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【结 构 式】 
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【分子编号】26492 【品名】2-[(chlorocarbonyl)oxy]propane 【CA登记号】108-23-6 |
【 分 子 式 】C4H7ClO2 【 分 子 量 】122.55108 【元素组成】C 39.2% H 5.76% Cl 28.93% O 26.11% |
合成路线1
该中间体在本合成路线中的序号：2) Synthesis of (2R,3S)-3-amino-4-cyclohexyl-2-hydroxybutyric acid isopropyl ester (II): Phenylalanine methyl ester (XIII) is protected with isopropyl chloroformate and triethylamine in THF to give N-(isopropoxycarbonyl)phenylalanine methyl ester (XIV), which is reduced with NaBH4 - LiCl in THF - ethanol, yielding N-(isopropoxycarbonyl)phenylalaninol (XV). The hydrogenation of (XV) with H2 over Rh/Al2O3 in methanol affords N-(isopropoxycarbonyl)cyclohexylalaninol (XVI), which is oxidized with pyridine - SO3 in DMSO to the corresponding aldehyde (XVII). The reaction of (XVII) with NaCN - HCl in CHCl3 - water affords (2R,3S)-3-amino-4-cyclohexyl-2-hydroxybutyric acid (XVIII), which is finally esterified with isopropanol - HCl to give (II). 3) Synthesis of KRY-1314: By condensation of N(tau)-tert-butoxycarbonyl-N(alpha)-[2(R)-(morpholinocarbonylmethyl)-3-(1-naphthyl)propionyl]histidine (I) with (2R,3S)-3-amino-4-cyclohexyl-2-hydroxybutyric acid isopropyl ester (II) by means of dicyclohexylcarbodiimide (DCC) and N-hydroxy-5-norbornene-2,3-dicarboximide (HONB) in acetonitrile - triethylamine.
| 【1】 Harada, H.; Iyobe, A.; Tsubaki, A.; Yamaguchi, T.; Kamijo, T.; Kiso, Y.; Iizuka, K.; Hirata, K.; A practical synthesis of an orally potent renin inhibitor, isopropyl (2R,3S)-4-cyclohexyl-2-hydroxy-3-[N-[(2R)-2-morpholinocarbonylmethyl-3-(1-naaphthyl)propionyl]-L-histidyl]aminobutyrate. J Chem Soc - Perkins Trans I 1990, 9, 2497-500. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 26492 | 2-[(chlorocarbonyl)oxy]propane | 108-23-6 | C4H7ClO2 | 详情 | 详情 | |
| (I) | 12312 | (2S)-3-[1-(tert-Butoxycarbonyl)-1H-imidazol-5-yl]-2-[[(2R)-4-(4-morpholinyl)-2-(1-naphthylmethyl)-4-oxobutanoyl]amino]propionic acid | C30H36N4O7 | 详情 | 详情 | |
| (II) | 12323 | isopropyl (2R,3S)-3-amino-4-cyclohexyl-2-hydroxybutanoate | C13H25NO3 | 详情 | 详情 | |
| (XIII) | 12324 | methyl (2R)-2-amino-3-phenylpropanoate | 21685-51-8 | C10H13NO2 | 详情 | 详情 |
| (XIV) | 12325 | methyl (2S)-2-[(isopropoxycarbonyl)amino]-3-phenylpropanoate | C14H19NO4 | 详情 | 详情 | |
| (XV) | 12326 | isopropyl N-[(1S)-1-benzyl-2-hydroxyethyl]carbamate | C13H19NO3 | 详情 | 详情 | |
| (XVI) | 12327 | isopropyl N-[(1S)-2-cyclohexyl-1-(hydroxymethyl)ethyl]carbamate | C13H25NO3 | 详情 | 详情 | |
| (XVII) | 12328 | isopropyl N-[(1S)-2-cyclohexyl-1-formylethyl]carbamate | C13H23NO3 | 详情 | 详情 | |
| (XVIII) | 12329 | (2R,3S)-3-Amino-4-cyclohexyl-2-hydroxybutyric acid | C10H19NO3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XII)The reaction of monolabeled diethyl malonate (I) with 2-benzyloxyethyl bromide (II) by means of NaH in refluxing THF gives the corresponding benzyloxyethyl derivative (III), which is reduced with LiAlH4 in ethyl ether yielding the diol (IV). The protection of (IV) by reaction with 2,2-dimethoxypropane (V) and p-toluenesulfonic acid affords the 1,3-dioxane (VI), which is debenzylated with H2 over Pd/C in THF giving the alcohol (VII). The reaction of (VII) with CBr4 and PPh3 in DMF yields the bromide (VIII), which is condensed with the purine (IX) by means of K2CO3 in DMF affording the expected purin-9-yl derivative (X). The hydrolysis of the 1,3-dioxane group with AcOH /water gives the diol (XI), which is monoacylated with isopropyl chloroformate (XII) by means of cool pyridine yielding the mixture of regioisomers (XIII), (XIV). Finally, this mixture is dechlorinated with ammonium formate over Pd/C in refluxing methanol afffording the target compound also as a mixture of regioisomers.
