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【结 构 式】 
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【分子编号】15148 【品名】1-phenylethylamine; DL-a-methylbenzylamine; 1-phenyl-1-ethanamine 【CA登记号】618-36-0 |
【 分 子 式 】C8H11N 【 分 子 量 】121.18208 【元素组成】C 79.29% H 9.15% N 11.56% |
合成路线1
该中间体在本合成路线中的序号：(A)Resolution of bicyclo[3.2.0]hept-2-en-6-one (I) via the R-(+)-alpha-methylbenzylamine-bisulfite (A) addition complex provides the 1S-(-)-enantiomer (II), which affords the 3-endo-acetoxy-2-exo-bromobicyclo[3.2.0]heptan-6-one (III) on treatment with 1,3-dibromo-5,5-dimethylhydantoin (DBDMH). Reaction with piperidine followed by hydrolysis gives the hydroxynorbornanone (IV), which is alkylated with biphenylmethylbromide (B) under phase-transfer catalysis to yield the norbornanone (V). Baeyer-Villiger oxidation followed by partial reduction with diisobutylaluminum hydride (Dibal) gives the aldehyde (VII), which is then homologated to the aldehyde (VIII) using methoxymethylene-phosphorane and subsequent treatment with 2N HCl. Condensation of (VIII) with carboxypropyltriphenylphosphorane in tetrahydrofuran followed by esterification with tritylchloride gives the ester (IX). The alcohol stereochemistry in (IX) is inverted via oxidation with pyridine-sulfur trioxide complex in dimethylsulfoxide followed by reduction with Dibal in the presence of 2,6-di-tert-butyl-4-methylphenol. Finally, the ester is hydrolyzed with hydrochloric acid to give the required acid.
| 【1】 Coleman, M.J.; et al.; Baeyer-villiger oxidation of 5-endo-(biphenyl-4-ylmethoxy)-7-anti-piperidinobicyclo[2.2.1] process development and scale-Up. Org Process Res Dev 1997, 1, 1, 20. |
| 【2】 Lumley, P.; Finch, H.; Collington, E.W.C.; Humphrey, P.P.A.; VAPIPROST HYDROCHLORIDE < Rec INNM; BAN >. Drugs Fut 1990, 15, 11, 1087. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 37404 | (3-carboxypropyl)(triphenyl)phosphonium bromide | 17857-14-6 | C22H22BrO2P | 详情 | 详情 | |
| (A) | 15148 | 1-phenylethylamine; DL-a-methylbenzylamine; 1-phenyl-1-ethanamine | 618-36-0 | C8H11N | 详情 | 详情 |
| (I), (II) | 24421 | (1S,5R)bicyclo[3.2.0]hept-2-en-6-one | C7H8O | 详情 | 详情 | |
| (B) | 31210 | 4-(bromomethyl)-1,1'-biphenyl | 2567-29-5 | C13H11Br | 详情 | 详情 |
| (III) | 31208 | (1R,2S,3S,5R)-2-bromo-6-oxobicyclo[3.2.0]hept-3-yl acetate | C9H11BrO3 | 详情 | 详情 | |
| (IV) | 31209 | 5-hydroxy-7-(1-piperidinyl)bicyclo[2.2.1]heptan-2-one | C12H19NO2 | 详情 | 详情 | |
| (V) | 31211 | 5-([1,1'-biphenyl]-4-ylmethoxy)-7-(1-piperidinyl)bicyclo[2.2.1]heptan-2-one | C25H29NO2 | 详情 | 详情 | |
| (VI) | 31212 | 6-([1,1'-biphenyl]-4-ylmethoxy)-8-(1-piperidinyl)-2-oxabicyclo[3.2.1]octan-3-one | C25H29NO3 | 详情 | 详情 | |
| (VII) | 31213 | 2-[(1R,2R,3R,5S)-5-([1,1'-biphenyl]-4-ylmethoxy)-3-hydroxy-2-(1-piperidinyl)cyclopentyl]acetaldehyde | C25H31NO3 | 详情 | 详情 | |
| (VIII) | 31214 | 3-[(1R,2R,3R,5S)-5-([1,1'-biphenyl]-4-ylmethoxy)-3-hydroxy-2-(1-piperidinyl)cyclopentyl]propanal | C26H33NO3 | 详情 | 详情 | |
| (IX) | 31215 | trityl (Z)-7-[(1R,2R,3R,5S)-5-([1,1'-biphenyl]-4-ylmethoxy)-3-hydroxy-2-(1-piperidinyl)cyclopentyl]-4-heptenoate | C49H53NO4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XXIIIb)The chiral intermediate (1R,2S)-N-(tert-butoxycarbonyl)-2-fluorocyclopropylamine (III) can also be obtained as follows: 3) A study of the influence of different substituents in the cis/trans ratio of the cyclopropanation process has been performed. The general method is as follows: the reaction of benzylamine (XXIII) with acetaldehyde and trichloromethyl chloroformate gives the N-benzyl-N-vinylcarbamoyl chloride (XXIV), which by treatment with alcohol yields the N-vinylcarbamate (XXV). The cyclopropanation of (XXV) with fluorodiiodomethane and diethyl zinc as before preferentially affords the cis-N-(2-fluorocyclopropyl)carbamate (XXVI), which is purified by crystallization. The hydrogenolysis of (XXVI) with H2 over Pd/C in acetic acid gives cis-racemic-2-fluorocyclopropylamine (XXVII), which is submitted to optical resolution with L-menthyl chloroformate to afford pure (1R,2S)-isomer (XXII). Finally, this compound is converted into (III) with tert-butoxycarbonyl anhydride as before.
