合成路线1
该中间体在本合成路线中的序号:
(I) The reaction of cyclohexane-1,3-dione (I) with ammonia gives 3-amino-2-cyclohexen-1-one (II), which is cyclized with acrylic acid (III) by heating at 140 C yielding 1,2,3,4,5,6,7,8-octahydroquinoline-2,5-dione (IV). The dehydrogenation of (IV) by means of Pd/C in refluxing decaline affords 5-hydroxy-1,2,3,4-tetrahydroquinolin-2-one (V), which is condensed with epichlorohydrin (VI) by means of NaOMe or NaOH in methanol giving 5-(2,3-epoxypropoxy)-1,2,3,4-tetrahydroquinolin-2-one (VII). Finally, this compound is treated with tert-butylamine in methanol.
【1】
Castaner, J.; Sungurbey, K.; Carteolol. Drugs Fut 1977, 2, 5, 288.
|
【2】
Shono, T.; et al.; A new practical synthesis of 5-hydroxy-3,4-dihydrocarbostyril and 5-hydroxycarbostyril. J Org Chem 1981, 46, 3719.
|
【3】
Von Winkler, W.; Chemical and analytical data for the pharmaceutically active substance carteolol hydrochloride. Arzneim-Forsch Drug Res 1983, 33, 2a, 279.
|
【4】
Mori, H.; Tamura, Y,.; Tominaga, M.; Yoshiaki, S.; Nakagawa, K.; Murakami, N. (Otsuka Pharmaceutical Co., Ltd.); 3,4-Dihydrocarbostyril derivs., their preparation, and pharmaceutical compsns. thereof. DE 2302027; GB 1424571 .
|
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) |
11244 |
1,3-Cyclohexanedione
|
504-02-9 |
C6H8O2 |
详情 | 详情
|
(II) |
31475 |
3-amino-2-cyclohexen-1-one
|
5220-49-5 |
C6H9NO |
详情 | 详情
|
(III) |
19139 |
acrylic acid
|
79-10-7 |
C3H4O2 |
详情 | 详情
|
(IV) |
31476 |
4,6,7,8-tetrahydro-2,5(1H,3H)-quinolinedione
|
|
C9H11NO2 |
详情 |
详情
|
(V) |
31477 |
5-hydroxy-3,4-dihydro-2(1H)-quinolinone
|
|
C9H9NO2 |
详情 |
详情
|
(VI) |
29648 |
2-oxiranylmethanol
|
556-52-5 |
C3H6O2 |
详情 | 详情
|
(VII) |
31478 |
5-(2-oxiranylmethoxy)-3,4-dihydro-2(1H)-quinolinone
|
|
C12H13NO3 |
详情 |
详情
|
(VIII) |
17895 |
2-Amino-2-methylpropane; tert-butylamine; 2-methyl-2-propanamine
|
75-64-9 |
C4H11N |
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 monohydroxylated metabolite of NIK-247, (+)-9-amino-2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]quinolin-8-ol (VI) has been synthesized as follows:
The condensation of cyclohexane-1,3-dione (I) with 2-amino-1-cyclopentene-1-carbonitrile (II) by means of PPE gives 2-(3-oxo-1-cyclohexen-1-yl)-1-cyclopentene-1-carbonitrile (III), which is cyclized by means of BF3.Et2O to yield 9-amino-2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]quinolin-8-one (IV). The reduction of (IV) with NaBH4 affords the corresponding racemic alcohol (V), which is submitted to optical resolution with (+)-di-p-toluyltartaric acid to give the desired compound (VI).
