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【结 构 式】 
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【分子编号】13597 【品名】2,2-Dimethylpropanoyl chloride; Pivaloyl chloride 【CA登记号】3282-30-2 |
【 分 子 式 】C5H9ClO 【 分 子 量 】120.57856 【元素组成】C 49.81% H 7.52% Cl 29.4% O 13.27% |
合成路线1
该中间体在本合成路线中的序号：(G)The hydrolysis of p-methoxybenzyl-7-aminocephalosporanate (XIV) with trifluoroacetic acid gives the corresponding tree acid (XXII), which is treated with tert-butoxycarbonylazide (F) yielding the tert-butoxycarbonylamidocephalosporanic acid (XXIII). This compound is deacetylated by treatment with citrus acetyl sterase in an aqueous phosphate buffer affording the 3-hydroxymethyl derivative (XXIV), which by reaction with chlorosulfonyl isocyanate gives the 3-carbamoyloxymethyl compound (XXV). The hydrolysis of (XXV) with TFA yields 3-carbamoyloxymethyl-7beta-amino-3-cephem-4-carboxylic acid (XXVI), which is esterified with diphenyldiazomethane in dioxane affording the benzhydryl ester (XXVII). The acylation of (XXVII) with 2-thienylcarbonyl chloride (E) in CH2Cl2 gives the acylated ester (XXVIII), which by methoxylation of (XXVIII) can also be performed through hydroxylation with phenyllithium and tert-butyl hypochlorite (G) in tert-butanol to the 7-hydroxy compound (XXXII), which is then methylated with diazomethane to (XXX). Finally, this compound is hydrolyzed with trifluoroacetic acid.
| 【1】 Castaner, J.; Loren, J.G.; Cefoxitin. Drugs Fut 1978, 3, 6, 434. |
| 【2】 Hazen, G.C. (Merck & Co., Inc.); Process for preparin cephalosporin compounds. DD 100957; ES 408969; US 3780033 . |
| 【3】 Christensen, B.G.; Firestone, R.A.; Process for preparing cephalosporin compounds. DD 100956; ES 408970; US 3775410 . |
| 【4】 Christensen, B.G.; Cama, L.D. (Merck & Co., Inc.); Process for preparing penicillin and cephalosporin compounds. FR 2163144; GB 1401060; US 3843641 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (G) | 13597 | 2,2-Dimethylpropanoyl chloride; Pivaloyl chloride | 3282-30-2 | C5H9ClO | 详情 | 详情 |
| (E) | 15673 | 2-(2-thienyl)acetyl chloride; 2-Thiopheneacetyl chloride | 39098-97-0 | C6H5ClOS | 详情 | 详情 |
| (F) | 39837 | 2,2-dimethylpropanoyl azide | C5H9N3O | 详情 | 详情 | |
| (XIV) | 39828 | 4-methoxybenzyl (6R,7R)-3-[(acetoxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C18H20N2O6S | 详情 | 详情 | |
| (XXII) | 22747 | (6R,7R)-3-[(acetoxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | C10H12N2O5S | 详情 | 详情 | |
| (XXIII) | 39838 | (6R,7R)-3-[(acetoxy)methyl]-7-[(2,2-dimethylpropanoyl)amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | C15H20N2O6S | 详情 | 详情 | |
| (XXIV) | 39839 | (6R,7R)-7-[(2,2-dimethylpropanoyl)amino]-3-(hydroxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | C13H18N2O5S | 详情 | 详情 | |
| (XXV) | 39840 | (6R,7R)-3-[[(aminocarbonyl)oxy]methyl]-7-[(2,2-dimethylpropanoyl)amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | C14H19N3O6S | 详情 | 详情 | |
| (XXVI) | 39805 | (6R,7R)-7-amino-3-[[(aminocarbonyl)oxy]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | C9H11N3O5S | 详情 | 详情 | |
| (XXVII) | 39804 | benzhydryl (6R,7R)-7-amino-3-[[(aminocarbonyl)oxy]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C22H21N3O5S | 详情 | 详情 | |
| (XXVIII) | 39841 | benzhydryl (6R,7R)-3-[[(aminocarbonyl)oxy]methyl]-8-oxo-7-[[2-(2-thienyl)acetyl]amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C28H25N3O6S2 | 详情 | 详情 | |
| (XXX) | 39843 | benzhydryl (6R,7S)-3-[[(aminocarbonyl)oxy]methyl]-7-methoxy-8-oxo-7-[[2-(2-thienyl)acetyl]amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C29H27N3O7S2 | 详情 | 详情 | |
| (XXXII) | 39842 | benzhydryl (6R,7S)-3-[[(aminocarbonyl)oxy]methyl]-7-hydroxy-7-[[(Z)-1-methoxy-2-(2-thienyl)ethylidene]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C29H27N3O7S2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IV)A new method for the preparation of citalopram has been reported: The Grignard reaction of 1-oxo-1,3-dihydroisobenzofuran-5-carbonitrile (I) with 4-fluorophenylmagnesium bromide (II) in THF gives the hydroxymethyl benzophenone (III), which is esterified with pivaloyl chloride in ethyl ether/THF to yield the ester (V). A new Grignard reaction of (V) with 3-(dimethylamino)propylmagnesium bromide in THF affords citalopram.
| 【1】 Ellegaard, P.; Petersen, H.; Rock, M.H. (H. Lundbeck A/S); Method for the preparation of citalopram. WO 0012044 . |
| 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) | 37601 | 1-oxo-1,3-dihydro-2-benzofuran-5-carbonitrile | 82104-74-3 | C9H5NO2 | 详情 | 详情 |
| (II) | 13643 | 4-fluorophenyl magnesium bromide;Bromo(4-fluorophenyl)magnesium;bromo(p-fluorophenyl)Magnesium;p-Fluorophenylmagnesium bromide | 352-13-6 | C6H4BrFMg | 详情 | 详情 |
| (III) | 37602 | 4-(4-fluorobenzoyl)-3-(hydroxymethyl)benzonitrile | C15H10FNO2 | 详情 | 详情 | |
| (IV) | 13597 | 2,2-Dimethylpropanoyl chloride; Pivaloyl chloride | 3282-30-2 | C5H9ClO | 详情 | 详情 |
| (V) | 37603 | 5-cyano-2-(4-fluorobenzoyl)benzyl pivalate | C20H18FNO3 | 详情 | 详情 | |
| (VI) | 37604 | bromo[3-(dimethylamino)propyl]magnesium | 120615-47-6 | C5H12BrMgN | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)3'-Hydroxyacetophenone (I) is acylated with pivaloylchloride (II) to form 3'-pivaloyloxyacetophenone (III). The latter is brominated with bromine to 3'-pivaloyloxy-2-bromoacetophenone (IV), which in turn reacts with N-ethylbenzylamine (V) to form 3'-pivaloyloxy-2-(benzylethylamino)acetophenone (VI). This compound is debenzylated and reduced with H2 in the presence of Pd/C in isopropanol containing hydrochloric acid to yield etilefrine pivalate hydrochloride.
| 【1】 St Janiak, P.; Etilefrine Pivalate. Drugs Fut 1979, 4, 6, 413. |
| 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) | 25331 | 3-hydroxyacetophenone; 1-(3-hydroxyphenyl)-1-ethanone | 121-71-1 | C8H8O2 | 详情 | 详情 |
| (II) | 13597 | 2,2-Dimethylpropanoyl chloride; Pivaloyl chloride | 3282-30-2 | C5H9ClO | 详情 | 详情 |
| (III) | 39466 | 3-acetylphenyl pivalate | C13H16O3 | 详情 | 详情 | |
| (IV) | 39467 | 3-(2-bromoacetyl)phenyl pivalate | C13H15BrO3 | 详情 | 详情 | |
| (V) | 39468 | N-benzyl-N-ethylamine; N-benzyl-1-ethanamine | 14321-27-8 | C9H13N | 详情 | 详情 |
| (VI) | 39469 | 3-[2-[benzyl(ethyl)amino]acetyl]phenyl pivalate | C22H27NO3 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(VIII)The reaction of cyclopentylamine (I) with tertbutyl bromoacetate (II) by means of NH3 in acetonitrile gives N-cyclopentylglycine tert-butyl ester (III), which is condensed with 3-(acetylthio)-2-methylpropionyl chloride (IV) [prepared from the corresponding acid (V) with SOCl2] by means of triethylamine in dioxane to yield the acylated glycine (VI). Deacetylation of (VI) with dry ammonia in methanol affords the mercapto derivative (VII), which is acylated with pivaloyl chloride (VIII) in the usual way giving the corresponding thio ester (IX). Finally, this compound is hydrolyzed partially with trimethylsilyl iodide in methylene chloride.
| 【1】 Suh, J.T.; et al.; Angiotensin-converting enzyme inhibitors. New orraly active antihypertensive (mercaptoalkanoyl)- and [(acylthio)alkanoyl]glycine derivatives. J Med Chem 1985, 28, 1, 57-66. |
| 【2】 Castaner, J.; Serradell, M.N.; Pivopril. Drugs Fut 1986, 11, 2, 116. |
| 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) | 28850 | cyclopentanamine | 1003-03-8 | C5H11N | 详情 | 详情 |
| (II) | 17430 | 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate | 5292-43-3 | C6H11BrO2 | 详情 | 详情 |
| (III) | 28851 | tert-butyl 2-(cyclopentylamino)acetate | C11H21NO2 | 详情 | 详情 | |
| (IV) | 28852 | (2R)-3-Acetylthio-2-methylpropionyl chloride;L-3-(Acetylthio)-2-methylpropanoyl chloride ;S-[(2R)-3-chloro-2-methyl-3-oxopropyl] ethanethioate | 74345-73-6 | C6H9ClO2S | 详情 | 详情 |
| (V) | 28853 | (2R)-3-(acetylsulfanyl)-2-methylpropionic acid;(R)-3-(acetylthio)-2-methylpropanoic acid | 74431-52-0 | C6H10O3S | 详情 | 详情 |
| (VI) | 28854 | tert-butyl 2-[[(2S)-3-(acetylsulfanyl)-2-methylpropanoyl](cyclopentyl)amino]acetate | C17H29NO4S | 详情 | 详情 | |
| (VII) | 28855 | tert-butyl 2-[cyclopentyl[(2S)-2-methyl-3-sulfanylpropanoyl]amino]acetate | C15H27NO3S | 详情 | 详情 | |
| (VIII) | 13597 | 2,2-Dimethylpropanoyl chloride; Pivaloyl chloride | 3282-30-2 | C5H9ClO | 详情 | 详情 |
| (IX) | 28856 | tert-butyl 2-(cyclopentyl[(2S)-3-[(2,2-dimethylpropanoyl)sulfanyl]-2-methylpropanoyl]amino)acetate | C20H35NO4S | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(IX)The reaction of 2-phenylbutyric acid (I) with LDA gives the enolate (II), which is condensed with ethyl 4-iodobenzoate (III) to yield the not isolated intermediate (IV), which decarboxylates to afford 1-(4-iodophenyl)-2-phenyl-1-butanone (V). The Grignard reaction of the ketone (V) with 4-[2-(1-pyrroliidnyl)ethyl]phenylmagnesium bromide (VI) (obtained from the corresponding bromobenzene (VII) and Mg in THF) affords the tertiary alcohol (VIII), which is esterified with pivaloyl chloride (IX) and KHMDS to provide the pivalate (X). Finally, this compound is treated with hexamethyldisylazane at 165 C to provide the target ethylene.
| 【1】 Ace, K.W.; et al.; Development of an efficient and stereoselective manufacturing route to idoxifene. Org Process Res Dev 2001, 5, 5, 479. |
| 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) | 21130 | 2-Phenylbutyric acid; alpha-Ethylbenzeneacetic acid | 90-27-7 | C10H12O2 | 详情 | 详情 |
| (II) | 51918 | C10H10Li2O2 | 详情 | 详情 | ||
| (III) | 23796 | ethyl 4-iodobenzoate | 51934-41-9 | C9H9IO2 | 详情 | 详情 |
| (IV) | 51919 | lithium 2-(4-iodobenzoyl)-2-phenylbutanoate | C17H14ILiO3 | 详情 | 详情 | |
| (V) | 51920 | 1-(4-iodophenyl)-2-phenyl-1-butanone | C16H15IO | 详情 | 详情 | |
| (VI) | 51921 | bromo[4-[2-(1-pyrrolidinyl)ethyl]phenyl]magnesium | C12H16BrMgN | 详情 | 详情 | |
| (VII) | 51922 | 1-(4-bromophenethyl)pyrrolidine | C12H16BrN | 详情 | 详情 | |
| (VIII) | 51923 | (1R,2R)-1-(4-iodophenyl)-2-phenyl-1-[4-[2-(1-pyrrolidinyl)ethyl]phenyl]-1-butanol | C28H32INO | 详情 | 详情 | |
| (IX) | 13597 | 2,2-Dimethylpropanoyl chloride; Pivaloyl chloride | 3282-30-2 | C5H9ClO | 详情 | 详情 |
| (X) | 51924 | 1-(tert-butyl)vinyl (1R,2R)-1-(4-iodophenyl)-2-phenyl-1-[4-[2-(1-pyrrolidinyl)ethyl]phenyl]butyl ether; 1-[4-[(1R,2R)-1-[[1-(tert-butyl)vinyl]oxy]-1-(4-iodophenyl)-2-phenylbutyl]phenethyl]pyrrolidine | C34H42INO | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(V)The methylation of N-(benzyloxycarbonyl)-L-isoleucine (I) with Me-I and NaH in THF gives the N-methyl derivative (II), which is reduced with BH3 in THF to yield the isoleucinol (III). The oxidation of (III) with SO3/pyridine in DMSO affords the isoleucinal (IV), which is condensed with tert-butyl acetate (V) by means of BuLi and THF to afford the chiral beta-hydroxyheptanoate (VI). Finally, this compound is O-methylated by means of diazomethane and BF3 in ethyl ether/dichloromethane and N-deprotected by hydrogenation with H2 over Pd/C in ethyl acetate/methanol to provide the desired intermediate, the chiral tert-butyl heptanoate (VII).
