合成路线1
该中间体在本合成路线中的序号:
(XXII) 4) The reaction of phenyl thiobutyrate (XIX) with 9-borabicyclo[3.3.1]nonane (9-BBN) gives the enol ester (XX), which is condensed with the optically active imine (XXI) [prepared from 3-(trimethylsilyl)propynal (XXIII) and (S)-alpha-methylbenzylamine (XXII)] to afford the adduct (XXIV). The cyclization of (XXIV) by means of tert-butylmagnesium chloride in ether yields 3alpha-ethyl-1-(alpha-methylbenzyl)-4beta-[2-(trimethylsilyl)ethynyl]azetidin-2-one (XXV), which is deprotected with tetrabutylammonium fluoride giving the free acetylene derivative (XXVI). The partial reduction of (XXVI) with H2 over Pd-CaCO3-PbO yields the corresponding ethylene compound (XXVII), which is hydroxylated with disiamylborane (DSB) to give the 2-hydroxyethylazetidinone (XXVIII). The protection of (XXVIII) with tert-butyldimethylsilyl chloride yields the silylated compound (XXIX), which is treated with Na-NH3 to afford 3alpha-ethyl-4beta-[2-(tert-butyldimethylsilyloxy)ethyl]azetidin-2-one (XXX). The protection of (XXX) with tert-butyldimethylsilyl chloride as before gives the fully silylated compound (XXXI), which is submitted to a controlled hydrolysis yielding 3alpha-ethyl-4beta-(2-hydroxyethyl)-1-(tert-butyldimethylsilyl)azetidin-2-one (XXXII). The oxidation of (XXXII) with CrO3 - pyridine gives the acetic acid derivative (XXXIII), which is deprotected to afford 2-(3alpha-ethyl-2-oxoazetidin-4beta-yl)acetic acid (XXXIV). The reaction of (XXXIV) with carbonyldiimidazole (XXXV) gives the corresponding imidazolide (XXXVI), which is condensed with magnesium 4-nitrobenzyl malonate (XXXVII) yielding 4-nitrobenzyl 4-(3alpha-ethyl-2-oxoazetidin-4beta-yl)-3-oxobutanoate (XXXVIII). The diazotation of (XXXVIII) with 4-azidobenzoic acid (XXXIX) gives the 2-diazo-3-oxobutanoate derivative (XL), which is finally cyclized to carbapen derivative (XII) in the presence of rhodium acetate. The reaction of (XII) with diphenyl chlorophosphate affords the enol phosphate (XIII), which is condensed with N-acetylcysteamine (XIV) to give 4-nitrobenzyl ester of PS-5 (XV). Finally, this compound is deprotected by hydrogenation with H2 over Pd/C.
【1】
Shibasaki, M.; Ishida, Y.; Iwasaki, G.; Iimori, T.; Asymmetric synthesis of the carbapenem antibiotic (+)-PS-5. J Org Chem 1987, 52, 15, 3488-9.
|
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
|
16074 |
Diphenyl phosphoryl chloride; 1,1'-Diphenylphosphoryl chloride; Chlorodiphenyl Phosphate; Diphenyl chlorophosphate; Diphenylchlorophosphate
|
2524-64-3 |
C12H10ClO3P |
详情 | 详情
|
|
44204 |
N,N-diethyl-2-propanamine; N,N-diethyl-N-isopropylamine
|
|
C7H17N |
详情 |
详情
|
(XII) |
20032 |
4-nitrobenzyl (5R,6R)-6-ethyl-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylate
|
|
C16H16N2O6 |
详情 |
详情
|
(XIII) |
20033 |
4-nitrobenzyl (5R,6R)-3-[(diphenoxyphosphoryl)oxy]-6-ethyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate
|
|
C28H25N2O9P |
详情 |
详情
|
(XIV) |
20034 |
N-(2-sulfanylethyl)acetamide
|
1190-73-4 |
C4H9NOS |
详情 | 详情
|
(XV) |
20035 |
4-nitrobenzyl (5R,6R)-3-[[2-(acetamido)ethyl]sulfanyl]-6-ethyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate
|
|
C20H23N3O6S |
详情 |
详情
|
(XIX) |
20039 |
S-phenyl butanethioate
|
|
C10H12OS |
详情 |
详情
|
(XX) |
20040 |
(E)-1-(9-borabicyclo[3.3.1]non-9-yloxy)-1-butenyl phenyl sulfide; 9-[[(E)-1-(phenylsulfanyl)-1-butenyl]oxy]-9-borabicyclo[3.3.1]nonane
|
|
C18H25BOS |
详情 |
详情
|
(XXI) |
20041 |
(1S)-1-phenyl-N-[(Z)-3-(trimethylsilyl)-2-propynylidene]-1-ethanamine; N-[(1S)-1-phenylethyl]-N-[(Z)-3-(trimethylsilyl)-2-propynylidene]amine
|
|
C14H19NSi |
详情 |
详情
|
(XXII) |
20042 |
(1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine
|
|
C8H11N |
详情 |
详情
|
(XXIII) |
20043 |
3-(trimethylsilyl)-2-propynal
|
|
C6H10OSi |
详情 |
详情
|
(XXIV) |
20044 |
S-phenyl (2R,3S)-2-ethyl-3-[[(1S)-1-phenylethyl]amino]-5-(trimethylsilyl)-4-pentynethioate
|
|
C24H31NOSSi |
详情 |
详情
|
(XXV) |
20045 |
(3R,4S)-3-ethyl-1-[(1S)-1-phenylethyl]-4-[2-(trimethylsilyl)ethynyl]-2-azetidinone
|
|
C18H25NOSi |
详情 |
详情
|
(XXVI) |
20046 |
(3R,4S)-3-ethyl-4-ethynyl-1-[(1S)-1-phenylethyl]-2-azetidinone
|
|
C15H17NO |
详情 |
详情
|
(XXVII) |
20047 |
(3R,4R)-3-ethyl-1-[(1S)-1-phenylethyl]-4-vinyl-2-azetidinone
|
|
C15H19NO |
详情 |
详情
|
(XXVIII) |
20048 |
(3R,4R)-3-ethyl-4-(2-hydroxyethyl)-1-[(1S)-1-phenylethyl]-2-azetidinone
|
|
C15H21NO2 |
详情 |
详情
|
(XXIX) |
20049 |
(3R,4R)-4-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-3-ethyl-1-[(1S)-1-phenylethyl]-2-azetidinone
|
|
C21H35NO2Si |
详情 |
详情
|
(XXX) |
20050 |
(3R,4R)-4-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-3-ethyl-2-azetidinone
|
|
C13H27NO2Si |
详情 |
详情
|
(XXXI) |
20051 |
(3R,4R)-1-[tert-butyl(dimethyl)silyl]-4-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-3-ethyl-2-azetidinone
|
|
C19H41NO2Si2 |
详情 |
详情
|
(XXXII) |
20052 |
(3R,4R)-1-[tert-butyl(dimethyl)silyl]-3-ethyl-4-(2-hydroxyethyl)-2-azetidinone
|
|
C13H27NO2Si |
详情 |
详情
|
(XXXIII) |
20053 |
2-[(2R,3R)-1-[tert-butyl(dimethyl)silyl]-3-ethyl-4-oxoazetidinyl]acetic acid
|
|
C13H25NO3Si |
详情 |
详情
|
(XXXIV) |
20054 |
2-[(2R,3R)-3-ethyl-4-oxoazetidinyl]acetic acid
|
|
C7H11NO3 |
详情 |
详情
|
(XXXV) |
11353 |
1,1'-Carbonyldiimidazole; Di(1H-imidazol-1-yl)methanone; N,N-Carbonyldiimidazole; 1,1'-Carbonylbis(1H-imidazole)
|
530-62-1 |
C7H6N4O |
详情 | 详情
|
(XXXVI) |
20056 |
(3R,4R)-3-ethyl-4-[2-(1H-imidazol-1-yl)-2-oxoethyl]-2-azetidinone
|
|
C10H13N3O2 |
详情 |
详情
|
(XXXVII) |
20057 |
Malonic acid monoethyl ester magnesium salt
|
|
C20H16MgN2O12 |
详情 |
详情
|
(XXXVIII) |
20058 |
4-nitrobenzyl 4-[(2R,3R)-3-ethyl-4-oxoazetidinyl]-3-oxobutanoate
|
|
C16H18N2O6 |
详情 |
详情
|
(XXXIX) |
20059 |
4-azidobenzoic acid
|
6427-66-3 |
C7H5N3O2 |
详情 | 详情
|
(XL) |
20060 |
(2R,3R)-2-Diazo-4-(3-ethyl-4-oxoazetidin-2-yl)-3-oxobutyric acid 4-nitrobenzyl ester
|
|
C16H16N4O6 |
详情 |
详情
|
合成路线2
该中间体在本合成路线中的序号:
(II) The synthesis of Bay u 3405 was carried out as follows:
Reductive amination of 3-oxo-1,2,3,4-tetrahydrocarbazole (I) with S-phenethylamine (II) afforded a mixture of diastereomeric amines, of which the desired isomer (III) crystallized in high diastereomeric purity as the hydrogensulfate. Cleavage of the phenethyl group by transfer hydrogenolysis with amminium formate and palladium on charcoal yielded the enantiomerically pure (3R)-3-amino-1,2,3,4-tetrahydrocarbazole (IV). Sulfonylation of (IV) with 4-fluorobenzenesulfonyl chloride (V) to the sulfonamide (VI) followed by addition of acrylonitrile and subsequent hydrolysis gave Bay u 3405.
【1】
Raz, A.; Needleman, P.; Minkes, M.; Thromboxanes: Selective biosynthesis and distinct biological properties. Science 1976, 193, 163-5.
|
【2】
Svensson, J.; Hamberg, M.; Samuelsson, B.; Thromboxanes: A new group of biologically active compounds derived from prostaglandin endoperoxides. Proc Natl Acad Sci USA 1975, 72, 8, 2994-8.
|
【3】
Gardiner, P.J.; Boberg, M.; Fiedler, V.B.; Perzborn, E.; Boshagen, H.; Buhner, K.; Muller, U.; Rosentreter, U.; Seuter, F.; Weber, H.; Norman, P.; Ritter, W.; Bay u 3405. Drugs Fut 1991, 16, 8, 701.
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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) |
12288 |
1,2,4,9-Tetrahydro-3H-carbazol-3-one
|
|
C12H11NO |
详情 |
详情
|
(II) |
20042 |
(1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine
|
|
C8H11N |
详情 |
详情
|
(III) |
12290 |
N-[(1S)-1-Phenylethyl]-N-[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amine; (3R)-N-[(1S)-1-Phenylethyl]-2,3,4,9-tetrahydro-1H-carbazol-3-amine
|
|
C20H22N2 |
详情 |
详情
|
(IV) |
12291 |
(3R)-2,3,4,9-Tetrahydro-1H-carbazol-3-ylamine; (3R)-2,3,4,9-Tetrahydro-1H-carbazol-3-amine
|
|
C12H14N2 |
详情 |
详情
|
(V) |
12292 |
4-Fluorobenzenesulfonyl chloride
|
349-88-2 |
C6H4ClFO2S |
详情 | 详情
|
(VI) |
12293 |
4-Fluoro-N-[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]benzenesulfonamide
|
|
C18H17FN2O2S |
详情 |
详情
|
合成路线3
该中间体在本合成路线中的序号:
(VI) The synthesis of [14C]-labeled Bay-u-3405 by two closely related ways has been described:
1) [14C]-Labeled aniline (I) is diazotized and reduced with sodium sulfite, yielding the labeled hydrazine (II), which is condensed with the monoketal of cyclohexane-1,4-dione (III) under Fisher's indole synthesis (ZnCl2) to afford the tetrahydrocarbazole (IV). The hydrolysis of (IV) with HCl in THF/water yields 1,2,3,4-tetrahydrocarbazol-3-one (V), which is submitted to a reductive condensation with (S)-1-phenylethylamine (VI) by means of tetrabutylammonium borohydride, yielding preferentially the secondary amine (VII), which, after purification, is dealkylated with ammonium formate and Pd/C to afford 1,2,3,4-tetrahydrocarbazole-3(R)-amine (VIII). The acylation of (VIII) with 4-fluorophenylsulfonyl chloride (IX) gives the corresponding sulfonamide (X), which is condensed with acrylonitrile by means of NaH, yielding 3-[3(R)-(4-fluorophenylsulfonamido)-1,2,3,4-tetrahydrocarbazol-9-yl]pro pionitrile (XI). Finally, this compound is hydrolyzed in the usual way.