【1】
Inada, H.; Yano, M.; Komatsu, T.; Iwamoto, M.; Suzuki, K.; Okada, K.; Synthesis of estimated metabolites of 9-amino-2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]quinoline monohydrochloride monohydrate (NIK-247). I.Synthesis of mono-hydroxylated metabolites. Yakugaku Zasshi 1995, 115, 12, 1016. |
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) |
11244 |
1,3-Cyclohexanedione
|
504-02-9 |
C6H8O2 |
详情 | 详情
|
(II) |
11242 |
2-Amino-1-cyclopentene-1-carbonitrile
|
|
C6H8N2 |
详情 |
详情
|
(III) |
11246 |
2-[(3-Oxo-1-cyclohexen-1-yl)amino]-1-cyclopentene-1-carbonitrile
|
|
C12H14N2O |
详情 |
详情
|
(IV) |
11247 |
9-Amino-1,2,3,5,6,7-hexahydro-8H-cyclopenta[b]quinolin-8-one
|
|
C12H14N2O |
详情 |
详情
|
(V) |
11248 |
9-Amino-2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]quinolin-8-ol
|
|
C12H16N2O |
详情 |
详情
|
(VI) |
63081 |
(+)-9-amino-2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]quinolin-8-ol
|
|
C12H16N2O |
详情 |
详情
|
合成路线3
该中间体在本合成路线中的序号:
(II) Condensation of 2-bromo-p-toluidine (I) with cyclohexane-1,3-dione (II) gives bromo enaminone (III), which is N-methylated with iodomethane and NaH, affording tertiary enaminone (IV). Treatment of (IV) with triphenylphosphine-palladium acetate complex/NHCO3 or palladium acetate in acetonitrile provides carbazolone (V). Treatment of carbazolone (V) with sodium metal in EtOH/dioxane (or sodium methoxide in 1,2-dimethoxyethane) and diethyl oxalate (VI) provides ethoxallyl derivative (VII), which is then converted into glyoxylic acid lactone (VIII). Coupling of (VIII) with 2-methylimidazol (IX) by means of benzyltriethylammonium chloride in CHCl3/H2O furnishes glyoxylate (X), which is converted into the target product by reaction again with 2-methylimidazol (IX) in dioxane and final treatment with HCl. Alternatively, glyoxylate (X) can be directly obtained from (VIII) by reaction with formaldehyde and 2-methylimidazol (IX) in dioxane.
【1】
Iida, H.; et al.; Intramolecular cyclization of enaminones involving arylpalladium complexes. Synthesis of carbazoles. J Org Chem 1980, 45, 15, 2938.
|
【2】
Harsanyi, K.; Bod, P.; Trischler, F.; Fekecs, E.; Horvath, E.; Csehl, A.; Hegedus, B.; Mersich, E.; Szabo, G. (Gedeon Richter Ltd.); Carbazolone derivs. and process for preparing the same. EP 0595111 .
|
【3】
Dobay, L.; Czibula, L.; Szantay, C.; Gazdag, M.; Greiner, I.; Werkne Papp, E.; Tarkanyi, G.; Zsoldosne Babjak, M.; Mihalyfi, K. (Gedeon Richter Ltd.); An intermediate and process for its synthesis. WO 0172716 .
|
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) |
27739 |
2-bromoaniline
|
615-36-1 |
C6H6BrN |
详情 | 详情
|
(II) |
11244 |
1,3-Cyclohexanedione
|
504-02-9 |
C6H8O2 |
详情 | 详情
|
(III) |
53887 |
3-(2-bromoanilino)-2-cyclohexen-1-one
|
n/a |
C12H12BrNO |
详情 | 详情
|
(IV) |
53888 |
3-[2-bromo(methyl)anilino]-2-cyclohexen-1-one
|
n/a |
C13H14BrNO |
详情 | 详情
|
(V) |
53889 |
9-methyl-1,2,3,9-tetrahydro-4H-carbazol-4-one
|
27387-31-1 |
C13H13NO |
详情 | 详情
|
(VI) |
17571 |
Diethyl oxalate; Ethyl 2-ethoxy-2-oxoacetate
|
95-92-1 |
C6H10O4 |
详情 | 详情
|
(VII) |
53890 |
ethyl 2-hydroxy-2-(9-methyl-4-oxo-1,2,4,9-tetrahydro-3H-carbazol-3-ylidene)acetate
|
n/a |
C17H17NO4 |
详情 | 详情
|
(VIII) |
53891 |
|
n/a |
C16H13NO4 |
详情 | 详情
|
(IX) |
15670 |
2-Methylimidazole; 2-Methyl-1H-imidazole
|
693-98-1 |
C4H6N2 |
详情 | 详情
|
(X) |
53892 |
2-methyl-1H-imidazol-3-ium 2-[3-(hydroxymethyl)-9-methyl-4-oxo-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-2-oxoacetate
|
n/a |
C20H21N3O5 |
详情 | 详情
|
合成路线4
该中间体在本合成路线中的序号:
(II) Condensation of 2-iodoaniline (I) with cyclohexane-1,3-dione (II) at 120 C yields secondary amine (III), which is then methylated with iodomethane by means of sodium hydride in refluxing benzene to provide tertiary amine (IV). Treatment of (IV) with lithium diisopropylamide (LDA) and dimethylaminomethylene iodide (Eschenmoser's salt) (V) in THF yields dimethylaminomethyl derivative (VI), which is then coupled with 2-methylindole (VII) in DMF to give compound (VIII). Cyclization of cyclohexenone derivative (VIII) by means of palladium (II) acetate and triethylamine in acetonitrile provides carbazolone derivative (IX), which is finally converted into the desired hydrochloride salt by treatment with HCl.
