Yaozh News Star Club Edu TOP100 Customer Service APP
Iphone Download Android Download
  • English
  • 简体中文
Login Register
Search
Current Location： Home > Feedback Help Print

【结 构 式】

【分子编号】19373

【品名】dimethyl malonate；Methyl malonate;Propanedioic acid dimethyl ester

【CA登记号】108-59-8

【 分 子 式 】C5H8O4

【 分 子 量 】132.11612

【元素组成】C 45.46% H 6.1% O 48.44%
与该中间体有关的原料药合成路线共 19 条
合成路线1合成路线2合成路线3合成路线4合成路线5合成路线6合成路线7合成路线8合成路线9合成路线10合成路线11合成路线12合成路线13合成路线14合成路线15合成路线16合成路线17合成路线18合成路线19

合成路线1

该中间体在本合成路线中的序号：(V)

The enantiocontrolled addition of phthalimide (I) to 1,3-butadiene monoepoxide (II) with a chiral palladium catalyst and Na2CO3 in dichloromethane gives N-(2-hydroxy-1(S)-vinylethyl)phthalimide (III), which is treated with triflic anhydride and TEA in dichloromethane to yield the triflate (IV). The condensation of (IV) with dimethyl malonate (V) by means of NaH in THF affords the alkylated malonate (VI), which is finally decarboxylated and deprotected by a treatment with aqueous refluxing HCl. Note that the synthesis of the biologically active (S)-enantiomer simply requires a change in the chirality of the Pd catalyst used in the first step of the synthesis.

参考文献 中间体
合成目标
【1】 Trost, B.M.; et al.; Dynamic kinetic asymetric transformation of diene monoepoxides: A practical asymmetric synthesis of vinylglycinol, vigabatrin, and ethambutol. J Am Chem Soc 2000, 122, 25, 5968.
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) 12376 Phthalimide; 1H-Isoindole-1,3(2H)-dione; Isoindole-1,3-dione;Phthalic dicarboximide;Phenylimide;Isoindole-1,3-dione 85-41-6 C8H5NO2 详情 详情
(II) 32805 2-vinyloxirane 930-22-3 C4H6O 详情 详情
(III) 38039 2-[(1S)-1-(hydroxymethyl)-2-propenyl]-1H-isoindole-1,3(2H)-dione C12H11NO3 详情 详情
(IV) 38040 (2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-butenyl trifluoromethanesulfonate C13H10F3NO5S 详情 详情
(V) 19373 dimethyl malonate；Methyl malonate;Propanedioic acid dimethyl ester 108-59-8 C5H8O4 详情 详情
(VI) 38041 dimethyl 2-[(2R)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-butenyl]malonate C17H17NO6 详情 详情

合成路线2

该中间体在本合成路线中的序号：(IV)

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.

参考文献 中间体
合成目标
【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：(II)

Reaction of benzaldehyde (I) with dimethyl malonate (II) in refluxing toluene in the presence of piperidine and HOAc provides dimethyl benzylidene malonate (III), which is then hydrogenated over Pd/C to afford dimethyl benzyl malonate (IV). Reduction of (IV) with LiAlH4 in refluxing THF furnishes 2-benzyl-1,3-propanediol (V), which is then subjected to reaction with vinyl acetate (VI) by means of Novozym 435 enzyme to yield diacetate (VII). Enantioselective removal of one acetyl group from (VII) by treatment with Pseudomonas fluorescens Lipase in acetone/phosphate buffer (pH = 7) at 30 C gives 3-acetoxy-2(S)-benzyl-propanol (S)-(VIII), which is then oxidized by means of Jones reagent in acetone/isopropanol to provide carboxylic acid (R)-(IX). The hydrolysis of (IX) with LiOH in THF/H2O gives 2(R)-benzyl-3-hydroxypropanoic acid (R)-(X). Alternatively, intermediate (X) can also be synthesized as follows: Condensation of benzaldehyde (I) with methyl acrylate (XV) by means of diaza-1,4-bicyclo[2.2.2.]octane affords methyl beta-hydroxy-alpha-methylene-benzenepropanoate (XVI), which is then subjected to hydrolysis with KOH in MeOH/H2O to yield carboxylic acid (XVII). Treatment of (XVII) with p-toluenesulfonic acid in refluxing HOAc gives (E)-2-(acetoxymethyl)-3-phenylpropionic acid (XVIII), which is finally converted into (X) by enantioselective hydrogenation in the presence of S-Binap and ruthenium catalyst [CodRu(all)2]. Derivative (R)-(X) is then converted into 3-(acetylsulfanyl)-2(S)-benzylpropionic acid (XI) by means of a Mitsunobu reaction with thioacetic acid, diisopropyl azodicarboxylate (DIAD) and triphenylphosphine (PPh3). Compound (XI) is then subjected to optical purification by formation and isolation of the corresponding salt with (-)-ephedrine and subsequent hydrolysis with HCl to furnish enantiomerically pure (S)-(XII). Finally, carboxylic acid (S)-(XII) is converted into ecadotril by its coupling with benzyl glycinate (XIV), either by means of Et3N, DCC and HOBt in CHCl3, or by first reaction with thionyl chloride to give acid chloride (S)-(XIII) and subsequent coupling with glycinate (XIV) by means of Et3N in CH2Cl2.

参考文献 中间体
合成目标
【1】 Monteil, T.; et al.; New asymmetric synthesis of dexecadotril and ecadotril starting from a single precursor. Synth Commun 2001, 31, 2, 211.
【2】 Duhamel, P.; Duhamel, L.; Danvy, D.; Plaquevent, J.-C.; Giros, B.; Gros, C.; Schwartz, J.-C.; Lecomte, J.-M. (Societe Civile Bioprojet); Enantiomeric derivs. of amino acids, process for their preparation and their pharmaceutical applications. EP 0318377; FR 2623498; JP 1990000161; JP 1996059606; US 5296509; US 5331008 .
【3】 Schwartz, J.-C.; Lecomte, J.-M. (Societe Civile Bioprojet); Novel pharmaceutical compsns. for the treatment of functional colophaties and their process of obtention. EP 0501870; JP 1993105627 .
【4】 Schwartz, J.-C.; Danvy, D.; Lecomte, J.-M.; Duhamel, P.; Duhamel, L.; Monteil, T. (Societe Civile Bioprojet); Method for the asymmetrical synthesis of S-acylated derivs. of 2-mercaptomethyl 3-phenyl propanoic acid, and use thereof for synthesising N-(mercaptoacyl)amino acid derivs.. WO 9729086 .
【5】 Lecomte, J.-M.; Duhamel, P.; Danvy, D.; Schwartz, J.-C.; Duhamel, L.; Monteil, T. (Societe Civile Bioprojet); Process for the synthesis of alpha-substd. acrylic acids and their application. EP 0729936 .
【6】 Henry, J.C.; Genet, J.P.; Dellis, P.; Vidal, V.; Binay, P. (Fournier Industrie et Santé); Preparation of S- and R-isomers of 2-mercaptomethyl-3-aryl propanoic acid by asymmetric reduction of an aryl propenoic acid. FR 2772027 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(S)-(VIII) 49464 (2S)-2-benzyl-3-hydroxypropyl acetate C12H16O3 详情 详情
(R)-(IX) 49465 (2R)-3-(acetoxy)-2-benzylpropionic acid C12H14O4 详情 详情
(R)-(X) 49466 (2R)-2-benzyl-3-hydroxypropionic acid C10H12O3 详情 详情
(XI),(S)-(XII) 49467 (2S)-3-(acetylsulfanyl)-2-benzylpropionic acid C12H14O3S 详情 详情
(I) 10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情
(II) 19373 dimethyl malonate；Methyl malonate;Propanedioic acid dimethyl ester 108-59-8 C5H8O4 详情 详情
(III) 49460 Dimethyl benzylidenemalonate C12H12O4 详情 详情
(IV) 49461 dimethyl 2-benzylmalonate C12H14O4 详情 详情
(V) 49462 2-Benzylpropane-1,3-diol C10H14O2 详情 详情
(VI) 24543 vinyl acetate 108-05-4 C4H6O2 详情 详情
(VII) 49463 3-(acetoxy)-2-benzylpropyl acetate C14H18O4 详情 详情
(XIII) 49468 S-[(2R)-2-benzyl-3-chloro-3-oxopropyl] ethanethioate C12H13ClO2S 详情 详情
(XIV) 49469 1-amino-3-phenylacetone C9H11NO 详情 详情
(XV) 14156 methyl acrylate 96-33-3 C4H6O2 详情 详情
(XVI) 49470 methyl 2-[hydroxy(phenyl)methyl]acrylate C11H12O3 详情 详情
(XVII) 49471 2-[hydroxy(phenyl)methyl]acrylic acid C10H10O3 详情 详情
(XVIII) 49472 (E)-2-[(acetoxy)methyl]-3-phenyl-2-propenoic acid C12H12O4 详情 详情

合成路线4

该中间体在本合成路线中的序号：(VI)

Alternatively, the condensation of dimethyl malonate (VI) with benzaldehyde (VII) by means of piperidine in refluxing toluene gives dimethyl benzylidenemalonate (VIII), which is reduced with H2 over Pd/C in toluene to yield the corresponding benzyl derivative (IX). The hydrolysis of (IX) with NaOH in water affords the benzylmalonic acid (X). Alternatively, intermediate (X) can also be obtained starting from diethyl malonate (XI), which is condensed with with benzaldehyde (VII) by means of piperidine in refluxing toluene to give diethyl benzylidenemalonate (XII). Reduction of (XII) with H2 over Pd/C in toluene yields the corresponding benzyl derivative (XIII), which is then hydrolized with NaOH in water. The monodecarboxylation of (X) and its condensation with paraformaldehyde and diethylamine in refluxing ethyl acetate provides 2-benzylacrylic acid (XIV), which is condensed with thioacetic acid (V) by heating at 70 C to afford 2-(acetylsulfanylmethyl)-3-phenylpropionic acid (XV). Finally, this compound is condensed with N-tosylglycine benzyl ester (XVI) by means of HOBt, DCC and TEA in THF.