| 【1】 Castaner, J.; Graul, A.; Prous, J.; DU-6859. Drugs Fut 1994, 19, 9, 827. |
| 【2】 Kobayashi, Y.; Hashimoto, M.; Tamura, O.; Terashima, S.; Katoh, T.; Hayakawa, I.; Akiba, T.; Nakatani, K.; Kamada, M.; Synthesis and optical resolution of dl-cis-2-fluorocyclopropylamine, the key component of the new generation of quinolonecarboxylic acid, DU-6859. Tetrahedron Lett 1992, 33, 24, 3483-6. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXIIIa) | 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 |
| (XXIIIb) | 15148 | 1-phenylethylamine; DL-a-methylbenzylamine; 1-phenyl-1-ethanamine | 618-36-0 | C8H11N | 详情 | 详情 |
| (XXIIIc) | 15149 | alpha-Aminodiphenylmethane; diphenylmethanamine; benzhydrylamine | 91-00-9 | C13H13N | 详情 | 详情 |
| (XXIVa) | 15150 | N-benzyl-N-vinylcarbamic chloride | C10H10ClNO | 详情 | 详情 | |
| (XXIVb) | 15151 | N-(1-phenylethyl)-N-vinylcarbamic chloride | C11H12ClNO | 详情 | 详情 | |
| (XXIVc) | 15152 | N-benzhydryl-N-vinylcarbamic chloride | C16H14ClNO | 详情 | 详情 | |
| (XXVa) | 15153 | benzyl N-benzyl-N-vinylcarbamate | C17H17NO2 | 详情 | 详情 | |
| (XXVb) | 15154 | benzyl N-(1-phenylethyl)-N-vinylcarbamate | C18H19NO2 | 详情 | 详情 | |
| (XXVc) | 15155 | benzyl N-benzhydryl-N-vinylcarbamate | C23H21NO2 | 详情 | 详情 | |
| (XXVd) | 15156 | butyl N-benzyl-N-vinylcarbamate | C14H19NO2 | 详情 | 详情 | |
| (XXVe) | 15157 | butyl N-(1-phenylethyl)-N-vinylcarbamate | C14H19NO2 | 详情 | 详情 | |
| (XXVf) | 15158 | butyl N-benzhydryl-N-vinylcarbamate | C20H23NO2 | 详情 | 详情 | |
| (XXVIa) | 15159 | benzyl N-benzyl-N-[(1R,2S)-2-fluorocyclopropyl]carbamate | C18H18FNO2 | 详情 | 详情 | |
| (XXVIb) | 15160 | benzyl N-[(1R,2S)-2-fluorocyclopropyl]-N-(1-phenylethyl)carbamate | C19H20FNO2 | 详情 | 详情 | |
| (XXVIc) | 15161 | benzyl N-benzhydryl-N-[(1R,2S)-2-fluorocyclopropyl]carbamate | C24H22FNO2 | 详情 | 详情 | |
| (XXVId) | 15162 | butyl N-benzyl-N-[(1R,2S)-2-fluorocyclopropyl]carbamate | C15H20FNO2 | 详情 | 详情 | |
| (XXVIe) | 15163 | butyl N-[(1R,2S)-2-fluorocyclopropyl]-N-(1-phenylethyl)carbamate | C16H22FNO2 | 详情 | 详情 | |
| (XXVIf) | 15164 | butyl N-benzhydryl-N-[(1R,2S)-2-fluorocyclopropyl]carbamate | C21H24FNO2 | 详情 | 详情 | |
| (III) | 15127 | tert-butyl N-[(1R,2S)-2-fluorocyclopropyl]carbamate | 127199-16-0 | C8H14FNO2 | 详情 | 详情 |
| (XXII) | 15146 | (1R,2S)-2-Fluorocyclopropanamine; (1R,2S)-2-Fluorocyclopropylamine | C3H6FN | 详情 | 详情 | |
| (XXVII) | 63957 | rac-(1R*,2S*)-2-Fluorocyclopropylamine | C3H6FN | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VIII)Michael addition of itaconic acid (II) to 4-tert-butylaniline (I), and further lactamization afforded pyrrolidone carboxylic acid (III). This was esterified with H2SO4 in MeOH, and the resulting methyl ester (IV) was reduced to alcohol (V) with NaBH4 in boiling tetrahydrofuran. Optical resolution of (V) was achieved by condensation with phthalic anhydride (VI) to give amide (VII), followed by coupling of the remaining carboxylic acid group of (VII) with chiral alpha-methylbenzyl amine (VIII) yielding (IX). After separation of the diastereomeric mixture (IX), hydrolysis of the phthalate ester furnished the required (S)-alcohol (X) (2). Mesylate (XI), prepared from alcohol (X) and MsCl in the presence of Et3N, was condensed with methyl 4-hydroxybenzoate (XII) to afford ether (XIII). Then, basic hydrolysis of the methyl ester of (XIII) provided the title compound.