【1】
Bell, J.A.; Ewan, G.B.; Humber, D.C.; Costes, I.H.; Godfrey, N. (GlaxoSmithKline plc); Process for the preparation of 3-imidazolylmethyltetrahydrocarbazolones. EP 0221629 .
|
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) |
27725 |
2-iodoaniline
|
615-43-0 |
C6H6IN |
详情 | 详情
|
(II) |
11244 |
1,3-Cyclohexanedione
|
504-02-9 |
C6H8O2 |
详情 | 详情
|
(III) |
53899 |
3-(2-iodoanilino)-2-cyclohexen-1-one
|
n/a |
C12H12INO |
详情 | 详情
|
(IV) |
53900 |
3-[2-iodo(methyl)anilino]-2-cyclohexen-1-one
|
n/a |
C13H14INO |
详情 | 详情
|
(V) |
48555 |
Eschenmoser's salt; N,N-Dimethylmethyleneimmonium chloride; N,N-Dimethylmethyleneimmonium iodide
|
|
C3H8IN |
详情 |
详情
|
(VI) |
53901 |
6-[(dimethylamino)methyl]-3-[2-iodo(methyl)anilino]-2-cyclohexen-1-one
|
n/a |
C16H21IN2O |
详情 | 详情
|
(VII) |
15670 |
2-Methylimidazole; 2-Methyl-1H-imidazole
|
693-98-1 |
C4H6N2 |
详情 | 详情
|
(VIII) |
53902 |
3-[2-iodo(methyl)anilino]-6-[(2-methyl-1H-imidazol-1-yl)methyl]-2-cyclohexen-1-one
|
n/a |
C18H20IN3O |
详情 | 详情
|
(IX) |
53903 |
9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-1,2,3,9-tetrahydro-4H-carbazol-4-one
|
n/a |
C18H19N3O |
详情 | 详情
|
合成路线5
该中间体在本合成路线中的序号:
(II) The condensation of anthranilonitrile (I) with cyclohexane-1,3-dione (II) in the presence of p-toluenesulfonic acid (removal of water) gives the enaminoketone (III). Cyclization of (III) in the presence of K2CO3 and CuCl yields the aminoketone (IV), which is then reduced with LiAlH4.
【1】
Shutske, G.M.; Pierrat, F.A. (Aventis Pharmaceuticals, Inc.); 9-Amino-1,2,3,4-tetrahydroacridin-1-ol and related cpds., a process for their preparation and their use as medicaments. AU 8549038; EP 0179383; ES 8701165; ES 8801213; ES 8802383; JP 1986148154; JP 1989125362; US 4631286; US 4839364 . |
【2】
Shutske, G.M.; VELNACRINE MALEATE < USAN >. Drugs Fut 1989, 14, 7, 643.
|
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) |
19493 |
2-aminobenzonitrile
|
1885-29-6 |
C7H6N2 |
详情 | 详情
|
(II) |
11244 |
1,3-Cyclohexanedione
|
504-02-9 |
C6H8O2 |
详情 | 详情
|
(III) |
19495 |
2-[(3-oxo-1-cyclohexen-1-yl)amino]benzonitrile
|
|
C13H12N2O |
详情 |
详情
|
(IV) |
19496 |
9-amino-3,4-dihydro-1(2H)-acridinone
|
104675-26-5 |
C13H12N2O |
详情 | 详情
|
合成路线6
该中间体在本合成路线中的序号:
(VI) The reaction of 1-indanone (I) with sodium azide in acetic acid/sulfuric acid gives the tetrahydroquinolone (II), which is reduced with LiAlH4 in THF, yielding the tetrahydroquinoline (III). The reaction of (III) with NaNO2 and sulfuric acid afords the N-nitroso derivative (IV), which is reduced wiith LiAlH4 in THF to the N-amino compound (V). The reaction of (V) with cyclohexane-1,3-dione (VI) gives the monohydrazone (VII), which is cyclized by means of HCl in refluxing acetic acid, yielding the tetracyclic compound (VIII). The reaction of (VIII) with dimethylamine and paraformaldehyde in hot acetic acid provides compound (IX), which is treated with 2-methylimidazole (X) in refluxing water to afford racemic cilansetron (XI). Finally, this racemate is submitted to optical resolution with di-p-toluyl-D-tartaric acid or D-pyroglutamic acid.