参考文献 中间体
合成目标
【1】 Roques, B.; Schwartz, J.-C.; Lecomte, J.-M. (Societe Civile Bioprojet); Amino acid derivs. and their therapeutic application. EP 0038758 .
【2】 Lecomte, J.-M.; Duhamel, P.; Danvy, D.; Schwartz, J.-C.; Duhamel, L.; Monteil, T. (Societe Civile Bioprojet); Process for the synthesis of alpha-substd. acrylic acids and their application. EP 0729936 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(V) 12893 Ethanethioic S-acid C2H4OS 详情 详情
(VI) 19373 dimethyl malonate；Methyl malonate;Propanedioic acid dimethyl ester 108-59-8 C5H8O4 详情 详情
(VII) 10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情
(VIII) 49460 Dimethyl benzylidenemalonate C12H12O4 详情 详情
(IX) 49461 dimethyl 2-benzylmalonate C12H14O4 详情 详情
(X) 37280 2-benzylmalonic acid 616-75-1 C10H10O4 详情 详情
(XI) 16829 Diethyl malonate 105-53-3 C7H12O4 详情 详情
(XII) 37482 diethyl 2-benzylidenemalonate 5292-53-5 C14H16O4 详情 详情
(XIII) 20208 diethyl 2-benzylmalonate 607-81-8 C14H18O4 详情 详情
(XIV) 37279 2-benzylacrylic acid C10H10O2 详情 详情
(XV) 55230 3-(acetylsulfanyl)-2-benzylpropanoic acid C12H14O3S 详情 详情
(XVI) 55228 N-p-Tosylglycine benzyl ester C16H17NO4S 详情 详情

合成路线5

该中间体在本合成路线中的序号：

The reduction of the enone (I) with Red Al or NaBH4 gives the corresponding alcohol (XIV), which is mesylated with methanesulfonyl chloride to the ester (XV). The condensation of (XV) with dimethyl malonate by means of NaH in toluene/methanol yields the malonic derivative (XVI), which is submitted to hydrolysis with KOH and partial decarboxylation in refluxing toluene to afford the substituted acetic acid (XVII). This compound is then reduced with Red Al or LiAlH4 to the ethanol derivative (IV), already obtained. The condensation of (IV) with sodium chloroacetate by means of BuLi in DMSO, followed by esterification with methanol in H2SO4 gives the ethoxyacetic ester (XVIII), which is treated with H2O2 and Na2WO4 in dichloromethane/water with a phase-transfer agent in order to obtain the epoxide (XIX). The cleavage of (XIX) with HIO4 in the same solvent mixture affords the dialdehyde (XX), which is submitted to an aldol condensation by means of piperidine/acetic acid, yielding a mixture of two hydroxy aldehydes (XXIa and XXIb). This mixture is submitted to a Wittig condensation with the phosphonate (X), already used, and a mixture of two isomeric hydroxy ketones (XXIIa and XXIIb) is obtained. The free hydroxy group of (XXIIa and XXIIb) is protected with tert-butyldimethylsilyl chloride, and then the oxo group is reduced with NaBH4 and CeCl3 to obtain the mixture of unsaturated alcohols (XXIIIa and XXIIIb).

参考文献 中间体
合成目标
【1】 Mealy, N.; Castaner, J.; Pimilprost. Drugs Fut 1996, 21, 4, 369.
【2】 Muraoka, M.; Nakamura, T.; Sugie, A.; Ono, K.; Yamamoto, M. (Sumitomo Pharmaceuticals Co., Ltd.); Bicyclooctane derivs. and their production and use. EP 0115954 .
【3】 Kawakami, H.; Muraoka, M.; Sugie, A.; Ono, K.; Kojima, A.; Syntheses of new 3-oxa-methano-PGI1 derivatives and their biological properties. Bioorg Med Chem Lett 1993, 3, 12, 2821-6.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
19373 dimethyl malonate；Methyl malonate;Propanedioic acid dimethyl ester 108-59-8 C5H8O4 详情 详情
63845 sodium 2-chloroacetate C2H2ClNaO2 详情 详情
(XXIa) 14836 methyl 2-[2-[(2S,3aR,4S,5S,6aR)-4-formyl-5-hydroxyoctahydro-2-pentalenyl]ethoxy]acetate C14H22O5 详情 详情
(XXIb) 14837 methyl 2-[2-[(2R,3aS,4R,5R,6aS)-4-formyl-5-hydroxyoctahydro-2-pentalenyl]ethoxy]acetate C14H22O5 详情 详情
(XXIIa) 14838 methyl 2-(2-[(2S,3aR,4R,5S,6aR)-5-hydroxy-4-[(E,5S)-5-methyl-3-oxo-1-nonenyl]octahydro-2-pentalenyl]ethoxy)acetate C23H38O5 详情 详情
(XXIIb) 14839 methyl 2-(2-[(2R,3aS,4S,5R,6aS)-5-hydroxy-4-[(E,5S)-5-methyl-3-oxo-1-nonenyl]octahydro-2-pentalenyl]ethoxy)acetate C23H38O5 详情 详情
(XXIIIa) 14840 methyl 2-(2-[(2S,3aR,4R,5S,6aR)-5-[[tert-butyl(dimethyl)silyl]oxy]-4-[(E,3R,5S)-3-hydroxy-5-methyl-1-nonenyl]octahydro-2-pentalenyl]ethoxy)acetate C29H54O5Si 详情 详情
(XXIIIb) 14841 methyl 2-(2-[(2R,3aS,4S,5R,6aS)-5-[[tert-butyl(dimethyl)silyl]oxy]-4-[(E,3S,5S)-3-hydroxy-5-methyl-1-nonenyl]octahydro-2-pentalenyl]ethoxy)acetate C29H54O5Si 详情 详情
(I) 14816 (3aR,7aS)-1,3,3a,4,7,7a-hexahydro-2H-inden-2-one C9H12O 详情 详情
(IV) 14819 2-[(3aR,7aS)-2,3,3a,4,7,7a-hexahydro-1H-inden-2-yl]-1-ethanol C11H18O 详情 详情
(X) 14825 dimethyl (4S)-4-methyl-2-oxooctylphosphonate C11H23O4P 详情 详情
(XIV) 14829 (3aR,7aS)-2,3,3a,4,7,7a-hexahydro-1H-inden-2-ol C9H14O 详情 详情
(XV) 14830 (3aR,7aS)-2,3,3a,4,7,7a-hexahydro-1H-inden-2-yl methanesulfonate C10H16O3S 详情 详情
(XVI) 14831 dimethyl 2-[(3aR,7aS)-2,3,3a,4,7,7a-hexahydro-1H-inden-2-yl]malonate C14H20O4 详情 详情
(XVII) 14832 2-[(3aR,7aS)-2,3,3a,4,7,7a-hexahydro-1H-inden-2-yl]acetic acid C11H16O2 详情 详情
(XVIII) 14833 methyl 2-[2-[(3aR,7aS)-2,3,3a,4,7,7a-hexahydro-1H-inden-2-yl]ethoxy]acetate C14H22O3 详情 详情
(XIX) 14834 methyl 2-[2-[(2aR,5aS)octahydro-1aH-indeno[5,6-b]oxiren-4-yl]ethoxy]acetate C14H22O4 详情 详情
(XX) 14835 methyl 2-[2-[(3R,4S)-3,4-bis(2-oxoethyl)cyclopentyl]ethoxy]acetate C14H22O5 详情 详情

合成路线6

该中间体在本合成路线中的序号：(VIII)

The nitration of 2,5-dichlorotoluene (I) with HNO3 in H2SO4/AcOH gives 2,5-dichloro-4-methylnitrobenzene (II), which is treated with t-butoxybis(dimethylamino)methane (III) in refluxing THF to yield 2,5-dichloro-4-[2-(dimethylamino)vinyl]nitrobenzene (IV). The condensation of (IV) with 1-(1,2-benzoisothiazol-3-yl)piperazine (V) in AcOH affords the disubstituted piperazine (VI), whose double bond is reduced by means of NaBH(OAc)3 in dichloroethane/AcOH to provide the saturated compound (VII). The condensation of (VII) with dimethyl malonate (VIII) by means of KOH in NMP gives the alkylated malonic ester (IX), which is hydrolyzed and monodecarboxylated with refluxing 3N HCl to yield the phenylacetic acid (X). The esterification of (X) with SOCl2 and methanol affords the methyl ester (XI), which is finally cyclized to the target indolone by reduction of its nitro group with sodium hydrosulfite in refluxing THF/ethanol. Alternatively, compound (VII) can be condensed with methyl cyanacetate (XII) by means of KOH in NMP to give the alkylated cyanacetic ester (XIII), which is hydrolyzed with refluxing 3N HCl to afford the already reported phenylacetic acid (X).

