000, 43, 2, 261. |
合成路线33
该中间体在本合成路线中的序号：(IV)Nitration of 1-(4-chlorophenyl)-1-cyclopropanecarboxylic acid (I) with fuming HNO3 produced the 3-nitro derivative (II). The chloride group of (III) was then displaced with methylamine to give the nitro aniline (III). Coupling of (III) with pyrrolidine (IV) by means of TBTU yielded amide (V). The nitro group of (V) was reduced by catalytic hydrogenation over Pd/C to afford the phenylenediamine (VI), which was subsequently acylated by N-(4-cyanophenyl)glycine (VII), yielding amide (VIII). Benzimidazole (IX) was then obtained by cyclization of (VIII) in refluxing HOAc. Pinner reaction of nitrile (IX) with ethanolic HCl produced the imidate (X), which was finally converted to the target amidine by treatment with ammonium carbonate.
| 【1】 Kauffmann, I.; Ries, U.; Priepke, H.; Hauel, N.; Stassen, J.M.; Nar, H.; Wienen, W. (Boehringer Ingelheim Pharma KG); Benzimidazoles, production thereof and use thereof as medicaments. DE 19829964; EP 1095025; WO 0001704 . |
| 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) | 51507 | 1-(4-Chlorophenyl)-1-cyclopropanecarboxylic acid | 72934-37-3 | C10H9ClO2 | 详情 | 详情 |
| (II) | 51508 | 1-(4-chloro-3-nitrophenyl)cyclopropanecarboxylic acid | C10H8ClNO4 | 详情 | 详情 | |
| (III) | 51509 | 1-[4-(methylamino)-3-nitrophenyl]cyclopropanecarboxylic acid | C11H12N2O4 | 详情 | 详情 | |
| (IV) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 |
| (V) | 51510 | [1-[4-(methylamino)-3-nitrophenyl]cyclopropyl](1-pyrrolidinyl)methanone | C15H19N3O3 | 详情 | 详情 | |
| (VI) | 51511 | [1-[3-amino-4-(methylamino)phenyl]cyclopropyl](1-pyrrolidinyl)methanone | C15H21N3O | 详情 | 详情 | |
| (VII) | 51512 | 2-(4-cyanoanilino)acetic acid | C9H8N2O2 | 详情 | 详情 | |
| (VIII) | 51513 | 2-(4-cyanoanilino)-N-[2-(methylamino)-5-[1-(1-pyrrolidinylcarbonyl)cyclopropyl]phenyl]acetamide | C24H27N5O2 | 详情 | 详情 | |
| (IX) | 51514 | 4-[([1-methyl-5-[1-(1-pyrrolidinylcarbonyl)cyclopropyl]-1H-benzimidazol-2-yl]methyl)amino]benzonitrile | C24H25N5O | 详情 | 详情 | |
| (X) | 51515 | ethyl 4-[([1-methyl-5-[1-(1-pyrrolidinylcarbonyl)cyclopropyl]-1H-benzimidazol-2-yl]methyl)amino]benzenecarboximidoate | C26H31N5O2 | 详情 | 详情 |
合成路线34
该中间体在本合成路线中的序号：(III)Condensation of 4-fluorophenylacetyl chloride (I) with ethylene in the presence of AlCl3 provided the beta-tetralone (II). After conversion of (III) into enamine (IV) upon reaction with pyrrolidine (III) in MeOH, alkylation with allyl bromide (V) afforded iminium salt (VI). Acid hydrolysis of (VI) generated the allyl tetralone (VII), which was subjected to reductive amination with ammonium acetate and sodium cyanoborohydride to produce the cis-1-allyl-2-aminotetralin (VIII) as the major isomer. Coupling of (VIII) with carboxylic acid (IX) using 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) gave amide (X), which was finally reduced to the target aminotetralin derivative with LiAlH4.
| 【1】 Lovenberg, T.W.; McNally, J.J.; Youngman, M.A.; et al.; alpha-Substituted N-(sulfonamido)alkyl-beta-aminotetralins: Potent and selective neuropeptide Y Y5 receptor antagonists. J Med Chem 2000, 43, 3, 346. |
| 【2】 Reitz, A.B.; Lovenberg, T.W.; Dax, S.L.; Youngman, M.A.; McNally, J.J. (Ortho-McNeil Pharmaceutical, Inc.); N-Substd. aminotetralins as ligands for the neuropeptide Y Y5 receptor useful in the treatment of obesity and other disorders. WO 9955667 . |
| 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) | 37014 | 2-(4-fluorophenyl)acetyl chloride | 459-04-1 | C8H6ClFO | 详情 | 详情 |
| (II) | 37015 | 6-fluoro-3,4-dihydro-2(1H)-naphthalenone | C10H9FO | 详情 | 详情 | |
| (III) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 |
| (IV) | 37016 | 1-(6-fluoro-3,4-dihydro-2-naphthalenyl)pyrrolidine | C14H16FN | 详情 | 详情 | |
| (V) | 11463 | 3-Bromo-1-propene; 3-Bromopropene；allyl bromide | 106-95-6 | C3H5Br | 详情 | 详情 |
| (VI) | 37017 | 1-[1-allyl-6-fluoro-3,4-dihydro-2(1H)-naphthalenylidene]pyrrolidinium bromide | C17H21BrFN | 详情 | 详情 | |
| (VII) | 37018 | 1-allyl-6-fluoro-3,4-dihydro-2(1H)-naphthalenone | C13H13FO | 详情 | 详情 | |
| (VIII) | 37019 | (1S,2R)-1-allyl-6-fluoro-1,2,3,4-tetrahydro-2-naphthalenamine; (1S,2R)-1-allyl-6-fluoro-1,2,3,4-tetrahydro-2-naphthalenylamine | C13H16FN | 详情 | 详情 | |
| (IX) | 37020 | 4-[[(phenylsulfonyl)amino]methyl]cyclohexanecarboxylic acid | C14H19NO4S | 详情 | 详情 | |
| (X) | 37021 | N-[(1S,2R)-1-allyl-6-fluoro-1,2,3,4-tetrahydro-2-naphthalenyl]-4-[[(phenylsulfonyl)amino]methyl]cyclohexanecarboxamide | C27H33FN2O3S | 详情 | 详情 |
合成路线35
该中间体在本合成路线中的序号：(IV)The reaction of 4-nitrophenol (I) with 1,5-dibromopentane (II) and NaOH in refluxing water gives the aryl ether (III), which is finally condensed with pyrrolidine (IV) in refluxing ethanol.
| 【1】 Ganellin, C.; et al.; Synthesis of potent non-imidazole histamine H3-receptor antagonists. Arch Pharm 1998, 331, 12, 395. |
| 【2】 Stark, H.; Ligneau, X.; Garbarg, M.; Schunack, W.G.; Ganellin, C.R.; Lecomte, J.-M.; Arrang, J.-M.; Leurquin, F.; Sigurd, E.; Schwartz, J.-C. (Societe Civile Bioprojet); Non-imidazole aryloxy (or arylthio) alkylamines as histamine H3-receptor antagonists and their therapeutic applications. EP 0978512 . |
合成路线36
该中间体在本合成路线中的序号：(II)Enamine (III), prepared from beta-tetralone (I) by condensation with pyrrolidine (II) in refluxing benzene, was alkylated with bromoacetonitrile to provide, after hydrolytic treatment, keto nitrile (IV). Reductive amination of (IV) with ammonium acetate and NaBH3CN in MeOH furnished the benzo[e]indole tricyclic derivative (V), isolated as the hydrochloride salt. Coupling of (V) with trans-4-[(benzenesulfonamido) methyl]cyclohexanecarboxylic acid (VI) using O-benzotriazol-1-yl-N,N,N’,N’-tetramethyluronium hexafluorophosphate (HBTU) gave amide (VII). This was finally reduced to the corresponding amine employing LiAlH4 in THF.
| 【1】 Wilson, S.J.; Dax, S.L.; Nepomuceno, D.H.; McNally, J.J.; Youngman, M.A.; Lovenverg, T.W.; N-(Sulfonamido)alkyl[tetrahydro-1H-benzo[e]indol-2-yl]amines: Potent antagonists of human neuropeptide Y Y5 receptor. Bioorg Med Chem Lett 2000, 10, 3, 213. |
| 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) | 40937 | 6-hydroxy-3,4-dihydro-2(1H)-naphthalenone | C10H10O2 | 详情 | 详情 | |
| (II) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 |
| (III) | 40938 | 6-(1-pyrrolidinyl)-7,8-dihydro-2-naphthalenol | C14H17NO | 详情 | 详情 | |
| (IV) | 40939 | 2-(6-hydroxy-2-oxo-1,2,3,4-tetrahydro-1-naphthalenyl)acetonitrile | C12H11NO2 | 详情 | 详情 | |
| (V) | 40940 | (3aS,9bR)-2-amino-3a,4,5,9b-tetrahydro-1H-benzo[e]indol-7-ol | C12H14N2O | 详情 | 详情 | |
| (VI) | 37020 | 4-[[(phenylsulfonyl)amino]methyl]cyclohexanecarboxylic acid | C14H19NO4S | 详情 | 详情 | |
| (VII) | 40941 | N-[(3aS,9bR)-7-hydroxy-3a,4,5,9b-tetrahydro-1H-benzo[e]indol-2-yl]-4-[[(phenylsulfonyl)amino]methyl]cyclohexanecarboxamide | C26H31N3O4S | 详情 | 详情 |
合成路线37
该中间体在本合成路线中的序号：(II)The condensation of 6-methoxy-2-tetralone (I) with pyrrolidine (II) in methanol gives the enamine (III), which is treated with 2-bromoacetonitrile (IV) to yield the pyrrolidinium salt (V). The hydrolysis of (V) with acetic acid in dichloromethane/methanol affords 2-(2-oxo-1,2,3,4-tetrahydronaphthalen-1-yl)acetonitrile (VI), which is cyclized with ammonium acetate and NaBH3CN in refluxing methanol to provide the benzoindole derivative (VII). The condensation of (VII) with trans-4-(phenylsulfonamidomethyl)cyclohexanecarboxylic acid (VIII) by means of HBTU and DIEA in DMF gives the corresponding amide (IX), which is reduced with LiAlH4 in THF to yield the secondary amine (X). Finally, this compound is demethylated by means of BBr3 in dichloromethane.