【1】
Castaner, J.; Rabasseda, X.; Silvestre, J.S.; Graul, A.; Cilansetron. Drugs Fut 1999, 24, 5, 475.
|
【2】
Haeck, H.H.; Hamminga, D.; Van Wijngaarden, I.; Wouters, W. (Duphar International Research BV); New anellated indole derivs.. AU 8818414; EP 0297651; JP 1989022870; US 4939136 .
|
【3】
Verbeek, J.-M.; Van der Meij, P.F.C. (Duphar International Research BV); Process for the preparation of enantiomerically pure imidazolyl cpds.. EP 0768309 .
|
【4】
de Jonge, A.; Tulp, M.T.M.; Olivier, B.; Tipker, J.; van Hes, R.; Mol, F.; Hamminga, D.; Standaar, P.J.; Van Wijngaarden, I.; Development of high-affinity 5-HT3 receptor antagonists. Structure-affinity relationships of novel 1,7-annelated indole derivatives. 1. J Med Chem 1993, 36, 23, 3693. |
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) |
23857 |
1-indanone
|
83-33-0 |
C9H8O |
详情 | 详情
|
(II) |
18553 |
3,4-dihydro-2(1H)-quinolinone
|
553-03-7 |
C9H9NO |
详情 | 详情
|
(III) |
23859 |
1,2,3,4-tetrahydroquinoline
|
635-46-1 |
C9H11N |
详情 | 详情
|
(IV) |
23860 |
1-nitroso-1,2,3,4-tetrahydroquinoline
|
|
C9H10N2O |
详情 |
详情
|
(V) |
23861 |
3,4-dihydro-1(2H)-quinolinylamine; 3,4-dihydro-1(2H)-quinolinamine
|
|
C9H12N2 |
详情 |
详情
|
(VI) |
11244 |
1,3-Cyclohexanedione
|
504-02-9 |
C6H8O2 |
详情 | 详情
|
(VII) |
23863 |
3-[3,4-dihydro-1(2H)-quinolinylimino]cyclohexanone
|
|
C15H18N2O |
详情 |
详情
|
(VIII) |
23864 |
5,6,9,10-tetrahydro-4H-pyrido[3,2,1-jk]carbazol-11(8H)-one
|
|
C15H15NO |
详情 |
详情
|
(IX) |
23865 |
10-[(dimethylamino)methyl]-5,6,9,10-tetrahydro-4H-pyrido[3,2,1-jk]carbazol-11(8H)-one
|
|
C18H22N2O |
详情 |
详情
|
(X) |
15670 |
2-Methylimidazole; 2-Methyl-1H-imidazole
|
693-98-1 |
C4H6N2 |
详情 | 详情
|
(XI) |
23867 |
10-[(2-methyl-1H-imidazol-1-yl)methyl]-5,6,9,10-tetrahydro-4H-pyrido[3,2,1-jk]carbazol-11(8H)-one
|
|
C20H21N3O |
详情 |
详情
|
合成路线7
该中间体在本合成路线中的序号:
(IV) The reaction of trifluoroacetoacetic acid ethyl ester (I) with (?)-isoborneol (II) at 130 C gives the corresponding isobornyl ester (III), which is condensed with cyclohexane-1,3-dione (IV) and 3-cyanobenzaldehyde (V) by means of ammonium acetate in refluxing ethanol to yield the octahydroquinolone (VI). The hydrolysis of the ester group of (VI), with simultaneous dehydration by means of TsOH in refluxing toluene affords 4-(3-cyanophenyl)-5-oxo-2-(trifluoromethyl)-1,4,5,6,7,8-hexahydroquinoline-3-carboxylic acid (VII) as a racemic mixture. Optical resolution of (VII) through the diastereomeric salt with 1(S)-phenylethylamine (VIII) in toluene/butanol provides the desired isomer (IX), which is finally decarboxylated in N-methyl-2-pyrrolidone at 210 C to furnish the target hexahydroquinolone.
