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【结 构 式】 
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【分子编号】12940 【品名】1,1-Diethoxyethyl ethyl ether; 1,1,1-Triethoxyethane; Triethyl orthoacetate 【CA登记号】78-39-7 |
【 分 子 式 】C8H18O3 【 分 子 量 】162.22912 【元素组成】C 59.23% H 11.18% O 29.59% |
合成路线1
该中间体在本合成路线中的序号：(III)The esterification of 4alpha-carboxymethyl-5beta-benzyloxymethyl-cyclopent-2-en-1alpha-ol (I) with methyl iodide and K2CO3 in acetone gives the corresponding methyl ester (II), which by reaction with triethyl - orthoacetate (III) at 145 C is converted into 3-ethoxycarbonylmethyl-4-methoxycarbonylmethyl-5-benzyloxymethyl-1-cyclopentene (IV). The cyclization of (IV) with potassium tert-butoxide in benzene yields 6-benzyloxymethyl-cis-bicyclo[3.3.0]oct-7-ene-3-one (V), which by reaction with N-bromosuccinimide in DMSO - water affords 6-benzyloxymethyl-7-hydroxy-8-bromo-cis-bicyclo[3.3.0]octan-3-one (VI). Debromination of (VI) with tributyltin hydride and azobisisobutyronitrile in benzene irradiated with UV light gives 6-benzyloxymethyl-7-hydroxy-cis-bicyclo[3.3.0]octan-3-one (VII), which is treated with dihydropyran and p-toluenesulfonic acid in methylene chloride yielding the corresponding protected compound (VIII). Elimination of the benzyl group of (VIII) with H2 over Pd/C in acetic acid affords 6-hydroxymethyl-7-(tetrahydropyranyloxy)-cis-bicyclo[3.3.0]octan-3-one (IX), which is submitted to a Wittig condensation with (4-carboxybutyl) triphenylphosphonium bromide (X) and the sodium salt of DMSO in this solvent, followed by a methylation with diazomethane, affording 3-(4-methoxycarbonylbutylidene)-6-hydroxymethyl-7-tetrahydropyranyloxy)-cis-bicyclo[3.3.0]octane (XI). Oxidation of (XI) with CrO3 in methylene chloride gives the corresponding 6-formyl derivative (XII), which is submitted to a new Wittig condensation with dimethyl 2-oxo-2-cyclopentylethylphosphonate (XIII) and NaH in THF yielding methyl 6,9-methano-11-(tetrahydropyranyloxy)-15-oxo-15-cyclopentyl-16,17,18,19,20-pentanorprosta-3,5-dienoate (XIV). Deprotection of (XIV) with acetic acid in THF - water gives the corresponding 11-hydroxy compound (XVI), which is reduced with NaBH4 in methanol affording the 11,15-dihydroxy ester (XVI). Finally, this compound is hydrolyzed with NaOH in methanol - water.
| 【1】 Hayashi, M.; Konishi, Y.; Arai, Y.; 6,9-Methano-PGI2 analogues. CH 639360; DE 2912409; FR 2422635; GB 2017699; IT 1113341; US 4479966 . |
| 【2】 Kottegoda, S.R.; Serradell, M.N.; Adaikan, P.G.; Castaner, J.; ONO-41483. Drugs Fut 1984, 9, 11, 833. |
| 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) | 34221 | 2-[(1S,4R,5S)-5-[(benzyloxy)methyl]-4-hydroxy-2-cyclopenten-1-yl]acetic acid | C15H18O4 | 详情 | 详情 | |
| (II) | 34222 | methyl 2-[(1S,4R,5S)-5-[(benzyloxy)methyl]-4-hydroxy-2-cyclopenten-1-yl]acetate | C16H20O4 | 详情 | 详情 | |
| (III) | 12940 | 1,1-Diethoxyethyl ethyl ether; 1,1,1-Triethoxyethane; Triethyl orthoacetate | 78-39-7 | C8H18O3 | 详情 | 详情 |
| (IV) | 34223 | methyl 2-[(1S,2R,5S)-2-[(benzyloxy)methyl]-5-(2-ethoxy-2-oxoethyl)-3-cyclopenten-1-yl]acetate | C20H26O5 | 详情 | 详情 | |
| (V) | 34224 | (3aS,4R,6aS)-4-[(benzyloxy)methyl]-3,3a,4,6a-tetrahydro-2(1H)-pentalenone | C16H18O2 | 详情 | 详情 | |