| 【1】 Dax, S.; McNally, J. (Ortho-McNeil Pharmaceutical, Inc.); 3a,4,5,9b-Tetrahydro-1H-benz[e]indol-2-yl amine-derived neuropeptide Y receptor ligands useful in the treatment of obesity and other disorders. WO 0068197 . |
| 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) | 47506 | 6-Methoxy-2-tetralone; 6-methoxy-3,4-dihydro-2(1H)-naphthalenone | 2472-22-2 | C11H12O2 | 详情 | 详情 |
| (II) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 |
| (III) | 47507 | methyl 6-(1-pyrrolidinyl)-7,8-dihydro-2-naphthalenyl ether; 1-(6-methoxy-3,4-dihydro-2-naphthalenyl)pyrrolidine | C15H19NO | 详情 | 详情 | |
| (IV) | 31883 | 2-bromoacetonitrile | 590-17-0 | C2H2BrN | 详情 | 详情 |
| (V) | 47508 | 1-[1-(cyanomethyl)-6-methoxy-3,4-dihydro-2(1H)-naphthalenylidene]pyrrolidinium | C17H21N2O | 详情 | 详情 | |
| (VI) | 47509 | 2-(6-methoxy-2-oxo-1,2,3,4-tetrahydro-1-naphthalenyl)acetonitrile | C13H13NO2 | 详情 | 详情 | |
| (VII) | 47510 | (3aS,9bR)-7-methoxy-3a,4,5,9b-tetrahydro-1H-benzo[e]indol-2-amine; (3aS,9bR)-7-methoxy-3a,4,5,9b-tetrahydro-1H-benzo[e]indol-2-ylamine | C13H16N2O | 详情 | 详情 | |
| (VIII) | 37020 | 4-[[(phenylsulfonyl)amino]methyl]cyclohexanecarboxylic acid | C14H19NO4S | 详情 | 详情 | |
| (IX) | 47511 | N-[(3aS,9bR)-7-methoxy-3a,4,5,9b-tetrahydro-1H-benzo[e]indol-2-yl]-4-[[(phenylsulfonyl)amino]methyl]cyclohexanecarboxamide | C27H33N3O4S | 详情 | 详情 | |
| (X) | 47512 | N-[[4-([[(3aS,9bR)-7-methoxy-3a,4,5,9b-tetrahydro-1H-benzo[e]indol-2-yl]amino]methyl)cyclohexyl]methyl]benzenesulfonamide | C27H35N3O3S | 详情 | 详情 |
合成路线38
该中间体在本合成路线中的序号：(II)Treatment of 1,5-dibromo-2,4-dinitrobenzene (I) with pyrrolidine (II) afforded dipyrrolidino derivative (III). Reduction of the nitro groups of (III) by catalytic hydrogenation, followed by acetylation of amine (IV) provided diamide (V). Oxidative cyclization of (V) using H2O2 in the presence of formic acid gave rise to the dipyrroloimidazobenzimidazole system (VI). Quinone elaboration involved nitration of (VI) to (VII), nitro group reduction to amine (VIII), and finally amine oxidation employing Fremy's salt.
| 【1】 Skibo, E.B.; Schulz, W.G.; Inhibitors of topoisomerase II based on the benzodiimidazole and dipyrroloimidazobenzimidazole ring systems: Controlling DT-diaphorase reductive inactivation with steric bulk. J Med Chem 2000, 43, 4, 629. |
| 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) | 39236 | 1,5-dibromo-2,4-dinitrobenzene | C6H2Br2N2O4 | 详情 | 详情 | |
| (II) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 |
| (III) | 39237 | 1-[2,4-dinitro-5-(1-pyrrolidinyl)phenyl]pyrrolidine | C14H18N4O4 | 详情 | 详情 | |
| (IV) | 39238 | 4,6-di(1-pyrrolidinyl)-1,3-benzenediamine; 5-amino-2,4-di(1-pyrrolidinyl)phenylamine | C14H22N4 | 详情 | 详情 | |
| (V) | 39239 | N-[5-(acetamido)-2,4-di(1-pyrrolidinyl)phenyl]acetamide | C18H26N4O2 | 详情 | 详情 | |
| (VI) | 39240 | 2,3,8,9-tetrahydro-1H,7H-pyrrolo[1,2-a]pyrrolo[1',2':1,2]imidazo[4,5-f]benzimidazole | C14H14N4 | 详情 | 详情 | |
| (VII) | 39241 | 5-nitro-2,3,8,9-tetrahydro-1H,7H-pyrrolo[1,2-a]pyrrolo[1',2':1,2]imidazo[4,5-f]benzimidazole | C14H13N5O2 | 详情 | 详情 | |
| (VIII) | 39242 | 2,3,8,9-tetrahydro-1H,7H-pyrrolo[1,2-a]pyrrolo[1',2':1,2]imidazo[4,5-f]benzimidazol-5-ylamine; 2,3,8,9-tetrahydro-1H,7H-pyrrolo[1,2-a]pyrrolo[1',2':1,2]imidazo[4,5-f]benzimidazol-5-amine | C14H15N5 | 详情 | 详情 |
合成路线39
该中间体在本合成路线中的序号：Methenamine is added to a solution of bromide (I) in CHCl3 and after treatment with concentrated HCl, amine (II) is obtained. NaOAc and palmitoyl chloride (III) are added to a solution of (II) in THF to yield derivative (IV) which is finally converted to (V) by treatment with paraformaldehyde and pyrrolidine in ethanol, followed by treatment with concentrated HCl, reduction with NaBH4 and final hydrolysis with diluted HCl.
| 【1】 Lee, L.; et al.; Improved inhibitors of glucosylceramide synthase. J Biol Chem 1999, 274, 21, 14662. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 | |
| (I) | 41363 | 2,3-dihydro-1,4-benzodioxine-6-carbonyl bromide | C9H7BrO3 | 详情 | 详情 | |
| (II) | 41364 | 2-amino-1-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-ethanone | C10H11NO3 | 详情 | 详情 | |
| (III) | 16480 | Palmitoyl Chloride; hexadecanoyl chloride | 112-67-4 | C16H31ClO | 详情 | 详情 |
| (IV) | 41365 | N-[2-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-oxoethyl]hexadecanamide | C26H41NO4 | 详情 | 详情 | |
| (V) | 65179 | N-[(2R)-2-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-hydroxy-1-(1-pyrrolidinylmethyl)ethyl]hexadecanamide | C31H52N2O4 | 详情 | 详情 |
合成路线40
该中间体在本合成路线中的序号：(IV)The condensation of 2,3-dihydrobenzodioxin-6-carbaldehyde (I) with 5(S)-phenylmorpholin-2-one (I) in refluxing toluene gives the adduct (III), which is treated first with pyrrolidine (IV) in chloroform and then with HCl in refluxing methanol to yield the pyrrolidide (V). The reduction of (V) with LiAlH4 in THF affords compound (VI), which is treated with H2 over Pd/C in THF/methanol/water to provide the aminoalcohol (VII). Finally, the amino group of (VII) is acylated by means of palmitoyl chloride (VIII) and DIEA in dichloromethane to furnish the target palmitoylamide.
| 【1】 Hirth, B.H.; Siegel, C. (Genzyme Corp.); Synthesis of UDP-glucose: N-Acylsphingosine glucosyltransferase inhibitors. US 2003050299; WO 0308399 . |
| 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) | 61797 | 2,3-dihydro-1,4-benzodioxine-6-carbaldehyde; 1,4-Benzodioxan-6-carboxaldehyde; 3,4-ethylenedioxybenzaldehyde ;benzodioxane-6-carboxaldehyde | 29668-44-8 | C9H8O3 | 详情 | 详情 |
| (II) | 61798 | (5S)-5-phenyl-2-morpholinone;5(S)-phenylmorpholin-2-one;(5S)-3,4,5,6-Tetrahydro-5-phenyl-4(H)-1,4-oxazin-2-one | 144896-92-4 | C10H11NO2 | 详情 | 详情 |
| (III) | 61799 | (1S,3S,5S)-1,3-di(2,3-dihydro-1,4-benzodioxin-6-yl)-5-phenyltetrahydro-8H-[1,3]oxazolo[4,3-c][1,4]oxazin-8-one | C28H25NO7 | 详情 | 详情 | |
| (IV) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 |
| (V) | 61800 | (2R,3R)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-3-hydroxy-2-[(2-hydroxy-1-phenylethyl)amino]-1-(1-pyrrolidinyl)-1-propanone | C23H28N2O5 | 详情 | 详情 | |
| (VI) | 61801 | (1R,2R)-1-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-[(2-hydroxy-1-phenylethyl)amino]-3-(1-pyrrolidinyl)-1-propanol | C23H30N2O4 | 详情 | 详情 | |
| (VII) | 61802 | (1R,2R)-2-amino-1-(2,3-dihydro-1,4-benzodioxin-6-yl)-3-(1-pyrrolidinyl)-1-propanol | C15H22N2O3 | 详情 | 详情 | |
| (VIII) | 19273 | acetyl chloride | 75-36-5 | C2H3ClO | 详情 | 详情 |
合成路线41
该中间体在本合成路线中的序号：(X)Condensation between 4-fluorophenylhydrazine (I) and 2-ketoglutaric acid (II) produced the intermediate hydrazone (III), which was cyclized and esterified to the indole diester (IV) under Fischer synthesis conditions. Alkylation of the indole nitrogen with iodomethane and NaH produced the N-methyl indole (V). This was condensed with dimethylformamide-dimethylacetal in refluxing DMF to furnish the enamino ester (VI). Condensation of enamine (VI) with aniline (VII), followed by cyclization of the intermediate enamino ester under basic conditions, gave rise to the pyridoindole (VIII). The remaining ester group of (VIII) was then hydrolyzed with NaOH to the corresponding carboxylic acid (IX), which was finally coupled with pyrrolidine (X) via activation with carbonyldiimidazole.
| 【1】 Sevrin, M.; Maloizel, C.; Evanno, Y.; Legalloudec, O.; George, P. (Sanofi-Synthelabo); 1H-Pyrido[3,4-b]indole-4-carboxamide derivs., preparation and application thereof in therapeutics. FR 2754262; JP 2001508403; US 6075021; WO 9815552 . |
| 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) | 22135 | 1-(4-fluorophenyl)hydrazine | 371-14-2 | C6H7FN2 | 详情 | 详情 |
| (II) | 52267 | 2-Ketoglutaric acid; 2-Oxoglutaric acid; alpha-Ketoglutaric acid; 2-Oxopentanedioic acid | 328-50-7 | C5H6O5 | 详情 | 详情 |
| (III) | 52268 | 2-[2-(4-fluorophenyl)hydrazono]pentanedioic acid | C11H11FN2O4 | 详情 | 详情 | |
| (IV) | 52269 | ethyl 3-[2-(ethyloxy)-2-oxoethyl]-5-fluoro-1H-indole-2-carboxylate | C15H16FNO4 | 详情 | 详情 | |
| (V) | 52270 | ethyl 3-[2-(ethyloxy)-2-oxoethyl]-5-fluoro-1-methyl-1H-indole-2-carboxylate | C16H18FNO4 | 详情 | 详情 | |
| (VI) | 52271 | ethyl 3-{2-(dimethylamino)-1-[(ethyloxy)carbonyl]ethenyl}-5-fluoro-1-methyl-1H-indole-2-carboxylate | C19H23FN2O4 | 详情 | 详情 | |
| (VII) | 12294 | Aniline; Phenylamine | 62-53-3 | C6H7N | 详情 | 详情 |
| (VIII) | 52272 | ethyl 6-fluoro-9-methyl-1-oxo-2-phenyl-2,9-dihydro-1H-beta-carboline-4-carboxylate | C21H17FN2O3 | 详情 | 详情 | |
| (IX) | 52273 | 6-fluoro-9-methyl-1-oxo-2-phenyl-2,9-dihydro-1H-beta-carboline-4-carboxylic acid | C19H13FN2O3 | 详情 | 详情 | |
| (X) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 |
合成路线42
该中间体在本合成路线中的序号：(II)The reaction of (S)-(+)-methyl lactate (I) with pyrrolidine (II) gives the corresponding acyl pyrrolidine (III), which is silylated with Tbdms-Cl and imidazole to yield the silyl ether (IV). The condensation of (IV) with 3,4-difluorobromobenzene (V) by means of BuLi in THF affords the chiral propiophenone derivative (VI), which is treated with hydroxylamine and NaOAc in methanol to provide the corresponding oxime (VII). The reduction of (VII) with LiAlH4 in refluxing ethyl ether gives the expected amine (VIII), which is treated with (Boc)2O in chloroform, yielding the carbamate (IX). The cyclization of (IX) by means of NaH in THF gives a mixture of cis- and trans-oxazolidinones, from which the desired trans-(4S,5S)-isomer (X) is separated by flash chromatography. The reaction of (X) with 4-nitrophenyl chloroformate (XI) by means of NaH yields the oxazolidinone-carboxylate (XII), which is finally condensed with 3-[4-(4-fluorophenyl)piperidin-1-yl]propylamine (XIII) in THF to afford the target amide.
