合成路线1
该中间体在本合成路线中的序号:
(VI) The Wittig condensation of protected bicyclic aldehyde (I) with methyl triphenyl phosphonium bromide and potassium tert-butoxide in THF gives the diene (II), which by hydroboration with disiamyl borane followed by oxidative hydrolysis with NaOH and H2O2 is converted into the alcohol (III). Oxidation of (III) with Collins' reagent followed by treatment with acetic anhydride yields the dienol acetate (IV), which is submitted to a 1,4-catalytic hydrogenation with naphthalene Cr(CO)3-H2 in THF and hydrolysis with K2CO3 to afford the allyl alcohol (V). The condensation of (V) with tert-butyl bromoacetate (VI) by means of tetrabutylammonium bisulfate, followed by partial deprotection with tetrabutylammonium fluoride gives the alcohol (VII), which is oxidized with the SO3-pyridine complex to the aldehyde (VIII). The condensation of (VIII) with 1,1-dibromo-3-methyl-5-octyn-2-one (IX) by means of Zn, diethylaluminum chloride and CuBr in THF yields the B-bromoenone (X), which is reduced stereoselectively with (S)-(-)-2,2'-dihydroxy-1,1'-binaphthyl and LiAlH4 in THF to afford the a bromodienol (XI). Finally, this compound is dehydrominated and saponified with tetrabutylammonium bisulfate and NaOH in ether toluene-water.
![](http://zy.yaozh.com/wmf/sch/11/11504701a.jpg)
【1】
Gillum, A.M.; Klem, R.E.; Klasa, R.J.; Frankel, S.R.; Oblimersen Bcl-2 antisense: facilitating apoptosis in anticancer treatment. J Org Chem 1988, 53, 6, 1227.
|
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) |
13776 |
(3aS,5R,6R,6aS)-6-([[tert-Butyl(dimethyl)silyl]oxy]methyl)-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1,3a,4,5,6,6a-hexahydro-2-pentalenecarbaldehyde
|
|
C22H38O4Si |
详情 |
详情
|
(II) |
23382 |
[(2R,3R,3aS,6aS)-3-([[tert-butyl(dimethyl)silyl]oxy]methyl)-5-vinyl-1,2,3,3a,4,6a-hexahydro-2-pentalenyl]methyl tetrahydro-2H-pyran-2-yl ether; ([(1R,2R,3aS,6aS)-2-[(tetrahydro-2H-pyran-2-yloxy)methyl]-5-vinyl-1,2,3,3a,6,6a-hexahydro-1-pentalenyl]methoxy)(tert-butyl)dimethylsilane |
|
C23H40O3Si |
详情 |
详情
|
(III) |
23383 |
2-[(3aS,5R,6R,6aS)-6-([[tert-butyl(dimethyl)silyl]oxy]methyl)-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1,3a,4,5,6,6a-hexahydro-2-pentalenyl]-1-ethanol
|
|
C23H42O4Si |
详情 |
详情
|
(IV) |
23384 |
(E)-2-[(3aS,5R,6R,6aS)-6-([[tert-butyl(dimethyl)silyl]oxy]methyl)-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1,3a,4,5,6,6a-hexahydro-2-pentalenyl]ethenyl acetate
|
|
C25H42O5Si |
详情 |
详情
|
(V) |
23385 |
2-[(3aS,4R,5R,6aR)-4-([[tert-butyl(dimethyl)silyl]oxy]methyl)-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexahydro-2(1H)-pentalenylidene]-1-ethanol
|
|
C23H42O4Si |
详情 |
详情
|
(VI) |
17430 |
2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate
|
5292-43-3 |
C6H11BrO2 |
详情 | 详情
|
(VII) |
23387 |
tert-butyl 2-[2-[(3aS,4R,5R,6aR)-4-(hydroxymethyl)-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexahydro-2(1H)-pentalenylidene]ethoxy]acetate
|
|
C23H38O6 |
详情 |
详情
|
(VIII) |
23388 |
tert-butyl 2-[2-[(3aS,4R,5R,6aR)-4-formyl-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexahydro-2(1H)-pentalenylidene]ethoxy]acetate
|
|
C23H36O6 |
详情 |
详情
|
(IX) |
23389 |
tert-butyl 2-[2-[(3aS,4R,5R,6aR)-4-[(Z,4S)-2-bromo-4-methyl-3-oxo-1-nonen-6-ynyl]-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexahydro-2(1H)-pentalenylidene]ethoxy]acetate
|
|
C32H47BrO6 |
详情 |
详情
|
(X) |
23390 |
tert-butyl 2-[2-[(3aS,4R,5R,6aR)-4-[(Z,4S)-2-bromo-4-methyl-3-oxo-1-nonen-6-ynyl]-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexahydro-2(1H)-pentalenylidene]ethoxy]acetate
|
|
C32H47BrO6 |
详情 |
详情
|
(XI) |
23391 |
tert-butyl 2-[2-[(3aS,4S,5R,6aS)-4-[(Z,3S,4S)-2-bromo-3-hydroxy-4-methyl-1-nonen-6-ynyl]-5-hydroxyhexahydro-2(1H)-pentalenylidene]ethoxy]acetate
|
|
C26H39BrO5 |
详情 |
详情
|
合成路线2
该中间体在本合成路线中的序号:
(XIII) 2) The reduction of (III) with NaBH4 followed by debenzoylation with NaOH and deprotection with acetic acid gives the dihydroxy ketone (X), which by silviation with dimethyl-tert-butylsilyl chloride in DMF is converted to the disilylated ketone (XI). A Horner Wittig reaction of ketone (XI) with phosphonate (VI), followed by reduction with LiAlH4 as before affords the pentalenylideneethanol (XII), which is etherified with ten butyl bromoacetate (XIII) in aqueous NaOH - toluene and tetrabutylammonium sulfate with simultaneous hydrolysis of the tert-butyl group yielding the silylated prostaglandin (XIV). Finally, this compound is deprotected with tetrabutylammonium fluoride in THF.
![](http://zy.yaozh.com/wmf/sch/11/11504703a.jpg)
【1】
Skuballa, W.; et al.; Synthesis of a new chemically and metabolically stable prostacyclin analogue with high and long-lasting oral activity. J Med Chem 1986, 29, 3, 313.
|
【2】
Castaner, J.; Prous, J.; Cicaprost. Drugs Fut 1986, 11, 11, 913.
|
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) |
24200 |
Benzoic acid (1'R,2'R,3'aR,6'aS)-1'-formylspiro[1,3-dioxolane-2,5'-perhydropentalen]-2'-yl ester
|
|
C18H20O5 |
详情 |
详情
|
(II) |
24201 |
dimethyl 3-methyl-2-oxo-5-octynylphosphonate
|
|
C11H19O4P |
详情 |
详情
|
(III) |
24202 |
Benzoic acid (2'R,3'aR,6'aS)-1'-(2-Bromo-4(S)-methyl-3-oxonon-1(E)-en-6-yn-1-yl)-spiro[1,3-dioxolane-2,5'-perhydropentalen]-2'-yl ester
|
|
C27H31BrO5 |
详情 |
详情
|
(VI) |
10019 |
Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate
|
867-13-0 |
C8H17O5P |
详情 | 详情
|
(X) |
24212 |
(3aS,5R,6aR)-5-hydroxy-4-[(3S,4S)-3-hydroxy-4-methyl-1,6-nonadiynyl]hexahydro-2(1H)-pentalenone
|
|
C18H24O3 |
详情 |
详情
|
(XI) |
24213 |
(3aS,5R,6aR)-5-[[tert-butyl(dimethyl)silyl]oxy]-4-((3S,4S)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-1,6-nonadiynyl)hexahydro-2(1H)-pentalenone
|
|
C30H52O3Si2 |
详情 |
详情
|
(XII) |
24215 |
2-[(3aS,5R,6aS)-5-[[tert-butyl(dimethyl)silyl]oxy]-4-((3S,4S)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-1,6-nonadiynyl)hexahydro-2(1H)-pentalenylidene]-1-ethanol
|
|
C32H56O3Si2 |
详情 |
详情
|
(XIII) |
17430 |
2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate
|
5292-43-3 |
C6H11BrO2 |
详情 | 详情
|
(XIV) |
24216 |
2-[2-[(3aS,5R,6aS)-5-[[tert-butyl(dimethyl)silyl]oxy]-4-((3S,4S)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-1,6-nonadiynyl)hexahydro-2(1H)-pentalenylidene]ethoxy]acetic acid
|
|
C34H58O5Si2 |
详情 |
详情
|
合成路线3
该中间体在本合成路线中的序号:
(II) 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.
![](http://zy.yaozh.com/wmf/sch/11/11646601a.jpg)
【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4
该中间体在本合成路线中的序号:
(VII) Alkylation of the sodium salt of diclofenac (I) with benzyl bromoacetate (II) in hot DMF yielded the (arylacetoxy)acetate (III). Subsequent hydrogenolysis of the benzyl ester of (III) in the presence of Pd/C gave the title carboxylic acid. Alternatively, the benzyl ester group of (III) was cleaved by means of the combination of chlorotrimethylsilane and sodium iodide. This method of selective ester hydrolysis with in situ generated iodotrimethylsilane was also applied to the corresponding methyl (IV) and tert-butyl (V) esters. In a related procedure, tert-butyl ester (V) was prepared by alkylation of diclofenac (VI) with tert-butyl bromoacetate (VII) in the presence of tertiary amines. Selective cleavage of the tert-butyl ester group of (V) was then performed by treatment with either trifluoroacetic or formic acid.
![](http://zy.yaozh.com/wmf/sch/11/11730101a.jpg)
【1】
Casas, A.V. (Almirall Prodesfarma, SA); 2-[(2,6-Dichlorophenyl)amino]phenylacetoxyacetyl derivs. and therapeutic compsns. containing same. EP 0119932; US 4548952 .
|
【2】
Ginebreda Martí, A.; Agustí Cruz, A. (Almirall Prodesfarma, SA); Process for obtaining 2-[(2,6-dichlorophenyl)amino]phenylacetoxyacetic acid. ES 2020146 . |
【3】
Schickaneder, H.; Nikolopoulos, A.; Murphy, T.; Process for the preparation of aceclofenac. WO 9955660 .
|
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) |
56535 |
sodium 2-[2-(2,6-dichloroanilino)phenyl]acetate
|
|
C14H10Cl2NNaO2 |
详情 |
详情
|
(II) |
12869 |
benzyl 2-bromoacetate
|
5437-45-6 |
C9H9BrO2 |
详情 | 详情
|
(III) |
56536 |
2-(benzyloxy)-2-oxoethyl 2-[2-(2,6-dichloroanilino)phenyl]acetate
|
|
C23H19Cl2NO4 |
详情 |
详情
|
(IV) |
56537 |
2-methoxy-2-oxoethyl 2-[2-(2,6-dichloroanilino)phenyl]acetate
|
|
C17H15Cl2NO4 |
详情 |
详情
|
(V) |
56538 |
2-(tert-butoxy)-2-oxoethyl 2-[2-(2,6-dichloroanilino)phenyl]acetate
|
|
C20H21Cl2NO4 |
详情 |
详情
|
(VI) |
33701 |
Diclofenac; 2-[2-(2,6-Dichloroanilino)phenyl]acetic acid
|
|
C14H11Cl2NO2 |
详情 |
详情
|
(VII) |
17430 |
2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate
|
5292-43-3 |
C6H11BrO2 |
详情 | 详情
|
合成路线5
该中间体在本合成路线中的序号:
(IX) 1) The reduction of 2-thiophenecarboxaldehyde cyanohydrin (I) with LiAlH4 gives 2-amino-1-(2-thienyl)ethanol (II), which is N-protected with di-tert-butyl pyrocarbonate yielding 2-(tert-butoxycarbonylamino)-1-(2-thienyl)ethanol (III). The reaction of (III) with PCl5 in dichloromethane affords 2-(tert-butoxycarbonylamino)-1-chloro-1-(2-thienyl)ethane (IV), which is condensed with benzhydryl N-phthaloylcysteinate (V) by means of Na2CO3 in hot DMF giving the S-substituted cysteinate (VI). The deprotection of (VI) with trifluoroacetic acid in anisole yields S-[2-amino-1-(2-thienyl)ethyl]-N-phthaloylcysteine (VII), which is cyclized by means of diphenylphosphoryl azide (DPA) in DMF giving 6-phthalimido-2-(2-thienyl)perhydro-1,4-thiazepin-5-one (VIII). The condensation of (VIII) with tert-butyl bromoacetate (IX) by means of NaH in DMF affords tert-butyl 2-[6-phthalimido-5-oxo-2-(2-thienyl)perhydro-1,4-thiazepin-4-yl]acetate (X), which is treated with methylhydrazine in methanol-dichloromethane yielding the 6-amino derivative (XI). The condensation of (XI) with ethyl 2-bromo-4-phenylbutyrate (XII) by means of Na2CO3 in hot DMF gives the tert-butyl ester of the desired product (XIII), which is finally deprotected with trifluoroacetic acid in anisole.
![](http://zy.yaozh.com/wmf/sch/13/13094501a.jpg)
【1】
Yanagisawa, H.; Ishihara, S.; Ando, A.; Kanazaki, T.; Koike, H.; Tsujita, Y. (Sankyo Co., Ltd.); Perhydrothiazepine derivatives, their preparation and their therapeutical use. AU 8541058; EP 0161801; ES 8702388; ES 8801229; JP 85215678; JP 86267579 . |
【2】
Prous, J.; Castaner, J.; RS-5142. Drugs Fut 1989, 14, 4, 336.
|
【3】
Ishihara, S.; Ando, A.; Miyamoto, S.; Kanazaki, T.; Hata, T.; Oizumi, K.; Matsushita, Y.; Koike, H.; Yanagisawa, H.; Iijima, Y.; Angiotensin-converting enzyme inhibitors: Perhydro-1,4-thiazepin-5-one derivatives. J Med Chem 1987, 30, 11, 1984.
|
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) |
20799 |
2-hydroxy-2-(2-thienyl)acetonitrile
|
|
C6H5NOS |
详情 |
详情
|
(II) |
20800 |
2-amino-1-(2-thienyl)-1-ethanol
|
|
C6H9NOS |
详情 |
详情
|
(III) |
20801 |
tert-butyl 2-hydroxy-2-(2-thienyl)ethylcarbamate
|
|
C11H17NO3S |
详情 |
详情
|
(IV) |
20802 |
tert-butyl 2-chloro-2-(2-thienyl)ethylcarbamate
|
|
C11H16ClNO2S |
详情 |
详情
|
(V) |
20803 |
benzhydryl 2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-sulfanylpropanoate
|
|
C24H19NO4S |
详情 |
详情
|
(VI) |
20804 |
benzhydryl 3-[[2-[(tert-butoxycarbonyl)amino]-1-(2-thienyl)ethyl]sulfanyl]-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propanoate
|
|
C35H34N2O6S2 |
详情 |
详情
|
(VII) |
20805 |
3-[[2-amino-1-(2-thienyl)ethyl]sulfanyl]-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propionic acid
|
|
C17H16N2O4S2 |
详情 |
详情
|
(VIII) |
20806 |
2-[5-oxo-2-(2-thienyl)-1,4-thiazepan-6-yl]-1H-isoindole-1,3(2H)-dione
|
|
C17H14N2O3S2 |
详情 |
详情
|
(IX) |
17430 |
2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate
|
5292-43-3 |
C6H11BrO2 |
详情 | 详情
|
(X) |
20808 |
tert-butyl 2-[6-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-5-oxo-2-(2-thienyl)-1,4-thiazepan-4-yl]acetate
|
|
C23H24N2O5S2 |
详情 |
详情
|
(XI) |
20809 |
tert-butyl 2-[6-amino-5-oxo-2-(2-thienyl)-1,4-thiazepan-4-yl]acetate
|
112968-38-4 |
C15H22N2O3S2 |
详情 | 详情
|
(XII) |
20810 |
ethyl 2-bromo-4-phenylbutanoate
|
|
C12H15BrO2 |
详情 |
详情
|
(XIII) |
20811 |
ethyl 2-[[4-[2-(tert-butoxy)-2-oxoethyl]-5-oxo-2-(2-thienyl)-1,4-thiazepan-6-yl]amino]-4-phenylbutanoate
|
|
C27H36N2O5S2 |
详情 |
详情
|
合成路线6
该中间体在本合成路线中的序号:
(XXII) 2) The addition of tert-butoxycarbonyl)-L-cysteine (XIV) to 2-(2-nitroethenyl)thiophene (XV) by means of N-methylmorpholine in toluene gives S-[2-nitro-1-(2-thienyl)ethyl-N-(tert-butoxycarbonyl-L-cysteine (XVI), which is reduced with H2 over Pd/C in acetic acid yielding the corresponding amine (XVII). The cyclization of (XVII) by means of diphenyl phosphorazidate (DPN) and N-methylmorpholine in DMF affords (2RS,6R)-6-(tert-butoxycarbonylamino)-2-(2-thienyl)perhydro-1,4-thiazepine (XVIII), which by hydrolysis and fractional crystallization gives (2S,6R)-6-amino-2-(2-thienyl)perhydro-1,4-thiazepine (XIX). The condensation of (XIX) with ethyl 2(R)-(trifluoromethylsulfonyloxy)-4-phenylbutanoate (XX) by means of triethylamine in dichloromethane yields (2S,2R)-6-[1(S)-(ethoxycarbonyl)-3-phenylpropylamino]-2-(2-thienyl)- perhydro-1,4-thiazepin-5-one (XXI), which is condensed with tert-butyl bromoacetate (XXII) by means of NaH in DMF to give the precursor (XXIII). Finally, this compound is hydrolyzed with 4N-HCl-dioxane at room temperature.
![](http://zy.yaozh.com/wmf/sch/13/13094502a.jpg)
【1】
Yanagisawa, H.; Ishihara, S.; Ando, A.; Kanazaki, T.; Koike, H.; Tsujita, Y. (Sankyo Co., Ltd.); Perhydrothiazepine derivatives, their preparation and their therapeutical use. AU 8541058; EP 0161801; ES 8702388; ES 8801229; JP 85215678; JP 86267579 . |
【2】
Ishihara, S.; Ando, A.; Miyamoto, S.; Kanazaki, T.; Hata, T.; Oizumi, K.; Matsushita, Y.; Koike, H.; Yanagisawa, H.; Iijima, Y.; Angiotensin-converting enzyme inhibitors: Perhydro-1,4-thiazepin-5-one derivatives. J Med Chem 1987, 30, 11, 1984.
|
【3】
Prous, J.; Castaner, J.; RS-5142. Drugs Fut 1989, 14, 4, 336.
|
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) |
20812 |
(2R)-2-[(tert-butoxycarbonyl)amino]-3-sulfanylpropionic acid
|
20887-95-0 |
C8H15NO4S |
详情 | 详情
|
(XV) |
20813 |
2-[(Z)-2-nitroethenyl]thiophene
|
|
C6H5NO2S |
详情 |
详情
|
(XVI) |
20814 |
(2R)-2-[(tert-butoxycarbonyl)amino]-3-[[2-nitro-1-(2-thienyl)ethyl]sulfanyl]propionic acid
|
|
C14H20N2O6S2 |
详情 |
详情
|
(XVII) |
20815 |
(2R)-3-[[2-amino-1-(2-thienyl)ethyl]sulfanyl]-2-[(tert-butoxycarbonyl)amino]propionic acid
|
|
C14H22N2O4S2 |
详情 |
详情
|
(XVIII) |
20816 |
tert-butyl (6R)-5-oxo-2-(2-thienyl)-1,4-thiazepan-6-ylcarbamate
|
|
C14H20N2O3S2 |
详情 |
详情
|
(XIX) |
20817 |
(2S,6R)-6-amino-2-(2-thienyl)-1,4-thiazepan-5-one
|
110221-26-6 |
C9H12N2OS2 |
详情 | 详情
|
(XX) |
20818 |
ethyl (2R)-4-phenyl-2-[[(trifluoromethyl)sulfonyl]oxy]butanoate
|
|
C13H15F3O5S |
详情 |
详情
|
(XXI) |
20819 |
ethyl (2S)-2-[[(2S,6R)-5-oxo-2-(2-thienyl)-1,4-thiazepan-6-yl]amino]-4-phenylbutanoate
|
|
C21H26N2O3S2 |
详情 |
详情
|
(XXII) |
17430 |
2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate
|
5292-43-3 |
C6H11BrO2 |
详情 | 详情
|
(XXIII) |
20821 |
ethyl (2S)-2-[[(2S,6R)-4-[2-(tert-butoxy)-2-oxoethyl]-5-oxo-2-(2-thienyl)-1,4-thiazepan-6-yl]amino]-4-phenylbutanoate
|
|
C27H36N2O5S2 |
详情 |
详情
|
合成路线7
该中间体在本合成路线中的序号:
(XII) The methylation of ethyl 2-(hydroxyimino)-3-oxobutyrate (I) with dimethyl sulfate and Na2CO3 in methanol gives ethyl 2-(methoxyimino)-3-oxobutyrate (II), which is brominated with Br2 in CHCl3 yielding ethyl 4-bromo-2-(methoxyimino)-3-oxobutyrate (III). The cyclization of (III) with thiourea (IV) in refluxing ethanol affords ethyl 2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetate (V), which is acylated with chloroacetyl chloride (VI) in DMA to give the corresponding N-chloroacetyl derivative (VII). The hydrolysis of (VII) with KOH in ethanol-water affords 2-(2-chloroacetamidothiazol-4-yl)-2-(methoxyimino)acetic acid (VIII), which is condensed with desacetoxycephalosporanic acid (IX) by means of N-hydroxysuccinimide (NOHS) and dicyclohexylcarbodiimide (DCC) in THF yielding 7beta-[2-(2-chloroacetamidothiazol-4-yl)-2(Z)-(methoxyimino)acetamido]desacetoxycephalosporanic acid (X). The deprotection of (X) with sodium acetate in THF gives the free acid (XI), which is finally esterified with pivaloyloxymethyl bromide (XII) by means of NaHCO3 in ethyl acetate-DMSO.
![](http://zy.yaozh.com/wmf/sch/13/13825001a.jpg)
【1】
Ochiai, M.; Morimoto, A.; Matsushita, Y. (Takeda Chemical Industries, Ltd.); Cephalosporin derivatives, process for their preparation and medicines containing them. DE 2715385 .
|
【2】
Nakao, H.; Sugawara, S. (Sankyo Co., Ltd.); Cephalosporin derivatives for oral administration. DE 3020625 .
|
【3】
Prous, J.; Castaner, J.; CEFETAMET PIVOXIL < Prop INNM >. Drugs Fut 1989, 14, 5, 420.
|
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) |
20853 |
ethyl 2-(hydroxyimino)-3-oxobutanoate;(Z)-ethyl 2-(hydroxyimino)-3-oxobutanoate |
|
C6H9NO4 |
详情 |
详情
|
(II) |
20854 |
ethyl 2-(methoxyimino)-3-oxobutanoate
|
|
C7H11NO4 |
详情 |
详情
|
(III) |
10181 |
ethyl 4-bromo-2-(methoxyimino)-3-oxobutanoate
|
60845-87-6 |
C7H10BrNO4 |
详情 | 详情
|
(IV) |
10180 |
Thiourea
|
62-56-6 |
CH4N2S |
详情 | 详情
|
(V) |
10182 |
Ethyl 2-(2-aminothiazole-4-yl)-2-methoxyiminoacetate; ethyl 2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetate; 2-(2-Amino-4-thiazolyl)-2-methoxyiminoacetic acid ethyl ester
|
64485-88-7 |
C8H11N3O3S |
详情 | 详情
|
(VI) |
11296 |
2-Chloroacetyl chloride; Chloroacetic chloride
|
79-04-9 |
C2H2Cl2O |
详情 | 详情
|
(VII) |
20859 |
ethyl 2-[2-[(2-chloroacetyl)amino]-1,3-thiazol-4-yl]-2-(methoxyimino)acetate
|
|
C10H12ClN3O4S |
详情 |
详情
|
(VIII) |
20860 |
2-[2-[(2-chloroacetyl)amino]-1,3-thiazol-4-yl]-2-(methoxyimino)acetic acid
|
64486-18-6 |
C8H8ClN3O4S |
详情 | 详情
|
(IX) |
20861 |
(6R,7R)-7-amino-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid; 7-ADCA |
22252-43-3 |
C8H10N2O3S |
详情 | 详情
|
(X) |
20862 |
(6R,7R)-7-[[2-[2-[(2-chloroacetyl)amino]-1,3-thiazol-4-yl]-2-(methoxyimino)acetyl]amino]-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid
|
|
C16H16ClN5O6S2 |
详情 |
详情
|
(XI) |
20863 |
(6R,7R)-7-[[2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino]-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid
|
|
C14H15N5O5S2 |
详情 |
详情
|
(XII) |
17430 |
2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate
|
5292-43-3 |
C6H11BrO2 |
详情 | 详情
|
合成路线8
该中间体在本合成路线中的序号:
(IV) The acylation of 4-hydroxypiperidine (I) with benzyl chloroformate (II) by means of triethylamine in dichloromethane gives 4-hydroxypiperidine-1-carboxylic acid benzyl ester (III), which is condensed with tert-butyl bromoacetate (IV) by means of tetrabutylammonium hydrogensulfate and NaOH in toluene/water, affording 2-[1-(benzyloxycarbonyl)piperidin-4-yloxy]acetic acid tert-butyl ester (V). The deprotection of (V) by hydrogenation with H2 over Pd/C in ethanol gives the piperidine (VI), which is condensed with N-(benzyloxycarbonyl)-4-O-tert-butyl-L-tyrosine (VII) by means of 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) and N-methylmorpholine (NMM) in dichloromethane, yielding the expected condensation product (VIII). The deprotection of the amino group of (VIII) by hydrogenation as before affords (IX), which is N-acylated with 4-amidinobenzoyl chloride (X), prepared by reaction of 4-amidinobenzoic acid (XI) with SOCl2, giving the bis-tert-butylated product (XII). Finally, this compound is deprotected by means of trifluoroacetic acid in dichloromethane.