2) The condensation of the sulfonamide (X) with methyl acrylate by means of NaH as before gives 3-[3(R)-(4-fluorophenylsulfonamido)-1,2,3,4-tetrahydrocarbazol-9-yl]propionic acid methyl ester (XII), which is finally hydrolyzed in the usual way.
【1】
Pleiss, U.; Radtke, M.; Rosentreter, U.; Boberg, M.; Synthesis of (+)-(3R)-3-(4-fluorophenylsulfonamido)-1,2,3,4-tetrahydro-9-[5,6,7,8,12,13-u-C-14]carbazolepropanoic acid, [C-14]BAY u 3405. J Label Compd Radiopharm 1994, 34, 12, 1207.
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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) |
12294 |
Aniline; Phenylamine
|
62-53-3 |
C6H7N |
详情 | 详情
|
(I) |
45117 |
|
|
C6H7N |
详情 |
详情
|
(II) |
11818 |
Phenyl hydrazine; 1-Phenylhydrazine
|
100-63-0 |
C6H8N2 |
详情 | 详情
|
(II) |
45118 |
|
|
C6H8N2 |
详情 |
详情
|
(III) |
11377 |
1,4-Dioxaspiro[4.5]decan-8-one
|
4746-97-8 |
C8H12O3 |
详情 | 详情
|
(IV) |
12297 |
1,2,3,4-Tetrahydrospiro[9H-carbazole-3,2'-1,3-dioxolane]
|
|
C14H15NO2 |
详情 |
详情
|
(IV) |
45119 |
|
|
C14H15NO2 |
详情 |
详情
|
(V) |
12288 |
1,2,4,9-Tetrahydro-3H-carbazol-3-one
|
|
C12H11NO |
详情 |
详情
|
(V) |
45120 |
|
|
C12H11NO |
详情 |
详情
|
(VI) |
20042 |
(1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine
|
|
C8H11N |
详情 |
详情
|
(VII) |
12290 |
N-[(1S)-1-Phenylethyl]-N-[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amine; (3R)-N-[(1S)-1-Phenylethyl]-2,3,4,9-tetrahydro-1H-carbazol-3-amine
|
|
C20H22N2 |
详情 |
详情
|
(VII) |
45121 |
|
|
C20H22N2 |
详情 |
详情
|
(VIII) |
12291 |
(3R)-2,3,4,9-Tetrahydro-1H-carbazol-3-ylamine; (3R)-2,3,4,9-Tetrahydro-1H-carbazol-3-amine
|
|
C12H14N2 |
详情 |
详情
|
(VIII) |
45122 |
|
|
C12H14N2 |
详情 |
详情
|
(IX) |
12292 |
4-Fluorobenzenesulfonyl chloride
|
349-88-2 |
C6H4ClFO2S |
详情 | 详情
|
(X) |
12293 |
4-Fluoro-N-[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]benzenesulfonamide
|
|
C18H17FN2O2S |
详情 |
详情
|
(X) |
45123 |
|
|
C18H17FN2O2S |
详情 |
详情
|
(XI) |
12304 |
N-[(3R)-9-(2-cyanoethyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-4-fluorobenzenesulfonamide
|
|
C21H20FN3O2S |
详情 |
详情
|
(XI) |
45124 |
|
|
C21H20FN3O2S |
详情 |
详情
|
(XII) |
12305 |
methyl 3-((3R)-3-[[(4-fluorophenyl)sulfonyl]amino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl)propanoate
|
|
C22H23FN2O4S |
详情 |
详情
|
(XII) |
45125 |
|
|
C22H23FN2O4S |
详情 |
详情
|
合成路线4
该中间体在本合成路线中的序号:
(S-X) 3) The reaction of 3-methyl-1-[2-(1-piperidinyl)phenyl]butan-1-imine (VI) with acetic acid, triphenylphosphine and CCl4 (or with acetic anhydride and NaHCO3) gives N-[3-methyl-2-(1-piperidinyl)phenyl]-1(Z)-butenyl]acetamide (VII), with some of the (E)-isomer. The stereoselective reduction of the (Z)-isomer (VII) with the chiral complex Ru(OAc)2[(S)-2,2'-bis(diphenylphosphino-1,1'-binaphthyl] (S-BINAP), triethylamine and titanium tetraisopropoxide in methanol/methylene chloride yields N-[3-methyl-1(S)-[2-(1-piperidinyl)phenyl]butyl]acetamide (VIII). The hydrolysis of the chiral amide (VIII) with refluxing concentrated HCl affords the chiral amine (S-I), which is then condensed with the phenylacetic acid (II) by means of triphenylphosphine as before (or with dicyclohexylcarbodiimide) to give the chiral amide-ester (S-III). Finally, this ester is hydrolyzed to repaglinide with NaOH in hot ethanol.
4) The reductocondensation of 3-methyl-1-[2-(1-piperidyl)-1-butanone (IX) with 1(S)-phenylethylamine (S-X) yields the (S)-chiral ketimine (XI), which is reduced with TiCl4 in toluene yielding the (S,S)-chiral secondary amine (S,S-XII). Finally, the 1(S)-phenylethyl group of (S,S-XII) is eliminated by hydrogenolysis with H2 over Pd/C in diluted aqueous HCl to afford the (S)-chiral amine (S-I), already obtained.
5) The condensation of 1(R)-phenylethylamine (R-X) with 2-(1-piperidinyl)benzaldehyde (XIII) gives the corresponding chiral (R)-aldimine (XIV), which is converted into the (S,R)-chiral secondary amine (S,R-XII) by a Grignard reaction with isobutyl bromide in THF. Finally, the 1(R)-phenylethyl group of (S,R-XII) is eliminated by hydrogenolysis as before to afford the previously obtained (S)-chiral amine (S-I).
【1】
Graul, A.; Castaner, J.; Repaglinide. Drugs Fut 1996, 21, 7, 694.
|
【2】
Grell, W.; Greischel, A.; Zahn, G.; Mark, M.; Knorr, H.; Rupprecht, E.; Muller, U. (Dr. Karl Thomae GmbH); (S)(+)-2-(Ethoxy-4-[N-[1-(2-piperidinophenyl)-3-methyl-1-butyl] aminocarbonylmethyl]benzoic acid. EP 0589874; JP 1994508816; WO 9300337 .
|
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
|
22876 |
bromo(isobutyl)magnesium
|
926-62-5 |
C4H9BrMg |
详情 | 详情
|
(R-X) |
10039 |
(1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine
|
3886-69-9 |
C8H11N |
详情 | 详情
|
(S,S-XII) |
15312 |
(1S)-3-methyl-N-[(1S)-1-phenylethyl]-1-(2-piperidinophenyl)-1-butanamine; N-[(1S)-3-methyl-1-(2-piperidinophenyl)butyl]-N-[(1S)-1-phenylethyl]amine
|
|
C24H34N2 |
详情 |
详情
|
(S;R-XII) |
15313 |
N-[(1S)-3-methyl-1-(2-piperidinophenyl)butyl]-N-[(1R)-1-phenylethyl]amine; (1S)-3-methyl-N-[(1R)-1-phenylethyl]-1-(2-piperidinophenyl)-1-butanamine
|
|
C24H34N2 |
详情 |
详情
|
(S-I) |
15315 |
(1S)-3-methyl-1-(2-piperidinophenyl)butylamine; (1S)-3-methyl-1-(2-piperidinophenyl)-1-butanamine
|
|
C16H26N2 |
详情 |
详情
|
(S-III) |
15316 |
ethyl 2-ethoxy-4-(2-[[(1S)-3-methyl-1-(2-piperidinophenyl)butyl]amino]-2-oxoethyl)benzoate
|
|
C29H40N2O4 |
详情 |
详情
|
(S-X) |
20042 |
(1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine
|
|
C8H11N |
详情 |
详情
|
(II) |
15302 |
ethyl 2-ethoxy-4-(2-[[3-methyl-1-(2-piperidinophenyl)butyl]amino]-2-oxoethyl)benzoate
|
|
C29H40N2O4 |
详情 |
详情
|
(VI) |
15305 |
3-methyl-1-(2-piperidinophenyl)-1-butanimine
|
|
C16H24N2 |
详情 |
详情
|
(VII) |
15306 |
N-[(Z)-3-methyl-1-(2-piperidinophenyl)-1-butenyl]acetamide
|
|
C18H26N2O |
详情 |
详情
|
(VIII) |
15307 |
N-[(1S)-3-methyl-1-(2-piperidinophenyl)butyl]acetamide
|
|
C18H28N2O |
详情 |
详情
|
(IX) |
15308 |
3-methyl-1-(2-piperidinophenyl)-1-butanone
|
|
C16H23NO |
详情 |
详情
|
(XI) |
15311 |
N-[(E)-3-methyl-1-(2-piperidinophenyl)butylidene]-N-[(1S)-1-phenylethyl]amine; (1S)-N-[(E)-3-methyl-1-(2-piperidinophenyl)butylidene]-1-phenyl-1-ethanamine
|
|
C24H32N2 |
详情 |
详情
|
(XIII) |
15314 |
2-piperidinobenzaldehyde
|
|
C12H15NO |
详情 |
详情
|
(XIV) |
63965 |
(1R)-1-phenyl-N-{(E)-[2-(1-piperidinyl)phenyl]methylidene}-1-ethanamine; N-[(1R)-1-phenylethyl]-N-{(E)-[2-(1-piperidinyl)phenyl]methylidene}amine
|
|
C20H24N2 |
详情 |
详情
|
合成路线5
该中间体在本合成路线中的序号:
(IV) A new synthesis of repaglinide has been described: The reaction of 2-(1-piperidinyl)benzonitrile (I) with isobutylmagnesium bromide (II) in THF followed by hydrolysis with aqueous NH4Cl/NH3 gives 3-methyl-1-[2-(1-piperidinyl)phenyl]butanone (III), which is condensed with 1(S)-phenylethylamine (IV) by means of TiCl4/triethylamine in toluene yielding the imine (V). The hydrogenation of (V) with H2 over Raney Nickel in ethanol affords the chiral secondary amine (IV), which is further hydrogenated with H2 over Pd/C in ethanol/aqueous HCl giving 3-methyl-2(S)-[2-(1-piperidinyl)phenyl]butylamine (VII). The condensation of (VII) with 4-(carboxymethyl)-2-ethoxybenzoic acid ethyl ester (VIII) by means of SOCl2 or carbonyldiimidazole (CDI) or triphenylphosphine/CCl4/triethylamine gives the ethyl ester of repaglinide (IX), which is finally hydrolyzed with NaOH as usual.