| 【1】 Pettit, G.R.; Singh, S.B.; Williams, M.D.; Herald, D.L.; Hogan, F.; Burkett, D.D.; Clewlow, P.J.; The absolute configuration and synthesis of natural (-)-Dolastatin 10. J Am Chem Soc 1989, 111, Suppl. 3, 5463. |
| 【2】 Pettit, G.R.; Srirangam, J.K.; Singh, S.B.; Williams, M.D.; Herald, D.L.; Barkóczy, J.; Kantoci, D.; Hogan, F.; Dolastatins 24. Synthesis of (-)-dolastatin 10. X-Ray molecular structure of N,N-dimethylvalyl-valyl-dolaisoleucine tert-butyl ester. J Chem Soc Perkins Trans I 1996, 8, Suppl. 3, 859-63. |
| 【3】 Pettit, G.R.; Singh, S.B. (Arizona State University); Synthesis of dolastatin 10. US 4978744 . |
| 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) | 23508 | (2S,3S)-2-[[(benzyloxy)carbonyl]amino]-3-methylpentanoic acid | 3160-59-6 | C14H19NO4 | 详情 | 详情 |
| (II) | 54627 | (2S,3S)-2-[[(benzyloxy)carbonyl](methyl)amino]-3-methylpentanoic acid | C15H21NO4 | 详情 | 详情 | |
| (III) | 54628 | benzyl (1S,2S)-1-(hydroxymethyl)-2-methylbutyl(methyl)carbamate | C15H23NO3 | 详情 | 详情 | |
| (IV) | 54629 | benzyl (1S,2S)-1-formyl-2-methylbutyl(methyl)carbamate | C15H21NO3 | 详情 | 详情 | |
| (V) | 13597 | 2,2-Dimethylpropanoyl chloride; Pivaloyl chloride | 3282-30-2 | C5H9ClO | 详情 | 详情 |
| (VI) | 54630 | tert-butyl (3R,4S,5S)-4-[[(benzyloxy)carbonyl](methyl)amino]-3-hydroxy-5-methylheptanoate | C21H33NO5 | 详情 | 详情 | |
| (VII) | 23514 | tert-butyl (3R,4S,5S)-3-methoxy-5-methyl-4-(methylamino)heptanoate | C14H29NO3 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(IV)The condensation of 4-(pivaloyloxy)benzenesulfonyl chloride (I) with the glycine benzyl ester (II) in pyridine gives N-[2-[4-(pivaloyloxy)phenylsulfonamido]benzoyl]glycine benzyl ester (III), which is then debenzylated by hydrogenolysis with H2 over Pd/C in methanol. The starting compounds (I) and (II) are obtained as follows: 1) The condensation of pivaloyl chloride (IV) with 4-hydroxybenzenesulfonic acid (V) by means of NaOH in THF - water gives 4-(pivaloyloxy)benzenesulfonic acid (VI), which is then treated with SOCl2 to afford the corresponding acyl chloride (I). 2) The condensation of 2-nitrobenzoyl chloride (VII) with glycine benzyl ester (VIII) by means of triethylamine in dichloromethane gives N-(2-nitrobenzoyl)glycine benzyl ester (IX), which is then reduced with Fe - HCl in THF - water to the amino derivative (II).
| 【1】 Imaki, K.; Arai, Y.; Okegawa, T. (Ono Pharmaceutical Co., Ltd.); Derivs. of p-substituted phenyl ester of pivalic acid. EP 0347168; JP 1991020253; JP 1994179645; US 5017610; US 5336681; US 5403850 . |
| 【2】 Imaki, K.; Wakatsuka, H. (Ono Pharmaceutical Co., Ltd.); Glycine deriv. monosodium salt tetrahydrate having an inhibitory effect on elastase. EP 0539223; JP 1993194366 . |
| 【3】 Castaner, J.; Graul, A.; Prous, J.; Ono-5046. Drugs Fut 1994, 19, 11, 1000. |
| 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) | 13594 | 4-(chlorosulfonyl)phenyl pivalate | C11H13ClO4S | 详情 | 详情 | |
| (II) | 13595 | benzyl 2-[(2-aminobenzoyl)amino]acetate | C16H16N2O3 | 详情 | 详情 | |
| (III) | 13596 | 4-[[2-([[2-(benzyloxy)-2-oxoethyl]amino]carbonyl)anilino]sulfonyl]phenyl pivalate | C27H28N2O7S | 详情 | 详情 | |
| (IV) | 13597 | 2,2-Dimethylpropanoyl chloride; Pivaloyl chloride | 3282-30-2 | C5H9ClO | 详情 | 详情 |
| (V) | 13598 | 4-Hydroxybenzenesulfonic acid; p-Phenolsulfonic acid | 98-67-9 | C6H6O4S | 详情 | 详情 |
| (VI) | 13599 | 4-[(2,2-Dimethylpropanoyl)oxy]benzenesulfonic acid | C11H14O5S | 详情 | 详情 | |
| (VII) | 21099 | o-nitrobenzoyl chloride; 2-nitrobenzoyl chloride | 610-14-0 | C7H4ClNO3 | 详情 | 详情 |
| (VIII) | 13601 | benzyl 2-aminoacetate; Glycine benzyl ester hydrochloride | 1738-68-7 | C9H11NO2 | 详情 | 详情 |
| (IX) | 13602 | benzyl 2-[(2-nitrobenzoyl)amino]acetate | C16H14N2O5 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(IX)Alternatively, the title compound was prepared by condensation between indanylacetic acid (IV) and thioprolylpyrrolidine (XI) either using EDC as the coupling reagent or via activation as the mixed anhydride (X) with pivaloyl chloride (IX) and triethylamine.
| 【1】 Arai, H.; Niwa, S.; Nishioka, H.; Yamanaka, T.; Torizuka, M.; Yoshinaga, K.; Kobayashi, N.; Ikeda, Y.; Tanaka, Y.; New potent prolyl endopeptidase inhibitors: Synthesis and structure-activity relationships of indan and tetralin derivatives and their analogues. J Med Chem 1994, 37, 13, 2071. |
| 【2】 Tanaka, Y.; Kobayashi, N.; Nakata, N.; Yamaguchi, I.; Mori, T. (Zeria Pharmaceutical Co., Ltd.); Cholinesterase activator. EP 0754454; JP 1995228529; US 6017929; WO 9522326 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IV) | 21721 | 2-(2,3-dihydro-1H-inden-2-yl)acetic acid | 37868-26-1 | C11H12O2 | 详情 | 详情 |
| (IX) | 13597 | 2,2-Dimethylpropanoyl chloride; Pivaloyl chloride | 3282-30-2 | C5H9ClO | 详情 | 详情 |
| (X) | 55164 | (6aS,12aR)-2,3-dimethoxy-6-propyl-6a,12a-dihydro-5H-[1,3]dioxolo[4',5':5,6]indeno[1,2-c]isoquinoline-5,12(6H)-dione | C22H21NO6 | 详情 | 详情 | |
| (XI) | 55165 | (6aS,12R,12aR)-2,3-dimethoxy-6-propyl-6,6a,12,12a-tetrahydro-5H-[1,3]dioxolo[4',5':5,6]indeno[1,2-c]isoquinolin-12-ol | C22H25NO5 | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(XXXII)The condensation of propane-1,3-diol (XXV) with benzaldehyde by means of p-toluenesulfonic acid gives the corresponding cyclic acetal (XXVI), which is reduced with diisobutylaluminum hydride in toluene yielding 3-benzoyloxy-1-propanol (XXVII). The oxidation of (XXVII) with oxalyl chloride as before affords the corresponding aldehyde (XXVIII), which is submitted to a Wittig condensation with 2-(triphenylphosphoranylidene)acetic acid methyl ester (XXIX) giving (E)-5-benzyloxy-2-pentenoic acid methyl ester (XXX). The hydrolysis of (XXX) with NaOH in THF-water yields the corresponding acid (XXXI), which is condensed with pivaloyl chloride (XXXII) to afford the mixed anhydride (XXXIII). The condensation of (XXXIII) with 4(S)-benzyloxazolidin-2-one (XXXIV) by means of BuLi in THF gives 4(S)-benzyl-3-[5-benzyloxy-2(E)-pentenoyl]oxazolidin-2-one (XXXV), which is submitted to a Diels-Alder cycloaddition with cyclopentadiene (XXXVI) to yield 4-benzyl-3-[(3R,4R,5S,6S)-5-(2-benzyloxyethyl)bicyclo[2.2.1]hept-2-en-4-ylcarbonyl]oxazolidin-2-one (XXXVII). Hydrogenation of (XXXVII) with H2 over Pt in ethylacetate, followed by hydrolysis with H2O2 and LiOH affords (1R,2R,3S,4S)-3-(2-benzyloxyethyl)bicyclo[2.2.1]heptane-2-carboxylic acid (XXXVIII). The formation of the corresponding azide with ethyl chloroformate and sodium azide followed by degradation in refluxing toluene gives the amine (XXXIX), which is acylated with benzenesulfonyl chloride as before yielding the sulfonamide (XL). The deprotection of (XL) by hydrogenolysis with H2 over Pd/C in ethanol affords the substituted ethanol (XLI). Oxidation of (XLI) with oxalyl chloride as before gives the aldehyde (XLII), which is finally submitted to a Wittig condensation with 4-carboxybutyl triphenylphosphonium bromide and t-BuOK to yield acid (XIV) enantiomerically pure, already obtained.
| 【1】 Wong and F.F. Sun (Eds.), Raven Press, Ltd., New York 1989, 19, 659-62. |
| 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) | 14674 | (Z)-7-[(1R,2S,3S,4S)-3-[(phenylsulfonyl)amino]bicyclo[2.2.1]hept-2-yl]-5-heptenoic acid | C20H27NO4S | 详情 | 详情 | |
| (XXV) | 14685 | 1,3-propanediol; Trimethylene Glycol | 504-63-2 | C3H8O2 | 详情 | 详情 |
| (XXVI) | 14686 | 2-phenyl-1,3-dioxane | C10H12O2 | 详情 | 详情 | |
| (XXVII) | 14687 | 3-(benzyloxy)-1-propanol; 3-(Benzyloxy)propanol | 4799-68-2 | C10H14O2 | 详情 | 详情 |
| (XXVIII) | 14688 | 3-(benzyloxy)propanal | C10H12O2 | 详情 | 详情 | |
| (XXIX) | 14689 | Methyl (triphenylphosphoranylidene)acetate; (methoxycarbonylmethylene)triphenylphosphorane；Methyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate | 2605-67-6 | C21H19O2P | 详情 | 详情 |
| (XXX) | 14690 | Methyl (E)-5-(benzyloxy)-2-pentenoate | C13H16O3 | 详情 | 详情 | |
| (XXXI) | 14691 | (E)-5-(Benzyloxy)-2-pentenoic acid | C12H14O3 | 详情 | 详情 | |
| (XXXII) | 13597 | 2,2-Dimethylpropanoyl chloride; Pivaloyl chloride | 3282-30-2 | C5H9ClO | 详情 | 详情 |
| (XXXIII) | 14693 | (E)-4-(Benzyloxy)-2-pentenoic 1,1-Dimethylpropionic anhydride | C17H22O4 | 详情 | 详情 | |
| (XXXIV) | 14694 | (S)-4-Benzyl-2-oxazolidinone; (4S)-4-Benzyl-1,3-oxazolan-2-one; (S)-(-)-4-Benzyl-2-oxazolidinone | 90719-32-7 | C10H11NO2 | 详情 | 详情 |
| (XXXV) | 14695 | (4S)-4-benzyl-3-[(E)-5-(benzyloxy)-2-pentenoyl]-1,3-oxazolan-2-one | C22H23NO4 | 详情 | 详情 | |
| (XXXVI) | 11183 | 1,3-Cyclopentadiene | C5H6 | 详情 | 详情 | |
| (XXXVII) | 14697 | (4S)-4-benzyl-3-([(1R,2S,3S,4S)-3-[2-(benzyloxy)ethyl]bicyclo[2.2.1]hept-5-en-2-yl]carbonyl)-1,3-oxazolan-2-one | C27H29NO4 | 详情 | 详情 | |
| (XXXVIII) | 14698 | (1S,2S,3S,4R)-3-[2-(benzyloxy)ethyl]bicyclo[2.2.1]heptane-2-carboxylic acid | C17H22O3 | 详情 | 详情 | |
| (XXXIX) | 14699 | (1S,2S,3S,4R)-3-[2-(benzyloxy)ethyl]bicyclo[2.2.1]heptan-2-amine; (1S,2S,3S,4R)-3-[2-(benzyloxy)ethyl]bicyclo[2.2.1]hept-2-ylamine | C16H23NO | 详情 | 详情 | |
| (XL) | 14700 | N-[(1S,2S,3S,4R)-3-[2-(benzyloxy)ethyl]bicyclo[2.2.1]hept-2-yl]benzenesulfonamide | C22H27NO3S | 详情 | 详情 | |
| (XLI) | 14701 | N-[(1S,2S,3S,4R)-3-(2-hydroxyethyl)bicyclo[2.2.1]hept-2-yl]benzenesulfonamide | C15H21NO3S | 详情 | 详情 | |
| (XLII) | 14673 | N-[(1S,2S,3S,4R)-3-(2-oxoethyl)bicyclo[2.2.1]hept-2-yl]benzenesulfonamide | C15H19NO3S | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(VII)1) The condensation of ethyl cyanoacetate (I) with 2-bromoacetaldehyde diethylacetal (II) by means of K2CO3 gives the alkylated cyanoacetate (III), which is cyclized with guanidine (IV) and sodium ethoxide to the pyrimidinone (V). The acidic cyclization of (V) by means of 0.5 N HCl affords the pyrrolopyrimidinone (VI), which is acylated with pivaloyl chloride (VII) to the heterocyclic amide (VIII). The iodination of (VIII) with N-iodosuccinimide (NIS) gives the diiodo derivative (IX), which by selective deiodination with Zn/acetic acid yields the 5-iodo derivative (X). The condensation of (X) with N-(4-ethynylbenzoyl)-L-glutamic acid dimethyl ester (XI) by means of tetrakis(triphenylphosphine)palladium and CuI affords the expected condensation product (XII), which is reduced with H2 over Pd/C in methanol/dichloromethane to the saturated compound (XIII). Finally, this compound is saponified with NaOH.