![](http://zy.yaozh.com/wmf/sch/19/19115801a.jpg)
【1】
Weller, T.; Hadvary, P.; Trzeciak, A.; Knopp, D.; Steiner, B.; Edenhofer, A.; Muller, M.; Hurzeler, M.; Alig, L.; Low molecular weight, non-peptide fibrinogen receptor antagonists. J Med Chem 1992, 35, 23, 4393.
|
【2】
Castaner, J.; Merlos, M.; Cases, A.; Rabasseda, X.; Lamifiban. Drugs Fut 1999, 24, 3, 261.
|
【3】
Alig, L.; Hadvary, P.; Huzeler, M.; Muller, M.; Steiner, B.; Weller, T. (F. Hoffmann-La Roche AG); N-acyl-alpha-aminoacids derivs.. EP 0505868; JP 1993148204; US 5378712; US 5545658; US 5658928; US 5670515; US 5747522 .
|
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) |
12076 |
4-Piperidinol; 4-Hydroxypiperidine
|
5382-16-1 |
C5H11NO |
详情 | 详情
|
(II) |
10101 |
Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene
|
501-53-1 |
C8H7ClO2 |
详情 | 详情
|
(III) |
19284 |
benzyl 4-hydroxy-1-piperidinecarboxylate
|
|
C13H17NO3 |
详情 |
详情
|
(IV) |
17430 |
2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate
|
5292-43-3 |
C6H11BrO2 |
详情 | 详情
|
(V) |
19286 |
benzyl 4-[2-(tert-butoxy)-2-oxoethoxy]-1-piperidinecarboxylate
|
|
C19H27NO5 |
详情 |
详情
|
(VI) |
19287 |
tert-butyl 2-(4-piperidinyloxy)acetate
|
|
C11H21NO3 |
详情 |
详情
|
(VII) |
22478 |
(2S)-2-[[(benzyloxy)carbonyl]amino]-3-[4-(tert-butoxy)phenyl]propionic acid
|
|
C21H25NO5 |
详情 |
详情
|
(VIII) |
22479 |
tert-butyl 2-[(1-[(2S)-2-[[(benzyloxy)carbonyl]amino]-3-[4-(tert-butoxy)phenyl]propanoyl]-4-piperidinyl)oxy]acetate
|
|
C32H44N2O7 |
详情 |
详情
|
(IX) |
22480 |
tert-butyl 2-[(1-[(2S)-2-amino-3-[4-(tert-butoxy)phenyl]propanoyl]-4-piperidinyl)oxy]acetate
|
|
C24H38N2O5 |
详情 |
详情
|
(X) |
22481 |
4-[amino(imino)methyl]benzoyl chloride
|
|
C8H7ClN2O |
详情 |
详情
|
(XI) |
22482 |
4-Amidinobenzic acid; 4-[amino(imino)methyl]benzoic acid
|
15535-95-2 |
C8H8N2O2 |
详情 | 详情
|
(XII) |
22483 |
tert-butyl 2-[(1-[(2S)-2-([4-[amino(imino)methyl]benzoyl]amino)-3-[4-(tert-butoxy)phenyl]propanoyl]-4-piperidinyl)oxy]acetate
|
|
C32H44N4O6 |
详情 |
详情
|
合成路线9
该中间体在本合成路线中的序号:
(XVI) 2) Lactone form: The regioselective opening of (R)-2-(tert-butyldimethylsilylethynyl)oxirane (XIV) with KCN in ethanol gives 3(S)-hydroxy-5-(tert-butyldimethylsilyl)-4-pentynenitrile (XV), which is condensed with tert-butyl bromoacetate (XVI) by means of Zn in refluxing THF to afford the 5(S)-hydroxyketoester (XVII). The controlled reduction of (XVII) with NaBH4/diethylmethoxyborane yields the 3(R),5(S)-dihydroxy ester (XVIII), which is deprotected with 2,2-dimethoxypropane and p-toluenesulfonic acid in THF/methanol to the protected heptynoic ester (XIX). The desilylation of (XIX) with tetrabutylammonium fluoride (TBAF) in THF affords the protected heptynoic ester (XX), which is condensed with 2-cyclopropyl-4-(4-fluorophenyl)-3-iodoquinoline (XXI, see Scheme 5) to give the protected NK-104 tert-butyl ester (XXII). Finally, this compound is treated with trifluoroacetic acid in dichloromethane.
![](http://zy.yaozh.com/wmf/sch/19/19200901b.jpg)
【1】
Castaner, J.; Sorbera, L.A.; Leeson, P.A.; NK-104. Drugs Fut 1998, 23, 8, 847-859.
|
【2】
Minami, T.; Hiyama, T.; Takahashi, K.; Ohara, Y.; Synthesis of an artificial HMG-CoA reductase inhibitor NK-104 via a hydrosilylation-cross-coupling reaction. Bull Chem Soc Jpn 1995, 68, 5, 2649-56.
|
【3】
Takahashi, K.; Minami, T.; Ohara, Y.; Hiyama, T.; A new synthesis of HMG-CoA reductase inhibitor NK-104 through hydrosilylation-cross coupling reaction. Tetrahedron Lett 1993, 34, 51, 8263-6.
|
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
(XIV) |
17428 |
tert-butyl(dimethyl)[2-[(2R)oxiranyl]ethynyl]silane
|
|
C10H18OSi |
详情 |
详情
|
(XV) |
17429 |
(3S)-5-[tert-butyl(dimethyl)silyl]-3-hydroxy-4-pentynenitrile
|
|
C11H19NOSi |
详情 |
详情
|
(XVI) |
17430 |
2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate
|
5292-43-3 |
C6H11BrO2 |
详情 | 详情
|
(XVII) |
17431 |
tert-butyl (5S)-7-[tert-butyl(dimethyl)silyl]-5-hydroxy-3-oxo-6-heptynoate
|
|
C17H30O4Si |
详情 |
详情
|
(XVIII) |
17432 |
tert-butyl (3R,5S)-7-[tert-butyl(dimethyl)silyl]-3,5-dihydroxy-6-heptynoate
|
|
C17H32O4Si |
详情 |
详情
|
(XIX) |
17433 |
tert-butyl 2-((4R,6S)-6-[2-[tert-butyl(dimethyl)silyl]ethynyl]-2,2-dimethyl-1,3-dioxan-4-yl)acetate
|
|
C20H36O4Si |
详情 |
详情
|
(XX) |
17434 |
tert-butyl 2-[(4R,6S)-6-ethynyl-2,2-dimethyl-1,3-dioxan-4-yl]acetate
|
|
C14H22O4 |
详情 |
详情
|
(XXI) |
17435 |
2-cyclopropyl-4-(4-fluorophenyl)-3-iodoquinoline
|
|
C18H13FIN |
详情 |
详情
|
(XXII) |
17436 |
tert-butyl 2-((4R,6S)-6-[(E)-2-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]ethenyl]-2,2-dimethyl-1,3-dioxan-4-yl)acetate
|
|
C32H36FNO4 |
详情 |
详情
|
(XLIV) |
64696 |
(4R,6S)-6-{(E)-2-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]ethenyl}-4-hydroxytetrahydro-2H-pyran-2-one
|
|
C25H22FNO3 |
详情 |
详情
|
合成路线10
该中间体在本合成路线中的序号:
(XI) 2) The reaction of 4-methylpentanoic acid (I) with SOCl2 in refluxing chloroform gives the acyl chloride (II), which is condensed with the chiral oxazolidinone (III) by means of BuLi in THF, yielding the corresponding N-acyl derivative (IV). The regioselective alkylation of (IV) with tert-butyl bromoacetate (XI) by means of LDA in THF affords the (S)-adduct (XII). The elimination of the chiral auxiliary with LiOH and H2O2 gives the glutaric acid monoester (XIII), which is reduced with BH3/SMe2 in THF, yielding compound (XIV). The reaction of (XIV) with tosyl chloride in pyridine yields the tosylate (XV), which is treated with sodium azide in DMSO, affording the azide (XVI). The hydrolysis of the tert-butyl group of (XVI) affords the free acid (XVII), which is reduced with H2 over Pd/C.
![](http://zy.yaozh.com/wmf/sch/19/19464402a.jpg)
【1】
Newhouse, B.J.; Ibrahim, P.; Burgess, L.E.; et al.; Potent selective nonpeptidic inhibitors of human lung tryptase. Proc Natl Acad Sci USA 1999, 96, 15, 8348.
|
【2】
Sobieray, D.M.; Hoekstra, M.S.; Schwindt, M.A.; et al.; Chemical development of CI-1008, an enantiomerically pure anticonvulsant. Org Process Res Dev 1997, 1, 1, 26.
|
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) |
25389 |
4-methylpentanoic acid
|
646-07-1 |
C6H12O2 |
详情 | 详情
|
(II) |
25390 |
4-methylpentanoyl chloride
|
38136-29-7 |
C6H11ClO |
详情 | 详情
|
(III) |
26040 |
(4R,5S)-4-methyl-5-phenyl-1,3-oxazolidin-2-one
|
|
C10H11NO2 |
详情 |
详情
|
(IV) |
26041 |
(4R,5S)-4-methyl-3-(4-methylpentanoyl)-5-phenyl-1,3-oxazolidin-2-one
|
|
C16H21NO3 |
详情 |
详情
|
(XI) |
17430 |
2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate
|
5292-43-3 |
C6H11BrO2 |
详情 | 详情
|
(XII) |
26047 |
tert-butyl (3S)-5-methyl-3-[[(4R,5S)-4-methyl-2-oxo-5-phenyl-1,3-oxazolidin-3-yl]carbonyl]hexanoate
|
|
C22H31NO5 |
详情 |
详情
|
(XIII) |
25393 |
(2R)-2-[2-(tert-butoxy)-2-oxoethyl]-4-methylpentanoic acid
|
|
C12H22O4 |
详情 |
详情
|
(XIV) |
26048 |
tert-butyl (3S)-3-(hydroxymethyl)-5-methylhexanoate
|
|
C12H24O3 |
详情 |
详情
|
(XV) |
26049 |
tert-butyl (3S)-5-methyl-3-([[(4-methylphenyl)sulfonyl]oxy]methyl)hexanoate
|
|
C19H30O5S |
详情 |
详情
|
(XVI) |
26050 |
tert-butyl (3S)-3-(azidomethyl)-5-methylhexanoate
|
|
C12H23N3O2 |
详情 |
详情
|
(XVII) |
26051 |
(3S)-3-(azidomethyl)-5-methylhexanoic acid
|
|
C8H15N3O2 |
详情 |
详情
|
合成路线11
该中间体在本合成路线中的序号:
(VIII) The acylation of O-benzyltyrosine (I) with ethyl trifluoroacetate in methanol gives O-benzyl-N-trifluroacetyltyrosine (II), which is condensed with N-(2-aminoethyl)carbamic acid benzyl ester (III) by means of ethyl chloroformate in THF, yielding the tyrosinamide (IV). The deacylation of (IV) by means of NaBH4 in ethanol affords the N-deprotected tyrosinamide (V), which is submitted to hydrogenolysis with H2 over Pd/C in methanol to provide tyrosine 2-aminoethylamide (VI). The reduction of (VI) with diborane gives 3-aza-1-(4-hydroxybenzyl)pentane-1,5-diamine (VII), which is alkylated with bromoacetic acid tert-butyl ester (VIII) and NaHCO3 to yield the 1-(4-hydroxybenzyl)-3-azapentane-1,5-diamine N,N,N'.N'',N''-pentaacetate penta-tert-butyl ester (IX) (1). The alkylation of the OH group of (IX) with ethyl iodide and NaH in THF affords the corresponding ethoxybenzyl derivative (X), which is treated with TFA to provide the pentaacetic acid derivative (XI). Finally, this compound is complexed with Gd2O3 and NaOH in hot water to furnish the target gadolinium complex.
![](http://zy.yaozh.com/wmf/sch/21/21762501a.jpg)
【1】
Schmitt-Willich, H.; Platzek, J.; Gries, H.; Schuhmann-Giampieri, G.; Vogler, H.; Weinmann, H.-J. (Schering AG); DTPA-complexes derivs., pharmaceutical compsns. containing them, their use and process for their preparation. AU 9058024; DE 3922005; EP 0405704; JP 1991215457; US 5695739; US 6039931 . |
【2】
Deutsch, J.; Gries, H.; Klieger, E.; Niedballa, U.; Renneke, F.J.; Conrad, J.; Mützel, W. (Schering AG); Substd. complex-builders, complexes and complex salts, process for their preparation and pharmaceutical compsns. containing them. DE 3710730; WO 8807521 . |
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) |
26716 |
(2S)-2-amino-3-[4-(benzyloxy)phenyl]propionic acid
|
16652-64-5 |
C16H17NO3 |
详情 | 详情
|
(II) |
53319 |
(2S)-3-[4-(benzyloxy)phenyl]-2-[(2,2,2-trifluoroacetyl)amino]propanoic acid
|
n/a |
C18H16F3NO4 |
详情 | 详情
|
(III) |
51002 |
benzyl 2-aminoethylcarbamate
|
|
C10H14N2O2 |
详情 |
详情
|
(IV) |
53320 |
benzyl 2-({(2S)-3-[4-(benzyloxy)phenyl]-2-[(2,2,2-trifluoroacetyl)amino]propanoyl}amino)ethylcarbamate
|
n/a |
C28H28F3N3O5 |
详情 | 详情
|
(V) |
53321 |
benzyl 2-({(2S)-2-amino-3-[4-(benzyloxy)phenyl]propanoyl}amino)ethylcarbamate
|
n/a |
C26H29N3O4 |
详情 | 详情
|
(VI) |
53322 |
(2S)-2-amino-N-(2-aminoethyl)-3-(4-hydroxyphenyl)propanamide
|
n/a |
C11H17N3O2 |
详情 | 详情
|
(VII) |
53323 |
4-{(2S)-2-amino-3-[(2-aminoethyl)amino]propyl}phenol
|
n/a |
C11H19N3O |
详情 | 详情
|
(VIII) |
17430 |
2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate
|
5292-43-3 |
C6H11BrO2 |
详情 | 详情
|
(IX) |
53324 |
tert-butyl (7S)-6,9,12-tris[2-(tert-butoxy)-2-oxoethyl]-7-(4-hydroxybenzyl)-2,2-dimethyl-4-oxo-3-oxa-6,9,12-triazatetradecan-14-oate
|
n/a |
C41H69N3O11 |
详情 | 详情
|
(X) |
53325 |
tert-butyl (7S)-6,9,12-tris[2-(tert-butoxy)-2-oxoethyl]-7-(4-ethoxybenzyl)-2,2-dimethyl-4-oxo-3-oxa-6,9,12-triazatetradecan-14-oate
|
n/a |
C43H73N3O11 |
详情 | 详情
|
(XI) |
53326 |
2-([(2S)-2-[bis(carboxymethyl)amino]-3-(4-ethoxyphenyl)propyl]{2-[bis(carboxymethyl)amino]ethyl}amino)acetic acid
|
n/a |
C23H33N3O11 |
详情 | 详情
|
合成路线12
该中间体在本合成路线中的序号:
(XXV) Reaction of 2-(1,3-dioxol-5-yl)acetic acid (XXI) with pivaloyl chloride and TEA gives the corresponding anhydride (XXII), which is condensed with the chiral oxazolidinone (XXIII) by means of n-BuLi in THF to yield the amide (XXIV). Condensation of (XXIV) with 2-bromoacetic acid tert-butyl ester (XXV) by means of NaHMDS in THF affords the adduct (XXVI). Elimination of the chiral auxiliary of (XXVI) by means of LiOOH in THF/water provides the chiral succinic acid hemiester (XXVII) (93% ee), which is selectively reduced with BH3THF complex to give the 4-hydroxysuccinate (XXVIII). Reaction of succinate (XXVIII) with 4-chlorophenylsulfonyl chloride, TEA and DMAP in dichloromethane yields the sulfonate (XXIX), which is condensed with 4-methoxybenzaldoxime (XXX) by means of Cs2CO3 in hot acetonitrile to afford the oxime ether (XXXI). Transesterification of the tert-butyl ester of (XXXI) with trimethyl orthoformate and p-toluenesulfonic acid in hot methanol provides the methyl ester (XXXII), which is cyclized by means of trimethylsilyl triflate and tributylamine in dichloroethane to afford a 9:1 diastereomeric mixture of perhydro-1,2-oxazines (XXXIII) and (XXXIV) which is easily separated. The reductive N-O-bond cleavage of the major oxazine diastereomer (XXXIII) by means of Zn/HOAc or H2 over Pd/C gives the trisubstituted 4-aminobutanol (XXXV), which is cyclized by means of CBr4, PPh3 and TEA to yield chiral pyrrolidine (XXXVI) (4). Finally, pyrrolidine (XXXVI) is alkylated with N,N-dibutyl-2-bromoacetamide (XIII) followed by ester hydrolysis as before.
![](http://zy.yaozh.com/wmf/sch/22/22663604a.jpg)
【1】
Leeson, P.; Castañer, R.M.; Sorbera, L.A.; Castañer, J.; Atrasentan. Drugs Fut 2001, 26, 10, 939.
|
【2】
McLaughlin, M.A.; Wittenberger, S.J.; Preparation of endothelin antagonist ABT-627. Tetrahedron Lett 1999, 40, 7175.
|
【3】
Winn, M.; et al.; 2,4-Diarylpyrrolidine-3-carboxylic acids-potent ETA selective endothelin receptor antagonists. 1. Discovery of A-127722. J Med Chem 1996, 39, 5, 1039.
|
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
|
15787 |
4-chlorobenzenesulfonyl chloride;4-chlorobenzene-1-sulfonyl chloride |
98-60-2 |
C6H4Cl2O2S |
详情 | 详情
|
(XIII) |
20685 |
2-Bromo-N,N-dibutylacetamide; N,N-Dibutylbromoacetamide
|
|
C10H20BrNO |
详情 |
详情
|
(XXI) |
18117 |
2-(1,3-benzodioxol-5-yl)acetic acid; 3,4-(Methylenedioxy)phenylacetic acid
|
2861-28-1 |
C9H8O4 |
详情 | 详情
|
(XXII) |
48688 |
1,3-benzodioxol-5-ylacetic 1,1-dimethylpropionic anhydride
|
|
C14H16O5 |
详情 |
详情
|
(XXIII) |
12867 |
(4S)-4-Isopropyl-1,3-oxazolidin-2-one; (R)-4-Isopropyl-2-oxazolidinone
|
17016-83-0 |
C6H11NO2 |
详情 | 详情
|
(XXIV) |
48689 |
(4S)-3-[2-(1,3-benzodioxol-5-yl)acetyl]-4-isopropyl-1,3-oxazolidin-2-one
|
|
C15H17NO5 |
详情 |
详情
|
(XXV) |
17430 |
2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate
|
5292-43-3 |
C6H11BrO2 |
详情 | 详情
|
(XXVI) |
48690 |
tert-butyl (3S)-3-(1,3-benzodioxol-5-yl)-4-[(4S)-4-isopropyl-2-oxo-1,3-oxazolidin-3-yl]-4-oxobutanoate
|
|
C21H27NO7 |
详情 |
详情
|
(XXVII) |
48691 |
(2S)-2-(1,3-benzodioxol-5-yl)-4-(tert-butoxy)-4-oxobutyric acid
|
|
C15H18O6 |
详情 |
详情
|
(XXVIII) |
48692 |
tert-butyl (3S)-3-(1,3-benzodioxol-5-yl)-4-hydroxybutanoate
|
|
C15H20O5 |
详情 |
详情
|
(XXIX) |
48693 |
tert-butyl (3S)-3-(1,3-benzodioxol-5-yl)-4-[[(4-chlorophenyl)sulfonyl]oxy]butanoate
|
|
C21H23ClO7S |
详情 |
详情
|
(XXX) |
48694 |
4-methoxybenzaldehyde oxime
|
|
C8H9NO2 |
详情 |
详情
|
(XXXI) |
48695 |
tert-butyl (3S)-3-(1,3-benzodioxol-5-yl)-4-([[(E)-(4-methoxyphenyl)methylidene]amino]oxy)butanoate
|
|
C23H27NO6 |
详情 |
详情
|
(XXXII) |
48696 |
methyl (3S)-3-(1,3-benzodioxol-5-yl)-4-([[(E)-(4-methoxyphenyl)methylidene]amino]oxy)butanoate
|
|
C20H21NO6 |
详情 |
详情
|
(XXXIII) |
48697 |
methyl (3R,4R,5S)-5-(1,3-benzodioxol-5-yl)-3-(4-methoxyphenyl)-1,2-oxazinane-4-carboxylate
|
|
C20H21NO6 |
详情 |
详情
|
(XXXIV) |
48698 |
methyl (3S,5S)-5-(1,3-benzodioxol-5-yl)-3-(4-methoxyphenyl)-1,2-oxazinane-4-carboxylate
|
|
C20H21NO6 |
详情 |
详情
|
(XXXV) |
48699 |
methyl (2R,3S)-2-[(R)-amino(4-methoxyphenyl)methyl]-3-(1,3-benzodioxol-5-yl)-4-hydroxybutanoate
|
|
C20H23NO6 |
详情 |
详情
|
(XXXVI) |
48700 |
methyl (2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-2-(4-methoxyphenyl)-3-pyrrolidinecarboxylate
|
|
C20H21NO5 |
详情 |
详情
|
合成路线13
该中间体在本合成路线中的序号:
(X) 2) The reaction of 4-hydroxypiperidine (VII) with benzyl chloroformate (VIII) by means of triethylamine in dichloromethane gives the expected benzyloxycarbonyl derivative (IX), which is condensed with tert-butyl 2-bromoacetate (X) by means of tetrabutylammonium bisulfate and NaOH, yielding 2-[1-(benzyloxycarbonyl)piperidin-4-yloxy]acetic acid tert-butyl ester (XI). The deprotection of (XI) as ususal affords 2-(4-piperidinyloxy)acetic acid tert-butyl ester (XII), which is condensed with N-(benzyloxycarbonyl)-L-alanine (XIII) by means of 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) and N-methyl-morpholine (NMM) in dichloromethane to yield the acylated piperidine (XIV). The deprotection of (XIV) as usual affords compound (XV), which is acylated at the free amino group with 4-cyanobenzoyl chloride (V) and tetrabutylammonium bisulfate to give 2-[1-[N-(4-cyanobenzoyl)-L-alanyl]piperidin-4-yloxy]acetic acid tert-butyl ester (XVI). The reaction of the cyano group of (XVI) with hydroxylamine affords compound (XVII) with a hydroxyamidino substituent. Finally, the tert-butyl ester group of (XVII) is converted in ethyl ester by hydrolysis with hot fomic acid to the corresponding acetic acid (XVIII) and subsequent esterification with ethanol/H2SO4.
