合成路线1
该中间体在本合成路线中的序号:
(IV) The synthesis of [14]-labeled stiripentol has been published:
The reaction of 3,4-methylenedioxybromobenzene (I) with 14CO2 by means of butyllithium in ether gives 3,4-methylenedioxybenzoic acid (II), which is reduced with LiAlH4 to the corresponding benzyl alcohol (III). Oxidation of (III) with CrO3-pyridine affords the aldehyde (IV), which is condensed with methyl tert-butyl ketone (V) by means of NaOH in refluxing ethanol to give the labeled pentanone (VI). Finally, this compound is reduced to [14C]-labeled stiripentol with NaBH4 in methanol.
【1】
Lepage, F. Veyre, A.; Madelmont, J.C.; Labarre, P.; Maurizis, J.C.; Rapp, M.; Dupuy, J.M.; Labelling by 14C and 3H of 4,4-dimethyl-1-(3,4-methylenedioxyphenyl)-1-pentene-3-ol or stiripentol. J Label Compd Radiopharm 1992, 31, 11, 961.
|
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) |
10124 |
5-Bromo-1,3-benzodioxole; 4-Bromo-1,2-(methylenedioxy)benzene
|
2635-13-4 |
C7H5BrO2 |
详情 | 详情
|
(II) |
10125 |
1,3-Benzodioxole-5-carboxylic acid
|
94-53-1 |
C8H6O4 |
详情 | 详情
|
(II) |
44584 |
1,3-benzodioxole-5-carboxylic acid
|
|
C8H6O4 |
详情 |
详情
|
(III) |
10126 |
1,3-Benzodioxol-5-ylmethanol; Helioalcohol
|
495-76-1 |
C8H8O3 |
详情 | 详情
|
(III) |
44585 |
1,3-benzodioxol-5-ylmethanol
|
|
C8H8O3 |
详情 |
详情
|
(IV) |
10127 |
1,3-Benzodioxole-5-carbaldehyde; Heliotropine
|
120-57-0 |
C8H6O3 |
详情 | 详情
|
(IV) |
44586 |
1,3-benzodioxole-5-carbaldehyde
|
|
C8H6O3 |
详情 |
详情
|
(V) |
10128 |
3,3-Dimethyl-2-butanone; Pinacolin
|
75-97-8 |
C6H12O |
详情 | 详情
|
(VI) |
10129 |
(E)-1-(1,3-Benzodioxol-5-yl)-4,4-dimethyl-1-penten-3-one
|
|
C14H16O3 |
详情 |
详情
|
(VI) |
44587 |
(E)-1-(1,3-benzodioxol-5-yl)-4,4-dimethyl-1-penten-3-one
|
|
C14H16O3 |
详情 |
详情
|
合成路线2
该中间体在本合成路线中的序号:
(I) The condensation of 3,4-methylenedioxybenzaldehyde (I) with 3,3-dimethyl-2-butanone (II) by means of NaOH in ethanol-water gives 4,4-dimethyl-1-[(3,4-methylenedioxy)phenyl]-1-penten-3-one (III), which is reduced with NaBH4 in methanol.
【1】
Vallet, F.M.J.; US 3910959 .
|
【2】
Astoin, J.; et al.; Action of new ethylenic alcohols on the central nervous system. Eur J Med Chem - Chim Ther 1978, 13, 1, 41-47.
|
【3】
Castaner, J.; Hillier, K.; Stiripentol. Drugs Fut 1980, 5, 8, 413.
|
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
(I) |
10127 |
1,3-Benzodioxole-5-carbaldehyde; Heliotropine
|
120-57-0 |
C8H6O3 |
详情 | 详情
|
(II) |
10128 |
3,3-Dimethyl-2-butanone; Pinacolin
|
75-97-8 |
C6H12O |
详情 | 详情
|
(III) |
10129 |
(E)-1-(1,3-Benzodioxol-5-yl)-4,4-dimethyl-1-penten-3-one
|
|
C14H16O3 |
详情 |
详情
|
合成路线3
该中间体在本合成路线中的序号:
(VII) Condensation of piperonyl chloride (I) with diethyl malonate (II) by means of Na in anhydrous refluxing EtOH (NaOEt) provides 2-[3,4-(methylenedioxy)benzyl]malonic acid diethyl ester (III), which is converted into the monoethyl ester (IV) by saponification with KOH in EtOH. Treatment of (IV) with diethylamine in paraformaldehyde/H2O affords acrylic ester (V), which is then subjected to saponification with NaOH in acetone/H2O to provide [3,4-(methylenedioxy)benzyl]-2-propenoic acid (VI). Alternatively, derivative (VI) can also be obtained by following this route: treatment of piperonal (VII) with diethyl malonate (II) in refluxing toluene in the presence of piperidine and acetic acid provides diethyl piperonylidene malonate (VIII), which is then hydrogenated over Pd/C to furnish diethyl piperonylmalonate (IX). Saponification of the ethyl ester moiety of (IX) by refluxing with NaOH in H2O affords piperonylmalonic acid (X), which is finally converted into intermediate (VI) by decarboxylation by treatment with diethylamine in refluxing paraformaldehyde. Reaction of (VI) with thioacetic acid at 70 C affords a racemic mixture of propionic acid derivatives (XI), which is resolved by first formation of a chiral salt (either by reaction with (R)-alpha-methylbenzylamine or by reaction with (+)-ephedrine in ether), recrystallization of the corresponding diastereomer and finally liberation of the 2-(S)-(acetylthiomethyl)-3-[3,4-(methylenedioxy)benzyl]propionic acid [(S)-(XII)] by hydrolysis with HCl in H2O/CH2Cl2. Finally, fasidotril is obtained by condensation of (S)-(XII) with benzyl alaninate (XIII) by means of HOBt and DCC in THF/CHCl3 in the presence of Et3N.
【1】
Plaquevent, J.-C.; Danvy, D.; Monteil, T.; Greciet, H.; Duhamel, L.; Duhamel, P.; Gros, C.; Schwartz, J.-C.; Lecomte, J.-M. (Societe Civile Bioprojet); Amino acid derivs., method for their preparation and their therapeutic application. EP 0419327; FR 2652087; WO 9104246 . |
【2】
Lecomte, J.-M.; Duhamel, P.; Danvy, D.; Schwartz, J.-C.; Duhamel, L.; Monteil, T. (Societe Civile Bioprojet); Process for the synthesis of alpha-substd. acrylic acids and their application. EP 0729936 .
|
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
(III),(IX) |
49496 |
diethyl 2-(1,3-benzodioxol-5-ylmethyl)malonate
|
|
C15H18O6 |
详情 |
详情
|
(S)-(XII) |
49501 |
(2S)-3-(acetylsulfanyl)-2-(1,3-benzodioxol-5-ylmethyl)propionic acid
|
|
C13H14O5S |
详情 |
详情
|
(I) |
28617 |
5-(chloromethyl)-1,3-benzodioxole
|
|
C8H7ClO2 |
详情 |
详情
|
(II) |
16829 |
Diethyl malonate
|
105-53-3 |
C7H12O4 |
详情 | 详情
|
(IV) |
49497 |
2-(1,3-benzodioxol-5-ylmethyl)-3-ethoxy-3-oxopropionic acid
|
|
C13H14O6 |
详情 |
详情
|
(V) |
38469 |
ethyl (E)-3-(1,3-benzodioxol-5-yl)-2-propenoate
|
|
C12H12O4 |
详情 |
详情
|
(VI) |
11634 |
(E)-3-(1,3-Benzodioxol-5-yl)-2-propenoic acid; 3,4-(Methylenedioxy)cinnamic acid
|
2373-80-0 |
C10H8O4 |
详情 | 详情
|
(VII) |
10127 |
1,3-Benzodioxole-5-carbaldehyde; Heliotropine
|
120-57-0 |
C8H6O3 |
详情 | 详情
|
(VIII) |
49499 |
diethyl 2-(1,3-benzodioxol-5-ylmethylene)malonate
|
|
C15H16O6 |
详情 |
详情
|
(X) |
49500 |
2-(1,3-benzodioxol-5-ylmethyl)malonic acid
|
|
C11H10O6 |
详情 |
详情
|
(XI) |
49498 |
3-(acetylsulfanyl)-2-(1,3-benzodioxol-5-ylmethyl)propionic acid
|
|
C13H14O5S |
详情 |
详情
|
(XIII) |
10143 |
benzyl (2S)-2-aminopropanoate
|
|
C10H13NO2 |
详情 |
详情
|
合成路线4
该中间体在本合成路线中的序号:
(X) The required (S)-alpha-propylpiperonyl alcohol (XV) was prepared by two alternative routes. Asymmetric addition of di-n-propyl zinc to piperonal (X) in the presence of titanium isopropoxide and the chiral bis-triflamide (XI) yielded the (S)-alcohol (XV) in high enantiomeric excess. Alternatively, ketone (XIII) was reduced with the oxazaborolidine-borane complex (XIV) to give (XV). Treatment of the (S)-alcohol (XV) with DPPA in the presence of DBU produced the (R)-azide (XVI). This was then reduced with LiAlH4 to yield amine (XVII) with some loss of optical purity. Optical enrichment was achieved by crystallization as the D-pyroglutamic acid salt. The (R)-amine (XVII) was converted to isocyanate (XVIII) by treatment with phosgene. Finally, coupling between isocyanate (XVIII) and azetidinone (IX) in the presence of DBU in acetonitrile led to the title compound.
