合成路线1
该中间体在本合成路线中的序号:
(VI) The condensation of ethyl acetate (I) with 4-picoline (II) by means of n-butyllithium in THF gives 1-(4-pyridyl)propanone (III), which by reaction with the dimethylacetal of dimethylformamide (IV) in refluxing HMPT is converted into 4-dimethylamino-3-(4-pyridyl)-3-buten-2-one (V). Finally, this compound is cyclized with cyanacetamide (VI) by means of sodium methoxide in refluxing DMF.
![](http://zy.yaozh.com/wmf/sch/09/09085701a.jpg)
【1】
Lehser, G.Y.; Philion, R.E.; Page, D.F.; Opalka, C.J. (Sterling Winthrop Inc.); 5-(pyridinyl)-2(1H)-pyridinones, useful as cardiotonic agents and their preparation. DE 3044568; FR 2470124; GB 2065642; NL 8006399 .
|
【2】
Serradell, M.N.; Castaner, J.; Blancafort, P.; WIN-47,203. Drugs Fut 1982, 7, 10, 757.
|
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) |
17491 |
ethyl acetate
|
141-78-6 |
C4H8O2 |
详情 | 详情
|
(II) |
31150 |
4-methylpyridine
|
108-89-4 |
C6H7N |
详情 | 详情
|
(III) |
32092 |
1-(4-pyridinyl)acetone
|
|
C8H9NO |
详情 |
详情
|
(IV) |
11984 |
N-(Dimethoxymethyl)-N,N-dimethylamine;dimethylformamide dimethylacetal;1,1-dimethoxy-N,N-dimethylmethanamine; Dimethoxy-N,N-dimethylmethanamine; N,N-Dimethylformamide dimethyl acetal |
4637-24-5 |
C5H13NO2 |
详情 | 详情
|
(V) |
32093 |
(E)-4-(dimethylamino)-3-(4-pyridinyl)-3-buten-2-one
|
|
C11H14N2O |
详情 |
详情
|
(VI) |
12122 |
Cyanoacetamide; 2-Cyanoacetamide
|
107-91-5 |
C3H4N2O |
详情 | 详情
|
合成路线2
该中间体在本合成路线中的序号:
(II) Compound can be prepared in several different ways:
1) The condensation of 2-(4-pyridinyl)-3-dimethylaminoacrolein (I) with cyanacetamide (II) by means of sodium methoxide in refluxing methanol gives 1,2-dihydro-5-(4-pyridinyl)-2-oxonicotinonitrile (III), which by hydrolysis with 90% H2SO4 at 100 C is converted into 1,2-dihydro-5-(4-pyridinyl)-2-oxonicotinamide (IV). Finally, this compound is submitted to a Hofmann degradation with Br2 and NaOH in water.
2) Compound (III) can also be obtained by condensation of 2-(4-pyridinyl)-malonodialdehyde (V) with cyanacetamide (II) by means of morpholine and acetic acid in refluxing benzene.
3) The hydrolysis of (III) with refluxing 50% H2SO4 gives 1,2-dihydro-5-(4-pyridinyl)-2-oxonicotinic acid (VI), which by reaction with 90% HNO3 in conc. H2SO4 at 80 C yields 3-nitro-5-(4-pyridinyl)-2(1H)-pyridinone (VII). Finally, this compound is reduced with H2 over Pd/C in DMF.
4) The decarboxylative hydrolysis of (III) with refluxing 80% H2SO4 gives 5-(4-pyridinyl)-2(1H)-pyridinone (VIII), which can be nitrated with conc. HNO3 in H2SO4 at 80 C to give also (VII).