![](http://zy.yaozh.com/wmf/sch/22/22905301b.jpg)
【1】
Alig, L.; Beresini, M.; Weller, T.; et al.; Orally active fibrinogen receptor antagonists. 2. Amidoximes as prodrugs of amidines. J Med Chem 1996, 39, 16, 3139.
|
【2】
Weller, T.; Hadvary, P.; Trzeciak, A.; Knopp, D.; Steiner, B.; Edenhofer, A.; Muller, M.; Hurzeler, M.; Alig, L.; Low molecular weight, non-peptide fibrinogen receptor antagonists. J Med Chem 1992, 35, 23, 4393.
|
【3】
Castañer, J.; Graul, A.; Merlos, M.; Sibrafiban . Drugs Fut 1998, 23, 12, 1297.
|
【4】
Alig, L.; Hadvary, P.; Hurzeler Muller, M.; Muller, M.; Steiner, B.; Weller, T. (F. Hoffmann-La Roche AG); Acetic acid derivs. as medicaments. EP 0656348; JP 1995196592; US 5726185 .
|
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
(V) |
19280 |
4-cyanobenzoyl chloride
|
6068-72-0 |
C8H4ClNO |
详情 | 详情
|
(VII) |
12076 |
4-Piperidinol; 4-Hydroxypiperidine
|
5382-16-1 |
C5H11NO |
详情 | 详情
|
(VIII) |
10101 |
Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene
|
501-53-1 |
C8H7ClO2 |
详情 | 详情
|
(IX) |
19284 |
benzyl 4-hydroxy-1-piperidinecarboxylate
|
|
C13H17NO3 |
详情 |
详情
|
(X) |
17430 |
2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate
|
5292-43-3 |
C6H11BrO2 |
详情 | 详情
|
(XI) |
19286 |
benzyl 4-[2-(tert-butoxy)-2-oxoethoxy]-1-piperidinecarboxylate
|
|
C19H27NO5 |
详情 |
详情
|
(XII) |
19287 |
tert-butyl 2-(4-piperidinyloxy)acetate
|
|
C11H21NO3 |
详情 |
详情
|
(XIII) |
61209 |
CBZ-L-Alanine; (2S)-2-[[(Benzyloxy)carbonyl]amino]propionic acid; N-((Phenylmethoxy)carbonyl)-alanine; Carbobenzyloxy-L-alanine
|
|
C11H13NO4 |
详情 |
详情
|
(XIV) |
19289 |
tert-butyl 2-[[1-((2S)-2-[[(benzyloxy)carbonyl]amino]propanoyl)-4-piperidinyl]oxy]acetate
|
|
C22H32N2O6 |
详情 |
详情
|
(XV) |
19290 |
tert-butyl 2-([1-[(2S)-2-aminopropanoyl]-4-piperidinyl]oxy)acetate
|
|
C14H26N2O4 |
详情 |
详情
|
(XVI) |
19291 |
tert-butyl 2-[(1-[(2S)-2-[(4-cyanobenzoyl)amino]propanoyl]-4-piperidinyl)oxy]acetate
|
|
C22H29N3O5 |
详情 |
详情
|
(XVII) |
19292 |
tert-butyl 2-([1-[(2S)-2-([4-[amino(hydroxyimino)methyl]benzoyl]amino)propanoyl]-4-piperidinyl]oxy)acetate
|
|
C22H32N4O6 |
详情 |
详情
|
(XVIII) |
19293 |
2-([1-[(2S)-2-([4-[amino(hydroxyimino)methyl]benzoyl]amino)propanoyl]-4-piperidinyl]oxy)acetic acid
|
|
C18H24N4O6 |
详情 |
详情
|
合成路线14
该中间体在本合成路线中的序号:
(III) Acylation of the chiral oxazolidinone (I) with undecanoyl chloride furnished the N-acyl oxazolidinone (II). The lithium enolate of (II) was diastereoselectively alkylated with tert-butyl bromoacetate (III) producing (IV) as the major isomer. Then, removal of the chiral auxiliary of (IV) with lithium benzyloxide yielded benzyl ester (V). Acidic cleavage of the tert-butyl ester group of (V) provided carboxylic acid (VI), which was subsequently converted to the trichloroethyl ester (VII) via formation of the corresponding acid chloride, followed by treatment with trichloroethanol. After removal of the benzyl ester group of (VII) by hydrogenolysis, chlorination by means of oxalyl chloride gave acid chloride (VIII). This was then coupled with the protected (S)-perhydropyrazine-3-carboxylic acid (IX) to afford amide (X).
![](http://zy.yaozh.com/wmf/sch/23/23125901a.jpg)
【1】
Tamaki, K.; et al.; Synthesis and structure-activity relationships of gelatinase inhibitors derived from Matlystatins. Chem Pharm Bull 1995, 43, 11, 1883.
|
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) |
12867 |
(4S)-4-Isopropyl-1,3-oxazolidin-2-one; (R)-4-Isopropyl-2-oxazolidinone
|
17016-83-0 |
C6H11NO2 |
详情 | 详情
|
(II) |
56879 |
(4S)-4-isopropyl-3-undecanoyl-1,3-oxazolidin-2-one
|
|
C17H31NO3 |
详情 |
详情
|
(III) |
17430 |
2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate
|
5292-43-3 |
C6H11BrO2 |
详情 | 详情
|
(IV) |
56880 |
tert-butyl (3R)-3-{[(4S)-4-isopropyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl}dodecanoate
|
|
C23H41NO5 |
详情 |
详情
|
(V) |
56881 |
1-benzyl 4-(tert-butyl) (2R)-2-nonylbutanedioate
|
|
C24H38O4 |
详情 |
详情
|
(VI) |
56882 |
(3R)-3-[(benzyloxy)carbonyl]dodecanoic acid
|
|
C20H30O4 |
详情 |
详情
|
(VII) |
56883 |
1-benzyl 4-(2,2,2-trichloroethyl) (2R)-2-nonylbutanedioate
|
|
C22H31Cl3O4 |
详情 |
详情
|
(VIII) |
56884 |
2,2,2-trichloroethyl (3R)-3-(chlorocarbonyl)dodecanoate
|
|
C15H24Cl4O3 |
详情 |
详情
|
(IX) |
56885 |
1-benzyl 3-(tert-butyl) (3S)tetrahydro-1,3(2H)-pyridazinedicarboxylate
|
|
C17H24N2O4 |
详情 |
详情
|
(X) |
56886 |
1-benzyl 3-(tert-butyl) (3S)-2-{(2R)-2-[2-oxo-2-(2,2,2-trichloroethoxy)ethyl]undecanoyl}tetrahydro-1,3(2H)-pyridazinedicarboxylate
|
|
C32H47Cl3N2O7 |
详情 |
详情
|
合成路线15
该中间体在本合成路线中的序号:
(V) The amidation of L-serine methyl ester (I) with ethylenediamine (II) gives the amide (III), which is reduced with borane/THF to 2(R)-(hydroxymethyl)diethylenetriamine (IV). The reaction of (IV) with bromoacetic acid tert-butyl ester (V) by means of DIEA in DMF affords the penta tert-butyl acetate (VI), which is condensed with the chlorophosphoramidite (VII) by means of DIEA in dichloromethane giving the phosphoramidite intermediate (VIII). The condensation of (VIII) with 4,4-diphenylcyclohexanol (IX) (see scheme 23537901b) by means of tetrazole in acetonitile, with simultaneous oxidation with tert-butyl hydroperoxide yields the phosphate (X), which is selectively hydrolyzed at the 2-cyanoethyl ester group with ammonia in methanol affording the ammonium phosphate (XI). Finally, the hydrolysis of (XI) with HCl in ether/water eliminates the tert-butyl groups affording the desired chelating ligand (XII)
![](http://zy.yaozh.com/wmf/sch/23/23537901a.jpg)
【1】
Scott, D.M.; Sajiki, H.; McMurray, T.J.; Lauffer, R.B. (Epix Medical, Inc.); Diagnostic imaging contrast agents with extended blood retention. WO 9623526 .
|
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) |
20915 |
methyl (2S)-2-amino-3-hydroxypropanoate
|
5680-80-8 |
C4H9NO3 |
详情 | 详情
|
(II) |
14754 |
ethylenediamine;1,2-Diaminoethane;ethane-1,2-diamine;1,2-Ethanediamine |
107-15-3 |
C2H8N2 |
详情 | 详情
|
(III) |
30315 |
(2S)-2-amino-N-(2-aminoethyl)-3-hydroxypropanamide
|
|
C5H13N3O2 |
详情 |
详情
|
(IV) |
30316 |
(2R)-2-amino-3-[(2-aminoethyl)amino]-1-propanol
|
|
C5H15N3O |
详情 |
详情
|
(V) |
17430 |
2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate
|
5292-43-3 |
C6H11BrO2 |
详情 | 详情
|
(VI) |
30317 |
3,6,9-Tris(tert-butoxycarbonylmethyl)-4(R)-(hydroxymethyl)-3,6,9-triazaundecanedioic acid di-tert-butyl ester
|
|
C35H65N3O11 |
详情 |
详情
|
(VII) |
22791 |
2-Cyanoethyl N,N-diisopropylphosphoramidochloridite
|
89992-70-1 |
C9H18ClN2OP |
详情 | 详情
|
(VIII) |
30318 |
3,6,9-Tris(tert-butoxycarbonylmethyl)-4(R)-[2-cyanoethoxy(diisopropylamino)phosphinyloxymethyl]-3,6,9-triazaundecanedioic acid di-tert-butyl ester
|
|
C44H82N5O12P |
详情 |
详情
|
(IX) |
30319 |
4,4-diphenylcyclohexanol
|
|
C18H20O |
详情 |
详情
|
(X) |
30320 |
3,6,9-Tris(tert-butoxycarbonylmethyl)-4(R)-[2-cyanoethoxy(4,4-diphenylcyclohexyloxy)phosphoryloxymethyl]-3,6,9-triazaundecanedioic acid di-tert-butyl ester
|
|
C56H87N4O14P |
详情 |
详情
|
(XI) |
30321 |
3,6,9-Tris(tert-butoxycarbonylmethyl)-4(R)-[4,4-diphenylcyclohexyloxy(hydroxy)phosphoryloxymethyl]-3,6,9-triazaundecanedioic acid di-tert-butyl ester ammonium salt
|
|
C53H87N4O14P |
详情 |
详情
|
(XII) |
30322 |
3,6,9-Tris(carboxymethyl)-4(R)-[4,4-diphenylcyclohexyloxy(hydroxy)phosphoryloxymethyl]-3,6,9-triazaundecanedioic acid
|
|
C33H44N3O14P |
详情 |
详情
|
合成路线16
该中间体在本合成路线中的序号:
Selective O-alkylation of trans-4-aminocyclohexanol (I) was effected by protection of the amino group as the triazinone (III) upon treatment with N,N-dimethylurea and formaldehyde. Subsequent alkylation of (III) with tert-butyl bromoacetate under phase-transfer conditions afforded ether (IV). The protecting group of (IV) was then removed by treatment with ammonium chloride.
![](http://zy.yaozh.com/wmf/sch/23/23738001a.jpg)
【1】
Ono, S.; Yoshida, T.; Ashimori, A.; Kosaka, K.; Okada, T.; Maeda, K.; Eda, M.; Mori, F.; Inoue, Y.; Ebisu, H.; Imada, T.; Ikegawa, R.; Wang, F.; Nakamura, N. (Welfide Corporation); Novel fused-ring carboxylic acid cpds. or salt thereof,and medicinal use thereof. EP 0712844; JP 1996053398; JP 1996231548; US 5635527; US 5753670; WO 9533720 . |
【2】
Nakamura, N.; Imada, T.; Inoue, Y.; Kosaka, K.; Yoshida, T.; Ono, S.; Fukaya, C.; Maeda, K.; Preparation and pharmacological evaluation of novel glycoprotein (Gp) IIb/IIIa antagonists. 2. Condensed heterocyclic derivatives. Chem Pharm Bull 1999, 47, 12, 1694. |
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
|
17430 |
2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate
|
5292-43-3 |
C6H11BrO2 |
详情 | 详情
|
(I) |
19581 |
trans-4-Aminocyclohexanol;trans-4-Amino-1-cyclohexanol;trans-4-Amino-1-cyclohexanol; |
27489-62-9 |
C6H13NO |
详情 | 详情
|
(II) |
21488 |
N,N'-dimethylurea
|
96-31-1 |
C3H8N2O |
详情 | 详情
|
(III) |
37350 |
5-(4-hydroxycyclohexyl)-1,3-dimethyl-1,3,5-triazinan-2-one
|
|
C11H21N3O2 |
详情 |
详情
|
(IV) |
37351 |
tert-butyl 2-[[4-(3,5-dimethyl-4-oxo-1,3,5-triazinan-1-yl)cyclohexyl]oxy]acetate
|
|
C17H31N3O4 |
详情 |
详情
|
(V) |
37352 |
tert-butyl 2-[(4-aminocyclohexyl)oxy]acetate
|
|
C12H23NO3 |
详情 |
详情
|
合成路线17
该中间体在本合成路线中的序号:
(X) 2) The chiral intermediates the amine (I) and the acid (II) have been obtained as follows: 2a) The bromination of 1-tetralone (IV) with Br2 in methanol gives the 2-bromotetralone (V), which is treated with hydroxylamine yielding the corresponding oximae (VI). The isomerization of (V) with polyphosphoric acid (PPA) at 80 C affords the benzazepinone (VII), which is treated with potassium phthalimide (VIII) in DMF to give the corresponding phthalimido derivative (IX). The reaction of (IX) with tert-butyl bromoacetate (X) by means of potassium tert-butoxide in DMF yields the benzazepinoacetic ester (XI), which is treated with hot ethanolamine to eliminate the phthalimido group yielding racemic (I). Finally, this racemate is submitted to optical resolution with L-(+)-tartaric acid to afford the chiral (S)-intermediate (I).
![](http://zy.yaozh.com/wmf/sch/24/24258502a.jpg)
【1】
Waldeck, H.; Höltje, D.; Messinger, J.; Antel, J.; Wurl, M.; Thormählen, D. (Kali-Chemie AG); Benzazepin-, benzoxazepin- and benzothiazepin-N-acetic acid-derivs., their preparation and their pharmaceutical compsns.. CA 2172354; EP 0733642; JP 1996269011; US 5677297 . |
【2】
Rozsa, S.; Gy Papp, J.; Thormahlen, D.; Waldeck, H. (Solvay SA); Drugs for increasing gastrointestinal blood supply. DE 19638020; EP 0830863; JP 1998101565 .
|
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
rac-(I) |
20728 |
tert-butyl 2-(3-amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)acetate
|
|
C16H22N2O3 |
详情 |
详情
|
(I) |
20717 |
tert-butyl 2-[(3S)-3-amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]acetate
|
|
C16H22N2O3 |
详情 |
详情
|
(IV) |
20720 |
3,4-dihydro-1(2H)-naphthalenone
|
529-34-0 |
C10H10O |
详情 | 详情
|
(V) |
20721 |
2-bromo-3,4-dihydro-1(2H)-naphthalenone
|
|
C10H9BrO |
详情 |
详情
|
(VI) |
20722 |
2-bromo-3,4-dihydro-1(2H)-naphthalenone oxime
|
|
C10H10BrNO |
详情 |
详情
|
(VII) |
20723 |
3-bromo-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one
|
|
C10H10BrNO |
详情 |
详情
|
(VIII) |
10926 |
(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)potassium
|
|
C8H4KNO2 |
详情 |
详情
|
(IX) |
20725 |
2-(2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl)-1H-isoindole-1,3(2H)-dione
|
|
C18H14N2O3 |
详情 |
详情
|
(X) |
17430 |
2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate
|
5292-43-3 |
C6H11BrO2 |
详情 | 详情
|
(XI) |
20727 |
tert-butyl 2-[3-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]acetate
|
|
C25H26N2O5 |
详情 |
详情
|
合成路线18
该中间体在本合成路线中的序号:
(X) 2a) The chiral intermediate amine (I) has been obtained as follows:
The bromination of 1-tetralone (IV) with Br2 in methanol gives the 2-bromotetralone (V), which is treated with hydroxylamine yielding the corresponding oximae (VI). The isomerization of (V) with polyphosphoric acid (PPA) at 80 C affords the benzazepinone (VII), which is treated with potassium phthalimide (VIII) in DMF to give the corresponding phthalimido derivative (IX). The reaction of (IX) with tert-butyl bromoacetate (X) by means of potassium tert-butoxide in DMF yields the benzazepinoacetic ester (XI), which is treated with hot ethanolamine to eliminate the phthalimido group yielding racemic (I). Finally, this racemate is submitted to optical resolution with L-(+)-tartaric acid to afford the chiral (S)-intermediate (I).
![](http://zy.yaozh.com/wmf/sch/24/24292502a.jpg)
【1】
Sorbera, L.A.; Leeson, P.A.; Castañer, J.; SLV-306. Drugs Fut 2002, 27, 1, 27.
|
【2】
Waldeck, H.; Höltje, D.; Messinger, J.; Antel, J.; Wurl, M.; Thormählen, D. (Kali-Chemie AG); Benzazepin-, benzoxazepin- and benzothiazepin-N-acetic acid-derivs., their preparation and their pharmaceutical compsns.. CA 2172354; EP 0733642; JP 1996269011; US 5677297 . |
【3】
Rozsa, S.; Gy Papp, J.; Thormahlen, D.; Waldeck, H. (Solvay SA); Drugs for increasing gastrointestinal blood supply. DE 19638020; EP 0830863; JP 1998101565 .
|
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
rac-(I) |
20728 |
tert-butyl 2-(3-amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)acetate
|
|
C16H22N2O3 |
详情 |
详情
|
(I) |
20717 |
tert-butyl 2-[(3S)-3-amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]acetate
|
|
C16H22N2O3 |
详情 |
详情
|
(IV) |
20720 |
3,4-dihydro-1(2H)-naphthalenone
|
529-34-0 |
C10H10O |
详情 | 详情
|
(V) |
20721 |
2-bromo-3,4-dihydro-1(2H)-naphthalenone
|
|
C10H9BrO |
详情 |
详情
|
(VI) |
20722 |
2-bromo-3,4-dihydro-1(2H)-naphthalenone oxime
|
|
C10H10BrNO |
详情 |
详情
|
(VII) |
20723 |
3-bromo-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one
|
|
C10H10BrNO |
详情 |
详情
|
(VIII) |
10926 |
(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)potassium
|
|
C8H4KNO2 |
详情 |
详情
|
(IX) |
20725 |
2-(2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl)-1H-isoindole-1,3(2H)-dione
|
|
C18H14N2O3 |
详情 |
详情
|
(X) |
17430 |
2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate
|
5292-43-3 |
C6H11BrO2 |
详情 | 详情
|
(XI) |
20727 |
tert-butyl 2-[3-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]acetate
|
|
C25H26N2O5 |
详情 |
详情
|
合成路线19
该中间体在本合成路线中的序号:
(II) Condensation of 2-(4-methylphenyl)ethanol (I) with t-Bu-bromoacetate (II) in toluene in the presence of NaOH and tetrabutylammonium bromide (TBAB) provides ethoxyacetic acid derivative (III), which is converted into acetamide (V) by reaction with oxalyl chloride (IV) in toluene/DMF followed by treatment with NH4OH. Reduction of (V) by reaction with borane-tetrahydrofuran (BH3·THF) in THF yields ethanamine (VI), which is then coupled to chlorosulfonyl derivative (VII) in CH2Cl2 in the presence of TEA to afford compound (VIII). Reduction of the ester group of (VIII) by treatment with diisobutylaluminium hydride (DIBAL) in toluene furnishes aldehyde (IX), which is finally subjected to a reductive amination with benzothiazol derivative (X) by means of NaCNBH3 in MeOH/HOAc.
![](http://zy.yaozh.com/wmf/sch/25/25062001a.jpg)
【1】
Bonnert, R.; et al.; The discovery of dual D2-receptor and beta2-adrenoceptor agonists for the treatment of airway diseases. 16th Int Symp Med Chem (Sept 18 2000, Bologna) 2000, Poster PC161.
|
【2】
Bonnert, R.V.; Brown, R.C.; Cage, P.A.; Ince, F.; Pairaudeau, G. (AstraZeneca plc); Benzothiazolone derivs.. JP 1999512422; US 5846989; WO 9710227 .
|
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) |
45458 |
2-(4-methylphenyl)-1-ethanol
|
699-02-5 |
C9H12O |
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) |
45459 |
2-[(4-methylphenethyl)oxy]acetic acid
|
|
C11H14O3 |
详情 |
详情
|
(IV) |
29841 |
Oxalyl chloride; 2-Chloro-2-oxoacetyl chloride
|
79-37-8 |
C2Cl2O2 |
详情 | 详情
|
(V) |
45460 |
2-[(4-methylphenethyl)oxy]acetamide
|
|
C11H15NO2 |
详情 |
详情
|
(VI) |
45461 |
2-[(4-methylphenethyl)oxy]ethylamine; 2-[(4-methylphenethyl)oxy]-1-ethanamine
|
|
C11H17NO |
详情 |
详情
|
(VII) |
45462 |
Methyl 3-(chlorosulfonyl)propanoate; 3-(Chlorosulfonyl)propionic acid methylester
|
15441-07-3 |
C4H7ClO4S |
详情 | 详情
|
(VIII) |
45463 |
methyl 3-[([2-[(4-methylphenethyl)oxy]ethyl]amino)sulfonyl]propanoate
|
|
C15H23NO5S |
详情 |
详情
|
(IX) |
45464 |
N-[2-[(4-methylphenethyl)oxy]ethyl]-3-oxo-1-propanesulfonamide
|
|
C14H21NO4S |
详情 |
详情
|
(X) |
25944 |
7-(2-aminoethyl)-4-hydroxy-1,3-benzothiazol-2(3H)-one
|
|
C9H10N2O2S |
详情 |
详情
|
合成路线20
该中间体在本合成路线中的序号:
(V) A new strategy for the synthesis of a key intermediate in the preparation of LY-333531 has been described: Condensation of indole (I) with the tosylate (II) by means of NaH in DMF gives 4-(1-indolyl)butane-1,2-diol (III), which is monotritylated with trityl bromide yielding ether (IV). Alkylation of compound (IV) with tert-butyl bromoacetate (V) and NaH in THF affords the hydroxyacetic derivative (VI), which is reduced with LiBH4 in THF/EtOH to provide the carbinol (VII). Reaction of compound (VII) with Ms2O and pyridine in THF gives the mesylate (VIII), which is condensed with oxalyl chloride (IX) in ethyl ether to yield the oxoacetyl chloride (X). The alcoholysis of (X) with NaOMe in methanol affords the oxoacetate (XI), which is finally cyclized with 2-(3-indolyl)acetamide (XII) by means of NaH in DMF to provide the target intermediate (XIII).
![](http://zy.yaozh.com/wmf/sch/25/25239602a.jpg)
【1】
Faul, M.M.; Kumrich, C.A.; Cyclization strategies for the synthesis of macrocyclic bisindolylmaleimides. J Org Chem 2001, 66, 6, 2024.
|
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) |
15292 |
Indole; 1H-indole
|
120-72-9 |
C8H7N |
详情 | 详情
|
(II) |
48674 |
2-(2,2-diethyl-1,3-dioxolan-4-yl)ethyl 4-methylbenzenesulfonate
|
|
C16H24O5S |
详情 |
详情
|
(III) |
48675 |
4-(1H-indol-1-yl)-1,2-butanediol
|
|
C12H15NO2 |
详情 |
详情
|
(IV) |
48676 |
4-(1H-indol-1-yl)-1-(trityloxy)-2-butanol
|
|
C31H29NO2 |
详情 |
详情
|
(V) |
17430 |
2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate
|
5292-43-3 |
C6H11BrO2 |
详情 | 详情
|
(VI) |
48677 |
tert-butyl 2-[3-(1H-indol-1-yl)-1-[(trityloxy)methyl]propoxy]acetate
|
|
C37H39NO4 |
详情 |
详情
|
(VII) |
48678 |
2-[3-(1H-indol-1-yl)-1-[(trityloxy)methyl]propoxy]-1-ethanol
|
|
C33H33NO3 |
详情 |
详情
|
(VIII) |
48679 |
2-[3-(1H-indol-1-yl)-1-[(trityloxy)methyl]propoxy]ethyl methanesulfonate
|
|
C34H35NO5S |
详情 |
详情
|
(IX) |
29841 |
Oxalyl chloride; 2-Chloro-2-oxoacetyl chloride
|
79-37-8 |
C2Cl2O2 |
详情 | 详情
|
(X) |
48680 |
2-[3-[3-(2-chloro-2-oxoacetyl)-1H-indol-1-yl]-1-[(trityloxy)methyl]propoxy]ethyl methanesulfonate
|
|
C36H34ClNO7S |
详情 |
详情
|
(XI) |
48681 |
methyl 2-[1-[3-[2-[(methylsulfonyl)oxy]ethoxy]-4-(trityloxy)butyl]-1H-indol-3-yl]-2-oxoacetate
|
|
C37H37NO8S |
详情 |
详情
|
(XII) |
48682 |
Indole-3-acetamide;3-Indoleacetamide;2-(1H-indol-3-yl) |
879-37-8 |
C10H10N2O |
详情 | 详情
|
(XIII) |
48683 |
18-[(trityloxy)methyl]-17-oxa-4,14,21-triazahexacyclo[19.6.1.1(7,14).0(2,6).0(8,13).0(22,27)]nonacosa-1(28),2(6),7(29),8,10,12,22,24,26-nonaene-3,5-dione
|
|
C45H37N3O4 |
详情 |
详情
|
合成路线21
该中间体在本合成路线中的序号:
A further route to benzyl ester (X) is shown in the next scheme: Protection of 2,4,6-trimethylaniline (XI) with Boc2O gave carbamate (XII). Condensation of (XII) with diethyl oxalate in the presence of sec-butyllithium produced the intermediate ketoester (XIII), which was deprotected and cyclized under acidic conditions to yield indole (V). Hydrolysis, followed by alkylation with benzyl bromide as above provided the corresponding benzyl ester (X). An alternative and more direct procedure consisted in the condensation of protected aniline (XII) with dibenzyl oxalate, and then cyclization upon treatment with trifluoroacetic acid.