【1】
Cvetovich, R.J.; et al.; An asymmetric synthesis of L-694,458, a human leukocyte elastase inhibitor, via novel enzyme resolution of beta-lactam esters. J Org Chem 1996, 61, 19, 6575.
|
【2】
Amato, J.S.; Cvetovich, R.; Hartner, F.W. (Merck & Co., Inc.); Process for preparing substd. azetidinones. WO 9716448 .
|
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) |
53626 |
(4S)-3,3-diethyl-4-{4-[(4-methyl-1-piperazinyl)carbonyl]phenoxy}-2-azetidinone
|
n/a |
C19H27N3O3 |
详情 | 详情
|
(X) |
10127 |
1,3-Benzodioxole-5-carbaldehyde; Heliotropine
|
120-57-0 |
C8H6O3 |
详情 | 详情
|
(XI) |
53627 |
trifluoro-N-((1R,2R)-2-{[(trifluoromethyl)sulfonyl]amino}cyclohexyl)methanesulfonamide
|
n/a |
C8H12F6N2O4S2 |
详情 | 详情
|
(XIII) |
53629 |
1-(1,3-benzodioxol-5-yl)-1-butanone
|
63740-97-6 |
C11H12O3 |
详情 | 详情
|
(XIV) |
20631 |
(R)-Methyl oxazaborolidine; (3aR)-1-methyl-3,3-diphenyltetrahydro-3H-pyrrolo[1,2-c][1,3,2]oxazaborole
|
112022-83-0 |
C18H20BNO |
详情 | 详情
|
(XV) |
53628 |
(1S)-1-(1,3-benzodioxol-5-yl)-1-butanol
|
n/a |
C11H14O3 |
详情 | 详情
|
(XVI) |
53630 |
(1R)-1-(1,3-benzodioxol-5-yl)butyl azide; 5-[(1R)-1-azidobutyl]-1,3-benzodioxole
|
n/a |
C11H13N3O2 |
详情 | 详情
|
(XVII) |
53631 |
(1R)-1-(1,3-benzodioxol-5-yl)-1-butanamine; (1R)-1-(1,3-benzodioxol-5-yl)butylamine
|
n/a |
C11H15NO2 |
详情 | 详情
|
(XVIII) |
53632 |
5-[(1R)-1-isocyanatobutyl]-1,3-benzodioxole; (1R)-1-(1,3-benzodioxol-5-yl)butyl isocyanate
|
n/a |
C12H13NO3 |
详情 | 详情
|
合成路线5
该中间体在本合成路线中的序号:
(X) Preparation of the intermediate chiral amine (XVII) was reported by a number of synthetic strategies. Piperonal (X) was condensed with D-phenylglycinol (XXIV) to give imine (XXV). Diastereoselective addition of allylmagnesium chloride (XXVI) to imine (XXV) afforded amine (XXVII). Simultaneous hydrogenation of the double bond and hydrogenolysis of the chiral auxiliary of (XXVII) furnished the desired amine (XVII).
【1】
Storace, L.; et al.; An efficient large-scale process for the human leukocyte elastase inhibitor, DMP 777. Org Process Res Dev 2002, 6, 1, 54.
|
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) |
10127 |
1,3-Benzodioxole-5-carbaldehyde; Heliotropine
|
120-57-0 |
C8H6O3 |
详情 | 详情
|
(XVII) |
53631 |
(1R)-1-(1,3-benzodioxol-5-yl)-1-butanamine; (1R)-1-(1,3-benzodioxol-5-yl)butylamine
|
n/a |
C11H15NO2 |
详情 | 详情
|
(XXIV) |
14376 |
(2R)-2-amino-2-phenyl-1-ethanol; (R)-(-)-2-phenylglycinol; (R)-2-amino-2-phenyl-1-ethanol
|
56613-80-0 |
C8H11NO |
详情 | 详情
|
(XXV) |
53637 |
(2R)-2-{[(E)-1,3-benzodioxol-5-ylmethylidene]amino}-2-phenyl-1-ethanol
|
n/a |
C16H15NO3 |
详情 | 详情
|
(XXVI) |
53638 |
allyl(chloro)magnesium
|
2622-05-1 |
C3H5ClMg |
详情 | 详情
|
(XXVII) |
53639 |
(2R)-2-{[(1R)-1-(1,3-benzodioxol-5-yl)-3-butenyl]amino}-2-phenyl-1-ethanol
|
n/a |
C19H21NO3 |
详情 | 详情
|
合成路线6
该中间体在本合成路线中的序号:
(XV) Condensation of 1,3-benzodioxole-5-carbaldehyde (XV) with nitromethane by means of ammonium acetate in HOAc gives the nitrostyrene (I), which is condensed with ethyl 2-(4-methoxybenzoyl)acetate (II) [obtained by reaction of acetophenone (XVI), diethyl carbonate and potassium tert-amyloxide] by means of NaOEt in THF to yield the 4-nitrobutyrate (III). Reductive cyclization of (III) with H2 over Raney-Ni in THF affords the (cis, cis)-pyrrolidine (VI), which is isomerized to the (trans,trans)-isomer (V) by means of NaOEt in refluxing ethanol. This racemic ester (V) is submitted to optical resolution with (S)-(+)-mandelic acid to provide the pure chiral ester (XVII). This compound is condensed with 2-bromo-N,N-dibutylacetamide (XIII) [obtained by reaction of 2-bromoacetyl bromide (XVIII) with dibutylamine (XIX) in toluene] by means of DIEA in acetonitrile to give the ethyl ester (XX), which is finally hydrolyzed with NaOH in hot ethanol.
【1】
Leeson, P.; Castañer, R.M.; Sorbera, L.A.; Castañer, J.; Atrasentan. Drugs Fut 2001, 26, 10, 939.
|
【2】
Winn, M.; Boyd, S.A.; Hutchins, C.W.; Tasker, A.S.; Von Geldern, T.W.; Kester, J.A.; Sorensen, B.K.; Szczepankiewicz, B.G.; Henry, K.J. Jr.; Liu, G.; Wittenberger, S.J.; King, S.A. (Abbott Laboratories Inc.); Novel benzo-1,3-dioxolyl- and benzofuranyl substd. pyrrolidine derivs. as endothelin antagonists. EP 0885215; WO 9730045 . |
【3】
Jae, H.-S.; Hutchins, C.W.; Szczepankiewicz, B.G.; King, S.A.; Winn, M.; Boyd, S.A.; Henry, K.J.; Geldern, T.W.; Wittenberger, S.J.; Tasker, A.S.; Sorensen, B.K.; Kester, J.A. (Abbott Laboratories Inc.); Endothelin antagonists. WO 9906397 .
|
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) |
20675 |
5-[(E)-2-nitroethenyl]-1,3-benzodioxole
|
1485-00-3 |
C9H7NO4 |
详情 | 详情
|
(II) |
20676 |
ethyl 3-(4-methoxyphenyl)-3-oxopropanoate
|
|
C12H14O4 |
详情 |
详情
|
(III) |
20677 |
ethyl 3-(1,3-benzodioxol-5-yl)-2-(4-methoxybenzoyl)-4-nitrobutanoate
|
|
C21H21NO8 |
详情 |
详情
|
(VI) |
20679 |
ethyl (2S,3R,4R)-4-(1,3-benzodioxol-5-yl)-2-(4-methoxyphenyl)-3-pyrrolidinecarboxylate
|
|
C21H23NO5 |
详情 |
详情
|
(XIII) |
20685 |
2-Bromo-N,N-dibutylacetamide; N,N-Dibutylbromoacetamide
|
|
C10H20BrNO |
详情 |
详情
|
(XV) |
10127 |
1,3-Benzodioxole-5-carbaldehyde; Heliotropine
|
120-57-0 |
C8H6O3 |
详情 | 详情
|
(XVI) |
11041 |
4-Methoxyacetophenone; 1-(4-Methoxyphenyl)-1-ethanone
|
100-06-1 |
C9H10O2 |
详情 | 详情
|
(XVII) |
20680 |
ethyl (2S,3S,4R)-4-(1,3-benzodioxol-5-yl)-2-(4-methoxyphenyl)-3-pyrrolidinecarboxylate
|
|
C21H23NO5 |
详情 |
详情
|
(XVIII) |
14005 |
2-Bromoacetyl bromide; Bromoacetyl bromide
|
598-21-0 |
C2H2Br2O |
详情 | 详情
|
(XIX) |
33492 |
N,N-dibutylamine; N-butyl-1-butanamine
|
111-92-2 |
C8H19N |
详情 | 详情
|
(XX) |
48687 |
ethyl (2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)-3-pyrrolidinecarboxylate
|
|
C31H42N2O6 |
详情 |
详情
|
合成路线7
该中间体在本合成路线中的序号:
(II) Cyclization of D-tryptophan methyl ester (I) with piperonal (II) by means of TFA in dichloromethane gives, after separation of the undesired trans-isomer by flash chromatography, the (1R,3R-cis)-pyrido-indole derivative (III). The acylation of (III) with chloroacetyl chloride (IV) and NaHCO3 in chloroform yields the chloroacetyl derivative (V), which is finally cyclized with methylamine in methanol.