| 【1】 Lagu, B.; Wetzel, J.M.; Forray, C.; Patane, M.A.; Bock, M.G.; Determination of the relative and absolute stereochemistry of a potent and alpha1A-selective adrenoceptor antagonist. Bioorg Med Chem Lett 2000, 10, 24, 2705. |
| 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) | 17075 | propionic acid, 2-hydroxy-, methyl ester, (S)-; methyl (2S)-2-hydroxypropanoate | 27871-49-4 | C4H8O3 | 详情 | 详情 |
| (II) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 |
| (III) | 17099 | (2S)-2-hydroxy-1-(1-pyrrolidinyl)-1-propanone | C7H13NO2 | 详情 | 详情 | |
| (IV) | 51565 | (2S)-2-[[tert-butyl(dimethyl)silyl]oxy]-1-(1-pyrrolidinyl)-1-propanone | C13H27NO2Si | 详情 | 详情 | |
| (V) | 51566 | 1-Bromo-3,4-difluorobenzene; 3,4-Difluorobromobenzene; 4-Bromo-1,2-difluorobenzene | 348-61-8 | C6H3BrF2 | 详情 | 详情 |
| (VI) | 51567 | (2S)-2-[[tert-butyl(dimethyl)silyl]oxy]-1-(3,4-difluorophenyl)-1-propanone | C15H22F2O2Si | 详情 | 详情 | |
| (VII) | 51568 | (2S)-2-[[tert-butyl(dimethyl)silyl]oxy]-1-(3,4-difluorophenyl)-1-propanone oxime | C15H23F2NO2Si | 详情 | 详情 | |
| (VIII) | 51569 | (2S)-1-amino-1-(3,4-difluorophenyl)-2-propanol | C9H11F2NO | 详情 | 详情 | |
| (IX) | 51570 | tert-butyl (2S)-1-(3,4-difluorophenyl)-2-hydroxypropylcarbamate | C14H19F2NO3 | 详情 | 详情 | |
| (X) | 43324 | (4S,5S)-4-(3,4-difluorophenyl)-5-methyl-1,3-oxazolidin-2-one | C10H9F2NO2 | 详情 | 详情 | |
| (XI) | 16605 | 4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene | 7693-46-1 | C7H4ClNO4 | 详情 | 详情 |
| (XII) | 43325 | 3,4-difluorobenzylamine; (3,4-difluorophenyl)methanamine | 72235-53-1 | C7H7F2N | 详情 | 详情 |
| (XIII) | 39302 | 3-[4-(4-fluorophenyl)-1-piperidinyl]propylamine; 3-[4-(4-fluorophenyl)-1-piperidinyl]-1-propanamine | C14H21FN2 | 详情 | 详情 |
合成路线43
该中间体在本合成路线中的序号：(II)6-Methoxy-2-tetralone (I) was condensed with pyrrolidine (II) to produce enamine (III). Alkylation of (III) with benzyl bromide, followed by hydrolysis of the enamine function, furnished the 1-benzylnaphthalenone (IV). After formation of the chiral enamine (VI) with (S)-alpha-methylbenzylamine (V), enantioselective Michael addition of methyl vinyl ketone (VII) provided the (R)-diketone (VIII), which underwent ring closure to the phenanthrene derivative (IX) upon treatment with NaOMe. Methyl ether cleavage by using boron trichloride in the presence of tetrabutylammonium iodide afforded phenol (X). The conjugated ketone system of (X) was diastereoselectively reduced to the trans-phenanthrenone (XI) by means of lithium in liquid ammonia. Addition of the lithium acetylide of propyne (XII) to the ketone (XI) produced a diastereomeric mixture of carbinols from which the desired isomer (XIII) was isolated by flash chromatography. The phenol group of (XIII) was then converted to the aryl triflate (XIV) by reaction with trifluoromethanesulfonic anhydride and 2,6-lutidine.
| 【1】 Liu, K.K.-C.; Morgan, B.P.; Dow, R.L.; Swick, A.G. (Pfizer Inc.); Glucocorticoid receptor modulators. EP 1175383; WO 0066522 . |
| 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) | 47506 | 6-Methoxy-2-tetralone; 6-methoxy-3,4-dihydro-2(1H)-naphthalenone | 2472-22-2 | C11H12O2 | 详情 | 详情 |
| (II) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 |
| (III) | 47507 | methyl 6-(1-pyrrolidinyl)-7,8-dihydro-2-naphthalenyl ether; 1-(6-methoxy-3,4-dihydro-2-naphthalenyl)pyrrolidine | C15H19NO | 详情 | 详情 | |
| (IV) | 51596 | 1-benzyl-6-methoxy-3,4-dihydro-2(1H)-naphthalenone | C18H18O2 | 详情 | 详情 | |
| (V) | 20042 | (1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine | C8H11N | 详情 | 详情 | |
| (VI) | 51597 | 1-benzyl-6-methoxy-N-[(1S)-1-phenylethyl]-3,4-dihydro-2-naphthalenamine; N-(1-benzyl-6-methoxy-3,4-dihydro-2-naphthalenyl)-N-[(1S)-1-phenylethyl]amine | C26H27NO | 详情 | 详情 | |
| (VII) | 30324 | 3-buten-2-one; methyl vinyl ketone | 78-94-4 | C4H6O | 详情 | 详情 |
| (VIII) | 51598 | (1R)-1-benzyl-6-methoxy-1-(3-oxobutyl)-3,4-dihydro-2(1H)-naphthalenone | C22H24O3 | 详情 | 详情 | |
| (IX) | 51599 | (4aS)-4a-benzyl-7-methoxy-4,4a,9,10-tetrahydro-2(3H)-phenanthrenone | C22H22O2 | 详情 | 详情 | |
| (X) | 51600 | (4aS)-4a-benzyl-7-hydroxy-4,4a,9,10-tetrahydro-2(3H)-phenanthrenone | C21H20O2 | 详情 | 详情 | |
| (XI) | 51601 | (4aS,10aR)-4a-benzyl-7-hydroxy-3,4,4a,9,10,10a-hexahydro-2(1H)-phenanthrenone | C21H22O2 | 详情 | 详情 | |
| (XII) | 51602 | 1-Propyne | C3H4 | 详情 | 详情 | |
| (XIII) | 51603 | (2R,4aS,10aR)-4a-benzyl-2-(1-propynyl)-1,2,3,4,4a,9,10,10a-octahydro-2,7-phenanthrenediol | C24H26O2 | 详情 | 详情 | |
| (XIV) | 51604 | (4bS,7R,8aR)-4b-benzyl-7-hydroxy-7-(1-propynyl)-4b,5,6,7,8,8a,9,10-octahydro-2-phenanthrenyl trifluoromethanesulfonate | C25H25F3O4S | 详情 | 详情 |
合成路线44
该中间体在本合成路线中的序号：(VII)Synthesis of oxazole intermediate (IX): The reaction of 2,2-dichloroacetonitrile (I) with sodium methoxide in methanol gives methyl 2,2-dichloroethanimidoate (II), which is cyclized with DL-serine methyl ester (III) in methanol to yield oxazoline (IV). The reaction of (IV) with sodium methoxide in methanol affords 2-(chloromethyl)-4-methoxy-4,5-dihydrooxazole-4-carboxylic acid methyl ester (V), which is treated with Ts-OH in refluxing toluene to provide the chloromethyloxazole (VI). The reaction of (VI) with pyrrolidine (VII) in toluene gives the 2-(1-pyrrolidinylmethyl)oxazole-4-carboxylic acid methyl ester (VIII), which is hydrolyzed with K2CO3 to yield the target oxazole (IX). Alternatively, the reaction of 2-(bromomethyl)oxazole-4-carboxylic acid ethyl ester (X) with pyrrolidine (VII) gives the precursor (XI), which is hydrolyzed with K2CO3 as before to afford the target oxazole intermediate (IX).
| 【1】 Hermitage, S.A.; et al.; An efficient, practical approach to the synthesis of 2,4-disubstituted thiazoles and oxazoles: Application to the synthesis of GW475151. Org Process Res Dev 2001, 5, 1, 37. |
| 【2】 Johnson, M.R.; Shah, P.; MacDonald, S.J.F.; Harrison, L.A.; Finch, H.; Smith, R.A.; Inglis, G.G.A.; Clarke, G.D.E.; Dowle, M.D. (Glaxo Group Ltd.); Pyrrolopyrrolone derivs. as inhibitors of neutrophil elastase. WO 9912933 . |
| 【3】 Hermitage, S.A.; Cardwell, K.S. (Glaxo Group Ltd.); Process for preparing oxazole derivs.. WO 0053589 . |
| 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) | 47789 | 2,2-dichloroacetonitrile; Dichloroacetonitrile | 3018-12-0 | C2HCl2N | 详情 | 详情 |
| (II) | 47790 | methyl 2,2-dichloroethanimidoate | C3H5Cl2NO | 详情 | 详情 | |
| (III) | 14224 | Serine, methyl ester; methyl 2-amino-3-hydroxypropanoate | 2104-89-4 | C4H9NO3 | 详情 | 详情 |
| (IV) | 47791 | methyl 2-(dichloromethyl)-4,5-dihydro-1,3-oxazole-4-carboxylate | C6H7Cl2NO3 | 详情 | 详情 | |
| (V) | 47792 | methyl 2-(chloromethyl)-4-methoxy-4,5-dihydro-1,3-oxazole-4-carboxylate | C7H10ClNO4 | 详情 | 详情 | |
| (VI) | 47793 | methyl 2-(chloromethyl)-1,3-oxazole-4-carboxylate | C6H6ClNO3 | 详情 | 详情 | |
| (VII) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 |
| (VIII) | 47794 | methyl 2-(1-pyrrolidinylmethyl)-1,3-oxazole-4-carboxylate | C10H14N2O3 | 详情 | 详情 | |
| (IX) | 47795 | potassium 2-(1-pyrrolidinylmethyl)-1,3-oxazole-4-carboxylate | C9H11KN2O3 | 详情 | 详情 | |
| (X) | 47796 | ethyl 2-(bromomethyl)-1,3-oxazole-4-carboxylate | C7H8BrNO3 | 详情 | 详情 | |
| (XI) | 47797 | ethyl 2-(1-pyrrolidinylmethyl)-1,3-oxazole-4-carboxylate | C11H16N2O3 | 详情 | 详情 |
合成路线45
该中间体在本合成路线中的序号：(III)Treatment of 6-nitroindole (I) with aqueous NaNO2 and HCl affords 3-indazolecarboxaldehyde (II), which is then subjected to reductive amination with pyrrolidine (III) by means of NaBH(OAc)3 in dichloroethane/DMF in the presence of acetic acid to provide compound (IV). Alkylation of (IV) with 2,6-dichlorobenzyl bromide (V) by means of KOH in THF yields compound (VI), whose nitro group is reduced with dimethyl hydrazine (Me2NNH2), FeCl3 and charcoal in refluxing MeOH to furnish aminoindazole intermediate (VII). The synthesis of intermediate (XIII) is performed as follows: Coupling of protected diaminobutyric acid (VIII) with benzylamine (IX) by means of DCC and HOBt in acetonitrile, followed by Fmoc removal after treatment with diethylamine, gives derivative (X), which is then condensed with protected difluorophenylalanine (XI) by means of DIC and HOBt in acetonitrile to afford protected dipeptide (XII). Finally, intermediate (XIII) is obtained by Fmoc removal of (XII) by treatment with ethylamine. The desired product is finally obtained by condensation of intermediates (VII) and (XIII) by means of 4-nitrophenyl chloroformate and DIEA in dichloromethane, followed by Boc removal with TFA in dichloromethane.