The intermediate indole (X) was N-alkylated with tert-butyl bromoacetate and NaH to give the indole diester (XIV). Subsequent deprotection of the benzyl ester group by hydrogenation over Pd/C gave rise to diacid mono tert-butyl ester (XV). Optionally, the analogous methyl ester (XVII) was prepared by alkylation of indole (X) with methyl bromoacetate, followed by benzyl group hydrogenolysis.
![](http://zy.yaozh.com/wmf/sch/25/25963201b.jpg)
【1】
Brodin, R.; Boigegrain, R.; Molimard, J.-C.; Bignon, E.; Olliero, D. (Sanofi-Synthelabo ); Carboxamidothiazole derivs., preparation, pharmaceutical compsns. containing them. EP 1017693; FR 2768737; FR 2777887; WO 9915525 .
|
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
|
12309 |
methyl 2-bromoacetate; methyl bromoacetate
|
96-32-2 |
C3H5BrO2 |
详情 | 详情
|
|
12912 |
1-(Bromomethyl)benzene; Alpha-bromotoluene
|
100-39-0 |
C7H7Br |
详情 | 详情
|
|
17430 |
2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate
|
5292-43-3 |
C6H11BrO2 |
详情 | 详情
|
|
40591 |
benzyl 2-(benzyloxy)-2-oxoacetate
|
|
C16H14O4 |
详情 |
详情
|
(V) |
32914 |
ethyl 5,7-dimethyl-1H-indole-2-carboxylate
|
|
C13H15NO2 |
详情 |
详情
|
(X) |
32919 |
benzyl 5,7-dimethyl-1H-indole-2-carboxylate
|
|
C18H17NO2 |
详情 |
详情
|
(XI) |
28804 |
2,4,6-trimethylaniline
|
88-05-1 |
C9H13N |
详情 | 详情
|
(XII) |
32920 |
tert-butyl mesitylcarbamate
|
|
C14H21NO2 |
详情 |
详情
|
(XIII) |
32921 |
ethyl 3-[2-[(tert-butoxycarbonyl)amino]-3,5-dimethylphenyl]-2-oxopropanoate
|
|
C18H25NO5 |
详情 |
详情
|
(XIV) |
32922 |
benzyl 1-[2-(tert-butoxy)-2-oxoethyl]-5,7-dimethyl-1H-indole-2-carboxylate
|
|
C24H27NO4 |
详情 |
详情
|
(XV) |
32923 |
1-[2-(tert-butoxy)-2-oxoethyl]-5,7-dimethyl-1H-indole-2-carboxylic acid
|
|
C17H21NO4 |
详情 |
详情
|
(XVI) |
32924 |
benzyl 1-(2-methoxy-2-oxoethyl)-5,7-dimethyl-1H-indole-2-carboxylate
|
|
C21H21NO4 |
详情 |
详情
|
(XVII) |
32925 |
1-(2-methoxy-2-oxoethyl)-5,7-dimethyl-1H-indole-2-carboxylic acid
|
|
C14H15NO4 |
详情 |
详情
|
合成路线22
该中间体在本合成路线中的序号:
(II) Nitrophenoxyacetate (III) (prepared from 2-nitrophenol (I) and tert-butyl bromoacetate), was reduced with H2 in the presence of Pd/C to give aniline (IV). This was condensed with Z-D-Phe (V) using 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide.HCl (EDC) and 1-hydroxybenzotriazole (HOBt) to yield amide (VI), which was deprotected to amine (VII) by hydrogenolysis in the presence of Pd/C. Subsequent coupling with Z-Pro (VIII), followed by hydrogenolytic deprotection produced (IX). This was coupled with methyl oxalyl chloride (X) to afford (XI). Then, treatment with trifluoroacetic acid in CH2Cl2 gave acid (XII). Finally, dipeptide (XV) (obtained by coupling of protected 3-amino-2-hydroxy-4-phenylbutyric acid (XIII) with tert-butyl prolinamide (XIV)), was condensed with acid (XII) to produce the title compound.
![](http://zy.yaozh.com/wmf/sch/26/26458401a.jpg)
【1】
Asagarasu, A.; et al.; Synthesis of dipeptide-type human immunodeficiency virus (HIV) protease inhibitors with a binding unit to GP120. Chem Pharm Bull 1998, 46, 5, 867.
|
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) |
19106 |
2-nitrophenol
|
88-75-5 |
C6H5NO3 |
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) |
19108 |
tert-butyl 2-(2-nitrophenoxy)acetate
|
|
C12H15NO5 |
详情 |
详情
|
(IV) |
19109 |
tert-butyl 2-(2-aminophenoxy)acetate
|
|
C12H17NO3 |
详情 |
详情
|
(V) |
19110 |
(2R)-2-[[(benzyloxy)carbonyl]amino]-3-phenylpropionic acid
|
|
C17H17NO4 |
详情 |
详情
|
(VI) |
19111 |
tert-butyl 2-[2-[((2R)-2-[[(benzyloxy)carbonyl]amino]-3-phenylpropanoyl)amino]phenoxy]acetate
|
|
C29H32N2O6 |
详情 |
详情
|
(VII) |
19112 |
tert-butyl 2-(2-[[(2R)-2-amino-3-phenylpropanoyl]amino]phenoxy)acetate
|
|
C21H26N2O4 |
详情 |
详情
|
(VIII) |
19113 |
(2S)-1-[(benzyloxy)carbonyl]-2-pyrrolidinecarboxylic acid
|
1148-11-4 |
C13H15NO4 |
详情 | 详情
|
(IX) |
19114 |
tert-butyl 2-[2-[((2R)-3-phenyl-2-[[(2S)pyrrolidinylcarbonyl]amino]propanoyl)amino]phenoxy]acetate
|
|
C26H33N3O5 |
详情 |
详情
|
(X) |
19115 |
[(chlorocarbonyl)oxy](methoxy)methane
|
|
C3H5ClO3 |
详情 |
详情
|
(XI) |
19116 |
methyl 2-((2S)-2-[[((1R)-1-benzyl-2-[2-[2-(tert-butoxy)-2-oxoethoxy]anilino]-2-oxoethyl)amino]carbonyl]pyrrolidinyl)-2-oxoacetate
|
|
C29H35N3O8 |
详情 |
详情
|
(XII) |
19117 |
2-(2-[[(2R)-2-([[(2S)-1-(2-methoxy-2-oxoacetyl)pyrrolidinyl]carbonyl]amino)-3-phenylpropanoyl]amino]phenoxy)acetic acid
|
|
C25H27N3O8 |
详情 |
详情
|
(XIII) |
19118 |
(2S,3S)-3-[[(benzyloxy)carbonyl]amino]-2-hydroxy-4-phenylbutyric acid
|
|
C18H19NO5 |
详情 |
详情
|
(XIV) |
19119 |
(2S)-N-(tert-butyl)-2-pyrrolidinecarboxamide
|
|
C9H18N2O |
详情 |
详情
|
(XV) |
19120 |
(2S)-1-[(2S,3S)-3-amino-2-hydroxy-4-phenylbutanoyl]-N-(tert-butyl)-2-pyrrolidinecarboxamide
|
|
C19H29N3O3 |
详情 |
详情
|
合成路线23
该中间体在本合成路线中的序号:
(VII) The cyclization of acetyl cyclopropane (I) with 2-nitroacetamide (II) and formamide dimethylacetal (III) by means of p-tolulenesulfonic acid gives the nitro-pyridinone (IV) (1), which is reduced with H2 over Pd/C affording 3-amino-6-propylpyridin-2(1H)-one (V). The protection of the amino group of (V) with benzyl chloroformate affords the carbamate (VI), which is condensed with tert-butyl bromoacetate (VII) by means of NaH in THF giving substituted acetate ester (VIII). The deprotection of (VIII) by hydrogenolysis with H2 over Pd/C in ethyl acetate yields intermediate (IX) with a free amino group, which is treated with benzylsulfonyl chloride (X) and pyridine to afford the sulfonamide (XI). Hydrolysis of the ester group of (XI) with HCl in ethyl acetate gives the carboxylic acid (XII), which is condensed with the pyridylmethylamine (XIII) by means of EDC and HOBT to afford the carboxamide (XIV). Finally, this compound is deprotected with HCl as usual.
![](http://zy.yaozh.com/wmf/sch/26/26635901a.jpg)
【1】
C6 modification of the pyridinone core of thrombin inhibitor L-374,087 as a means of enhancing its oral absorption. Bioorg Med Chem Lett 1998, 8, 13, 1719.
|
【2】
Sanderson, P.E.; Naylor-Olsen, A.M.; Dyer, D.L.; Vacca, J.P.; Isaacs, R.C.A.; Dorsey, B.D.; Fraley, M.E. (Merck & Co., Inc.); Pyridinone-thrombin inhibitors. EP 0835109; JP 1999508558; WO 9701338 .
|
【3】
Dorsey, B.D.; Isaacs, R.C.A.; Sanderson, P.E.; Dyer, D.L.; Naylor-Olsen, A.M.; Fraley, M.E.; Vacca, J.P. (Merck & Co., Inc.); Pyridinone thrombin inhibitors. US 5668289 .
|
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
|
10101 |
Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene
|
501-53-1 |
C8H7ClO2 |
详情 | 详情
|
(I) |
12435 |
Acetylcyclopropane; 1-Cyclopropyl-1-ethanone; Cyclopropylmethylketone
|
765-43-5 |
C5H8O |
详情 | 详情
|
(II) |
27209 |
2-nitroacetamide
|
|
C2H4N2O3 |
详情 |
详情
|
(III) |
11984 |
N-(Dimethoxymethyl)-N,N-dimethylamine;dimethylformamide dimethylacetal;1,1-dimethoxy-N,N-dimethylmethanamine; Dimethoxy-N,N-dimethylmethanamine; N,N-Dimethylformamide dimethyl acetal |
4637-24-5 |
C5H13NO2 |
详情 | 详情
|
(IV) |
27210 |
6-cyclopropyl-3-nitro-2(1H)-pyridinone
|
|
C8H8N2O3 |
详情 |
详情
|
(V) |
27211 |
3-amino-6-propyl-2(1H)-pyridinone
|
|
C8H12N2O |
详情 |
详情
|
(VI) |
27212 |
benzyl 2-oxo-6-propyl-1,2-dihydro-3-pyridinylcarbamate
|
|
C16H18N2O3 |
详情 |
详情
|
(VII) |
17430 |
2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate
|
5292-43-3 |
C6H11BrO2 |
详情 | 详情
|
(VIII) |
27213 |
tert-butyl 2-[3-[[(benzyloxy)carbonyl]amino]-2-oxo-6-propyl-1(2H)-pyridinyl]acetate
|
|
C22H28N2O5 |
详情 |
详情
|
(IX) |
27214 |
tert-butyl 2-[3-amino-2-oxo-6-propyl-1(2H)-pyridinyl]acetate
|
|
C14H22N2O3 |
详情 |
详情
|
(X) |
27215 |
phenylmethanesulfenyl chloride
|
|
C7H7ClS |
详情 |
详情
|
(XI) |
27216 |
tert-butyl 2-[3-[(benzylsulfonyl)amino]-2-oxo-6-propyl-1(2H)-pyridinyl]acetate
|
|
C21H28N2O5S |
详情 |
详情
|
(XII) |
27217 |
2-[3-[(benzylsulfonyl)amino]-2-oxo-6-propyl-1(2H)-pyridinyl]acetic acid
|
|
C17H20N2O5S |
详情 |
详情
|
(XIII) |
27218 |
tert-butyl 5-(aminomethyl)-6-methyl-2-pyridinylcarbamate
|
|
C12H19N3O2 |
详情 |
详情
|
(XIV) |
27219 |
tert-butyl 5-[([2-[3-[(benzylsulfonyl)amino]-2-oxo-6-propyl-1(2H)-pyridinyl]acetyl]amino)methyl]-6-methyl-2-pyridinylcarbamate
|
|
C29H37N5O6S |
详情 |
详情
|
合成路线24
该中间体在本合成路线中的序号:
(VII) The reaction of succinic anhydride (I) with the lithium salt of the chiral oxazolidinone (II) in THF gives 3-(hydroxysucccinyl)-4(S)-isopropyloxazolidin-2-one (III), which is treated successively with oxalyl chloride, CH2N2 and HBr to yield the bromomethyl derivative (IV). The cyclization of (IV) with thiourea in refluxing isopropanol affords the 2-aminothiazol derivative (V), which is protected with 2,2,2-trichloroethyl chloroformate by means of DIEA and DMAP in dichloromethane giving the carbamate (VI). The reaction of (VI) with tert-butyl 2-bromoacetate (VII) by means of sodium hexamethyldisilazane (NaHMDS) in THF yields the chiral butyrate (VIII), which is hydrolyzed with TFA in dichloromethane to the chiral butyric acid (IX). The condensation of (IX) with the intermediate amine (X) by means of BOP-PF6 and DIEA in DMF affords the corresponding amide (XI), which is treated with magnesium methoxide in methanol to eliminate the oxazolidinone group (the chiral inductor) providing the methyl ester (XII). The hydrolysis of (XII) with NaOH, followed by condensation with amine (XIII) (J Org Chem 1988, 53: 6109; J Med Chem 1993, 36: 449) gives the protected intermediate (XIV), which is finally deprotected by reaction with Zn/HCl in aqueous dioxane.
![](http://zy.yaozh.com/wmf/sch/26/26676401a.jpg)
【1】
Simoneau, B.; Lavallee, P.; Anderson, P.C.; et al.; Discovery of non-peptidic P2-P3 butanediamide renin inhibitors with high oral efficacy. Bioorg Med Chem 1999, 7, 3, 489.
|
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
|
10180 |
Thiourea
|
62-56-6 |
CH4N2S |
详情 | 详情
|
|
13664 |
1,1,1-Trichloro-2-[(chlorocarbonyl)oxy]ethane; 2,2,2-Trichloroethyl chloroformate
|
17341-93-4 |
C3H2Cl4O2 |
详情 | 详情
|
(I) |
11291 |
Dihydro-2,5-furandione; Succinic anhydride
|
108-30-5 |
C4H4O3 |
详情 | 详情
|
(II) |
29533 |
[(4S)-4-isopropyl-2-oxo-1,3-oxazolidin-3-yl]lithium
|
|
C6H10LiNO2 |
详情 |
详情
|
(III) |
29534 |
4-[(4S)-4-isopropyl-2-oxo-1,3-oxazolidin-3-yl]-4-oxobutyric acid
|
|
C10H15NO5 |
详情 |
详情
|
(IV) |
29535 |
5-bromo-1-[(4S)-4-isopropyl-2-oxo-1,3-oxazolidin-3-yl]-1,4-pentanedione
|
|
C11H16BrNO4 |
详情 |
详情
|
(V) |
29536 |
(4S)-3-[3-(2-amino-1,3-thiazol-4-yl)propanoyl]-4-isopropyl-1,3-oxazolidin-2-one
|
|
C12H17N3O3S |
详情 |
详情
|
(VI) |
29537 |
2,2,2-trichloroethyl 4-[3-[(4S)-4-isopropyl-2-oxo-1,3-oxazolidin-3-yl]-3-oxopropyl]-1,3-thiazol-2-ylcarbamate
|
|
C15H18Cl3N3O5S |
详情 |
详情
|
(VII) |
17430 |
2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate
|
5292-43-3 |
C6H11BrO2 |
详情 | 详情
|
(VIII) |
29538 |
tert-butyl (3R)-4-[(4S)-4-isopropyl-2-oxo-1,3-oxazolidin-3-yl]-4-oxo-3-[(2-[[(2,2,2-trichloroethoxy)carbonyl]amino]-1,3-thiazol-4-yl)methyl]butanoate
|
|
C21H28Cl3N3O7S |
详情 |
详情
|
(IX) |
29539 |
(3R)-4-[(4S)-4-isopropyl-2-oxo-1,3-oxazolidin-3-yl]-4-oxo-3-[(2-[[(2,2,2-trichloroethoxy)carbonyl]amino]-1,3-thiazol-4-yl)methyl]butyric acid
|
|
C17H20Cl3N3O7S |
详情 |
详情
|
(X) |
29540 |
2-[(cyclohexylmethyl)amino]-N-methyl-N-[2-(2-pyridinyl)ethyl]acetamide
|
|
C17H27N3O |
详情 |
详情
|
(XI) |
29541 |
2,2,2-trichloroethyl 4-((2R)-4-[(cyclohexylmethyl)(2-[methyl[2-(2-pyridinyl)ethyl]amino]-2-oxoethyl)amino]-2-[[(4S)-4-isopropyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl]-4-oxobutyl)-1,3-thiazol-2-ylcarbamate
|
|
C34H45Cl3N6O7S |
详情 |
详情
|
(XII) |
29542 |
methyl (2R)-4-[(cyclohexylmethyl)(2-[methyl[2-(2-pyridinyl)ethyl]amino]-2-oxoethyl)amino]-4-oxo-2-[(2-[[(2,2,2-trichloroethoxy)carbonyl]amino]-1,3-thiazol-4-yl)methyl]butanoate
|
|
C29H38Cl3N5O6S |
详情 |
详情
|
(XIII) |
29543 |
(2S,3R,4S)-2-amino-1-cyclohexyl-6-methyl-3,4-heptanediol
|
|
C14H29NO2 |
详情 |
详情
|
(XIV) |
29544 |
2,2,2-trichloroethyl 4-[(2R)-2-([[(1S,2R,3S)-1-(cyclohexylmethyl)-2,3-dihydroxy-5-methylhexyl]amino]carbonyl)-4-[(cyclohexylmethyl)(2-[methyl[2-(2-pyridinyl)ethyl]amino]-2-oxoethyl)amino]-4-oxobutyl]-1,3-thiazol-2-ylcarbamate
|
|
C42H63Cl3N6O7S |
详情 |
详情
|
合成路线25
该中间体在本合成路线中的序号:
(IV) The condensation of dimethyl malonate (I) with 2-cloroallyl chloride (II) by means of sodium methoxide in hot methanol gives the alkylmalonate (III), which is treated with tert-butyl bromoacetate (IV), NaOH and benzyltriethylammonium chloride to yield the tricarboxylic ester (V). Partial decarboxylation of (V) with KOH in hot methanol/water affords the succinic acid derivative (VI), which is submitted to enzymatic hydrolysis with Alcalase 2.4L to provide the chiral monoester (VII). The condensation of monoacid (VII) with amine (VIII) by means of HOBT, DCC, and DIEA in THF gives the amide (IX), which is treated with TFA to eliminate the tert-butyl protecting group yielding the acid (X). The condensation of (X) with amine (XI) by means of NMM and pivaloyl chloride affords the amide (XII), which is treated with 2-methoxypropene (XIII) and TsOH in dichloromethane to protect the vicinal hydroxy groups giving the dioxolane (XIV). The bromination of the allyl double bond of (XIV) with NBS in tert-butyl methyl ether/water gives 3-bromo-2-oxopropyl derivative (XV).
![](http://zy.yaozh.com/wmf/sch/26/26676402a.jpg)
【1】
Beaulieu, P.L.; et al.; Practical synthesis of BILA 2157 BS, a potent and orally active renin inhibitor: Use of an enzayme-catalyzed hydrolysis for the preparation of homochiral succinic acid derivatives. J Org Chem 1999, 64, 18, 6622.
|
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
(I) |
19373 |
dimethyl malonate;Methyl malonate;Propanedioic acid dimethyl ester |
108-59-8 |
C5H8O4 |
详情 | 详情
|
(II) |
31608 |
2,3-dichloro-1-propene
|
78-88-6 |
C3H4Cl2 |
详情 | 详情
|
(III) |
31609 |
dimethyl 2-(2-chloro-2-propenyl)malonate
|
|
C8H11ClO4 |
详情 |
详情
|
(IV) |
17430 |
2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate
|
5292-43-3 |
C6H11BrO2 |
详情 | 详情
|
(V) |
31610 |
1-(tert-butyl) 2,2-dimethyl 4-chloro-4-pentene-1,2,2-tricarboxylate
|
|
C14H21ClO6 |
详情 |
详情
|
(VI) |
31611 |
4-(tert-butyl) 1-methyl 2-(2-chloro-2-propenyl)succinate
|
|
C12H19ClO4 |
详情 |
详情
|
(VII) |
31612 |
(2S)-2-[2-(tert-butoxy)-2-oxoethyl]-4-chloro-4-pentenoic acid
|
|
C11H17ClO4 |
详情 |
详情
|
(VIII) |
29543 |
(2S,3R,4S)-2-amino-1-cyclohexyl-6-methyl-3,4-heptanediol
|
|
C14H29NO2 |
详情 |
详情
|
(IX) |
31613 |
tert-butyl (3S)-5-chloro-3-([[(1S,2R,3S)-1-(cyclohexylmethyl)-2,3-dihydroxy-5-methylhexyl]amino]carbonyl)-5-hexenoate
|
|
C25H44ClNO5 |
详情 |
详情
|
(X) |
31614 |
(3S)-5-chloro-3-([[(1S,2R,3S)-1-(cyclohexylmethyl)-2,3-dihydroxy-5-methylhexyl]amino]carbonyl)-5-hexenoic acid
|
|
C21H36ClNO5 |
详情 |
详情
|
(XI) |
29540 |
2-[(cyclohexylmethyl)amino]-N-methyl-N-[2-(2-pyridinyl)ethyl]acetamide
|
|
C17H27N3O |
详情 |
详情
|
(XII) |
31615 |
(2S)-2-(2-chloro-2-propenyl)-N(4)-(cyclohexylmethyl)-N(1)-[(1S,2R,3S)-1-(cyclohexylmethyl)-2,3-dihydroxy-5-methylhexyl]-N(4)-(2-[methyl[2-(2-pyridinyl)ethyl]amino]-2-oxoethyl)butanediamide
|
|
C38H61ClN4O5 |
详情 |
详情
|
(XIII) |
17354 |
isopropenyl methyl ether; 2-methoxy-1-propene
|
116-11-0 |
C4H8O |
详情 | 详情
|
(XIV) |
31616 |
(2S)-2-(2-chloro-2-propenyl)-N(1)-[(1S)-2-cyclohexyl-1-[(4R,5S)-5-isobutyl-2,2-dimethyl-1,3-dioxolan-4-yl]ethyl]-N(4)-(cyclohexylmethyl)-N(4)-(2-[methyl[2-(2-pyridinyl)ethyl]amino]-2-oxoethyl)butanediamide
|
|
C41H65ClN4O5 |
详情 |
详情
|
(XV) |
31617 |
(2R)-2-(3-bromo-2-oxopropyl)-N(1)-[(1S)-2-cyclohexyl-1-[(4R,5S)-5-isobutyl-2,2-dimethyl-1,3-dioxolan-4-yl]ethyl]-N(4)-(cyclohexylmethyl)-N(4)-(2-[methyl[2-(2-pyridinyl)ethyl]amino]-2-oxoethyl)butanediamide
|
|
C41H65BrN4O6 |
详情 |
详情
|
合成路线26
该中间体在本合成路线中的序号:
(VI) The condensation of gamma-butyrolactone (I) with phenethyl amine (II) at high temperatures afforded phenethylpyrrolidinone (III). This was alkylated with isobutyl iodide (IV) in the presence of lithium diisopropylamide in cold THF yielding the 3-isobutyl pyrrolidinone (V), and further alkylated with tert-butyl bromoacetate (VI) to give (VII). Subsequent alkylation of (VII) at the alpha-position of carboxylate group with allyl bromide provided (VIII). Ozonolysis of the double bond of (VIII), followed by reductive treatment with NaBH4 produced alcohol (IX), which was coupled with dibenzyl iminodicarboxylate (X) under Mitsunobu conditions giving (XI). The biscarbamate (XI) was deprotected by hydrogenolysis over Pd/C, and the resulting primary amine (XII) was condensed with 3,4-difluorobenzoyl chloride (XIII) to furnish amide (XIV). Then, trifluoroacetic acid-promoted cleavage of the tert-butyl ester of (XIV) provided the corresponding carboxylic acid, which was finally coupled with hydroxylamine by means of EDC and HOBt to afford the target hydroxamic acid
![](http://zy.yaozh.com/wmf/sch/26/26687101a.jpg)
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) |
20576 |
dihydro-2(3H)-furanone
|
96-48-0 |
C4H6O2 |
详情 | 详情
|
(II) |
18333 |
Phenethylamine; 2-Phenyl-1-ethanamine
|
64-04-0 |
C8H11N |
详情 | 详情
|
(III) |
28259 |
1-phenethyl-2-pyrrolidinone
|
|
C12H15NO |
详情 |
详情
|
(IV) |
18168 |
1-iodo-2-methylpropane
|
513-38-2 |
C4H9I |
详情 | 详情
|
(V) |
28267 |
3-isobutyl-1-phenethyl-2-pyrrolidinone
|
|
C16H23NO |
详情 |
详情
|
(VI) |
17430 |
2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate
|
5292-43-3 |
C6H11BrO2 |
详情 | 详情
|
(VII) |
28260 |
tert-butyl 2-(3-isobutyl-2-oxo-1-phenethyl-3-pyrrolidinyl)acetate
|
|
C22H33NO3 |
详情 |
详情
|
(VIII) |
28261 |
tert-butyl 2-(3-isobutyl-2-oxo-1-phenethyl-3-pyrrolidinyl)-4-pentenoate
|
|
C25H37NO3 |
详情 |
详情
|
(IX) |
28268 |
tert-butyl 4-hydroxy-2-(3-isobutyl-2-oxo-1-phenethyl-3-pyrrolidinyl)butanoate
|
|
C24H37NO4 |
详情 |
详情
|
(X) |
28262 |
1-[[([[(benzyloxy)carbonyl]amino]carbonyl)oxy]methyl]benzene
|
|
C16H15NO4 |
详情 |
详情
|
(XI) |
28263 |
tert-butyl 4-[bis[(benzyloxy)carbonyl]amino]-2-(3-isobutyl-2-oxo-1-phenethyl-3-pyrrolidinyl)butanoate
|
|
C40H50N2O7 |
详情 |
详情
|
(XII) |
28264 |
tert-butyl 4-amino-2-(3-isobutyl-2-oxo-1-phenethyl-3-pyrrolidinyl)butanoate
|
|
C24H38N2O3 |
详情 |
详情
|
(XIII) |
28265 |
3,4-difluorobenzoyl chloride
|
76903-88-3 |
C7H3ClF2O |
详情 | 详情
|
(XIV) |
28266 |
tert-butyl 4-[(3,4-difluorobenzoyl)amino]-2-(3-isobutyl-2-oxo-1-phenethyl-3-pyrrolidinyl)butanoate
|
|
C31H40F2N2O4 |
详情 |
详情
|
合成路线27
该中间体在本合成路线中的序号:
(VIII) The reaction of 4-ethyl-3,5-dimethoxybenzaldehyde (I) with (ethoxycarbonylmethyl)triphenylphosphonium bromide (II) by means o butyllithium in THF gives the acrylate (III), which is allowed to react with nitromethane/triton B in hot methanol yielding the 4-nitrobutyrate (IV). The reduction of (IV) with H2 over RaNi in ethanol affords the 4-aminobutyrate (V), which is cyclized to the pyrrolidinone (VI) by means of p-toluenesulfonic acid in refluxing ethanol. The methylation of (VI) with NaH/methyl iodide in THF gives the corresponding N-methylpyrrolidinone (VII), which is condensed with tert-butyl bromoacetate (VIII) by means of butyllithium/diisopropylamine in THF yielding the intermediate (IX). The reduction of the ketonic grupof (IX) with the complex borane/THF in THF affords the pyrrolidineacetate ester (X), which is cyclized by means of polyphosphoric acid (PPA) at 120 C giving the benzisoindole (XI). Finally, this compound is selectively demethylate by menas of BBr3 in dichloromethane.