【1】
Daugan, A.; Grondin, P.; Ruault, C.; et al.; The discovery of tadalafil: A novel and highly selective PDE5 inhibitor. 2: 2,3,6,7,12,12a-Hexahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione analogues. J Med Chem 2003, 46, 21, 4533.
|
【2】
Martin, L.; Sorbera, L.A.; Leeson, P.A.; Castaner, J.; IC-351. Drugs Fut 2001, 26, 1, 15.
|
【3】
Daugan, A.C.-M. (Icos Corp.); Tetracyclic derivs., process of preparation and use. EP 0740668; JP 1997508113; US 5859006; US 6025494; US 6127542; WO 9519978 .
|
【4】
Daugan, A.C.-M. (Icos Corp.); Use of cGMP-phosphodiesterase inhibitors to treat impotence. JP 1999509221; US 6140329; WO 9703675 .
|
【5】
Gellibert, F.; Daugan, A.C.-M. (Icos Corp.); Tetracyclic cyclic GMP-specific phosphodiesterase inhibitors, process of preparation and use. US 6143746 .
|
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) |
20416 |
methyl (2R)-2-amino-3-(1H-indol-3-yl)propanoate
|
|
C12H14N2O2 |
详情 |
详情
|
(II) |
10127 |
1,3-Benzodioxole-5-carbaldehyde; Heliotropine
|
120-57-0 |
C8H6O3 |
详情 | 详情
|
(III) |
43790 |
methyl (1R,3R)-1-(1,3-benzodioxol-5-yl)-2,3,4,9-tetrahydro-1H-beta-carboline-3-carboxylate
|
|
C20H18N2O4 |
详情 |
详情
|
(IV) |
11296 |
2-Chloroacetyl chloride; Chloroacetic chloride
|
79-04-9 |
C2H2Cl2O |
详情 | 详情
|
(V) |
43791 |
methyl (1R,3R)-1-(1,3-benzodioxol-5-yl)-2-(2-chloroacetyl)-2,3,4,9-tetrahydro-1H-beta-carboline-3-carboxylate
|
|
C22H19ClN2O5 |
详情 |
详情
|
合成路线8
该中间体在本合成路线中的序号:
(I) Aldol condensation of piperonal (I) with 4-methoxyacetophenone (II) afforded chalcone (III). Subsequent addition of KCN to (III) in the presence of AcOH gave nitrile (IV), which was hydrolyzed in methanol in the presence of p-TsOH to provide ketoester (V). Subsequent base-catalyzed condensation of (V) with aldehyde (VI), followed by cyclization in refluxing AcOH furnished the target butenolide.
【1】
Repine, J.T.; Patt, W.C.; Cheng, X.-M.; et al.; Butenolide endothelin antagonists with improved aqueous solubility. J Med Chem 1999, 42, 12, 2162.
|
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) |
10127 |
1,3-Benzodioxole-5-carbaldehyde; Heliotropine
|
120-57-0 |
C8H6O3 |
详情 | 详情
|
(II) |
11041 |
4-Methoxyacetophenone; 1-(4-Methoxyphenyl)-1-ethanone
|
100-06-1 |
C9H10O2 |
详情 | 详情
|
(III) |
25775 |
(E)-3-(1,3-benzodioxol-5-yl)-1-(4-methoxyphenyl)-2-propen-1-one
|
|
C17H14O4 |
详情 |
详情
|
(IV) |
25776 |
2-(1,3-benzodioxol-5-yl)-4-(4-methoxyphenyl)-4-oxobutanenitrile
|
|
C18H15NO4 |
详情 |
详情
|
(V) |
25777 |
ethyl 2-(1,3-benzodioxol-5-yl)-4-(4-methoxyphenyl)-4-oxobutanoate
|
|
C20H20O6 |
详情 |
详情
|
(VI) |
25778 |
3-(5-formyl-2,3-dimethoxyphenoxy)-1-propanesulfonate
|
|
C12H15O7S |
详情 |
详情
|
合成路线9
该中间体在本合成路线中的序号:
(I) Condensation of piperonal (I) with nitromethane in the presence of ammonium acetate in AcOH provided nitrostyrene (II). Ketoester (IV) was prepared by carbethoxylation of 4'-propoxyacetophenone (III) with diethyl carbonate. Subsequent conjugate addition of ketoester (IV) to nitrostyrene (II) using DBU provided adduct (V). Hydrogenation of the nitro group of (V) over Raney Nickel, with concomitant ring closure formed the cyclic imine (VI), and further reduction of (VI) with NaBH3CN yielded the corresponding pyrrolidine as a diastereomeric mixture. Chromatographic separation removed the cis,cis isomer, affording a mixture of trans,trans and cis,trans pyrrolidines (VIIa, VIIb). 2,6-Diethylbromoacetanilide (IX) was prepared by acylation of 2,6-diethylaniline (VIII) with bromoacetyl bromide. N-Alkylation of the mixture of pyrrolidines (VIIa, VIIb) with bromoacetanilide (IX) furnished (Xa, Xb).
【1】
Sorensen, B.K.; Tasker, A.S.; von Geldern, T.W.; et al.; Pyrrolide-3-carboxylic acids as endothelin antagonists. 4. Side chain conformational restriction leads to ETB selectivity. J Med Chem 1999, 42, 18, 3668.
|
【2】
Tasker, A.S.; Boyd, S.A.; Sorensen, B.K.; Winn, M.; Jae, H.-S.; Von Geldern, T.W.; Henry, K.J. (Abbott Laboratories Inc.); 4-(Benzo-1,3-dioxolyl)-pyrrolidine-3-carboxylic acid derivs. as endothelin antagonists. EP 0888340; JP 2000504727; WO 9730046 . |
【3】
Tasker, A.S.; Henry, K.J.; Boyd, S.A.; Von Geldern, T.W.; Sorensen, B.K.; Jae, H.-S.; Winn, M. (Abbott Laboratories Inc.); Pyrrolidine carboxylic acid derivs. as endothelin antagonists. EP 0991620; WO 9857933 .
|
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
|
14005 |
2-Bromoacetyl bromide; Bromoacetyl bromide
|
598-21-0 |
C2H2Br2O |
详情 | 详情
|
|
17470 |
diethyl carbonate; diethylcarbonate
|
105-58-8 |
C5H10O3 |
详情 | 详情
|
|
39563 |
nitromethane
|
75-52-5 |
CH3NO2 |
详情 | 详情
|
(VIIa) |
35056 |
ethyl (2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-2-(4-propoxyphenyl)-3-pyrrolidinecarboxylate
|
|
C23H27NO5 |
详情 |
详情
|
(VIIb) |
35057 |
ethyl (2S,3R,4S)-4-(1,3-benzodioxol-5-yl)-2-(4-propoxyphenyl)-3-pyrrolidinecarboxylate
|
|
C23H27NO5 |
详情 |
详情
|
(Xa) |
35060 |
ethyl (2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-1-[2-(2,6-diethylanilino)-2-oxoethyl]-2-(4-propoxyphenyl)-3-pyrrolidinecarboxylate
|
|
C35H42N2O6 |
详情 |
详情
|
(Xb),(XI) |
35061 |
ethyl (2S,3R,4S)-4-(1,3-benzodioxol-5-yl)-1-[2-(2,6-diethylanilino)-2-oxoethyl]-2-(4-propoxyphenyl)-3-pyrrolidinecarboxylate
|
|
C35H42N2O6 |
详情 |
详情
|
(I) |
10127 |
1,3-Benzodioxole-5-carbaldehyde; Heliotropine
|
120-57-0 |
C8H6O3 |
详情 | 详情
|
(II) |
20675 |
5-[(E)-2-nitroethenyl]-1,3-benzodioxole
|
1485-00-3 |
C9H7NO4 |
详情 | 详情
|
(III) |
35052 |
1-(4-propoxyphenyl)-1-ethanone
|
|
C11H14O2 |
详情 |
详情
|
(IV) |
35053 |
ethyl 3-oxo-3-(4-propoxyphenyl)propanoate
|
|
C14H18O4 |
详情 |
详情
|
(V) |
35054 |
ethyl 3-(1,3-benzodioxol-5-yl)-4-nitro-2-(4-propoxybenzoyl)butanoate
|
|
C23H25NO8 |
详情 |
详情
|
(VI) |
35055 |
ethyl 3-(1,3-benzodioxol-5-yl)-5-(4-propoxyphenyl)-3,4-dihydro-2H-pyrrole-4-carboxylate
|
|
C23H25NO5 |
详情 |
详情
|
(VIII) |
35058 |
2,6-diethylphenylamine; 2,6-diethylaniline
|
579-66-8 |
C10H15N |
详情 | 详情
|
(IX) |
35059 |
2-bromo-N-(2,6-diethylphenyl)acetamide
|
|
C12H16BrNO |
详情 |
详情
|
合成路线10
该中间体在本合成路线中的序号:
(V) 6-Fluoro-8-hydroxychroman-4-one (I) was converted to ethylene ketal (II) upon treatment with ethylene glycol and triethyl orthoformate, and subsequently alkylated with 1,2-dibromoethane under phase-transfer conditions to afford the bromoethyl ether (III). Wittig condensation of piperonal (V) with the (3-phthalimidopropyl)phosphonium salt (IV) in the presence of NaOMe in dioxan provided olefin (VI), which was hydrogenated over Pd/C to furnish the arylbutyl phthalimide (VII). Further deprotection of the phthalimido group of (VII) with CH3NH2 gave amine (VIII). Then, alkylation of (VIII) with bromide (III), followed by acid hydrolysis of the ketal function yielded the title compound.