【1】
Grell, W.; Hurnaus, R.; Griss, G.; Sauter, R.; Rupprecht, E.; Mark, M.; Luger, P.; Nar, H.; Wittneben, H.; Muller, P.; Repaglinide and related hypoglycemic benzoic acid derivatives. J Med Chem 1998, 41, 26, 5219.
|
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) |
25112 |
2-(1-piperidinyl)benzonitrile
|
72752-52-4 |
C12H14N2 |
详情 | 详情
|
(II) |
22876 |
bromo(isobutyl)magnesium
|
926-62-5 |
C4H9BrMg |
详情 | 详情
|
(III) |
15308 |
3-methyl-1-(2-piperidinophenyl)-1-butanone
|
|
C16H23NO |
详情 |
详情
|
(IV) |
20042 |
(1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine
|
|
C8H11N |
详情 |
详情
|
(V) |
15311 |
N-[(E)-3-methyl-1-(2-piperidinophenyl)butylidene]-N-[(1S)-1-phenylethyl]amine; (1S)-N-[(E)-3-methyl-1-(2-piperidinophenyl)butylidene]-1-phenyl-1-ethanamine
|
|
C24H32N2 |
详情 |
详情
|
(VI) |
15312 |
(1S)-3-methyl-N-[(1S)-1-phenylethyl]-1-(2-piperidinophenyl)-1-butanamine; N-[(1S)-3-methyl-1-(2-piperidinophenyl)butyl]-N-[(1S)-1-phenylethyl]amine
|
|
C24H34N2 |
详情 |
详情
|
(VII) |
15315 |
(1S)-3-methyl-1-(2-piperidinophenyl)butylamine; (1S)-3-methyl-1-(2-piperidinophenyl)-1-butanamine
|
|
C16H26N2 |
详情 |
详情
|
(VIII) |
15301 |
2-[3-ethoxy-4-(ethoxycarbonyl)phenyl]acetic acid
|
|
C13H16O5 |
详情 |
详情
|
(IX) |
15316 |
ethyl 2-ethoxy-4-(2-[[(1S)-3-methyl-1-(2-piperidinophenyl)butyl]amino]-2-oxoethyl)benzoate
|
|
C29H40N2O4 |
详情 |
详情
|
合成路线6
该中间体在本合成路线中的序号:
(V) 3-Bromobenzotrifluoride (I) is converted into the corresponding Grignard reagent (II), which is then condensed with 1,2-dibromo-1-methoxyethane (III) producing the phenethyl bromide (IV). Reaction of bromide (IV) with (S)-alpha-methylbenzylamine (V) yields amine (VI) as a diastereomeric mixture. Recrystallization of (VI) from isopropanol leads to a pure diastereoisomer, which is subsequently treated with ethyl bromoacetate to furnish amino ester (VII). Reduction of (VII) using LiAlH4 provides alcohol (VIII), and further chlorination with SOCl2 leads to chloro amine (IX). Acid (X) is then alkylated with chloride (IX) producing ester (XI). The chiral auxiliary alpha-methylbenzyl group is finally removed by hydrogenolysis to afford the title compound.
【1】
Wierzbicki, M.; Hugon, P.; Duhault, J.; Lacour, F.; Boulanger, M. (ADIR et Cie.); Ethanolaminebenzoate deriv., process for their preparation and pharmaceutical compsns. containing them. EP 0518769; FR 2677647; JP 1993238997; US 5266718 .
|
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) |
26348 |
1-bromo-3-(trifluoromethyl)benzene; 3-Bromobenzotrifluoride
|
401-78-5 |
C7H4BrF3 |
详情 | 详情
|
(II) |
12028 |
Bromo[3-(trifluoromethyl)phenyl]magnesium
|
402-26-6 |
C7H4BrF3Mg |
详情 | 详情
|
(III) |
58091 |
1,2-dibromo-1-methoxyethane; 1,2-dibromoethyl methyl ether
|
|
C3H6Br2O |
详情 |
详情
|
(IV) |
58092 |
1-(2-bromo-1-methoxyethyl)-3-(trifluoromethyl)benzene; 2-bromo-1-[3-(trifluoromethyl)phenyl]ethyl methyl ether
|
|
C10H10BrF3O |
详情 |
详情
|
(V) |
20042 |
(1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine
|
|
C8H11N |
详情 |
详情
|
(VI) |
58093 |
2-methoxy-N-[(1S)-1-phenylethyl]-2-[3-(trifluoromethyl)phenyl]-1-ethanamine; N-{2-methoxy-2-[3-(trifluoromethyl)phenyl]ethyl}-N-[(1S)-1-phenylethyl]amine
|
|
C18H20F3NO |
详情 |
详情
|
(VII) |
58094 |
ethyl 2-{{2-methoxy-2-[3-(trifluoromethyl)phenyl]ethyl}[(1R)-1-phenylethyl]amino}acetate
|
|
C22H26F3NO3 |
详情 |
详情
|
(VIII) |
58095 |
2-{{2-methoxy-2-[3-(trifluoromethyl)phenyl]ethyl}[(1R)-1-phenylethyl]amino}-1-ethanol
|
|
C20H24F3NO2 |
详情 |
详情
|
(IX) |
58096 |
N-(2-chloroethyl)-N-{2-methoxy-2-[3-(trifluoromethyl)phenyl]ethyl}-N-[(1R)-1-phenylethyl]amine; N-(2-chloroethyl)-2-methoxy-N-[(1R)-1-phenylethyl]-2-[3-(trifluoromethyl)phenyl]-1-ethanamine
|
|
C20H23ClF3NO |
详情 |
详情
|
(X) |
58097 |
4-(2-{[2-(9H-fluoren-9-yl)acetyl]amino}ethyl)benzoic acid
|
|
C24H21NO3 |
详情 |
详情
|
(XI) |
58098 |
2-{{2-methoxy-2-[3-(trifluoromethyl)phenyl]ethyl}[(1R)-1-phenylethyl]amino}ethyl 4-(2-{[2-(9H-fluoren-9-yl)acetyl]amino}ethyl)benzoate
|
|
C44H43F3N2O4 |
详情 |
详情
|
合成路线7
该中间体在本合成路线中的序号:
(VI) 1) The condensation of 4-fluoroanisole (I) with maleic anhydride (II) by means of AlCl3 in hot 1,2-dichloroethane gives (E)-4-(5-fluoro-2-hydroxyphenyl)-4-oxo-2-butenoic acid (III), which is cyclized by means of NaHCO3 in boiling water to yield racemic 6-fluoro-4-oxo-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid (IV). The reaction of (IV) with refluxing SOCl2 affords the corresponding acyl chloride (V), which is condensed with (S)-(-)-1-phenylethylamine (VI) affording the amide (VII) as a diastereomeric mixture (R,S + S,S), which is submitted to a fractional crystallization to give the suitable isomer (S,S)-(VII). The hydrolysis of (S,S)-(VII) with concentrated HCl in refluxing dioxane yields the corresponding acid (S)-(IV) as a pure enantiomer. The cyclization of (S)-(IV) with KCN and (NH4)2CO3 in hot water affords the acidic spiro compound (VIII), again as a diastereomeric mixture (2S,4R + 2S,4S), which is separated by fractional crystallization to obtain the desired (2S,4S)-(VIII) compound. The esterification of (2S,4S)-(VIII) with propanol/sulfuric acid affords the corresponding propyl ester (IX), which is finally treated with dry ammonia in methanol.
【1】
Mealy, N.; Castaner, J.; SNK-860. Drugs Fut 1996, 21, 3, 261.
|
【2】
Yamaguchi, T.; Miura, K.; Usui, T.; Unno, R.; Matsumoto, Y.; Fukushima, M.; Mizuno, K.; Kondo, Y.; Baba, Y.; Kurono, M.; Synthesis and aldose reductase inhibitory activity of 2-substituted-6-fluoro-2,3-dihydrospiro[4H-1-benzopyran-4,4'--imidazolidine]-2',5'-diones. Arzneim-Forsch Drug Res 1994, 44, 3, 344-8. |
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
((S)-IV) |
16064 |
(2S)-6-fluoro-4-oxo-3,4-dihydro-2H-chromene-2-carboxylic acid
|
|
C10H7FO4 |
详情 |
详情
|
(I) |
16057 |
4-Fluoroanisole; 4-fluorophenyl methyl ether; 1-fluoro-4-methoxybenzene; p-Fluoroanisole
|
459-60-9 |
C7H7FO |
详情 | 详情
|
(II) |
11182 |
2,5-Furandione; Maleic anhydride
|
108-31-6 |
C4H2O3 |
详情 | 详情
|
(III) |
16059 |
(E)-4-(5-fluoro-2-hydroxyphenyl)-4-oxo-2-butenoic acid
|
|
C10H7FO4 |
详情 |
详情
|
(IV) |
16060 |
6-fluoro-4-oxo-2-chromanecarboxylic acid
|
|
C10H7FO4 |
详情 |
详情
|
(V) |
16061 |
6-fluoro-4-oxo-2-chromanecarbonyl chloride
|
|
C10H6ClFO3 |
详情 |
详情
|
(VI) |
20042 |
(1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine
|
|
C8H11N |
详情 |
详情
|
(VII) |
16063 |
(2S)-6-fluoro-4-oxo-N-[(1S)-1-phenylethyl]-3,4-dihydro-2H-chromene-2-carboxamide
|
|
C18H16FNO3 |
详情 |
详情
|
(VIII) |
16065 |
(2S,4S)-6-fluoro-2',5'-dioxo-3,4-dihydro-2H-spiro[1-benzopyran-4,4'-imidazolidin]2-ylcarboxylic acid
|
|
C12H9FN2O5 |
详情 |
详情
|
(IX) |
16066 |
(2S,4S)-6-Fluoro-2',5'-dioxo-3,4-dihydro-2H-spiro[1-benzopyran-4,4'-imidazolidin]-2-ylcarboxylic acid propyl ester
|
|
C15H15FN2O5 |
详情 |
详情
|
合成路线8
该中间体在本合成路线中的序号:
(IX) A synthesis of the R-(+) isomer has also been reported:
Reaction of phenethyl alcohol (I) and ethyl 3,3-diethoxypropionate (VI) in the presence of titanium tetrachloride affords the isochromane (VII), which is hydrolyzed to acid (VIII) with NaOH in aqueous ethanol. Resolution of the racemic acid (VIII) is effected by conversion into the diastereomeric salt with R-(+)-a-methylbenzylamine (IX) which, after recrystallization from dichloromethane and ethyl acetate, is liberated by treatment with hydrochloric acid, to yield the R-(-) acid (X). This acid is reduced to alcohol (XI) with borane-dimethyl sulfide in tetrahydrofuran. Treatment of XI with methanesulfonyl chloride, diisopropylethylamine, and a trace of dimethylaminopyridine (DMAP) in tetrahydrofuran affords mesylate (XII), which is subsequently treated with piperazine (V) in ethylene glycol to afford the R-(+) compound, isolated as the methanesulfonate salt.
【1】
TenBrink, R.E.; et al.; (S)-(-)-4-[4-[2-(Isochroman-1-yl)ethyl]-piperazin-1-yl]benzenesulfonamide, a selective dopamine D(4) antagonist. J Med Chem 1996, 39, 13, 2435.
|
【2】
Ten Brink, R.E.; Ennis, M.D.; Lin, C.-H.; Lahti, R.A.; Romero, A.G.; Sih, J.C. (Pharmacia Corp.); Heterocyclic cpds. for the treatment of CNS and cardiovascular disorders. EP 0737189; JP 1997507224; US 5877317; WO 9518118 .
|
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) |
17897 |
Phenethyl alcohol; 2-phenyl-1-ethanol
|
60-12-8 |
C8H10O |
详情 | 详情
|
(V) |
12143 |
1-(4-Fluorophenyl)piperazine |
2252-63-3 |
C10H13FN2 |
详情 | 详情
|
(VI) |
17901 |
Ethyl 3,3-diethoxypropanoate
|
10601-80-6 |
C9H18O4 |
详情 | 详情
|
(VII) |
17902 |
ethyl 2-(3,4-dihydro-1H-isochromen-1-yl)acetate
|
|
C13H16O3 |
详情 |
详情
|
(VIII) |
17903 |
2-(3,4-dihydro-1H-isochromen-1-yl)acetic acid
|
|
C11H12O3 |
详情 |
详情
|
(IX) |
20042 |
(1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine
|
|
C8H11N |
详情 |
详情
|
(X) |
17905 |
2-[(1R)-3,4-dihydro-1H-isochromen-1-yl]acetic acid
|
|
C11H12O3 |
详情 |
详情
|
(XI) |
17906 |
2-[(1R)-3,4-dihydro-1H-isochromen-1-yl]-1-ethanol
|
|
C11H14O2 |
详情 |
详情
|
(XII) |
17907 |
2-[(1R)-3,4-dihydro-1H-isochromen-1-yl]ethyl methanesulfonate
|
|
C12H16O4S |
详情 |
详情
|
合成路线9
该中间体在本合成路线中的序号:
(VI) Condensation of alpha-methyl tryptophan methyl ester (I) with benzylchloroformate (II) in the presence of Et3N in THF yields urethane (III), which is hydrolyzed with LiOH in THF/MeOH/H2O and then activated with DCCI and pentafluorophenol (IV) to furnish ester (V). Treatment of (V) with alpha-methyl-benzylamine (VI) gives derivative (VII), which is then debenzylated by hydrogenation over Pd(OH)2 in EtOH to afford (VIII). Finally, amine (VIII) reacts in DMF with DMAP and carbonate (IX), which has been previously prepared from 2-benzofuranylmethanol (X), 4-nitrophenylchloroformate (XI) and pyridine in CH2Cl2.