![](http://zy.yaozh.com/wmf/sch/09/09094901a.jpg)
【1】
Lesher, G.Y.; Opalka, C.J. (Sanofi-Synthelabo); 3-Cyano-5-(pyridinyl)-2(1H)-pyridinones. US 4004012; ZA 7606042 .
|
【2】
Hillier, K.; Amrinone. Drugs Fut 1979, 4, 4, 245.
|
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) |
33314 |
(Z)-3-(dimethylamino)-2-(4-pyridinyl)-2-propenal
|
|
C10H12N2O |
详情 |
详情
|
(II) |
12122 |
Cyanoacetamide; 2-Cyanoacetamide
|
107-91-5 |
C3H4N2O |
详情 | 详情
|
(III) |
33315 |
2-oxo-5-(4-pyridinyl)-1,2-dihydro-3-pyridinecarbonitrile
|
|
C11H7N3O |
详情 |
详情
|
(IV) |
33316 |
2-oxo-5-(4-pyridinyl)-1,2-dihydro-3-pyridinecarboxamide
|
|
C11H9N3O2 |
详情 |
详情
|
(V) |
33317 |
2-(4-pyridinyl)malonaldehyde
|
|
C8H7NO2 |
详情 |
详情
|
(VI) |
33318 |
2-oxo-5-(4-pyridinyl)-1,2-dihydro-3-pyridinecarboxylic acid
|
|
C11H8N2O3 |
详情 |
详情
|
(VII) |
33319 |
3-nitro-5-(4-pyridinyl)-2(1H)-pyridinone
|
|
C10H7N3O3 |
详情 |
详情
|
(VIII) |
33320 |
5-(4-pyridinyl)-2(1H)-pyridinone
|
|
C10H8N2O |
详情 |
详情
|
合成路线3
该中间体在本合成路线中的序号:
(IX) Reduction of 3,5-dichlorobenzoyl chloride (I) with NaBH4 in THF in the presence of N-methyl pyrrolidone (NMP) provides benzyl alcohol derivative (II), which is then treated with tert-butyl dimethylsilyl chloride (TBDMSCl) in DMF in the presence of imidazole and DMAP to furnish protected compound (III). Lithiation of (III) with BuLi (occasionally in the presence of tetramethylethylenediamine) in THF followed by reaction with p-chlorobenzoyl chloride (IV) in THF affords benzophenone derivative (V), which is then deprotected by means of concentrated HCl to yield benzyl alcohol derivative (VI). Conversion of alcohol (VI) into chloride (VII) is then performed by reaction with SOCl2. Next, reaction of (VII) with NaN3 and NaI in refluxing ethanol gives benzylazide derivative (VIII), which is finally converted into the desired product by reaction with cyanoacetamide (IX) and K2CO3 in DMSO.
![](http://zy.yaozh.com/wmf/sch/11/11326501a.jpg)
【1】
Bochis, R.J.; Chabala, J.C.; Fisher, M.H. (Merck & Co., Inc.); 5-(Amino or substd.amino)-1,2,3-triazoles. EP 0151529; JP 1985188376; US 4590201 .
|
【2】
Hube, D. (Merck & Co., Inc.); 5-Amino or substd. amino-1,2,3-triazoles useful as anti-metastasis agents. JP 1991056417; US 5045543 .
|
【3】
Hupe, D.; Azzolina, B.A.; Argenbright, L.; Behrens, N. (Merck & Co., Inc.); 5-Amino or substd. amino 1,2,3-triazoles useful as antiproliferative agents. EP 0304221; JP 1989068321; US 4847257 .