| 【1】 Yano, S.; Ogawa, K.; Shirasaka, T.; Ohno, T. (Taiho Pharmaceutical Co., Ltd.); Optically active 1-phenylpyrrolidine derivative, intermediate for producing the same, and process for producing both. WO 9406767 . |
| 【2】 Watanabe, S.; et al.; Synthesis of 4-[1-(substituted phenyl)-2-oxo-pyrrolidin-4-yl]methyloxybenzoic acids and related compounds, and their inhibitory capacities toward fatty-acid and sterol biosyntheses. Eur J Med Chem 1994, 29, 675. |
| 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) | 27492 | 4-(tert-butyl)aniline | 769-92-6 | C10H15N | 详情 | 详情 |
| (II) | 27493 | 2-methylenesuccinic acid | 97-65-4 | C5H6O4 | 详情 | 详情 |
| (III) | 27494 | 1-[4-(tert-butyl)phenyl]-5-oxo-3-pyrrolidinecarboxylic acid | C15H19NO3 | 详情 | 详情 | |
| (IV) | 27495 | methyl 1-[4-(tert-butyl)phenyl]-5-oxo-3-pyrrolidinecarboxylate | C16H21NO3 | 详情 | 详情 | |
| (V) | 27496 | 1-[4-(tert-butyl)phenyl]-4-(hydroxymethyl)-2-pyrrolidinone | C15H21NO2 | 详情 | 详情 | |
| (VI) | 11900 | 2-Benzofuran-1,3-dione;1,2-Benzenedicarboxylic Anhydride;1,2-BENZENE DICARBOXYLIC ACID ANHYDRIDE;1,2-BENZENEDICARBONIC ACID, ANHYDRIDE;1,3-DIOXOPHTHALAN;1,3-ISOBENZOFURANDIONE;o-phthalic anhydride; Phthalic anhydride | 85-44-9 | C8H4O3 | 详情 | 详情 |
| (VII) | 27497 | 2-[([1-[4-(tert-butyl)phenyl]-5-oxo-3-pyrrolidinyl]methoxy)carbonyl]benzoic acid | C23H25NO5 | 详情 | 详情 | |
| (VIII) | 15148 | 1-phenylethylamine; DL-a-methylbenzylamine; 1-phenyl-1-ethanamine | 618-36-0 | C8H11N | 详情 | 详情 |
| (IX) | 27498 | [1-[4-(tert-butyl)phenyl]-5-oxo-3-pyrrolidinyl]methyl 2-[[(1-phenylethyl)amino]carbonyl]benzoate | C31H34N2O4 | 详情 | 详情 | |
| (X) | 27499 | (4S)-1-[4-(tert-butyl)phenyl]-4-(hydroxymethyl)-2-pyrrolidinone | C15H21NO2 | 详情 | 详情 | |
| (XI) | 27500 | [(3S)-1-[4-(tert-butyl)phenyl]-5-oxopyrrolidinyl]methyl methanesulfonate | C16H23NO4S | 详情 | 详情 | |
| (XII) | 10251 | methyl 4-hydroxybenzoate; Methyl p-hydroxybenzoate | 99-76-3 | C8H8O3 | 详情 | 详情 |
| (XIII) | 27501 | methyl 4-([(3S)-1-[4-(tert-butyl)phenyl]-5-oxopyrrolidinyl]methoxy)benzoate | C23H27NO4 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)The intermediate tetrahydroisoquinoline (IV) has been prepared by two synthetic strategies. Condensation of alpha-methyl benzylamine (I) with alpha-chloro-alpha-(methylsulfanyl)acetyl chloride (II) in the presence of SnCl2 furnished the tetrahydroisoquinolinone (III). Reductive cleavage of the methylsulfanyl group of (III) employing Raney-Ni, followed by lactam reduction, provided intermediate (IV).