参考文献 中间体
合成目标
【1】 Urban, F.J.; et al.; A novel synthesis of the antipsychotic agent ziprasidone. Synth Commun 1996, 26, 8, 1629.
【2】 Urban, F.J. (Pfizer Inc.); Processes and intermediates for the preparation of 5-[2-(4-(benzoisothiazol-3-yl)-piperazin-1-yl)ethyl]-6-chloro-1,3-dihydro-indol-2-one. WO 9500510 .
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) 62890 1,4-dichloro-2-methylbenzene C7H6Cl2 详情 详情
(II) 62891 1,4-dichloro-2-methyl-5-nitrobenzene C7H5Cl2NO2 详情 详情
(III) 21487 N-[tert-butoxy(dimethylamino)methyl]-N,N-dimethylamine C9H22N2O 详情 详情
(IV) 62892 (E)-2-(2,5-dichloro-4-nitrophenyl)-N,N-dimethyl-1-ethenamine; N-[(E)-2-(2,5-dichloro-4-nitrophenyl)ethenyl]-N,N-dimethylamine C10H10Cl2N2O2 详情 详情
(V) 16280 3-piperazino-1,2-benzisothiazole; 1,2-Benzisothiazole-3-(1-piperazinyl) 87691-87-0 C11H13N3S 详情 详情
(VI) 62893 3-{4-[(E)-2-(2,5-dichloro-4-nitrophenyl)ethenyl]-1-piperazinyl}-1,2-benzisothiazole C19H16Cl2N4O2S 详情 详情
(VII) 62894 3-[4-(2,5-dichloro-4-nitrophenethyl)-1-piperazinyl]-1,2-benzisothiazole C19H18Cl2N4O2S 详情 详情
(VIII) 19373 dimethyl malonate；Methyl malonate;Propanedioic acid dimethyl ester 108-59-8 C5H8O4 详情 详情
(IX) 62895 dimethyl 2-(5-{2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]ethyl}-4-chloro-2-nitrophenyl)malonate C24H25ClN4O6S 详情 详情
(X) 62896 2-(5-{2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]ethyl}-4-chloro-2-nitrophenyl)acetic acid C21H21ClN4O4S 详情 详情
(XI) 62897 methyl 2-(5-{2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]ethyl}-4-chloro-2-nitrophenyl)acetate C22H23ClN4O4S 详情 详情
(XII) 34458 Cyanoacetic acid methyl ester; methyl 2-cyanoacetate 105-34-0 C4H5NO2 详情 详情
(XIII) 62898 methyl 2-(5-{2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]ethyl}-4-chloro-2-nitrophenyl)-2-cyanoacetate C23H22ClN5O4S 详情 详情

合成路线7

该中间体在本合成路线中的序号：(I)

The reaction of dimethyl malonate (I) with 3-(tert-butyldimethylsilyloxy)propyl iodide (II) by means of NaH in THF gives the alkylmalonate (III), which by a new alkylation with allyl bromide (IV) and NaH in DME affords the dialkylmalonate (V). The reduction of (V) with LiBH4 in THF yields the 1,3-propanediol (VI), which is cyclized with 2,2-dimethoxypropane and CSA in dichloromethane giving the 1,3-dioxane (VII). The ozonolysis of the double bond of (VII) with O3 in dichloromethane yields the aldehyde (VIII), which is protected by heating with cyclohexylamine (IX) to afford the imine (X).The condensation of (X) with 8(E)-decenal (XI) by means of LDA in ethyl ether gives the unsaturated aldehyde (XII), which is treated with Pmb-Cl and KH in DME/HMPA to yield the enol ether (XIII). The desilylation of (XIII) with TBAF in THF gives the propanol derivative (XIV), which is oxidized with SO3/pyridine to the corresponding aldehyde (XV). The condensation of (XV) with 4-(triisopropylsilyloxy)-1(E)-butenyl iodide (XVI) by means of BuLi in THF, followed by oxidation of the intermediate alcohol with SO3/pyridine provides the unsaturated ketone (XVII).

参考文献 中间体
合成目标
【1】 Nicolaou, K.C.; et al.; Total synthesis of the CP molecules CP-263,114 and CP-225,917 - Part 1: Synthesis of key intermediates and intelligence gathering. Angew Chem. Int Ed Engl 1999, 38, 11, 1669.
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) 10722 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane 77-76-9 C5H12O2 详情 详情
(I) 19373 dimethyl malonate；Methyl malonate;Propanedioic acid dimethyl ester 108-59-8 C5H8O4 详情 详情
(II) 35676 tert-butyl(3-iodopropoxy)dimethylsilane; tert-butyl(dimethyl)silyl 3-iodopropyl ether C9H21IOSi 详情 详情
(III) 35677 dimethyl 2-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)malonate C14H28O5Si 详情 详情
(IV) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(V) 35678 dimethyl 2-allyl-2-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)malonate C17H32O5Si 详情 详情
(VI) 35679 2-allyl-2-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)-1,3-propanediol C15H32O3Si 详情 详情
(VII) 35680 3-(5-allyl-2,2-dimethyl-1,3-dioxan-5-yl)propyl tert-butyl(dimethyl)silyl ether; [3-(5-allyl-2,2-dimethyl-1,3-dioxan-5-yl)propoxy](tert-butyl)dimethylsilane C18H36O3Si 详情 详情
(VIII) 35681 2-[5-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)-2,2-dimethyl-1,3-dioxan-5-yl]acetaldehyde C17H34O4Si 详情 详情
(IX) 17966 cyclohexanamine; cyclohexyl amine; cyclohexylamine 108-91-8 C6H13N 详情 详情
(X) 35682 N-[(E)-2-[5-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)-2,2-dimethyl-1,3-dioxan-5-yl]ethylidene]-N-cyclohexylamine; N-[(E)-2-[5-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)-2,2-dimethyl-1,3-dioxan-5-yl]ethylidene]cyclohexanamine C23H45NO3Si 详情 详情
(XI) 35683 (E)-8-decenal C10H18O 详情 详情
(XII) 35684 (2Z,10E)-2-[5-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)-2,2-dimethyl-1,3-dioxan-5-yl]-2,10-dodecadienal C27H50O4Si 详情 详情
(XIII) 35685 tert-butyl[3-(5-[(2E,9E)-1-[(E)-2-(4-methoxyphenyl)ethylidene]-2,9-undecadienyl]-2,2-dimethyl-1,3-dioxan-5-yl)propoxy]dimethylsilane; tert-butyl(dimethyl)silyl 3-(5-[(2E,9E)-1-[(E)-2-(4-methoxyphenyl)ethylidene]-2,9-undecadienyl]-2,2-dimethyl-1,3-dioxan-5-yl)propyl ether C35H58O4Si 详情 详情
(XIV) 35686 3-(5-[(2E,9E)-1-[(E)-2-(4-methoxyphenyl)ethylidene]-2,9-undecadienyl]-2,2-dimethyl-1,3-dioxan-5-yl)-1-propanol C29H44O4 详情 详情
(XV) 35687 3-(5-[(2E,9E)-1-[(E)-2-(4-methoxyphenyl)ethylidene]-2,9-undecadienyl]-2,2-dimethyl-1,3-dioxan-5-yl)propanal C29H42O4 详情 详情
(XVI) 35688 (E)-4-iodo-3-butenyl triisopropylsilyl ether; [[(E)-4-iodo-3-butenyl]oxy](triisopropyl)silane C13H27IOSi 详情 详情
(XVII) 35689 (E)-1-(5-[(2E,9E)-1-[(E)-2-(4-methoxyphenyl)ethylidene]-2,9-undecadienyl]-2,2-dimethyl-1,3-dioxan-5-yl)-7-[(triisopropylsilyl)oxy]-4-hepten-3-one C42H68O5Si 详情 详情

合成路线8

该中间体在本合成路线中的序号：(I)

The intermediate aldehyde (XV) has been obtained as follows: The reaction of dimethyl malonate (I) with 3-(tert-butyldimethylsilyloxy)propyl iodide (II) by means of NaH in THF gives the alkylmalonate (III), which by a new alkylation with allyl bromide (IV) and NaH in DME affords the dialkylmalonate (V). The reduction of (V) with LiBH4 in THF yields the 1,3-propanediol (VI), which is cyclized with 2,2-dimethoxypropane and CSA in dichloromethane giving the 1,3-dioxane (VII). The ozonolysis of the double bond of (VII) with O3 in dichloromethane yields the aldehyde (VIII), which is protected by heating with cyclohexylamine (IX) to afford the imine (X). The condensation of (X) with 8(E)-decenal (XI) by means of LDA in ethyl ether gives the unsaturated aldehyde (XII), which is treated with PmbCl and KH in DME/HMPA to yield the enol ether (XIII). The desilylation of (XIII) with TBAF in THF gives the propanol derivative (XIV), which is oxidized with SO3.Pyr to the corresponding aldehyde (XV).