【1】
Yasunaga, T.; Wanibuchi, F.; Yamaguchi, T.; Yamashita, H.; Kontani, T.; Tsukamoto, S.; Nomura, T.; Naito, R.; Kimura, T.; Mase, T.; Synthesis and pharmacological characterization of novel 6-fluorochroman derivatives as potential 5-HT1A receptor antagonists. J Med Chem 1998, 41, 15, 2765. |
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) |
24409 |
6-fluoro-8-hydroxy-2,3-dihydro-4H-chromen-4-one
|
|
C9H7FO3 |
详情 |
详情
|
(II) |
24410 |
6-Fluoro-3,4-dihydro-2H-spiro[1-benzopyran-4,2'-1,3-dioxolan]-8-ol
|
|
C11H11FO4 |
详情 |
详情
|
(III) |
24411 |
8-(2-Bromoethoxy)-6-fluoro-3,4-dihydro-2H-spiro[1-benzopyran-4,2'-1,3-dioxolane]
|
|
C13H14BrFO4 |
详情 |
详情
|
(IV) |
24412 |
[3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propyl](triphenyl)phosphonium bromide
|
|
C29H25BrNO2P |
详情 |
详情
|
(V) |
10127 |
1,3-Benzodioxole-5-carbaldehyde; Heliotropine
|
120-57-0 |
C8H6O3 |
详情 | 详情
|
(VI) |
24414 |
2-[(E)-4-(1,3-benzodioxol-5-yl)-3-butenyl]-1H-isoindole-1,3(2H)-dione
|
|
C19H15NO4 |
详情 |
详情
|
(VII) |
24415 |
2-[4-(1,3-benzodioxol-5-yl)butyl]-1H-isoindole-1,3(2H)-dione
|
|
C19H17NO4 |
详情 |
详情
|
(VIII) |
24416 |
4-(1,3-benzodioxol-5-yl)-1-butanamine
|
|
C11H15NO2 |
详情 |
详情
|
合成路线11
该中间体在本合成路线中的序号:
(I) Condensation of piperonal (I) with N-acetyl-2-pyrrolidone (II) in the presence of NaH in THF afforded the benzylidene pyrrolidone (III). The title formamide was then obtained upon refluxing of (III) with formic acid with azeotropical removal of water.
【1】
Fuse, Y.; Kitahara, M.; Yamamoto, K.; Yokota, S.; Morikawa, S. (Kaneka Corp.); Heat shock factor activity inhibitors. EP 0995745; WO 9900382 .
|
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) |
10127 |
1,3-Benzodioxole-5-carbaldehyde; Heliotropine
|
120-57-0 |
C8H6O3 |
详情 | 详情
|
(II) |
41624 |
1-acetyl-2-pyrrolidinone
|
932-17-2 |
C6H9NO2 |
详情 | 详情
|
(III) |
41625 |
3-[(E)-1,3-benzodioxol-5-ylmethylidene]-2-pyrrolidinone
|
|
C12H11NO3 |
详情 |
详情
|
合成路线12
该中间体在本合成路线中的序号:
(I) Condensation of piperonal (I) with nitromethane in the presence of NaOH provided nitrostyrene (II). Subsequent conjugate addition of (II) to ketoester (III) using DBU provided adduct (IV). Reduction of the nitro group of (IV), with concomitant ring closure and olefinic double bond hydrogenation formed the cyclic imine (V), which was reduced with NaBH3CN to yield the pyrrolidine (VI) as a diastereomeric mixture. The crude mixture was isomerized to a mixture of only cis,trans and trans,trans pyrrolidines (VII) by base-catalyzed equilibration with NaOEt. N-Alkylation of the pyrrolidines (VII) with N,N-dibutyl bromoacetamide (VIII) furnished (IX). Basic hydrolysis of the ester group of (IX) with either NaOH or LiOH gave rise to the target trans,trans pyrrolidine-3-carboxylic acid. The undesired cis,trans isomeric ester (X) was not hydrolyzed under these conditions, allowing its removal from the product by means of differential extraction.
【1】
Boyd, S.A.; Mantei, R.A.; Tasker, A.S.; et al.; Discovery of a series of pyrrolidine-based endothelin receptor antagonists with enhanced ETA receptor selectivity. Bioorg Med Chem 1999, 7, 6, 991.
|
【2】
Dive, V.; Toma, F.; Yiotakis, A. (Commissariat a l'Energie Atomique); Derivs. of peptides usable as inhibitors of bacterial collagenases. US 5500414 .
|
【3】
Winn, M.; Boyd, S.A.; Hutchins, C.W.; Tasker, A.S.; Von Geldern, T.W.; Kester, J.A.; Sorensen, B.K.; Szczepankiewicz, B.G.; Henry, K.J. Jr.; Liu, G.; Wittenberger, S.J.; King, S.A. (Abbott Laboratories Inc.); Novel benzo-1,3-dioxolyl- and benzofuranyl substd. pyrrolidine derivs. as endothelin antagonists. EP 0885215; WO 9730045 . |
【4】
Jae, H.-S.; Hutchins, C.W.; Szczepankiewicz, B.G.; King, S.A.; Winn, M.; Boyd, S.A.; Henry, K.J.; Geldern, T.W.; Wittenberger, S.J.; Tasker, A.S.; Sorensen, B.K.; Kester, J.A. (Abbott Laboratories Inc.); Endothelin antagonists. WO 9906397 .
|
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
|
39563 |
nitromethane
|
75-52-5 |
CH3NO2 |
详情 | 详情
|
(VIIa) |
35045 |
methyl (2S,3R,4S)-4-(1,3-benzodioxol-5-yl)-2-pentyl-3-pyrrolidinecarboxylate
|
|
C18H25NO4 |
详情 |
详情
|
(VIIb) |
35046 |
methyl (2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-2-pentyl-3-pyrrolidinecarboxylate
|
|
C18H25NO4 |
详情 |
详情
|
(IXa) |
35047 |
methyl (2S,3R,4S)-4-(1,3-benzodioxol-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-pentyl-3-pyrrolidinecarboxylate
|
|
C28H44N2O5 |
详情 |
详情
|
(IXb),(X) |
35048 |
methyl (2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-pentyl-3-pyrrolidinecarboxylate
|
|
C28H44N2O5 |
详情 |
详情
|
(I) |
10127 |
1,3-Benzodioxole-5-carbaldehyde; Heliotropine
|
120-57-0 |
C8H6O3 |
详情 | 详情
|
(II) |
20675 |
5-[(E)-2-nitroethenyl]-1,3-benzodioxole
|
1485-00-3 |
C9H7NO4 |
详情 | 详情
|
(III) |
35041 |
methyl (E)-3-oxo-6-octenoate
|
|
C9H14O3 |
详情 |
详情
|
(IV) |
35042 |
methyl (E)-2-[1-(1,3-benzodioxol-5-yl)-2-nitroethyl]-3-oxo-6-octenoate
|
|
C18H21NO7 |
详情 |
详情
|
(V) |
35043 |
methyl 3-(1,3-benzodioxol-5-yl)-5-pentyl-3,4-dihydro-2H-pyrrole-4-carboxylate
|
|
C18H23NO4 |
详情 |
详情
|
(VI) |
35044 |
methyl 4-(1,3-benzodioxol-5-yl)-2-pentyl-3-pyrrolidinecarboxylate
|
|
C18H25NO4 |
详情 |
详情
|
(VIII) |
20685 |
2-Bromo-N,N-dibutylacetamide; N,N-Dibutylbromoacetamide
|
|
C10H20BrNO |
详情 |
详情
|
合成路线13
该中间体在本合成路线中的序号:
(I) Condensation of piperonal (I) with nitromethane in the presence of NaOH provided nitrostyrene (II) (1-3). Ketoester (IV) was prepared by treatment of n-heptanoic acid (III) with 1,1'-carbonyldiimidazole and further condensation with ethyl magnesium malonate (1). Subsequent conjugate addition of (II) to ketoester (IV) using DBU provided adduct (V). Reduction of the nitro group of (V), with concomitant ring closure formed the cyclic imine (VI), which was reduced with NaBH3CN to yield the pyrrolidine (VII) as a diastereomeric mixture. The crude mixture was isomerized to a mixture of only cis,trans and trans,trans pyrrolidines (VIII) by base-catalyzed equilibration with NaOEt. N-Alkylation of the pyrrolidines (VIII) with N,N-dibutyl bromoacetamide (IX) furnished (X). Basic hydrolysis of the ester group of (X) with either NaOH or LiOH gave rise to the target trans,trans pyrrolidine-3-carboxylic acid. The undesired cis,trans isomeric ester (XI) was not hydrolyzed under these conditions, allowing its removal from the product by means of differential extraction.