| 【1】 Castaner, J.; Graul, A.; Tracy, M.; Penetrexed Disodium. Drugs Fut 1998, 23, 5, 498. |
| 【2】 Taylor, E.C.; Design and synthesis of inhibitors of folate-dependent enzymes as antitumor agents. Adv Exp Med Biol 1993, 338, 387-408. |
| 【3】 Taylor, E.C.; Kuhnt, D.G.; Shih, C.; Grindey, G.B. (Eli Lilly and Company; Princeton University); N-(Pyrrolo[2,3-d]pyrimidin-3-ylacyl)-glutamic acid derivs. AU 9167791; EP 0432677; JP 1996003166; US 5028608 . |
| 【4】 Jannatipour, M.; Kuhnt, D.; Shih, C.; Rinzel, S.M.; Grindey, G.B.; Taylor, E.C.; Moran, R.G.; Barredo, J.; A dideazatetrahydrofolate analogue lacking a chiral center at C-6, N-[4-[2-(2-amino-3,4-dihydro-4-oxo-7H-pyrrolo[2,3-d]pyrimidin-5-yl) ethyl]benzoyl-L-glutamic acid, is an inhibitor of thymidylate synthase. J Med Chem 1992, 35, 23, 4450-4. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 11877 | Cyanoacetic acid ethyl ester; Ethyl 2-cyanoacetate; Ethyl cyanoacetate; Ethyl isocyanacetate | 105-56-6 | C5H7NO2 | 详情 | 详情 |
| (II) | 12113 | 2-Bromo-1-ethoxyethyl ethyl ether; 2-Bromo-1,1-diethoxyethane; Bromoacetaldehyde diethylacetal | 2032-35-1 | C6H13BrO2 | 详情 | 详情 |
| (III) | 14789 | ethyl 2-cyano-4,4-diethoxybutanoate | C11H19NO4 | 详情 | 详情 | |
| (IV) | 14790 | Guanidine | 113-00-8 | CH5N3 | 详情 | 详情 |
| (V) | 14791 | 2,6-diamino-5-(2,2-diethoxyethyl)-4(3H)-pyrimidinone | C10H18N4O3 | 详情 | 详情 | |
| (VI) | 14792 | 2-amino-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one | 7355-55-7 | C6H6N4O | 详情 | 详情 |
| (VII) | 13597 | 2,2-Dimethylpropanoyl chloride; Pivaloyl chloride | 3282-30-2 | C5H9ClO | 详情 | 详情 |
| (VIII) | 14794 | 2,2-dimethyl-N-(4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-2-yl)propanamide | C11H14N4O2 | 详情 | 详情 | |
| (IX) | 14795 | N-(5,6-diiodo-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-2-yl)-2,2-dimethylpropanamide | C11H12I2N4O2 | 详情 | 详情 | |
| (X) | 14796 | N-(5-iodo-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-2-yl)-2,2-dimethylpropanamide | C11H13IN4O2 | 详情 | 详情 | |
| (XI) | 14797 | dimethyl (2S)-2-[(4-ethynylbenzoyl)amino]pentanedioate | C16H17NO5 | 详情 | 详情 | |
| (XII) | 14798 | dimethyl (2S)-2-[[4-(2-[2-[(2,2-dimethylpropanoyl)amino]-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl]ethynyl)benzoyl]amino]pentanedioate | C27H29N5O7 | 详情 | 详情 | |
| (XIII) | 14799 | dimethyl (2S)-2-[[4-(2-[2-[(2,2-dimethylpropanoyl)amino]-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl]ethyl)benzoyl]amino]pentanedioate | C27H33N5O7 | 详情 | 详情 |
合成路线11
该中间体在本合成路线中的序号：(IV)SR 27417 (N-(2-dimethylaminoethyl)-N-(3-pyridinylmethyl)[4-(2,4,6-triisopropylphenyl)thiazol-2-yl]amine difumarate) was prepared via a convergent route. Reductive amination of N,N-dimethylaminoethanamine (I) and pyridyl-3-carboxaldehyde (II) by sodium borohydride gave the amine (III). Eaction of pivaloyl chloride (IV) and potassium thiocyanate in anhydrous acetone provided the pivaloyl isothiocyanate (V), which was condensed in situ with the amine (III) to afford the protected thiourea (VI). Chlorhydric hydrolysis of (IV) gave the thiourea (VII) with the bromoketene (IX) in refluxing ethanol led to SR 27417.
| 【1】 Herbert, J.M.; Valette, G.; Bernat, A.; Savi, P.; Maffrand, J.P.; Le Fur, G.; SR 27417, a highly potent, selective and long-acting antagonist of the PAF receptor. Drugs Fut 1992, 17, 11, 1011. |
| 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) | 14881 | N-(2-aminoethyl)-N,N-dimethylamine; N(1),N(1)-dimethyl-1,2-ethanediamine; 2-Dimethylaminoethylamine | 108-00-9 | C4H12N2 | 详情 | 详情 |
| (II) | 12849 | Nicotinaldehyde; 3-Pyridinecarboxaldehyde | 500-22-1 | C6H5NO | 详情 | 详情 |
| (III) | 14883 | N-[2-(dimethylamino)ethyl]-N-(3-pyridinylmethyl)amine; N(1),N(1)-dimethyl-N(2)-(3-pyridinylmethyl)-1,2-ethanediamine | C10H17N3 | 详情 | 详情 | |
| (IV) | 13597 | 2,2-Dimethylpropanoyl chloride; Pivaloyl chloride | 3282-30-2 | C5H9ClO | 详情 | 详情 |
| (V) | 14885 | 2,2-dimethylpropanoyl isothiocyanate | C6H9NOS | 详情 | 详情 | |
| (VI) | 14886 | N-[2-(dimethylamino)ethyl]-N'-(2,2-dimethylpropanoyl)-N-(3-pyridinylmethyl)thiourea | C16H26N4OS | 详情 | 详情 | |
| (VII) | 14887 | N-[2-(dimethylamino)ethyl]-N-(3-pyridinylmethyl)thiourea | C11H18N4S | 详情 | 详情 | |
| (VIII) | 14888 | 1,3,5-triisopropylbenzene | 717-74-8 | C15H24 | 详情 | 详情 |
| (IX) | 14889 | 2-bromo-1-(2,4,6-triisopropylphenyl)-1-ethanone | C17H25BrO | 详情 | 详情 |
合成路线12
该中间体在本合成路线中的序号：(I)Pivagabine is prepared by reacting pivaloyl chloride (I) and 4-aminobutyric acid (II) in aqueous sodium hydroxide solution; by adding dilute hydrochloric acid the crude product is isolated and then purified by crystallization from water.
| 【1】 Mezzich, J.E.; Mezzich, A.C.; Fabrega, H.; Adjustment disorder as a marginal or transitional illness category in DSM-III. Arch Gen Psychiatry 1987, 44, 6, 567-72. |
| 【2】 Esposito, G.; Lazzarini, R.; Pivagabine. Drugs Fut 1998, 23, 4, 390. |
合成路线13
该中间体在本合成路线中的序号：(II)Efavirenz has been obtained by two related ways: 1) The acylation of 4-chloroaniline (I) with pivaloyl chloride (II) by means of Na2CO3 in toluene gives the expected anilide (III), which is acylated with ethyl trifluoroacetate by means of butyllithium in THF yielding, after hydrolysis with HCl, 2'-amino-5'-chloro-2,2,2-trifluoroacetophenone (IV). The benzylation of (IV) with 4-methoxybenzyl chloride (V) in basic alumina affords the protected acetophenone (VI), which is regioselectively condensed with cyclopropylacetylene (VII) [obtained by cyclization of 5-chloro-1-pentyne (VIII) by means of butyllithium in cyclohexane] by means of butyllithium in THF in the presence of (1R,2S)-1-phenyl-2-(1-pyrrolidinyl)-1-propanol (IX) giving the (S)-isomer of the tertiary alcohol (X) exclusively. The cyclization of (X) with phosgene and triethylamine or K2CO3 in toluene/THF yields the benzoxazinone (XI), which is finally deprotected with ceric ammonium nitrate in acetonitrile/water. 2) The condensation of 2'-amino-5'-chloro-2,2,2-trifluoroacetophenone (IV) with cyclopropylacetylene (VIII) by means of butyllithium or ethylmagnesium bromide in THF gives (?-2-(2-amino-5-chlorophenyl)-4-cyclopropyl-1,1,1-trifluoro-3-butyn-2-ol (XII). The cyclization of (XII) with carbonyldiimidazole (XIII) in hot THF yields the racemic benzoxazinone (XIV). Compound (XIV) is submitted to optical resolution by condensation with (S)-(-)-camphanoyl chloride by means of dimethylaminopyridine (DMAP) in dichloromethane to give the acyl derivative (XVI) as a diastereomeric mixture that is resolved by crystallization and finally decomposed with HCl in ethanol or butanol.
| 【1】 Choudhury, A.; Moore, J.R.; Pierce, M.E.; Fortunak, J.M.; Valvis, I.; Confalone, P.N.; In situ recycling of chiral ligand and surplus nucleophile for a noncatalytic reaction: Amplification of process throughput in the asymmetric addition step of efavirenz (DMP 266). Org Process Res Dev 2003, 7, 3, 324. |
| 【2】 Britcher, S.F.; Tran, L.O.; Young, S.D.; L-743,726 (DMP-266): A novel, highly potent nonnucleoside inhibitor of the human immunodeficiency virus type 1 reverse transcriptase. Antimicrob Agents Chemother 1995, 39, 12, 2602-5. |
| 【3】 Corley, E.G.; Thompson, A.S.; Huntington, M.F.; Grabowski, E.J.J.; Use of an ephedrine alkoxide to mediate enantioselective addition of an acetylide to a prochiral ketone: Asymmetric synthesis of the reverse transcriptase inhibitor L-743,726. Tetrahedron Lett 1995, 36, 49, 8937-40. |
| 【4】 Graul, A.; Rabasseda, X.; Castañer, J.; Efavirenz. Drugs Fut 1998, 23, 2, 133. |
| 【5】 Young, S.D.; Britcher, S.F.; Payne, L.S.; Tran, L.O.; Lumma, W.C. Jr. (Merck & Co., Inc.); Benzoxazinones as inhibitors of HIV reverse transcriptase. WO 9520389 . |
| 【6】 Young, S.D.; Tran, L.O.; Britcher, S.F.; Lumma, W.C. Jr.; Payne, L.S. (Merck & Co., Inc.); Benzoxazinones as inhibitors of HIV reverse transcriptase. EP 0582455; JP 1994184124; WO 9403440 . |
| 【7】 Thompson, A.S.; Corley, E.G.; Huntington, M. (Merck & Co., Inc.); Improved synthesis of cyclopropylacetylene. JP 1998512880; WO 9622955 . |
| 【8】 Thompson, A.S.; Corley, E.G.; Grabowski, E.J.J.; Yasuda, N. (Merck & Co., Inc.); Asymmetric synthesis of (-)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1 -benzoxazin-2-one. WO 9637457 . |
| 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) | 12034 | 4-Chlorophenylamine; 4-Chloroaniline; p-Chloroaniline | 106-47-8 | C6H6ClN | 详情 | 详情 |
| (II) | 13597 | 2,2-Dimethylpropanoyl chloride; Pivaloyl chloride | 3282-30-2 | C5H9ClO | 详情 | 详情 |
| (III) | 16571 | 4'-Chloro-2,2-dimethylpropionanilide; N-(4-Chlorophenyl)-2,2-dimethylpropanamide | 65854-91-3 | C11H14ClNO | 详情 | 详情 |
| (IV) | 16572 | 1-(2-amino-5-chlorophenyl)-2,2,2-trifluoro-1-ethanone | C8H5ClF3NO | 详情 | 详情 | |
| (V) | 11910 | 4-Methoxybenzyl chloride; 1-(Chloromethyl)-4-methoxybenzene; alpha-Chloro-4-methoxytoluene; 4-(Chloromethyl)phenyl methyl ether | 824-94-2 | C8H9ClO | 详情 | 详情 |
| (VI) | 16574 | 1-[5-chloro-2-[(4-methoxybenzyl)amino]phenyl]-2,2,2-trifluoro-1-ethanone | C16H13ClF3NO2 | 详情 | 详情 | |
| (VII) | 16575 | 1-ethynylcyclopropane; cyclopropyl acetylene | 6746-94-7 | C5H6 | 详情 | 详情 |
| (VIII) | 16576 | 5-chloro-1-pentyne | 14267-92-6 | C5H7Cl | 详情 | 详情 |
| (IX) | 16577 | (1R,2S)-1-phenyl-2-(1-pyrrolidinyl)-1-propanol | C13H19NO | 详情 | 详情 | |
| (X) | 16578 | (2S)-2-[5-chloro-2-[(4-methoxybenzyl)amino]phenyl]-4-cyclopropyl-1,1,1-trifluoro-3-butyn-2-ol | C21H19ClF3NO2 | 详情 | 详情 | |
| (XI) | 16579 | (4S)-6-chloro-4-(2-cyclopropylethynyl)-1-(4-methoxybenzyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one | C22H17ClF3NO3 | 详情 | 详情 | |
| (XII) | 16580 | 2-(2-amino-5-chlorophenyl)-4-cyclopropyl-1,1,1-trifluoro-3-butyn-2-ol | 168834-43-3 | C13H11ClF3NO | 详情 | 详情 |
| (XIII) | 11353 | 1,1'-Carbonyldiimidazole; Di(1H-imidazol-1-yl)methanone; N,N-Carbonyldiimidazole; 1,1'-Carbonylbis(1H-imidazole) | 530-62-1 | C7H6N4O | 详情 | 详情 |
| (XIV) | 16582 | 6-chloro-4-(2-cyclopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one | C14H9ClF3NO2 | 详情 | 详情 | |
| (XV) | 16583 | (1S,4R)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carbonyl chloride; (-)-Camphanic chloride | 39637-74-6 | C10H13ClO3 | 详情 | 详情 |
| (XVI) | 16584 | 6-chloro-4-(2-cyclopropylethynyl)-4-(trifluoromethyl)-1-[[(4R)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]hept-1-yl]carbonyl]-1,4-dihydro-2H-3,1-benzoxazin-2-one | C24H21ClF3NO5 | 详情 | 详情 |
合成路线14
该中间体在本合成路线中的序号：(VI)Synthesis of intermediate (XI): Treatment of 2,4-difluorophenol (I) with triethylamine and ethyl chloroformate (II) in dichloromethane yields O-ethoxycarbonyl-2,4-difluorophenol (III), which is then nitrated by means of HNO3/H2SO4 and hydrolyzed with Na2CO3 or NaHCO3 in MeOH/H2O to provide (IV). The nitro group of (IV) is then hydrogenated over Pd/C in EtOAc to afford 5-amino-2,4-difluorophenol (V), which is N-protected by reaction with pivaloyl chloride (VI) in pyridine to furnish pivaloylamino derivative (VII). Treatment of (VII) with 3,4-dihydro-2H pyran (VIII) and camphorsulfonic acid (CSA) in dichloromethane gives O-protected derivative (IX), which is converted into ethyl benzoate (X) by first reaction in THF with hexamethylphosphoric triamide (HMPA) and n-BuLi in hexane, followed by treatment with ethyl chloroformate (II). Finally, methylation of (X) by means of iodomethane (MeI) and LDA in THF/hexane yields intermediate (XI). Alternatively, intermediate (XI) can be also obtained by following this pathway: lithiation of derivative (IX) with LDA followed by treatment with TMSCl in THF affords trimethylsilylated compound (XII), which is converted into ethyl benzoate (XIII) by reaction with BuLi and ethyl chloroformate (II). Finally, TMS removal of (XIII) is achieved by treatment with tetrabutyl ammonium fluoride (TBAF) in THF to furnish derivative (X), which is methylated as described above.