【1】
Boyle, S.; et al.; Rational design of high affinity tachykinin NK1 receptor antagonists. Bioorg Med Chem 1994, 2, 5, 357.
|
【2】
Horwell, D.C.; Howson, W.; Rees, D.C.; Roberts, E.; Pritchard, M.C. (Pfizer Inc.); Tachykinin antagonists. EP 0655055; EP 1000930; US 5594022; WO 9404494 .
|
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) |
44166 |
methyl (2R)-2-amino-3-(1H-indol-3-yl)-2-methylpropanoate
|
|
C13H16N2O2 |
详情 |
详情
|
(II) |
10101 |
Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene
|
501-53-1 |
C8H7ClO2 |
详情 | 详情
|
(III) |
44167 |
methyl (2R)-2-[[(benzyloxy)carbonyl]amino]-3-(1H-indol-3-yl)-2-methylpropanoate
|
|
C21H22N2O4 |
详情 |
详情
|
(IV) |
22662 |
2,3,4,5,6-pentafluorophenol
|
771-61-9 |
C6HF5O |
详情 | 详情
|
(V) |
44168 |
2,3,4,5,6-pentafluorophenyl (2R)-2-[[(benzyloxy)carbonyl]amino]-3-(1H-indol-3-yl)-2-methylpropanoate
|
|
C26H19F5N2O4 |
详情 |
详情
|
(VI) |
20042 |
(1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine
|
|
C8H11N |
详情 |
详情
|
(VII) |
44169 |
benzyl (1R)-1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-[[(1S)-1-phenylethyl]amino]ethylcarbamate
|
|
C28H29N3O3 |
详情 |
详情
|
(VIII) |
44170 |
(2R)-2-amino-3-(1H-indol-3-yl)-2-methyl-N-[(1S)-1-phenylethyl]propanamide
|
|
C20H23N3O |
详情 |
详情
|
(IX) |
44171 |
1-benzofuran-2-ylmethyl 4-nitrophenyl carbonate
|
|
C16H11NO6 |
详情 |
详情
|
(X) |
38335 |
1-benzofuran-2-ylmethanol
|
|
C9H8O2 |
详情 |
详情
|
(XI) |
16605 |
4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene
|
7693-46-1 |
C7H4ClNO4 |
详情 | 详情
|
合成路线10
该中间体在本合成路线中的序号:
(IV) Treatment of [U-ring-14C] acetophenone (I) with O-methylhydroxylamine hydrochloride in pyridine/EtOH and catalytic MgSO4 yields labeled acetophenone oxime methyl ether (II), which is then subjected to Didier's enantioselective reduction with BH3·THF and 1S,2R-1-amino-indan-2-ol (III) to provide labeled (S)-(IV). Finally, phenylethylamine (S)-(IV) is coupled to chiral acid (V) with 1-hydroxybenzotriazole hydrate (HOBt), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) and N-methylmorpholine (NMM).
【1】
Zhang, Y.S.; Synthesis of 14C-labeled S-(-)-1-phenylethylamine and its application to the synthesis of [14C] CI-1021, a potential antiemetic agent(1). J Label Compd Radiopharm 2000, 43, 11, 1087.
|
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) |
10317 |
Acetophenone
|
98-86-2 |
C8H8O |
详情 | 详情
|
(I) |
45337 |
|
|
C8H8O |
详情 |
详情
|
(II) |
44172 |
1-phenyl-1-ethanone O-methyloxime
|
|
C9H11NO |
详情 |
详情
|
(II) |
45338 |
|
|
C9H11NO |
详情 |
详情
|
(III) |
16239 |
(1S,2R)-1-amino-2,3-dihydro-1H-inden-2-ol; Cis-(1S)-1-amino-2,3-dihydro-1H-inden-2-ol
|
126456-43-7 |
C9H11NO |
详情 | 详情
|
(IV) |
20042 |
(1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine
|
|
C8H11N |
详情 |
详情
|
(IV) |
45339 |
|
|
C8H11N |
详情 |
详情
|
(V) |
44173 |
(2R)-2-[[(1-benzofuran-2-ylmethoxy)carbonyl]amino]-3-(1H-indol-3-yl)-2-methylpropionic acid
|
|
C22H20N2O5 |
详情 |
详情
|
合成路线11
该中间体在本合成路线中的序号:
(XII) Treatment of N(alpha)-Cbz-D-tryptophan (I) with diazomethane (CH2N2) in Et2O/CH2Cl2 provides methyl ester derivative (II), which is then cyclized to afford pyrrolo-indole derivative (III) by long treatment with TFA. N-protection of (III) by reaction with benzyl chloroformate (IV) and Na2CO3 in dioxane yields derivative (V), which is then converted into labeled methylated derivative (VI) by first deprotonation with LHDMS followed by treatment with labeled methyl iodide (MeI) in THF. Ring opening of (VI) by means of TFA furnishes protected methyltryptophan (VII), whose Cbz groups are removed by hydrogenolysis over Pd/C in EtOH to yield derivative (VIII). Coupling of (VIII) with carbonate (IX) by means of DMAP in DMF affords derivative (X), which is then subjected to saponification with LiOH in MeOH to provide carboxylic acid derivative (XI). Finally, (XI) is coupled with methylbenzylamine (XII) by means of HOBt, EDC and N-methylmorpholine (NMM).
【1】
Ekhato, I.V.; Huang, Y.; Tetrahydro-pyrrolo-[2,3-b]indole-1,2,8-tricarboxylic acid ester in the enantiospecific preparation of alpha-methyltryptophan: Application in the preparation of carbon-14 labeled PD 145942 and PD 154075. J Label Compd Radiopharm 1997, 39, 12, 1019. |
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) |
44180 |
(2R)-2-[[(benzyloxy)carbonyl]amino]-3-(1H-indol-3-yl)propionic acid
|
|
C19H18N2O4 |
详情 |
详情
|
(II) |
44174 |
methyl (2R)-2-[[(benzyloxy)carbonyl]amino]-3-(1H-indol-3-yl)propanoate
|
|
C20H20N2O4 |
详情 |
详情
|
(III) |
44175 |
1-benzyl 2-methyl (2R,3aS,8aS)-3,3a,8,8a-tetrahydropyrrolo[2,3-b]indole-1,2(2H)-dicarboxylate
|
|
C20H20N2O4 |
详情 |
详情
|
(IV) |
10101 |
Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene
|
501-53-1 |
C8H7ClO2 |
详情 | 详情
|
(V) |
44176 |
1,8-dibenzyl 2-methyl (2R,3aS,8aR)-2,3,3a,8a-tetrahydropyrrolo[2,3-b]indole-1,2,8-tricarboxylate
|
|
C28H26N2O6 |
详情 |
详情
|
(VI) |
44177 |
1,8-dibenzyl 2-methyl (2R,3aS,8aS)-2-methyl-2,3,3a,8a-tetrahydropyrrolo[2,3-b]indole-1,2,8-tricarboxylate
|
|
C29H28N2O6 |
详情 |
详情
|
(VI) |
45341 |
1,8-dibenzyl 2-methyl (2R,3aS,8aS)-2-methyl-2,3,3a,8a-tetrahydropyrrolo[2,3-b]indole-1,2,8-tricarboxylate
|
|
C29H28N2O6 |
详情 |
详情
|
(VII) |
44178 |
benzyl 3-((2R)-2-[[(benzyloxy)carbonyl]amino]-3-methoxy-2-methyl-3-oxopropyl)-1H-indole-1-carboxylate
|
|
C29H28N2O6 |
详情 |
详情
|
(VII) |
45340 |
benzyl 3-((2R)-2-[[(benzyloxy)carbonyl]amino]-3-methoxy-2-methyl-3-oxopropyl)-1H-indole-1-carboxylate
|
|
C29H28N2O6 |
详情 |
详情
|
(VIII) |
44166 |
methyl (2R)-2-amino-3-(1H-indol-3-yl)-2-methylpropanoate
|
|
C13H16N2O2 |
详情 |
详情
|
(VIII) |
45342 |
methyl (2R)-2-amino-3-(1H-indol-3-yl)-2-methylpropanoate
|
|
C13H16N2O2 |
详情 |
详情
|
(IX) |
44171 |
1-benzofuran-2-ylmethyl 4-nitrophenyl carbonate
|
|
C16H11NO6 |
详情 |
详情
|
(X) |
44179 |
methyl (2R)-2-[[(1-benzofuran-2-ylmethoxy)carbonyl]amino]-3-(1H-indol-3-yl)-2-methylpropanoate
|
|
C23H22N2O5 |
详情 |
详情
|
(X) |
45343 |
methyl (2R)-2-[[(1-benzofuran-2-ylmethoxy)carbonyl]amino]-3-(1H-indol-3-yl)-2-methylpropanoate
|
|
C23H22N2O5 |
详情 |
详情
|
(XI) |
44173 |
(2R)-2-[[(1-benzofuran-2-ylmethoxy)carbonyl]amino]-3-(1H-indol-3-yl)-2-methylpropionic acid
|
|
C22H20N2O5 |
详情 |
详情
|
(XI) |
45344 |
(2R)-2-[[(1-benzofuran-2-ylmethoxy)carbonyl]amino]-3-(1H-indol-3-yl)-2-methylpropionic acid
|
|
C22H20N2O5 |
详情 |
详情
|
(XII) |
20042 |
(1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine
|
|
C8H11N |
详情 |
详情
|
合成路线12
该中间体在本合成路线中的序号:
(VIII) Treatment of carboxylic acid (I) with MeOH and H2SO4 yields methyl ester (II), which is then converted into cyano derivative (III) by reaction with LiCN in DMF and AcOH. Hydrolysis of (III) with aqueous KOH in EtOH provides dicarboxylic acid (IV), which is cyclized by means of Ac2O to give the dicarboxylic anhydride (V).
Alternatively, (V) can be obtained by condensation of ester (VI) with diethyl oxalate (A) in Et2O in the presence of t-BuOK to afford (VII), which is cyclized with H2SO4 and submitted to catalytic hydrogenation over Pd/C.
Condensation of anhydride (V) with (S)-alpha-methylbenzylamine yields a mixture of imides, from which (3aR,9bR)-(IX) is obtained by crystallization. Reduction of (3aR,9bR)-(IX) with BH3·THF followed by hydrogenation over Pd/C affords isoindole derivative (X), which is then alkylated with chloroacetonitrile (XI) in acetonitrile in the presence of DIEA and reduced with LiAlH4 to give the primary amine (XII).