【1】
Boyd, S.A.; Mantei, R.A.; Tasker, A.S.; et al.; Discovery of a series of pyrrolidine-based endothelin receptor antagonists with enhanced ETA receptor selectivity. Bioorg Med Chem 1999, 7, 6, 991.
|
【2】
Winn, M.; Boyd, S.A.; Hutchins, C.W.; Tasker, A.S.; Von Geldern, T.W.; Kester, J.A.; Sorensen, B.K.; Szczepankiewicz, B.G.; Henry, K.J. Jr.; Liu, G.; Wittenberger, S.J.; King, S.A. (Abbott Laboratories Inc.); Novel benzo-1,3-dioxolyl- and benzofuranyl substd. pyrrolidine derivs. as endothelin antagonists. EP 0885215; WO 9730045 . |
【3】
Jae, H.-S.; Hutchins, C.W.; Szczepankiewicz, B.G.; King, S.A.; Winn, M.; Boyd, S.A.; Henry, K.J.; Geldern, T.W.; Wittenberger, S.J.; Tasker, A.S.; Sorensen, B.K.; Kester, J.A. (Abbott Laboratories Inc.); Endothelin antagonists. WO 9906397 .
|
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
|
14338 |
potassium 3-ethoxy-3-oxopropanoate
|
6148-64-7 |
C5H7KO4 |
详情 | 详情
|
|
39563 |
nitromethane
|
75-52-5 |
CH3NO2 |
详情 | 详情
|
(VIIIa) |
35037 |
methyl (2S,3R,4S)-4-(1,3-benzodioxol-5-yl)-2-hexyl-3-pyrrolidinecarboxylate
|
|
C19H27NO4 |
详情 |
详情
|
(VIIIb) |
35038 |
methyl (2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-2-hexyl-3-pyrrolidinecarboxylate
|
|
C19H27NO4 |
详情 |
详情
|
(Xa),(XI) |
35039 |
methyl (2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-hexyl-3-pyrrolidinecarboxylate
|
|
C29H46N2O5 |
详情 |
详情
|
(Xb) |
35040 |
methyl (2S,3R,4S)-4-(1,3-benzodioxol-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-hexyl-3-pyrrolidinecarboxylate
|
|
C29H46N2O5 |
详情 |
详情
|
(I) |
10127 |
1,3-Benzodioxole-5-carbaldehyde; Heliotropine
|
120-57-0 |
C8H6O3 |
详情 | 详情
|
(II) |
20675 |
5-[(E)-2-nitroethenyl]-1,3-benzodioxole
|
1485-00-3 |
C9H7NO4 |
详情 | 详情
|
(III) |
35032 |
heptanoic acid
|
111-14-8 |
C7H14O2 |
详情 | 详情
|
(IV) |
35033 |
methyl 3-oxononanoate
|
|
C10H18O3 |
详情 |
详情
|
(V) |
35034 |
methyl 2-[1-(1,3-benzodioxol-5-yl)-2-nitroethyl]-3-oxononanoate
|
|
C19H25NO7 |
详情 |
详情
|
(VI) |
35035 |
methyl 3-(1,3-benzodioxol-5-yl)-5-hexyl-3,4-dihydro-2H-pyrrole-4-carboxylate
|
|
C19H25NO4 |
详情 |
详情
|
(VII) |
35036 |
methyl 4-(1,3-benzodioxol-5-yl)-2-hexyl-3-pyrrolidinecarboxylate
|
|
C19H27NO4 |
详情 |
详情
|
(IX) |
20685 |
2-Bromo-N,N-dibutylacetamide; N,N-Dibutylbromoacetamide
|
|
C10H20BrNO |
详情 |
详情
|
合成路线14
该中间体在本合成路线中的序号:
(I) Condensation of piperonal (I) with nitromethane in the presence of NaOH provided nitrostyrene (II). Subsequent conjugate addition of (II) to ketoester (III) using DBU provided adduct (IV). Reduction of the nitro group of (IV), with concomitant ring closure formed the cyclic imine (V), which was reduced with NaBH3CN to yield the pyrrolidine (VI) as a diastereomeric mixture. The crude mixture was isomerized to a mixture of only cis,trans and trans,trans pyrrolidines (VII) by base-catalyzed equilibration with NaOEt. N-Alkylation of the pyrrolidines (VII) with N,N-dibutyl bromoacetamide (VIII) furnished (IX). Basic hydrolysis of the ester group of (IX) with either NaOH or LiOH gave rise to the target trans,trans pyrrolidine-3-carboxylic acid. The undesired cis,trans isomeric ester (X) was not hydrolyzed under these conditions, allowing its removal from the product by means of differential extraction.
【1】
Boyd, S.A.; Mantei, R.A.; Tasker, A.S.; et al.; Discovery of a series of pyrrolidine-based endothelin receptor antagonists with enhanced ETA receptor selectivity. Bioorg Med Chem 1999, 7, 6, 991.
|
【2】
Winn, M.; Boyd, S.A.; Hutchins, C.W.; Tasker, A.S.; Von Geldern, T.W.; Kester, J.A.; Sorensen, B.K.; Szczepankiewicz, B.G.; Henry, K.J. Jr.; Liu, G.; Wittenberger, S.J.; King, S.A. (Abbott Laboratories Inc.); Novel benzo-1,3-dioxolyl- and benzofuranyl substd. pyrrolidine derivs. as endothelin antagonists. EP 0885215; WO 9730045 . |
【3】
Jae, H.-S.; Hutchins, C.W.; Szczepankiewicz, B.G.; King, S.A.; Winn, M.; Boyd, S.A.; Henry, K.J.; Geldern, T.W.; Wittenberger, S.J.; Tasker, A.S.; Sorensen, B.K.; Kester, J.A. (Abbott Laboratories Inc.); Endothelin antagonists. WO 9906397 .
|
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
|
39563 |
nitromethane
|
75-52-5 |
CH3NO2 |
详情 | 详情
|
(VIIa) |
35028 |
methyl (2S,3R,4S)-4-(1,3-benzodioxol-5-yl)-2-(4-methylcyclohexyl)-3-pyrrolidinecarboxylate
|
|
C20H27NO4 |
详情 |
详情
|
(VIIb) |
35029 |
methyl (2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-2-(4-methylcyclohexyl)-3-pyrrolidinecarboxylate
|
|
C20H27NO4 |
详情 |
详情
|
(IXa) |
35030 |
methyl (2S,3R,4S)-4-(1,3-benzodioxol-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methylcyclohexyl)-3-pyrrolidinecarboxylate
|
|
C30H46N2O5 |
详情 |
详情
|
(IXb),(X) |
35031 |
methyl (2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methylcyclohexyl)-3-pyrrolidinecarboxylate
|
|
C30H46N2O5 |
详情 |
详情
|
(I) |
10127 |
1,3-Benzodioxole-5-carbaldehyde; Heliotropine
|
120-57-0 |
C8H6O3 |
详情 | 详情
|
(II) |
20675 |
5-[(E)-2-nitroethenyl]-1,3-benzodioxole
|
1485-00-3 |
C9H7NO4 |
详情 | 详情
|
(III) |
35024 |
methyl 3-(4-methylcyclohexyl)-3-oxopropanoate
|
|
C11H18O3 |
详情 |
详情
|
(IV) |
35025 |
methyl 3-(1,3-benzodioxol-5-yl)-2-[(4-methylcyclohexyl)carbonyl]-4-nitrobutanoate
|
|
C20H25NO7 |
详情 |
详情
|
(V) |
35026 |
methyl 3-(1,3-benzodioxol-5-yl)-5-(4-methylcyclohexyl)-3,4-dihydro-2H-pyrrole-4-carboxylate
|
|
C20H25NO4 |
详情 |
详情
|
(VI) |
35027 |
methyl 4-(1,3-benzodioxol-5-yl)-2-(4-methylcyclohexyl)-3-pyrrolidinecarboxylate
|
|
C20H27NO4 |
详情 |
详情
|
(VIII) |
20685 |
2-Bromo-N,N-dibutylacetamide; N,N-Dibutylbromoacetamide
|
|
C10H20BrNO |
详情 |
详情
|
合成路线15
该中间体在本合成路线中的序号:
(X) The reductive alkylation of tropinone (I) with aniline (II) using either NaBH4 or NaBH(OAc)3 as the reducing agent furnished the endo-isomer (III). Arylation of amine (III) with t-butyl 4-bromobenzoate (IV) produced the (diarylamino)tropane (V). Acid cleavage of the tert-butyl ester of (V) gave acid (VI), which was further coupled to diethylamine, yielding amide (VII). Demethylation of tropane (VII) with 1-chloroethyl chloroformate, followed by methanolysis of the resulting carbamate (VIII), provided the secondary amine (IX). This was finally subjected to reductive alkylation with 3,4-methylenedioxybenzaldehyde (X) to give the title compound.