| 【1】 Akama, T.; et al.; Synthesis of an ethyl 6-amino-3,5-difluorosalicylate derivative by sequential regioselective direct ortho-metalation; a practical synthesis of 4',5-diamino-3',6,8-trifluoroflavone, a potent antitumor agent. Synthesis 1997, 1446. |
| 【2】 Saito, H.; Ishida, H.; Akama, T.; Kimura, U.; Gomi, K.; Structure-activity relationships of the 7-substituents of 5,4'-diamino-6,8,3'-trifluoroflavone, a potent antitumor agent. J Med Chem 1998, 41, 12, 2056. |
| 【3】 Akama, T.; Ikeda, S.; Ishida, H.; Kimura, U.; Gomi, K.; Saito, H. (Kyowa Hakko Kogyo Co., Ltd.); 5-Aminoflavone derivs., their preparation and their use as antibacterial, anti-estrogenic and/or antitumor agent. EP 0638566; JP 1995109268 . |
| 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) | 21486 | 2,4-difluorophenol | 367-27-1 | C6H4F2O | 详情 | 详情 |
| (II) | 11229 | 1-[(Chlorocarbonyl)oxy]ethane;ethyl carbonochloridate; Carbonchloridic acid ethyl ester;Ethyl chloroformate;Ethyl chlorocarbonate | 541-41-3 | C3H5ClO2 | 详情 | 详情 |
| (III) | 46822 | 2,4-difluorophenyl ethyl carbonate | C9H8F2O3 | 详情 | 详情 | |
| (IV) | 46823 | 2,4-difluoro-5-nitrophenol | C6H3F2NO3 | 详情 | 详情 | |
| (V) | 46824 | 5-amino-2,4-difluorophenol | C6H5F2NO | 详情 | 详情 | |
| (VI) | 13597 | 2,2-Dimethylpropanoyl chloride; Pivaloyl chloride | 3282-30-2 | C5H9ClO | 详情 | 详情 |
| (VII) | 46825 | N-(2,4-difluoro-5-hydroxyphenyl)-2,2-dimethylpropanamide | C11H13F2NO2 | 详情 | 详情 | |
| (VIII) | 13684 | 3,4-Dihydro-2H-pyran;2,3-Dihydro-4H-pyran; 5,6-Dihydro-4H-pyran;Dihydropyran | 110-87-2 | C5H8O | 详情 | 详情 |
| (IX) | 46826 | N-[2,4-difluoro-5-(tetrahydro-2H-pyran-2-yloxy)phenyl]-2,2-dimethylpropanamide | C16H21F2NO3 | 详情 | 详情 | |
| (X) | 46827 | ethyl 2-[(2,2-dimethylpropanoyl)amino]-3,5-difluoro-6-(tetrahydro-2H-pyran-2-yloxy)benzoate | C19H25F2NO5 | 详情 | 详情 | |
| (XI) | 46828 | ethyl 2-[(2,2-dimethylpropanoyl)amino]-3,5-difluoro-4-methyl-6-(tetrahydro-2H-pyran-2-yloxy)benzoate | C20H27F2NO5 | 详情 | 详情 | |
| (XII) | 46829 | N-[2,4-difluoro-5-(tetrahydro-2H-pyran-2-yloxy)-3-(trimethylsilyl)phenyl]-2,2-dimethylpropanamide | C19H29F2NO3Si | 详情 | 详情 | |
| (XIII) | 46830 | ethyl 2-[(2,2-dimethylpropanoyl)amino]-3,5-difluoro-6-(tetrahydro-2H-pyran-2-yloxy)-4-(trimethylsilyl)benzoate | C22H33F2NO5Si | 详情 | 详情 |
合成路线15
该中间体在本合成路线中的序号：(VI)Synthesis of intermediate (XVII): Coupling of 4-bromo-2-fluoroaniline (XIV) with pivaloyl chloride (VI) in pyridine affords N-protected substituted aniline (XV), which is then treated with 1-ethoxyvinyltributyltin (XVI) and bis(triphenylphosphine) palladium chloride (PdCl2(PPh3)2) in toluene to provide acetophenone derivative (XVII). Coupling of intermediates (XI) and (XVII): Ethyl benzoate (XI) is treated with NaH and added to a solution of acetophenone (XVII) in refluxing toluene/dioxane to furnish benzopyranone (XVIII), which is finally deprotected with HCl in dioxane to give the desired product.
| 【1】 Akama, T.; et al.; Synthesis of an ethyl 6-amino-3,5-difluorosalicylate derivative by sequential regioselective direct ortho-metalation; a practical synthesis of 4',5-diamino-3',6,8-trifluoroflavone, a potent antitumor agent. Synthesis 1997, 1446. |
| 【2】 Saito, H.; Ishida, H.; Akama, T.; Kimura, U.; Gomi, K.; Structure-activity relationships of the 7-substituents of 5,4'-diamino-6,8,3'-trifluoroflavone, a potent antitumor agent. J Med Chem 1998, 41, 12, 2056. |
| 【3】 Akama, T.; Ikeda, S.; Ishida, H.; Kimura, U.; Gomi, K.; Saito, H. (Kyowa Hakko Kogyo Co., Ltd.); 5-Aminoflavone derivs., their preparation and their use as antibacterial, anti-estrogenic and/or antitumor agent. EP 0638566; JP 1995109268 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VI) | 13597 | 2,2-Dimethylpropanoyl chloride; Pivaloyl chloride | 3282-30-2 | C5H9ClO | 详情 | 详情 |
| (XI) | 46828 | ethyl 2-[(2,2-dimethylpropanoyl)amino]-3,5-difluoro-4-methyl-6-(tetrahydro-2H-pyran-2-yloxy)benzoate | C20H27F2NO5 | 详情 | 详情 | |
| (XIV) | 14723 | 4-Bromo-2-fluorophenylamine; 4-Bromo-2-fluoroaniline | 367-24-8 | C6H5BrFN | 详情 | 详情 |
| (XV) | 46831 | N-(4-bromo-2-fluorophenyl)-2,2-dimethylpropanamide | C11H13BrFNO | 详情 | 详情 | |
| (XVI) | 19760 | ethyl 1-(tributylstannyl)vinyl ether; tributyl(1-ethoxyvinyl)stannane | 97674-02-7 | C16H34OSn | 详情 | 详情 |
| (XVII) | 46832 | N-(4-acetyl-2-fluorophenyl)-2,2-dimethylpropanamide | C13H16FNO2 | 详情 | 详情 | |
| (XVIII) | 46833 | N-(4-[5-[(2,2-dimethylpropanoyl)amino]-6,8-difluoro-7-methyl-4-oxo-4H-chromen-2-yl]-2-fluorophenyl)-2,2-dimethylpropanamide | C26H27F3N2O4 | 详情 | 详情 |
合成路线16
该中间体在本合成路线中的序号：(II)The activation of 5-(4-fluorophenyl)-5-oxopentanoic acid (I) with pivaloyl chloride (II) gives the mixed anhydride (III), which is condensed with the chiral oxazolidinone (IV) by means of DMAP to yield the acylated oxazolidine (V) (1). The asymmetric reduction of (V) by means of BH3/Me2S catalyzed by the chiral boron catalyst (VI) affords the chiral alcohol (VII) (1-3), which is condensed with the imine (VIII) by means of Tms-Cl, DIEA and TiCl4 to provide the adduct (IX). The cyclization of (IX) by means of bis(trimethylsilyl)acetamide and TBAF gives the protected azetidinone (X), which is finally desilylated by means of sulfuric acid in isopropanol
| 【1】 Fu, X.Y.; et al.; Process for preparing ezetimibe intermediate by an acid enhanced chemo- and enantioselective CBS catalyzed ketone reduction. Tetrahedron Lett 2003, 44, 4, 801. |
| 【2】 Thiruvengadam, T.K.; Tann, C.-H.; Fu, X.; McAllister, T.L. (Schering Corp.); Enantioselective synthesis of azetidinone intermediate cpds.. US 2002193607; WO 0279174 . |
| 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) | 62208 | 4-(4-Fluorobenzoyl)butyric acid; 4-(4-fluorobenzoyl) butyric acid; 4-(4'-Fluorobenzoyl)butyric acid; 4-(p-Fluorobenzoyl) butyric acid; 5-(4'-Fluorophenyl)-5-oxopentanoic acid | 149437-76-3 | C11H11FO3 | 详情 | 详情 |
| (II) | 13597 | 2,2-Dimethylpropanoyl chloride; Pivaloyl chloride | 3282-30-2 | C5H9ClO | 详情 | 详情 |
| (III) | 62209 | 1,1-dimethylpropanoic 4-(4-fluorophenyl)-4-oxopentanoic anhydride | C16H19FO4 | 详情 | 详情 | |
| (IV) | 12173 | (4S)-4-Phenyl-1,3-oxazolan-2-one; (4S)-4-Phenyl-2-oxazolidinone; (S)-(+)-4-Phenyl-2-oxazolidinone | 99395-88-7 | C9H9NO2 | 详情 | 详情 |
| (V) | 53476 | 1-(4-fluorophenyl)-5-[(4S)-2-oxo-4-phenyl-1,3-oxazolidin-3-yl]-1,5-pentanedione | n/a | C20H18FNO4 | 详情 | 详情 |
| (VI) | 20631 | (R)-Methyl oxazaborolidine; (3aR)-1-methyl-3,3-diphenyltetrahydro-3H-pyrrolo[1,2-c][1,3,2]oxazaborole | 112022-83-0 | C18H20BNO | 详情 | 详情 |
| (VII) | 53477 | (4S)-3-[(5S)-5-(4-fluorophenyl)-5-hydroxypentanoyl]-4-phenyl-1,3-oxazolidin-2-one | n/a | C20H20FNO4 | 详情 | 详情 |
| (VIII) | 62210 | 4-fluoro-N-((Z)-{4-[(trimethylsilyl)oxy]phenyl}methylidene)aniline; N-(4-fluorophenyl)-N-((Z)-{4-[(trimethylsilyl)oxy]phenyl}methylidene)amine | C16H18FNOSi | 详情 | 详情 | |
| (IX) | 62211 | (4S)-3-{(2R,5S)-2-((S)-(4-fluoroanilino){4-[(trimethylsilyl)oxy]phenyl}methyl)-5-(4-fluorophenyl)-5-[(trimethylsilyl)oxy]pentanoyl}-4-phenyl-1,3-oxazolidin-2-one | C39H46F2N2O5Si2 | 详情 | 详情 | |
| (X) | 62212 | (3R,4S)-1-(4-fluorophenyl)-3-{(3S)-3-(4-fluorophenyl)-3-[(trimethylsilyl)oxy]propyl}-4-{4-[(trimethylsilyl)oxy]phenyl}-2-azetidinone | C30H37F2NO3Si2 | 详情 | 详情 |
合成路线17
该中间体在本合成路线中的序号：(XII)Friedel-Crafts reaction between 4-hydroxyphenylacetic acid (I) and resorcinol (II) by means of BF3.Et2O provides trihydroxydeoxy benzoin (III), which is then protected with dihydropyran (IV) in the presence of TsOH to give the bis-THP ether (V). Knoevenagel reaction of (V) with 4-hydroxybenzaldehyde (VI) in the presence of piperidine in refluxing benzene, followed by alkylation with 1-(2-chloroethyl)piperidine (VII) in the presence of Cs2CO3 in refluxing acetone:H2O to yield chromanone (VIII). Alternatively, (VIII) can be synthesized by reaction of (V) with compound (IX) (obtained in turn from reaction between aldehyde (VI) and chloro derivative (VII) with K2CO3 in DMF) by means of piperidine in refluxing toluene, followed by treatment with NaOAc in refluxing MeOH. Chromanone (VIII) is then alkylated either with MeLi or with methylmagnesium bromide in THF and then dehydrated and deprotected in HOAc furnishing chromene (X). Racemic compound (X) is then resolved to afford enantiomer (XI) either by preparative chiral HPLC or by chemical resolution of the corresponding diastereomeric salt obtained by reaction with (+)-CSA in DMF/CH2Cl2, and treatment of the resulting salt with saturated K2CO3 . Finally, the target product is obtained by acylation of (XI) by reaction with pivaloyl chloride (XII) and Et3N in CH2Cl2.
| 【1】 Caron, B.; Cloutier, J.; Gauthier, S.; (S)-(+)-4-[7-(2, 2-Dimethyl-1-oxopropoxy)-4-methyl-2-[4-[2-(1-piperidinyl)ethoxy]phenyl]-2H-1-benzopyran-3-yl]phenyl 2, 2-dimethylpropanoate (EM-800): A highly potent, specific, and orally active nonsteroidal antiestrogen. J Med Chem 1997, 40, 14, 2117. |
| 【2】 Labrie, F.; Merand, Y.; Gauthier, S. (Endorecherche Inc.); Benzopyran-containing cpds. and method for their use. EP 0811006; EP 1167364; JP 1999500133; WO 9626201 . |
| 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) | 18430 | 2-(4-Hydroxyphenyl)acetic acid; 4-Hydroxyphenylacetic acid | 156-38-7 | C8H8O3 | 详情 | 详情 |
| (II) | 10361 | 1,3-Dihydroxybenzene; m-Dihydroxybenzene; Resorcinol; Resorcin; 1,3-Benzenediol | 108-46-3 | C6H6O2 | 详情 | 详情 |
| (III) | 51229 | 1-(2,4-dihydroxyphenyl)-2-(4-hydroxyphenyl)-1-ethanone | C14H12O4 | 详情 | 详情 | |
| (IV) | 13684 | 3,4-Dihydro-2H-pyran;2,3-Dihydro-4H-pyran; 5,6-Dihydro-4H-pyran;Dihydropyran | 110-87-2 | C5H8O | 详情 | 详情 |
| (V) | 51230 | 1-[2-hydroxy-4-(tetrahydro-2H-pyran-2-yloxy)phenyl]-2-[4-(tetrahydro-2H-pyran-2-yloxy)phenyl]-1-ethanone | C24H28O6 | 详情 | 详情 | |
| (VI) | 13433 | 4-Hydroxybenzaldehyde; p-Hydroxybenzaldehyde | 123-08-0 | C7H6O2 | 详情 | 详情 |
| (VII) | 10117 | 1-(2-Chloroethyl)piperidine; N-(2-Chloroethyl)piperidine | 1932-03-2 | C7H14ClN | 详情 | 详情 |
| (VIII) | 51231 | 2-[4-[2-(1-piperidinyl)ethoxy]phenyl]-7-(tetrahydro-2H-pyran-2-yloxy)-3-[4-(tetrahydro-2H-pyran-2-yloxy)phenyl]-2,3-dihydro-4H-chromen-4-one | C38H45NO7 | 详情 | 详情 | |
| (IX) | 35795 | 4-[2-(1-piperidinyl)ethoxy]benzaldehyde | 26815-04-3 | C14H19NO2 | 详情 | 详情 |
| (X) | 51232 | 3-(4-hydroxyphenyl)-4-methyl-2-[4-[2-(1-piperidinyl)ethoxy]phenyl]-2H-chromen-7-ol | C29H31NO4 | 详情 | 详情 | |
| (XI) | 51233 | (2S)-3-(4-hydroxyphenyl)-4-methyl-2-[4-[2-(1-piperidinyl)ethoxy]phenyl]-2H-chromen-7-ol | C29H31NO4 | 详情 | 详情 | |
| (XII) | 13597 | 2,2-Dimethylpropanoyl chloride; Pivaloyl chloride | 3282-30-2 | C5H9ClO | 详情 | 详情 |
合成路线18
该中间体在本合成路线中的序号：The reaction of 3-aminophenol (I) with pivaloyl chloride and then with DHP and TsOH gives the protected pivalanilide (II), which is condensed with ethyl chloroformate by means of BuLi in THF yielding the benzoate ester (III). The condensation of benzoate (III) with acetophenone (IV) by means of NaH in refluxing dioxane affords the intermediate diketone (V), which, without purification, was treated with HCl in ethanol at room temperature to give the protected flavone (VI). Finally, thee removal of the two pivaloyl protecting groups was effected with HCl in refluxing ethanol.