Treatment of (XIII) with POCl3 and Et3N yields 2-chloro-3-cyanopyrazine (XIV), which is oxidized to provide (XV) by means of K2S2O8 in H2SO4. Treatment of N-oxide (XV) with ethyl thioglycolate (XVI) and NaOEt in DMF affords pyrazinothiophene (XVII), which is then chlorinated with POCl3 to give (XVIII). Finally, reaction of amine (XII) with (XVIII) and triphosgene in toluene and Et3N affords the desired product.
【1】
Meyer, M.D.; Altenbach, R.J.; Basha, F.Z.; Carroll, W.A.; Drizin, I.; Kerwin, J.F. Jr.; Lebold, S.A.; Lee, E.L.; Elmore, S.W.; Sippy, K.B.; Tietje, K.R.; Wendt, M.D.; Yamamoto, D.M. (Abbott Laboratories Inc.); Tricyclic substd. hexahydrobenz[e]isoindole alpha-1 adrenergic antagonists. EP 0808318; US 5597823; WO 9622992 . |
【2】
Basha, F.Z.; Meyer, M.D.; Altenbach, R.J.; et al.; Structure-activity studies for a novel series of tricycic substituted hexahydrobenz[e]isoindole alpha1A adrenoceptor antagonists as potential agents for the symptomatic treatment of bening prostatic hyperplasia (BPH). J Med Chem 2000, 43, 8, 1586. |
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
(A) |
17571 |
Diethyl oxalate; Ethyl 2-ethoxy-2-oxoacetate
|
95-92-1 |
C6H10O4 |
详情 | 详情
|
(I) |
42524 |
5-methoxy-3,4-dihydro-1-naphthalenecarboxylic acid
|
|
C12H12O3 |
详情 |
详情
|
(II) |
42525 |
methyl 5-methoxy-3,4-dihydro-1-naphthalenecarboxylate
|
|
C13H14O3 |
详情 |
详情
|
(III) |
42526 |
methyl 2-cyano-5-methoxy-1,2,3,4-tetrahydro-1-naphthalenecarboxylate
|
|
C14H15NO3 |
详情 |
详情
|
(IV) |
42527 |
5-methoxy-1,2,3,4-tetrahydro-1,2-naphthalenedicarboxylic acid
|
|
C13H14O5 |
详情 |
详情
|
(V) |
42528 |
(3aR,9bR)-6-methoxy-3a,4,5,9b-tetrahydronaphtho[1,2-c]furan-1,3-dione
|
|
C13H12O4 |
详情 |
详情
|
(VI) |
42529 |
ethyl 4-(2-methoxyphenyl)butanoate
|
|
C13H18O3 |
详情 |
详情
|
(VII) |
42530 |
diethyl 2-(2-methoxyphenethyl)-3-oxosuccinate
|
|
C17H22O6 |
详情 |
详情
|
(VIII) |
20042 |
(1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine
|
|
C8H11N |
详情 |
详情
|
(IX) |
42531 |
(3aR,9bR)-6-methoxy-2-[(1S)-1-phenylethyl]-3a,4,5,9b-tetrahydro-1H-benzo[e]isoindole-1,3(2H)-dione
|
|
C21H21NO3 |
详情 |
详情
|
(X) |
42532 |
(3aR,9bR)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]isoindol-6-yl methyl ether; (3aR,9bR)-6-methoxy-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]isoindole
|
|
C13H17NO |
详情 |
详情
|
(XI) |
14443 |
2-chloroacetonitrile; chloroacetonitrile
|
107-14-2 |
C2H2ClN |
详情 | 详情
|
(XII) |
42533 |
(3aR,9bR)-2-(2-aminoethyl)-6-methoxy-3a,4,5,9b-tetrahydro-1H-benzo[e]isoindole-1,3(2H)-dione
|
|
C15H18N2O3 |
详情 |
详情
|
(XIII) |
42534 |
3-hydroxy-2-pyrazinecarboxamide
|
55321-99-8 |
C5H5N3O2 |
详情 | 详情
|
(XIV) |
42535 |
3-chloro-2-pyrazinecarbonitrile
|
55557-52-3 |
C5H2ClN3 |
详情 | 详情
|
(XV) |
42536 |
3-chloro-2-cyanopyrazin-1-ium-1-olate
|
|
C5H2ClN3O |
详情 |
详情
|
(XVI) |
23995 |
ethyl 2-sulfanylacetate
|
2713-34-0 |
C4H8O2S |
详情 | 详情
|
(XVII) |
42537 |
7-amino-6-(ethoxycarbonyl)thieno[2,3-b]pyrazin-1-ium-1-olate
|
|
C9H9N3O3S |
详情 |
详情
|
(XVIII) |
42538 |
ethyl 7-amino-2-chlorothieno[2,3-b]pyrazine-6-carboxylate
|
|
C9H8ClN3O2S |
详情 |
详情
|
合成路线13
该中间体在本合成路线中的序号:
(V) The chiral intermediate (X) was synthesized from 3-cyanobenzoic acid (I) through the following sequence. Hydrogenation of the cyano group over Raney-nickel provided 3-(aminomethyl)benzoic acid (II), which was protected as the tert-buyl carbamate (III) with Boc2O. Subsequent hydrogenation of the benzene ring of (III) over PtO2 yielded the racemic amino acid (IV), predominantly as the cis isomer. The chiral resolution of (IV) with (S)-a-methylbenzyl amine (V) in EtOAc provided the optically pure 1(R),3(S) compound (VI), which was then reduced with borane in THF. The resulting aminoalcohol (VII), after conversion to mesylate (VIII) with methanesulfonyl chloride, was treated with NaN3 to give azide (IX), and this was then reduced to amine (X) with H2 over Pd/C.
【1】
Yang, L.; et al.; Spiro[1H-indene-1,4'-piperidine] derivatives as potent and selective non-peptide human somatostatin receptor subtype 2 (sst2) agonists. J Med Chem 1998, 41, 13, 2175.
|
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) |
20406 |
3-cyanobenzoic acid
|
1877-72-1 |
C8H5NO2 |
详情 | 详情
|
(II) |
20407 |
3-(aminomethyl)benzoic acid
|
|
C8H9NO2 |
详情 |
详情
|
(III) |
20408 |
3-[[(tert-butoxycarbonyl)amino]methyl]benzoic acid
|
|
C13H17NO4 |
详情 |
详情
|
(IV) |
20409 |
3-[[(tert-butoxycarbonyl)amino]methyl]cyclohexanecarboxylic acid
|
|
C13H23NO4 |
详情 |
详情
|
(V) |
20042 |
(1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine
|
|
C8H11N |
详情 |
详情
|
(VI) |
20411 |
(1R,3S)-3-(Tert-butoxycarbonylamino)cyclohexanecarboxylic acid (S)-1-phenylethylamine salt
|
|
C21H34N2O4 |
详情 |
详情
|
(VII) |
20412 |
tert-butyl [(1S,3R)-3-(hydroxymethyl)cyclohexyl]methylcarbamate
|
|
C13H25NO3 |
详情 |
详情
|
(VIII) |
20413 |
((1R,3S)-3-[[(tert-butoxycarbonyl)amino]methyl]cyclohexyl)methyl methanesulfonate
|
|
C14H27NO5S |
详情 |
详情
|
(IX) |
20414 |
tert-butyl [(1S,3R)-3-(azidomethyl)cyclohexyl]methylcarbamate
|
|
C13H24N4O2 |
详情 |
详情
|
(X) |
20415 |
tert-butyl [(1S,3R)-3-(aminomethyl)cyclohexyl]methylcarbamate
|
|
C13H26N2O2 |
详情 |
详情
|
合成路线14
该中间体在本合成路线中的序号:
(V) The intermediate fluoropyrrolidine (XIV) was obtained as follows: Alkylation of ethyl acetoacetate (I) with 1,2-dibromoethane (II) led to the cyclopropane derivative (III). Bromination of (III) provided bromo ketone (IV), which was condensed with (S)-1-phenylethylamine (V), yielding amino ketone (VI). Acylation of amine (VI) with (diethylfosfonyl)fluoroacetyl chloride (VII) gave amide (VIII). Intramolecular Wadsworth-Emmons condensation of keto phosphonate (VIII) in the presence of potassium tert-butoxide produced the pyrrolinone (IX). Catalytic hydrogenation of the pyrroline double bond of (IX), followed by separation of the resultant diastereomeric mixture, furnished pyrrolidinone (X). After saponification of the ethyl ester group of (X), the resulting acid (XI) was subjected to Curtius rearrangement in the presence of DPPA and t-BuOH, giving rise to carbamate (XII). Lactam (XII) reduction by means of borane in THF afforded pyrrolidine (XIII). The N-phenylethyl group of (XIII) was then removed by hydrogenation over Pd/C to furnish the required intermediate pyrrolidine (XIV) (See scheme no. 27170201a, intermediate (IX)).
【1】
Takahashi, H.; et al.; DQ-113 (D61-1113), a potent fluoroquinolone against multi-drug resistance Gram-positive bacteria: Practical synthesis, and in vitro and in vivo activities. 41st Intersci Conf Antimicrob Agents Chemother (Dec 16 2001, Chicago) 2001, Abst F-550. |
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) |
11819 |
ethyl acetoacetate; ethyl 3-oxobutanoate;Acetoacetic ester;Ethyl beta-ketobutyrate;ethyl 3-oxobutyrate |
141-97-9 |
C6H10O3 |
详情 | 详情
|
(II) |
10252 |
1,2-Dibromoethane; Ethylene dibromide
|
106-93-4 |
C2H4Br2 |
详情 | 详情
|
(III) |
15171 |
ethyl 1-acetylcyclopropanecarboxylate
|
|
C8H12O3 |
详情 |
详情
|
(IV) |
15172 |
ethyl 1-(2-bromoacetyl)cyclopropanecarboxylate
|
|
C8H11BrO3 |
详情 |
详情
|
(V) |
20042 |
(1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine
|
|
C8H11N |
详情 |
详情
|
(VI) |
55739 |
ethyl 1-(2-{[(1S)-1-phenylethyl]amino}acetyl)cyclopropanecarboxylate
|
|
C16H21NO3 |
详情 |
详情
|
(VII) |
55740 |
diethyl 2-chloro-1-fluoro-2-oxoethylphosphonate
|
|
C6H11ClFO4P |
详情 |
详情
|
(VIII) |
55741 |
ethyl 1-(2-{[2-(diethoxyphosphoryl)-2-fluoroacetyl][(1S)-1-phenylethyl]amino}acetyl)cyclopropanecarboxylate
|
|
C22H31FNO7P |
详情 |
详情
|
(IX) |
55742 |
ethyl 1-{4-fluoro-5-oxo-1-[(1S)-1-phenylethyl]-2,5-dihydro-1H-pyrrol-3-yl}cyclopropanecarboxylate
|
|
C18H20FNO3 |
详情 |
详情
|
(X) |
44225 |
ethyl 1-[(3S,4S)-4-fluoro-5-oxo-1-[(1S)-1-phenylethyl]pyrrolidinyl]cyclopropanecarboxylate
|
|
C18H22FNO3 |
详情 |
详情
|
(XI) |
55743 |
1-{(3S,4S)-4-fluoro-5-oxo-1-[(1S)-1-phenylethyl]pyrrolidinyl}cyclopropanecarboxylic acid
|
|
C16H18FNO3 |
详情 |
详情
|
(XII) |
55744 |
tert-butyl 1-{(3R,4S)-4-fluoro-5-oxo-1-[(1S)-1-phenylethyl]pyrrolidinyl}cyclopropylcarbamate
|
|
C20H27FN2O3 |
详情 |
详情
|
(XIII) |
55745 |
tert-butyl 1-{(3R,4S)-4-fluoro-1-[(1S)-1-phenylethyl]pyrrolidinyl}cyclopropylcarbamate
|
|
C20H29FN2O2 |
详情 |
详情
|
(XIV) |
44231 |
tert-butyl 1-[(3R,4S)-4-fluoropyrrolidinyl]cyclopropylcarbamate
|
|
C12H21FN2O2 |
详情 |
详情
|
合成路线15
该中间体在本合成路线中的序号:
(IV) Hydrogenation of the enantiomerically pure 1-(alpha-methylbenzyl)-3-(hydroxymethyl)pyrrolidine (I) in the presence of Pearlman's catalyst and di-tert-butyl dicarbonate produced the N-Boc pyrrolidine (II). Reaction of (II) with methanesulfonyl chloride, followed by condensation of the resulting mesylate (III) with (S)-alpha-methylbenzylamine (IV) in toluene at 150 C in a sealed tube afforded the aminomethyl pyrrolidine derivative (V). Then, acidic cleavage of the Boc protecting group yielded pyrrolidine (VI).