| 【1】 Andrade-Gordon, P.; Zhang, H.-C.; Derian, C.K.; et al.; Discovery and optimization of a novel series of thrombin receptor (PAR-1) antagonists: Potent, selective peptide mimetics based on indole and indazole templates. J Med Chem 2001, 44, 7, 1021. |
| 【2】 Zhang, H.-C.; Pandey, A.; Scarborough, R.M.; Maryanoff, B.E. (COR Therapeutics, Inc.; Ortho-McNeil Pharmaceutical, Inc.); Novel indazole peptidomimetics as thrombin receptor antagonists. WO 0100656 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 16605 | 4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene | 7693-46-1 | C7H4ClNO4 | 详情 | 详情 | |
| (I) | 39294 | 6-Nitroindole; 6-Nnitro-1H-indole | 4769-96-4 | C8H6N2O2 | 详情 | 详情 |
| (II) | 48891 | 6-nitro-1H-indazole-3-carbaldehyde | C8H5N3O3 | 详情 | 详情 | |
| (III) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 |
| (IV) | 48892 | 6-nitro-3-(1-pyrrolidinylmethyl)-1H-indazole | C12H14N4O2 | 详情 | 详情 | |
| (V) | 40793 | 2-(bromomethyl)-1,3-dichlorobenzene | 20443-98-5 | C7H5BrCl2 | 详情 | 详情 |
| (VI) | 48893 | 1-(2,6-dichlorobenzyl)-6-nitro-3-(1-pyrrolidinylmethyl)-1H-indazole | C19H18Cl2N4O2 | 详情 | 详情 | |
| (VII) | 48894 | 1-(2,6-dichlorobenzyl)-3-(1-pyrrolidinylmethyl)-1H-indazol-6-ylamine; 1-(2,6-dichlorobenzyl)-3-(1-pyrrolidinylmethyl)-1H-indazol-6-amine | C19H20Cl2N4 | 详情 | 详情 | |
| (VIII) | 42257 | (2S)-4-[(tert-butoxycarbonyl)amino]-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]butyric acid | 125238-99-5 | C24H28N2O6 | 详情 | 详情 |
| (IX) | 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 |
| (X) | 48895 | tert-butyl (3S)-3-amino-4-(benzylamino)-4-oxobutylcarbamate | C16H25N3O3 | 详情 | 详情 | |
| (XI) | 42260 | (2S)-3-(3,4-difluorophenyl)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]propionic acid | C24H19F2NO4 | 详情 | 详情 | |
| (XII) | 48896 | 9H-fluoren-9-ylmethyl (1S)-2-([(1S)-1-[(benzylamino)carbonyl]-3-[(tert-butoxycarbonyl)amino]propyl]amino)-1-(3,4-difluorobenzyl)-2-oxoethylcarbamate | C40H42F2N4O6 | 详情 | 详情 | |
| (XIII) | 48897 | tert-butyl (3S)-3-[[(2S)-2-amino-3-(3,4-difluorophenyl)propanoyl]amino]-4-(benzylamino)-4-oxobutylcarbamate | C25H32F2N4O4 | 详情 | 详情 |
合成路线46
该中间体在本合成路线中的序号：(VII)Diphenylmethane (I) is nitrated to the tetranitro derivative (II) employing KNO3 in concentrated H2SO4. Oxidation of the diarylmethane (II) with CrO3 in boiling HOAc provides benzophenone (III). Cyclization of (III) under reductive conditions gives rise to the diamino acridone (IV), which is further acylated by 3-chloropropionyl chloride (V) to the bis-chloropropionamide (VI). Nucleophilic substitution of the chloride groups of (VI) with pyrrolidine (VII) furnishes the bis-pyrrolidino derivative (VIII). Chlorination of acridone (VIII) with POCl3 yields the chloroacridine (IX). This is finally condensed with 4-(dimethylamino)aniline (X) to produce the title compound.
| 【1】 Read, M.; et al.; Structure-based design of selective and potent G quadruplex-mediated telomerase inhibitors. Proc Natl Acad Sci USA 2001, 98, 9, 4844. |
| 【2】 Neidle, S.; Harrison, R.J.; Kelland, L.R.; Gowan, S.M.; Read, M.; Reszka, T. (Cancer Research Technology Ltd.); Therapeutic acridone and acridine cpds.. WO 0208193 . |
| 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) | 57799 | Benzylbenzene; Benzylphenyl; Diphenylmethane; Ditane; Methylenedibenzene | 101-81-5 | C13H12 | 详情 | 详情 |
| (II) | 57800 | bis(2,4-Dinitrophenyl)methane | C13H8N4O8 | 详情 | 详情 | |
| (III) | 57801 | bis(2,4-dinitrophenyl)methanone | C13H6N4O9 | 详情 | 详情 | |
| (IV) | 57802 | 3,6-diamino-9(10H)-acridinone | C13H11N3O | 详情 | 详情 | |
| (V) | 18936 | 3-chloropropanoyl chloride | 625-36-5 | C3H4Cl2O | 详情 | 详情 |
| (VI) | 57803 | 3-chloro-N-{6-[(3-chloropropanoyl)amino]-9-oxo-9,10-dihydro-3-acridinyl}propanamide | C19H17Cl2N3O3 | 详情 | 详情 | |
| (VII) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 |
| (VIII) | 57804 | N-(9-oxo-6-{[3-(1-pyrrolidinyl)propanoyl]amino}-9,10-dihydro-3-acridinyl)-3-(1-pyrrolidinyl)propanamide | C27H33N5O3 | 详情 | 详情 | |
| (IX) | 57805 | N-(9-chloro-6-{[3-(1-pyrrolidinyl)propanoyl]amino}-3-acridinyl)-3-(1-pyrrolidinyl)propanamide | C27H32ClN5O2 | 详情 | 详情 | |
| (X) | 35075 | N-(4-aminophenyl)-N,N-dimethylamine; N(1),N(1)-dimethyl-1,4-benzenediamine | 6219-73-4 | C8H12N2 | 详情 | 详情 |
合成路线47
该中间体在本合成路线中的序号：(V)Alkylation of hydroxylamine with propargyl bromide (I) provided N-propargyl hydroxylamine (II), which was subsequently acylated with 3-chloropropionyl chloride (III) in the presence of pyridine to yield the N-hydroxy amide (IV). Mannich reaction of the propargyl compound (IV) with paraformaldehyde and pyrrolidine (V) with simultaneous cyclization of the N-hydroxy chloropropionamide furnished the title compound.
| 【1】 Amstutz, R.; et al.; Position 5 at the oxotremorinic skeleton as the stearing position for activity at the muscarinic receptors. Helv Chim Acta 1987, 70, 2232. |
| 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) | 11176 | 3-Bromopropyne; 3-Bromo-1-propyne | 106-96-7 | C3H3Br | 详情 | 详情 |
| (II) | 50918 | 3-(hydroxyamino)-1-propyne; N-(2-propynyl)hydroxylamine | C3H5NO | 详情 | 详情 | |
| (III) | 18935 | 3,4-dimethoxyphenylamine; 3,4-dimethoxyaniline | 6315-89-5 | C8H11NO2 | 详情 | 详情 |
| (IV) | 50919 | 3-chloro-N-hydroxy-N-(2-propynyl)propanamide | C6H8ClNO2 | 详情 | 详情 | |
| (V) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 |
合成路线48
该中间体在本合成路线中的序号：(V)Condensation of 16-alpha-bromo-3-beta-hydroxy-5-androsten-17-one (I) with piperidine (II) produced the 16-piperidino derivative (III). Oppenauer oxidation of alcohol (III) with concomitant double-bond migration afforded the unsaturated ketone (IV), which was subsequently condensed with pyrrolidine (V) to yield the dienamine (VI). Reduction of the enamine and ketone functions of (VI) with NaBH4 gave the pyrrolidino alcohol (VII). This was then esterified with acetic anhydride in hot pyridine, yielding acetate (VIII). Finally, quaternization of (VIII) with methyl iodide provided the title bis-ammonium salt.