| 【1】 Akama, T.; et al.; Novel 5-aminoflavone derivatives as specific antitumor agents in breast cancer. J Med Chem 1996, 39, 18, 3461. |
| 【2】 Shida, Y.; Sagaya, T.; Gomi, K.; Kasai, M.; Morimoto, M. (Kyowa Hakko Kogyo Co., Ltd.); 5-Aminoflavone derivs.. EP 0374789; JP 1990256673 . |
| 【3】 Sugaya, T.; et al.; Synthesis of a 6H-pyrazolo[4,5,1-de]acridin-6-one derivative: A useful intermediate of antitumor agents. Synthesis 1994, 73. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 13597 | 2,2-Dimethylpropanoyl chloride; Pivaloyl chloride | 3282-30-2 | C5H9ClO | 详情 | 详情 | |
| (I) | 23766 | 3-aminophenol | 591-27-5 | C6H7NO | 详情 | 详情 |
| (II) | 36663 | 2,2-dimethyl-N-[3-(tetrahydro-2H-pyran-2-yloxy)phenyl]propanamide | C16H23NO3 | 详情 | 详情 | |
| (III) | 36664 | ethyl 2-[(2,2-dimethylpropanoyl)(ethoxycarbonyl)amino]-6-(tetrahydro-2H-pyran-2-yloxy)benzoate | C22H31NO7 | 详情 | 详情 | |
| (IV) | 36665 | N-(4-acetylphenyl)-2,2-dimethylpropanamide | C13H17NO2 | 详情 | 详情 | |
| (V) | 36666 | N-[2-(3-[4-[(2,2-dimethylpropanoyl)amino]phenyl]-3-oxopropanoyl)-3-(tetrahydro-2H-pyran-2-yloxy)phenyl]-2,2-dimethylpropanamide | C30H38N2O6 | 详情 | 详情 | |
| (VI) | 36667 | N-(4-[5-[(2,2-dimethylpropanoyl)amino]-4-oxo-4H-chromen-2-yl]phenyl)-2,2-dimethylpropanamide | C25H28N2O4 | 详情 | 详情 |
合成路线19
该中间体在本合成路线中的序号：(VIII)The esterification of N-(tert-butoxycarbonyl)-L-tert-butylglycine (I) with DBU and methyl iodide gives the corresponding methyl ester (II), which is condensed with dimethyl methylphosphonate by means of butyllithium in THF yielding N-(tert-butoxycarbonyl)-L-tert-butylglycylmethylphosphonic acid dimethyl ester (III). The reaction of benzyl glyoxylate (IV) (obtained by IO4H oxidation of dibenzyl L-tartrate (V)) with phosphonic ester (III) by means of triethylamine in acetonitrile affords 5(S)-(tert-butoxycarbonylamino)-6,6-dimethyl-4-oxo-2-heptenoic acid benzyl ester (VI). The condensation of (VI) with allyl 2-pivaloylacetate (VII)(obtained by reaction of pivaloyl chloride (VIII) with allyl acetate (A) by means of LHDMS in THF) by means of NaH in THF provides the intermediate (IX). Selective elimination of the allyloxycarbonyl group of (IX) by means of Pd(PPh3)4 and pyrrolidine in dichloromethane/acetonitrile gives 5(S)-(tert-butoxycarbonylamino)-6,6-dimethyl-4-oxo-2(R)-(pivaloylmethyl)heptanoic acid benzyl ester (X). Hydrogenolysis of the benzyl ester group of (X) with H2 over Pd/C in ethanol gives the heptanoic acid (XI), which is condensed with the amino group of the cyclopentanecarboxylic ester (XII) by means of TBTU and NMM in dichloromethane to afford the corresponding amide (XIII).
| 【1】 Gauthier, J.-A.; Moss, N. (Bio-Mega, Inc.; Boehringer Ingelheim GmbH); Herpes ribonucleotide reductase inhibitors. EP 0837845; JP 1999508246; US 5672586; WO 9700855 . |
| 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) | 27147 | allyl acetate | 591-87-7 | C5H8O2 | 详情 | 详情 |
| (I) | 22251 | (2S)-2-[(tert-butoxycarbonyl)amino]-3,3-dimethylbutyric acid;2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoic acid;N-(tert-butoxycarbonyl)-3-methyl-L-valine | 62965-35-9 | C11H21NO4 | 详情 | 详情 |
| (II) | 27141 | methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3,3-dimethylbutanoate | C12H23NO4 | 详情 | 详情 | |
| (III) | 27142 | dimethyl (3S)-3-[(tert-butoxycarbonyl)amino]-4,4-dimethyl-2-oxopentylphosphonate | C14H28NO6P | 详情 | 详情 | |
| (IV) | 27143 | benzyl 2-oxoacetate | C9H8O3 | 详情 | 详情 | |
| (V) | 27144 | dibenzyl 2,3-dihydroxysuccinate | C18H18O6 | 详情 | 详情 | |
| (VI) | 27145 | benzyl (E,5S)-5-[(tert-butoxycarbonyl)amino]-6,6-dimethyl-4-oxo-2-heptenoate | C21H29NO5 | 详情 | 详情 | |
| (VII) | 27146 | allyl 4,4-dimethyl-3-oxopentanoate | C10H16O3 | 详情 | 详情 | |
| (VIII) | 13597 | 2,2-Dimethylpropanoyl chloride; Pivaloyl chloride | 3282-30-2 | C5H9ClO | 详情 | 详情 |
| (IX) | 27148 | 4-allyl 1-benzyl (2S,3S)-2-[(3S)-3-[(tert-butoxycarbonyl)amino]-4,4-dimethyl-2-oxopentyl]-3-(2,2-dimethylpropanoyl)butanedioate | C31H45NO8 | 详情 | 详情 | |
| (X) | 27149 | benzyl (2R,5S)-5-[(tert-butoxycarbonyl)amino]-2-(3,3-dimethyl-2-oxobutyl)-6,6-dimethyl-4-oxoheptanoate | C27H41NO6 | 详情 | 详情 | |
| (XI) | 27150 | (2R,5S)-5-[(tert-butoxycarbonyl)amino]-2-(3,3-dimethyl-2-oxobutyl)-6,6-dimethyl-4-oxoheptanoic acid | C20H35NO6 | 详情 | 详情 | |
| (XII) | 27151 | benzyl 1-((1S)-1-amino-2-[[(1R)-1-ethyl-2,2-dimethylpropyl]amino]-2-oxoethyl)cyclopentanecarboxylate | C22H34N2O3 | 详情 | 详情 | |
| (XIII) | 27152 | benzyl 1-((1S)-1-[[(2R,5S)-5-[(tert-butoxycarbonyl)amino]-2-(3,3-dimethyl-2-oxobutyl)-6,6-dimethyl-4-oxoheptanoyl]amino]-2-[[(1R)-1-ethyl-2,2-dimethylpropyl]amino]-2-oxoethyl)cyclopentanecarboxylate | C42H67N3O8 | 详情 | 详情 |
合成路线20
该中间体在本合成路线中的序号：(XI)Synthesis of morpholine intermediate (I): Treatment of 4-fluorophenyl acetic acid (X) with trimethylacetyl chloride (XI) and Et3N in Et2O followed by reaction with 4-(S)-benzyl-2-oxazolidinone (XII) in THF and n-BuLi in hexane affords oxazolidinone derivative (XIII). Conversion of (XIII) into azido derivative (XV) is achieved by first treatment of (XIII) in THF with a potassium bis(trimethylsilyl)amide solution in toluene followed by treatment with 2,4,6-triisopropylphenylsulfonyl azide (XIV) in THF. Hydrolysis of azido-oxazolidinone derivative (XV) by means of LiOH in THF/H2O yields azido acetic acid derivative (XVI), which is then hydrogenated over Pd/C in H2O/HOAc to afford (S)-(4-fluorophenyl)glycine (XVII). Treatment of (S)-(4-fluorophenyl)glycine (XVII) with benzaldehyde (XVIII), NaOH and NaBH4 in MeOH yields N-benzyl (S)-(4-fluorophenyl)glycine (XIX), which is then cyclized with 1,2-dibromoethane (XX) in the presence of DIEA in DMF to furnish morpholine intermediate (I).
| 【1】 Castaner, J.; Silvestre, J.S.; Bayes, M.; Sorbera, L.A.; Aprepitant and L-758298. Drugs Fut 2002, 27, 3, 211. |
| 【2】 Dorn, C.P.; Hale, J.J.; Maccoss, M.; Mills, S.G. (Merck & Co., Inc.); Prodrugs of morpholine tachykinin receptor antagonists. EP 0748320; JP 1997509935; US 5691336; WO 9523798 . |
| 【3】 Dorn, C.P.; Hale, J.J.; Maccoss, M.; Mills, S.G.; Ladduwahetty, T.; Shah, S.K. (Merck & Co., Inc.); Morpholine and thiomorpholine tachykinin receptor antagonists. EP 0577394; JP 1994172178; US 5719147; WO 9400440; WO 9516679 . |
| 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) | 18288 | (3S)-4-benzyl-3-(4-fluorophenyl)-2-morpholinone | C17H16FNO2 | 详情 | 详情 | |
| (X) | 18999 | 4-Fluorophenylacetic acid; 2-(4-Fluorophenyl)acetic acid | 405-50-5 | C8H7FO2 | 详情 | 详情 |
| (XI) | 13597 | 2,2-Dimethylpropanoyl chloride; Pivaloyl chloride | 3282-30-2 | C5H9ClO | 详情 | 详情 |
| (XII) | 14694 | (S)-4-Benzyl-2-oxazolidinone; (4S)-4-Benzyl-1,3-oxazolan-2-one; (S)-(-)-4-Benzyl-2-oxazolidinone | 90719-32-7 | C10H11NO2 | 详情 | 详情 |
| (XIII) | 44186 | (4S)-4-benzyl-3-[2-(4-fluorophenyl)acetyl]-1,3-oxazolidin-2-one | C18H16FNO3 | 详情 | 详情 | |
| (XIV) | 44187 | 2,4,6-triisopropylbenzenesulfonyl azide | C15H23N3O2S | 详情 | 详情 | |
| (XV) | 44188 | (4S)-3-[(2S)-2-azido-2-(4-fluorophenyl)ethanoyl]-4-benzyl-1,3-oxazolidin-2-one | C18H15FN4O3 | 详情 | 详情 | |
| (XVI) | 44189 | (2S)-2-azido-2-(4-fluorophenyl)ethanoic acid | C8H6FN3O2 | 详情 | 详情 | |
| (XVII) | 43098 | (2R)-2-amino-2-(4-fluorophenyl)ethanoic acid | 7292-73-1 | C8H8FNO2 | 详情 | 详情 |
| (XVIII) | 10498 | Benzaldehyde;Benzoic aldehyde;Phenylmethanal | 100-52-7 | C7H6O | 详情 | 详情 |
| (XIX) | 44190 | (2S)-2-(benzylamino)-2-(4-fluorophenyl)ethanoic acid | C15H14FNO2 | 详情 | 详情 | |
| (XX) | 10252 | 1,2-Dibromoethane; Ethylene dibromide | 106-93-4 | C2H4Br2 | 详情 | 详情 |
合成路线21
该中间体在本合成路线中的序号：(VII)The cyclization of N-benzyl-N'-propylurea (I) with cyanacetic acid (II) in hot acetic anhydride gives 6-amino-1-benzyl-3-propyluracil (III), which is nitrosated with NaNO2/acetic acid and reduced with sodium dithionite to yield 5,6-diamino-1-benzyl-3-propyluracil (IV). The cyclization of (IV) with cyclopentylcarbonyl chloride (V) by means of NaOH in refluxing ethanol affords 3-benzyl-8-cyclopentyl-1-propylxanthine (VI), which is acylated with pivaloyl chloride (VII)/Na2CO3 in DMF giving the expected 7-acyl derivative (VIII). The debenzylation of (VIII) by hydrogenation over Pd/C as usual yields 8-cyclopentyl-7-pivaloyl-1-propylxanthine (IX), which is condensed with 1-bromo-3-fluoropropane (X) by means of Na2CO3 in DMF to afford 8-cyclopentyl-3-(3-fluoropropyl)-7-pivaloyl-1-propylxanthine (XI). Finally, this compound is deprotected with NaOH in DMSO/water.