|
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
|
49483 |
N,N,N',N'-Tetramehylenediamine; 1,2-Bis(dimethylamino)ethane
|
|
C6H16N2 |
详情 |
详情
|
(I) |
27769 |
3,5-dichlorobenzoyl chloride
|
2905-62-6 |
C7H3Cl3O |
详情 | 详情
|
(II) |
24168 |
(3,5-dichlorophenyl)methanol
|
60211-57-6 |
C7H6Cl2O |
详情 | 详情
|
(III) |
49482 |
tert-butyl(dimethyl)silyl 3,5-dichlorobenzyl ether; tert-butyl[(3,5-dichlorobenzyl)oxy]dimethylsilane
|
|
C13H20Cl2OSi |
详情 |
详情
|
(IV) |
10295 |
p-Chlorobenzoyl chloride; 4-Chlorobenzoyl chloride
|
122-01-0 |
C7H4Cl2O |
详情 | 详情
|
(V) |
49484 |
[4-([[tert-butyl(dimethyl)silyl]oxy]methyl)-2,6-dichlorophenyl](4-chlorophenyl)methanone
|
|
C20H23Cl3O2Si |
详情 |
详情
|
(VI) |
49485 |
(4-chlorophenyl)[2,6-dichloro-4-(hydroxymethyl)phenyl]methanone
|
|
C14H9Cl3O2 |
详情 |
详情
|
(VII) |
49486 |
(4-chlorophenyl)[2,6-dichloro-4-(chloromethyl)phenyl]methanone
|
|
C14H8Cl4O |
详情 |
详情
|
(VIII) |
49487 |
[4-(azidomethyl)-2,6-dichlorophenyl](4-chlorophenyl)methanone
|
|
C14H8Cl3N3O |
详情 |
详情
|
(IX) |
12122 |
Cyanoacetamide; 2-Cyanoacetamide
|
107-91-5 |
C3H4N2O |
详情 | 详情
|
合成路线4
该中间体在本合成路线中的序号:
(IX) Alternatively, the target compound can be obtained as follows: Condensation between 2,6-dichloro-4-methylbenzonitrile (X) and 4-chloroiodobenzene (XI) by means of Mg in refluxing ether gives methyleneimine derivative (XII), which is then converted into 4-(4-chlorobenzoyl)-3,5-dichlorotoluene (XIII) by refluxing in dioxane-aqueous phosphate buffer. (Alternatively, compound (XIII) can also be obtained either by condensation of 3,5-dichlorotoluene (XIV) with p-chlorobenzoyl chloride (IV) by means of BuLi in THF or by treatment of 2,6-dichloro-4-methylbenzoic acid (XV) with thionyl chloride (SOCl2) in refluxing DMF to give (XVI), which then reacts with chlorobenzene (XVII) by means of AlCl3 in refluxing CCl4). Bromination of (XIII) is then performed by reaction with N-bromosuccinimide and dibenzoyl peroxide in refluxing benzene to give 4-(4-chlorobenzoyl)-3,5-dichlorobenzyl bromide (XVIII). (Alternatively, (XVIII) can also be synthesized by treatment of the already reported benzophenone derivative (V) with HOAc in THF/H2O followed by reaction with phosphorus tribromide in diethyl ether.) Finally, (XVIII) is converted into the desired compound either by treatment with 5-amino-1,2,3-triazole-4-carboxamide (XIX) by means of NaH in refluxing EtOH or by first reaction of (XVIII) with KN3 in refluxing EtOH to furnish benzyl azide (VIII), followed by reaction with cyanoacetamide (IX) and NaOMe in refluxing EtOH.