【1】
Gauthier, A.D.; Neilson, L.A.; Carson, J.R.; Codd, E.E.; Zhang, S.-P.; Boyd, R.E.; Synthesis and binding affinities of 4-diarylaminotropanes, a new class of delta opioid agonists. Bioorg Med Chem Lett 2000, 10, 10, 1109.
|
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) |
16443 |
(1R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-one
|
|
C8H13NO |
详情 |
详情
|
(II) |
12294 |
Aniline; Phenylamine
|
62-53-3 |
C6H7N |
详情 | 详情
|
(III) |
51368 |
(1R,5S)-8-methyl-N-phenyl-8-azabicyclo[3.2.1]octan-3-amine; N-[(1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]-N-phenylamine
|
|
C14H20N2 |
详情 |
详情
|
(IV) |
14286 |
tert-butyl 4-bromobenzoate
|
|
C11H13BrO2 |
详情 |
详情
|
(V) |
51369 |
tert-butyl 4-[[(1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]anilino]benzoate
|
|
C25H32N2O2 |
详情 |
详情
|
(VI) |
51370 |
4-[[(1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]anilino]benzoic acid
|
|
C21H24N2O2 |
详情 |
详情
|
(VII) |
51371 |
N,N-diethyl-4-[[(1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]anilino]benzamide
|
|
C25H33N3O |
详情 |
详情
|
(VIII) |
51372 |
1-chloroethyl (1R,5S)-3-[4-[(diethylamino)carbonyl](phenyl)anilino]-8-azabicyclo[3.2.1]octane-8-carboxylate
|
|
C27H34ClN3O3 |
详情 |
详情
|
(IX) |
51373 |
4-[(1R,5S)-8-azabicyclo[3.2.1]oct-3-ylanilino]-N,N-diethylbenzamide
|
|
C24H31N3O |
详情 |
详情
|
(X) |
10127 |
1,3-Benzodioxole-5-carbaldehyde; Heliotropine
|
120-57-0 |
C8H6O3 |
详情 | 详情
|
合成路线16
该中间体在本合成路线中的序号:
(IV) The condensation of 4-iodo-1,3-benzodioxole-5-carbaldehyde (I) with dimethyl succinate (II) by means of NaOMe in aqueous methanol gives the benzylidene derivative (III), which is condensed with 1,3-benzodioxole-5-carbaldehyde (IV) by means of NaOMe in methanol, affording the bis-benzylidene hemiester (V). The selective reduction of (V) with LiEt3BH, followed by lactonization with ethyl chloroformate and TEA in THF, yields the lactone (VI), which is finally cyclized by means of Pd(OAc)2 and K2CO3 at 110 C through the nonisolated intermediate (VII), providing the target compound.
【1】
Mizufune, H.; et al.; The first regiospecific synthesis of helioxanthin by novel palladium-catalyzed benzannulation reaction of alpha,beta-bisbenzylidene-gamma-lactone. Tetrahedron Lett 2001, 42, 3, 437.
|
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) |
46632 |
4-iodo-1,3-benzodioxole-5-carbaldehyde
|
|
C8H5IO3 |
详情 |
详情
|
(II) |
41056 |
dimethyl succinate
|
106-65-0 |
C6H10O4 |
详情 | 详情
|
(III) |
46633 |
dimethyl 2-[(E)-(4-iodo-1,3-benzodioxol-5-yl)methylidene]succinate
|
|
C14H13IO6 |
详情 |
详情
|
(IV) |
10127 |
1,3-Benzodioxole-5-carbaldehyde; Heliotropine
|
120-57-0 |
C8H6O3 |
详情 | 详情
|
(V) |
46634 |
(E)-4-(1,3-benzodioxol-5-yl)-2-[(E)-(4-iodo-1,3-benzodioxol-5-yl)methylidene]-3-(methoxycarbonyl)-3-butenoic acid
|
|
C21H15IO8 |
详情 |
详情
|
(VI) |
46635 |
4-[(E)-1,3-benzodioxol-5-ylmethylidene]-3-[(E)-(4-iodo-1,3-benzodioxol-5-yl)methylidene]dihydro-2(3H)-furanone
|
|
C20H13IO6 |
详情 |
详情
|
(VII) |
46636 |
[(10S)-10-(1,3-benzodioxol-5-yl)-7-oxo-7,10-dihydrofuro[3',4':6,7]naphtho[1,2-d][1,3]dioxol-9(9H)-yl](iodo)palladium
|
|
C20H13IO6Pd |
详情 |
详情
|
合成路线17
该中间体在本合成路线中的序号:
(IV) Alternatively, the condensation of 1,3-benzodioxole-5-carbaldehyde ethylene ketal (VIII) with carbaldehyde (V) by means of n-BuLi gives the hydroxy ketal (IX), which is treated with Ac2O, HOAc and maleic anhydride (XI) at 140 C to perform a Diels-Alder cyclization between the nonisolated isobenzofuran (X) (a reactive diene) and the maleic anhydride (the dienophile), giving rise to the cyclic anhydride (XII). Finally, this compound is reduced with NaBH4 to the target compound along with some structural isomer (XIII) that is separated by chromatography.
【1】
Urasaki, Y.; et al.; Activity of a novel camptothecin analogue, homocamptothecin, in camptothecin-resistant cell lines with topoisomerase I alterations. Cancer Res 2000, 60, 23, 6577.
|
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
(IV) |
10127 |
1,3-Benzodioxole-5-carbaldehyde; Heliotropine
|
120-57-0 |
C8H6O3 |
详情 | 详情
|
(VIII) |
46637 |
5-(1,3-dioxolan-2-yl)-1,3-benzodioxole
|
|
C10H10O4 |
详情 |
详情
|
(IX) |
46638 |
1,3-benzodioxol-5-yl[5-(1,3-dioxolan-2-yl)-1,3-benzodioxol-4-yl]methanol
|
|
C18H16O7 |
详情 |
详情
|
(X) |
46639 |
8-(1,3-benzodioxol-5-yl)furo[3,4-e][1,3]benzodioxole
|
|
C16H10O5 |
详情 |
详情
|
(XI) |
11182 |
2,5-Furandione; Maleic anhydride
|
108-31-6 |
C4H2O3 |
详情 | 详情
|
(XII) |
46640 |
10-(1,3-benzodioxol-5-yl)furo[3',4':6,7]naphtho[1,2-d][1,3]dioxole-7,9-dione
|
|
C20H10O7 |
详情 |
详情
|
(XIII) |
46641 |
10-(1,3-benzodioxol-5-yl)furo[3',4':6,7]naphtho[1,2-d][1,3]dioxol-9(7H)-one
|
|
C20H12O6 |
详情 |
详情
|
合成路线18
该中间体在本合成路线中的序号:
(XII) The esterification of 4(R)-hydroxypyrrolidine-2(S)-carboxylic acid (I) gives the methyl ester (II), which is N-protected to yield 1-Boc-4(R)-hydroxypyrrolidine-2(S)-carboxylic acid methyl ester (III). Compound (III) which is mesylated to afford 1-Boc-4(R)-(mesyloxy)pyrrolidine-2(S)-carboxylic acid methyl ester (IV). The reaction of (IV) with sodium azide affords (V), which is reduced with H2 over Pd/C in ethanol to provide 4(S)-amino-1-Boc-pyrrolidine-2(S)-carboxylic acid methyl ester (VI). The reductocondensation of (VI) with 3-methoxybenzaldehyde (VII) by means of NaBH(OAc)3 provides the secondary amine (VIII), which is acylated with 3,3-dimethylbutyryl chloride (IX) and TEA in dichloromethane to give the amide (X). The deprotection of the pyrrolidine NH of (X) by means of TFA yields the pyrrolidine (XI), which is reductocondensed with piperonal (XII) by means of NaBH3CN to afford the N-substituted pyrrolidine (XIII). The hydrolysis of the ester group of (XIII) with LiOH in methanol/water provides the carboxylic acid (XIV), which is condensed with N-Boc-piperazine (XV) by means of TBTU and DIEA in DMF to give the protected intermediate (XVI). Finally, this compound is deprotected by means of TFA in dichloromethane to furnish the target carboxamide.