| 【1】 Holschbach, M.H.; et al.; A1 adenosine receptor antagonists as ligands for positron emission tomography (PET) and single-photon emission tomography (SPET). J Med Chem 1998, 41, 4, 555. |
| 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) | 19803 | N-benzyl-N'-propylurea | C11H16N2O | 详情 | 详情 | |
| (II) | 12591 | Cyanoacetic Acid; 2-Cyanoacetic acid | 372-09-8 | C3H3NO2 | 详情 | 详情 |
| (III) | 19805 | 6-amino-1-benzyl-3-propyl-2,4(1H,3H)-pyrimidinedione | C14H17N3O2 | 详情 | 详情 | |
| (IV) | 19806 | 5,6-diamino-1-benzyl-3-propyl-2,4(1H,3H)-pyrimidinedione | C14H18N4O2 | 详情 | 详情 | |
| (V) | 19807 | 1,4-cyclopentadiene-1-carbonyl chloride | C6H5ClO | 详情 | 详情 | |
| (VI) | 19808 | 3-benzyl-8-cyclopentyl-1-propyl-3,7-dihydro-1H-purine-2,6-dione | C20H24N4O2 | 详情 | 详情 | |
| (VII) | 13597 | 2,2-Dimethylpropanoyl chloride; Pivaloyl chloride | 3282-30-2 | C5H9ClO | 详情 | 详情 |
| (VIII) | 19810 | 3-benzyl-8-cyclopentyl-7-(2,2-dimethylpropanoyl)-1-propyl-3,7-dihydro-1H-purine-2,6-dione | C25H32N4O3 | 详情 | 详情 | |
| (IX) | 19811 | 8-cyclopentyl-7-(2,2-dimethylpropanoyl)-1-propyl-3,7-dihydro-1H-purine-2,6-dione | C18H26N4O3 | 详情 | 详情 | |
| (X) | 19812 | 1-bromo-3-fluoropropane | 352-91-0 | C3H6BrF | 详情 | 详情 |
| (XI) | 19813 | 8-Cyclopentyl-3-(3-fluoropropyl)-7-pivaloyl-1-propylxanthine | C21H31FN4O3 | 详情 | 详情 |
合成路线22
该中间体在本合成路线中的序号：(XVI)The intermediate 4-hydroxy-myrtenyl pivalate (XIII) has been obtained as follows: The reaction of (1R,5S)-myrtenol (XV) with pivaloyl chloride (XVI) and pyridine in dichloromethane gives the pivalate ester (XVII), which by an allylic oxidation with CrO3 and 3,5-dimethylpyrazole in dichloromethane yields 4-oxo-myrtenyl pivalate (XVIII). Finally, this compound is reduced with LiAlH(OBu)3 in THF to afford the target 4-hydroxy-myrtenyl pivalate (XIII) intermediate.
| 【1】 Huffman, J.W.; Liddle, J.; Enantioselective synthesis of 11-hydroxy-(1'S,2'R)-dimethylheptyl-DELTA8-THC, a very potent CB1 agonist. Tetrahedron 2001, 57, 36, 7607. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIII) | 24407 | [(1R,5S)-4-hydroxy-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl]methyl pivalate | C15H24O3 | 详情 | 详情 | |
| (XV) | 51423 | [(1R,5R)-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl]methanol | C10H16O | 详情 | 详情 | |
| (XVI) | 13597 | 2,2-Dimethylpropanoyl chloride; Pivaloyl chloride | 3282-30-2 | C5H9ClO | 详情 | 详情 |
| (XVII) | 51424 | [(1R,5R)-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl]methyl pivalate | C15H24O2 | 详情 | 详情 | |
| (XVIII) | 51425 | [(1R,5S)-6,6-dimethyl-4-oxobicyclo[3.1.1]hept-2-en-2-yl]methyl pivalate | C15H22O3 | 详情 | 详情 |
合成路线23
该中间体在本合成路线中的序号：(II)The acylation of 4-methoxyaniline (I) with pivaloyl chloride (II) and TEA in CH2Cl2 gives the anilide (III), which is condensed with ethyl trifluoroacetate (IV) by means of n-BuLi in THF yielding the trifluoroacetyl derivative (V). The hydrolysis of the amido group of (V) with 6N HCl in refluxing DMF affords the 2-aminoacetophenone (VI), which is condensed with cyclopropylacetylene (VII) by means of n-BuLi in THF to give the tertiary alcohol (VIII). Finally, this compound is cyclized with phosgene and DIPEA in toluene yielding the racemic form of target compound.
| 【1】 Ko, S.S.; Patel, M.; Cordova, B.C.; Klabe, R.M.; Srivastava, A.S.; Markwalder, J.A.; McHugh, R.J. Jr.; Seitz, S.P.; Trainor, G.L.; Erickson-Vittanen, S.; Synthesis and evaluation of analogs of efavirenz (Sustiva(TM)) as HIV-1 reverse transcriptase inhibitors. Bioorg Med Chem Lett 1999, 9, 19, 2805. |
| 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) | 10478 | p-Anisidine; 4-Methoxyaniline; 4-Methoxyphenylamine | 104-94-9 | C7H9NO | 详情 | 详情 |
| (II) | 13597 | 2,2-Dimethylpropanoyl chloride; Pivaloyl chloride | 3282-30-2 | C5H9ClO | 详情 | 详情 |
| (III) | 40412 | N-(4-methoxyphenyl)-2,2-dimethylpropanamide | C12H17NO2 | 详情 | 详情 | |
| (IV) | 14588 | Ethyl 2,2,2-trifluoroacetate; Trifluoroethyl acetate | 383-63-1 | C4H5F3O2 | 详情 | 详情 |
| (V) | 40413 | N-[4-methoxy-2-(2,2,2-trifluoroacetyl)phenyl]-2,2-dimethylpropanamide | C14H16F3NO3 | 详情 | 详情 | |
| (VI) | 40414 | 1-(2-amino-5-methoxyphenyl)-2,2,2-trifluoro-1-ethanone | C9H8F3NO2 | 详情 | 详情 | |
| (VII) | 16575 | 1-ethynylcyclopropane; cyclopropyl acetylene | 6746-94-7 | C5H6 | 详情 | 详情 |
| (VIII) | 40415 | 2-(2-amino-5-methoxyphenyl)-4-cyclopropyl-1,1,1-trifluoro-3-butyn-2-ol | C14H14F3NO2 | 详情 | 详情 |
合成路线24
该中间体在本合成路线中的序号：(XVII)Resolution of the racemic acid (X) was carried out via activation as the mixed anhydride (XVIII) upon treatment with pivaloyl chloride (XVII) and triethylamine. Anhydride (XVIII) was then condensed with (S)-2-phenylglycinol (XIX), producing a separable mixture of diastereomeric amides. Isolation of the desired (S,S)-isomer (XX) by silica gel chromatography, followed by amide hydrolysis under acidic conditions, furnished the target (S)-enantiomer.
| 【2】 Kalchar, S.; Lohray, V.B.; Lohray, B.B.; Chakrabarti, R.; Bajji, A.C.; Ramanujam, R. (Dr. Reddy's Research Foundation); Novel tricyclic cpds. and their use in medicine; process for their preparation and pharmaceutical compsns. containing them. EP 1049684; JP 2001519422; WO 9919313 . |
| 【3】 Rajagopalan, R.; Ashok, C.B.; Shivaramayya, K.; Gurram, R.M.; Lohray, B.B.; Paraselli, B.R.; Rajan, C.; Lohray, V.B. (Dr. Reddy's Research Foundation); Novel tricyclic cpds. and their use in medicine; process for their preparation and pharmaceutical compsn. containing them. EP 1155006; WO 0050414 . |
| 【1】 Lohray, B.B.; et al.; (-)-3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid[(-)DRF 2725]: A dual PPAR agonist with potent antihyperglycemic and lipid modulating activity. J Med Chem 2001, 44, 16, 2675. |
| 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) | 51681 | 2-ethoxy-3-[4-[2-(10H-phenoxazin-10-yl)ethoxy]phenyl]propionic acid | C25H25NO5 | 详情 | 详情 | |
| (XVII) | 13597 | 2,2-Dimethylpropanoyl chloride; Pivaloyl chloride | 3282-30-2 | C5H9ClO | 详情 | 详情 |
| (XVIII) | 51691 | 1,1-dimethylpropionic 1-ethoxy-2-[4-[2-(10H-phenoxazin-10-yl)ethoxy]phenyl]propionic anhydride | C30H33NO6 | 详情 | 详情 | |
| (XIX) | 10973 | (2S)-2-Amino-2-phenyl-1-ethanol; (S)-2-Hydroxy-1-phenylethylamine; (S)-(+)-2-Phenylglycinol; (S)-2-Amino-2-phenyl-1-ethanol | 20989-17-7 | C8H11NO | 详情 | 详情 |
| (XX) | 51692 | (2S)-2-ethoxy-N-[(1S)-2-hydroxy-1-phenylethyl]-3-[4-[2-(10H-phenoxazin-10-yl)ethoxy]phenyl]propanamide | C33H34N2O5 | 详情 | 详情 |
合成路线25
该中间体在本合成路线中的序号：(II)Esterification of (1S,5R)-myrtenol (I) with pivalyl chloride (II) yields ester (III), which is then oxidized with Na2CrO4 in HOAc-Ac2O to give 4-oxo-myrtenyl pivalate (IV). Reduction of (IV) with lithium tri-t-butoxyaluminohydride in THF affords 4-hydroxymyrtenyl pivalate (V), which is then condensed with 5-(1,1-dimethylheptyl)resorcinol (VI) in the presence of p-TsOH in CH2Cl2 to furnish compound (VII). Treatment of (VII) with K2CO3 in MeOH provides methyl ether derivative (VIII), which is finally reduced with LiAlH4.
| 【1】 Mechoulam, R.; et al.; Synthesis of the individual, pharmacologically distinct, enantiomers of a tetrahydrocannabinol derivative. Tetrahedron Asymmetry 1990, 1, 5, 315. |
| 【2】 Goldenberg, D.; Horowitz, M.; Hanus, L.; Breuer, A.; Ross, R.A.; Pertwee, R.G.; Mechoulam, R.; Shiloah, S.; Tchilibon, S.; Fride, E.; HU - 308: A specific agonist for CB2, a peripheral cannabinoid receptor. Proc Natl Acad Sci USA 1999, 96(25): 14228 1999, 96, 25, 14228. |
| 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) | 44155 | (6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)methanol | 515-00-4 | C10H16O | 详情 | 详情 |
| (II) | 13597 | 2,2-Dimethylpropanoyl chloride; Pivaloyl chloride | 3282-30-2 | C5H9ClO | 详情 | 详情 |
| (III) | 44156 | (6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)methyl pivalate | C15H24O2 | 详情 | 详情 | |
| (IV) | 44157 | (6,6-dimethyl-4-oxobicyclo[3.1.1]hept-2-en-2-yl)methyl pivalate | C15H22O3 | 详情 | 详情 | |
| (V) | 44158 | [(4R)-4-hydroxy-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl]methyl pivalate | C15H24O3 | 详情 | 详情 | |
| (VI) | 20233 | 5-(1,1-dimethylheptyl)-1,3-benzenediol | C15H24O2 | 详情 | 详情 | |
| (VII) | 44159 | [(4R)-4-[4-(1,1-dimethylheptyl)-2,6-dihydroxyphenyl]-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl]methyl pivalate | C30H46O4 | 详情 | 详情 | |
| (VIII) | 44160 | [(4R)-4-[4-(1,1-dimethylheptyl)-2,6-dimethoxyphenyl]-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl]methyl pivalate | C32H50O4 | 详情 | 详情 |
合成路线26
该中间体在本合成路线中的序号：(XVI)The A ring fragment (XXV) was synthesized as follows. Ring opening of epoxide (XIII) with 1,3-propanediol (XIV) in the presence of potassium tert-butoxide afforded the hydroxy ether (XV). The primary alcohol group of (XV) was then esterified with pivaloyl chloride (XVI) in the presence of pyridine to give (XVII). After hydrogenolysis of the benzyl ethers of (XVII), the 1,2-diol moiety was protected as the corresponding acetonide (XVIII) by means of 2,2-dimethoxypropane. Swern oxidation of the free alcohol group of (XVIII) generated aldehyde (XIX), and subsequent addition of vinylmagnesium bromide to (XIX) provided the allylic alcohol (XX) as a diastereomeric mixture. After protection of the hydroxyl group of (XX) as the pivalate ester, acid hydrolysis of the acetonide furnished diol (XXI). This was then converted to epoxide (XXII) under Mitsunobu conditions. Addition of lithium trimethylsilylacetylide (XXIII) to the epoxide (XXII) and then hydrolysis of the pivalate esters yielded (XXIV). This compound was protected as the tris(tert-butyldimethylsilyl) ether, and the diastereomeric mixture was separated by flash chromatography to provide intermediate (XXV).
| 【1】 Hatakeyama, S.; et al.; Synthesis and biological characterization of 1alpha,24,25-trihydroxy-2beta-(3-hydroxypropoxy)vitamin D3 (24-hydroxylated ED-71). Steroids 2001, 66, 3-5, 267. |
| 【2】 Watanabe, H.; Hatakeyama, S.; Kawase, A. (Chugai Pharmaceutical Co. Ltd.); 24-Hydroxyvitamin D derivs.. EP 1061070; WO 9943645 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIII) | 46307 | benzyl [(2R,3S)-3-[(benzyloxy)methyl]oxiranyl]methyl ether; (2R,3S)-2,3-bis[(benzyloxy)methyl]oxirane | C18H20O3 | 详情 | 详情 | |
| (XIV) | 14685 | 1,3-propanediol; Trimethylene Glycol | 504-63-2 | C3H8O2 | 详情 | 详情 |
| (XV) | 46308 | (2R,3S)-1,4-bis(benzyloxy)-3-(3-hydroxypropoxy)-2-butanol | C21H28O5 | 详情 | 详情 | |
| (XVI) | 13597 | 2,2-Dimethylpropanoyl chloride; Pivaloyl chloride | 3282-30-2 | C5H9ClO | 详情 | 详情 |
| (XVII) | 46309 | 3-([(1S,2R)-3-(benzyloxy)-1-[(benzyloxy)methyl]-2-hydroxypropyl]oxy)propyl pivalate | C26H36O6 | 详情 | 详情 | |
| (XVIII) | 46310 | 3-([(1S)-1-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-hydroxyethyl]oxy)propyl pivalate | C15H28O6 | 详情 | 详情 | |
| (XIX) | 46311 | 3-([(1R)-1-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-oxoethyl]oxy)propyl pivalate | C15H26O6 | 详情 | 详情 | |
| (XX) | 46312 | 3-([(1S)-1-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-hydroxy-3-butenyl]oxy)propyl pivalate | C17H30O6 | 详情 | 详情 | |
| (XXI) | 46313 | 3-([(1R)-1-[(1R)-1,2-dihydroxyethyl]-2-[(2,2-dimethylpropanoyl)oxy]-3-butenyl]oxy)propyl pivalate | C19H34O7 | 详情 | 详情 | |
| (XXII) | 46314 | 3-([(1R)-2-[(2,2-dimethylpropanoyl)oxy]-1-[(2R)oxiranyl]-3-butenyl]oxy)propyl pivalate | C19H32O6 | 详情 | 详情 | |
| (XXIII) | 16299 | Lithium (trimethylsilyl)acetylide; [2-(Trimethylsilyl)ethynyl]lithium | 54655-07-1 | C5H9LiSi | 详情 | 详情 |
| (XXIV) | 46315 | (4R,5R)-4-(3-hydroxypropoxy)-1-octen-7-yne-3,5-diol | C11H18O4 | 详情 | 详情 | |
| (XXV) | 46316 | (5R,6R)-6-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]-3-butynyl)-2,2,3,3,12,12,13,13-octamethyl-5-vinyl-4,7,11-trioxa-3,12-disilatetradecane; tert-butyl(dimethyl)silyl 3-[[(1R,2R)-2-[[tert-butyl(dimethyl)silyl]oxy]-1-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]-2-propenyl)-4-pentynyl]oxy]propyl ether | C29H60O4Si3 | 详情 | 详情 |
合成路线27
该中间体在本合成路线中的序号：(IX)Indole derivative (I) is converted into acetyl indoline (II) by first reduction with NaBH3CN in HOAc followed by acetylation with Ac2O in benzene or in CHCl3. Bromination of (II) with Br2 in HOAc yields derivative (III), which is then nitrated with fuming nitric acid in H2SO4/HOAc or with HNO3/Ac2O to afford nitroindoline (IV). Removal of the acetyl group of (IV) by means of NaOH or HCl in MeOH, followed by alkylation of the resulting indoline with NaH and octyl iodide (V) or octyl bromide (VI) in DMF, provides derivative (VII). Hydrogenation of (VII) over Pd/C in MeOH or benzene yields aminoindoline derivative (VIII), which is finally condensed with pivaloyl chloride (IX) in CHCl3 in the presence of Et3N to furnish the desired compound. Alternatively, conversion of (IV) into the target compound can be achieved as follows: Hydrogenation of the nitro moiety of (IV) over Pd/C in MeOH gives acetyl aminoindoline derivative (X), which is then coupled to pivaloyl chloride (IX) in CHCl3 in the presence of Et3N to afford derivative (XI). Finally, (XI) is hydrolyzed with NaOH in MeOH and the resulting secondary amide is condensed with octyl bromide (VI) in DMF in the presence of K2CO3.