![](http://zy.yaozh.com/wmf/sch/11/11326502a.jpg)
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
(IV) |
10295 |
p-Chlorobenzoyl chloride; 4-Chlorobenzoyl chloride
|
122-01-0 |
C7H4Cl2O |
详情 | 详情
|
(V) |
49484 |
[4-([[tert-butyl(dimethyl)silyl]oxy]methyl)-2,6-dichlorophenyl](4-chlorophenyl)methanone
|
|
C20H23Cl3O2Si |
详情 |
详情
|
(VIII) |
49487 |
[4-(azidomethyl)-2,6-dichlorophenyl](4-chlorophenyl)methanone
|
|
C14H8Cl3N3O |
详情 |
详情
|
(IX) |
12122 |
Cyanoacetamide; 2-Cyanoacetamide
|
107-91-5 |
C3H4N2O |
详情 | 详情
|
(X) |
49488 |
2,6-dichloro-4-methylbenzonitrile
|
|
C8H5Cl2N |
详情 |
详情
|
(XI) |
19395 |
1-chloro-4-iodobenzene
|
637-87-6 |
C6H4ClI |
详情 | 详情
|
(XII) |
49489 |
(4-chlorophenyl)(2,6-dichloro-4-methylphenyl)methanimine
|
|
C14H10Cl3N |
详情 |
详情
|
(XIII) |
49490 |
(4-chlorophenyl)(2,6-dichloro-4-methylphenyl)methanone
|
|
C14H9Cl3O |
详情 |
详情
|
(XIV) |
49491 |
1,3-dichloro-5-methylbenzene
|
|
C7H6Cl2 |
详情 |
详情
|
(XV) |
49492 |
2,6-dichloro-4-methylbenzoic acid
|
|
C8H6Cl2O2 |
详情 |
详情
|
(XVI) |
49493 |
2,6-dichloro-4-methylbenzoyl chloride
|
|
C8H5Cl3O |
详情 |
详情
|
(XVII) |
10190 |
1-Chlorobenzene
|
108-90-7 |
C6H5Cl |
详情 | 详情
|
(XVIII) |
49494 |
[4-(bromomethyl)-2,6-dichlorophenyl](4-chlorophenyl)methanone
|
|
C14H8BrCl3O |
详情 |
详情
|
(XIX) |
49495 |
5-amino-1H-1,2,3-triazole-4-carboxamide
|
|
C3H5N5O |
详情 |
详情
|
合成路线5
该中间体在本合成路线中的序号:
(IX) The demethylation of 1-(4-methoxyphenyl)acetone (I) by means of AlCl3 gives the corresponding 4-hydroxy compound (III), which is condensed with epichlorohydrin (III), yielding the expected oxiranylmethyl ether (IV). The addition of 1-(2-methoxyphenyl)piperazine (V) to the epoxide ring of (IV) affords the isopropyl alcohol derivative (VI), which is condensed with dimethylformamide dimethylacetal (VII) to afford the dimethylaminobutenone (VIII). Finally, this compound is cyclized with 2-cyanoacetamide (IX) by means of sodium ethoxide, providing the target pyridone.
![](http://zy.yaozh.com/wmf/sch/11/11723101a.jpg)
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
(I) |
10038 |
4-Methoxyphenylacetone; 1-(4-Methoxyphenyl)acetone
|
122-84-9 |
C10H12O2 |
详情 | 详情
|
(II) |
43654 |
1-(4-hydroxyphenyl)acetone
|
|
C9H10O2 |
详情 |
详情
|
(III) |
10146 |
Epichlorohydrin; 2-(Chloromethyl)oxirane
|
106-89-8 |
C3H5ClO |
详情 | 详情
|
(IV) |
43655 |
1-[4-(2-oxiranylmethoxy)phenyl]acetone
|
|
C12H14O3 |
详情 |
详情
|
(V) |
11882 |
1-(2-Methoxyphenyl)piperazine; Methyl 2-piperazinophenyl ether; 1-(2-Methoxyphenyl)-piperazine
|
35386-24-4 |
C11H16N2O |
详情 | 详情
|
(VI) |
43656 |
1-(4-[2-hydroxy-3-[4-(2-methoxyphenyl)-1-piperazinyl]propoxy]phenyl)acetone
|
|
C23H30N2O4 |
详情 |
详情
|
(VII) |
11984 |
N-(Dimethoxymethyl)-N,N-dimethylamine;dimethylformamide dimethylacetal;1,1-dimethoxy-N,N-dimethylmethanamine; Dimethoxy-N,N-dimethylmethanamine; N,N-Dimethylformamide dimethyl acetal |
4637-24-5 |
C5H13NO2 |
详情 | 详情
|
(VIII) |
43657 |
(Z)-4-(dimethylamino)-3-(4-[2-hydroxy-3-[4-(2-methoxyphenyl)-1-piperazinyl]propoxy]phenyl)-3-buten-2-one
|
|
C26H35N3O4 |
详情 |
详情
|
(IX) |
12122 |
Cyanoacetamide; 2-Cyanoacetamide
|
107-91-5 |
C3H4N2O |
详情 | 详情
|
合成路线6
该中间体在本合成路线中的序号:
(IX) This compound can be prepared by several different ways:
1) The reaction ot 4-(chloromethyl)pyridine (I) with NaCN in toluene - water gives 4-(cyanomethyl)pyridine (II), which is condensed with methyl acrylate (III) yielding dimethyl 4-cyano 4-(4-pyridyl)pimelate (IV). The hydrolysis and decarboxylation of (IV) atfords 4-(4-pyridyl)pimelic acid (V), which is cyclized by means of potassium tert-butoxide giving 4-(4-pyridyl)cyclohexanone (VI). The acetylation of (VI) with acetic anhydride or acetylimidazole affords 2-acetyl(4-4 pyridyl)cyclohexanone (VII), which is finally cyclized with acetylacetamide (VIII) by means of dimethylamine.