【1】
Ashworth, I.; Hopes, P.; Levin, D.; Patel, I.; Salloo, R.; An asymmetric synthesis of a 4-substituted-1,4-dihydropyridine. Tetrahedron Lett 2002, 43, 28, 4931.
|
【2】
Warawa, J.E.; Ohnmacht, C.J. Jr.; Trainor, D.A.; Hulsizer, J.M. (AstraZeneca plc); Quinolone deriv. for treatment of urinary incontinence. EP 0755382; JP 1997512254; WO 9528388 .
|
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) |
62025 |
propyl 4,4,4-trifluoro-3-oxobutanoate
|
|
C7H9F3O3 |
详情 |
详情
|
(II) |
62026 |
(1R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ol
|
|
C10H18O |
详情 |
详情
|
(III) |
62027 |
(1R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl 4,4,4-trifluoro-3-oxobutanoate
|
|
C14H19F3O3 |
详情 |
详情
|
(IV) |
11244 |
1,3-Cyclohexanedione
|
504-02-9 |
C6H8O2 |
详情 | 详情
|
(V) |
13245 |
3-Formylbenzonitrile; 3-Cyanobenzaldehyde
|
24964-64-5 |
C8H5NO |
详情 | 详情
|
(VI) |
62028 |
(1R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl 4-(3-cyanophenyl)-2-hydroxy-5-oxo-2-(trifluoromethyl)-1,2,3,4,5,6,7,8-octahydro-3-quinolinecarboxylate
|
|
C28H31F3N2O4 |
详情 |
详情
|
(VII) |
62029 |
4-(3-cyanophenyl)-5-oxo-2-(trifluoromethyl)-1,4,5,6,7,8-hexahydro-3-quinolinecarboxylic acid
|
|
C18H13F3N2O3 |
详情 |
详情
|
(VIII) |
10039 |
(1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine
|
3886-69-9 |
C8H11N |
详情 | 详情
|
(IX) |
62030 |
(4S)-4-(3-cyanophenyl)-5-oxo-2-(trifluoromethyl)-1,4,5,6,7,8-hexahydro-3-quinolinecarboxylic acid
|
|
C18H13F3N2O3 |
详情 |
详情
|
合成路线8
该中间体在本合成路线中的序号:
(IV) The condensation of 3-cyanobenzaldehyde (I) with trifluoroacetone (II) in piperidine gives 3-(4,4,4-trifluoro-3-oxo-2-butenyl)benzonitrile (III). The condensation of cyclohexane-1,3-dione (IV) with 1(R)-phenylethylamine (V) in refluxing toluene or THF yields the secondary enamine (VI), which is condensed with benzonitrile (III) by means of Tms-Cl in hot acetonitrile to afford the chiral adduct (VII). The cyclization of (VII) by means of NH3 in hot acetonitrile provides the chiral octahydroquinolone (VIII), which is finally dehydrated by means of TFA, MsOH, TsOH or HCl in refluxing acetonitrile to give the target hexahydroquinolone.
【1】
Patel, I.; Hopes, P. (AstraZeneca AB); Process for synthesis of alpha,beta-unsaturated ketones. WO 0210103 .
|
【2】
Patel, I.; Ashworth, I.; Levin, D. (AstraZeneca AB); Process for asymmetric synthesis of substd. 1,4-dihydropyridines. WO 0210134 .
|
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) |
13245 |
3-Formylbenzonitrile; 3-Cyanobenzaldehyde
|
24964-64-5 |
C8H5NO |
详情 | 详情
|
(II) |
35450 |
3,3-dibromo-1,1,1-trifluoroacetone
|
431-67-4 |
C3HBr2F3O |
详情 | 详情
|
(III) |
62031 |
3-[(E)-4,4,4-trifluoro-3-oxo-1-butenyl]benzonitrile
|
|
C11H6F3NO |
详情 |
详情
|
(IV) |
11244 |
1,3-Cyclohexanedione
|
504-02-9 |
C6H8O2 |
详情 | 详情
|
(V) |
10039 |
(1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine
|
3886-69-9 |
C8H11N |
详情 | 详情
|
(VI) |
62032 |
3-{[(1R)-1-phenylethyl]amino}-2-cyclohexen-1-one
|
|
C14H17NO |
详情 |
详情
|
(VII) |
62033 |
3-[(1S)-4,4-dimethyl-3-oxo-1-(6-oxo-2-{[(1R)-1-phenylethyl]amino}-1-cyclohexen-1-yl)pentyl]benzonitrile
|
|
C28H32N2O2 |
详情 |
详情
|
(VIII) |
62034 |
3-[(4S)-2-hydroxy-5-oxo-2-(trifluoromethyl)-1,2,3,4,5,6,7,8-octahydro-4-quinolinyl]benzonitrile
|
|
C17H15F3N2O2 |
详情 |
详情
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合成路线9
该中间体在本合成路线中的序号:
(II) The condensation of trifluoroacetoacetic acid ethyl ester (I) with cyclohexane-1,3-dione (II) and 3-cyanobenzaldehyde (III) by means of ammonium acetate in refluxing ethanol gives the octahydroquinolone (IV), which is hydrolyzed at its ester group by means of LiOH in hot ethanol/water to yield the corresponding carboxylic acid (V). Finally, this compound is dehydrated by means of TsOH in refluxing toluene to afford the target intermediate (rac)-4-(3-cyanophenyl)-5-oxo-2-(trifluoromethyl)-1,4,5,6,7,8-hexahydroquinoline-3-carboxylic acid (VI).