| 【1】 Fajrak, H.; Piplani, P.; Marshall, I.G.; Prior, C.; Jindal, D.P.; Synthesis and neuromuscular blocking activity of 16beta-piperidinosteroidal derivatives. Eur J Med Chem 2001, 36, 2, 195. |
| 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) | 30080 | (3S,8R,9S,10R,13S,14S,16R)-16-bromo-3-hydroxy-10,13-dimethyl-1,2,3,4,7,8,9,10,11,12,13,14,15,16-tetradecahydro-17H-cyclopenta[a]phenanthren-17-one | C19H27BrO2 | 详情 | 详情 | |
| (II) | 10158 | Piperidine | 110-89-4 | C5H11N | 详情 | 详情 |
| (III) | 50970 | (3S,8R,9S,10R,13S,14S,16S)-3-hydroxy-10,13-dimethyl-16-(1-piperidinyl)-1,2,3,4,7,8,9,10,11,12,13,14,15,16-tetradecahydro-17H-cyclopenta[a]phenanthren-17-one | C24H37NO2 | 详情 | 详情 | |
| (IV) | 50971 | (8R,9S,10R,13S,14S,16S)-10,13-dimethyl-16-(1-piperidinyl)-3-(1-pyrrolidinyl)-1,2,7,8,9,10,11,12,13,14,15,16-dodecahydro-17H-cyclopenta[a]phenanthren-17-one | C28H42N2O | 详情 | 详情 | |
| (V) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 |
| (VI) | 50972 | (3S,8R,9S,10R,13S,14S,16S,17R)-10,13-dimethyl-16-(1-piperidinyl)-3-(1-pyrrolidinyl)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-ol | C28H46N2O | 详情 | 详情 | |
| (VII) | 50973 | (3S,8R,9S,10R,13S,14S,16S,17R)-10,13-dimethyl-16-(1-piperidinyl)-3-(1-pyrrolidinyl)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl acetate | C30H48N2O2 | 详情 | 详情 | |
| (VIII) | 50974 | (1S,2S,13R,21R)-14-oxa-11,22-diazaheptacyclo[13.9.1.0(1,13).0(2,21).0(4,12).0(5,10).0(19,25)]pentacosa-4(12),5,7,9,15(25),16,18-heptaene-2,16-diol | C22H20N2O3 | 详情 | 详情 |
合成路线49
该中间体在本合成路线中的序号：(IV)Metalation of N-Boc-pyrrole (I) with the lithium amide of tetramethylpiperidine, followed by boronation with triethyl borate and acidic work-up leads to the pyrroleboronic acid (II). Subsequent catalytic hydrogenation over Pt/C provides the racemic pyrrolidineboronic acid (III). Alternatively, protection of pyrrolidine (IV) with Boc2O affords (V). After metalation of N-Boc-pyrrolidine (V) with s-butyllithium, treatment with triethyl borate gives rise to the boronic acid (III). Condensation of the racemic boronic acid (III) with (+)-pinanediol (VI) furnishes the corresponding mixture of diastereoisomeric pinanediol boronates, from which the desired isomer (VII) can be isolated by column chromatography. Further removal of the N-Boc protecting group under acidic conditions yields the pyrrolidineboronic ester (VIII). Coupling of pyrrolidine (VIII) with N-Boc-L-valine (IX) produces amide (X). The N-Boc group is then cleaved with HCl in Et2O to afford the deprotected amine (XI). Finally, removal of the pinanediol moiety by transesterification of the boronic ester (XI) with phenylboronic acid provides the desired boronic dipeptide
| 【1】 Gibson, F.S.; Singh, A.K.; Soumeillant, M.C.; Manchand, P.S.; Humora, M.; Kronenthal, D.R.; A practical synthesis of L-valyl-pyrrolidine-(2R)-boronic acid: Efficient recycling of the costly chiral auxiliary (+)-pinanediol. Org Process Res Dev 2002, 6, 6, 814. |
| 【2】 Coutts, S.J.; Kelly, T.A.; Snow, R.J.; Kennedy, C.A.; Barton, R.W.; Adams, J.; Krolikowski, D.A.; Freeman, D.M.; Campbell, S.J.; Ksiazek, J.F.; Bachovchin, W.W.; Structure-activity relationships of boronic acid inhibitors of dipeptidyl peptidase IV. 1. Variation of the P2 position of Xaa-boroPro dipeptides. J Med Chem 1996, 39, 10, 2087. |
| 【3】 Wallner, B.P. (Point Therapeutics, Inc.); Cyclic boroproline cpds.. JP 2002517401; WO 9962914 . |
| 【4】 Hoshi, H.; Okumura, J.; Naito, T.; Abe, Y.; Abukari, S. (Bristol-Myers Squibb Co.); Substituted vinyl cephalosporins. DE 3402642; US 4520022 . |
| 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) | 16432 | tert-Butyl pyrrole-1-carboxylate; tert-Butyl-1H-pyrrole-1-carboxylate; tert-Butyl-1-pyrrolecarboxylate | 5176-27-2 | C9H13NO2 | 详情 | 详情 |
| (II) | 63008 | 1-{[(1,1-dimethylethyl)oxy]carbonyl}-1H-pyrrol-2-ylboronic acid; 1-(tert-butoxycarbonyl)-1H-pyrrol-2-ylboronic acid | C9H14BNO4 | 详情 | 详情 | |
| (III) | 63002 | 1-{[(1,1-dimethylethyl)oxy]carbonyl}-2-pyrrolidinylboronic acid; 1-(tert-butoxycarbonyl)-2-pyrrolidinylboronic acid | 149682-75-7 | C9H18BNO4 | 详情 | 详情 |
| (IV) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 |
| (V) | 16439 | tert-butyl 1-pyrrolidinecarboxylate | 86953-79-9 | C9H17NO2 | 详情 | 详情 |
| (VI) | 63005 | (1S,2S,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]heptane-2,3-diol; (+)-Pinanediol | 18680-27-8 | C10H18O2 | 详情 | 详情 |
| (VII) | 63006 | tert-butyl (2R)-2-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0~2,6~]dec-4-yl]-1-pyrrolidinecarboxylate | C19H32BNO4 | 详情 | 详情 | |
| (VIII) | 63007 | (2R)-2-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0~2,6~]dec-4-yl]pyrrolidine | 205116-75-2 | C14H24BNO2 | 详情 | 详情 |
| (IX) | 19733 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutyric acid | C10H19NO4 | 详情 | 详情 | |
| (X) | 63011 | tert-butyl (1S)-2-methyl-1-({(2R)-2-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0~2,6~]dec-4-yl]pyrrolidinyl}carbonyl)propylcarbamate | C24H41BN2O5 | 详情 | 详情 | |
| (XI) | 63012 | (2S)-2-amino-3-methyl-1-{(2R)-2-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0~2,6~]dec-4-yl]pyrrolidinyl}-1-butanone | C19H33BN2O3 | 详情 | 详情 |
合成路线50
该中间体在本合成路线中的序号：(VIII)The title compound has been synthesized by two closely related methods. Claisen condensation of 3,4-dimethoxyphenylacetonitrile (I) with ethyl formate produced the cyano aldehyde sodium enolate (II), which was further O-acylated with benzenesulfonyl chloride to afford (III). The aminothiophene derivative (V) was prepared by cyclization of (III) with methyl thioglycolate (IV) under basic conditions. A pyrrole ring was then introduced in (V) through a Paal-Knorr synthesis employing 2,5-dimethoxytetrahydrofuran (VI) in the presence of 4-chloropyridinium chloride, yielding (VII). Refluxing of ester (VII) in pyrrolidine (VIII) gave rise to amide (IX). The intramolecular cyclization of (IX) under Vilsmeier conditions furnished the tricyclic system (X). Finally, regioselective cleavage of the meta methoxy group of (X) by means of AlCl3 yielded the target compound.
| 【1】 Caignard, D.-H.; Enghehard, C.; Robba, M.; Lancelot, J.-C.; Pierre, A.; Renard, P.; Rault, S.; Atassi, G. (ADIR et Cie.); Derivs. of the 8H-(2,3-b)-pyrrolizine-8-one, process for their preparation and pharmaceutical compsns. containing them. EP 0982308; FR 2781482; JP 2000044572; US 6071945 . |
| 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) | 25857 | 2-(3,4-dimethoxyphenyl)acetonitrile | 93-17-4 | C10H11NO2 | 详情 | 详情 |
| (II) | 52226 | sodium (Z)-2-cyano-2-(3,4-dimethoxyphenyl)-1-ethenolate | C11H10NNaO3 | 详情 | 详情 | |
| (III) | 52227 | (Z)-2-cyano-2-(3,4-dimethoxyphenyl)ethenyl benzenesulfonate | C17H15NO5S | 详情 | 详情 | |
| (IV) | 18838 | methyl 2-sulfanylacetate | 2365-48-2 | C3H6O2S | 详情 | 详情 |
| (V) | 52228 | methyl 3-amino-4-(3,4-dimethoxyphenyl)-2-thiophenecarboxylate | C14H15NO4S | 详情 | 详情 | |
| (VI) | 12132 | 2,5-Dimethoxytetrahydrofuran; 5-Methoxytetrahydro-2-furanyl methyl ether | 696-59-3 | C6H12O3 | 详情 | 详情 |
| (VII) | 52229 | methyl 4-(3,4-dimethoxyphenyl)-3-(1H-pyrrol-1-yl)-2-thiophenecarboxylate | C18H17NO4S | 详情 | 详情 | |
| (VIII) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 |
| (IX) | 52230 | [4-(3,4-dimethoxyphenyl)-3-(1H-pyrrol-1-yl)-2-thienyl](1-pyrrolidinyl)methanone | C21H22N2O3S | 详情 | 详情 | |
| (X) | 52231 | 3-(3,4-dimethoxyphenyl)-8H-thieno[2,3-b]pyrrolizin-8-one | C17H13NO3S | 详情 | 详情 |
合成路线51
该中间体在本合成路线中的序号：(VIII)In an alternative procedure, isovanillin (XI) was protected by O-benzylation, giving (XII), and its aldehyde group was subsequently reduced to alcohol (XIII) with NaBH4. The benzylic alcohol (XIII) was chlorinated to (XIV), which was converted to nitrile (XV) by chloride displacement with tetraethylammonium cyanide. Nitrile (XV) was subjected to Claisen condensation with ethyl formate, yielding (XVI), followed by sulfonylation with benzenesulfonyl chloride to afford (XVII), which was cyclized to the amino thiophene (XVIII) by treatment with ethyl thioglycolate (IV) as above. Condensation of (XVIII) with 2,5-dimethoxytetrahydrofuran (VI) produced the corresponding pyrrole derivative (XIX). After conversion of the ester group of (XIX) to amide (XX) upon heating with pyrrolidine (VIII), its cyclization with POCl3 furnished the thienopyrrolizinone (XXI). The O-benzyl protecting group of (XXI) was finally cleaved by treatment with HBr in HOAc.