![](http://zy.yaozh.com/wmf/sch/26/26697401a.jpg)
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) |
20754 |
4-ethyl-3,5-dimethoxybenzaldehyde
|
|
C11H14O3 |
详情 |
详情
|
(II) |
20755 |
(2-ethoxy-2-oxoethyl)(triphenyl)phosphonium bromide
|
1530-45-6 |
C22H22BrO2P |
详情 | 详情
|
(III) |
20756 |
ethyl (E)-3-(4-ethyl-3,5-dimethoxyphenyl)-2-propenoate
|
|
C15H20O4 |
详情 |
详情
|
(IV) |
20757 |
ethyl 3-(4-ethyl-3,5-dimethoxyphenyl)-4-nitrobutanoate
|
|
C16H23NO6 |
详情 |
详情
|
(V) |
20758 |
ethyl 4-amino-3-(4-ethyl-3,5-dimethoxyphenyl)butanoate
|
|
C16H25NO4 |
详情 |
详情
|
(VI) |
20759 |
4-(4-ethyl-3,5-dimethoxyphenyl)-2-pyrrolidinone
|
|
C14H19NO3 |
详情 |
详情
|
(VII) |
20760 |
4-(4-ethyl-3,5-dimethoxyphenyl)-1-methyl-2-pyrrolidinone
|
|
C15H21NO3 |
详情 |
详情
|
(VIII) |
17430 |
2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate
|
5292-43-3 |
C6H11BrO2 |
详情 | 详情
|
(IX) |
20762 |
tert-butyl 2-[4-(4-ethyl-3,5-dimethoxyphenyl)-1-methyl-2-oxo-3-pyrrolidinyl]acetate
|
|
C21H31NO5 |
详情 |
详情
|
(X) |
20763 |
tert-butyl 2-[4-(4-ethyl-3,5-dimethoxyphenyl)-1-methyl-3-pyrrolidinyl]acetate
|
|
C21H33NO4 |
详情 |
详情
|
(XI) |
20764 |
(3aS,9bS)-7-ethyl-6,8-dimethoxy-2-methyl-1,2,3,3a,4,9b-hexahydro-5H-benzo[e]isoindol-5-one
|
|
C17H23NO3 |
详情 |
详情
|
合成路线28
该中间体在本合成路线中的序号:
(V) 4-Methylvaleric acid (I) was converted to acid chloride (II) and then condensed with (S)-4-benzyl-2-oxazolidinone (III) to give (IV). Subsequent alkylation of (IV) with tert-butyl bromoacetate (V) in the presence of sodium bis(trimethylsilyl)amide produced the chiral intermediate (VI), which was hydrolyzed with lithium peroxide to yield (R)-2-isobutylsuccinic acid 4-tert-butyl ester (VII). Further alkylation of (VII) with 4-bromo-1-butene (VIII) afforded a 6:1 mixture of syn/anti isobutenyl compounds (IX), which upon isomerization with LDA in THF at -20 C, followed by quenching with MeOH, provided a 1:1.5 mixture of isomers. Condensation of N-Boc-L-tyrosine (X) with methylamine in the presence of EDC and HOBt gave amide (XI). Then, removal of the Boc protecting group with HCl in dioxan yielded tyrosinamide (XII). This was coupled to succinic acid derivative (IX) using EDC and HOBt to afford the corresponding amide (XIII) as an epimeric mixture. Hydroboration of the butenyl double bond, followed by oxidative treatment with H2O2 produced alcohol (XIV).
![](http://zy.yaozh.com/wmf/sch/26/26978001a.jpg)
【1】
Sheppard, G.S.; Guo, Y.; Siummers, J.B.; Holms, J.H.; Steinman, D.H.; Michaelides, M.R.; Florjancic, A.S.; Xu, L.; Davidsen, S.K. (Abbott Laboratories Inc.); Macrocyclic inhibitors of matrix metalloproteinases and TNFalpha secretion. EP 1021423; WO 9830551 . |
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) |
25389 |
4-methylpentanoic acid
|
646-07-1 |
C6H12O2 |
详情 | 详情
|
(II) |
25390 |
4-methylpentanoyl chloride
|
38136-29-7 |
C6H11ClO |
详情 | 详情
|
(III) |
25351 |
(4R)-4-benzyl-1,3-oxazolidin-2-one; (R)-(+)-4-benzyl-2-oxazolidinone
|
102029-44-7 |
C10H11NO2 |
详情 | 详情
|
(IV) |
25391 |
(4S)-4-benzyl-3-(4-methylpentanoyl)-1,3-oxazolidin-2-one
|
|
C16H21NO3 |
详情 |
详情
|
(V) |
17430 |
2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate
|
5292-43-3 |
C6H11BrO2 |
详情 | 详情
|
(VI) |
25392 |
tert-butyl (3R)-3-[[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl]-5-methylhexanoate
|
|
C22H31NO5 |
详情 |
详情
|
(VII) |
25393 |
(2R)-2-[2-(tert-butoxy)-2-oxoethyl]-4-methylpentanoic acid
|
|
C12H22O4 |
详情 |
详情
|
(VIII) |
11720 |
4-Bromo-1-butene
|
5162-44-7 |
C4H7Br |
详情 | 详情
|
(IX) |
25394 |
(2R)-3-(tert-butoxycarbonyl)-2-isobutyl-6-heptenoic acid
|
|
C16H28O4 |
详情 |
详情
|
(X) |
25395 |
(2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-hydroxyphenyl)propionic acid
|
3978-80-1 |
C14H19NO5 |
详情 | 详情
|
(XI) |
25396 |
tert-butyl (1S)-1-(4-hydroxybenzyl)-2-(methylamino)-2-oxoethylcarbamate
|
|
C15H22N2O4 |
详情 |
详情
|
(XII) |
25397 |
(2S)-2-amino-3-(4-hydroxyphenyl)-N-methylpropanamide
|
|
C10H14N2O2 |
详情 |
详情
|
(XIII) |
25398 |
tert-butyl 2-[(1R)-1-([[(1S)-1-(4-hydroxybenzyl)-2-(methylamino)-2-oxoethyl]amino]carbonyl)-3-methylbutyl]-5-hexenoate
|
|
C26H40N2O5 |
详情 |
详情
|
(XIV) |
25399 |
tert-butyl (3R)-3-([[(1S)-1-(4-hydroxybenzyl)-2-(methylamino)-2-oxoethyl]amino]carbonyl)-2-(4-hydroxybutyl)-5-methylhexanoate
|
|
C26H42N2O6 |
详情 |
详情
|
合成路线29
该中间体在本合成路线中的序号:
(V) The intermediate alcohol (VIII) was prepared as shown in Scheme 27060901a:
Aldol condensation of 3,4-dimethoxybenzaldehyde (I) with 3-hydroxyacetophenone (II) in the presence of KOH provided chalcone (III), which was hydrogenated over Pd/C to yield the corresponding diarylpropanone (IV). Subsequent alkylation of the phenolic hydroxyl group of (IV) with tert-butyl bromoacetate (V) using NaH in DMF gave ether (VI). Then, enantioselective reduction of ketone by means of (+)-beta-chlorodiisopinocampheylborane (VII) at -20 C furnished the (R)-alcohol (VIII).
![](http://zy.yaozh.com/wmf/sch/27/27060901a.jpg)
【1】
Yang, W.; Guo, T.; Keenan, T.P.; Laborde, E.; Holt, D.A. (Ariad Pharmaceuticals Inc.); Synthetic derivs. of rapamycin as multimerizing agents for chimeric proteins with immunophilin-derived domains. JP 2000505475; WO 9731898 .
|
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) |
18304 |
3,4-Dimethoxybenzaldehyde; Veratraldehyde
|
120-14-9 |
C9H10O3 |
详情 | 详情
|
(II) |
25331 |
3-hydroxyacetophenone; 1-(3-hydroxyphenyl)-1-ethanone
|
121-71-1 |
C8H8O2 |
详情 | 详情
|
(III) |
25332 |
(E)-3-(3,4-dimethoxyphenyl)-1-(3-hydroxyphenyl)-2-propen-1-one
|
|
C17H16O4 |
详情 |
详情
|
(IV) |
25341 |
3-(3,4-dimethoxyphenyl)-1-(3-hydroxyphenyl)-1-propanone
|
|
C17H18O4 |
详情 |
详情
|
(V) |
17430 |
2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate
|
5292-43-3 |
C6H11BrO2 |
详情 | 详情
|
(VI) |
25342 |
tert-butyl 2-[3-[3-(3,4-dimethoxyphenyl)propanoyl]phenoxy]acetate
|
|
C23H28O6 |
详情 |
详情
|
(VII) |
25343 |
chloro[bis[(1S,2R,3S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]]borane
|
112246-73-8 |
C20H34BCl |
详情 | 详情
|
(VIII) |
25348 |
tert-butyl 2-[3-[(1R)-3-(3,4-dimethoxyphenyl)-1-hydroxypropyl]phenoxy]acetate
|
|
C23H30O6 |
详情 |
详情
|
合成路线30
该中间体在本合成路线中的序号:
2-Chloro-4-propionylpyridine (I) was protected as the cyclic ketal (II) with 1,3-propanediol and p-toluenesulfonic acid in refluxing toluene with azeotropical removal of water. Subsequent halogen displacement in (II) with sodium methoxide in boiling acetonitrile gave methoxypyridine (III). Lithiation of (III) with mesityllithium, followed by condensation with dimethylformamide provided formylpyridine (IV), which was reduced to alcohol (V) using NaBH4 in MeOH. The hydroxyl group of (V) was protected as the benzyl ether (VI), and the ketal group was then hydrolyzed to ketone (VII) with aqueous trifluoroacetic acid. Reformatskii reaction of (VII) with tert-butyl bromoacetate and zinc afforded the beta-hydroxyester (VIII). Further hydrogenolysis of benzyl ether of (VIII) over Pd/C gave alcohol (IX). Then, treatment of (IX) with trifluoroacetic acid produced lactone (X), and hydrolysis of the methoxy group of (X) with aqueous HCl furnished pyridone (XI). Condensation of 3,4-difluoroacetanilide (XII) with Vilsmeier reagent yielded quinolinecarboxaldehyde (XIII), which was reduced to alcohol (XIV) with NaBH4. This was then coupled with pyridone (XI) under Mitsunobu conditions to give (XV). Finally, Heck reaction of (XV) with palladium acetate and triphenyl phosphine generated the target pentacyclic compound.
![](http://zy.yaozh.com/wmf/sch/27/27157001a.jpg)
【1】
Lavergne, O.; Lesuer-Ginot, L.; Pla Rodas, F.; Kasprzyk, P.G.; Pommier, J.; Demarquay, D.; Prevost, G.; Ulibarri, G.; Rolland, A.; Schiano-Liberatore, A.M.; Harnett, J.; Pons, D.; Camara, J.; Bigg, D.C.; Homocamptothecins: Synthesis and antitumor activity of novel E-ring-modified camptothecin analogues. J Med Chem 1998, 41, 27, 5410. |
【2】
Bigg, D.; Lavergne, O.; Pla Rodas, F.; Pommier, J.; Ulibarri, G. (SCRAS (Societé de Conseils de Recherches et d'Applications Scientifiques)); Novel camptothecin analogues, preparation methods therefor, use thereof as drugs, and pharmaceutical compsns. containing said analogues. EP 0835258; JP 1999508249; US 5981542; WO 9700876 . |
【3】
Lanco, C.; Rolland, A.; Bigg, D.; Lavergne, O.; Harnett, J.; Liberatore, A.-M. (SCRAS (Societé de Conseils de Recherches et d'Applications Scientifiques)); Pro-drugs and counterparts of camptothecin, their application as medicines . EP 0946566; WO 9828304 . |
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
|
12912 |
1-(Bromomethyl)benzene; Alpha-bromotoluene
|
100-39-0 |
C7H7Br |
详情 | 详情
|
|
14685 |
1,3-propanediol; Trimethylene Glycol
|
504-63-2 |
C3H8O2 |
详情 | 详情
|
|
17430 |
2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate
|
5292-43-3 |
C6H11BrO2 |
详情 | 详情
|
(I) |
25461 |
1-(2-chloro-4-pyridinyl)-1-propanone
|
|
C8H8ClNO |
详情 |
详情
|
(II) |
25462 |
2-chloro-4-(2-ethyl-1,3-dioxan-2-yl)pyridine
|
|
C11H14ClNO2 |
详情 |
详情
|
(III) |
25463 |
4-(2-ethyl-1,3-dioxan-2-yl)-2-pyridinyl methyl ether; 4-(2-ethyl-1,3-dioxan-2-yl)-2-methoxypyridine
|
|
C12H17NO3 |
详情 |
详情
|
(IV) |
25464 |
4-(2-ethyl-1,3-dioxan-2-yl)-2-methoxynicotinaldehyde
|
|
C13H17NO4 |
详情 |
详情
|
(V) |
25465 |
[4-(2-ethyl-1,3-dioxan-2-yl)-2-methoxy-3-pyridinyl]methanol
|
|
C13H19NO4 |
详情 |
详情
|
(VI) |
25466 |
3-[(benzyloxy)methyl]-4-(2-ethyl-1,3-dioxan-2-yl)-2-methoxypyridine; benzyl [4-(2-ethyl-1,3-dioxan-2-yl)-2-methoxy-3-pyridinyl]methyl ether
|
|
C20H25NO4 |
详情 |
详情
|
(VII) |
25467 |
1-[3-[(benzyloxy)methyl]-2-methoxy-4-pyridinyl]-1-propanone
|
|
C17H19NO3 |
详情 |
详情
|
(VIII) |
25468 |
tert-butyl 3-[3-[(benzyloxy)methyl]-2-methoxy-4-pyridinyl]-3-hydroxypentanoate
|
|
C23H31NO5 |
详情 |
详情
|
(IX) |
25469 |
tert-butyl 3-hydroxy-3-[3-(hydroxymethyl)-2-methoxy-4-pyridinyl]pentanoate
|
|
C16H25NO5 |
详情 |
详情
|
(X) |
25470 |
5-ethyl-5-hydroxy-9-methoxy-4,5-dihydrooxepino[3,4-c]pyridin-3(1H)-one
|
|
C12H15NO4 |
详情 |
详情
|
(XI) |
25471 |
5-ethyl-5-hydroxy-1,4,5,8-tetrahydrooxepino[3,4-c]pyridine-3,9-dione
|
|
C11H13NO4 |
详情 |
详情
|
(XII) |
25472 |
N-(3,4-difluorophenyl)acetamide
|
458-11-7 |
C8H7F2NO |
详情 | 详情
|
(XIII) |
25473 |
2-chloro-6,7-difluoro-3-quinolinecarbaldehyde
|
|
C10H4ClF2NO |
详情 |
详情
|
(XIV) |
25474 |
(2-chloro-6,7-difluoro-3-quinolinyl)methanol
|
|
C10H6ClF2NO |
详情 |
详情
|
(XV) |
25475 |
8-[(2-chloro-6,7-difluoro-3-quinolinyl)methyl]-5-ethyl-5-hydroxy-1,4,5,8-tetrahydrooxepino[3,4-c]pyridine-3,9-dione
|
|
C21H17ClF2N2O4 |
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 condensation of 5-(hydroxymethyl)-4-methyl-1H-imidazole (I) with tert-butyl bromoacetate (II) by means of K2CO3 in DMF gives the imidazolylacetic ester (III), which is treated with diphenylphosphoryl azide and DBU in DMF yielding the azidomethyl compound (IV). The reduction of (IV) with H2 over Pd/C in ethyl acetate affords the aminomethyl compound (V), which is acylated with 2-[3-(benzylsulfonamido)-6-methyl-2-oxo-1,2-dihydropyridin-1-yl]acetic acid (VI) by means of EDC and HOBT in DMF providing the carboxamide (VII). Elimination of the tert-butyl group of (VII) with HCl in ethyl acetate gives the free carboxylic acid (VIII), which is finally amidated with tert-butylamine by means of EDC and HOBT in DMF.
![](http://zy.yaozh.com/wmf/sch/27/27369001a.jpg)
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) |
26595 |
(4-methyl-1H-imidazol-5-yl)methanol
|
38585-62-5 |
C5H8N2O |
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) |
26596 |
tert-butyl 2-[5-(hydroxymethyl)-4-methyl-1H-imidazol-1-yl]acetate
|
|
C11H18N2O3 |
详情 |
详情
|
(IV) |
26597 |
tert-butyl 2-[5-(azidomethyl)-4-methyl-1H-imidazol-1-yl]acetate
|
|
C11H17N5O2 |
详情 |
详情
|
(V) |
26598 |
tert-butyl 2-[5-(aminomethyl)-4-methyl-1H-imidazol-1-yl]acetate
|
|
C11H19N3O2 |
详情 |
详情
|
(VI) |
26599 |
2-[3-[(benzylsulfonyl)amino]-6-methyl-2-oxo-1(2H)-pyridinyl]acetic acid
|
|
C15H16N2O5S |
详情 |
详情
|
(VII) |
26600 |
tert-butyl 2-[5-[([2-[3-[(benzylsulfonyl)amino]-6-methyl-2-oxo-1(2H)-pyridinyl]acetyl]amino)methyl]-4-methyl-1H-imidazol-1-yl]acetate
|
|
C26H33N5O6S |
详情 |
详情
|
(VIII) |
26601 |
2-[5-[([2-[3-[(benzylsulfonyl)amino]-6-methyl-2-oxo-1(2H)-pyridinyl]acetyl]amino)methyl]-4-methyl-1H-imidazol-1-yl]acetic acid
|
|
C22H25N5O6S |
详情 |
详情
|
合成路线32
该中间体在本合成路线中的序号:
(X) The intermediate 2-(2(S)-amino-3-phenylpropoxy)ethanol (VII) has been obtained as follows: The condensation of 2(S)-(dibenzylamino)-3-phenyl-1-propanol (IX) with tert-butyl 2-bromoacetate (X) by means of tetrabutylammonium hydrogen sulfate and NaOH in dichloromethane/water gives 2-[2(S)-(dibenzylamino)-3-phenylpropoxy]acetic acid tert-butyl ester (XI), which is reduced with LiAlH4 in THF yielding 2-[2(S)-(dibenzylamino)-3-phenylpropoxy]ethanol (XII). Finally, this compound is debenzylated by hydrogenation with H2 over Pd/C in methanol/acetic acid affording the target intermediate (VII).
![](http://zy.yaozh.com/wmf/sch/27/27369701b.jpg)
【1】
Brundish, D.E.; Brown, L.N.; Le Grand, D.M.; Menear, K.A.; Smith, G.P.; Allen, M.C.; Butler, P.I.; Cockroft, X.-L.; Matthews, I.T.W.; Walker, C.V.; Wathey, W.B. (Novartis AG); Thrombin inhibitors. WO 9746553 .
|
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) |
30455 |
2-[[(2S)-2-amino-3-phenylpropyl]oxy]-1-ethanol
|
|
C11H17NO2 |
详情 |
详情
|
(IX) |
30457 |
(2S)-2-(dibenzylamino)-3-phenyl-1-propanol
|
111060-52-7 |
C23H25NO |
详情 | 详情
|
(X) |
17430 |
2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate
|
5292-43-3 |
C6H11BrO2 |
详情 | 详情
|
(XI) |
30458 |
tert-butyl 2-[[(2S)-2-(dibenzylamino)-3-phenylpropyl]oxy]acetate
|
|
C29H35NO3 |
详情 |
详情
|
(XII) |
30459 |
2-[[(2S)-2-(dibenzylamino)-3-phenylpropyl]oxy]-1-ethanol
|
|
C25H29NO2 |
详情 |
详情
|
合成路线33
该中间体在本合成路线中的序号:
(VI) The condensation of 4-benzyloxy-2-hydroxy-6-methoxyacetophenone (I) with 3,4-dimethoxybenzaldehyde (II) by means of KOH in ethanol/water gives the chalcone (III), which is cyclized by means of SeO2 in refluxing isoamyl alcohol to yield the benzopyran (IV). The hydrogenolysis of the benzyl group of (IV) with H2 over Pd/C in chloroform affords the 7-hydroxybenzopyran (V), which is condensed with tert-butyl bromoacetate (VII) by means of CaCO3 in DMF to provide the benzopyranyloxy acetate (VIII). Finally, this compound is deprotected by reaction with p-toluenesulfonic acid in refluxing benzene.