【1】
Ohnmacht, C.J.; Trainor, D.A.; Forst, J.M.; Stein, M.M.; Harris, R.J. (AstraZeneca plc); Quinolone and acridinone derivs. for the treatment of urinary incontinence. EP 0665834; JP 1996502282; US 5622964; WO 9408966 .
|
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) |
62025 |
propyl 4,4,4-trifluoro-3-oxobutanoate
|
|
C7H9F3O3 |
详情 |
详情
|
(II) |
11244 |
1,3-Cyclohexanedione
|
504-02-9 |
C6H8O2 |
详情 | 详情
|
(III) |
13245 |
3-Formylbenzonitrile; 3-Cyanobenzaldehyde
|
24964-64-5 |
C8H5NO |
详情 | 详情
|
(IV) |
62035 |
propyl 4-(3-cyanophenyl)-2-hydroxy-5-oxo-2-(trifluoromethyl)-1,2,3,4,5,6,7,8-octahydro-3-quinolinecarboxylate
|
|
C21H21F3N2O4 |
详情 |
详情
|
(V) |
62036 |
4-(3-cyanophenyl)-2-hydroxy-5-oxo-2-(trifluoromethyl)-1,2,3,4,5,6,7,8-octahydro-3-quinolinecarboxylic acid
|
|
C18H15F3N2O4 |
详情 |
详情
|
(VI) |
62029 |
4-(3-cyanophenyl)-5-oxo-2-(trifluoromethyl)-1,4,5,6,7,8-hexahydro-3-quinolinecarboxylic acid
|
|
C18H13F3N2O3 |
详情 |
详情
|
合成路线10
该中间体在本合成路线中的序号:
(I) 1,3-Cyclohexanedione (I) was brominated in cold water, and the resulting 2-bromo-1,3-cyclohexanedione (II) was condensed with 2-aminopyridine (III) in boiling EtOH to afford the dihydropyridobenzimidazolone (IV). Further bromination in concentrated HBr at 70 C gave bromoketone (V), which was finally condensed with thiourea (VI) in EtOH to yield the target tetracyclic compound.
【1】
Yoo, H.Y.; Chung, K.J.; Chai, J.P.; Chang, M.S.; Kim, S.G.; Choi, W.S.; Kim, Y.H.; Chun, J.K.; Chung, Y.K.; Kim, Y.H.; Paek, J.H.; Seo, K.H.; Kang, D.P. (Yung-Jin Pharmaceutical Co., Ltd.); Heterocycle-fused thiazole derivs.. EP 0843681; JP 1998508877; WO 9703076 . |
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) |
11244 |
1,3-Cyclohexanedione
|
504-02-9 |
C6H8O2 |
详情 | 详情
|
(II) |
21027 |
2-bromo-1,3-cyclohexanedione
|
|
C6H7BrO2 |
详情 |
详情
|
(III) |
11305 |
2-Pyridinamine; 2-Pyridinylamine; 2-Aminopyridine
|
504-29-0 |
C5H6N2 |
详情 | 详情
|
(IV) |
10180 |
Thiourea
|
62-56-6 |
CH4N2S |
详情 | 详情
|
(IV) |
21029 |
7,8-dihydropyrido[1,2-a]benzimidazol-9(6H)-one
|
|
C11H10N2O |
详情 |
详情
|
(V) |
21030 |
8-bromo-7,8-dihydropyrido[1,2-a]benzimidazol-9(6H)-one
|
|
C11H9BrN2O |
详情 |
详情
|
合成路线11
该中间体在本合成路线中的序号:
(VIII) By condensation of substituted nicotinamide (VI) with the carbazolyoxymethyl-oxirane (XII) in hot methanol/water.