| 【1】 Lee, J.W.; Chae, J.S.; Kim, C.S.; Kim, J.K.; Lim, D.S.; Lee, J.W.; Shon, M.K.; Jo, D.W. (Yuhan Corp.); Quinazoline derivs.. EP 0677049; WO 9414795 . |
| 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) | 15148 | 1-phenylethylamine; DL-a-methylbenzylamine; 1-phenyl-1-ethanamine | 618-36-0 | C8H11N | 详情 | 详情 |
| (II) | 54969 | 2-chloro-2-(methylsulfanyl)acetyl chloride | C3H4Cl2OS | 详情 | 详情 | |
| (III) | 54970 | 1-methyl-4-(methylsulfanyl)-1,4-dihydro-3(2H)-isoquinolinone | C11H13NOS | 详情 | 详情 | |
| (IV) | 54971 | 1-methyl-1,2,3,4-tetrahydroisoquinoline | C10H13N | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(I)In a different method, amine (I) was alkylated with 2-bromoethanol (V) to give the N-(hydroxyethyl) amine (VI), which was further converted to bromo amine (VII) by treatment with concentrated HBr. Friedel-Crafts cyclization of (VII) upon heating in the presence of AlCl3 furnished tetrahydroisoquinoline (IV).
| 【1】 Lee, Y.N.; Hong, Y.W.; Kim, H.B. (Yuhan Corp.); Process for preparation of pyrmidine derivs.. US 5990311; WO 9742186 . |
| 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) | 15148 | 1-phenylethylamine; DL-a-methylbenzylamine; 1-phenyl-1-ethanamine | 618-36-0 | C8H11N | 详情 | 详情 |
| (IV) | 54971 | 1-methyl-1,2,3,4-tetrahydroisoquinoline | C10H13N | 详情 | 详情 | |
| (V) | 10059 | Ethylene bromohydrin; 2-Bromo-1-ethanol | 540-51-2 | C2H5BrO | 详情 | 详情 |
| (VI) | 54972 | 2-[(1-phenylethyl)amino]-1-ethanol | C10H15NO | 详情 | 详情 | |
| (VII) | 54973 | N-(2-bromoethyl)-1-phenyl-1-ethanamine; N-(2-bromoethyl)-N-(1-phenylethyl)amine | C10H14BrN | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(III)The cyclization of 2-oxoacetic acid ethyl ester (I), 1-phenylethylamine (II) and cyclopentadiene (III) by means of BF3 and TFA in dichloromethane gives the 2-azabicyclo[2.2.1]heptene (IV), which is debenzylated with H2 over Pd/C in ethanol to yield 2-azabicyclo[2.2.1]hept-5-ene-3-carboxylic acid ethyl ester (V) The acylation of (V) with 5-chloro-2-nitrobenzoyl chloride (VI) and TEA in dichloromethane affords the bicyclic amide (VII), which is submitted to a reductive cyclization with Fe in refluxing acetic acid to afford the polycyclic benzodiazepinedione (VIII). The reduction of the carbonyl groups of (VIII) by means of LiAlH4 in THF provides the benzodiazepine (IX), which is acylated with 4-nitrobenzoyl chloride (X) and TEA in dichloromethane to give the polycyclic amide (XI). The reduction of the nitro group of (XI) with Zn and NH4Cl in refluxing methanol yields the corresponding amino derivative (XII), which is finally acylated with 4'-methylbiphenyl-2-carbonyl chloride (XIII) and TEA in dichloromethane to furnish the target polycyclic benzodiazepine.