![](http://zy.yaozh.com/wmf/sch/27/27624101a.jpg)
【1】
Yoo, M.; Son, M.W.; Kin, I.Y.; Kin, W.B.; Kin, S.H.; Lee, S.D.; Lim, G.J.; Lim, J.I.; Ahn, B.O.; Baik, N.G.; Kin, D.S.; Oh, T.Y.; Ryu, B.K.; Yang, J.S.; Shin, H.C. (Dong-A Pharmaceutical Co., Ltd.); Gastroprotective flavone/flavone cpds. with therapeutic effect on inflammatory bowel disease. JP 1999514015; US 6025387; WO 9804541 . |
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) |
27802 |
1-[4-(benzyloxy)-2-hydroxy-6-methoxyphenyl]-1-ethanone
|
|
C16H16O4 |
详情 |
详情
|
(II) |
18304 |
3,4-Dimethoxybenzaldehyde; Veratraldehyde
|
120-14-9 |
C9H10O3 |
详情 | 详情
|
(III) |
27803 |
(E)-1-[4-(benzyloxy)-2-hydroxy-6-methoxyphenyl]-3-(3,4-dimethoxyphenyl)-2-propen-1-one
|
|
C25H24O6 |
详情 |
详情
|
(IV) |
27804 |
7-(benzyloxy)-2-(3,4-dimethoxyphenyl)-5-methoxy-4H-chromen-4-one
|
|
C25H22O6 |
详情 |
详情
|
(V) |
27805 |
2-(3,4-dimethoxyphenyl)-7-hydroxy-5-methoxy-4H-chromen-4-one
|
|
C18H16O6 |
详情 |
详情
|
(VI) |
17430 |
2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate
|
5292-43-3 |
C6H11BrO2 |
详情 | 详情
|
(VII) |
27806 |
tert-butyl 2-[[2-(3,4-dimethoxyphenyl)-5-methoxy-4-oxo-4H-chromen-7-yl]oxy]acetate
|
|
C24H26O8 |
详情 |
详情
|
合成路线34
该中间体在本合成路线中的序号:
Condensation of 4-methylpentanoyl chloride (I) with (S)-4-benzyl-2-oxazolidinone using n-BuLi afforded the N-acyloxazolidinone (III). Asymmetric alkylation of (III) with tert-butyl bromoacetate and LDA gave (IV), and subsequent removal of the chiral auxiliary by hydrolysis with lithium peroxide yielded (R)-2-isobutylsuccinic acid mono tert-butyl ester (V). This was further alkylated with allyl bromide (VI) and LDA to provide the (R,R)-2,3-disubstituted succinate (VII). Epimerization of (VII) to the required (2R,3S)-isomer (VIII) was accomplished by treatment with LDA and Et2AlCl. Benzyl ester (IX) was then prepared by reaction of (VIII) with benzyl bromide and DBU. Hydroboration of the olefinic double bond of (IX) by means of 9-borabicyclononane, followed by oxidative treatment with H2O2 gave rise to the primary alcohol (X). This was converted to carbonate (XI) upon reaction with p-nitrophenyl chloroformate and N-methylmorpholine (NMM). Coupling of (XI) with lysine derivative (XII) then yielded carbamate (XIII).
![](http://zy.yaozh.com/wmf/sch/27/27949001a.jpg)
【1】
Xue, C.-B.; Cherney, R.J.; DeCicco, C.P.; Degrado, W.F.; He, X.; Hodge, C.N.; Jacobson, I.C.; Magolda, R.L.; Arner, E.C.; Duan, J.; Nelson, D.J. (DuPont Pharmaceuticals Co.); Novel macrocyclic cpds. as metalloprotease inhibitors. EP 0863885; JP 2000502050; WO 9718207 . |
【2】
Nelson, D.; Magolda, R.L.; Jacobson, I.C.; He, X.; Arner, E.; Cherney, R.J.; Duan, J.; Xue, C.-B.; Decicco, C.P.; Degrado, W.F. (DuPont Pharmaceuticals Co.); Novel macrocyclic cpds. as metalloprotease inhibitors. EP 0981521; WO 9851665 .
|
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
|
12912 |
1-(Bromomethyl)benzene; Alpha-bromotoluene
|
100-39-0 |
C7H7Br |
详情 | 详情
|
|
16605 |
4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene
|
7693-46-1 |
C7H4ClNO4 |
详情 | 详情
|
|
17430 |
2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate
|
5292-43-3 |
C6H11BrO2 |
详情 | 详情
|
(I) |
25390 |
4-methylpentanoyl chloride
|
38136-29-7 |
C6H11ClO |
详情 | 详情
|
(II) |
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
|
(III) |
25391 |
(4S)-4-benzyl-3-(4-methylpentanoyl)-1,3-oxazolidin-2-one
|
|
C16H21NO3 |
详情 |
详情
|
(IV) |
25392 |
tert-butyl (3R)-3-[[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl]-5-methylhexanoate
|
|
C22H31NO5 |
详情 |
详情
|
(V) |
25393 |
(2R)-2-[2-(tert-butoxy)-2-oxoethyl]-4-methylpentanoic acid
|
|
C12H22O4 |
详情 |
详情
|
(VI) |
11463 |
3-Bromo-1-propene; 3-Bromopropene;allyl bromide |
106-95-6 |
C3H5Br |
详情 | 详情
|
(VII) |
35082 |
(2R,3R)-3-(tert-butoxycarbonyl)-2-isobutyl-5-hexenoic acid
|
|
C15H26O4 |
详情 |
详情
|
(VIII) |
35083 |
(2R,3S)-3-(tert-butoxycarbonyl)-2-isobutyl-5-hexenoic acid
|
|
C15H26O4 |
详情 |
详情
|
(IX) |
35084 |
4-benzyl 1-(tert-butyl) (2S,3R)-2-allyl-3-isobutylbutanedioate
|
|
C22H32O4 |
详情 |
详情
|
(X) |
35085 |
4-benzyl 1-(tert-butyl) (2S,3R)-2-(3-hydroxypropyl)-3-isobutylbutanedioate
|
|
C22H34O5 |
详情 |
详情
|
(XI) |
35086 |
1-benzyl 4-(tert-butyl) (2R,3S)-2-isobutyl-3-(3-[[(4-nitrophenoxy)carbonyl]oxy]propyl)butanedioate
|
|
C29H37NO9 |
详情 |
详情
|
(XII) |
35087 |
methyl (2S)-6-amino-2-[[(benzyloxy)carbonyl]amino]hexanoate
|
|
C15H22N2O4 |
详情 |
详情
|
(XIII) |
35088 |
17-benzyl 16-(tert-butyl) 5-methyl (5S,16S,17R)-19-methyl-3,11-dioxo-1-phenyl-2,12-dioxa-4,10-diazaicosane-5,16,17-tricarboxylate
|
|
C38H54N2O10 |
详情 |
详情
|
合成路线35
该中间体在本合成路线中的序号:
6-Methoxy-alpha-tetralone (I) was converted to the corresponding oxime (II) by treatment with hydroxylamine in the presence of sodium acetate. Subsequent Beckmann rearrangement of (II) employing polyphosphoric acid produced a mixture of two regioisomeric lactams from which the required 1-benzazepine (III) was isolated by flash chromatography. Iodination of (III) to give (IV) was carried out following a previously described metodolgy. Displacement of the iodolactam (IV) with ammonia in aqueous ethanol furnished the racemic primary amine, which was resolved by means of L-pyroglutamic acid. The desired (S)-amine (V) was protected as the benzyl carbamate (VII) by treatment with N-(benzyloxycarbonyloxy)succinimide (VI). Then, selective alkylation of the lactam ring nitrogen of (VII) with tert-butyl bromoacetate in the presence of lithium hexamethyldisilazide provided ester (VIII). After hydrogenolysis of the carbobenzoy moiety of (VIII), the resulting amino lactam (IX) was condensed with benzylsulfonyl chloride (X) to give sulfonamide (XI). Deprotection of the tert-butyl ester of (XI) with trifluoroacetic acid afforded carboxylic acid (XII), which was coupled with nitroargininal ethyl aminal (XIII), yielding amide (XIV).
![](http://zy.yaozh.com/wmf/sch/28/28067101a.jpg)
【1】
Tamura, S.Y.; Goldman, E.A.; Semple, J.E.; Bergum, P.W.; Novel benzo-fused lactam scaffolds as factor Xa inhibitors. Bioorg Med Chem Lett 1999, 9, 17, 2573.
|
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
|
17430 |
2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate
|
5292-43-3 |
C6H11BrO2 |
详情 | 详情
|
(I) |
17594 |
6-methoxy-3,4-dihydro-1(2H)-naphthalenone; 6-Methoxytetralone; 6-Methoxy-1-tetralone; 3,4-dihydro-6-methoxy-1(2H)-naphthalenone
|
1078-19-9 |
C11H12O2 |
详情 | 详情
|
(II) |
38125 |
6-methoxy-3,4-dihydro-1(2H)-naphthalenone oxime
|
|
C11H13NO2 |
详情 |
详情
|
(III) |
38126 |
7-methoxy-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one
|
|
C11H13NO2 |
详情 |
详情
|
(IV) |
38127 |
3-iodo-7-methoxy-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one
|
|
C11H12INO2 |
详情 |
详情
|
(V) |
38128 |
(3S)-3-amino-7-methoxy-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one
|
|
C11H14N2O2 |
详情 |
详情
|
(VI) |
30663 |
N-benzyloxycarbonyloxysuccinimide; 1-[[(Benzyloxy)carbonyl]oxy]-2,5-pyrrolidinedione
|
13139-17-8 |
C12H11NO5 |
详情 | 详情
|
(VII) |
38129 |
benzyl (3S)-7-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-ylcarbamate
|
|
C19H20N2O4 |
详情 |
详情
|
(VIII) |
38130 |
tert-butyl 2-((3S)-3-[[(benzyloxy)carbonyl]amino]-7-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)acetate
|
|
C25H30N2O6 |
详情 |
详情
|
(IX) |
38131 |
tert-butyl 2-[(3S)-3-amino-7-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]acetate
|
|
C17H24N2O4 |
详情 |
详情
|
(X) |
25151 |
phenylmethanesulfonyl chloride
|
1939-99-7 |
C7H7ClO2S |
详情 | 详情
|
(XI) |
38132 |
tert-butyl 2-[(3S)-3-[(benzylsulfonyl)amino]-7-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]acetate
|
|
C24H30N2O6S |
详情 |
详情
|
(XII) |
38133 |
2-[(3S)-3-[(benzylsulfonyl)amino]-7-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]acetic acid
|
|
C20H22N2O6S |
详情 |
详情
|
(XIII) |
38136 |
|
|
C8H17N5O3 |
详情 |
详情
|
(XIV) |
38134 |
|
|
C28H37N7O8S |
详情 |
详情
|
合成路线36
该中间体在本合成路线中的序号:
2-Pyrrolidinone (I) was protected as the N-Boc derivative (II) and then alkylated with 3-bromo-2-methylpropene (III) in the presence of LDA to yield (IV). Further alkylation of (IV) with tert-butyl bromoacetate gave the dialkylated pyrrolidinone (V). Catalytic hydrogenation of the 2-methylpropenyl substituent of (V) produced the racemic isobutyl analogue (VI), which was resolved by means of chiral HPLC. The desired (S)-enantiomer (VII) was deprotected by treatment with magnesium ethoxide, affording pyrrolidinone (VIII). N-Alkylation of the pyrrolidinone (VIII) with triflate (IX) furnished adduct (X), which was hydrolyzed to carboxylic acid (XI) with methanolic NaOH. After activation of (XI) with carbonyl diimidazole, coupling with methylamine gave rise to amide (XII). Cleavage of the tert-butyl ester group of (XII) employing trifluoroacetic acid produced carboxylic acid (XIII). This was finally coupled with hydroxylamine using EDC and HOBt.
![](http://zy.yaozh.com/wmf/sch/28/28212101a.jpg)
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
|
11021 |
Methanamine; Methylamine
|
74-89-5 |
CH5N |
详情 | 详情
|
|
17430 |
2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate
|
5292-43-3 |
C6H11BrO2 |
详情 | 详情
|
(I) |
27397 |
2-Pyrrolidinone
|
616-45-5 |
C4H7NO |
详情 | 详情
|
(II) |
40014 |
tert-butyl 2-oxo-1-pyrrolidinecarboxylate
|
|
C9H15NO3 |
详情 |
详情
|
(III) |
40015 |
3-bromo-2-methyl-1-propene
|
1458-98-6 |
C4H7Br |
详情 | 详情
|
(IV) |
40016 |
tert-butyl 3-(2-methyl-2-propenyl)-2-oxo-1-pyrrolidinecarboxylate
|
|
C13H21NO3 |
详情 |
详情
|
(V) |
40017 |
tert-butyl 3-[2-(tert-butoxy)-2-oxoethyl]-3-(2-methyl-2-propenyl)-2-oxo-1-pyrrolidinecarboxylate
|
|
C19H31NO5 |
详情 |
详情
|
(VI) |
40018 |
tert-butyl 3-[2-(tert-butoxy)-2-oxoethyl]-3-isobutyl-2-oxo-1-pyrrolidinecarboxylate
|
|
C19H33NO5 |
详情 |
详情
|
(VII) |
40019 |
tert-butyl (3S)-3-[2-(tert-butoxy)-2-oxoethyl]-3-isobutyl-2-oxo-1-pyrrolidinecarboxylate
|
|
C19H33NO5 |
详情 |
详情
|
(VIII) |
40020 |
tert-butyl 2-[(3S)-3-isobutyl-2-oxopyrrolidinyl]acetate
|
|
C14H25NO3 |
详情 |
详情
|
(IX) |
40025 |
methyl (2R)-2-cyclohexyl-2-[[(trifluoromethyl)sulfonyl]oxy]ethanoate
|
|
C10H15F3O5S |
详情 |
详情
|
(X) |
40021 |
methyl (2S)-2-[(3S)-3-[2-(tert-butoxy)-2-oxoethyl]-3-isobutyl-2-oxopyrrolidinyl]-2-cyclohexylethanoate
|
|
C23H39NO5 |
详情 |
详情
|
(XI) |
40022 |
(2S)-2-[(3S)-3-[2-(tert-butoxy)-2-oxoethyl]-3-isobutyl-2-oxopyrrolidinyl]-2-cyclohexylethanoic acid
|
|
C22H37NO5 |
详情 |
详情
|
(XII) |
40023 |
tert-butyl 2-[(3S)-1-[(1S)-1-cyclohexyl-2-(methylamino)-2-oxoethyl]-3-isobutyl-2-oxopyrrolidinyl]acetate
|
|
C23H40N2O4 |
详情 |
详情
|
(XIII) |
40024 |
2-[(3S)-1-[(1S)-1-cyclohexyl-2-(methylamino)-2-oxoethyl]-3-isobutyl-2-oxopyrrolidinyl]acetic acid
|
|
C19H32N2O4 |
详情 |
详情
|
合成路线37
该中间体在本合成路线中的序号:
2-Pyrrolidinone (I) was protected as the N-Boc derivative (II) and then alkylated with 3-bromo-2-methylpropene (III) in the presence of LDA to yield (IV). Further alkylation of (IV) with tert-butyl bromoacetate gave the dialkylated pyrrolidinone (V). Catalytic hydrogenation of the 2-methylpropenyl substituent of (V) produced the racemic isobutyl analogue (VI), which was resolved by means of chiral HPLC. The desired (S)-enantiomer (VII) was deprotected by treatment with magnesium ethoxide, affording pyrrolidinone (VIII). Triflate (XI) was obtained from D-phenyllactic acid (IX) by formation of the methyl ester (X) upon treatment with iodomethane, followed by reaction with trifluoromethanesulfonic anhydride and pyridine. N-Alkylation of the pyrrolidinone (VIII) with triflate (XI) furnished adduct (XII), which was hydrolyzed to carboxylic acid (XIII) with methanolic NaOH. After activation of (XIII) with carbonyl diimidazole, coupling with methylamine gave rise to amide (XIV). Cleavage of the tert-butyl ester group of (XIV) employing trifluoroacetic acid produced carboxylic acid (XV). This was finally coupled with hydroxylamine using EDC and HOBt.
![](http://zy.yaozh.com/wmf/sch/28/28688101a.jpg)
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
|
11021 |
Methanamine; Methylamine
|
74-89-5 |
CH5N |
详情 | 详情
|
|
17430 |
2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate
|
5292-43-3 |
C6H11BrO2 |
详情 | 详情
|
(I) |
27397 |
2-Pyrrolidinone
|
616-45-5 |
C4H7NO |
详情 | 详情
|
(II) |
40014 |
tert-butyl 2-oxo-1-pyrrolidinecarboxylate
|
|
C9H15NO3 |
详情 |
详情
|
(III) |
40015 |
3-bromo-2-methyl-1-propene
|
1458-98-6 |
C4H7Br |
详情 | 详情
|
(IV) |
40016 |
tert-butyl 3-(2-methyl-2-propenyl)-2-oxo-1-pyrrolidinecarboxylate
|
|
C13H21NO3 |
详情 |
详情
|
(V) |
40017 |
tert-butyl 3-[2-(tert-butoxy)-2-oxoethyl]-3-(2-methyl-2-propenyl)-2-oxo-1-pyrrolidinecarboxylate
|
|
C19H31NO5 |
详情 |
详情
|
(VI) |
40018 |
tert-butyl 3-[2-(tert-butoxy)-2-oxoethyl]-3-isobutyl-2-oxo-1-pyrrolidinecarboxylate
|
|
C19H33NO5 |
详情 |
详情
|
(VII) |
40019 |
tert-butyl (3S)-3-[2-(tert-butoxy)-2-oxoethyl]-3-isobutyl-2-oxo-1-pyrrolidinecarboxylate
|
|
C19H33NO5 |
详情 |
详情
|
(VIII) |
40020 |
tert-butyl 2-[(3S)-3-isobutyl-2-oxopyrrolidinyl]acetate
|
|
C14H25NO3 |
详情 |
详情
|
(IX) |
40026 |
(2R)-2-hydroxy-3-phenylpropionic acid
|
7326-19-4 |
C9H10O3 |
详情 | 详情
|
(X) |
13878 |
methyl (2R)-2-hydroxy-3-phenylpropanoate
|
|
C10H12O3 |
详情 |
详情
|
(XI) |
40027 |
methyl (2R)-3-phenyl-2-[[(trifluoromethyl)sulfonyl]oxy]propanoate
|
|
C11H11F3O5S |
详情 |
详情
|
(XII) |
40028 |
methyl (2S)-2-[(3S)-3-[2-(tert-butoxy)-2-oxoethyl]-3-isobutyl-2-oxopyrrolidinyl]-3-phenylpropanoate
|
|
C24H35NO5 |
详情 |
详情
|
(XIII) |
40029 |
(2S)-2-[(3S)-3-[2-(tert-butoxy)-2-oxoethyl]-3-isobutyl-2-oxopyrrolidinyl]-3-phenylpropionic acid
|
|
C23H33NO5 |
详情 |
详情
|
(XIV) |
40030 |
tert-butyl 2-[(3S)-1-[(1S)-1-benzyl-2-(methylamino)-2-oxoethyl]-3-isobutyl-2-oxopyrrolidinyl]acetate
|
|
C24H36N2O4 |
详情 |
详情
|
(XV) |
40031 |
2-[(3S)-1-[(1S)-1-benzyl-2-(methylamino)-2-oxoethyl]-3-isobutyl-2-oxopyrrolidinyl]acetic acid
|
|
C20H28N2O4 |
详情 |
详情
|
合成路线38
该中间体在本合成路线中的序号:
Condensation of 3-nitro-1,2-phenylenediamine (I) with trifluoroacetic acid provided benzimidazole (II). Reduction of the nitro group of (II) by means of hydrazine in the presence of FeCl3 and activated carbon gave amine (III), which was coupled with 2,6-dichlorobenzoyl chloride (IV) yielding amide (V). Alkylation of (V) with tert-butyl bromoacetate afforded benzimidazoleacetic acid tert-butyl ester (VI). After trifluoroacetic acid-promoted cleavage of the tert-butyl ester of (VI) the resulting carboxylic acid (VII) was coupled with morpholine (VIII) using EDC to furnish the title morpholide.
![](http://zy.yaozh.com/wmf/sch/28/28703401a.jpg)
【1】
Oku, T.; Kawai, Y.; Yatabe, T.; Sato, S.; Yamazaki, H.; Kayakiri, N.; Yoshihara, K. (Fujisawa Pharmaceutical Co., Ltd.); Benzimidazole derivs. and their use in the prevention and/or the treatment of bone diseases. EP 0863881; JP 1999513364; WO 9710219 . |
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
|
17430 |
2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate
|
5292-43-3 |
C6H11BrO2 |
详情 | 详情
|
(I) |
38446 |
2-amino-3-nitrophenylamine; 3-nitro-1,2-benzenediamine
|
3694-52-8 |
C6H7N3O2 |
详情 | 详情
|
(II) |
38447 |
4-nitro-2-(trifluoromethyl)-1H-benzimidazole
|
|
C8H4F3N3O2 |
详情 |
详情
|
(III) |
38448 |
2-(trifluoromethyl)-1H-benzimidazol-4-ylamine; 2-(trifluoromethyl)-1H-benzimidazol-4-amine
|
|
C8H6F3N3 |
详情 |
详情
|
(IV) |
25087 |
2,6-dichlorobenzoyl chloride
|
4659-45-4 |
C7H3Cl3O |
详情 | 详情
|
(V) |
38449 |
2,6-dichloro-N-[2-(trifluoromethyl)-1H-benzimidazol-4-yl]benzamide
|
|
C15H8Cl2F3N3O |
详情 |
详情
|
(VI) |
38450 |
tert-butyl 2-[4-[(2,6-dichlorobenzoyl)amino]-2-(trifluoromethyl)-1H-benzimidazol-1-yl]acetate
|
|
C21H18Cl2F3N3O3 |
详情 |
详情
|
(VII) |
38451 |
2-[4-[(2,6-dichlorobenzoyl)amino]-2-(trifluoromethyl)-1H-benzimidazol-1-yl]acetic acid
|
|
C17H10Cl2F3N3O3 |
详情 |
详情
|
(VIII) |
10388 |
Morpholine
|
110-91-8 |
C4H9NO |
详情 | 详情
|
合成路线39
该中间体在本合成路线中的序号:
(III) Synthesis of the dipeptide intermediate (IX): The esterification of D-cyclohexylalanine (I) by means of SOCl2 and methanol gives the methyl ester (II), which is condensed with tert-butyl bromoacetate (III) by means of DIEA in acetonitrile to yield the N-substituted cyclohexylalanine (IV). The reaction of (IV) with Boc2O and DIEA in DMF affords the N-protected compound (V), which is hydrolyzed with NaOH in dioxane/water to provide the free N-substituted cyclohexylalanine (VI). The condensation of (VI) with L-proline benzyl ester (VII) by means of HOBT and DCC in DMF gives the dipeptide (VIII), which is finally debenzylated by means of H2 over Pd/C in methanol to yield the target dipeptide intermediate (IX).
![](http://zy.yaozh.com/wmf/sch/28/28706801a.jpg)
【1】
Adang, A.E.P.; De Man, A.P.A.; Vogel, G.M.T.; Grootenhuis, P.D.J.; Smit, M.J.; Peters, C.A.M.; Visser, A.; Rewinkel, J.B.M.; van Dinther, T; Lucas, H.; Kelder, J.; van Aelst, S.; Meuleman, D.G.; van Boeckel, C.A.A.; Unique overlap in the prerequisites for thrombin inhibition and oral bioavailability resulting in potent oral antithrombotics. J Med Chem 2002, 45, 20, 4419. |
【2】
Adang, A.E.P.; Peters, J.A.M.; Van Boeckel, C.A.A.; Rewinkel, J.B.M. (Akzo Nobel N.V.); Thrombin inhibitors. WO 9807308 .
|
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) |
39357 |
(2S)-2-amino-3-cyclohexylpropionic acid; L-Cyclohexylalanine
|
27527-05-5 |
C9H17NO2 |
详情 | 详情
|
(II) |
60226 |
methyl 2-amino-3-cyclohexylpropanoate
|
|
C10H19NO2 |
详情 |
详情
|
(III) |
17430 |
2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate
|
5292-43-3 |
C6H11BrO2 |
详情 | 详情
|
(IV) |
60227 |
methyl 3-cyclohexyl-2-({2-[(1,1-dimethylethyl)oxy]-2-oxoethyl}amino)propanoate
|
|
C16H29NO4 |
详情 |
详情
|
(V) |
60228 |
methyl 3-cyclohexyl-2-({[(1,1-dimethylethyl)oxy]carbonyl}{2-[(1,1-dimethylethyl)oxy]-2-oxoethyl}amino)propanoate
|
|
C21H37NO6 |
详情 |
详情
|
(VI) |
60229 |
3-cyclohexyl-N-{[(1,1-dimethylethyl)oxy]carbonyl}-N-{2-[(1,1-dimethylethyl)oxy]-2-oxoethyl}alanine
|
|
C20H35NO6 |
详情 |
详情
|
(VII) |
20930 |
benzyl (2S)-2-pyrrolidinecarboxylate
|
16652-71-4 |
C12H15NO2 |
详情 | 详情
|
(VIII) |
60230 |
phenylmethyl 1-[3-cyclohexyl-2-({[(1,1-dimethylethyl)oxy]carbonyl}{2-[(1,1-dimethylethyl)oxy]-2-oxoethyl}amino)propanoyl]-2-pyrrolidinecarboxylate
|
|
C32H48N2O7 |
详情 |
详情
|
(IX) |
23165 |
(2S)-1-((2R)-2-[(tert-butoxycarbonyl)[2-(tert-butoxy)-2-oxoethyl]amino]-3-cyclohexylpropanoyl)-2-pyrrolidinecarboxylic acid
|
|
C25H42N2O7 |
详情 |
详情
|
合成路线40
该中间体在本合成路线中的序号:
(XII) Synthesis of intermediate (VI):
Treatment of pyridone (X) with diphenyl phosphoryl azide (DPPA) followed by reaction with benzyl alcohol affords the protected derivative (XI), which then reacts with tert-butyl bromoacetate (XII) by means of Cs2CO3 to provide the acetate derivative (XIII). Hydrogenation of (XIII) over Pd/C allows Cbz removal, giving amine (XIV), which is then condensed with iodo derivative (XV) to furnish sulfonamide compound (XVI). Finally, hydrolysis of (XVI) is achieved by treatment with TFA to afford the target intermediate (VI).