参考文献 中间体
合成目标
【1】 Nicolaou, K.C.; et al.; Total synthesis of the CP molecules CP-263,114 and CP-225,917 - Part 1: Synthesis of key intermediates and intelligence gathering. Angew Chem. Int Ed Engl 1999, 38, 11, 1669.
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) 19373 dimethyl malonate；Methyl malonate;Propanedioic acid dimethyl ester 108-59-8 C5H8O4 详情 详情
(II) 35676 tert-butyl(3-iodopropoxy)dimethylsilane; tert-butyl(dimethyl)silyl 3-iodopropyl ether C9H21IOSi 详情 详情
(III) 35677 dimethyl 2-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)malonate C14H28O5Si 详情 详情
(IV) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(V) 35678 dimethyl 2-allyl-2-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)malonate C17H32O5Si 详情 详情
(VI) 35679 2-allyl-2-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)-1,3-propanediol C15H32O3Si 详情 详情
(VII) 35680 3-(5-allyl-2,2-dimethyl-1,3-dioxan-5-yl)propyl tert-butyl(dimethyl)silyl ether; [3-(5-allyl-2,2-dimethyl-1,3-dioxan-5-yl)propoxy](tert-butyl)dimethylsilane C18H36O3Si 详情 详情
(VIII) 35681 2-[5-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)-2,2-dimethyl-1,3-dioxan-5-yl]acetaldehyde C17H34O4Si 详情 详情
(IX) 17966 cyclohexanamine; cyclohexyl amine; cyclohexylamine 108-91-8 C6H13N 详情 详情
(X) 35682 N-[(E)-2-[5-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)-2,2-dimethyl-1,3-dioxan-5-yl]ethylidene]-N-cyclohexylamine; N-[(E)-2-[5-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)-2,2-dimethyl-1,3-dioxan-5-yl]ethylidene]cyclohexanamine C23H45NO3Si 详情 详情
(XI) 35683 (E)-8-decenal C10H18O 详情 详情
(XII) 35684 (2Z,10E)-2-[5-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)-2,2-dimethyl-1,3-dioxan-5-yl]-2,10-dodecadienal C27H50O4Si 详情 详情
(XIII) 35685 tert-butyl[3-(5-[(2E,9E)-1-[(E)-2-(4-methoxyphenyl)ethylidene]-2,9-undecadienyl]-2,2-dimethyl-1,3-dioxan-5-yl)propoxy]dimethylsilane; tert-butyl(dimethyl)silyl 3-(5-[(2E,9E)-1-[(E)-2-(4-methoxyphenyl)ethylidene]-2,9-undecadienyl]-2,2-dimethyl-1,3-dioxan-5-yl)propyl ether C35H58O4Si 详情 详情
(XIV) 35686 3-(5-[(2E,9E)-1-[(E)-2-(4-methoxyphenyl)ethylidene]-2,9-undecadienyl]-2,2-dimethyl-1,3-dioxan-5-yl)-1-propanol C29H44O4 详情 详情
(XV) 35687 3-(5-[(2E,9E)-1-[(E)-2-(4-methoxyphenyl)ethylidene]-2,9-undecadienyl]-2,2-dimethyl-1,3-dioxan-5-yl)propanal C29H42O4 详情 详情

合成路线9

该中间体在本合成路线中的序号：(XVII)

2) The chiral intermediate (X) has been obtained by two different ways: a) The Knovenagel condensation of dimethyl malonate (XVII) with 3-nitrobenzaldehyde (XVIII) gives the corresponding benzylidenemalonate (XIX), which is alkylated with diethyl zinc and CuBr in DMSO yielding 2-[1-(3-nitrophenyl)propyl]malonic acid dimethyl ester (XX). The partial decarboxylation of (XX) with 6N HCl affords racemic 3-(3-nitrophenyl)pentanoic acid (XXI), which is esterified with methanol/HCl to the racemic methyl ester (XXII). Finally, this racemate is resolved by chromatography over a chiral (R,R)Whelk-O1 column giving the desired intermediate (X). b) The regioselective acetylation of 1-(3-nitrophenyl)-1-propanol (XXIII) with isopropenyl acetate (XXIV) catalyzed by Amano P30 lipase gives a mixture of the (S)-acetate (XXV) and unreacted (R)-alcohol (XXVI). After separation, (XXVI) was mesylated with mesyl chloride as usual yielding mesylate (XXVII), which was condensed with the sodium salt of diethyl malonate (XXVIII) affording the chiral malonic ester (XXIX). Partial decarboxylation of (XXIX) with 6N HCl gives the chiral pentanoic acid (XXX), which is finally esterified to the desired intermediate (X) with methanol/HCl.

参考文献 中间体
合成目标
【1】 Fors, K.S.; et al.; A convergent, scalable synthesis of HIV protease inhibitor PNU-140690. J Org Chem 1998, 63, 21, 7348.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(X) 21164 methyl (3S)-3-(3-nitrophenyl)pentanoate C12H15NO4 详情 详情
(XVII) 19373 dimethyl malonate；Methyl malonate;Propanedioic acid dimethyl ester 108-59-8 C5H8O4 详情 详情
(XVIII) 12646 3-Nitrobenzaldehyde 99-61-6 C7H5NO3 详情 详情
(XIX) 21173 dimethyl 2-(3-nitrobenzylidene)malonate C12H11NO6 详情 详情
(XX) 21174 dimethyl 2-[1-(3-nitrophenyl)propyl]malonate C14H17NO6 详情 详情
(XXI) 21175 3-(3-nitrophenyl)pentanoic acid C11H13NO4 详情 详情
(XXII) 21176 methyl 3-(3-nitrophenyl)pentanoate C12H15NO4 详情 详情
(XXIII) 21177 1-(3-nitrophenyl)-1-propanol C9H11NO3 详情 详情
(XXIV) 21178 isopropenyl acetate 108-22-5 C5H8O2 详情 详情
(XXV) 21179 (1S)-1-(3-nitrophenyl)propyl acetate C11H13NO4 详情 详情
(XXVI) 21180 (1R)-1-(3-nitrophenyl)-1-propanol C9H11NO3 详情 详情
(XXVII) 21181 (1R)-1-(3-nitrophenyl)propyl methanesulfonate C10H13NO5S 详情 详情
(XXVIII) 21182 Diethyl malonate sodium salt C7H11NaO4 详情 详情
(XXIX) 21183 diethyl 2-[(1S)-1-(3-nitrophenyl)propyl]malonate C16H21NO6 详情 详情
(XXX) 21184 (3S)-3-(3-nitrophenyl)pentanoic acid C11H13NO4 详情 详情

合成路线10

该中间体在本合成路线中的序号：(I)

The reaction of dimethyl malonate (I) with 3-(tert-butyldimethylsilyloxy)propyl iodide (II) by means of NaH in THF gives the alkylmalonate (III), which by a new alkylation with allyl bromide (IV) and NaH in DME affords the dialkylmalonate (V). The reduction of (V) with LiBH4 in THF yields the 1,3-propanediol (VI), which is cyclized with 2,2-dimethoxypropane and CSA in dichloromethane giving the 1,3-dioxane (VII). The ozonolysis of the double bond of (VII) with O3 in dichloromethane yields the aldehyde (VIII), which is protected by heating with cyclohexylamine (IX) to afford the imine (X).The condensation of (X) with 8(E)-decenal (XI) by means of LDA in ethyl ether gives the unsaturated aldehyde (XII), which is treated with Pmb-Cl and KH in DME/HMPA to yield the enol ether (XIII). The desilylation of (XIII) with TBAF in THF gives the propanol derivative (XIV), which is oxidized with SO3/pyridine to the corresponding aldehyde (XV). The condensation of (XV) with 4-(triisopropylsilyloxy)-1(E)-butenyl iodide (XVI) by means of BuLi in THF, followed by oxidation of the intermediate alcohol with SO3/pyridine provides the unsaturated ketone (XVII).