【1】
Sternfeld, F.; Guiblin, A.R.; Jelley, R.A.; et al.; Synthesis and serotonergic activity of 3-[2-(pyrrolidin-1-yl)ethyl]indoles: Potent agonists for the h5-HT1D receptor with high selectivity over the h5-HT1B receptor. J Med Chem 1999, 42, 4, 677.
|
【2】
Ogawa, T.; Terai, T.; Haruna, K.; Watanabe, A.; Tominaga, T.; Taguchi, H. (Senju Pharmaceuticals Co., Ltd.; Toyobo Co., Ltd.); Pharmaceutical compsn. for topical administration to the eye for treating allergic conjunctivitis. CA 2165999; EP 0719553; JP 1996231393 . |
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) |
34461 |
[(3R)-1-[(1R)-1-phenylethyl]pyrrolidinyl]methanol
|
|
C13H19NO |
详情 |
详情
|
(II) |
34462 |
tert-butyl (3R)-3-(hydroxymethyl)-1-pyrrolidinecarboxylate
|
|
C10H19NO3 |
详情 |
详情
|
(III) |
34463 |
1-Boc-3-methanesulfonyloxymethylpyrrolidine; 1-Boc-3-methanesulfonyloxymethylpyrrolidine |
141699-56-1 |
C11H21NO5S |
详情 | 详情
|
(IV) |
20042 |
(1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine
|
|
C8H11N |
详情 |
详情
|
(V) |
34464 |
tert-butyl (3S)-3-([[(1S)-1-phenylethyl]amino]methyl)-1-pyrrolidinecarboxylate
|
|
C18H28N2O2 |
详情 |
详情
|
(VI) |
34465 |
N-[(1S)-1-phenylethyl]-N-[(3R)pyrrolidinylmethyl]amine; (1S)-1-phenyl-N-[(3R)pyrrolidinylmethyl]-1-ethanamine
|
|
C13H20N2 |
详情 |
详情
|
合成路线16
该中间体在本合成路线中的序号:
(IX) Condensation of the anion resulting from 2-fluoro-4-methylpyridine (I) and LDA with N-methoxy-N-methyl-3-trifluoromethylbenzamide (II) afforded ketone (III). Subsequent alpha-oximination of (III) with tert-butyl nitrite and HCl provided the required E-oxime (IV) as the major isomer. Cyclization of (IV) with N-(benzyloxycarbonyl)piperidine-4-carboxaldehyde (V) and ammonium acetate in refluxing AcOH afforded hydroxyimidazole (VI). Further reduction of (VI) to imidazole (VII) was carried out with titanium trichloride. Methylation of the imidazole ring of (VII) by treatment with N,N-dimethylformamide dimethylacetal in boiling toluene gave rise to a mixture of both N-methylated imidazoles, from which the desired compound (VIII) was isolated by column chromatography as the minor isomer. Nucleophilic displacement of the fluoropyridine of (VIII) by (S)-alpha-methylbenzylamine (IX) at 150 C gave the corresponding aminopyridine derivative (X). The N-benzyloxycarbonyl protecting group was finally removed by catalytic hydrogenation over Pd/C.
【1】
Claiborne, C.F.; Liverton, N.J.; Butcher, J.W.; et al.; Design and synthesis of potent, selective, and orally bioavailable tetrasubstituted imidazole inhibitors of p38 mitogen-activated protein kinase. J Med Chem 1999, 42, 12, 2180.
|
【2】
Selnick, H.G.; Claremon, D.A.; Liverton, N.J. (Merck & Co., Inc.); Substd. imidazoles having anti-cancer and cytokine inhibitory activity. JP 1999514353; US 5717100; WO 9712876 .
|
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) |
18296 |
2-Fluoro-4-methylpyridine
|
461-87-0 |
C6H6FN |
详情 | 详情
|
(II) |
35153 |
N-methoxy-N-methyl-3-(trifluoromethyl)benzamide
|
|
C10H10F3NO2 |
详情 |
详情
|
(III) |
35154 |
2-(2-fluoro-4-pyridinyl)-1-[3-(trifluoromethyl)phenyl]-1-ethanone
|
|
C14H9F4NO |
详情 |
详情
|
(IV) |
35155 |
1-(2-fluoro-4-pyridinyl)-2-[3-(trifluoromethyl)phenyl]-1,2-ethanedione 1-oxime
|
|
C14H8F4N2O2 |
详情 |
详情
|
(V) |
35156 |
4-Formyl-N-Cbz-piperidine; benzyl 4-formyl-1-piperidinecarboxylate
|
138163-08-3 |
C14H17NO3 |
详情 | 详情
|
(VI) |
35157 |
benzyl 4-[5-(2-fluoro-4-pyridinyl)-1-hydroxy-4-[3-(trifluoromethyl)phenyl]-1H-imidazol-2-yl]-1-piperidinecarboxylate
|
|
C28H24F4N4O3 |
详情 |
详情
|
(VII) |
35158 |
benzyl 4-[5-(2-fluoro-4-pyridinyl)-4-[3-(trifluoromethyl)phenyl]-1H-imidazol-2-yl]-1-piperidinecarboxylate
|
|
C28H24F4N4O2 |
详情 |
详情
|
(VIII) |
35159 |
benzyl 4-[5-(2-fluoro-4-pyridinyl)-1-methyl-4-[3-(trifluoromethyl)phenyl]-1H-imidazol-2-yl]-1-piperidinecarboxylate
|
|
C29H26F4N4O2 |
详情 |
详情
|
(IX) |
20042 |
(1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine
|
|
C8H11N |
详情 |
详情
|
(X) |
35160 |
benzyl 4-[1-methyl-5-(2-[[(1S)-1-phenylethyl]amino]-4-pyridinyl)-4-[3-(trifluoromethyl)phenyl]-1H-imidazol-2-yl]-1-piperidinecarboxylate
|
|
C37H36F3N5O2 |
详情 |
详情
|
合成路线17
该中间体在本合成路线中的序号:
(IX) In a modified procedure, displacement of fluoropyridine (VII) by (S)-alpha-methylbenzylamine (IX) afforded aminopyridine derivative (XI). This was then alkylated with iodomethane and Cs2CO3 to provide the required N-methyl imidazole (X) as the major isomer, which was finally deprotected by catalytic hydrogenation over Pd/C.
【1】
Claiborne, C.F.; Liverton, N.J.; Butcher, J.W.; et al.; Design and synthesis of potent, selective, and orally bioavailable tetrasubstituted imidazole inhibitors of p38 mitogen-activated protein kinase. J Med Chem 1999, 42, 12, 2180.
|
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) |
35158 |
benzyl 4-[5-(2-fluoro-4-pyridinyl)-4-[3-(trifluoromethyl)phenyl]-1H-imidazol-2-yl]-1-piperidinecarboxylate
|
|
C28H24F4N4O2 |
详情 |
详情
|
(IX) |
20042 |
(1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine
|
|
C8H11N |
详情 |
详情
|
(X) |
35160 |
benzyl 4-[1-methyl-5-(2-[[(1S)-1-phenylethyl]amino]-4-pyridinyl)-4-[3-(trifluoromethyl)phenyl]-1H-imidazol-2-yl]-1-piperidinecarboxylate
|
|
C37H36F3N5O2 |
详情 |
详情
|
(XI) |
35161 |
benzyl 4-[5-(2-[[(1S)-1-phenylethyl]amino]-4-pyridinyl)-4-[3-(trifluoromethyl)phenyl]-1H-imidazol-2-yl]-1-piperidinecarboxylate
|
|
C36H34F3N5O2 |
详情 |
详情
|
合成路线18
该中间体在本合成路线中的序号:
(I) The desired enantiomer was prepared by two chiral routes. Monoalkylation of (S)-alpha-methylbenzylamine (I) with benzyl bromide in N,N'-dimethylpropyleneurea gave the chiral secondary amine (II). Diastereoselective Michael addition of the lithium amide of (II) to benzyl crotonate (III) provided adduct (IV). The chiral ester (IV) was then reacted with the Grignard reagent (V) to yield the diaryl carbinol (VI). This was subsequently dehydrated to (VII) using H2SO4 in glacial HOAc. Double bond reduction and N-debenzylation of (VII) over Pearlman抯 catalyst provided the target primary amine, which was finally isolated as the hydrochloride salt.
【1】
Moe, S.T.; DelMar, E.G.; Smith, D.L.; et al.; Chiral synthesis and pharmacological evaluation of NPS 1407: A potent, stereoselective NMDA receptor antagonist. Bioorg Med Chem Lett 2000, 10, 21, 2411.
|
【2】
Moe, S.T.; Mueller, A.L. (NPS Pharmaceuticals, Inc.); Cpds. active at a novel site on receptor-operated calcium channels useful for treatment of neurological disorders and diseases. WO 9856752 .
|
【3】
Moe, S.T.; Mueller, A.L.; Vanwagenen, B.C.; Barmore, R.M.; Delmar, E.G.; Artman, L.D.; Balandrin, M.F.; Smith, D.L. (NPS Pharmaceuticals, Inc.); Cpds. active at a novel site on receptor-operated calcium channels useful for treatment of neurological disorders and diseases. WO 9746511 . |
【4】
Barmore, R.M.; DelMar, E.G.; Balandrin, M.F.; VanWagenen, B.C.; Artman, L.D.; Mueller, A.L.; Moe, S.T. (NPS Pharmaceuticals, Inc.); Cpds. active at a novel site on receptor-operated calcium channels useful for treatment of neurological disorders and diseases. US 6071970 . |
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) |
20042 |
(1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine
|
|
C8H11N |
详情 |
详情
|
(II) |
38470 |
(1S)-N-benzyl-1-phenyl-1-ethanamine; N-benzyl-N-[(1S)-1-phenylethyl]amine
|
38235-77-7 |
C15H17N |
详情 | 详情
|
(III) |
46908 |
benzyl (E)-2-butenoate
|
|
C11H12O2 |
详情 |
详情
|
(IV) |
46909 |
benzyl (3S)-3-[benzyl[(1S)-1-phenylethyl]amino]butanoate
|
|
C26H29NO2 |
详情 |
详情
|
(V) |
35384 |
bromo(3-fluorophenyl)magnesium
|
|
C6H4BrFMg |
详情 |
详情
|
(VI) |
46910 |
(3S)-3-[benzyl[(1S)-1-phenylethyl]amino]-1,1-bis(3-fluorophenyl)-1-butanol
|
|
C31H31F2NO |
详情 |
详情
|
(VII) |
46911 |
(2S)-N-benzyl-4,4-bis(3-fluorophenyl)-N-[(1S)-1-phenylethyl]-3-buten-2-amine; N-benzyl-N-[(1S)-3,3-bis(3-fluorophenyl)-1-methyl-2-propenyl]-N-[(1S)-1-phenylethyl]amine
|
|
C31H29F2N |
详情 |
详情
|
合成路线19
该中间体在本合成路线中的序号:
(V) 6-Methoxy-2-tetralone (I) was condensed with pyrrolidine (II) to produce enamine (III). Alkylation of (III) with benzyl bromide, followed by hydrolysis of the enamine function, furnished the 1-benzylnaphthalenone (IV). After formation of the chiral enamine (VI) with (S)-alpha-methylbenzylamine (V), enantioselective Michael addition of methyl vinyl ketone (VII) provided the (R)-diketone (VIII), which underwent ring closure to the phenanthrene derivative (IX) upon treatment with NaOMe. Methyl ether cleavage by using boron trichloride in the presence of tetrabutylammonium iodide afforded phenol (X). The conjugated ketone system of (X) was diastereoselectively reduced to the trans-phenanthrenone (XI) by means of lithium in liquid ammonia. Addition of the lithium acetylide of propyne (XII) to the ketone (XI) produced a diastereomeric mixture of carbinols from which the desired isomer (XIII) was isolated by flash chromatography. The phenol group of (XIII) was then converted to the aryl triflate (XIV) by reaction with trifluoromethanesulfonic anhydride and 2,6-lutidine.