| 【1】 Kim, D.K.; et al.; Synthesis of carbon-14 labelled 2-amino-9-(3-hydroxymethyl-4-isopropoxycarbonyloxybut-1-yl)purine (SK 1875), a potential prodrug of penciclovir. J Label Compd Radiopharm 1999, 42, 6, 597. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VII),(VIII) | 10916 | 2-(2,2-Dimethyl-1,3-dioxan-5-yl)-1-ethanol | C8H16O3 | 详情 | 详情 | |
| (XIII),(XIV) | 35533 | 4-(2-amino-6-chloro-9H-purin-9-yl)-2-(hydroxymethyl)butyl isopropyl carbonate | C14H20ClN5O4 | 详情 | 详情 | |
| (I) | 16829 | Diethyl malonate | 105-53-3 | C7H12O4 | 详情 | 详情 |
| (I) | 45348 | diethyl malonate | C7H12O4 | 详情 | 详情 | |
| (II) | 35528 | 1-[(2-bromoethoxy)methyl]benzene; benzyl 2-bromoethyl ether | 1462-37-9 | C9H11BrO | 详情 | 详情 |
| (III) | 35529 | diethyl 2-[2-(benzyloxy)ethyl]malonate | C16H22O5 | 详情 | 详情 | |
| (III) | 45349 | diethyl 2-[2-(benzyloxy)ethyl]malonate | C16H22O5 | 详情 | 详情 | |
| (IV) | 35523 | 2-[2-(benzyloxy)ethyl]-1,3-propanediol | C12H18O3 | 详情 | 详情 | |
| (IV) | 45350 | 2-[2-(benzyloxy)ethyl]-1,3-propanediol | C12H18O3 | 详情 | 详情 | |
| (V) | 10722 | 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane | 77-76-9 | C5H12O2 | 详情 | 详情 |
| (VI) | 35530 | 5-[2-(benzyloxy)ethyl]-2,2-dimethyl-1,3-dioxane; benzyl 2-(2,2-dimethyl-1,3-dioxan-5-yl)ethyl ether | C15H22O3 | 详情 | 详情 | |
| (VI) | 45351 | 5-[2-(benzyloxy)ethyl]-2,2-dimethyl-1,3-dioxane; benzyl 2-(2,2-dimethyl-1,3-dioxan-5-yl)ethyl ether | C15H22O3 | 详情 | 详情 | |
| (VII) | 45352 | 2-(2,2-dimethyl-1,3-dioxan-5-yl)-1-ethanol | C8H16O3 | 详情 | 详情 | |
| (VIII) | 45353 | 2-(2,2-dimethyl-1,3-dioxan-5-yl)-1-ethanol | C8H16O3 | 详情 | 详情 | |
| (IX) | 11644 | 6-Chloro-9H-purin-2-amine; 6-Chloro-9H-purin-2-ylamine; 2-Amino-6-chloropurine | 10310-21-1 | C5H4ClN5 | 详情 | 详情 |
| (X) | 35531 | 6-chloro-9-[2-(2,2-dimethyl-1,3-dioxan-5-yl)ethyl]-9H-purin-2-ylamine; 6-chloro-9-[2-(2,2-dimethyl-1,3-dioxan-5-yl)ethyl]-9H-purin-2-amine | C13H18ClN5O2 | 详情 | 详情 | |
| (X) | 45354 | 6-chloro-9-[2-(2,2-dimethyl-1,3-dioxan-5-yl)ethyl]-9H-purin-2-amine; 6-chloro-9-[2-(2,2-dimethyl-1,3-dioxan-5-yl)ethyl]-9H-purin-2-ylamine | C13H18ClN5O2 | 详情 | 详情 | |
| (XI) | 35532 | 2-[2-(2-amino-6-chloro-9H-purin-9-yl)ethyl]-1,3-propanediol | C10H14ClN5O2 | 详情 | 详情 | |
| (XI) | 45355 | 2-[2-(2-amino-6-chloro-9H-purin-9-yl)ethyl]-1,3-propanediol | C10H14ClN5O2 | 详情 | 详情 | |