参考文献 中间体
合成目标
【1】 Nicolaou, K.C.; et al.; Total synthesis of the CP molecules CP-263,114 and CP-225,917 - Part 1: Synthesis of key intermediates and intelligence gathering. Angew Chem. Int Ed Engl 1999, 38, 11, 1669.
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) 10722 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane 77-76-9 C5H12O2 详情 详情
(I) 19373 dimethyl malonate；Methyl malonate;Propanedioic acid dimethyl ester 108-59-8 C5H8O4 详情 详情
(II) 35676 tert-butyl(3-iodopropoxy)dimethylsilane; tert-butyl(dimethyl)silyl 3-iodopropyl ether C9H21IOSi 详情 详情
(III) 35677 dimethyl 2-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)malonate C14H28O5Si 详情 详情
(IV) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(V) 35678 dimethyl 2-allyl-2-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)malonate C17H32O5Si 详情 详情
(VI) 35679 2-allyl-2-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)-1,3-propanediol C15H32O3Si 详情 详情
(VII) 35680 3-(5-allyl-2,2-dimethyl-1,3-dioxan-5-yl)propyl tert-butyl(dimethyl)silyl ether; [3-(5-allyl-2,2-dimethyl-1,3-dioxan-5-yl)propoxy](tert-butyl)dimethylsilane C18H36O3Si 详情 详情
(VIII) 35681 2-[5-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)-2,2-dimethyl-1,3-dioxan-5-yl]acetaldehyde C17H34O4Si 详情 详情
(IX) 17966 cyclohexanamine; cyclohexyl amine; cyclohexylamine 108-91-8 C6H13N 详情 详情
(X) 35682 N-[(E)-2-[5-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)-2,2-dimethyl-1,3-dioxan-5-yl]ethylidene]-N-cyclohexylamine; N-[(E)-2-[5-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)-2,2-dimethyl-1,3-dioxan-5-yl]ethylidene]cyclohexanamine C23H45NO3Si 详情 详情
(XI) 35683 (E)-8-decenal C10H18O 详情 详情
(XII) 35684 (2Z,10E)-2-[5-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)-2,2-dimethyl-1,3-dioxan-5-yl]-2,10-dodecadienal C27H50O4Si 详情 详情
(XIII) 35685 tert-butyl[3-(5-[(2E,9E)-1-[(E)-2-(4-methoxyphenyl)ethylidene]-2,9-undecadienyl]-2,2-dimethyl-1,3-dioxan-5-yl)propoxy]dimethylsilane; tert-butyl(dimethyl)silyl 3-(5-[(2E,9E)-1-[(E)-2-(4-methoxyphenyl)ethylidene]-2,9-undecadienyl]-2,2-dimethyl-1,3-dioxan-5-yl)propyl ether C35H58O4Si 详情 详情
(XIV) 35686 3-(5-[(2E,9E)-1-[(E)-2-(4-methoxyphenyl)ethylidene]-2,9-undecadienyl]-2,2-dimethyl-1,3-dioxan-5-yl)-1-propanol C29H44O4 详情 详情
(XV) 35687 3-(5-[(2E,9E)-1-[(E)-2-(4-methoxyphenyl)ethylidene]-2,9-undecadienyl]-2,2-dimethyl-1,3-dioxan-5-yl)propanal C29H42O4 详情 详情
(XVI) 35688 (E)-4-iodo-3-butenyl triisopropylsilyl ether; [[(E)-4-iodo-3-butenyl]oxy](triisopropyl)silane C13H27IOSi 详情 详情
(XVII) 35689 (E)-1-(5-[(2E,9E)-1-[(E)-2-(4-methoxyphenyl)ethylidene]-2,9-undecadienyl]-2,2-dimethyl-1,3-dioxan-5-yl)-7-[(triisopropylsilyl)oxy]-4-hepten-3-one C42H68O5Si 详情 详情

合成路线11

该中间体在本合成路线中的序号：(I)

The intermediate aldehyde (XV) has been obtained as follows: The reaction of dimethyl malonate (I) with 3-(tert-butyldimethylsilyloxy)propyl iodide (II) by means of NaH in THF gives the alkylmalonate (III), which by a new alkylation with allyl bromide (IV) and NaH in DME affords the dialkylmalonate (V). The reduction of (V) with LiBH4 in THF yields the 1,3-propanediol (VI), which is cyclized with 2,2-dimethoxypropane and CSA in dichloromethane giving the 1,3-dioxane (VII). The ozonolysis of the double bond of (VII) with O3 in dichloromethane yields the aldehyde (VIII), which is protected by heating with cyclohexylamine (IX) to afford the imine (X).The condensation of (X) with 8(E)-decenal (XI) by means of LDA in ethyl ether gives the unsaturated aldehyde (XII), which is treated with Pmb-Cl and KH in DME/HMPA to yield the enol ether (XIII). The desilylation of (XIII) with TBAF in THF gives the propanol derivative (XIV), which is oxidized with SO3.Pyr to the corresponding aldehyde (XV).

参考文献 中间体
合成目标
【1】 Nicolaou, K.C.; et al.; Total synthesis of the CP molecules CP-263,114 and CP-225,917 - Part 1: Synthesis of key intermediates and intelligence gathering. Angew Chem. Int Ed Engl 1999, 38, 11, 1669.
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) 19373 dimethyl malonate；Methyl malonate;Propanedioic acid dimethyl ester 108-59-8 C5H8O4 详情 详情
(II) 35676 tert-butyl(3-iodopropoxy)dimethylsilane; tert-butyl(dimethyl)silyl 3-iodopropyl ether C9H21IOSi 详情 详情
(III) 35677 dimethyl 2-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)malonate C14H28O5Si 详情 详情
(IV) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(V) 35678 dimethyl 2-allyl-2-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)malonate C17H32O5Si 详情 详情
(VI) 35679 2-allyl-2-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)-1,3-propanediol C15H32O3Si 详情 详情
(VII) 35680 3-(5-allyl-2,2-dimethyl-1,3-dioxan-5-yl)propyl tert-butyl(dimethyl)silyl ether; [3-(5-allyl-2,2-dimethyl-1,3-dioxan-5-yl)propoxy](tert-butyl)dimethylsilane C18H36O3Si 详情 详情
(VIII) 35681 2-[5-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)-2,2-dimethyl-1,3-dioxan-5-yl]acetaldehyde C17H34O4Si 详情 详情
(IX) 17966 cyclohexanamine; cyclohexyl amine; cyclohexylamine 108-91-8 C6H13N 详情 详情
(X) 35682 N-[(E)-2-[5-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)-2,2-dimethyl-1,3-dioxan-5-yl]ethylidene]-N-cyclohexylamine; N-[(E)-2-[5-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)-2,2-dimethyl-1,3-dioxan-5-yl]ethylidene]cyclohexanamine C23H45NO3Si 详情 详情
(XI) 35683 (E)-8-decenal C10H18O 详情 详情
(XII) 35684 (2Z,10E)-2-[5-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)-2,2-dimethyl-1,3-dioxan-5-yl]-2,10-dodecadienal C27H50O4Si 详情 详情
(XIII) 35685 tert-butyl[3-(5-[(2E,9E)-1-[(E)-2-(4-methoxyphenyl)ethylidene]-2,9-undecadienyl]-2,2-dimethyl-1,3-dioxan-5-yl)propoxy]dimethylsilane; tert-butyl(dimethyl)silyl 3-(5-[(2E,9E)-1-[(E)-2-(4-methoxyphenyl)ethylidene]-2,9-undecadienyl]-2,2-dimethyl-1,3-dioxan-5-yl)propyl ether C35H58O4Si 详情 详情
(XIV) 35686 3-(5-[(2E,9E)-1-[(E)-2-(4-methoxyphenyl)ethylidene]-2,9-undecadienyl]-2,2-dimethyl-1,3-dioxan-5-yl)-1-propanol C29H44O4 详情 详情
(XV) 35687 3-(5-[(2E,9E)-1-[(E)-2-(4-methoxyphenyl)ethylidene]-2,9-undecadienyl]-2,2-dimethyl-1,3-dioxan-5-yl)propanal C29H42O4 详情 详情

合成路线12

该中间体在本合成路线中的序号：(I)

The condensation of dimethyl malonate (I) with 2-cloroallyl chloride (II) by means of sodium methoxide in hot methanol gives the alkylmalonate (III), which is treated with tert-butyl bromoacetate (IV), NaOH and benzyltriethylammonium chloride to yield the tricarboxylic ester (V). Partial decarboxylation of (V) with KOH in hot methanol/water affords the succinic acid derivative (VI), which is submitted to enzymatic hydrolysis with Alcalase 2.4L to provide the chiral monoester (VII). The condensation of monoacid (VII) with amine (VIII) by means of HOBT, DCC, and DIEA in THF gives the amide (IX), which is treated with TFA to eliminate the tert-butyl protecting group yielding the acid (X). The condensation of (X) with amine (XI) by means of NMM and pivaloyl chloride affords the amide (XII), which is treated with 2-methoxypropene (XIII) and TsOH in dichloromethane to protect the vicinal hydroxy groups giving the dioxolane (XIV). The bromination of the allyl double bond of (XIV) with NBS in tert-butyl methyl ether/water gives 3-bromo-2-oxopropyl derivative (XV).