【1】
Baxter, A.D.; Boyd, E.A.; Price, S.; Guicherit, O.M.; Rubin, L. (Curis, Inc.); Mediators of hedgehog signaling pathways, compsns. and uses related thereto. WO 0126644 .
|
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) |
14489 |
(2S,4R)-4-hydroxytetrahydro-1H-pyrrole-2-carboxylic acid; L-Hydroxyproline
|
51-35-4 |
C5H9NO3 |
详情 | 详情
|
(II) |
15796 |
methyl (2S,4R)-4-hydroxytetrahydro-1H-pyrrole-2-carboxylate
|
|
C6H11NO3 |
详情 |
详情
|
(III) |
15780 |
1-(tert-butyl) 2-methyl (2S,4S)-4-hydroxytetrahydro-1H-pyrrole-1,2-dicarboxylate;(2S,4S)-1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate |
|
C11H19NO5 |
详情 |
详情
|
(IV) |
15781 |
1-(tert-butyl) 2-methyl (2S,4R)-4-[(methylsulfonyl)oxy]tetrahydro-1H-pyrrole-1,2-dicarboxylate
|
|
C12H21NO7S |
详情 |
详情
|
(V) |
43411 |
1-(tert-butyl) 2-methyl (2S,4S)-4-azido-1,2-pyrrolidinedicarboxylate
|
|
C11H18N4O4 |
详情 |
详情
|
(VI) |
55407 |
1-(tert-butyl) 2-methyl (2S,4S)-4-amino-1,2-pyrrolidinedicarboxylate
|
|
C11H20N2O4 |
详情 |
详情
|
(VII) |
20589 |
3-methoxybenzaldehyde; m-Anisaldehyde
|
591-31-1 |
C8H8O2 |
详情 | 详情
|
(VIII) |
55407 |
1-(tert-butyl) 2-methyl (2S,4S)-4-amino-1,2-pyrrolidinedicarboxylate
|
|
C11H20N2O4 |
详情 |
详情
|
(IX) |
21738 |
3,3-dimethylbutanoyl chloride
|
7065-46-5 |
C6H11ClO |
详情 | 详情
|
(X) |
55409 |
1-(tert-butyl) 2-methyl (2S,4S)-4-[(3,3-dimethylbutanoyl)(3-methoxybenzyl)amino]-1,2-pyrrolidinedicarboxylate
|
|
C25H38N2O6 |
详情 |
详情
|
(XI) |
55410 |
methyl (2S,4S)-4-[(3,3-dimethylbutanoyl)(3-methoxybenzyl)amino]-2-pyrrolidinecarboxylate
|
|
C20H30N2O4 |
详情 |
详情
|
(XII) |
10127 |
1,3-Benzodioxole-5-carbaldehyde; Heliotropine
|
120-57-0 |
C8H6O3 |
详情 | 详情
|
(XIII) |
55411 |
methyl (2S,4S)-1-(1,3-benzodioxol-5-ylmethyl)-4-[(3,3-dimethylbutanoyl)(3-methoxybenzyl)amino]-2-pyrrolidinecarboxylate
|
|
C28H36N2O6 |
详情 |
详情
|
(XIV) |
55412 |
(2S,4S)-1-(1,3-benzodioxol-5-ylmethyl)-4-[(3,3-dimethylbutanoyl)(3-methoxybenzyl)amino]-2-pyrrolidinecarboxylic acid
|
|
C27H34N2O6 |
详情 |
详情
|
(XV) |
13225 |
N-tert-Butoxycarbonyl piperazine; tert-butyl 1-piperazinecarboxylate;tert-butyl piperazine-1-carboxylate |
143238-38-4 |
C9H18N2O2 |
详情 | 详情
|
(XVI) |
55413 |
tert-butyl 4-({(2S,4S)-1-(1,3-benzodioxol-5-ylmethyl)-4-[(3,3-dimethylbutanoyl)(3-methoxybenzyl)amino]pyrrolidinyl}carbonyl)-1-piperazinecarboxylate
|
|
C36H50N4O7 |
详情 |
详情
|
合成路线19
该中间体在本合成路线中的序号:
(III) The lithium derivative (II), prepared from p-bromo-alpha-methylbenzylamine (I), was added to piperonal (III) to obtain the diaryl carbinol (IV), which was further deoxygenated to (V) using triethylsilane and trifluoroacetic acid. Basic hydrolysis of the trifluoroacetamide function of (V) provided amine (VI). This was then alkylated with the chiral triflate (VII) to afford amino ester (VIII). Subsequent acylation of amine (VIII) with chloroacetyl chloride (IX), followed by cyclization of the resulting chloroacetamide (X) with ammonia, led to the diketopiperazine (XI). Reduction of the carbonyl groups of (XI), followed by reductive amination of the resulting piperazine (XII) with N-Boc-4-piperidinone (XIII), gave the piperidinyl piperazine (XIV). After acidic Boc group cleavage of (XIV), the resulting piperidine (XV) was finally condensed with 2,6-dimethylbenzoic acid (XVI) to yield the target benzamide.
【1】
Tagat, J.R.; et al.; Piperazine-based CCR5 antagonists as HIV-1 inhibitors. I: 2(S)-methyl piperazine as a key pharmacophore element. Bioorg Med Chem Lett 2001, 11, 16, 2143.
|
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) |
50550 |
N-[(1S)-1-(4-bromophenyl)ethyl]-2,2,2-trifluoroacetamide
|
|
C10H9BrF3NO |
详情 |
详情
|
(II) |
50551 |
|
|
C10H8F3Li2NO |
详情 |
详情
|
(III) |
10127 |
1,3-Benzodioxole-5-carbaldehyde; Heliotropine
|
120-57-0 |
C8H6O3 |
详情 | 详情
|
(IV) |
50552 |
N-((1S)-1-[4-[1,3-benzodioxol-5-yl(hydroxy)methyl]phenyl]ethyl)-2,2,2-trifluoroacetamide
|
|
C18H16F3NO4 |
详情 |
详情
|
(V) |
50553 |
N-[(1S)-1-[4-(1,3-benzodioxol-5-ylmethyl)phenyl]ethyl]-2,2,2-trifluoroacetamide
|
|
C18H16F3NO3 |
详情 |
详情
|
(VI) |
50554 |
(1S)-1-[4-(1,3-benzodioxol-5-ylmethyl)phenyl]-1-ethanamine; (1S)-1-[4-(1,3-benzodioxol-5-ylmethyl)phenyl]ethylamine
|
|
C16H17NO2 |
详情 |
详情
|
(VII) |
50555 |
ethyl (2R)-2-[[(trifluoromethyl)sulfonyl]oxy]propanoate
|
|
C6H9F3O5S |
详情 |
详情
|
(VIII) |
50556 |
ethyl (2S)-2-([(1S)-1-[4-(1,3-benzodioxol-5-ylmethyl)phenyl]ethyl]amino)propanoate
|
|
C21H25NO4 |
详情 |
详情
|
(IX) |
11296 |
2-Chloroacetyl chloride; Chloroacetic chloride
|
79-04-9 |
C2H2Cl2O |
详情 | 详情
|
(X) |
50557 |
ethyl (2S)-2-[[(1S)-1-[4-(1,3-benzodioxol-5-ylmethyl)phenyl]ethyl](2-chloroacetyl)amino]propanoate
|
|
C23H26ClNO5 |
详情 |
详情
|
(XI) |
50558 |
(6S)-1-[(1S)-1-[4-(1,3-benzodioxol-5-ylmethyl)phenyl]ethyl]-6-methyl-2,5-piperazinedione
|
|
C21H22N2O4 |
详情 |
详情
|
(XII) |
50559 |
(2S)-1-[(1S)-1-[4-(1,3-benzodioxol-5-ylmethyl)phenyl]ethyl]-2-methylpiperazine
|
|
C21H26N2O2 |
详情 |
详情
|
(XIII) |
18620 |
tert-butyl 4-oxo-1-piperidinecarboxylate;BOC-Piperidone;N-(tert-Butoxycarbonyl)-4-piperidone; N-Boc-4-piperidone |
79099-07-3 |
C10H17NO3 |
详情 | 详情
|
(XIV) |
50560 |
tert-butyl 4-((3S)-4-[(1S)-1-[4-(1,3-benzodioxol-5-ylmethyl)phenyl]ethyl]-3-methylpiperazinyl)-1-piperidinecarboxylate
|
|
C31H43N3O4 |
详情 |
详情
|
(XV) |
50561 |
(2S)-1-[(1S)-1-[4-(1,3-benzodioxol-5-ylmethyl)phenyl]ethyl]-2-methyl-4-(4-piperidinyl)piperazine
|
|
C26H35N3O2 |
详情 |
详情
|
(XVI) |
50562 |
m-Xylylic acid; 2,6-Dimethylbenzoic acid; m-Xylene-2-carboxylic acid
|
632-46-2 |
C9H10O2 |
详情 | 详情
|
合成路线20
该中间体在本合成路线中的序号:
(III) Isosafrole (II) was obtained by isomerization of safrole (I) under basic conditions. Ozonolysis of (II), followed by reductive decomposition of the intermediate ozonide with Zn, furnished piperonal (III). Oxidation of aldehyde (III) with methanolic iodine produced the methyl ester (IV), which was converted to the corresponding hydrazide (V) upon treatment with hydrazine in refluxing EtOH. Finally, condensation of (V) with thiophene-2-carboxaldehyde (VI) yielded the title hydrazone.