| 【1】 Lisowski, V.; et al.; Design, synthesis and antiproliferative activity of tripentones: A new series of antitubulin agents. Bioorg Med Chem Lett 2001, 11, 16, 2205. |
| 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) | 18838 | methyl 2-sulfanylacetate | 2365-48-2 | C3H6O2S | 详情 | 详情 |
| (VI) | 12121 | (Z)-4-(Dimethylamino)-3-imidazo[1,2-a]pyridin-6-yl-3-buten-2-one | C13H15N3O | 详情 | 详情 | |
| (VIII) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 |
| (XI) | 18455 | 3-hydroxy-4-methoxybenzaldehyde; Isovanillin | 621-59-0 | C8H8O3 | 详情 | 详情 |
| (XII) | 10966 | 3-(Benzyloxy)-4-methoxybenzaldehyde; 3-Benzyloxy-4-methoxybenzaldehyde | 6346-05-0 | C15H14O3 | 详情 | 详情 |
| (XIII) | 23823 | 5-[4-hydroxy-2-(3-hydroxybutyl)-3,5,6-trimethylphenoxy]-2,2-dimethylpentanoic acid | C20H32O5 | 详情 | 详情 | |
| (XIV) | 52232 | benzyl 5-(chloromethyl)-2-methoxyphenyl ether; 2-(benzyloxy)-4-(chloromethyl)-1-methoxybenzene | C15H15ClO2 | 详情 | 详情 | |
| (XV) | 52233 | (3-Benzyloxy-4-methoxyphenyl)acetonitrile | C16H15NO2 | 详情 | 详情 | |
| (XVI) | 52234 | sodium (Z)-2-[3-(benzyloxy)-4-methoxyphenyl]-2-cyano-1-ethenolate | C17H14NNaO3 | 详情 | 详情 | |
| (XVII) | 52235 | (Z)-2-[3-(benzyloxy)-4-methoxyphenyl]-2-cyanoethenyl benzenesulfonate | C23H19NO5S | 详情 | 详情 | |
| (XVIII) | 52236 | methyl 3-amino-4-[3-(benzyloxy)-4-methoxyphenyl]-2-thiophenecarboxylate | C20H19NO4S | 详情 | 详情 | |
| (XIX) | 52234 | sodium (Z)-2-[3-(benzyloxy)-4-methoxyphenyl]-2-cyano-1-ethenolate | C17H14NNaO3 | 详情 | 详情 | |
| (XX) | 52238 | [4-[3-(benzyloxy)-4-methoxyphenyl]-3-(1H-pyrrol-1-yl)-2-thienyl](1-pyrrolidinyl)methanone | C27H26N2O3S | 详情 | 详情 | |
| (XXI) | 52239 | 3-[3-(benzyloxy)-4-methoxyphenyl]-8H-thieno[2,3-b]pyrrolizin-8-one | C23H17NO3S | 详情 | 详情 |
合成路线52
该中间体在本合成路线中的序号：(VI)6-Chloronicotinic acid (I) is converted to the corresponding acid chloride (II) employing either SOCl2 or PCl5/POCl3. Treatment of acid chloride (II) with EtOH and Et3N, followed by reduction of the resultant ethyl ester with LiAlH4, furnishes 6-chloro-3-pyridylmethanol (III). Alcohol (III) is alternatively prepared by NaBH4 reduction of acid chloride (II). Chlorination of (III) by using SOCl2 gives the chloromethyl pyridine (IV), and further chloride displacement with KCN leads to nitrile (V). Substitution of the remaining chloride group of (V) upon heating with pyrrolidine (VI) furnishes the pyrrolidinyl pyridine (VII). Then hydrolysis of the nitrile function of (VII) under acidic conditions provides carboxylic acid (VIII). Bromination of 4-(methylsulfonyl)acetophenone (IX) in the presence of AlCl3 produces the phenacyl bromide (X). Finally, condensation between acid (VIII) and bromo ketone (X) under basic conditions gives rise to the title diaryl furanone
| 【1】 Almansa, C.; Alfon, J.; Cavalcanti, F.L.; Gomez, L.; Miralles, A.; Synthesis and SAR of 4-pyrrolidinylarylheterocycles as COX-2 selective inhibitors. Drugs Fut 2002, 27, Suppl. A. |
| 【2】 Almansa Rosales, C.; Gonzalez Gonzalez, C.; Torres Barreda, M.C. (J. Uriach & Cia., SA); Novel heterocyclic cpds. with anti-inflammatory activity. EP 1281709; ES 2166710; WO 0183475 . |
| 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) | 12996 | 6-Chloronicotinic acid | 5326-23-8 | C6H4ClNO2 | 详情 | 详情 |
| (II) | 30256 | 6-chloronicotinoyl chloride | 58757-38-3 | C6H3Cl2NO | 详情 | 详情 |
| (III) | 60372 | (6-chloro-3-pyridinyl)methanol | C6H6ClNO | 详情 | 详情 | |
| (IV) | 60373 | 2-chloro-5-(chloromethyl)pyridine | C6H5Cl2N | 详情 | 详情 | |
| (V) | 60374 | 2-(6-chloro-3-pyridinyl)acetonitrile | C7H5ClN2 | 详情 | 详情 | |
| (VI) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 |
| (VII) | 60375 | 2-[6-(1-pyrrolidinyl)-3-pyridinyl]acetonitrile | C11H13N3 | 详情 | 详情 | |
| (VIII) | 60376 | 2-[6-(1-pyrrolidinyl)-3-pyridinyl]acetic acid | C11H14N2O2 | 详情 | 详情 | |
| (IX) | 19263 | 1-[4-(methylsulfonyl)phenyl]-1-ethanone; 4-methylsulfonylacetophenone | 10297-73-1 | C9H10O3S | 详情 | 详情 |
| (X) | 19264 | 2-bromo-1-[4-(methylsulfonyl)phenyl]-1-ethanone | C9H9BrO3S | 详情 | 详情 |
合成路线53
该中间体在本合成路线中的序号：(VIII)4-Chloro-1-butanol (I) is protected as the tetrahydropyranyl ether (III) by treatment with dihydropyran (II) in the presence of pyridinium p-toluenesulfonate (PPTS). Alkylation of the sodium derivative of phenothiazine (IV) with chloride (III) yields adduct (V), which is subsequently deprotected to alcohol (VI) with PPTS in MeOH-THF. The free alcohol (VI) is then chlorinated to (VII) by using SOCl2 in benzene. Finally, condensation of chloride (VII) with pyrrolidine (VIII) in THF at 100 C in a sealed tube provides the title compound.
| 【1】 Guan, J.; et al.; Design, synthesis, and evaluation of new chemosensitizers in multi-drug-resistant Plasmodium falciparum. J Med Chem 2002, 45, 13, 2741. |
| 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) | 22336 | 4-chloro-1-butanol | 928-51-8 | C4H9ClO | 详情 | 详情 |
| (II) | 13684 | 3,4-Dihydro-2H-pyran;2,3-Dihydro-4H-pyran; 5,6-Dihydro-4H-pyran;Dihydropyran | 110-87-2 | C5H8O | 详情 | 详情 |
| (III) | 57750 | 2-(4-Chlorobutoxy)tetrahydropyran | C9H17ClO2 | 详情 | 详情 | |
| (IV) | 57751 | 10H-Phenothiazine; 2,3,5,6-Dibenzo-1,4-thiazine; Dibenzo-1.4-thiazine; Dibenzothiazine; Phenothiazine; Thiodiphenylamine | 92-84-2 | C12H9NS | 详情 | 详情 |
| (V) | 57752 | 4-(10H-phenothiazin-10-yl)butyl tetrahydro-2H-pyran-2-yl ether; 10-[4-(tetrahydro-2H-pyran-2-yloxy)butyl]-10H-phenothiazine | C21H25NO2S | 详情 | 详情 | |
| (VI) | 57753 | 4-(10H-phenothiazin-10-yl)-1-butanol | C16H17NOS | 详情 | 详情 | |
| (VII) | 57754 | 10-(4-chlorobutyl)-10H-phenothiazine | C16H16ClNS | 详情 | 详情 | |
| (VIII) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 |
合成路线54
该中间体在本合成路线中的序号：(II)A mixture of 2-(3-methoxyphenyl)cyclohexanone (I), pyrrolidine (II) and formic acid is heated at 130-40 C to give cis-2-(3-methoxyphenyl)-1-pyrrolidylcyclohexane (III), which is demethylated with refluxing HBr (47%) giving cis-2-(3-hydroxyphenyl)-1-pyrrolidylcyclohexane (IV). Finally this tertiary amine is quaternized with CH3Br.
| 【1】 Castaner, J.; Hopkins, S.J.; RX 72601. Drugs Fut 1976, 1, 6, 304. |
| 【2】 Singh, S.K.; Saibaba, V.; Ravikumar, V.; Rudrawar, S.V.; Daga, P.; Rao, C.S.; Akhila, V.; Hedge, P.; Rao, Y.K.; Synthesis and biological evaluation of 2,3-diarylpyrazines and quinoxalines as selective COX-2 inhibitors. J Pharm Pharmac 1974, 26, 8, 134. |
| 【3】 Lewis, J.W. (Reckitt & Colman Pharmaceuticals); FR 2187296 . |
| 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) | 61376 | 2-(3-Methoxyphenyl)cyclohexanone | 15547-89-4 | C13H16O2 | 详情 | 详情 |
| (II) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 |
| (III) | 61377 | 1-[(1R,2R)-2-(3-methoxyphenyl)cyclohexyl]pyrrolidine; methyl 3-[(1R,2R)-2-(1-pyrrolidinyl)cyclohexyl]phenyl ether | C17H25NO | 详情 | 详情 | |
| (IV) | 61378 | 3-[(1R,2R)-2-(1-pyrrolidinyl)cyclohexyl]phenol | C16H23NO | 详情 | 详情 |
合成路线55
该中间体在本合成路线中的序号：(I)Protection of pyrrolidine (I) with Boc2O in MTBE provides the corresponding N-Boc derivative (II) , which after metalation with sec-BuLi in THF and quenching with B(OMe)3 gives N-Boc-boroproline (III) . Condensation of racemic boronic acid (III) with (+)-pinanediol (IV) in isopropyl acetate or MTBE affords the boronate ester (V) as a diastereomeric mixture. After deprotection by removing the Boc group with HCl in i-PrOH or Et2O , the 2(R)-boroproline pinanediol ester hydrochloride (VI) diastereomer is separated by recrystallization from i-PrOH (1-3). Acylation of compound (VI) with 2-chloroacetyl chloride (VII) in the presence of NMM in CH2Cl2 provides the 2-chloroacetamide (VIII), which is then condensed with 3(R)-amino-1-Boc-pyrrolidine (IX) by means of K2CO3 in THF to give the glycinamide derivative (X). Finally, simultaneous hydrolysis of the N-Boc and boronate ester groups in compound (X) using phenylboronic acid in H2O/hexane provides dutogliptin free base (XI) .
Alternatively, coupling of the 2(R)-boroproline derivative (VI) with either the diprotected N-(benzyloxycarbonyl)-N-[1-(benzyloxycarbonyl)-3(R)-pyrrolidinyl]glycine (XII) via activation as the corresponding mixed anhydride with isobutyl chloroformate and NMM in 2-MeTHF , or by means of EDC, HOBt and NMM in CH2Cl2 , or also with the dicyclohexylamine salt (XIII) in the presence of EDC, HOBt and NMM , affords amide (XIV), which is deprotected by catalytic hydrogenolysis over Pd/C in MeOH to give diamine (XV). Finally, diamine (XV) undergoes boronate ester cleavage by means of phenylboronic acid in the presence of L-tartaric acid in H2O/MTBE to afford dutogliptin tartrate .