![](http://zy.yaozh.com/wmf/sch/29/29268501b.jpg)
【1】
Soll, R.M.; Lu, T.; Tomczuk, B.E.; Spurlino, J.; Pan, W.; Bone, R.; Green, D.W.; Heteroaryl keto thrombin inhibitors: Design and synthesis. 220th ACS Natl Meet (Aug 20 2000, Washington DC) 2000, Abst MEDI 285.
|
【2】
Tumczuk, B.E.; Pan, W.; Soll, R.M.; Lu, T. (3-Dimensional Pharmaceuticals, Inc.); Heteroaryl protease inhibitors and diagnostic imaging agents. WO 0104117 .
|
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) |
44786 |
2-[3-[[(2-iodobenzyl)sulfonyl]amino]-6-methyl-2-oxo-1(2H)-pyridinyl]acetic acid
|
|
C15H15IN2O5S |
详情 |
详情
|
(X) |
44789 |
6-methyl-2-oxo-1,2-dihydro-3-pyridinecarboxylic acid
|
|
C7H7NO3 |
详情 |
详情
|
(XI) |
26603 |
benzyl 6-methyl-2-oxo-1,2-dihydro-3-pyridinylcarbamate
|
|
C14H14N2O3 |
详情 |
详情
|
(XII) |
17430 |
2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate
|
5292-43-3 |
C6H11BrO2 |
详情 | 详情
|
(XIII) |
26604 |
tert-butyl 2-[3-[[(benzyloxy)carbonyl]amino]-6-methyl-2-oxo-1(2H)-pyridinyl]acetate
|
|
C20H24N2O5 |
详情 |
详情
|
(XIV) |
26605 |
tert-butyl 2-[3-amino-6-methyl-2-oxo-1(2H)-pyridinyl]acetate
|
|
C12H18N2O3 |
详情 |
详情
|
(XV) |
44791 |
(2-iodophenyl)methanesulfonyl chloride
|
|
C7H6ClIO2S |
详情 |
详情
|
(XVI) |
44790 |
tert-butyl 2-[3-[[(2-iodobenzyl)sulfonyl]amino]-6-methyl-2-oxo-1(2H)-pyridinyl]acetate
|
|
C19H23IN2O5S |
详情 |
详情
|
合成路线41
该中间体在本合成路线中的序号:
(XIII) The reaction of N-(benzyloxycarbonyl)-L-valine (I) with paraformaldehyde and Ts-OH gives the oxazolidinone (II), which is treated with trimethyl trifluoromethylsilane and CsF in THF to yield the trifluoromethyloxazolidine (III). The cleavage of the oxazolidine ring of (III) by means of ZnCl2 and NaBH4 in t-butyl methyl ether affords the protected aminoalcohol (IV), which is deprotected by means of H2 over Pd(OH)2 in ethyl acetate to provide the free aminoalcohol (V). The condensation of (V) with N-(benzyloxycarbonyl)-L-valyl-L-proline (VI) by means of EDC in dichloromethane gives the protected tripeptide analogue (VII), which is deprotected with H2 over Pd(OH)2 in ethanol to yield the tripeptide analogue (VIII). The condensation of (VIII) with the imidazolidinoneacetic acid derivative (IX) by means of EDC, as before, affords the acylated tripeptide (X), which is oxidized with DMP in dichloromethane to provide the acylated-L-valyl-L-prolyl-L-valyl-trifluoromethane (XI). Finally, this compound is deprotected with TFA in dichloromethane to give the target peptide analogue.
The imidazolidinoneacetic acid derivative (IX) intermediate is obtained as follows: the reaction of 2-imidazolidinone (XII) with tert-butyl 2-bromoacetate (XIII) by means of lithium tert-butoxide in DMF gives the bis tert-butyl acetate (XIV), which is selectively monohydrolyzed by means of KOH in hot ethanol/water to afford the target imidazolidinoneacetic acid derivative (IX).
![](http://zy.yaozh.com/wmf/sch/29/29480001a.jpg)
【1】
Sato, F.; Inoue, Y.; Honda, S.; Komiya, M.; Takemura, T.; Omodani, T.; Shiratake, R. (Dainippon Pharmaceutical Co., Ltd.); Heterocyclic cpds., intermediates thereof and elastase inhibitors. EP 1157998; JP 2000256396; WO 0052032 .
|
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) |
18092 |
(2S)-2-[[(benzyloxy)carbonyl]amino]-3-methylbutyric acid
|
|
C13H17NO4 |
详情 |
详情
|
(II) |
55779 |
benzyl (4S)-4-isopropyl-5-oxo-1,3-oxazolidine-3-carboxylate
|
|
C14H17NO4 |
详情 |
详情
|
(III) |
55780 |
benzyl (4S,5R)-5-hydroxy-4-isopropyl-5-(trifluoromethyl)-1,3-oxazolidine-3-carboxylate
|
|
C15H18F3NO4 |
详情 |
详情
|
(IV) |
55781 |
benzyl (1S,2S)-3,3,3-trifluoro-2-hydroxy-1-isopropylpropylcarbamate
|
|
C14H18F3NO3 |
详情 |
详情
|
(V) |
55782 |
(2S,3S)-3-amino-1,1,1-trifluoro-4-methyl-2-pentanol
|
|
C6H12F3NO |
详情 |
详情
|
(VI) |
22787 |
(2S)-1-((2S)-2-[[(benzyloxy)carbonyl]amino]-3-methylbutanoyl)-2-pyrrolidinecarboxylic acid
|
|
C18H24N2O5 |
详情 |
详情
|
(VII) |
55783 |
benzyl (1S)-2-methyl-1-{[(2S)-2-({[(1S,2S)-3,3,3-trifluoro-2-hydroxy-1-isopropylpropyl]amino}carbonyl)pyrrolidinyl]carbonyl}propylcarbamate
|
|
C24H34F3N3O5 |
详情 |
详情
|
(VIII) |
55784 |
(2S)-1-[(2S)-2-amino-3-methylbutanoyl]-N-[(1S,2S)-3,3,3-trifluoro-2-hydroxy-1-isopropylpropyl]-2-pyrrolidinecarboxamide
|
|
C16H28F3N3O3 |
详情 |
详情
|
(IX) |
55785 |
2-{3-[2-(tert-butoxy)-2-oxoethyl]-2-oxo-1-imidazolidinyl}acetic acid
|
|
C11H18N2O5 |
详情 |
详情
|
(X) |
55786 |
tert-butyl 2-(3-{2-[((1S)-2-methyl-1-{[(2S)-2-({[(1S,2S)-3,3,3-trifluoro-2-hydroxy-1-isopropylpropyl]amino}carbonyl)pyrrolidinyl]carbonyl}propyl)amino]-2-oxoethyl}-2-oxo-1-imidazolidinyl)acetate
|
|
C27H44F3N5O7 |
详情 |
详情
|
(XI) |
55787 |
tert-butyl 2-(3-{2-[((1S)-2-methyl-1-{[(2S)-2-({[(1S)-3,3,3-trifluoro-1-isopropyl-2-oxopropyl]amino}carbonyl)pyrrolidinyl]carbonyl}propyl)amino]-2-oxoethyl}-2-oxo-1-imidazolidinyl)acetate
|
|
C27H42F3N5O7 |
详情 |
详情
|
(XII) |
36228 |
2-imidazolidinone
|
120-93-4 |
C3H6N2O |
详情 | 详情
|
(XIII) |
17430 |
2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate
|
5292-43-3 |
C6H11BrO2 |
详情 | 详情
|
(XIV) |
55788 |
tert-butyl 2-{3-[2-(tert-butoxy)-2-oxoethyl]-2-oxo-1-imidazolidinyl}acetate
|
|
C15H26N2O5 |
详情 |
详情
|
合成路线42
该中间体在本合成路线中的序号:
(V) The hydroxyl group of 3,5-dichlorosalicylaldehyde (I) is protected as the methoxyethoxymethyl (MEM) ether (II) with MEM chloride in DMF. Condensation of the protected salicylaldehyde (II) with (S)-phenylglycinol (III) yields the chiral aldimine (IV). This is then reacted with the Reformatski reagent (VI), prepared from t-butyl bromoacetate (V), to provide adduct (VII). Oxidative removal of the chiral auxiliary group of (VII) with lead tetraacetate, followed by acidic cleavage of the t-butyl and MEM groups, leads to amino ester (VIII). Coupling of (VIII) with the succinimidyl ester of N-Boc-glycine (IX) furnishes amide (X). The N-Boc protecting group of (X) is then removed under acidic conditions to yield amine (XI) (1).
![](http://zy.yaozh.com/wmf/sch/30/30167101a.jpg)
【1】
Miyashiro, J.M.; Gasiecki, A.F.; Khanna, I.K.; Chandrakumar, N.S.; Desai, B.N.; Russell, M.A.; Devadas, B.; Rico, J.G.; Rogers, T.E.; Rao, S.N.; Malecha, J.W.; Ruminski, P.G.; Yu, Y.; Huff, R. (Pfizer Inc.); Heterocyclic glycyl beta-alanine derivs. as vitronectin antagonists. EP 1070060; JP 2002511462; WO 9952896 . |
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) |
21323 |
3,5-dichloro-2-hydroxybenzaldehyde; 3,5-Dichlorosalicylaldehyde
|
90-60-8 |
C7H4Cl2O2 |
详情 | 详情
|
(II) |
47968 |
3,5-dichloro-2-[(2-methoxyethoxy)methoxy]benzaldehyde
|
|
C11H12Cl2O4 |
详情 |
详情
|
(III) |
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
|
(IV) |
47969 |
(2R)-2-[((E)-[3,5-dichloro-2-[(2-methoxyethoxy)methoxy]phenyl]methylidene)amino]-2-phenyl-1-ethanol
|
|
C19H21Cl2NO4 |
详情 |
详情
|
(V) |
17430 |
2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate
|
5292-43-3 |
C6H11BrO2 |
详情 | 详情
|
(VI) |
40586 |
bromo[2-(tert-butoxy)-2-oxoethyl]zinc
|
|
C6H11BrO2Zn |
详情 |
详情
|
(VII) |
47970 |
tert-butyl (3S)-3-[3,5-dichloro-2-[(2-methoxyethoxy)methoxy]phenyl]-3-[[(1R)-2-hydroxy-1-phenylethyl]amino]propanoate
|
|
C25H33Cl2NO6 |
详情 |
详情
|
(VIII) |
47972 |
ethyl (3S)-3-amino-3-(3,5-dichloro-2-hydroxyphenyl)propanoate
|
|
C11H13Cl2NO3 |
详情 |
详情
|
(IX) |
16364 |
tert-butyl N-[2-[(2,5-dioxo-1-pyrrolidinyl)oxy]-2-oxoethyl]carbamate; N-T-BOC-glycine N-hydroxysuccinimide ester
|
3392-07-2 |
C11H16N2O6 |
详情 | 详情
|
(X) |
47973 |
ethyl (3S)-3-([2-[(tert-butoxycarbonyl)amino]acetyl]amino)-3-(3,5-dichloro-2-hydroxyphenyl)propanoate
|
|
C18H24Cl2N2O6 |
详情 |
详情
|
(XI) |
47974 |
ethyl (3S)-3-[(2-aminoacetyl)amino]-3-(3,5-dichloro-2-hydroxyphenyl)propanoate
|
|
C13H16Cl2N2O4 |
详情 |
详情
|
合成路线43
该中间体在本合成路线中的序号:
(IV) The reaction of pyrimidine-2,4(1H,3H)-dione (I) with benzyl 2-bromoacetate (II) by means of K2CO3 in DMF gives the pyrimidine-1-acetic acid benzyl ester (III), which is condensed with tert-butyl 2-bromoacetate (IV) by means of NaH in DMF to yield the pyrimidine bis acetate (V). Selective deprotection of the benzyl ester of (V) by means of H2 over Pd(OH)2 in ethyl acetate affords the mono acetic acid derivative (VI), which is condensed with the free amino group of the tripeptide analogue (VII) by means of EDC in pyridine to provide the acylated tripeptide analogue (VIII). The oxidation of the secondary OH group of (VIII) by means of DMP in dichloromethane furnishes the acylated 2-(L-valyl-L-prolyl-L-valyl)benzoxazole derivative (IX), which is finally deprotected with TFA in dichloromethane to give the target tripeptide analogue.
![](http://zy.yaozh.com/wmf/sch/30/30231801a.jpg)
【1】
Sato, F.; Inoue, Y.; Honda, S.; Komiya, M.; Takemura, T.; Omodani, T.; Shiratake, R. (Dainippon Pharmaceutical Co., Ltd.); Heterocyclic cpds., intermediates thereof and elastase inhibitors. EP 1157998; JP 2000256396; WO 0052032 .
|
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) |
30912 |
(2R,3S)-N,6-dimethoxy-2-(4-methoxyphenyl)-N-methyl-2,3-dihydro-1-benzothiophene-3-carboxamide
|
|
C19H21NO4S |
详情 |
详情
|
(II) |
12869 |
benzyl 2-bromoacetate
|
5437-45-6 |
C9H9BrO2 |
详情 | 详情
|
(III) |
55789 |
benzyl 2-[2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]acetate
|
|
C13H12N2O4 |
详情 |
详情
|
(IV) |
17430 |
2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate
|
5292-43-3 |
C6H11BrO2 |
详情 | 详情
|
(V) |
55790 |
tert-butyl 2-[3-[2-(benzyloxy)-2-oxoethyl]-2,6-dioxo-1(2H,6H)-pyrimidinyl]acetate
|
|
C19H22N2O6 |
详情 |
详情
|
(VI) |
55791 |
2-[3-[2-(tert-butoxy)-2-oxoethyl]-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]acetic acid
|
|
C12H16N2O6 |
详情 |
详情
|
(VII) |
55792 |
(2S)-1-[(2S)-2-amino-3-methylbutanoyl]-N-{(1S)-1-[(S)-1,3-benzoxazol-2-yl(hydroxy)methyl]-2-methylpropyl}-2-pyrrolidinecarboxamide
|
|
C22H32N4O4 |
详情 |
详情
|
(VIII) |
55793 |
tert-butyl 2-[3-(2-{[(1S)-1-({(2S)-2-[({(1S)-1-[(S)-1,3-benzoxazol-2-yl(hydroxy)methyl]-2-methylpropyl}amino)carbonyl]pyrrolidinyl}carbonyl)-2-methylpropyl]amino}-2-oxoethyl)-2,6-dioxo-3,6-dihydro-1(2H)-pyrimidinyl]acetate
|
|
C34H46N6O9 |
详情 |
详情
|
(IX) |
55794 |
tert-butyl 2-[3-{2-[((1S)-1-{[(2S)-2-({[(1S)-1-(1,3-benzoxazol-2-ylcarbonyl)-2-methylpropyl]amino}carbonyl)pyrrolidinyl]carbonyl}-2-methylpropyl)amino]-2-oxoethyl}-2,6-dioxo-3,6-dihydro-1(2H)-pyrimidinyl]acetate
|
|
C34H44N6O9 |
详情 |
详情
|
合成路线44
该中间体在本合成路线中的序号:
(X) Alkylation of the allylic alcohol (IX) with tert-butyl bromoacetate (X) under phase-transfer conditions afforded ester (XI), which was then subjected to titanium isopropoxide-mediated transesterification to the corresponding isopropyl ester (XII). Conversion of secondary alcohol (XII) into chloride (XIV) was performed via the mesylate (XIII), which was then treated with tetrabutylammonium chloride in hot toluene. Finally, acidic cleavage of the tetrahydropyranyl ether groups of (XIV) led to the title compound.
![](http://zy.yaozh.com/wmf/sch/30/30342101b.jpg)
【1】
Hellberg, M.R.; et al.; 3-Oxa-15-cyclohexyl prostaglandin DP receptor agonists as topical antiglaucoma agents. Bioorg Med Chem 2002, 10, 6, 2031.
|
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
(IX) |
56287 |
(1S,2R,3R,4R)-3-[(3R)-3-cyclohexyl-3-(tetrahydro-2H-pyran-2-yloxy)propyl]-2-[(Z)-4-hydroxy-2-butenyl]-4-(tetrahydro-2H-pyran-2-yloxy)cyclopentanol
|
|
C28H48O6 |
详情 |
详情
|
(X) |
17430 |
2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate
|
5292-43-3 |
C6H11BrO2 |
详情 | 详情
|
(XI) |
56288 |
tert-butyl 2-({(Z)-4-[(1R,2R,3R,5S)-2-[(3R)-3-cyclohexyl-3-(tetrahydro-2H-pyran-2-yloxy)propyl]-5-hydroxy-3-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl]-2-butenyl}oxy)acetate
|
|
C34H58O8 |
详情 |
详情
|
(XII) |
56291 |
isopropyl 2-({(Z)-4-[(1R,2R,3R,5S)-2-[(3R)-3-cyclohexyl-3-(tetrahydro-2H-pyran-2-yloxy)propyl]-5-hydroxy-3-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl]-2-butenyl}oxy)acetate
|
|
C33H56O8 |
详情 |
详情
|
(XIII) |
56292 |
isopropyl 2-({(Z)-4-[(1R,2R,3R,5S)-2-[(3R)-3-cyclohexyl-3-(tetrahydro-2H-pyran-2-yloxy)propyl]-5-[(methylsulfonyl)oxy]-3-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl]-2-butenyl}oxy)acetate
|
|
C34H58O10S |
详情 |
详情
|
(XIV) |
56293 |
isopropyl 2-({(Z)-4-[(1R,2R,3R,5R)-5-chloro-2-[(3R)-3-cyclohexyl-3-(tetrahydro-2H-pyran-2-yloxy)propyl]-3-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl]-2-butenyl}oxy)acetate
|
|
C33H55ClO7 |
详情 |
详情
|
合成路线45
该中间体在本合成路线中的序号:
(X) In a different route, hydrogenation of (R)-3-chloro-1-phenyl-1-propanol (XV) over Rh/Al2O3 gave the cyclohexyl carbinol (XVI), which was protected as the ethoxyethyl ether (XVII) by treatment with ethyl vinyl ether in the presence of pyridinium tosylate. Lithiation of chloride (XVII), followed by exchange with lithium (2-thienyl)cyanocuprate, generated the organocuprate reagent (XVIII), which produced a conjugate addition to enone (XIX) to afford the methylene ketone (XX). Protecting group exchange in (XX) was effected by acidic cleavage of the ethoxyethyl group, followed by silylation with t-butyldimethylsilyl triflate, yielding the bis-silylated compound (XXI). The Z-vinylstannane reagent (XXII) was subjected to a stereospecific transmetalation with Me2Cu(CN)Li2 and the resulting cuprate underwent conjugate addition to enone (XXI) yielding adduct (XXIII). Reduction of ketone (XXIII) with L-Selectride®, followed by acidic cleavage of the ethoxyethyl group, provided diol (XXIV). Alkylation of (XXIV) with tert-butyl bromoacetate (X), followed by transterification as above, furnished the isopropyl ester (XXV). The remaining hydroxyl group of (XXV) was subsequently exchanged by a chloride (XXVI) via the corresponding mesylate. Finally, desilylation of (XXVI) with HF in THF gave rise to the title compound.
![](http://zy.yaozh.com/wmf/sch/30/30342102a.jpg)
【1】
Hellberg, M.R.; et al.; 3-Oxa-15-cyclohexyl prostaglandin DP receptor agonists as topical antiglaucoma agents. Bioorg Med Chem 2002, 10, 6, 2031.
|
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) |
17430 |
2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate
|
5292-43-3 |
C6H11BrO2 |
详情 | 详情
|
(XV) |
37782 |
(1R)-3-chloro-1-phenyl-1-propanol
|
|
C9H11ClO |
详情 |
详情
|
(XVI) |
56294 |
(1R)-3-chloro-1-cyclohexyl-1-propanol
|
|
C9H17ClO |
详情 |
详情
|
(XVII) |
56295 |
(1R)-3-chloro-1-cyclohexylpropyl 2-ethoxyethyl ether; 1-[(1R)-3-chloro-1-(2-ethoxyethoxy)propyl]cyclohexane
|
|
C13H25ClO2 |
详情 |
详情
|
(XVIII) |
56296 |
{[(3R)-3-cyclohexyl-3-(2-ethoxyethoxy)propyl]cuprio}lithium
|
|
C13H25CuLiO2 |
详情 |
详情
|
(XIX) |
56297 |
(4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-[(diethylamino)methyl]-2-cyclopenten-1-one
|
|
C16H31NO2Si |
详情 |
详情
|
(XX) |
56298 |
(3R,4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-3-[(3R)-3-cyclohexyl-3-(2-ethoxyethoxy)propyl]-2-methylenecyclopentanone
|
|
C25H46O4Si |
详情 |
详情
|
(XXI) |
56299 |
(3R,4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-3-((3R)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-cyclohexylpropyl)-2-methylenecyclopentanone
|
|
C27H52O3Si2 |
详情 |
详情
|
(XXII) |
56300 |
2-ethoxyethyl (Z)-3-(tributylstannyl)-2-propenyl ether; tributyl[(Z)-3-(2-ethoxyethoxy)-1-propenyl]stannane
|
|
C19H40O2Sn |
详情 |
详情
|
(XXIII) |
56301 |
(2R,3R,4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-3-((3R)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-cyclohexylpropyl)-2-[(Z)-4-(2-ethoxyethoxy)-2-butenyl]cyclopentanone
|
|
C34H66O5Si2 |
详情 |
详情
|
(XXIV) |
56302 |
(1S,2R,3R,4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-3-((3R)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-cyclohexylpropyl)-2-[(Z)-4-hydroxy-2-butenyl]cyclopentanol
|
|
C30H60O4Si2 |
详情 |
详情
|
(XXV) |
56303 |
isopropyl 2-({(Z)-4-[(1R,2R,3R,5S)-3-{[tert-butyl(dimethyl)silyl]oxy}-2-((3R)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-cyclohexylpropyl)-5-hydroxycyclopentyl]-2-butenyl}oxy)acetate
|
|
C35H68O6Si2 |
详情 |
详情
|
(XXVI) |
56304 |
isopropyl 2-({(Z)-4-[(1R,2R,3R,5R)-3-{[tert-butyl(dimethyl)silyl]oxy}-2-((3R)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-cyclohexylpropyl)-5-chlorocyclopentyl]-2-butenyl}oxy)acetate
|
|
C35H67ClO5Si2 |
详情 |
详情
|
合成路线46
该中间体在本合成路线中的序号:
(VI) Esterification of 3-(4-hydroxyphenyl)propionic acid (I), followed by alkylation of the phenolic hydroxyl, provided methyl 3-(4-benzyloxyphenyl)propionate (II), which was hydrolyzed to the corresponding carboxylic acid (III) by means of LiOH. Coupling of carboxylic acid (III) with the chiral auxiliary (S)-4-benzyl-2-oxazolidinone (IV) gave the oxazolide (V), which was subjected to diastereoselective alkylation with tert-butyl bromoacetate (VI), yielding (VII). Subsequent removal of the chiral auxiliary group of (VII) using lithium hydroperoxide afforded the (R)-acid (VIII). Alkylation of the dianion of acid (VIII) with allyl bromide (IX) and further epimerization in the presence of LDA and Et2AlCl furnished the anti-dialkylated succinate (X). The carboxyl group of (X) was then alkylated using benzyl bromide and DBU to produce the corresponding benzyl ester (XI). Olefin (XI) hydroboration followed by oxidative work-up gave rise to the primary alcohol (XII). This was acylated with 4-nitrophenyl chloroformate (XIII) to provide the activated carbonate (XIV).