| 【1】 Dyatkin, A.B.; Demarest, K.; Look, R.; Maryanoff, B.E.; Hoekstra, W.J.; Gunnet, J.; Andrade-Gordon, P.; DeGaravilla, L.; Hlasta, D.J.; Structurally novel V2-selective and dual V1A/V2 vasopressin receptor antagonists. 223rd ACS Natl Meet (April 7 2002, Orlando) 2002, Abst MEDI 35. |
| 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) | 48591 | Ethyl glyoxylate; Ethyl oxoacetate; Glyoxylic acid ethyl ester | 924-44-7 | C4H6O3 | 详情 | 详情 |
| (II) | 11183 | 1,3-Cyclopentadiene | C5H6 | 详情 | 详情 | |
| (III) | 15148 | 1-phenylethylamine; DL-a-methylbenzylamine; 1-phenyl-1-ethanamine | 618-36-0 | C8H11N | 详情 | 详情 |
| (IV) | 54051 | ethyl 2-(1-phenylethyl)-2-azabicyclo[2.2.1]hept-5-ene-3-carboxylate | n/a | C17H21NO2 | 详情 | 详情 |
| (V) | 54052 | ethyl 2-azabicyclo[2.2.1]hept-5-ene-3-carboxylate | n/a | C9H13NO2 | 详情 | 详情 |
| (VI) | 44133 | 5-chloro-2-nitrobenzoyl chloride | C7H3Cl2NO3 | 详情 | 详情 | |
| (VII) | 54053 | ethyl 2-(5-chloro-2-nitrobenzoyl)-2-azabicyclo[2.2.1]hept-5-ene-3-carboxylate | n/a | C16H15ClN2O5 | 详情 | 详情 |
| (VIII) | 54054 | 6-chloro-2,10-diazatetracyclo[11.2.1.0~2,12~.0~4,9~]hexadeca-4,6,8,14-tetraene-3,11-dione | n/a | C14H11ClN2O2 | 详情 | 详情 |
| (IX) | 54055 | 6-chloro-2,10-diazatetracyclo[11.2.1.0~2,12~.0~4,9~]hexadeca-4,6,8,14-tetraene | n/a | C14H15ClN2 | 详情 | 详情 |
| (X) | 18941 | p-nitrobenzoyl chloride; 4-nitrobenzoyl chloride | 122-04-3 | C7H4ClNO3 | 详情 | 详情 |
| (XI) | 54056 | (6-chloro-2,10-diazatetracyclo[11.2.1.0~2,12~.0~4,9~]hexadeca-4,6,8,14-tetraen-10-yl)(4-nitrophenyl)methanone | n/a | C21H18ClN3O3 | 详情 | 详情 |
| (XII) | 54057 | (4-aminophenyl)(6-chloro-2,10-diazatetracyclo[11.2.1.0~2,12~.0~4,9~]hexadeca-4,6,8,14-tetraen-10-yl)methanone | n/a | C21H20ClN3O | 详情 | 详情 |
| (XIII) | 54058 | 4'-methyl[1,1'-biphenyl]-2-carbonyl chloride | n/a | C14H11ClO | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(V)The cyclization of 1,2,4-triazol-5-amine (I) with 3-acetyltetrahydrofuran-2-one (II) by heating at 155 C gives the triazolopyrimidinone (III) (1), which is treated with refluxing POCl3 to yield 7-chloro-6-(2-chloroethyl)5-methyl-1,2,4-triazolo[1,5-a]pyrimidine (IV). Finally this compound is cyclized with 1-phenylethylamine (V) by means of Na2CO3 in refluxing ethanol to afford the target pyrrolo-triazolo-pyrimidine derivative.
| 【1】 Sato, Y.; et al.; Studies on cardiovascular agents. 6. Synthesis and coronary vasodilating and antihypertensive activities of 1,2,4-triazolo[1,5-a]pyrimidines fused to heterocyclic systems. J Med Chem 1980, 23, 8, 927. |
| 【2】 Takagi, H.; Sato, Y.; Shimoji, Y.; Kumakura, S. (Sankyo Co., Ltd.); Pyrrolotriazolopyrimidine derivs. and process for the preparation thereof. US 4007189 . |
| 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) | 55760 | 1H-1,2,4-triazol-5-amine; 1H-1,2,4-triazol-5-ylamine | C2H4N4 | 详情 | 详情 | |
| (II) | 24709 | 3-acetyldihydro-2(3H)-furanone | 517-23-7 | C6H8O3 | 详情 | 详情 |
| (III) | 55761 | 6-(2-hydroxyethyl)-5-methyl[1,2,4]triazolo[1,5-a]pyrimidin-7(4H)-one | C8H10N4O2 | 详情 | 详情 | |
| (IV) | 55762 | 7-chloro-6-(2-chloroethyl)-5-methyl[1,2,4]triazolo[1,5-a]pyrimidine | C8H8Cl2N4 | 详情 | 详情 | |
| (V) | 15148 | 1-phenylethylamine; DL-a-methylbenzylamine; 1-phenyl-1-ethanamine | 618-36-0 | C8H11N | 详情 | 详情 |