| (VI) | 34225 | (3aR,4S,5S,6aR)-4-[(benzyloxy)methyl]-6-bromo-5-hydroxyhexahydro-2(1H)-pentalenone | C16H19BrO3 | 详情 | 详情 | |
| (VII) | 34226 | (3aS,4S,5R,6aR)-4-[(benzyloxy)methyl]-5-hydroxyhexahydro-2(1H)-pentalenone | C16H20O3 | 详情 | 详情 | |
| (VIII) | 34227 | (3aS,4R,5R,6aR)-4-[(benzyloxy)methyl]-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexahydro-2(1H)-pentalenone | C22H30O4 | 详情 | 详情 | |
| (IX) | 34228 | (3aS,4R,5R,6aR)-4-(hydroxymethyl)-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexahydro-2(1H)-pentalenone | C15H24O4 | 详情 | 详情 | |
| (X) | 13616 | (4-Carboxybutyl)triphenylphosphonium bromide | 17814-85-6 | C23H24BrO2P | 详情 | 详情 |
| (XI) | 34229 | methyl 5-[(3aS,4R,5R,6aR)-4-(hydroxymethyl)-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexahydro-2(1H)-pentalenylidene]pentanoate | C21H34O5 | 详情 | 详情 | |
| (XII) | 34230 | methyl 5-[(3aS,4R,5R,6aR)-4-formyl-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexahydro-2(1H)-pentalenylidene]pentanoate | C21H32O5 | 详情 | 详情 | |
| (XIII) | 34231 | dimethyl 2-cyclopentyl-2-oxoethylphosphonate | C9H17O4P | 详情 | 详情 | |
| (XIV) | 34232 | methyl 5-[(3aS,4S,5R,6aR)-4-[(E)-3-cyclopentyl-3-oxo-1-propenyl]-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexahydro-2(1H)-pentalenylidene]pentanoate | C28H42O5 | 详情 | 详情 | |
| (XV) | 32433 | (2S,3S,4S,5S,6R,9S,11S)-2-((2S,3S)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-6-heptynyl)-9-ethyl-3,5,11-trimethyl-4-[(triethylsilyl)oxy]-1-oxa-7-azaspiro[5.5]undecan-8-one | C34H65NO4Si2 | 详情 | 详情 | |
| (XVI) | 34234 | methyl 5-[(3aS,4S,5R,6aS)-4-[(E,3S)-3-cyclopentyl-3-hydroxy-1-propenyl]-5-hydroxyhexahydro-2(1H)-pentalenylidene]pentanoate | C22H34O4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IX)The reaction of 7-chloro-5-(2-fluorophenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one (I) with methylamine by means of TiCl4 in refluxing benzene gives 7-chloro-5-(2-fluorophenyl)-2-(methylamino)-3H-1,4-benzodiazepine (II), which is treated with NaNO2 and HOAc to yield the nitroso derivative (III). The condensation of (III) with dimethyl malonate (IV) by means of potassium tert-butoxide in DMF affords 2-[7-chloro-5-(2-fluorophenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-ylidene]malonic acid dimethyl ester (V), which is monodecarboxylated with KOH in refluxing methanol, providing the corresponding acetate (VI). The reaction of (VI) with NaNO2 and HOAc gives the hydroxyimino derivative (VII), which is reduced with H2 over RaNi in hot methanol to provide the expected amino derivative (VIII). The cyclization of (VIII) with triethyl orthoacetate (IX) and HCl in refluxing ethanol affords 8-chloro-6-(2-fluorophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid methyl ester (X), which is hydrolyzed with KOH in refluxing methanol/water to provide the corresponding free acid (XI). Finally, this compound is decarboxylated by heating in refluxing ethyleneglycol to give the target compound along with some 6H-isomer that is separated by chromatography. Alternatively, the decarboxylation of (XI) can also be performed in mineral oil at 230 C to obtain a better yield of the target compound.