参考文献 中间体
合成目标
【1】 Beaulieu, P.L.; et al.; Practical synthesis of BILA 2157 BS, a potent and orally active renin inhibitor: Use of an enzayme-catalyzed hydrolysis for the preparation of homochiral succinic acid derivatives. J Org Chem 1999, 64, 18, 6622.
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) 19373 dimethyl malonate；Methyl malonate;Propanedioic acid dimethyl ester 108-59-8 C5H8O4 详情 详情
(II) 31608 2,3-dichloro-1-propene 78-88-6 C3H4Cl2 详情 详情
(III) 31609 dimethyl 2-(2-chloro-2-propenyl)malonate C8H11ClO4 详情 详情
(IV) 17430 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate 5292-43-3 C6H11BrO2 详情 详情
(V) 31610 1-(tert-butyl) 2,2-dimethyl 4-chloro-4-pentene-1,2,2-tricarboxylate C14H21ClO6 详情 详情
(VI) 31611 4-(tert-butyl) 1-methyl 2-(2-chloro-2-propenyl)succinate C12H19ClO4 详情 详情
(VII) 31612 (2S)-2-[2-(tert-butoxy)-2-oxoethyl]-4-chloro-4-pentenoic acid C11H17ClO4 详情 详情
(VIII) 29543 (2S,3R,4S)-2-amino-1-cyclohexyl-6-methyl-3,4-heptanediol C14H29NO2 详情 详情
(IX) 31613 tert-butyl (3S)-5-chloro-3-([[(1S,2R,3S)-1-(cyclohexylmethyl)-2,3-dihydroxy-5-methylhexyl]amino]carbonyl)-5-hexenoate C25H44ClNO5 详情 详情
(X) 31614 (3S)-5-chloro-3-([[(1S,2R,3S)-1-(cyclohexylmethyl)-2,3-dihydroxy-5-methylhexyl]amino]carbonyl)-5-hexenoic acid C21H36ClNO5 详情 详情
(XI) 29540 2-[(cyclohexylmethyl)amino]-N-methyl-N-[2-(2-pyridinyl)ethyl]acetamide C17H27N3O 详情 详情
(XII) 31615 (2S)-2-(2-chloro-2-propenyl)-N(4)-(cyclohexylmethyl)-N(1)-[(1S,2R,3S)-1-(cyclohexylmethyl)-2,3-dihydroxy-5-methylhexyl]-N(4)-(2-[methyl[2-(2-pyridinyl)ethyl]amino]-2-oxoethyl)butanediamide C38H61ClN4O5 详情 详情
(XIII) 17354 isopropenyl methyl ether; 2-methoxy-1-propene 116-11-0 C4H8O 详情 详情
(XIV) 31616 (2S)-2-(2-chloro-2-propenyl)-N(1)-[(1S)-2-cyclohexyl-1-[(4R,5S)-5-isobutyl-2,2-dimethyl-1,3-dioxolan-4-yl]ethyl]-N(4)-(cyclohexylmethyl)-N(4)-(2-[methyl[2-(2-pyridinyl)ethyl]amino]-2-oxoethyl)butanediamide C41H65ClN4O5 详情 详情
(XV) 31617 (2R)-2-(3-bromo-2-oxopropyl)-N(1)-[(1S)-2-cyclohexyl-1-[(4R,5S)-5-isobutyl-2,2-dimethyl-1,3-dioxolan-4-yl]ethyl]-N(4)-(cyclohexylmethyl)-N(4)-(2-[methyl[2-(2-pyridinyl)ethyl]amino]-2-oxoethyl)butanediamide C41H65BrN4O6 详情 详情

合成路线13

该中间体在本合成路线中的序号：(IX)

The alkylation of dimethyl malonate (IX) with 4-(methylsulfonyl)phenacyl bromide (VIII) by means of K2CO3 in hot acetone gives the substituted malonic ester (X), which is condensed with 2-(3,5-difluorophenyl)acetyl chloride (XI) by means of MgBr2 and pyridine in acetonitrile yielding the disubstituted malonic ester (XII). The cyclization of (XII) by means of triethylamine affords the cylopentenone dicarboxylic ester (XIII), which is finally decarboxylated with H2SO4 in hot acetic acid to provide the target compound.

参考文献 中间体
合成目标
【1】 Grabowski, E.J.J.; Zhaol, D.L.; Prasit, P.; Xu, F.; Ouimet, N.; Tillyer, R.D.; Black, C.; Chen, C.Y.; Reider, P.J.; Efficient syntheses of 2-(3 ',5 '-difluorophenyl)-3-(4 '-methylsulfonylphenyl)-cyclopent-2-enone, a potent COX-2 inhibitor. Tetrahedron 1999, 55, 19, 6001.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VIII) 19624 (4R,5S,6S,7R)-4,7-dibenzyl-1,3-bis(3-iodobenzyl)-5,6-bis(methoxymethoxy)-1,3-diazepan-2-one C37H40I2N2O5 详情 详情
(IX) 19373 dimethyl malonate；Methyl malonate;Propanedioic acid dimethyl ester 108-59-8 C5H8O4 详情 详情
(X) 31626 dimethyl 2-[2-[4-(methylsulfonyl)phenyl]-2-oxoethyl]malonate C14H16O7S 详情 详情
(XI) 28362 2-(3,5-difluorophenyl)acetyl chloride C8H5ClF2O 详情 详情
(XII) 31624 dimethyl 2-[2-(3,5-difluorophenyl)acetyl]-2-[2-[4-(methylsulfonyl)phenyl]-2-oxoethyl]malonate C22H20F2O8S 详情 详情
(XIII) 31625 dimethyl 3-(3,5-difluorophenyl)-4-[4-(methylsulfonyl)phenyl]-2-oxo-3-cyclopentene-1,1-dicarboxylate C22H18F2O7S 详情 详情

合成路线14

该中间体在本合成路线中的序号：(II)

The asymetric Michael addition of malonic ester (II) to 2-cyclohexenone (I) catalyzed by (R)-ALB and t-BuOK in THF gives the (R)-enantiomer (III), which is cyclized with phenylhydrazine (IV) in hot acetic acid yielding the tetrahydrocarbazole (V). The protection of (V) with Boc2O, TEA and DMAP in dichloromethane gives protected (VI), which is condensed with acetaldehyde (VII) by means of LDA in THF affording crotonate (VIII). The reduction of the ester group of (VIII) with DIBAL, followed by oxidation with MnO2 gives the corresponding aldehyde (IX), which is reductocondensed with 2-aminoacetaldehyde dimethylacetal (XI) by means of titanium tetraisopropoxide and NaBH4 in toluene/methanol providing adduct (XI). The deprotection of (XI) with TFA and anisole gives the free tetrahydrocarbazole (XII), which is cyclized by means of DDQ in THF yielding the tetracyclic compound (XIII). The reduction of the exocyclic double bond of (XIII) with RhCl(PPh3)3 in benzene/isopropanol affords the (S)-ethyl derivative (XIV), which is treated with Et-SH and BF3/Et2O in dichloromethane to give the thioacetal (XV). Finally, this compound is cyclized with DMTSF, LiAlH4 and Raney-Ni in refluxing ethanol.

参考文献 中间体
合成目标
【1】 Shimizu, S.; et al.; Catalytic asymmetric synthesis of tubifolidine. J Org Chem 1998, 63, 21, 7547.
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) 26253 2-cyclohexen-1-one；Cyclohex-2-enone；2-cyclohexenone 930-68-7 C6H8O 详情 详情
(II) 19373 dimethyl malonate；Methyl malonate;Propanedioic acid dimethyl ester 108-59-8 C5H8O4 详情 详情
(III) 37225 dimethyl 2-[(1R)-3-oxocyclohexyl]malonate C11H16O5 详情 详情
(IV) 11818 Phenyl hydrazine; 1-Phenylhydrazine 100-63-0 C6H8N2 详情 详情
(V) 37226 methyl 2-[(2R)-2,3,4,9-tetrahydro-1H-carbazol-2-yl]acetate C15H17NO2 详情 详情
(VI) 37227 tert-butyl (2R)-2-(2-methoxy-2-oxoethyl)-1,2,3,4-tetrahydro-9H-carbazole-9-carboxylate C20H25NO4 详情 详情
(VII) 11974 Acetaldehyde 75-07-0 C2H4O 详情 详情
(VIII) 37228 tert-butyl (2R)-2-[(E)-1-(methoxycarbonyl)-1-propenyl]-1,2,3,4-tetrahydro-9H-carbazole-9-carboxylate C22H27NO4 详情 详情
(IX) 37229 tert-butyl (2R)-2-[(E)-1-formyl-1-propenyl]-1,2,3,4-tetrahydro-9H-carbazole-9-carboxylate C21H25NO3 详情 详情
(X) 37158 ethyl 5-[3-(benzyloxy)-2-formylphenoxy]pentanoate C21H24O5 详情 详情
(XI) 37230 tert-butyl (2R)-2-((E)-1-[[(2,2-dimethoxyethyl)amino]methyl]-1-propenyl)-1,2,3,4-tetrahydro-9H-carbazole-9-carboxylate C25H36N2O4 详情 详情
(XII) 37231 (E)-N-(2,2-dimethoxyethyl)-2-[(2R)-2,3,4,9-tetrahydro-1H-carbazol-2-yl]-2-buten-1-amine; N-(2,2-dimethoxyethyl)-N-[(E)-2-[(2R)-2,3,4,9-tetrahydro-1H-carbazol-2-yl]-2-butenyl]amine C20H28N2O2 详情 详情
(XIII) 37232 2-[(1S,12R)-13-[(E)ethylidene]-9,15-diazatetracyclo[10.3.1.0(2,10).0(3,8)]hexadeca-2(10),3,5,7-tetraen-15-yl]-1-methoxyethyl methyl ether; (1S,12R)-15-(2,2-dimethoxyethyl)-13-[(E)ethylidene]-9,15-diazatetracyclo[10.3.1.0(2,10).0(3,8)]hexadeca-2(10),3,5,7-tetraene C20H26N2O2 详情 详情
(XIV) 37233 2-[(1S,12R,13S)-13-ethyl-9,15-diazatetracyclo[10.3.1.0(2,10).0(3,8)]hexadeca-2(10),3,5,7-tetraen-15-yl]-1-methoxyethyl methyl ether; (1S,12R,13S)-15-(2,2-dimethoxyethyl)-13-ethyl-9,15-diazatetracyclo[10.3.1.0(2,10).0(3,8)]hexadeca-2(10),3,5,7-tetraene C20H28N2O2 详情 详情
(XV) 37234 ethyl 2-[(1S,12R,13S)-13-ethyl-9,15-diazatetracyclo[10.3.1.0(2,10).0(3,8)]hexadeca-2(10),3,5,7-tetraen-15-yl]-1-(ethylsulfanyl)ethyl sulfide; (1S,12R,13S)-15-[2,2-bis(ethylsulfanyl)ethyl]-13-ethyl-9,15-diazatetracyclo[10.3.1.0(2,10).0(3,8)]hexadeca-2(10),3,5,7-tetraene C22H32N2S2 详情 详情