| 【1】 Wu, Z.P., Campbell, D.A., Cherrington, J.M. (Phenomix Corp.). Solid citrate and tartrate salts of DPP-IV inhibitors. EP 2061474, JP 2010502610, WO 2008027273. |
| 【2】 Campbell, D.A., Winn, D. (Phenomix Corp.). Heterocyclic boronic acid compounds. CA 2545311, EP 1689757, EP 1743676, EP 1997533, JP 2007512254, JP 2009007377, US 2007060547, WO 2005047297. |
| 【3】 Campbell, D.A., Winn, D.T., Betancort, J.M. (Phenomix Corp.). Pyrrolidine compounds and methods for selective inhibition of dipeptidyl peptidase-IV. US 2006264400, US 7317109. |
| 【4】 Campbell, D.A., Winn, D.T. (Phenomix Corp.). Methods of preparing heterocyclic boronic acids and derivatives thereof. EP 1919485, JP 2009503077, US 2008300413, WO2007016356. |
| 【5】 Wu, Z.-P. (Phenomix Corp.). A crystalline synthetic intermediate for preparation of a DPP-IV inhibitor and method of purification thereof. EP 2175727, WO 2009009751. |
| 【6】 Campbell, D.A., Leitao, E.P.T., Wu, Z.-P., Wang, P. (Phenomix Corp.). Methods and intermediates for synthesis of selective DPP-IV inhibitors. EP 2173709, WO 2008109681. |
| 【7】 Wang, P. (Phenomix Corp.). A crystalline synthetic intermediate for pyrrolidin-3-yl-glycylaminoalkylboronates. WO 2009094462. |
| 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) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 |
| (II) | 16439 | tert-butyl 1-pyrrolidinecarboxylate | 86953-79-9 | C9H17NO2 | 详情 | 详情 |
| (III) | 63002 | 1-{[(1,1-dimethylethyl)oxy]carbonyl}-2-pyrrolidinylboronic acid; 1-(tert-butoxycarbonyl)-2-pyrrolidinylboronic acid | 149682-75-7 | C9H18BNO4 | 详情 | 详情 |
| (IV) | 63005 | (1S,2S,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]heptane-2,3-diol; (+)-Pinanediol | 18680-27-8 | C10H18O2 | 详情 | 详情 |
| (V) | 63006 | tert-butyl (2R)-2-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0~2,6~]dec-4-yl]-1-pyrrolidinecarboxylate | C19H32BNO4 | 详情 | 详情 | |
| (VI) | 63007 | (2R)-2-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0~2,6~]dec-4-yl]pyrrolidine | 205116-75-2 | C14H24BNO2 | 详情 | 详情 |
| (VII) | 11296 | 2-Chloroacetyl chloride; Chloroacetic chloride | 79-04-9 | C2H2Cl2O | 详情 | 详情 |
| (VIII) | 65981 | C16H25BClNO3 | 详情 | 详情 | ||
| (IX) | 65982 | (3R)-(+)-1-Boc-3-aminopyrrolidine; (3R)-(+)-N-Boc-3-aminopyrrolidine; (3R)-(+)-N-tert-Butoxycarbonyl-3-aminopyrrolidine | 147081-49-0 | C9H18N2O2 | 详情 | 详情 |
| (X) | 65983 | C25H42BN3O5 | 详情 | 详情 | ||
| (XI) | 65984 | [(2R)-1-[[(3R)-3-Pyrrolidinylamino]acetyl]-2-pyrrolidinyl]-boronic acid; Dutogliptin | 852329-66-9 | C10H20BN3O3 | 详情 | 详情 |
| (XII) | 65985 | C21H24N2O6 | 详情 | 详情 | ||
| (XIII) | 65986 | C21H24N2O6.C12H23N | 详情 | 详情 | ||
| (XIV) | 65987 | C35H44BN3O7 | 详情 | 详情 | ||
| (XV) | 65988 | C20H34BN3O3 | 详情 | 详情 |
合成路线56
该中间体在本合成路线中的序号：(XIV)Lithiationof 5-fluoro-2-methoxybenzoic acid (I) with sec-BuLi in the presence of TMEDA in THF, followed by methylation of the resulting anion with methyliodide, gives 3-fluoro-6-methoxy-2-methylben methyl benzoic acid (II). Chlorination of carboxylic acid (II) with (COCl)2 in the presence of DMF in CH2Cl2 and subsequent reaction of the resulting acid chloride with PhOH by means of Et3N and DMAP in CH2Cl2 provides the corresponding phenyl ester (III). O-Demethylation of ether (III) by means of BBr3 in CH2Cl2 at −78° Cyields the 6-hydroxybenzoate (IV),which is then protected with Boc2O and DMAP in CH2Cl2 to generate the tert-butyl carbonate (V). Treatment of compound (V) with LDA and TMEDA in THF at −78°C, followed by coupling with enone (VI) in THF, produces the tetraceno[2,3-d] isoxazole derivative (VII),which is subsequently deprotected with HF and TFA in acetonitrile to give the octa hydrotetracene derivative (VIII). Reductive cleavage of the isoxazolering of tetracycline (VIII) with H2 over Pd/Cin methanol/dioxane affords the 2-hydroxyamide (IX),which by nitration with HNO3 and H2SO4 affords the 9-nitro-tetracycline derivative (X). Reduction of the nitro group of compound(X) with H2 over Pd/Cin methanol/dioxane gives the corresponding amine(XI).Then, reaction of amine (XI) with bromoacetyl bromide(XII) in the presence of Na2CO3 in DMPU/acetonitrile provides the bromoacetamide(XIII), which is finally condensed with pyrrolidine(XIV). Alternatively,amine(XI) is directly condensed withp yrrolidin-1-ylacetyl chloride(XV) orits hydrochloride salt in DMF.
| 【1】 Zhou,J.,Xiao,X.-Y.,Plamondon,L.,Hunt,D.K.,Clark,R.B.,Zahler,R.B. (TetraphasePharmaceuticals, Inc.). CA2732883, CN102177134, EP 2323972,EP2682387, JP2011530534, KR2011058800, US2010105671, US2012302527, US2013109657, US8501716,WO 2010017470. |
| 【2】 Xiao,X.Y.,Hunt,D.K.,Zhou,J. etal.Fluorocyclines.1. 7-Fluoro-9-pyrrolidinoacetamido-6-demethyl-6-deoxytetracycline: A potent, broad spectrum antibacterial agent. JMed Chem 2012, 55(2):597-605. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| （III) | 67727 | phenyl 3-fluoro-6-methoxy-2-methylbenzoate | C15H13FO3 | 详情 | 详情 | |
| （V) | 67729 | phenyl 6-((tert-butoxycarbonyl)oxy)-3-fluoro-2-methylbenzoate | C19H19FO5 | 详情 | 详情 | |
| (I) | 67725 | 5-fluoro-2-methoxybenzoic acid；2-Methoxy-5-fluorobenzoic acid | 394-04-7 | C8H7FO3 | 详情 | 详情 |
| (II) | 67726 | 3-fluoro-6-methoxy-2-methylbenzoic acid | C9H9FO3 | 详情 | 详情 | |
| (IV) | 67728 | phenyl 3-fluoro-6-hydroxy-2-methylbenzoate | C14H11FO3 | 详情 | 详情 | |
| (VI) | 67730 | (4aR,8aR,9R)-3-(benzyloxy)-4a-((tert- butyldimethylsilyl)oxy)-9-(dimethylamino)-8,8a,9,9a- tetrahydronaphtho[2,3-d]isoxazole-4,5(3aH,4aH)-dione | C26H34N2O5Si | 详情 | 详情 | |
| (VII) | 67731 | (4aR,11aS,12aR,13R)-3-(benzyloxy)-4a-((tert- butyldimethylsilyl)oxy)-13-(dimethylamino)-10- fluoro-5-hydroxy-4,6-dioxo- 3a,4,4a,6,11,11a,12,12a,13,13a-decahydrotetraceno [2,3-d]isoxazol-7-yl tert-butyl carbonate | C39H47FN2O9Si | 详情 | 详情 | |
| (VIII) | 67732 | (4aR,11aS,12aR,13R)-3-(benzyloxy)-13- (dimethylamino)-10-fluoro-4a,5,7-trihydroxy- 11,11a,12,12a,13,13a-hexahydrotetraceno[2,3-d] isoxazole-4,6(3aH,4aH)-dione | C28H25FN2O7 | 详情 | 详情 | |
| (IX) | 67733 | (4R,4aR,5aS,12aR)-4-(dimethylamino)-7-fluoro- 3,10,12,12a-tetrahydroxy-1,11-dioxo- 1,2,3,4,4a,5,5a,6,11,12a-decahydrotetracene-2- carboxamide | C21H23FN2O7 | 详情 | 详情 | |
| (X) | 67734 | (4R,4aR,5aS,12aR)-4-(dimethylamino)-7-fluoro-3,10,12,12a-tetrahydroxy-9-nitro-1,11-dioxo-1,2,3,4,4a,5,5a,6,11,12a-decahydrotetracene-2-carboxamide | C21H22FN3O9 | 详情 | 详情 | |
| (XI) | 67735 | (4R,4aR,5aS,12aR)-9-amino-4-(dimethylamino)-7-fluoro-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,2,3,4,4a,5,5a,6,11,12a-decahydrotetracene-2-carboxamide | C21H24FN3O7 | 详情 | 详情 | |
| (XII) | 14005 | 2-Bromoacetyl bromide; Bromoacetyl bromide | 598-21-0 | C2H2Br2O | 详情 | 详情 |
| (XIII) | 67736 | (4R,4aR,5aS,12aR)-9-(2-bromoacetamido)-4-(dimethylamino)-7-fluoro-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,2,3,4,4a,5,5a,6,11,12a-decahydrotetracene-2-carboxamide | C23H25BrFN3O8 | 详情 | 详情 | |
| (XIV) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 |
| (XV) | 67737 | 2-(pyrrolidin-1-yl)acetyl chloride | C6H10ClNO | 详情 | 详情 |
合成路线57
该中间体在本合成路线中的序号：(XI)O-Alkylation of 5-nitrosalicylaldehyde (I) with 1,2-dichloroethane (IIa) or 1-bromo-2-chloroethane (IIb) (3) by means of K2CO3 in DMF at 100-5 °c or 60 °c affords 2-(2-chloroethoxy)-5-nitrobenzaldehyde (III), which by reduction with nabH4 in THF or MeoH yields the corresponding alcohol (IV). O-Alkylation of alcohol (IV) with allyl bromide (V) and KoH and Bu4NHSo4 or Bu4Ni at 40 °c gives 2-(allyloxymethyl)-1-(2-chloroethoxy)-4-nitrobenzene (VI), which is then reduced with Fe in the presence of nH4cl in EtoH to yield the corresponding aniline (VII). condensation of amine (VII) with 4-[3-(allyloxymethyl)phenyl]-2-chloropyrimidine (VIII) by means of Hcl in buoH at 80 °c affords the 2-anilinopyrimidine derivative (IX), which then undergoes ring-closing metathesis in the presence of Grubbs’ second-generation catalyst and HCl in CH2Cl2 at 40-45 °c to yield macrocycle (X). Finally, compound (X) is submitted to microwave-assisted condensation with pyrrolidine (XI) in dimethylacetamide at 80 °c .
intermediate (VIII) can be prepared by Suzuki coupling of 2,4-dichloropyrimidine (XII) with 3-(hydroxymethyl)phenylboronic acid (XIII) in the presence of Pd(OAc)2, PPh3 and na2co3 in THF at 70 °c or Pd(PPh3)4 and Na2CO3 in DME at 80-5 °c to give [3-(2-chloropyrimidin-4-yl)phenyl]methanol (XIV), which is finally O-alkylated with allyl bromide (V) and KOH and Bu4NHSO4 or Cs2CO3 in DMF at 40 °c .