The intermediates the nicotinamide (VI) and the oxirane (XII) have been obtained as follows:
1.- Nicotinamide (VI): The reaction of 4-hydroxybenzyl alcohol (I) with 2-nitropropane (II) by means of potassium tert-butoxide in hot diglyme gives 4-(2-methyl-2-nitropropyl)phenol (III), which is reduced to the corresponding amino derivative (IV) with H2 over Pd/C in methanol/ethanol/acetic acid. Finally, this compound is condensed with 6-chloronicotinamide (V) by means of K2CO3 in dimethylacetamide/isooctane.
2.- Oxirane (XII): The reaction of phenylhydrazine (VII) with cyclohexane-1,3-dione (VIII) by means of NaHCO3 in isopropanol/water gives the monohydrazone (IX), which is cyclized with hotpolyphosphoric acid yielding the 4-hydroxycarbazole (X). Finally, this compound is condensed with the glycidyl 3-nitrophenylsulfonate (XI) by means of K2CO3 in refluxing acetone.
【1】
Crowell, T.A.; Evrard, D.A.; Jones, C.D.; Muehl, B.S.; Rito, C.J.; Shuker, A.J.; Thorpe, A.J.; Thrasher, K.J. (Eli Lilly and Company); Carbazole analogues as selective B3 adrenergic agonists. EP 0827746; WO 9809625 .
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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) |
29474 |
4-(hydroxymethyl)phenol; 4-hydroxyphenylmethanol
4-hydroxybenzenemethanol; 4-Hydroxybenzyl alcohol
|
623-05-2 |
C7H8O2 |
详情 | 详情
|
(II) |
21819 |
2-nitropropane
|
79-46-9 |
C3H7NO2 |
详情 | 详情
|
(III) |
29475 |
4-(2-methyl-2-nitropropyl)phenol
|
|
C10H13NO3 |
详情 |
详情
|
(IV) |
29476 |
4-(2-amino-2-methylpropyl)phenol
|
51706-55-9 |
C10H15NO |
详情 | 详情
|
(V) |
29477 |
6-chloronicotinamide
|
6271-78-9 |
C6H5ClN2O |
详情 | 详情
|
(VI) |
29478 |
6-[4-(2-amino-2-methylpropyl)phenoxy]nicotinamide
|
|
C16H19N3O2 |
详情 |
详情
|
(VII) |
11818 |
Phenyl hydrazine; 1-Phenylhydrazine
|
100-63-0 |
C6H8N2 |
详情 | 详情
|
(VIII) |
11244 |
1,3-Cyclohexanedione
|
504-02-9 |
C6H8O2 |
详情 | 详情
|
(IX) |
29479 |
3-hydroxy-2-cyclohexen-1-one N-phenylhydrazone
|
|
C12H14N2O |
详情 |
详情
|
(X) |
29480 |
4-Hydroxycarbazole; 9H-carbazol-4-ol
|
52602-39-8 |
C12H9NO |
详情 | 详情
|
(XI) |
16259 |
(2S)oxiranylmethyl 3-nitrobenzenesulfonate; (S)-(+)-Glycidyl nosylate
|
115314-14-2 |
C9H9NO6S |
详情 | 详情
|
(XII) |
29481 |
9H-carbazol-4-yl (2S)oxiranylmethyl ether; 4-[(2S)oxiranylmethoxy]-9H-carbazole
|
|
C15H13NO2 |
详情 |
详情
|
合成路线12
该中间体在本合成路线中的序号:
(I) Mannich reaction of 1,3-cyclohexanedione (I) with paraformaldehyde and dipropylamine affords intermediate (II) which, without isolation is condensed with acetone under Robinson annulation conditions, to produce the bicyclic amino ketone (III). Enamine reduction in (III) using NaBH3CN in AcOH gives a racemic amine, which is resolved via formation of the corresponding diastereoisomeric salts with (-)-ditoluyltartaric acid, and finally isolated as the hydrochloride salt.
【1】
Venhuis, B.J.; Wikstrom, H.V.; Rodenhuis, N.; Sundell, S.; Dijkstra, D.; A new type of prodrug of catecholamines: An opportunity to improve the treatment of Parkinson's disease. J Med Chem 2002, 45, 12, 2349.
|
【2】
Wise, L.D.; Wikstrom, H.V.; Wustrow, D.J.; Meltzer, L.T.; Dijkstra, D.; Venhuis, B.J. (Pfizer Inc.); Method for treating Parkinson's disease by administering (-)-5-keto-2-N,N-di-N-propylamino-tetrahydrotetralin. WO 0128977 .