| (XII) | 26492 | 2-[(chlorocarbonyl)oxy]propane | 108-23-6 | C4H7ClO2 | 详情 | 详情 |
| (XIII) | 45356 | 4-(2-amino-6-chloro-9H-purin-9-yl)-2-(hydroxymethyl)butyl isopropyl carbonate | C14H20ClN5O4 | 详情 | 详情 | |
| (XIV) | 45357 | 4-(2-amino-6-chloro-9H-purin-9-yl)-2-(hydroxymethyl)butyl isopropyl carbonate | C14H20ClN5O4 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XXXIV)In an alternative procedure, acid (XXVII) was activated as the mixed anhydride (XXXV) with isopropyl chloroformate (XXXIV), and then condensed with taxane intermediate (XIV) to give ester (XXVI). Hydrogenolytic deprotection of the N-carbobenzoy group of (XXVI) yielded the title compound.
| 【1】 Tsujihari, K.; Hashiyama, T.; Ohashi, M.; Nakanishi, N. (Tanabe Seiyaku Co., Ltd.); Baccatin derivs. and processes for preparing the same. CA 2162759; EP 0712854; JP 1997151181; US 5589502 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIV) | 26474 | methyl (9S,12S)-4-methoxy-12-[[(2S,5S,8S,11R)-5-(4-methoxybenzyl)-2,6,8,11,15,15-hexamethyl-4,7,10,13-tetraoxo-14-oxa-3,6,9,12-tetraazahexadec-1-anoyl](methyl)amino]-11-oxo-2-oxa-10-azatricyclo[12.2.2.1(3,7)]nonadeca-1(16),3(19),4,6,14,17-hexaene-9-carboxylate | C40H53NO14 | 详情 | 详情 | |
| (XXVI) | 26484 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4-(acetoxy)-2-(benzoyloxy)-1,9,12-trihydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-15-yl (5S,12R)-5-(aminocarbonyl)-12-[(S)-[(tert-butoxycarbonyl)amino](cyclopropyl)methyl]-3,7,10-trioxo-1-phenyl-2,8,11-trioxa-4-azatridecan-13-oate | C54H67N3O20 | 详情 | 详情 | |
| (XXVII) | 26485 | 1-(dimethoxymethyl)-4-methoxybenzene | 2186-92-7 | C10H14O3 | 详情 | 详情 |
| (XXXIV) | 26492 | 2-[(chlorocarbonyl)oxy]propane | 108-23-6 | C4H7ClO2 | 详情 | 详情 |
| (XXXV) | 26493 | 4-Amino-3(S)-(benzyloxycarbonylamino)-4-oxobutyric acid 2-(isopropoxycarbonyloxy)-2-oxoethyl ester | C18H22N2O9 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(V)The condensation of 2,4-difluoronitrobenzene (I) with 2(S)-aminobutyric acid (II) by means of triethylamine in refluxing acetone gives 2(S)-(5-fluoro-2-nitrophenylamino)butyric acid (III), which is reductocyclized with H2 over Raney-Ni in methanol/acetic acid, yielding 3(S)-ethyl-6-fluoro-1,2,3,4-tetrahydroquinoxalin-2-one (IV). Finally, this compound is treated with isopropyl chloroformate (V) and 4-methylpyridine in dichloromethane.