【1】
Liu, K.K.-C.; Morgan, B.P.; Dow, R.L.; Swick, A.G. (Pfizer Inc.); Glucocorticoid receptor modulators. EP 1175383; WO 0066522 .
|
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) |
47506 |
6-Methoxy-2-tetralone; 6-methoxy-3,4-dihydro-2(1H)-naphthalenone
|
2472-22-2 |
C11H12O2 |
详情 | 详情
|
(II) |
11376 |
Pyrrolidine
|
123-75-1 |
C4H9N |
详情 | 详情
|
(III) |
47507 |
methyl 6-(1-pyrrolidinyl)-7,8-dihydro-2-naphthalenyl ether; 1-(6-methoxy-3,4-dihydro-2-naphthalenyl)pyrrolidine
|
|
C15H19NO |
详情 |
详情
|
(IV) |
51596 |
1-benzyl-6-methoxy-3,4-dihydro-2(1H)-naphthalenone
|
|
C18H18O2 |
详情 |
详情
|
(V) |
20042 |
(1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine
|
|
C8H11N |
详情 |
详情
|
(VI) |
51597 |
1-benzyl-6-methoxy-N-[(1S)-1-phenylethyl]-3,4-dihydro-2-naphthalenamine; N-(1-benzyl-6-methoxy-3,4-dihydro-2-naphthalenyl)-N-[(1S)-1-phenylethyl]amine
|
|
C26H27NO |
详情 |
详情
|
(VII) |
30324 |
3-buten-2-one; methyl vinyl ketone
|
78-94-4 |
C4H6O |
详情 | 详情
|
(VIII) |
51598 |
(1R)-1-benzyl-6-methoxy-1-(3-oxobutyl)-3,4-dihydro-2(1H)-naphthalenone
|
|
C22H24O3 |
详情 |
详情
|
(IX) |
51599 |
(4aS)-4a-benzyl-7-methoxy-4,4a,9,10-tetrahydro-2(3H)-phenanthrenone
|
|
C22H22O2 |
详情 |
详情
|
(X) |
51600 |
(4aS)-4a-benzyl-7-hydroxy-4,4a,9,10-tetrahydro-2(3H)-phenanthrenone
|
|
C21H20O2 |
详情 |
详情
|
(XI) |
51601 |
(4aS,10aR)-4a-benzyl-7-hydroxy-3,4,4a,9,10,10a-hexahydro-2(1H)-phenanthrenone
|
|
C21H22O2 |
详情 |
详情
|
(XII) |
51602 |
1-Propyne
|
|
C3H4 |
详情 |
详情
|
(XIII) |
51603 |
(2R,4aS,10aR)-4a-benzyl-2-(1-propynyl)-1,2,3,4,4a,9,10,10a-octahydro-2,7-phenanthrenediol
|
|
C24H26O2 |
详情 |
详情
|
(XIV) |
51604 |
(4bS,7R,8aR)-4b-benzyl-7-hydroxy-7-(1-propynyl)-4b,5,6,7,8,8a,9,10-octahydro-2-phenanthrenyl trifluoromethanesulfonate
|
|
C25H25F3O4S |
详情 |
详情
|
合成路线20
该中间体在本合成路线中的序号:
(IX) Esterification of N-benzyloxycarbonyl-(R)-tryptophan (I) with allyl alcohol (II) using DCC gave ester (III). The cyclization of (III) to afford diastereoselectively the pyrroloindole derivative (IV) was achieved in trifluoroacetic acid as the solvent. A second N-benzyloxycarbonyl protecting group was then introduced at the indoline nitrogen of (IV), yielding (V). Mannich reaction of the lithium anion of (V) with Eschenmoser's salt provided the (dimethylamino)methyl compound (VI). Ring opening of (VI) to the indole (VII) was performed with sulfuric acid in aqueous methanol. The allyl ester of (VII) was then removed by means of morpholine and palladium catalyst to produce acid (VIII), which was coupled with (S)-alpha-methylbenzylamine (IX) to give amide (X). After hydrogenolysis of the two benzyloxycarbonyl protecting groups of (X), the free amine (XI) was acylated with 2-benzofuranylmethyl chloroformate to furnish the title carbamate.
【1】
Ashwood, V.A.; et al.; Utilization of an intramolecular hydrogen bond to increase the CNS penetration of an NK1 receptor antagonist. J Med Chem 2001, 44, 14, 2276.
|
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) |
18652 |
(2S)-2-[[(benzyloxy)carbonyl]amino]-3-(1H-indol-3-yl)propionic acid
|
7432-21-5 |
C19H18N2O4 |
详情 | 详情
|
(II) |
12234 |
2-Propen-1-ol; Allyl alcohol
|
107-18-6 |
C3H6O |
详情 | 详情
|
(III) |
51359 |
allyl (2R)-2-[[(benzyloxy)carbonyl]amino]-3-(1H-indol-3-yl)propanoate
|
|
C22H22N2O4 |
详情 |
详情
|
(IV) |
51360 |
2-allyl 1-benzyl (2R,3aS,8aS)-3,3a,8,8a-tetrahydropyrrolo[2,3-b]indole-1,2(2H)-dicarboxylate
|
|
C22H22N2O4 |
详情 |
详情
|
(V) |
51361 |
2-allyl 1,8-dibenzyl (2R,3aS,8aR)-2,3,3a,8a-tetrahydropyrrolo[2,3-b]indole-1,2,8-tricarboxylate
|
|
C30H28N2O6 |
详情 |
详情
|
(VI) |
51362 |
2-allyl 1,8-dibenzyl (2S,3aS,8aS)-2-[(dimethylamino)methyl]-2,3,3a,8a-tetrahydropyrrolo[2,3-b]indole-1,2,8-tricarboxylate
|
|
C33H35N3O6 |
详情 |
详情
|
(VII) |
51363 |
benzyl 3-[(2S)-3-(allyloxy)-2-[[(benzyloxy)carbonyl]amino]-2-[(dimethylamino)methyl]-3-oxopropyl]-1H-indole-1-carboxylate
|
|
C33H35N3O6 |
详情 |
详情
|
(VIII) |
51364 |
(2S)-2-[[(benzyloxy)carbonyl]amino]-3-[1-[(benzyloxy)carbonyl]-1H-indol-3-yl]-2-[(dimethylamino)methyl]propionic acid
|
|
C30H31N3O6 |
详情 |
详情
|
(IX) |
20042 |
(1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine
|
|
C8H11N |
详情 |
详情
|
(X) |
51365 |
benzyl 3-((2S)-2-[[(benzyloxy)carbonyl]amino]-2-[(dimethylamino)methyl]-3-oxo-3-[[(1S)-1-phenylethyl]amino]propyl)-1H-indole-1-carboxylate
|
|
C38H40N4O5 |
详情 |
详情
|
(XI) |
51367 |
(2S)-2-amino-3-(dimethylamino)-2-(1H-indol-3-ylmethyl)-N-[(1S)-1-phenylethyl]propanamide
|
|
C22H28N4O |
详情 |
详情
|
(XII) |
51366 |
2-[[(chlorocarbonyl)oxy]methyl]-1-benzofuran
|
|
C10H7ClO3 |
详情 |
详情
|
合成路线21
该中间体在本合成路线中的序号:
(I) Condensation between (S)-alpha-methylbenzylamine (I) and ethyl glyoxylate (II) afforded imine (III), which was subjected to hetero-Diels-Alder cycloaddition with 2-(trimethylsilyloxy)-1,3-butadiene (IV) producing piperidinecarboxylate (V) as the major diastereoisomer. Ketalization of (V) with triethyl orthoformate gave the corresponding the diethyl acetal (VI). The ester group of (VI) was then reduced to alcohol (VII) employing LiAlH4. Mitsunobu condensation of alcohol (VII) with phthalimide (VIII) gave (IX) which, followed by acidic ketal hydrolysis, furnished (X). Condensation of piperidinone (X) with t-butyl cyanoacetate (XI) in the presence of sulfur and morpholine gave rise to two regioisomeric thienopyridine derivatives (XII) and (XIII), which were separated by column chromatography.
【1】
Lau, J.; Andersen, H.S.; Newman, M.J.; Hansen, T.K.; Olsen, O.H.; Bakir, F.; Holsworth, D.D.; Axe, F.U.; Ge, Y.; Uyeda, R.T.; Judge, L.M.; Moeller, N.P.H.; Shapira, B.Z. (Novo Nordisk A/S; Ontogen Corp.); Modulators of protein tyrosine phosphatases (PTPases). WO 0204459 . |
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) |
20042 |
(1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine
|
|
C8H11N |
详情 |
详情
|
(II) |
48591 |
Ethyl glyoxylate; Ethyl oxoacetate; Glyoxylic acid ethyl ester
|
924-44-7 |
C4H6O3 |
详情 | 详情
|
(III) |
58785 |
ethyl 2-{[(1S)-1-phenylethyl]imino}acetate
|
|
C12H15NO2 |
详情 |
详情
|
(IV) |
18557 |
1-methylene-2-propenyl trimethylsilyl ether; trimethyl[(1-methylene-2-propenyl)oxy]silane
|
38053-91-7 |
C7H14OSi |
详情 | 详情
|
(V) |
58786 |
ethyl (2R)-4-oxo-1-[(1S)-1-phenylethyl]-2-piperidinecarboxylate
|
|
C16H21NO3 |
详情 |
详情
|
(VI) |
58787 |
ethyl (2R)-4,4-diethoxy-1-[(1S)-1-phenylethyl]-2-piperidinecarboxylate
|
|
C20H31NO4 |
详情 |
详情
|
(VII) |
58788 |
{(2R)-4,4-diethoxy-1-[(1S)-1-phenylethyl]piperidinyl}methanol
|
|
C18H29NO3 |
详情 |
详情
|
(VIII) |
12376 |
Phthalimide; 1H-Isoindole-1,3(2H)-dione; Isoindole-1,3-dione;Phthalic dicarboximide;Phenylimide;Isoindole-1,3-dione |
85-41-6 |
C8H5NO2 |
详情 | 详情
|
(IX) |
58789 |
2-({(2R)-4,4-diethoxy-1-[(1S)-1-phenylethyl]piperidinyl}methyl)-1H-isoindole-1,3(2H)-dione
|
|
C26H32N2O4 |
详情 |
详情
|
(X) |
58790 |
2-({(2R)-4-oxo-1-[(1S)-1-phenylethyl]piperidinyl}methyl)-1H-isoindole-1,3(2H)-dione
|
|
C22H22N2O3 |
详情 |
详情
|
(XI) |
14330 |
tert-Butyl cyanoacetate; tert-butyl 2-cyanoacetate
|
1116-98-9 |
C7H11NO2 |
详情 | 详情
|
(XII) |
58791 |
tert-butyl (7S)-2-amino-7-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-6-[(1S)-1-phenylethyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate
|
|
C29H31N3O4S |
详情 |
详情
|
(XIII) |
58792 |
tert-butyl (5R)-2-amino-5-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-6-[(1S)-1-phenylethyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate
|
|
C29H31N3O4S |
详情 |
详情
|
合成路线22
该中间体在本合成路线中的序号:
(IV) The acylation of N-[4-(4-aminophenyl)-2-thiazolyl]carbamic acid tert-butyl ester (I) with bromoacetyl bromide (II) gives the bromoacetamide (III), which is then condensed with (S)-alpha-methylbenzylamine (IV) to yield the glycinamide derivative (V). The acylation of (V) with 4-pyridylcarbonyl chloride affords the protected precursor (VI), which is finally deprotected to provide the target BILS 179 BS.