![](http://zy.yaozh.com/wmf/sch/30/30912301a.jpg)
【1】
Xue, C.-B.; et al.; Discovery of macrocyclic hydroxamic acids containing biphenylmethyl derivatives at P1', a series of selective TNF-alpha converting enzyme inhibitors with potent cellular activity in the inhibition of TNF-alpha release. J Med Chem 2001, 44, 21, 3351. |
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) |
25691 |
3-(4-hydroxyphenyl)propionic acid
|
501-97-3 |
C9H10O3 |
详情 | 详情
|
(II) |
53167 |
methyl 3-[4-(benzyloxy)phenyl]propanoate
|
n/a |
C17H18O3 |
详情 | 详情
|
(III) |
53168 |
3-[4-(benzyloxy)phenyl]propanoic acid
|
50463-48-4 |
C16H16O3 |
详情 | 详情
|
(IV) |
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
|
(V) |
53169 |
(4S)-4-benzyl-3-{3-[4-(benzyloxy)phenyl]propanoyl}-1,3-oxazolidin-2-one
|
n/a |
C26H25NO4 |
详情 | 详情
|
(VI) |
17430 |
2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate
|
5292-43-3 |
C6H11BrO2 |
详情 | 详情
|
(VII) |
53170 |
tert-butyl (3R)-4-[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-3-[4-(benzyloxy)benzyl]-4-oxobutanoate
|
n/a |
C32H35NO6 |
详情 | 详情
|
(VIII) |
53171 |
(2R)-2-[4-(benzyloxy)benzyl]-4-(tert-butoxy)-4-oxobutanoic acid
|
n/a |
C22H26O5 |
详情 | 详情
|
(IX) |
11463 |
3-Bromo-1-propene; 3-Bromopropene;allyl bromide |
106-95-6 |
C3H5Br |
详情 | 详情
|
(X) |
53172 |
(2R,3S)-2-[4-(benzyloxy)benzyl]-3-(tert-butoxycarbonyl)-5-hexenoic acid
|
n/a |
C25H30O5 |
详情 | 详情
|
(XI) |
53173 |
4-benzyl 1-(tert-butyl) (2S,3R)-2-allyl-3-[4-(benzyloxy)benzyl]butanedioate
|
n/a |
C32H36O5 |
详情 | 详情
|
(XII) |
53174 |
1-benzyl 4-(tert-butyl) (2R,3S)-2-[4-(benzyloxy)benzyl]-3-(3-hydroxypropyl)butanedioate
|
n/a |
C32H38O6 |
详情 | 详情
|
(XIII) |
16605 |
4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene
|
7693-46-1 |
C7H4ClNO4 |
详情 | 详情
|
(XIV) |
53175 |
1-benzyl 4-(tert-butyl) (2R,3S)-2-[4-(benzyloxy)benzyl]-3-(3-{[(4-nitrophenoxy)carbonyl]oxy}propyl)butanedioate
|
n/a |
C39H41NO10 |
详情 | 详情
|
合成路线47
该中间体在本合成路线中的序号:
(IV) Acylation of Evans oxazolidinone (II) with heptanoyl chloride (I) provides the chiral adduct (III). The lithium enolate of (III) is then diastereoselectively alkylated with tert-butyl bromoacetate (IV) to afford the succinate derivative (V). Removal of the chiral auxiliary group of (V) with lithium peroxide furnishes the carboxylic acid (VI), which is further activated as the succinimidyl ester (VII) upon treatment with N-hydroxysuccinimide and DCC. The activated ester (VII) is then condensed with L-valine (VIII), producing amide (IX). Subsequent coupling of (IX) with N-aminoproline methyl ester (X) leads to hydrazide (XI). After acidic tert-butyl ester cleavage in (XI), the resultant carboxylic acid (XII) is condensed with hydroxylamine to yield the desired hydroxamic acid.
![](http://zy.yaozh.com/wmf/sch/31/31841901a.jpg)
【1】
Borella, C.; et al.; Asymmetric solid phase and solution parallel synthesis and antitumor properties of actinonin analogs. Proc Am Assoc Cancer Res 2002, 43.
|
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) |
57557 |
Enanthic chloride; Enanthyl chloride; Heptanoic acid chloride; Heptanoyl chloride; Heptanoyl chloride; n-Heptanoyl chloride; Oenanthic chloride
|
2528-61-2 |
C7H13ClO |
详情 | 详情
|
(II) |
12867 |
(4S)-4-Isopropyl-1,3-oxazolidin-2-one; (R)-4-Isopropyl-2-oxazolidinone
|
17016-83-0 |
C6H11NO2 |
详情 | 详情
|
(III) |
57558 |
(4S)-3-heptanoyl-4-isopropyl-1,3-oxazolidin-2-one
|
|
C13H23NO3 |
详情 |
详情
|
(IV) |
17430 |
2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate
|
5292-43-3 |
C6H11BrO2 |
详情 | 详情
|
(V) |
57559 |
tert-butyl (3R)-3-{[(4S)-4-isopropyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl}octanoate
|
|
C19H33NO5 |
详情 |
详情
|
(VI) |
57560 |
(2R)-2-[2-(tert-butoxy)-2-oxoethyl]heptanoic acid
|
|
C13H24O4 |
详情 |
详情
|
(VII) |
57561 |
tert-butyl (3R)-3-{[(2,5-dioxo-1-pyrrolidinyl)oxy]carbonyl}octanoate
|
|
C17H27NO6 |
详情 |
详情
|
(VIII) |
37828 |
L-2-Amino-3-methylbutyric acid; L-2-Aminoisovaleric acid; 2-Aminoisovaleric acid; L-2-Amino-3-methylbutyric acid; L-alpha-Aminoisovaleric acid; L-valine; (S)-(+)-Valine; (S)-alpha-Aminoisovaleric acid
|
72-18-4 |
C5H11NO2 |
详情 | 详情
|
(IX) |
57562 |
(2S)-2-({(2R)-2-[2-(tert-butoxy)-2-oxoethyl]heptanoyl}amino)-3-methylbutanoic acid
|
|
C18H33NO5 |
详情 |
详情
|
(X) |
57563 |
methyl (2S)-1-amino-2-pyrrolidinecarboxylate
|
|
C6H12N2O2 |
详情 |
详情
|
(XI) |
57564 |
methyl (2S)-1-{[(2S)-2-({(2R)-2-[2-(tert-butoxy)-2-oxoethyl]heptanoyl}amino)-3-methylbutanoyl]amino}-2-pyrrolidinecarboxylate
|
|
C24H43N3O6 |
详情 |
详情
|
(XII) |
57565 |
(3R)-3-({[(1S)-1-({[(2S)-2-(methoxycarbonyl)pyrrolidinyl]amino}carbonyl)-2-methylpropyl]amino}carbonyl)octanoic acid
|
|
C20H35N3O6 |
详情 |
详情
|
合成路线48
该中间体在本合成路线中的序号:
(X) Alkylation of the allylic alcohol (IX) with tert-butyl bromoacetate (X) under phase-transfer conditions afforded ester (XI), which was then converted into chloro derivative (XII) by treatment with a mixture of CH3CN/CCl4/pyridine and then PPh3. Acidic cleavage of the tetrahydropyranyl ether groups of (XII) led to the dihydroxy derivative (XIII), which was finally subjected to saponification with LiOH in MeOH to yield the desired product.
![](http://zy.yaozh.com/wmf/sch/31/31935701b.jpg)
【1】
Hellberg, M.R.; et al.; 3-Oxa-15-cyclohexyl prostaglandin DP receptor agonists as topical antiglaucoma agents. Bioorg Med Chem 2002, 10, 6, 2031.
|
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
(IX) |
56287 |
(1S,2R,3R,4R)-3-[(3R)-3-cyclohexyl-3-(tetrahydro-2H-pyran-2-yloxy)propyl]-2-[(Z)-4-hydroxy-2-butenyl]-4-(tetrahydro-2H-pyran-2-yloxy)cyclopentanol
|
|
C28H48O6 |
详情 |
详情
|
(X) |
17430 |
2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate
|
5292-43-3 |
C6H11BrO2 |
详情 | 详情
|
(XI) |
56288 |
tert-butyl 2-({(Z)-4-[(1R,2R,3R,5S)-2-[(3R)-3-cyclohexyl-3-(tetrahydro-2H-pyran-2-yloxy)propyl]-5-hydroxy-3-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl]-2-butenyl}oxy)acetate
|
|
C34H58O8 |
详情 |
详情
|
(XII) |
56289 |
tert-butyl 2-({(Z)-4-[(1R,2R,3R,5R)-5-chloro-2-[(3R)-3-cyclohexyl-3-(tetrahydro-2H-pyran-2-yloxy)propyl]-3-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl]-2-butenyl}oxy)acetate
|
|
C34H57ClO7 |
详情 |
详情
|
(XIII) |
56290 |
tert-butyl 2-[((Z)-4-{(1R,2R,3R,5R)-5-chloro-2-[(3R)-3-cyclohexyl-3-hydroxypropyl]-3-hydroxycyclopentyl}-2-butenyl)oxy]acetate
|
|
C24H41ClO5 |
详情 |
详情
|
合成路线49
该中间体在本合成路线中的序号:
(II) Alkylation of 3-hydroxybenzaldehyde (I) with t-butyl bromoacetate (II) affords t butyl (3-formylphenoxy)acetate (III). Aldehyde (III) is then converted to oxime (IV) upon treatment with hydroxylamine in MeOH. Reduction of oxime (IV) to the benzylic amine (V) is carried out by catalytic hydrogenation in the presence of Raney nickel. Subsequent reductive alkylation of amine (V) with 4-t-butylbenzaldehyde (VI) furnishes the secondary amine (VII). This is then acylated by pyridine-3-sulfonyl chloride (VIII) producing sulfonamide (IX). The t-butyl ester group of (IX) is finally cleaved with trifluoroacetic acid to give the corresponding carboxylic acid.
![](http://zy.yaozh.com/wmf/sch/32/32002601a.jpg)
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) |
28537 |
3-hydroxybenzaldehyde
|
100-83-4 |
C7H6O2 |
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) |
64442 |
tert-butyl 2-(3-formylphenoxy)acetate
|
|
C13H16O4 |
详情 |
详情
|
(IV) |
64443 |
tert-butyl 2-{3-[(hydroxyimino)methyl]phenoxy}acetate
|
|
C13H17NO4 |
详情 |
详情
|
(V) |
64444 |
tert-butyl 2-[3-(aminomethyl)phenoxy]acetate
|
|
C13H19NO3 |
详情 |
详情
|
(VI) |
16638 |
4-(tert-butyl)benzaldehyde; 4-tert-Butyl-benzaldehyde
|
939-97-9 |
C11H14O |
详情 | 详情
|
(VII) |
64445 |
tert-butyl 2-[3-({[4-(tert-butyl)benzyl]amino}methyl)phenoxy]acetate
|
|
C24H33NO3 |
详情 |
详情
|
(VIII) |
64446 |
3-pyridinesulfonyl chloride
|
|
C5H4ClNO2S |
详情 |
详情
|
(IX) |
64447 |
tert-butyl 2-(3-{[[4-(tert-butyl)benzyl](3-pyridinylsulfonyl)amino]methyl}phenoxy)acetate
|
|
C29H36N2O5S |
详情 |
详情
|
合成路线50
该中间体在本合成路线中的序号:
(II) 4-Hydroxydiphenylmethane (I) is condensed with tert-butyl bromoacetate (II) in the presence of NaH and Bu-4NI to form the aryloxyacetate adduct (III). Ester group reduction in (III) employing LiAlH4 provides alcohol (IV), which is further treated with p-toluenesulfonyl chloride in pyridine, yielding tosylate (V) (1,2). Finally, condensation of tosylate (V) with ethyl isonipecotate (VI) furnishes the title compound (1-3).
![](http://zy.yaozh.com/wmf/sch/33/33054701a.jpg)
【1】
Pyrrolidine and piperidine analogues of SC-57461A as potent, orally active inhibitors of leukotriene A(4) hydrolase. Bioorg Med Chem Lett 2002, 12, 23, 3383.
|
【2】
Chandrakumar, N.S.; Chen, B.B.; Clare, M.; Desai, B.N.; Djuric, S.W.; Docter, S.H.; Gasiecki, A.F.; Haack, R.A.; Liang, C.-D.; Miyashiro, J.M.; Penning, T.D.; Russell, M.A.; Yu, S.S. (Pfizer Inc.); LTA4 hydrolase inhibitor pharmaceutical compsns. and methods of use. JP 1998512542; WO 9610999 . |
【3】
Chandrakumar, N.S.; Chen, B.B.; Clare, M.; Desai, B.N.; Djuric, S.W.; Docter, S.H.; Gasiecki, A.; Haack, R.A.; Liang, C.-D.; Miyashiro, J.M.; Penning, T.D.; Russell, M.A.; Yu, S.S. (Pfizer Inc.); LTA4 hydrolase inhibitors. EP 0804427; EP 1221441; JP 1998512848; WO 9611192 . |
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) |
50817 |
4-Hydroxydiphenylmethane; 4-Benzylphenol; alpha-Phenyl-p-cresol; p-Benzylphenol
|
101-53-1 |
C13H12O |
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) |
64434 |
tert-butyl 2-(4-benzylphenoxy)acetate
|
|
C19H22O3 |
详情 |
详情
|
(IV) |
64435 |
2-(4-benzylphenoxy)-1-ethanol
|
|
C15H16O2 |
详情 |
详情
|
(V) |
64436 |
2-(4-benzylphenoxy)ethyl 4-methylbenzenesulfonate
|
|
C22H22O4S |
详情 |
详情
|
(VI) |
17410 |
Ethyl isonipecotate; ethyl 4-piperidinecarboxylate
|
1126-09-6 |
C8H15NO2 |
详情 | 详情
|
合成路线51
该中间体在本合成路线中的序号:
(II) Alkylation of 4-hydroxydiphenylmethane (I) with tert-butyl bromoacetate (II) in the presence of NaH and Bu4NI in DMF affords ether (III). The ester function of (III) is then reduced by LiAlH4 to furnish the primary alcohol (IV), which is subsequently activated as the corresponding tosylate (V) (1,2). Condensation of tosylate (V) with 5-azabenzimidazole (VI) gives rise to a mixture of the three possible regioisomers (VII), (VIII) and (IX), which can be separated by means of flash chromatography. The desired isomer (IX) is then converted to the N-oxide (X) employing m-chloroperbenzoic acid in CHCl3 (1-3). Finally, reaction of N-oxide (X) with cyanotrimethylsilane produces the target nitrile (3).
![](http://zy.yaozh.com/wmf/sch/33/33821201a.jpg)
【1】
Synthesis of imidazopyridines and purines as potent inhibitors of leukotriene A4 hydrolase. Bioorg Med Chem Lett 2003, 13, 6, 1137.
|
【2】
Chandrakumar, N.S.; Chen, B.B.; Clare, M.; Desai, B.N.; Djuric, S.W.; Docter, S.H.; Gasiecki, A.; Haack, R.A.; Liang, C.-D.; Miyashiro, J.M.; Penning, T.D.; Russell, M.A.; Yu, S.S. (Pfizer Inc.); LTA4 hydrolase inhibitors. EP 0804427; EP 1221441; JP 1998512848; WO 9611192 . |
【3】
Chandrakumar, N.S.; Chen, B.B.; Clare, M.; Desai, B.N.; Djuric, S.W.; Docter, S.H.; Gasiecki, A.F.; Haack, R.A.; Liang, C.-D.; Miyashiro, J.M.; Penning, T.D.; Russell, M.A.; Yu, S.S. (Pfizer Inc.); LTA4 hydrolase inhibitor pharmaceutical compsns. and methods of use. JP 1998512542; WO 9610999 . |
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) |
50817 |
4-Hydroxydiphenylmethane; 4-Benzylphenol; alpha-Phenyl-p-cresol; p-Benzylphenol
|
101-53-1 |
C13H12O |
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) |
64434 |
tert-butyl 2-(4-benzylphenoxy)acetate
|
|
C19H22O3 |
详情 |
详情
|
(IV) |
64435 |
2-(4-benzylphenoxy)-1-ethanol
|
|
C15H16O2 |
详情 |
详情
|
(V) |
64436 |
2-(4-benzylphenoxy)ethyl 4-methylbenzenesulfonate
|
|
C22H22O4S |
详情 |
详情
|
(VI) |
64437 |
1H-imidazo[4,5-c]pyridine
|
|
C6H5N3 |
详情 |
详情
|
(VII) |
64438 |
4-benzylphenyl 2-(5H-imidazo[4,5-c]pyridin-5-yl)ethyl ether; 5-[2-(4-benzylphenoxy)ethyl]-5H-imidazo[4,5-c]pyridine
|
|
C21H19N3O |
详情 |
详情
|
(VIII) |
64439 |
4-benzylphenyl 2-(3H-imidazo[4,5-c]pyridin-3-yl)ethyl ether; 3-[2-(4-benzylphenoxy)ethyl]-3H-imidazo[4,5-c]pyridine
|
|
C21H19N3O |
详情 |
详情
|
(IX) |
64440 |
1-[2-(4-benzylphenoxy)ethyl]-1H-imidazo[4,5-c]pyridine; 4-benzylphenyl 2-(1H-imidazo[4,5-c]pyridin-1-yl)ethyl ether
|
|
C21H19N3O |
详情 |
详情
|
(X) |
64441 |
1-[2-(4-benzylphenoxy)ethyl]-1H-imidazo[4,5-c]pyridin-5-ium-5-olate
|
|
C21H19N3O2 |
详情 |
详情
|
合成路线52
该中间体在本合成路线中的序号:
(II)
![](http://zy.yaozh.com/wmf/sch/21/21361702a.jpg)
【1】
Krishnan L, Sum PE, Daigneault S, et aL. 2006. Process for the prepantion of tigecycline and methods of preparing 9-aminominocycline. W0 2006130500 |
【2】
Krishnan L, Sum PE, Daigneault S, et al. 2006. Preparation of tigecycline and 9-nitrominocycline. W0 2006130501 |
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
(IX) |
66846 |
(4S,4aS,5aR,12aS)-9-amino-4,7-bis(dimethylamino)-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydro-2-naphthacenecarboxamide hydrochloride |
|
C23H28N4O7.HCl |
详情 | 详情
|
(I) |
17895 |
2-Amino-2-methylpropane; tert-butylamine; 2-methyl-2-propanamine
|
75-64-9 |
C4H11N |
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) |
66841 |
tert-butyl 2-(tert-butylamino)acetate |
|
C10H21NO2 |
详情 | 详情
|
(IV) |
66842 |
2-(tert-butylamino)acetic acid hydrochloride |
|
C6H13NO2.HCl |
详情 | 详情
|
(V) |
66843 |
2-(tert-butylamino)acetyl chloride hydrochloride |
|
C6H12ClNO.HCl |
详情 | 详情
|
(VI) |
65813 |
Minocycline hydrochloride; [4S-(4alpha,4aalpha,5aalpha,12aalpha)]-4,7-Bis(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxonaphthacene-2-carboxamide monohydrochloride |
13614-98-7 |
C23H27N3O7.HCl |
详情 | 详情
|
(VII) |
66844 |
(4S,4aS,5aR,12aS)-4,7-bis(dimethylamino)-3,10,12,12a-tetrahydroxy-9-nitro-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydro-2-naphthacenecarboxamide monosulfate |
|
C23H26N4O9.2H2SO4 |
详情 | 详情
|
(VIII) |
66845 |
(4S,4aS,5aR,12aS)-9-amino-4,7-bis(dimethylamino)-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydro-2-naphthacenecarboxamide monosulfate |
|
C23H28N4O7.2H2SO4 |
详情 | 详情
|
合成路线53
该中间体在本合成路线中的序号:
(IX) Chlorination of 6-bromo-2-naphthoic acid (I) with SOCl2 , optionally in the presence of DMF in THF , affords the corresponding acid chloride (II), which by reaction with (i-Pr)2NH , optionally in the presence of Et3N in THF , provides amide (III). Metalation of 6-bromo-N,N-diisopropyl-2-naphthamide (III) with BuLi in THF followed by condensation with 1-tritylimidazole-4-carbaldehyde (IV) gives the diarylcarbinol (V), which by oxidation with MnO2 in CH2Cl2 yields the corresponding ketone (VI) . Compound (VI) can also be obtained directly by condensation of lithiated naphthamide (III) (by means of BuLi in THF) with N-methoxy-N-methyl-1-tritylimidazole-4-carboxamide (VII) . Asymmetric Reformatsky reaction of ketone (VI) with either bromo (2-ethoxy-2-oxoethyl)zinc (VIIIa) or bromo (2-tert-butoxy-2-oxoethyl)zinc (VIIIb) [prepared in situ by reaction of tert-butyl bromoacetate (IX) with Zn and TMSCl ] by means of cinchonine, and optionally pyridine, in THF provides the 3(S)-hydroxy-3-(4-imidazolyl)-3-(2-naphthyl)propionic acid ethyl and tert-butyl esters (Xa) and (Xb) , respectively. Reduction of esters (Xa) or (Xb) by means of Red-Al in toluene yields the propane-1,3-diol derivative (XI), which by activation with MsCl in the presence of DIEA in THF followed by cyclization with MeOH in the presence of DIEA in acetonitrile affords the 7(S)-(2-naphthyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-ol derivative (XII). Finally, the N,N-diisopropylnaphthamide derivative (XII) is treated with CH3NH2 in the presence of BuLi in THF .
![](http://zy.yaozh.com/wmf/sch/46/46897101a.jpg)
【1】
Kaku, T., Hitaka, T., Ojida, A. et al. Discovery of TAK-700, a naphthylmethylimidazole derivative, as a highly selective, orally active 17, 20 lyase inhibitor for prostate cancer. 240th ACS Natl Meet (Aug 22-26, Boston) 2010, Abst MEDI 96. |
【2】
Hitaka, T., Kusaka, M., Aoki, I., Ojida, A., Matsunaga, N., Adachi, M., Tasaka, A. (Takeda Pharmaceutical Co., Ltd.). Novel imidazole derivatives, production method thereof and use thereof. EP 1334106, EP 1681290, JP 2003201282, JP 2006045239, US 7141598, WO 2002040484. |
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
(VIIIa) |
68259 |
bromo (2-ethoxy-2-oxoethyl)zinc;(2-ethoxy-2-oxoethyl)zinc bromide |
|
C4H7BrO2Zn |
详情 | 详情
|
(VIIIb) |
68260 |
bromo (2-tert-butoxy-2-oxoethyl)zinc;(2-(tert-butoxy)-2-oxoethyl)zinc bromide |
|
C6H11BrO2Zn |
详情 | 详情
|
(Xa) |
68262 |
3(S)-hydroxy-3-(4-imidazolyl)-3-(2-naphthyl)propionic acid ethyl |
|
C44H45N3O4 |
详情 | 详情
|
(Xb) |
68263 |
(S)-tert-butyl 3-(6-(diisopropylcarbamoyl)naphthalen-2-yl)-3-hydroxy-3-(1-trityl-1H-imidazol-4-yl)propanoate |
|
C46H49N3O4 |
详情 | 详情
|
(I) |
42564 |
6-Bromo-2-naphthoic acid;(6-Bromonaphthalen-2-yl)acetic acid;6-Bromo-2-naphthalenecarboxylic acid |
5773-80-8 |
C11H7BrO2 |
详情 | 详情
|
(II) |
68255 |
6-bromo-2-naphthoyl chloride |
|
C11H6BrClO |
详情 | 详情
|
(III) |
68256 |
6-bromo-N,N-diisopropyl-2-naphthamide |
|
C17H20BrNO |
详情 | 详情
|
(IV) |
27712 |
1-trityl-1H-imidazole-4-carbaldehyde;1-Tritylimidazole-4-carboxaldehyde |
33016-47-6 |
C23H18N2O |
详情 | 详情
|
(V) |
68257 |
6-(hydroxy(1-trityl-1H-imidazol-4-yl)methyl)-N,N-diisopropyl-2-naphthamide |
|
C40H39N3O2 |
详情 | 详情
|
(VI) |
68258 |
N,N-diisopropyl-6-(1-trityl-1H-imidazole-4-carbonyl)-2-naphthamide |
|
C40H37N3O2 |
详情 | 详情
|
(VII) |
68261 |
N-methoxy-N-methyl-1-trityl-1H-imidazole-4-carboxamide |
|
C25H23N3O2 |
详情 | 详情
|
(IX) |
17430 |
2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate
|
5292-43-3 |
C6H11BrO2 |
详情 | 详情
|
(XI) |
68264 |
(S)-6-(1,3-dihydroxy-1-(1-trityl-1H-imidazol-4-yl)propyl)-N,N-diisopropyl-2-naphthamide |
|
C42H43N3O3 |
详情 | 详情
|
(XII) |
68265 |
7(S)-(2-naphthyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-ol;(S)-6-(7-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-yl)-N,N-diisopropyl-2-naphthamide |
|
C23H27N3O2 |
详情 | 详情
|