| 【1】 Rosner, M.; Billhardt-Troughton, U.-M.; Kirsch, R.; Kleim, J.-P.; Meichsner, C.; Riess, G.; Winkler, I. (Aventis SA); Quinoxalines, process for their preparation, and their use. CA 2160859; DE 4437406; EP 0708093; JP 1996225544; US 5723461 . |
| 【2】 Graul, A.; Castañer, J.; Rabasseda, X.; GW-420867X. Drugs Fut 2000, 25, 1, 24. |
| 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) | 32036 | 2,4-difluoro-1-nitrobenzene | 446-35-5 | C6H3F2NO2 | 详情 | 详情 |
| (II) | 32037 | (2S)-2-aminobutyric acid | 1492-24-6 | C4H9NO2 | 详情 | 详情 |
| (III) | 32038 | (2S)-2-(5-fluoro-2-nitroanilino)butyric acid | C10H11FN2O4 | 详情 | 详情 | |
| (IV) | 32039 | (3S)-3-ethyl-6-fluoro-3,4-dihydro-2(1H)-quinoxalinone | C10H11FN2O | 详情 | 详情 | |
| (V) | 26492 | 2-[(chlorocarbonyl)oxy]propane | 108-23-6 | C4H7ClO2 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(B)Oxidation of 5-hydroxy-5,6,7,8-tetrahydroisoquinoline (I) using CrO3 in pyridine produced the corresponding ketone (II). Subsequent condensation of (II) with methyl cyanoformate (A) in the presence of lithium hexamethyldisilazide gave ketoester (III), which was reduced to hydroxyester (IV) by means of catalytic hydrogenation. Dehydration of (IV) to the unsaturated ester (V) was achieved by treatment with methanesulfonyl chloride and triethylamine, followed by basic elimination with DBU. Saponification of the ester group of (V) produced carboxylic acid (VI). After activation of (VI) as the mixed anhydride (VII) with isopropyl chloroformate (B), coupling with tryptamine (VIII) furnished the title amide, which was finally isolated as the hydrochloride salt.
| 【1】 May, S.; Chan, L.; Chen, Y.; Jin, H.; Hu, Z.; Bedard, J.; Stefanac, T.; Turcotte, N.; Design and evaluation of dihydroisoquinolines as potent and orally bioavailable human cytomegalovirus inhibitors. Bioorg Med Chem Lett 2000, 10, 13, 1477. |
| 【2】 Bedard, J.; Rando, R.; Falardeau, G.; Lavallee, J.-F. (BioChem Pharma Inc.); Antiviral cpds.. WO 9929318 . |
| 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) | 18001 | methyl 2-nitriloacetate; carbonocyanic acid, methyl ester | 17640-15-2 | C3H3NO2 | 详情 | 详情 |
| (B) | 26492 | 2-[(chlorocarbonyl)oxy]propane | 108-23-6 | C4H7ClO2 | 详情 | 详情 |
| (I) | 40530 | 5,6,7,8-tetrahydro-5-isoquinolinol | C9H11NO | 详情 | 详情 | |
| (II) | 40531 | 7,8-dihydro-5(6H)-isoquinolinone | C9H9NO | 详情 | 详情 | |
| (III) | 40532 | methyl 5-hydroxy-7,8-dihydro-6-isoquinolinecarboxylate | C11H11NO3 | 详情 | 详情 | |
| (IV) | 40533 | methyl 5-hydroxy-5,6,7,8-tetrahydro-6-isoquinolinecarboxylate | C11H13NO3 | 详情 | 详情 | |
| (V) | 40534 | methyl 7,8-dihydro-6-isoquinolinecarboxylate | C11H11NO2 | 详情 | 详情 | |
| (VI) | 40535 | 7,8-dihydro-6-isoquinolinecarboxylic acid | C10H9NO2 | 详情 | 详情 | |
| (VII) | 40536 | C14H15NO4 | 详情 | 详情 | ||
| (VIII) | 40537 | Tryptamine; 2-(1H-Indol-3-yl)-1-ethanamine; 2-(1H-Indol-3-yl)ethylamine | 61-54-1 | C10H12N2 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(II)The activation of N-Boc-L-aspartic acid 4-O-tert-butyl ester (I) with isopropyl chloroformate (II) in THF gives the mixed anhydride (III), which is reduced with NaBH4 to yield the hydroxyester (IV). The Swern oxidation of (IV) affords the aldehyde (V), which is condensed with the phosphonate (VI) by means of BuLi to provide the hexenedioic diester (VII). The stepwise reduction of (VII) first by means of H2 over Pd/C and then with NaBH4 gives rise to the omega-hydroxy hexanoate (VIII). This is treated first with MsCl and TEA and then with NaN3 to yield a diastereomeric mixture of azido hexanoates (IX) and (X). After separation, the desired isomer (X) is hydrolyzed with LiOH to afford the corresponding carboxylic acid (XI), which is condensed with 2-(1-methylhydrazino)acetic acid tert-butyl ester (XII) by means of HATU and DIEA to provide the corresponding hydrazide (XIII). The reduction of the azido group of (XIII) by means of H2 over Pd/C or with PPh3 in THF/water provides the corresponding amino derivative (XIV), which is finally hydrolyzed and N-deprotected by means of 4M HCl in dioxane to furnish the target fluorinated deoxynegamycin.