【1】
Crute, J.J.; et al.; Herpes simplex virus helicase-primase inhibitors are active in animal models of human disease. Nat Med 2002, 8, 4, 386.
|
【2】
Hargrave, K.D.; Simoneau, B.; Faucher, A.-M.; Thavonekham, B.; Grygon, C.A.; Crute, J.J. (Boehringer Ingelheim (Canada) Ltd.; Boehringer Ingelheim Pharmaceuticals Inc.); Phenyl thiazole derivs. with anti-herpes virus properties. EP 0871619; JP 2000502702; US 6057451; WO 9724343 . |
【3】
Hargrave, K.D.; Simoneau, B.; Faucher, A.-M.; Crute, J.J.; Thavonekham, B.; Grygon, C. (Boehringer Ingelheim (Canada) Ltd.; Boehringer Ingelheim Pharmaceuticals Inc.); Antiherpes virus cpds. and methods for their preparation and use. US 6288091 .
|
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) |
54066 |
tert-butyl 4-(4-aminophenyl)-1,3-thiazol-2-ylcarbamate
|
n/a |
C14H17N3O2S |
详情 | 详情
|
(II) |
14005 |
2-Bromoacetyl bromide; Bromoacetyl bromide
|
598-21-0 |
C2H2Br2O |
详情 | 详情
|
(III) |
54067 |
tert-butyl 4-{4-[(2-bromoacetyl)amino]phenyl}-1,3-thiazol-2-ylcarbamate
|
n/a |
C16H18BrN3O3S |
详情 | 详情
|
(IV) |
20042 |
(1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine
|
|
C8H11N |
详情 |
详情
|
(V) |
54068 |
tert-butyl 4-{4-[(2-{[(1S)-1-phenylethyl]amino}acetyl)amino]phenyl}-1,3-thiazol-2-ylcarbamate
|
n/a |
C24H28N4O3S |
详情 | 详情
|
(VI) |
27850 |
isonicotinoyl chloride
|
39178-35-3 |
C6H4ClNO |
详情 | 详情
|
(VII) |
54069 |
tert-butyl 4-{4-[(2-{isonicotinoyl[(1S)-1-phenylethyl]amino}acetyl)amino]phenyl}-1,3-thiazol-2-ylcarbamate
|
n/a |
C30H31N5O4S |
详情 | 详情
|
合成路线23
该中间体在本合成路线中的序号:
(IV) The acylation of N-[4-(4-aminophenyl)-2-thiazolyl]carbamic acid tert-butyl ester (I) with bromoacetyl bromide (II) gives the bromoacetamide (III), which is then condensed with 4-pyridylmethylamine (IV) to yield the glycinamide derivative (V). The acylation of (V) with cyclohexanecarbonyl chloride affords the protected precursor (VI), which is finally deprotected to provide the target BILS 103 BS.
【1】
Crute, J.J.; et al.; Herpes simplex virus helicase-primase inhibitors are active in animal models of human disease. Nat Med 2002, 8, 4, 386.
|
【2】
Hargrave, K.D.; Simoneau, B.; Faucher, A.-M.; Thavonekham, B.; Grygon, C.A.; Crute, J.J. (Boehringer Ingelheim (Canada) Ltd.; Boehringer Ingelheim Pharmaceuticals Inc.); Phenyl thiazole derivs. with anti-herpes virus properties. EP 0871619; JP 2000502702; US 6057451; WO 9724343 . |
【3】
Hargrave, K.D.; Simoneau, B.; Faucher, A.-M.; Crute, J.J.; Thavonekham, B.; Grygon, C. (Boehringer Ingelheim (Canada) Ltd.; Boehringer Ingelheim Pharmaceuticals Inc.); Antiherpes virus cpds. and methods for their preparation and use. US 6288091 .
|
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) |
54066 |
tert-butyl 4-(4-aminophenyl)-1,3-thiazol-2-ylcarbamate
|
n/a |
C14H17N3O2S |
详情 | 详情
|
(II) |
14005 |
2-Bromoacetyl bromide; Bromoacetyl bromide
|
598-21-0 |
C2H2Br2O |
详情 | 详情
|
(III) |
54067 |
tert-butyl 4-{4-[(2-bromoacetyl)amino]phenyl}-1,3-thiazol-2-ylcarbamate
|
n/a |
C16H18BrN3O3S |
详情 | 详情
|
(IV) |
20042 |
(1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine
|
|
C8H11N |
详情 |
详情
|
(V) |
54068 |
tert-butyl 4-{4-[(2-{[(1S)-1-phenylethyl]amino}acetyl)amino]phenyl}-1,3-thiazol-2-ylcarbamate
|
n/a |
C24H28N4O3S |
详情 | 详情
|
(VI) |
17220 |
cyclohexanecarbonyl chloride; Cyclohexanecarboxylic acid chloride
|
2719-27-9 |
C7H11ClO |
详情 | 详情
|
(VII) |
54070 |
tert-butyl 4-[4-({2-[(cyclohexylcarbonyl)(4-pyridinylmethyl)amino]acetyl}amino)phenyl]-1,3-thiazol-2-ylcarbamate
|
n/a |
C29H35N5O4S |
详情 | 详情
|
合成路线24
该中间体在本合成路线中的序号:
(IV) 6-Methoxy-2-tetralone (I) is converted into enamine (II) by treatment with pyrrolidine in toluene by azeotropic removal of water. Alkylation of (II) with benzyl bromide, followed by hydrolysis of the enamine, provides the 1-benzyl tetralone (III). This is then condensed with (S)-alpha-methylbenzylamine (IV), and the resultant imine (V) is treated with methyl vinyl ketone (VI) to furnish, after hydrolysis of the chiral auxiliary, the tricyclic ketone (VII). Rearrangement of (VII) in the presence of NaOMe results in the phenanthrenone (VIII). Cleavage of the methyl ether of (VIII) is accomplished by treatment with boron trichloride and tetrabutylammonium iodide to form phenol (IX). Reduction of enone (IX) with lithium metal in liquid ammonia leads to the saturated ketone (X). Finally, addition of the lithium acetylide of propyne (XI) to the ketone (X) affords the title carbinol adduct.
【1】
Morgan, B.P.; Swick, A.G.; Hargrove, D.M.; LaFlamme, J.A.; Moynihan, M.S.; Carroll, R.S.; Martin, K.A.; Lee, E.; Decosta, D.; Bordner, J.; Discovery of potent, nonsteroidal, and highly selective glucocorticoid receptor antagonists. J Med Chem 2002, 45, 12, 2417. |
【2】
Liu, K.K.-C.; Morgan, B.P.; Dow, R.L.; Swick, A.G. (Pfizer Inc.); Glucocorticoid receptor modulators. EP 1175383; WO 0066522 .
|
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) |
47506 |
6-Methoxy-2-tetralone; 6-methoxy-3,4-dihydro-2(1H)-naphthalenone
|
2472-22-2 |
C11H12O2 |
详情 | 详情
|
(II) |
47507 |
methyl 6-(1-pyrrolidinyl)-7,8-dihydro-2-naphthalenyl ether; 1-(6-methoxy-3,4-dihydro-2-naphthalenyl)pyrrolidine
|
|
C15H19NO |
详情 |
详情
|
(III) |
51596 |
1-benzyl-6-methoxy-3,4-dihydro-2(1H)-naphthalenone
|
|
C18H18O2 |
详情 |
详情
|
(IV) |
20042 |
(1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine
|
|
C8H11N |
详情 |
详情
|
(V) |
61649 |
(1S)-N-[1-benzyl-6-methoxy-3,4-dihydro-2(1H)-naphthalenylidene]-1-phenyl-1-ethanamine
|
|
C26H27NO |
详情 |
详情
|
(VI) |
30324 |
3-buten-2-one; methyl vinyl ketone
|
78-94-4 |
C4H6O |
详情 | 详情
|
(VII) |
61650 |
(1R)-1-benzyl-10-hydroxy-5-methoxy-10-methyltricyclo[7.3.1.0~2,7~]trideca-2,4,6-trien-13-one
|
|
C22H24O3 |
详情 |
详情
|
(VIII) |
51599 |
(4aS)-4a-benzyl-7-methoxy-4,4a,9,10-tetrahydro-2(3H)-phenanthrenone
|
|
C22H22O2 |
详情 |
详情
|
(IX) |
51600 |
(4aS)-4a-benzyl-7-hydroxy-4,4a,9,10-tetrahydro-2(3H)-phenanthrenone
|
|
C21H20O2 |
详情 |
详情
|
(X) |
51601 |
(4aS,10aR)-4a-benzyl-7-hydroxy-3,4,4a,9,10,10a-hexahydro-2(1H)-phenanthrenone
|
|
C21H22O2 |
详情 |
详情
|
(XI) |
51602 |
1-Propyne
|
|
C3H4 |
详情 |
详情
|
合成路线25
该中间体在本合成路线中的序号:
(VIII) 5-Formylsalicylic acid (I) is protected by esterification with H2SO4/MeOH to give the methyl ester (II). After alkylation of the phenolic hydroxyl group of (II) with propyl bromide, the resultant ortho-propoxy benzoate ester (III) is hydrolyzed to carboxylic acid (IV) with LiOH in aqueous THF. Condensation of the aldehyde-acid (IV) with 2,4-thiazolidinedione (V) in the presence of morpholine leads to the benzylidene thiazolidinedione (VI). Activation of the carboxyl group of (VI) with oxalyl chloride gives rise to the corresponding acid chloride (VII), which is then condensed with (S)-alpha-methylbenzylamine (VIII) to furnish the target amide.
【1】
Allen, S.H.; Pfohl, J.L.; Wallace, E.; Truax, J.F.; Worley, J.K.; Townsend, C.; Peat, A.J.; Garrido, D.M.; McKay, C.; Aryl 1,3-thiazolidine-2,4-diones acting as KATP channel agonists as a class of potent antidiabetic agents. 224th ACS Natl Meet (Aug 18 2002, Boston) 2002, Abst MEDI 364. |
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) |
32357 |
5-Formylsalicylic acid; 5-formyl-2-hydroxybenzoic acid
|
616-76-2 |
C8H6O4 |
详情 | 详情
|
(II) |
58380 |
ethyl 5-formyl-2-hydroxybenzoate
|
|
C10H10O4 |
详情 |
详情
|
(III) |
58381 |
ethyl 5-formyl-2-propoxybenzoate
|
|
C13H16O4 |
详情 |
详情
|
(IV) |
58382 |
5-formyl-2-propoxybenzoic acid
|
|
C11H12O4 |
详情 |
详情
|
(V) |
10883 |
1,3-Thiazolane-2,4-dione; 2,4-Thiazolidinedione
|
2295-31-0 |
C3H3NO2S |
详情 | 详情
|
(VI) |
58383 |
5-[(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-2-propoxybenzoic acid
|
|
C14H13NO5S |
详情 |
详情
|
(VII) |
58384 |
5-[(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-2-propoxybenzoyl chloride
|
|
C14H12ClNO4S |
详情 |
详情
|
(VIII) |
20042 |
(1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine
|
|
C8H11N |
详情 |
详情
|