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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) |
11244 |
1,3-Cyclohexanedione
|
504-02-9 |
C6H8O2 |
详情 | 详情
|
(II) |
61021 |
2-[(dipropylamino)methyl]-1,3-cyclohexanedione
|
|
C13H23NO2 |
详情 |
详情
|
(III) |
61022 |
6-(dipropylamino)-3,4,7,8-tetrahydro-1(2H)-naphthalenone
|
|
C16H25NO |
详情 |
详情
|
合成路线13
该中间体在本合成路线中的序号:
(I) The chlorination of cyclohexane-1,3-dione (I) with chloramine T in acetonitrile gives 2-chlorocyclohexane-1,3-dione (II), which is finally condensed with cyclopropanecarbonyl chloride (III) by means of potassium tert-butoxide in THF to yield the target cyclohexenyl ester.
【1】
Wu, C.-S.; Huang, J.-L.; Sun, Y.-S.; Yang, D.-Y.; Lin, S.-W.; Lin, Y.-L.; SAR studies of 3-cyclopropanecarbonyloxy-2-cyclohexen-1-one as inhibitors of 4-hydroxyphenylpyruvate dioxygenase. Bioorg Med Chem 2002, 10, 3, 685.
|
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) |
11244 |
1,3-Cyclohexanedione
|
504-02-9 |
C6H8O2 |
详情 | 详情
|
(II) |
54418 |
2-chloro-1,3-cyclohexanedione
|
|
C6H7ClO2 |
详情 |
详情
|
(III) |
14061 |
Cyclopropanecarbonyl chloride; Cyclopropanecarboxylic acid chloride
|
4023-34-1 |
C4H5ClO |
详情 | 详情
|
合成路线14
该中间体在本合成路线中的序号:
(V)
【1】
Hauptschein M,Nodiff EA.Saggiomo AJ.1954.Trifluoromethyl derivatives of hydroxybeznoic acids and related compounds. J Am Chem Soc.76. 1051--1054 |
【2】
Przemystaw S,Gryff-Keller A, Molchanov S 2006. 1HNMR, 13CNMR, and computationa IDFT studies of the structure of 2-acyl cyclohexane-l, 3-diones and their alkali metal salts in solution. J Org Chem,711 4636 - 4641 |
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) |
66545 |
4-Amino-3-nitrobenzotrifluoride;2-Nitro-alpha,alpha,alpha-trifluoro-p-toluidine;2-Nitro-4-(trifluoromethyl)aniline |
400-98-6 |
C7H5F3N2O2 |
详情 | 详情
|
(II) |
66546 |
2-nitro-4-(trifluoromethyl)benzonitrile |
|
C8H3F3N2O2 |
详情 | 详情
|
(III) |
66547 |
2-nitro-4-(trifluoromethyl)benzoic acid |
|
C8H4F3NO4 |
详情 | 详情
|
(IV) |
66548 |
methyl 2-nitro-4-(trifluoromethyl)benzoate |
|
C9H6F3NO4 |
详情 | 详情
|
(V) |
11244 |
1,3-Cyclohexanedione
|
504-02-9 |
C6H8O2 |
详情 | 详情
|
合成路线15
该中间体在本合成路线中的序号:
(II)
【1】
Bay E, 1988. Converting enol ester precursor of a benzoyl-1,3-cydoalkyldione to a beruoyl-1,3-cycloalkyldione. US 4774360 |
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) |
66549 |
2-nitro-4-(trifluoromethyl)benzoyl chloride |
|
C8H3ClF3NO3 |
详情 | 详情
|
(II) |
11244 |
1,3-Cyclohexanedione
|
504-02-9 |
C6H8O2 |
详情 | 详情
|
合成路线16
该中间体在本合成路线中的序号:
(III)
【1】
Ellis MK, Lindstedt SK, Lock EA, et aL 1996. Pharmaceutical compositions for the treatment of hereditary tyosrnenua type I. US 5550165 |
【2】
Rawlinson H, Wiffen JW, Brown SM. 1998. Process for the production of 2-(substituted benzoyl)-l,3 cyclohexanediones. US 5728889 |
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) |
66547 |
2-nitro-4-(trifluoromethyl)benzoic acid |
|
C8H4F3NO4 |
详情 | 详情
|
(II) |
66549 |
2-nitro-4-(trifluoromethyl)benzoyl chloride |
|
C8H3ClF3NO3 |
详情 | 详情
|
(III) |
11244 |
1,3-Cyclohexanedione
|
504-02-9 |
C6H8O2 |
详情 | 详情
|