| 【1】 Raju, B.; Anandan, S.K.; Gu, S.; et al.; Fluorinated deoxynegamycin analogs: Synthesis and antimicrobial properties. 42nd Intersci Conf Antimicrob Agents Chemother (Sept 27 2002, San Diego) 2002, Abst F-1686. |
| 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) | 37623 | (2S)-4-(tert-butoxy)-2-[(tert-butoxycarbonyl)amino]-4-oxobutyric acid | C13H23NO6 | 详情 | 详情 | |
| (II) | 26492 | 2-[(chlorocarbonyl)oxy]propane | 108-23-6 | C4H7ClO2 | 详情 | 详情 |
| (III) | 61849 | C17H29NO8 | 详情 | 详情 | ||
| (IV) | 61901 | tert-butyl (3S)-3-[(tert-butoxycarbonyl)amino]-4-hydroxybutanoate | C13H25NO5 | 详情 | 详情 | |
| (V) | 61902 | tert-butyl (3S)-3-[(tert-butoxycarbonyl)amino]-4-oxobutanoate | C13H23NO5 | 详情 | 详情 | |
| (VI) | 61903 | propyl 2-(dipropoxyphosphoryl)-2-fluoroacetate | C11H22FO5P | 详情 | 详情 | |
| (VII) | 61904 | 6-(tert-butyl) 1-propyl (Z,4S)-4-[(tert-butoxycarbonyl)amino]-2-fluoro-2-hexenedioate | C18H30FNO6 | 详情 | 详情 | |
| (VIII) | 61905 | tert-butyl (3S)-3-[(tert-butoxycarbonyl)amino]-5-fluoro-6-hydroxyhexanoate | C15H28FNO5 | 详情 | 详情 | |
| (IX) | 61906 | tert-butyl (3S,5S)-6-azido-3-[(tert-butoxycarbonyl)amino]-5-fluorohexanoate | C15H27FN4O4 | 详情 | 详情 | |
| (X) | 61907 | tert-butyl (3S,5R)-6-azido-3-[(tert-butoxycarbonyl)amino]-5-fluorohexanoate | C15H27FN4O4 | 详情 | 详情 | |
| (XI) | 61908 | (3S,5R)-6-azido-3-[(tert-butoxycarbonyl)amino]-5-fluorohexanoic acid | C11H19FN4O4 | 详情 | 详情 | |
| (XII) | 61909 | tert-butyl 2-(1-methylhydrazino)acetate | C7H16N2O2 | 详情 | 详情 | |
| (XIII) | 61910 | tert-butyl (7S)-7-[(2S)-3-azido-2-fluoropropyl]-3,11,11-trimethyl-5,9-dioxo-10-oxa-3,4,6,8-tetraazadodecan-1-oate | C17H32FN7O5 | 详情 | 详情 | |
| (XIV) | 61911 | tert-butyl (7R)-7-[(2R)-3-amino-2-fluoropropyl]-3,11,11-trimethyl-5,9-dioxo-10-oxa-3,4,6,8-tetraazadodecan-1-oate | C17H34FN5O5 | 详情 | 详情 |