| 【1】 Bhatia, A.V.; Dhaon, M.K.; Davis, D.A.; Esser, G.L. (Abbott Laboratories Inc.); Process for the preparation of midazolam. WO 0102402 . |
| 【2】 Walser, A.; Fryer, R.I. (F. Hoffmann-La Roche AG); Process for the preparation of diazepine derivs.. DE 2609486; GB 1549836 . |
| 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) | 33355 | 7-chloro-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one | 2886-65-9 | C15H10ClFN2O | 详情 | 详情 |
| (II) | 33558 | N-[7-chloro-5-(2-fluorophenyl)-3H-1,4-benzodiazepin-2-yl]-N-methylamine; 7-chloro-5-(2-fluorophenyl)-N-methyl-3H-1,4-benzodiazepin-2-amine | C16H13ClFN3 | 详情 | 详情 | |
| (III) | 33559 | N-[7-Chloro-5-(2-fluorophenyl)-3H-1,3-benzodiazepin-2-yl]-N-methyl-N-nitrosoamine | C16H12ClFN4O | 详情 | 详情 | |
| (IV) | 19373 | dimethyl malonate；Methyl malonate;Propanedioic acid dimethyl ester | 108-59-8 | C5H8O4 | 详情 | 详情 |
| (V) | 44390 | dimethyl 2-[7-chloro-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-ylidene]malonate | C20H16ClFN2O4 | 详情 | 详情 | |
| (VI) | 44391 | methyl 2-[7-chloro-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-ylidene]acetate | C18H14ClFN2O2 | 详情 | 详情 | |
| (VII) | 44392 | methyl 2-[7-chloro-5-(2-fluorophenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-yl]-2-(hydroxyimino)acetate | C18H15ClFN3O3 | 详情 | 详情 | |
| (VIII) | 44393 | methyl 2-amino-2-[7-chloro-5-(2-fluorophenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-yl]acetate | C18H17ClFN3O2 | 详情 | 详情 | |
| (IX) | 12940 | 1,1-Diethoxyethyl ethyl ether; 1,1,1-Triethoxyethane; Triethyl orthoacetate | 78-39-7 | C8H18O3 | 详情 | 详情 |
| (X) | 44394 | methyl 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate | C20H15ClFN3O2 | 详情 | 详情 | |
| (XI) | 44395 | 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid | C19H13ClFN3O2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(A)The reaction of 2,6-dichloro-4-phenylquinoline (I) with refluxing hydrazine hydrate gives 6-chloro-2-hydrazino-4-phenylquinoline (II), which is cyclocondensed with triethyl orthoacetate (A) in refluxing xylene yielding 7-chloro-1-methyl-5-phenyl-s-triazolo[4,3-a]quinoline (III). The oxidation of (III) to 5-chloro-2-(3-methyl-4H-1,2,4-triazol-4-yl)benzophenone (V) can be performed with sodium periodate and ruthenium dioxide in acetone-water, or first with ozone in CH2Cl2 giving 4-(2-benzoyl-4-chlorophenyl)-5-methyl-4H-1,2,4-triazol-3-carboxaldehyde (IV), which is then oxidized to (V) with silver oxide in methanol. The condensation of (V) with formaldehyde in xylene at 125 C affords 5-chloro-2-(3-(hydroxymethyl)-5-methyl-4H-1,2,4-triazol-4-yl)benzophenon (VI), which by reaction with PBr3 in chloroform is converted into 5-chloro-2-(3-bromoethyl-5-methyl-4H-1,2,4-triazol-4-yl)benzophenon (VII). Finally, this product is cyclized with ammonia in THF - methanol.