| 【1】 Matsui, H.; Kamiya, S.; Shirahase, H.; Nakamura, S.; Wada, K. (Kyoto Pharmaceutical Industries, Ltd.); Novel heterocyclic derivs., process for producing the same, and medicinal use thereof. EP 0782986; JP 1996092210; US 5990150; WO 9609287 . |
| 【2】 Yoshimi, A.; Kasai, M.; Shirahase, H.; Matsui, H.; Kanda, M.; Kurahashi, K.; Kamiya, S.; Takahashi, K.; Nakamura, S.; Bioavailable acyl-CoA: Cholesterol acyltransferase inhibitor with anti-peroxidative activity: Synthesis and biological activity of novel indolinyl amide and urea derivatives. Chem Pharm Bull 2000, 48, 6, 817. |
| 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) | 40796 | 4,6-dimethylindoline | C10H13N | 详情 | 详情 | |
| (II) | 40797 | 1-(4,6-dimethyl-2,3-dihydro-1H-indol-1-yl)-1-ethanone | C12H15NO | 详情 | 详情 | |
| (III) | 40798 | 1-(5-bromo-4,6-dimethyl-2,3-dihydro-1H-indol-1-yl)-1-ethanone | C12H14BrNO | 详情 | 详情 | |
| (IV) | 40799 | 1-(5-bromo-4,6-dimethyl-7-nitro-2,3-dihydro-1H-indol-1-yl)-1-ethanone | C12H13BrN2O3 | 详情 | 详情 | |
| (V) | 45901 | 1-heptyl-1lambda(3)-diiodane | C7H16I2 | 详情 | 详情 | |
| (VI) | 45902 | bromo(heptyl)-lambda(3)-iodane | C7H16BrI | 详情 | 详情 | |
| (VII) | 45903 | 5-bromo-4,6-dimethyl-7-nitro-1-octylindoline | C18H27BrN2O2 | 详情 | 详情 | |
| (VIII) | 45904 | 5-bromo-4,6-dimethyl-1-octyl-7-indolinamine; 5-bromo-4,6-dimethyl-1-octyl-2,3-dihydro-1H-indol-7-ylamine | C18H29BrN2 | 详情 | 详情 | |
| (IX) | 13597 | 2,2-Dimethylpropanoyl chloride; Pivaloyl chloride | 3282-30-2 | C5H9ClO | 详情 | 详情 |
| (X) | 45905 | 1-(7-amino-5-bromo-4,6-dimethyl-2,3-dihydro-1H-indol-1-yl)-1-ethanone | C12H15BrN2O | 详情 | 详情 | |
| (XI) | 45906 | N-(1-acetyl-5-bromo-4,6-dimethyl-2,3-dihydro-1H-indol-7-yl)-2,2-dimethylpropanamide | C17H23BrN2O2 | 详情 | 详情 |
合成路线28
该中间体在本合成路线中的序号：(XI)N-Protection of L-Dopa (I) by means of Boc2O and Et3N in H2O-dioxane yields Boc derivative (II), which is then benzylated by reaction with benzyl bromide (III) and K2CO3 in refluxing acetone to provide (IV). Benzyl ester moiety of (IV) is saponified by treatment with NaOH in H2O-dioxane to give carboxylic acid (V), and deprotection of the amino group by means of TFA in CH2Cl2 furnishes trifluoroacetate salt (VI). Acylation of the amine group of (VI) with chloroacetyl chloride (VII) in NaOH yields N-chloroacetyl derivative (VIII), which is cyclized by heating in DMF in the presence of Et3N to afford morpholinedione (IX). Hydrogenation of (IX) over Pd/C in HCl/EtOH provides debenzylated derivative (X), which is finally converted into the desired compound by selective acylation with pivaloyl chloride (XI) in TFA.
| 【1】 Gingolani, G.M.; et al.; Synthesis of L-(+)-3-(3-hydroxy-4-pivaloyloxybenzyl)-2,5-diketomorpholine as potential prodrug of L-Dopa. Bioorg Med Chem Lett 2000, 10, 12, 1385. |
| 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) | 15272 | (2S)-2-amino-3-(3,4-dihydroxyphenyl)propionic acid; 3-hydroxy-L-tyrosine; Levodopa | 59-92-7 | C9H11NO4 | 详情 | 详情 |
| (II) | 15273 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-(3,4-dihydroxyphenyl)propionic acid | C14H19NO6 | 详情 | 详情 | |
| (III) | 12912 | 1-(Bromomethyl)benzene; Alpha-bromotoluene | 100-39-0 | C7H7Br | 详情 | 详情 |
| (IV) | 46700 | phenyl (3S)-4-[3,4-bis(benzyloxy)phenyl]-3-[(tert-butoxycarbonyl)amino]butanoate | C35H37NO6 | 详情 | 详情 | |
| (V) | 46701 | (2S)-3-[3,4-bis(benzyloxy)phenyl]-2-[(tert-butoxycarbonyl)amino]propionic acid | C28H31NO6 | 详情 | 详情 | |
| (VI) | 46702 | (2S)-2-amino-3-[3,4-bis(benzyloxy)phenyl]propionic acid | C23H23NO4 | 详情 | 详情 | |
| (VII) | 11296 | 2-Chloroacetyl chloride; Chloroacetic chloride | 79-04-9 | C2H2Cl2O | 详情 | 详情 |
| (VIII) | 46703 | (2S)-3-[3,4-bis(benzyloxy)phenyl]-2-[(2-chloroacetyl)amino]propionic acid | C25H24ClNO5 | 详情 | 详情 | |
| (IX) | 46704 | (3S)-3-[3,4-bis(benzyloxy)benzyl]-2,5-morpholinedione | C25H23NO5 | 详情 | 详情 | |
| (X) | 46705 | (3S)-3-(3,4-dihydroxybenzyl)-2,5-morpholinedione | C11H11NO5 | 详情 | 详情 | |
| (XI) | 13597 | 2,2-Dimethylpropanoyl chloride; Pivaloyl chloride | 3282-30-2 | C5H9ClO | 详情 | 详情 |
合成路线29
该中间体在本合成路线中的序号：(XII)An alternative procedure for the resolution of (VIII) consisted in the O-acylation of oxime group with pivaloyl chloride (XII) to give (XIII), which was resolved into enantiomers by means of chiral HPLC. Hydrazinolysis of the desired (R)-enantiomer provided (XI).
| 【1】 Carruthers, N.I.; Alaimo, C.A.; Shih, N.-Y.; Lavey, B.J.; Ting, P.C.; Reichard, G.A. (Schering Corp.); Substd. oximes as neurokinin antagonists. EP 1032561; WO 9926924 . |
| 【2】 Carruthers, N.I.; Reichard, G.A.; Shih, N.-Y.; Lavey, B.J.; Alaimo, C.A.; Ting, P.C. (Schering Corp.); Substd. oximes as neurokinin antagonists. US 6063926 . |
| 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) | 44271 | 3,5-dichloro-N-[3-(3,4-dichlorophenyl)-2-(hydroxyimino)-6-methyl-5-heptenyl]-N-methylbenzamide | C22H22Cl4N2O2 | 详情 | 详情 | |
| (XI) | 44273 | 3,5-dichloro-N-[(3R)-3-(3,4-dichlorophenyl)-2-(hydroxyimino)-6-methyl-5-heptenyl]-N-methylbenzamide | C22H22Cl4N2O2 | 详情 | 详情 | |
| (XII) | 13597 | 2,2-Dimethylpropanoyl chloride; Pivaloyl chloride | 3282-30-2 | C5H9ClO | 详情 | 详情 |
| (XIII) | 44274 | 3,5-dichloro-N-(3-(3,4-dichlorophenyl)-2-[[(2,2-dimethylpropanoyl)oxy]imino]-6-methyl-5-heptenyl)-N-methylbenzamide | C27H30Cl4N2O3 | 详情 | 详情 |
合成路线30
该中间体在本合成路线中的序号：(XIV)Alternatively, compound (R)-(IX) can be obtained as follows: treatment of butylmalonic acid (XI) with formaldehyde (XII) in ethanol in the presence of piperidine provides 2-butyl acrylic acid (XIII), which is converted into oxazolidinone derivative (XVI) by first reaction with pivaloyl chloride (XIV) and Et3N in THF followed by treatment with derivative (XV) and BuLi in THF. Oxazolidinone (XVI) is then enantioselectively condensed with O-benzylhydroxylamine (XVII) and treated with p-TsOH to afford a single diastereoisomer (XVIII), which is then hydrolyzed with LiOH in THF to yield (XIX). Finally, hexanoic acid (XIX) is coupled to tert-Leucine-N,N-dimethylamide (VII) by means of EDC and HOBt in DMF.
| 【1】 Spavold, Z.M.; Launchbury, S.; Clements, J.M.; Hunter, M.G.; Davies, S.J.; Pratt, L.M.; Beckett, R.P.; Whittaker, M. (British Biotech Pharmaceuticals Ltd.); Antibacterial agents. WO 9939704 . |
| 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) | 45886 | (2S)-2-amino-N,N,3,3-tetramethylbutanamide | C8H18N2O | 详情 | 详情 | |
| (IX) | 45888 | (2R)-2-[[(benzyloxy)amino]methyl]-N-[(1S)-1-[(dimethylamino)carbonyl]-2,2-dimethylpropyl]hexanamide | C22H37N3O3 | 详情 | 详情 | |
| (XI) | 45891 | 2-butylmalonic acid | 534-59-8 | C7H12O4 | 详情 | 详情 |
| (XII) | 22075 | Formaldehyde; Paraformaldehyde | 1118-66-7 | CH2O | 详情 | 详情 |
| (XIII) | 45892 | 2-[(ethylsulfanyl)methyl]acrylic acid | C6H10O2S | 详情 | 详情 | |
| (XIV) | 13597 | 2,2-Dimethylpropanoyl chloride; Pivaloyl chloride | 3282-30-2 | C5H9ClO | 详情 | 详情 |
| (XV) | 45893 | (4S)-4-benzyl-5,5-dimethyl-1,3-oxazolidin-2-one | C12H15NO2 | 详情 | 详情 | |
| (XVI) | 45894 | (4S)-4-benzyl-3-[2-[(ethylsulfanyl)methyl]acryloyl]-5,5-dimethyl-1,3-oxazolidin-2-one | C18H23NO3S | 详情 | 详情 | |
| (XVII) | 14640 | O-benzylhydroxylamine; 1-[(aminooxy)methyl]benzene | 622-33-3 | C7H9NO | 详情 | 详情 |
| (XVIII) | 45895 | (4S)-4-benzyl-3-[(2R)-3-[(benzyloxy)amino]-2-[(ethylsulfanyl)methyl]propanoyl]-5,5-dimethyl-1,3-oxazolidin-2-one | C25H32N2O4S | 详情 | 详情 | |
| (XIX) | 45897 | 3-[4-[2-(benzyloxy)ethoxy]phenyl]-2-ethoxypropanamide | C20H25NO4 | 详情 | 详情 |
合成路线31
该中间体在本合成路线中的序号：(II)The title compound is synthesized starting from the natural isoflavone formononetin (I). Esterification of (I) with pivaloyl chloride (II) affords pivalate (III). Catalytic hydrogenation of (III) in the presence of Pd/BaSO4 leads to the chromane derivative (IV). The Grignard reagent (VI), prepared from 4-(benzyloxy)benzyl chloride (V), is then condensed with ketone (IV) to furnish the tertiary alcohol (VII). The O-benzyl protecting group of (VII) is then removed by catalytic hydrogenolysis to afford phenol (VIII). Alkylation of (VIII) with N-(2-chloroethyl)piperidine (IX) and K2CO3, with simultaneous pivalate ester hydrolysis, leads to the piperidylethyl ether (X). The tertiary alcohol of (X) is finally dehydrated by means of HCl in acetonitrile to provide the target compound (1,2).