合成路线15

该中间体在本合成路线中的序号：(VIII)

The condensation of 2,3-dimethylphenol (I) with 3-bromoanisole (II) by means of K2CO3 and CuO in pyridine gives the diaryl ether (III), which is demethylated by means of HBr in refluxing acetic acid to yield the phenol (IV). The condensation of (IV) with 4,4,4-trifluorobutylsulfonyl chloride (V) by means of t-BuOK in THF affords the sulfonate (VI), which is brominated by means of NBS in refluxing CCl4 to provide the bis(bromomethyl)compound (VII). The cyclization of (VII) with dimethyl malonate (VIII) by means of K2CO3 in refluxing butanone furnishes the indane-dicarboxylate (IX), which is hydrolyzed and monodecarboxylated by means of HBr in refluxing acetic acid/water to give the indane-carboxylic acid (X). The reduction of the CO2H group of (X) by means of BH3/Me2S in THF yields the racemic hydroxymethyl derivative (XI), which is finally submitted to optical resolution by means of chiral preparative HPLC over Chiracel OD to provide the target (R)-enantiomer.

参考文献 中间体
合成目标
【1】 Dressel, J.; Matzke, M.; Mittendorf, J.; De Vry, J.-M.V.; Mauler, F.; Friedl, A.; Horvath, E.; Keldenich, J.; Franz, J.; Spreyer, P.; Vöhringer, V.; Rock, M.-H.; Schumacher, J. (Bayer AG); Novel aryl sulphonamide amino acid esters and analogues. CA 2341028; DE 19837627; EP 1105371; US 6545050; WO 0010968 .
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) 60555 4,4,4-trifluorobutyl methanesulfonate C5H9F3O3S 详情 详情
(A) 60556 4,4,4-trifluoro-1-butanol C4H7F3O 详情 详情
(I) 40074 2,3-dimethylphenol 526-75-0 C8H10O 详情 详情
(II) 35983 m-bromoanisole; 1-Bromo-3-methoxybenzene; 3-Bromoanisole; 3-Bromophenyl methyl ether 2398-37-0 C7H7BrO 详情 详情
(III) 60552 3-(2,3-dimethylphenoxy)phenyl methyl ether; 1-(3-methoxyphenoxy)-2,3-dimethylbenzene C15H16O2 详情 详情
(IV) 60553 3-(2,3-dimethylphenoxy)phenol C14H14O2 详情 详情
(V) 26779 1-butanesulfonyl chloride 2386-60-9 C4H9ClO2S 详情 详情
(VI) 60557 3-(2,3-dimethylphenoxy)phenyl 4,4,4-trifluoro-1-butanesulfonate C18H19F3O4S 详情 详情
(VII) 60558 3-[2,3-bis(bromomethyl)phenoxy]phenyl 4,4,4-trifluoro-1-butanesulfonate C18H17Br2F3O4S 详情 详情
(VIII) 19373 dimethyl malonate；Methyl malonate;Propanedioic acid dimethyl ester 108-59-8 C5H8O4 详情 详情
(IX) 60559 dimethyl 4-(3-{[(4,4,4-trifluorobutyl)sulfonyl]oxy}phenoxy)-1,3-dihydro-2H-indene-2,2-dicarboxylate C23H23F3O8S 详情 详情
(X) 60560 4-(3-{[(4,4,4-trifluorobutyl)sulfonyl]oxy}phenoxy)-2-indanecarboxylic acid C20H19F3O6S 详情 详情
(XI) 60551 3-{[2-(hydroxymethyl)-2,3-dihydro-1H-inden-4-yl]oxy}phenyl 4,4,4-trifluoro-1-butanesulfonate C20H21F3O5S 详情 详情
(C) 60554 4,4,4-trifluoro-1-butanesulfenyl cyanide C5H6F3NS 详情 详情

合成路线16

该中间体在本合成路线中的序号：(XX)

A different protection strategy involves masking the ring nitrogens as amide groups. Methyl acrylate (XVII) is reacted with neat ethylenediamine (XVIII) to yield the aminopropionamide derivative (XIX), which is then cyclized with dimethyl malonate (XX), producing the trioxocyclam (XXI). After condensation of (XXI) with p-dibromoxylene (IIIa), the resulting hexaoxo bis-cyclam (XXII) is reduced to the title compound employing borane-dimethyl sulfide complex in refluxing THF (10). Alternatively, protection of the linear tetraamine (XXIII) with pyruvic aldehyde (XXIV) generates the tricyclic bisaminal (XXV) along with its minor isomer (XXVI). The crude mixture of bis-aminals (XXV) and (XXVI) is then cyclized to (XXVIII) with 1,3-dibromopropane (XXVII) and K2CO3. After condensation of (XXVIII) with dibromide (IIIa), the resulting bis-ammonium dimer (XXIX) is hydrolyzed to the title compound upon heating with 3M NaOH (11). Scheme 3.

参考文献 中间体
合成目标
【10】 Achmatowicz, M., Hegedus, L.S. Direct synthesis of 1,1’-[1,4-phenylenebis(methylene)]-bis-1,4,8,11-tetraazacyclotetradecane octahydrochloride (AMD 3100) without the use of protecting groups. J Org Chem 2003, 68(16): 6435-6.
【11】 Boschetti, F., Denat, F., Espinosa, E., Tabard, A., Dory, Y., Guilard, R. Regioselective N-functionalization of tetraazacycloalkanes. J Org Chem 2005, 70(18): 7042-53.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IIIa) 18697 1,4-bis(bromomethyl)benzene 623-24-5 C8H8Br2 详情 详情
(XVII) 14156 methyl acrylate 96-33-3 C4H6O2 详情 详情
(XVIII) 14754 ethylenediamine;1,2-Diaminoethane;ethane-1,2-diamine；1,2-Ethanediamine 107-15-3 C2H8N2 详情 详情
(XIX) 65221 　 　 C7H18N4O 详情 详情
(XX) 19373 dimethyl malonate；Methyl malonate;Propanedioic acid dimethyl ester 108-59-8 C5H8O4 详情 详情
(XXI) 65222 　 　 C10H18N4O3 详情 详情
(XXII) 65223 　 　 C28H42N8O6 详情 详情
(XXIII) 53968 1,4,8,11-Tetraazaundecane; 3,7-Diaza-1,9-nonanediamine; N,N'-Bis(2-aminoethyl)-1,3-propanediamine; N,N[-Bis(2-aminoethyl)-1,3-propanediamine 4741-99-5 C7H20N4 详情 详情
(XXIV) 25598 2-oxopropanal 78-98-8 C3H4O2 详情 详情
(XXV) 65224 　 　 C10H20N4 详情 详情
(XXVI) 65225 　 　 C10H20N4 详情 详情
(XXVII) 12581 1,3-Dibromopropane 109-64-8 C3H6Br2 详情 详情
(XXVIII) 65526 　 　 C26H37O7P 详情 详情
(XXIX) 65227 　 　 C34H54Br2N8 详情 详情

合成路线17

该中间体在本合成路线中的序号：(V)

Reduction of 2-aminonicotinic acid (I) with LiAlH4 in THF gives (2-amino-3-pyridinyl)methanol (II), which by bromination with Br2 in AcOH yields (2-amino-5-bromo-3-pyridinyl)methanol hydrobromide (III). Substitution of alcohol (III) with aqueous HBr at reflux provides the corresponding bromide (IV), which by cyclocondensation with dimethyl malonate (V) in the presence of NaH in DMF/THF provides methyl 6-bromo-2-oxo-1,2,3,4-tetrahydro-1,8-naphthyridine-3-carboxylate (VI). Hydrolysis of ester (VI) with NaOH in refluxing MeOH, followed by decarboxylation in refluxing HCl leads to 6-bromo-3,4-dihydro-1,8-naphthyridin-2-one (VII) . Heck coupling of aryl bromide (VII) with t-butyl acrylate (VIII) in the presence of Pd(OAc)2, DIEA and P(o-tol)3 in propionitrile/DMF or acetonitrile/DMF affords the naphthyridinyl-acrylate (IX) , whose t-butyl ester group is then cleaved using TFA in CH2Cl2 to afford, after treatment with HCl in dioxane, (E)-3-(7-oxo-6,8-dihydro-5H-1,8-naphthyridin-3-yl)acrylic acid hydrochloride (Xa) . Similarly, hydrolysis of t-butyl ester (IX) using HBr in AcOH yields 3-(7-oxo-6,8-dihydro-5H-1,8-naphthyridin-3-yl)acrylic acid hydrobromide (Xb) . Finally, acrylic acids (Xa) or (Xb) are condensed with N-methyl-N-(3-methylbenzofuran-2-ylmethyl)-amine (XI) using EDC, HOBt and DIEA in DMF .
Chlorination of 3-methylbenzofuran-2-carboxylic acid (XII) with (COCl)2 and catalytic DMF, followed by condensation with CH3NH2 in CH2Cl2 yields the corresponding benzofuran-2-carboxamide (XIII), which is finally reduced with LiAlH4 in THF .Alternatively, 3-methylbenzofuran-2-carbaldehyde (XIV) is condensed with CH3NH2 in MeOH and subsequently reduced with NaBH4 in EtOH .