| 【1】 Hester, J.B. Jr.; Process for the production of triazolobenzodiazepines and intermediates. DE 2203782; FR 2124559; GB 1374822; GB 1374823; GB 1374824; GB 1374825; JP 49066679; US 3709898 . |
| 【2】 Castaner, J.; Chatterjee, S.S.; Alprazolam. Drugs Fut 1976, 1, 12, 551. |
| 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) | 12940 | 1,1-Diethoxyethyl ethyl ether; 1,1,1-Triethoxyethane; Triethyl orthoacetate | 78-39-7 | C8H18O3 | 详情 | 详情 |
| (I) | 34092 | 2,6-dichloro-4-phenylquinoline | C15H9Cl2N | 详情 | 详情 | |
| (II) | 34093 | 6-chloro-2-hydrazino-4-phenylquinoline | C15H12ClN3 | 详情 | 详情 | |
| (III) | 34094 | 7-chloro-1-methyl-5-phenyl[1,2,4]triazolo[4,3-a]quinoline | C17H12ClN3 | 详情 | 详情 | |
| (IV) | 34095 | 4-(2-benzoyl-4-chlorophenyl)-5-methyl-4H-1,2,4-triazole-3-carbaldehyde | C17H12ClN3O2 | 详情 | 详情 | |
| (V) | 34096 | [5-chloro-2-(3-methyl-4H-1,2,4-triazol-4-yl)phenyl](phenyl)methanone | C16H12ClN3O | 详情 | 详情 | |
| (VI) | 34097 | [5-chloro-2-[3-(hydroxymethyl)-5-methyl-4H-1,2,4-triazol-4-yl]phenyl](phenyl)methanone | C17H14ClN3O2 | 详情 | 详情 | |
| (VII) | 34098 | [2-[3-(bromomethyl)-5-methyl-4H-1,2,4-triazol-4-yl]-5-chlorophenyl](phenyl)methanone | C17H13BrClN3O | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(X)A new synthesis of Y-24180 has been published: The reaction of 2-(2-chlorobenzoyl)acetonitrile (I) with 4-(4-isobutylphenyl)butyraldehyde (II) and sulfur by means of triethylamine in DMF gives the benzoylthiophene (III), which is condensed with 2-phthalimidopropionyl chloride (IV) yielding the propionamidothiophene (V). Elimination of the phthalimido group of (V) first with hydrazine and then with HCl affords the alanylaminothiophene (VI), which is cyclized by means of acetic acid giving 5-(2-chlorophenyl)-7-[2-(4-isobutylphenyl)ethyl]-3-methyl-2,3-dihydro-1 H-thieno[3,2-f][1,4]diazepin-2-one (VII). The reaction of (VII) with P2S5 yields the corresponding thioketone (VIII), which by reaction with hydrazine is converted into the hydrazone (IX). Finally, this compound is cyclized with triethyl orthoacetate (X).
| 【1】 Kawakami, Y.; Moriwaki, M.; Kitani, H.; Kagoshima, M.; Abe, M.; Tahara, T.; Terasawa, M.; Yuasa, S.; Structural optimization of 4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f][1, 2,4]triazolo[4,3-a][1,4]diazepines as antagonists for platelet activating factor: Pharmacological contribution of substituents at the 2- and 6-positions of a condensed ring system. Eur J Med Chem 1996, 31, 9, 683. |
| 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) | 12923 | 3-(2-Chlorophenyl)-3-oxopropanenitrile | 40018-25-5 | C9H6ClNO | 详情 | 详情 |
| (II) | 12924 | 4-(4-Isobutylphenyl)butanal | C14H20O | 详情 | 详情 | |
| (III) | 12925 | [2-Amino-5-(4-isobutylphenethyl)-3-thienyl](2-chlorophenyl)methanone | C23H24ClNOS | 详情 | 详情 | |
| (IV) | 12934 | 2-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)propanoyl chloride | C11H8ClNO3 | 详情 | 详情 | |
| (V) | 12935 | N-[3-(2-Chlorobenzoyl)-5-(4-isobutylphenethyl)-2-thienyl]-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propanamide | C34H31ClN2O4S | 详情 | 详情 | |
| (VI) | 12928 | 2-Amino-N-[3-(2-chlorobenzoyl)-5-(4-isobutylphenethyl)-2-thienyl]propanamide | C26H29ClN2O2S | 详情 | 详情 | |
| (VII) | 12929 | 5-(2-Chlorophenyl)-7-(4-isobutylphenethyl)-3-methyl-1,3-dihydro-2H-thieno[2,3-e][1,4]diazepin-2-one | C26H27ClN2OS | 详情 | 详情 | |
| (VIII) | 12930 | 5-(2-Chlorophenyl)-7-(4-isobutylphenethyl)-3-methyl-1,3-dihydro-2H-thieno[2,3-e][1,4]diazepine-2-thione | C26H27ClN2S2 | 详情 | 详情 | |
| (IX) | 12939 | 5-(2-Chlorophenyl)-7-(4-isobutylphenethyl)-3-methyl-1,3-dihydro-2H-thieno[2,3-e][1,4]diazepin-2-one hydrazone | C26H29ClN4S | 详情 | 详情 | |
| (X) | 12940 | 1,1-Diethoxyethyl ethyl ether; 1,1,1-Triethoxyethane; Triethyl orthoacetate | 78-39-7 | C8H18O3 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(II)The reaction of adenosine (I) with triethyl orthoacetate (II) by means of Ts-OH in acetonitrile gives the bicyclic dioxolane (III), which is treated with acetyl bromide in dichloroethane to yield the acetylated bromonucleoside (IV). The debromination of (IV) by means of Bu3SnH in toluene affords the acetylated target compound (V), which is finally deprotected with ammonia in methanol.