| 【1】 Ghirardi, S.; Armani, E.; Amari, G.; Delcanale, M.; Civelli, M.; Caruso, P.; Galbiati, E.; Synthesis and pharmacological activity of CHF 4227, one of the most potent in vitro and in vivo SERMs till new discovered. Drugs Fut 2002, 27, Suppl. A. |
| 【2】 Delcanale, M.; Civelli, M.; Armani, E.; Amari, G.; Galbiati, E. (Chiesi Farmaceutici SpA); 2H-1-Benzopyran derivs., processes for their preparation and pharmaceutical compsns. thereof. EP 1229036; EP 1281710; EP 1355906; WO 0259113 . |
| 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) | 65118 | 7-hydroxy-3-(4-methoxyphenyl)-4H-chromen-4-one | C16H12O4 | 详情 | 详情 | |
| (II) | 13597 | 2,2-Dimethylpropanoyl chloride; Pivaloyl chloride | 3282-30-2 | C5H9ClO | 详情 | 详情 |
| (III) | 65119 | 3-(4-methoxyphenyl)-4-oxo-4H-chromen-7-yl pivalate | C21H20O5 | 详情 | 详情 | |
| (IV) | 65120 | 3-(4-methoxyphenyl)-4-oxo-3,4-dihydro-2H-chromen-7-yl pivalate | C21H22O5 | 详情 | 详情 | |
| (V) | 65125 | 1-(benzyloxy)-4-(chloromethyl)benzene; benzyl 4-(chloromethyl)phenyl ether | C14H13ClO | 详情 | 详情 | |
| (VI) | 65124 | [4-(benzyloxy)benzyl](chloro)magnesium | C14H13ClMgO | 详情 | 详情 | |
| (VII) | 65121 | 4-[4-(benzyloxy)benzyl]-4-hydroxy-3-(4-methoxyphenyl)-3,4-dihydro-2H-chromen-7-yl pivalate | C35H36O6 | 详情 | 详情 | |
| (VIII) | 65122 | 4-hydroxy-4-(4-hydroxybenzyl)-3-(4-methoxyphenyl)-3,4-dihydro-2H-chromen-7-yl pivalate | C28H30O6 | 详情 | 详情 | |
| (IX) | 10117 | 1-(2-Chloroethyl)piperidine; N-(2-Chloroethyl)piperidine | 1932-03-2 | C7H14ClN | 详情 | 详情 |
| (X) | 65123 | 3-(4-methoxyphenyl)-4-{4-[2-(1-piperidinyl)ethoxy]benzyl}-4,7-chromanediol | C30H35NO5 | 详情 | 详情 |
合成路线32
该中间体在本合成路线中的序号：(V)Azetidinone acetate (I) was treated with sodium methanethiolate to produce thioether (II). Lactam (II) N-alkylation with p-nitrobenzyl iodoacetate (III) furnished the azetidineacetate (IV). The lithium enolate of ester (IV) was subsequently acylated with pivaloyl chloride (V) at low temperature to afford keto ester (VI). The silyl protecting group of (VI) was then removed by treatment with tetrabutylammonium fluoride, yielding alcohol (VII). Chlorination of (VII) with concomitant oxidative cleavage of the methylthio group at -78 C gave rise to the chloroazetidine (VIII). Cyclization of (VIII) to the key oxapenem bicyclic system was accomplished by treatment with triethylamine in cold THF. Chromatographic separation of the resultant mixture of cis/trans bicyclic compounds afforded the desired isomer (IX). After hydrogenolysis of the p-nitrobenzyl ester group of (IX), the resultant carboxylic acid was converted to the required potassium salt by treatment with aqueous potassium bicarbonate.
| 【1】 Pfaendler, H.R.; Weisner, F.; Synthesis and antibacterial activity of 1'R,5R,6R)-2-tert-butyl-6-(1'hydroxyethyl)oxapenem-3-carboxylic acid. Bioorg Med Chem Lett 1993, 3, 11, 2211. |
| 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) | 11687 | (2R,3R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetanyl acetate | C13H25NO4Si | 详情 | 详情 | |
| (II) | 54840 | (3S,4R)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-(methylsulfanyl)-2-azetidinone | C12H25NO2SSi | 详情 | 详情 | |
| (III) | 54841 | 4-nitrobenzyl 2-iodoacetate | C9H8INO4 | 详情 | 详情 | |
| (IV) | 54842 | 4-nitrobenzyl 2-[(2R,3S)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-2-(methylsulfanyl)-4-oxoazetidinyl]acetate | C21H32N2O6SSi | 详情 | 详情 | |
| (V) | 13597 | 2,2-Dimethylpropanoyl chloride; Pivaloyl chloride | 3282-30-2 | C5H9ClO | 详情 | 详情 |
| (VI) | 54843 | 4-nitrobenzyl 2-[(2R,3S)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-2-(methylsulfanyl)-4-oxoazetidinyl]-4,4-dimethyl-3-oxopentanoate | C26H40N2O7SSi | 详情 | 详情 | |
| (VII) | 54844 | 4-nitrobenzyl 2-[(2R,3S)-3-[(1R)-1-hydroxyethyl]-2-(methylsulfanyl)-4-oxoazetidinyl]-4,4-dimethyl-3-oxopentanoate | C20H26N2O7S | 详情 | 详情 | |
| (VIII) | 54845 | 4-nitrobenzyl 2-{(2R,3S)-2-chloro-3-[(1R)-1-hydroxyethyl]-4-oxoazetidinyl}-4,4-dimethyl-3-oxopentanoate | C19H23ClN2O7 | 详情 | 详情 | |
| (IX) | 54846 | 4-nitrobenzyl 2-{(2S,3S)-2-chloro-3-[(1R)-1-hydroxyethyl]-4-oxoazetidinyl}-4,4-dimethyl-3-oxopentanoate | C19H23ClN2O7 | 详情 | 详情 | |
| (X) | 54847 | 4-nitrobenzyl (5R,6R)-3-(tert-butyl)-6-[(1R)-1-hydroxyethyl]-7-oxo-4-oxa-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C19H22N2O7 | 详情 | 详情 |
合成路线33
该中间体在本合成路线中的序号：(II)The title compound has been prepared starting from the known azetidinone (I). The lithium enolate of ester (I) was acylated with pivaloyl chloride (II) at low temperature to afford keto ester (III). The silyl protecting group of (III) was then removed by treatment with tetrabutylammonium fluoride, yielding alcohol (IV). Inversion of the configuration of alcohol (IV) was accomplished by Mitsunobu coupling with formic acid to produce the formate ester (V), which was subsequently hydrolyzed to the desired alcohol (VI) under acidic conditions. Protection of alcohol (VI) with p-nitrobenzyl chloroformate (VII) gave carbonate (VIII). Chlorination of (VIII) with concomitant oxidative cleavage of the methylthio group at -40 C led to the chloroazetidine (IX). Cyclization of (IX) to the key oxapenem bicyclic system (X) was then performed by treatment with potassium tert-butoxide in cold t-BuOH/THF.
| 【1】 Pfaendler, H.R. (Eli Lilly and Company); (1'S)-Hydroxyalkyloxapenem-3-carboxylic acids and their use as beta-lactamase inhibitors. DE 4142423; EP 0548790 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IXa) | 54851 | 4-nitrobenzyl 2-{(2R,3S)-2-chloro-3-[(1S)-1-({[(4-nitrobenzyl)oxy]carbonyl}oxy)ethyl]-4-oxoazetidinyl}-4,4-dimethyl-3-oxopentanoate | C27H28ClN3O11 | 详情 | 详情 | |
| (IXb) | 54852 | 4-nitrobenzyl 2-{(2S,3S)-2-chloro-3-[(1S)-1-({[(4-nitrobenzyl)oxy]carbonyl}oxy)ethyl]-4-oxoazetidinyl}-4,4-dimethyl-3-oxopentanoate | C27H28ClN3O11 | 详情 | 详情 | |
| (Xa) | 54853 | 4-nitrobenzyl (5R,6R)-3-(tert-butyl)-6-[(1S)-1-({[(4-nitrobenzyl)oxy]carbonyl}oxy)ethyl]-7-oxo-4-oxa-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C27H27N3O11 | 详情 | 详情 | |
| (Xb) | 54854 | 4-nitrobenzyl (5S,6R)-3-(tert-butyl)-6-[(1S)-1-({[(4-nitrobenzyl)oxy]carbonyl}oxy)ethyl]-7-oxo-4-oxa-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C27H27N3O11 | 详情 | 详情 | |
| (I) | 54842 | 4-nitrobenzyl 2-[(2R,3S)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-2-(methylsulfanyl)-4-oxoazetidinyl]acetate | C21H32N2O6SSi | 详情 | 详情 | |
| (II) | 13597 | 2,2-Dimethylpropanoyl chloride; Pivaloyl chloride | 3282-30-2 | C5H9ClO | 详情 | 详情 |
| (III) | 54843 | 4-nitrobenzyl 2-[(2R,3S)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-2-(methylsulfanyl)-4-oxoazetidinyl]-4,4-dimethyl-3-oxopentanoate | C26H40N2O7SSi | 详情 | 详情 | |
| (IV) | 54844 | 4-nitrobenzyl 2-[(2R,3S)-3-[(1R)-1-hydroxyethyl]-2-(methylsulfanyl)-4-oxoazetidinyl]-4,4-dimethyl-3-oxopentanoate | C20H26N2O7S | 详情 | 详情 | |
| (V) | 54848 | 4-nitrobenzyl 2-[(2R,3S)-3-[(1S)-1-(formyloxy)ethyl]-2-(methylsulfanyl)-4-oxoazetidinyl]-4,4-dimethyl-3-oxopentanoate | C21H26N2O8S | 详情 | 详情 | |
| (VI) | 54849 | 4-nitrobenzyl 2-[(2R,3S)-3-[(1S)-1-hydroxyethyl]-2-(methylsulfanyl)-4-oxoazetidinyl]-4,4-dimethyl-3-oxopentanoate | C20H26N2O7S | 详情 | 详情 | |
| (VII) | 33055 | 1-[[(chlorocarbonyl)oxy]methyl]-4-nitrobenzene | 4457-32-3 | C8H6ClNO4 | 详情 | 详情 |
| (VIII) | 54850 | 4-nitrobenzyl 4,4-dimethyl-2-{(2R,3S)-2-(methylsulfanyl)-3-[(1S)-1-({[(4-nitrobenzyl)oxy]carbonyl}oxy)ethyl]-4-oxoazetidinyl}-3-oxopentanoate | C28H31N3O11S | 详情 | 详情 |
合成路线34
该中间体在本合成路线中的序号：(II)In an alternative route, intermediate (VI) was prepared from the previously reported azetidinone (XIII), possessing the adequate alcohol group configuration. Displacement of the acetoxy group of (XIII) with sodium methanethiolate gave sulfide (XIV). The azetidinone N was then alkylated with p-nitrobenzyl iodoacetate (XV) to afford azetidineacetate (XVI). Acylation of the lithium enolate of ester (XVI) by pivaloyl chloride (II) provided keto ester (XVII). Intermediate (VI) was then obtained by desilylation of (XVII) with tetrabutylammonium fluoride.
| 【1】 Pfaendler, H.R. (Eli Lilly and Company); (1'S)-Hydroxyalkyloxapenem-3-carboxylic acids and their use as beta-lactamase inhibitors. DE 4142423; EP 0548790 . |
| 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) | 13597 | 2,2-Dimethylpropanoyl chloride; Pivaloyl chloride | 3282-30-2 | C5H9ClO | 详情 | 详情 |
| (VI) | 54849 | 4-nitrobenzyl 2-[(2R,3S)-3-[(1S)-1-hydroxyethyl]-2-(methylsulfanyl)-4-oxoazetidinyl]-4,4-dimethyl-3-oxopentanoate | C20H26N2O7S | 详情 | 详情 | |
| (XIII) | 54855 | (2R,3R)-3-((1S)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-oxoazetidinyl acetate | C13H25NO4Si | 详情 | 详情 | |
| (XIV) | 54856 | (3S,4R)-3-((1S)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-(methylsulfanyl)-2-azetidinone | C12H25NO2SSi | 详情 | 详情 | |
| (XV) | 54841 | 4-nitrobenzyl 2-iodoacetate | C9H8INO4 | 详情 | 详情 | |
| (XVI) | 54857 | 4-nitrobenzyl 2-[(2R,3S)-3-((1S)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-2-(methylsulfanyl)-4-oxoazetidinyl]acetate | C21H32N2O6SSi | 详情 | 详情 | |
| (XVII) | 54858 | 4-nitrobenzyl 2-[(2R,3S)-3-((1S)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-2-(methylsulfanyl)-4-oxoazetidinyl]-4,4-dimethyl-3-oxopentanoate | C26H40N2O7SSi | 详情 | 详情 |
合成路线35
该中间体在本合成路线中的序号：(III)The amino acid building block (XI) was prepared as follows. Friedel-Crafts condensation of dimethylacrylic acid (I) with benzene in the presence of AlCl3 afforded 3-methyl-3-phenylbutanoic acid (II). After activation of acid (II) as the mixed anhydride (IV) by treatment with pivaloyl chloride (III) and Et3N, coupling with the lithium salt of (S)-4-isopropyl-2-oxazolidinone (V) furnished the chiral N-acyl oxazolidinone (VI). Diastereoselective introduction of an azido group into the lithium enolate of (VI) by means of 2,4,6-triisopropylbenzenesulfonyl azide led to the (S,S)-azido compound (VII). Catalytic hydrogenation of azide (VII) in the presence of Boc2O provided the Boc-protected amine (VIII). The chiral auxiliary of (VIII) was removed by hydrolysis with lithium hydroperoxide, and the resultant carboxylic acid was further converted to the methyl ester (IX) upon treatment with an ethereal solution of diazomethane. The N-methyl derivative (X) was then prepared by alkylation of the tert-butyl carbamate (IX) with iodomethane in the presence of NaH. Basic hydrolysis of ester (X) provided the target N-Boc amino acid (XI).
| 【1】 Roberge, M.; Andersen, R.; Piers, E.; Nieman, J.; Coleman, J. (University of British Columbia); Hemiasterlin analogs. WO 9932509 . |
| 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) | 34677 | 3-methyl-2-butenoic acid | 541-47-9 | C5H8O2 | 详情 | 详情 |
| (II) | 38637 | 3-methyl-3-phenylbutyric acid | C11H14O2 | 详情 | 详情 | |
| (III) | 13597 | 2,2-Dimethylpropanoyl chloride; Pivaloyl chloride | 3282-30-2 | C5H9ClO | 详情 | 详情 |
| (IV) | 55112 | 1,1-dimethylpropanoic 2-methyl-2-phenylbutanoic anhydride | C16H22O3 | 详情 | 详情 | |
| (V) | 12867 | (4S)-4-Isopropyl-1,3-oxazolidin-2-one; (R)-4-Isopropyl-2-oxazolidinone | 17016-83-0 | C6H11NO2 | 详情 | 详情 |
| (VI) | 55113 | (4S)-4-isopropyl-3-(3-methyl-3-phenylbutanoyl)-1,3-oxazolidin-2-one | C17H23NO3 | 详情 | 详情 | |
| (VII) | 55114 | (4S)-3-[(2S)-2-azido-3-methyl-3-phenylbutanoyl]-4-isopropyl-1,3-oxazolidin-2-one | C17H22N4O3 | 详情 | 详情 | |
| (VIII) | 55115 | tert-butyl (1S)-1-{[(4S)-4-isopropyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl}-2-methyl-2-phenylpropylcarbamate | C22H32N2O5 | 详情 | 详情 | |
| (IX) | 55116 | methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-methyl-3-phenylbutanoate | C17H25NO4 | 详情 | 详情 | |
| (X) | 55117 | methyl (2S)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-methyl-3-phenylbutanoate | C18H27NO4 | 详情 | 详情 | |
| (XI) | 55118 | (2S)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-methyl-3-phenylbutanoic acid | C17H25NO4 | 详情 | 详情 |