| 【1】 William, A.D., Lee, A.c., blanchard, S. et al. Discovery of the macrocycle 11-(2-pyrrolidin-1-yl-ethoxy)-14,19-dioxa-5,7,26-triaza-tetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene (SB1518), a potent Janus kinase 2/fms-like tyrosine kinase-3 (JAK2/FLT3) inhibitor for the treatment of myelofibrosis and lymphoma. J Med chem 2011, 54(13): 4638-58. |
| 【2】 Lee, A., William, A., Poulsen, A. et al. Design, synthesis and SAR studies leading to SB1518, a novel macrocyclic JAK2/FLT3 inhibitor in phase 2 clinical trials for myelofibrosis and lymphoma. 102nd Annu Meet Am Assoc cancer Res (AAcR) (April 2-6, orlando) 2011, Abst 3564. |
| 【3】 blanchard, S., Lee, c.H.A., nagaraj, H.K.M., Poulsen, A., Sun, E.t., tan, Y.L.E., William, A.D. (S*bio Pte. Ltd.). EP 1951729, JP 2009515954, US 8153632, Wo 2007058627. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IIa) | 16170 | 1,2-dichloroethane | 107-06-2 | C2H4Cl2 | 详情 | 详情 |
| (IIb) | 24271 | 1-bromo-2-chloroethane | 107-04-0 | C2H4BrCl | 详情 | 详情 |
| (IX) | 68053 | N-(3-((allyloxy)methyl)-4-(2-chloroethoxy)phenyl)-4-(3-((allyloxy)methyl)phenyl)pyrimidin-2-amine | C26H28ClN3O3 | 详情 | 详情 | |
| (I) | 42307 | 2-hydroxy-5-nitrobenzaldehyde；5-nitrosalicylaldehyde | 97-51-8 | C7H5NO4 | 详情 | 详情 |
| (III) | 68048 | 2-(2-chloroethoxy)-5-nitrobenzaldehyde | C9H8ClNO4 | 详情 | 详情 | |
| (IV) | 68049 | (2-(2-chloroethoxy)-5-nitrophenyl)methanol | C9H10ClNO4 | 详情 | 详情 | |
| (V) | 11463 | 3-Bromo-1-propene; 3-Bromopropene；allyl bromide | 106-95-6 | C3H5Br | 详情 | 详情 |
| (VI) | 68050 | 2-((allyloxy)methyl)-1-(2-chloroethoxy)-4-nitrobenzene | C12H14ClNO4 | 详情 | 详情 | |
| (VII) | 68051 | 3-((allyloxy)methyl)-4-(2-chloroethoxy)aniline | C12H16ClNO2 | 详情 | 详情 | |
| (VIII) | 68052 | 4-[3-(allyloxymethyl)phenyl]-2-chloropyrimidine | C14H13ClN2O | 详情 | 详情 | |
| (X) | 68054 | C24H24ClN3O3 | 详情 | 详情 | ||
| (XI) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 |
| (XII) | 54377 | 2,4-Dichloropyrimidine | 3934-20-1 | C4H2Cl2N2 | 详情 | 详情 |
| (XIII) | 68055 | 3-(hydroxymethyl)phenylboronic acid；(3-Hydroxymethyl)phenylboronic acid;(m-Hydroxymethyl)phenylboronic acid;3-Hydroxymethylbenzeneboronic acid | 87199-15-3 | C7H9BO3 | 详情 | 详情 |
| (XIV) | 68056 | [3-(2-chloropyrimidin-4-yl)phenyl]methanol | C11H9ClN2O | 详情 | 详情 |
合成路线58
该中间体在本合成路线中的序号：(II)condensation of 2-(allyloxymethyl)-1-(2-chloroethoxy)-4-nitrobenzene (VI) with pyrrolidine (XI) in dimethylacetamide at 60 °c affords 1-[2-[2-(allyloxymethyl)-4-nitrophenoxy]ethyl]pyrrolidine (XII), which by reduction with SnCl2 in MeoH/cH2cl2 or with Fe and NH4Cl provides the corresponding aniline (XIII). coupling of amine (XIII) with 4-[3-(allyloxymethyl)phenyl]-2-chloropyrimidine (VIII) In the presence of HCl in BuOH at 100 °c gives the diallyl derivative (XIV), which finally undergoes ring-closing metathesIs In the presence of Grubbs’ second-generation catalyst and TFA in CH2Cl2 at 50 °c or in the presence of the Zhan-1B catalyst .
| 【1】 Lee, A., William, A., Poulsen, A. et al. Design, synthesis and SAR studies leading to SB1518, a novel macrocyclic JAK2/FLT3 inhibitor in phase 2 clinical trials for myelofibrosis and lymphoma. 102nd Annu Meet Am Assoc cancer Res (AAcR) (April 2-6, orlando) 2011, Abst 3564. |
| 【2】 William, A.D., Lee, A.c., blanchard, S. et al. Discovery of the macrocycle 11-(2-pyrrolidin-1-yl-ethoxy)-14,19-dioxa-5,7,26-triaza-tetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene (SB1518), a potent Janus kinase 2/fms-like tyrosine kinase-3 (JAK2/FLT3) inhibitor for the treatment of myelofibrosis and lymphoma. J Med chem 2011, 54(13): 4638-58. |
| 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) | 68050 | 2-((allyloxy)methyl)-1-(2-chloroethoxy)-4-nitrobenzene | C12H14ClNO4 | 详情 | 详情 | |
| (II) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 |
| (III) | 68057 | 1-(2-(2-((allyloxy)methyl)-4-nitrophenoxy)ethyl)pyrrolidine | C16H22N2O4 | 详情 | 详情 | |
| (IV) | 68058 | 3-((allyloxy)methyl)-4-(2-(pyrrolidin-1-yl)ethoxy)aniline | C16H24N2O2 | 详情 | 详情 | |
| (V) | 68052 | 4-[3-(allyloxymethyl)phenyl]-2-chloropyrimidine | C14H13ClN2O | 详情 | 详情 | |
| (VI) | 68059 | N-(3-((allyloxy)methyl)-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-5-(3-((allyloxy)methyl)phenyl)pyrimidin-2-amine | C30H36N4O3 | 详情 | 详情 |
合成路线59
该中间体在本合成路线中的序号：(VIII)Reaction of bromoacetyl bromide (I) with phenol at 80 °C gives the phenyl ester (II) , which by cyclization with (S)-(+)-phenylglycinol (III), previously treated with DIEA, in acetonitrile provides 5(S)-phenylmorpholin-2-one (IV) . Treatment of compound (IV) with HCl affords the corresponding HCl salt (V), which is reacted with NaHCO3 followed by coupling with benzodioxane-6-carboxaldehyde (VI) in refluxing EtOAc/toluene to yield the oxazine adduct (VII). Oxazine derivative (VII) can also be obtained by direct coupling of 5(S)-phenylmorpholin-2-one (IV) with aldehyde (VI) in refluxing toluene. Opening of adduct (VII) with pyrrolidine (VIII) in CH2Cl2, CHCl3 or refluxing THF followed by addition of HCl in refluxing MeOH leads to 3-(1,4-benzodioxan-6-yl)-3(R)-hydroxy-2(R)-(2-hydroxy-1-phenylethylamino)-1-(pyrrolidin-1-yl)propanone (IX), which is reduced with LiAlH4 in refluxing THF to give diol (X). Cleavage of diol (X) by means of H2 and Pd(OH)2 in the presence of either CF3COOH or HCl in MeOH or EtOH/H2O provides amine (XI), which is finally coupled with octanoic acid N-hydroxysuccinimide ester (XII) in CH2Cl2 . Ester (XII) is prepared by condensation of octanoyl chloride (XIII) with N-hydroxysuccinimide (XIV) by means of Et3N in CH2Cl2 .
| 【1】 Dellaria, J.F. Jr., Santarsiero, B.D. Enantioselective synthesis of alphaamino acid derivatives via the stereoselective alkylation of a homochiral glycine enolate synthon. J Org Chem 1989, 54(16): 3916-26. |
| 【2】 Siegel, C., Hirth, B.H. (Genzyme Corp.). Synthesis of UDP-glucose:N-acylsphingosine glucosyltransferase inhibitors. CA 2453978, EP 1409467, EP 2067775, JP 2005255686, JP 2005502635, JP 2010095546, US 2003050299, US 6855830, WO 2003008399. |
| 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) | 14005 | 2-Bromoacetyl bromide; Bromoacetyl bromide | 598-21-0 | C2H2Br2O | 详情 | 详情 |
| (II) | 69187 | phenyl 2-bromoacetate;Phenyl bromoacetate;alpha-Phenyl Bromoacetate;Phenyl a-bromoacetate;bromoacetic acidphenyl ester | 620-72-4 | C8H7BrO2 | 详情 | 详情 |
| (III) | 10973 | (2S)-2-Amino-2-phenyl-1-ethanol; (S)-2-Hydroxy-1-phenylethylamine; (S)-(+)-2-Phenylglycinol; (S)-2-Amino-2-phenyl-1-ethanol | 20989-17-7 | C8H11NO | 详情 | 详情 |
| (IV) | 61798 | (5S)-5-phenyl-2-morpholinone;5(S)-phenylmorpholin-2-one;(5S)-3,4,5,6-Tetrahydro-5-phenyl-4(H)-1,4-oxazin-2-one | 144896-92-4 | C10H11NO2 | 详情 | 详情 |
| (V) | 69188 | 5(S)-phenylmorpholin-2-one hydrochloride | C10H11NO2.HCl | 详情 | 详情 | |
| (VI) | 61797 | 2,3-dihydro-1,4-benzodioxine-6-carbaldehyde; 1,4-Benzodioxan-6-carboxaldehyde; 3,4-ethylenedioxybenzaldehyde ;benzodioxane-6-carboxaldehyde | 29668-44-8 | C9H8O3 | 详情 | 详情 |
| (VII) | 61799 | (1S,3S,5S)-1,3-di(2,3-dihydro-1,4-benzodioxin-6-yl)-5-phenyltetrahydro-8H-[1,3]oxazolo[4,3-c][1,4]oxazin-8-one | C28H25NO7 | 详情 | 详情 | |
| (VIII) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 |
| (IX) | 61800 | (2R,3R)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-3-hydroxy-2-[(2-hydroxy-1-phenylethyl)amino]-1-(1-pyrrolidinyl)-1-propanone | C23H28N2O5 | 详情 | 详情 | |
| (X) | 61801 | (1R,2R)-1-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-[(2-hydroxy-1-phenylethyl)amino]-3-(1-pyrrolidinyl)-1-propanol | C23H30N2O4 | 详情 | 详情 | |
| (XI) | 61802 | (1R,2R)-2-amino-1-(2,3-dihydro-1,4-benzodioxin-6-yl)-3-(1-pyrrolidinyl)-1-propanol | C15H22N2O3 | 详情 | 详情 | |
| (XII) | 69189 | octanoic acid N-hydroxysuccinimide ester;2,5-Dioxopyrrolidin-1-yl octanoate;Caprylic acid N-hydroxysuccinimide ester;N-(Octanoyloxy)succinimide;N-Hydroxysuccinimidyl caprylate | 14464-30-3 | C12H19NO4 | 详情 | 详情 |
| (XIII) | 11123 | Octanoyl chloride; n-Caprylyl chloride;Capryloyl chloride | 111-64-8 | C8H15ClO | 详情 | 详情 |
| (XIV) | 10264 | 1-Hydroxydihydro-1H-pyrrole-2,5-dione; N-Hydroxysuccinimide; 1-Hydroxy-2,5-pyrrolidinedione | 6066-82-6 | C4H5NO3 | 详情 | 详情 |
合成路线60
该中间体在本合成路线中的序号：(II)
| 【1】 Zepp CM.Method for preparation captopril and its analogues:WO,Patent 9,002,732,1990. |
| 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) | 33550 | 2-methylacrylic acid | 79-41-4 | C4H6O2 | 详情 | 详情 |
| (II) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 |
| (III) | 16731 | L-proline | 147-85-3 | C5H9NO2 | 详情 | 详情 |
| (IV) | 69593 | (S)-1-((S)-2-methyl-3-((pyrrolidine-1-carbonothioyl)thio)propanoyl)pyrrolidine-2-carboxylic acid | C14H22N2O3S2 | 详情 | 详情 |