| 【1】 Norman, D.G.; Reese, C.B.; A convenient preparation of 3'-deoxyadenosine. Synthesis 1983, 304. |
| 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) | 11988 | Adenosine; (2R,3R,4S,5R)-2-(6-Amino-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydro-3,4-furandiol | 58-61-7 | C10H13N5O4 | 详情 | 详情 |
| (II) | 12940 | 1,1-Diethoxyethyl ethyl ether; 1,1,1-Triethoxyethane; Triethyl orthoacetate | 78-39-7 | C8H18O3 | 详情 | 详情 |
| (III) | 49214 | [(3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2-ethoxy-2-methyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methanol | C14H19N5O5 | 详情 | 详情 | |
| (IV) | 17629 | [(2R,3S,4S,5R)-4-(acetoxy)-5-(6-amino-9H-purin-9-yl)-3-bromotetrahydro-2-furanyl]methyl acetate | C14H16BrN5O5 | 详情 | 详情 | |
| (V) | 49215 | [(2S,4R,5R)-4-(acetoxy)-5-(6-amino-9H-purin-9-yl)tetrahydro-2-furanyl]methyl acetate | C14H17N5O5 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(II)Condensation of malononitrile (I) with triethyl orthoacetate (II) in pyridine produced the intermediate (III), which was cyclized to pyridine (IV) by acidic treatment. Reductive dechlorination of (IV) by hydrogenation over Pd/BaCO3 afforded 2-aminopyridine-3,5-dicarbonitrile (V). Subsequent condensation of (V) with guanidine (VI) gave rise to the pyridopyrimidine system (VII). Finally, reductive amination of (VII) with 2-chloroaniline (VIII) by means of H2 and Raney-Ni afforded the title compound.
| 【1】 Boutli, F.; Mourellou, O.; Avgoustinaki, N.; Zioga, M.; Rammnos, C.H.; Chin Journal of Medicinal Chemistry 1995, 5, 2, 79-85. |
| 【2】 Gangjee, A.; Adair, O.; Queener, S.F.; Pneumocystis carinii Toxoplasma gondii dihydrofolate reductase inhibitors and antitumor agents: Synthesis and biological activities of 2,4-diamino-5-methyl-6-[(monosubstituted anilino)methyl]-pyrido[2,3-d]pyrimidines. J Med Chem 1999, 42, 13, 2447. |
| 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) | 12061 | Malononitrile | 109-77-3 | C3H2N2 | 详情 | 详情 |
| (II) | 12940 | 1,1-Diethoxyethyl ethyl ether; 1,1,1-Triethoxyethane; Triethyl orthoacetate | 78-39-7 | C8H18O3 | 详情 | 详情 |
| (III) | 35800 | C13H9N5 | 详情 | 详情 | ||
| (IV) | 35801 | 2-amino-6-chloro-4-methyl-3,5-pyridinedicarbonitrile | C8H5ClN4 | 详情 | 详情 | |
| (V) | 35802 | 2-amino-4-methyl-3,5-pyridinedicarbonitrile | C8H6N4 | 详情 | 详情 | |
| (VI) | 14790 | Guanidine | 113-00-8 | CH5N3 | 详情 | 详情 |
| (VII) | 35803 | 2,4-diamino-5-methylpyrido[2,3-d]pyrimidine-6-carbonitrile | C9H8N6 | 详情 | 详情 | |
| (VIII) | 35804 | 2-chloroaniline; 2-chlorophenylamine | 95-51-2 | C6H6ClN | 详情 | 详情 |