参考文献 中间体
合成目标
【1】 Burgess, W.J., Huffman, W.F., Miller, W.H., Uzinskas, I.N., Jakas, D., Newlander, K.A., Seefeld, M.A. (Affinium Pharmaceuticals, Inc.). CA 2447597, EP 1560584, JP 2005519984, US 2004147580, US 7049310, US 8153652, WO 2003088897.
【2】 Schmid, M.B., Mendlein, J.D., Berman, J.M., Kaplan, N. (Affinium Pharmaceuticals, Inc.). EP 1608377, JP 2006523207, US 2006142265, US 7879872, US 2012010127, WO 2004082586.
【3】 Pauls, H., Ramnauth, J. (Affinium Pharmaceuticals, Inc.). EP 2125802, US 8263613, US 2013150400, WO 2008098374.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(Xa) 67798 (E)-3-(7-oxo-6,8-dihydro-5H-1,8-naphthyridin-3-yl)acrylic acid hydrochloride 　 C11H10N2O3.HCl 详情 详情
(Xb) 67799 3-(7-oxo-6,8-dihydro-5H-1,8-naphthyridin-3-yl)acrylic acid hydrobromide 　 C11H10N2O3.HBr 详情 详情
(I) 55933 2-Aminonicotinic acid; 2-Aminopyridine-3-carboxylic acid 5345-47-1 C6H6N2O2 详情 详情
(II) 56112 (2-amino-3-pyridinyl)methanol 23612-57-9 C6H8N2O 详情 详情
(III) 67797 (2-amino-5-bromo-3-pyridinyl)methanol hydrobromide 443956-55-6 C6H72N2O.HBr 详情 详情
(IV) 56114 5-bromo-3-(bromomethyl)-2-pyridinamine; 5-bromo-3-(bromomethyl)-2-pyridinylamine 335033-38-0 C6H6Br2N2.HBr 详情 详情
(V) 19373 dimethyl malonate；Methyl malonate;Propanedioic acid dimethyl ester 108-59-8 C5H8O4 详情 详情
(VI) 56115 methyl 6-bromo-2-oxo-1,2,3,4-tetrahydro[1,8]naphthyridine-3-carboxylate 335031-10-2 C10H9BrN2O3 详情 详情
(VII) 56116 6-bromo-3,4-dihydro[1,8]naphthyridin-2(1H)-one C8H7BrN2O 详情 详情
(VIII) 12760 tert-butyl acrylate 1663-39-4 C7H12O2 详情 详情
(IX) 56117 tert-butyl (E)-3-(7-oxo-5,6,7,8-tetrahydro[1,8]naphthyridin-3-yl)-2-propenoate C15H18N2O3 详情 详情
(XI) 67800 N-methyl-N-(3-methylbenzofuran-2-ylmethyl)-amine 　 C11H13NO 详情 详情
(XII) 67801 3-methylbenzofuran-2-carboxylic acid 　 C10H8O3 详情 详情
(XIII) 67802 N,3-dimethylbenzofuran-2-carboxamide 　 C11H11NO2 详情 详情
(XIV) 67803 3-methylbenzofuran-2-carbaldehyde 　 C10H8O2 详情 详情

合成路线18

该中间体在本合成路线中的序号：(XIII)

Treatment of cinnamonitrile (X) with HCl in toluene/EtOH gives the O-ethyl imidate.HCl (XI), which is aminated by means of methanolic ammonia in EtOH to provide amidine (XII). Cyclization of compound (XII) with dimethylmalonate (XIII) in the presence of NaOMe in MeOH at 90 °C affords the pyrimidindione (XIV), which is chlorinated with POCl3 to generate the dichloro derivative (XV). Coupling of dichloro compound (XV) with 5-methyl-3-aminopyrazole (V) by means of NaI and DIEA in DMA at 90 °C affords the secondary amine (XVI), which is finally condensed with Nmethylpiperazine (VII) to give the free base (IX) .

参考文献 中间体
合成目标
【1】 Xiao, X.-Y., Patel, D.V., Ward, J.S., Bray, M.R., Agoston, G.E., Treston, A.M.(Miikana Therapeutics, Inc.). Substituted pyrazole compounds. EP 1928456, JP 2009510107, US 2007142368, WO 2007041358.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(V) 68679 5-methyl-3-aminopyrazole;3-Amino-5-methylpyrazole;3-Methyl-1H-pyrazol-5-amine 31230-17-8 C4H7N3 详情 详情
(VII) 10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 详情 详情
(IX) 68681 N-(5-methyl-1H-pyrazol-3-yl)-6-(4-methylpiperazin-1-yl)-2-styrylpyrimidin-4-amine;6-(4-Methyl-1-piperazinyl)-N-(5-methyl-1H-pyrazol-3-yl)-2-[(1E)-2-phenylethenyl]-4-pyrimidinamine 934353-76-1 C21H25N7 详情 详情
(X) 68682 Cinnamonitrile;E-3-Phenyl-2-propenenitriletrans-Cinnamonitrile 1885-38-7 C9H7N 详情 详情
(XI) 68683 ethyl cinnamimidate hydrochloride 　 C11H13NO.HCl 详情 详情
(XII) 68684 cinnamimidamide 　 C9H10N2 详情 详情
(XIII) 19373 dimethyl malonate；Methyl malonate;Propanedioic acid dimethyl ester 108-59-8 C5H8O4 详情 详情
(XIV) 68685 (E)-2-styrylpyrimidine-4,6(1H,5H)-dione 　 C12H10N2O2 详情 详情
(XV) 68686 (E)-4,6-dichloro-2-styrylpyrimidine 　 C12H8Cl2N2 详情 详情
(XVI) 68687 (E)-6-chloro-N-(5-methyl-1H-pyrazol-3-yl)-2-styrylpyrimidin-4-amine 　 C16H14ClN5 详情 详情

合成路线19

该中间体在本合成路线中的序号：(XVIII)

The Meldrum’s acid derivative (II) is prepared by the following method. Sharpless asymmetric dihydroxylation of 1-pentene (XIV) by means of AD-mix-β in tert-butanol/water produces (R)-1,2-pentanediol (XV), which is treated with SOCl2 in chloroform to generate the cyclic sulfite (XVI). This compound, without isolation, is oxidized with RuCl3 and NaIO4 to afford the cyclic sulfate (XVII), which is then condensed with dimethyl malonate (XVIII) by means of NaH in dimethoxyethane to provide the spirocyclopropane (XIX). Hydrolysis of the ester groups of (XIX) by means of aqueous NaOH gives the corresponding diacid (XX), which is reacted with acetone in the presence of H2SO4 to yield the target dioxane dione (II) .

参考文献 中间体
合成目标
【1】 Ates, C., Schule, A. (UCB SA). 3-Carboxy-2-oxo-1-pyrrolidine derivatives and their uses. EP 1993998, JP 2009518335, US 2009012313, WO 2007065634.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(II) 69027 (R)-6,6-dimethyl-1-propyl-5,7-dioxaspiro[2.5]octane-4,8-dione 　 C11H16O4 详情 详情
(XIV) 69037 1-pentene;pent-1-ene;1-Methyl-3-butene;Propylethylene;a-n-Amylene 109-67-1 C5H10 详情 详情
(XV) 69038 (R)-1,2-pentanediol；(R)-Pentane-1,2-diol；(2R)-1,2-Pentanediol 108340-61-0 C5H12O2 详情 详情
(XVI) 69039 (4R)-4-propyl-1,3,2-dioxathiolane 2-oxide 　 C5H10O3S 详情 详情
(XVII) 69040 (R)-4-propyl-1,3,2-dioxathiolane 2,2-dioxide 　 C5H10O4S 详情 详情
(XVIII) 19373 dimethyl malonate；Methyl malonate;Propanedioic acid dimethyl ester 108-59-8 C5H8O4 详情 详情
(XIX) 69041 (R)-dimethyl 2-propylcyclopropane-1,1-dicarboxylate 　 C10H16O4 详情 详情
(XX) 69042 (R)-2-propylcyclopropane-1,1-dicarboxylic acid 　 C8H12O4 详情 详情
Extended Information