【1】
Gonzalez-Serratos, H.; et al.; A novel thienylhydrazone, (2-thienylidene)3,4-methylenedioxybenzoylhydrazine, increases inotropism and decreases fatigue of skeletal muscle. J Pharmacol Exp Ther 2001, 299, 2, 588.
|
【2】
Sudo, R.T.; Alburquerque, E.X.; De Barreiro, E.J. (University of Maryland); Thienylhydrazon with digitalis-like properties (positive inotropic effects). WO 0078754 .
|
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) |
46334 |
5-allyl-1,3-benzodioxole
|
|
C10H10O2 |
详情 |
详情
|
(II) |
53072 |
5-[(E)-1-propenyl]-1,3-benzodioxole
|
n/a |
C10H10O2 |
详情 | 详情
|
(III) |
10127 |
1,3-Benzodioxole-5-carbaldehyde; Heliotropine
|
120-57-0 |
C8H6O3 |
详情 | 详情
|
(IV) |
53073 |
methyl 1,3-benzodioxole-5-carboxylate
|
n/a |
C9H8O4 |
详情 | 详情
|
(V) |
53074 |
1,3-benzodioxole-5-carbohydrazide
|
n/a |
C8H8N2O3 |
详情 | 详情
|
(VI) |
30732 |
2-thiophenecarbaldehyde; Thiophene-2-carboxaldehyde
|
98-03-3 |
C5H4OS |
详情 | 详情
|
合成路线21
该中间体在本合成路线中的序号:
(I) Piperonal (I) is brominated by means of Br2 in AcOH to produce (II). Subsequent Suzuki coupling of aryl bromide (II) with 4-(methylsulfanyl)benzeneboronic acid (III) furnishes adduct (IV). Addition of 3-fluorophenylmagnesium bromide (V) to aldehyde (IV) leads to carbinol (VI). The sulfide group is further oxidized to sulfone (VII) employing oxone in aqueous MeOH. Finally, oxidation of alcohol (VII) with pyridinium chlorochromate provides the target ketone. (1,2)
【1】
Ezawa, M.; Khanapure, S.P.; Garvey, D.S.; Young, D.; Earl, R.; Gaston, R.; Fang, F.; Marek, P.; Shumway, M.; Trocha, M.; Tam, S.W.; Janero, D.R.; Letts, L.G.; Design and synthesis of novel benzo-dioxolane cyclooxygenase (COX-2) selective inhibitors. 225th ACS Natl Meet (March 23 2003, New Orleans) 2003, Abst MEDI 243. |
【2】
Earl, R.A.; Garvey, D.S.; Khanapure, S.P.; Gaston, R.D.; Fang, X.; Ezawa, M. (NitroMed Inc.); Substd. aryl cpds. as novel cyclooxygenase-2 selective inhibitors, compsns. and methods of use. US 2002119977; WO 0260378 .
|
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) |
10127 |
1,3-Benzodioxole-5-carbaldehyde; Heliotropine
|
120-57-0 |
C8H6O3 |
详情 | 详情
|
(II) |
46376 |
ethyl 3-(3-[2-[[(6-bromo-1,3-benzodioxol-5-yl)methyl](2-ethoxy-2-oxoacetyl)amino]phenyl]-3-oxopropyl)benzoate
|
|
C30H28BrNO8 |
详情 |
详情
|
(III) |
18561 |
4-(methylsulfanyl)phenylboronic acid
|
98546-51-1 |
C7H9BO2S |
详情 | 详情
|
(IV) |
64023 |
6-[4-(methylsulfanyl)phenyl]-1,3-benzodioxole-5-carbaldehyde
|
|
C15H12O3S |
详情 |
详情
|
(V) |
35384 |
bromo(3-fluorophenyl)magnesium
|
|
C6H4BrFMg |
详情 |
详情
|
(VI) |
64024 |
(3-fluorophenyl){6-[4-(methylsulfanyl)phenyl]-1,3-benzodioxol-5-yl}methanol
|
|
C21H17FO3S |
详情 |
详情
|
(VII) |
64025 |
(3-fluorophenyl){6-[4-(methylsulfonyl)phenyl]-1,3-benzodioxol-5-yl}methanol
|
|
C21H17FO5S |
详情 |
详情
|
合成路线22
该中间体在本合成路线中的序号:
(III)
【1】
Jiang WQ, Alford VC, Qiu YH. 2004. Synthesis and SAR of tetracyclic pyrroloquinolones as phosphodies-terase 5 inhibitors. Bioorg Med Chem, 12(6):1505~1515 |
【2】
Orme MW, Maninelli MJ, Doecke CW, et aL. 2004. Preparation of tetrahydro-β-carboline diastereomers by modified Pictet-Spengler reaction. W0 2004011463 |
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
(III) |
10127 |
1,3-Benzodioxole-5-carbaldehyde; Heliotropine
|
120-57-0 |
C8H6O3 |
详情 | 详情
|
(I) |
66756 |
(R)-2-amino-3-(1H-indol-3-yl)propanoic acid |
|
C11H12N2O2 |
详情 | 详情
|
(II) |
66757 |
(R)-methyl 2-amino-3-(1H-indol-3-yl)propanoate hydrochloride |
|
C12H14N2O2.HCl |
详情 | 详情
|
(IV) |
66758 |
methyl (1R,3R)-1-(1,3-benzodioxol-5-yl)-2,3,4,9-tetrahydro-1H-beta-carboline-3-carboxylate hydrochloride |
|
C20H18N2O4.HCl |
详情 | 详情
|
(V) |
43791 |
methyl (1R,3R)-1-(1,3-benzodioxol-5-yl)-2-(2-chloroacetyl)-2,3,4,9-tetrahydro-1H-beta-carboline-3-carboxylate
|
|
C22H19ClN2O5 |
详情 |
详情
|
合成路线23
该中间体在本合成路线中的序号:
(II)
【1】
Revell JD, Srinivasan N, Ganesan A. 2004. Two concise syntheses of Cialis via the N-acyliminium Pictet-Spengler reaction. Synlett, (8):1428~1430 |
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) |
66757 |
(R)-methyl 2-amino-3-(1H-indol-3-yl)propanoate hydrochloride |
|
C12H14N2O2.HCl |
详情 | 详情
|
(V) |
66761 |
(1R,3R)-methyl 2-(2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)acetyl)-1-(benzo[d][1,3]dioxol-5-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylate |
|
C38H33N3O7 |
详情 | 详情
|
(II) |
10127 |
1,3-Benzodioxole-5-carbaldehyde; Heliotropine
|
120-57-0 |
C8H6O3 |
详情 | 详情
|
(III) |
66759 |
(R,E)-methyl 2-((benzo[d][1,3]dioxol-5-ylmethylene)amino)-3-(1H-indol-3-yl)propanoate |
|
C20H18N2O4 |
详情 | 详情
|
(IV) |
66760 |
(9H-fluoren-9-yl)methyl (2-chloro-2-oxoethyl)(methyl)carbamate |
|
C18H16ClNO3 |
详情 | 详情
|
合成路线24
该中间体在本合成路线中的序号:
(II)
【1】
Sajja E, Vetukuri VR, Ningam SR, et aL. 2007. Process for producing tadalafiL. W0 2007100387 |
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
(III) |
66758 |
methyl (1R,3R)-1-(1,3-benzodioxol-5-yl)-2,3,4,9-tetrahydro-1H-beta-carboline-3-carboxylate hydrochloride |
|
C20H18N2O4.HCl |
详情 | 详情
|
(I) |
20416 |
methyl (2R)-2-amino-3-(1H-indol-3-yl)propanoate
|
|
C12H14N2O2 |
详情 |
详情
|
(II) |
10127 |
1,3-Benzodioxole-5-carbaldehyde; Heliotropine
|
120-57-0 |
C8H6O3 |
详情 | 详情
|
(IV) |
32138 |
Sarcosine ethyl ester; Ethyl 2-(methylamino)acetate
|
52605-49-9 |
C5H11NO2 |
详情 | 详情
|