2) The cyclization of (VII) with cyanoacetamide (IX) by means of piperidine gives 4-cyano-1-methyl-7-(4-pyridyl)-5,6,7,8-tetrahydro-3(2H)-isoquinolinone (X), which is finally treated with methyl magnesium iodide in ether.
3) The condensation of 4 bromopyridine (XI) and cyclohexanedione monoethyleneketal (XII) by means of butyllithium in THF gives 4-hydroxy-4-(4-pyridyil)cyclohexanone ethyleneketal (XIII), which is dehydrated by treatment with SOCl2 and then with NaOH to afford 4-(4-pyridyl)-3-cyclohexenone ethyleneketal (XIV). Finally, this compound is hydrolyzed with HCl and reduced with H2 over Pd/C in 0.5 N HCl yielding cyclohexanone (VII), already obtained.
![](http://zy.yaozh.com/wmf/sch/13/13108401a.jpg)
【1】
Hirayama, M.; Ito, T.; Kitano, T.; Maruyama, M.; Otsuka, K.; Sannohe, K. (Mitsui Chemicals, Inc.); Isoquinoline derivs.. EP 0207500; US 4639521 .
|
【2】
Fukazawa, N.; Kaiho, T.; Yamashita, H. (Mitsui Chemicals, Inc.); Process for preparing 4-acetyl isoquinolinone cpds. JP 1987187467; US 4814458 .
|
【3】
Prous, J.; Castaner, J.; MS-857. Drugs Fut 1988, 13, 9, 831.
|
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
|
10158 |
Piperidine
|
110-89-4 |
C5H11N |
详情 | 详情
|
(I) |
10844 |
4-(Chloromethyl)pyridine
|
10445-91-7 |
C6H6ClN |
详情 | 详情
|
(II) |
23556 |
2-(4-pyridinyl)acetonitrile
|
|
C7H6N2 |
详情 |
详情
|
(III) |
14156 |
methyl acrylate
|
96-33-3 |
C4H6O2 |
详情 | 详情
|
(IV) |
23558 |
dimethyl 4-cyano-4-(4-pyridinyl)heptanedioate
|
|
C15H18N2O4 |
详情 |
详情
|
(V) |
23559 |
4-(4-pyridinyl)heptanedioic acid
|
|
C12H15NO4 |
详情 |
详情
|
(VI) |
23560 |
4-(4-pyridinyl)cyclohexanone
|
|
C11H13NO |
详情 |
详情
|
(VII) |
23561 |
2-acetyl-4-(4-pyridinyl)cyclohexanone
|
|
C13H15NO2 |
详情 |
详情
|
(VIII) |
23562 |
3-oxobutanamide
|
5977-14-0 |
C4H7NO2 |
详情 | 详情
|
(IX) |
12122 |
Cyanoacetamide; 2-Cyanoacetamide
|
107-91-5 |
C3H4N2O |
详情 | 详情
|
(X) |
23564 |
1-methyl-3-oxo-7-(4-pyridinyl)-2,3,5,6,7,8-hexahydro-4-isoquinolinecarbonitrile
|
|
C16H15N3O |
详情 |
详情
|
(XI) |
23565 |
4-bromopyridine
|
1120-87-2 |
C5H4BrN |
详情 | 详情
|
(XII) |
11377 |
1,4-Dioxaspiro[4.5]decan-8-one
|
4746-97-8 |
C8H12O3 |
详情 | 详情
|
(XIII) |
23567 |
8-(4-pyridinyl)-1,4-dioxaspiro[4.5]decan-8-ol
|
|
C13H17NO3 |
详情 |
详情
|
(XIV) |
23568 |
4-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)pyridine
|
|
C13H15NO2 |
详情 |
详情
|
合成路线7
该中间体在本合成路线中的序号:
(X) Three related new synthetic routes for E-1020 have been reported:
1) The cyclization of 2-bromoacetaldehyde diethylacetal (I) with 2-aminopyridine-5-carboxylic acid methyl ester (II) by means of HCl in hot water gives imidazo[1,2-a]pyridine-6-carboxylic acid methyl ester (III), which is reduced with dibutylaluminum hydride in dichloromethane to the corresponding aldehyde (IV). The condensation of (IV) with nitroethane (V) by means of butylamine in refluxing ethanol affords 6-(2-nitro-1-propenyl)imidazo[1,2-a]pyridine (VI), which is treated with Fe-FeCl2-HCl in hot ethanol-water to give 1-(imidazo[1,2-a]pyridyl-6-yl)-2-propanone (VII). The condensation of (VII) with dimethylformamide dimethylacetal (VIII) in hot DMF yields 4-(dimethylamino)-3-(imidazo[1,2-a]pyridin-6-yl)-3-buten-2-one (IX), which is finally cyclized with cyanacetamide (X) by means of sodium methoxide in hot DMF.
2) The cyclization of acetal (I) with 2-amino-5-bromopyridine (XI) as before gives 6-bromoimidazo[1,2-a]pyridine (XII), which is condensed with potassium acetylacetonate (XIII) by means of KI and Cu2I2 in hot DMF yielding the adduct (XIV). The cleavage of (XIV) with NaOH and then with HCl gives the propanone (VII), already obtained.
3) The condensation of the bromo derivative (XII) with 3-chloro-2-methylpropene (XV) by means of ethylmagnesium bromide in hot THF gives 6-isobutenylimidazo[1,2-a]pyridine (XVI), which is ozonolyzed with O3 in methanol-water-HCl to yield the propanone (VII), already obtained.
![](http://zy.yaozh.com/wmf/sch/13/13581301a.jpg)
【1】
Yamanaka, M.; Miyake, K.; Suda, S.; Ohhara, H.; Ogawa, T.; Imidazo[1,2-a]pyridines. I. Synthesis and inotropic activity of new 5-imidazo[1,2-a]pyridinyl-2(1H)-pyridinone derivatives. Chem Pharm Bull 1991, 39, 6, 1556-67.
|
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) |
12113 |
2-Bromo-1-ethoxyethyl ethyl ether; 2-Bromo-1,1-diethoxyethane; Bromoacetaldehyde diethylacetal
|
2032-35-1 |
C6H13BrO2 |
详情 | 详情
|
(II) |
12114 |
methyl 6-aminonicotinate
|
|
C7H8N2O2 |
详情 |
详情
|
(III) |
12115 |
methyl imidazo[1,2-a]pyridine-6-carboxylate
|
|
C9H8N2O2 |
详情 |
详情
|
(IV) |
12116 |
Imidazo[1,2-a]pyridine-6-carbaldehyde
|
|
C8H6N2O |
详情 |
详情
|
(V) |
12117 |
Nitroethane; 1-Nitroethane
|
79-24-3 |
C2H5NO2 |
详情 | 详情
|
(VI) |
12118 |
6-[(E)-2-Nitro-1-propenyl]imidazo[1,2-a]pyridine
|
|
C10H9N3O2 |
详情 |
详情
|
(VII) |
12119 |
1-Imidazo[1,2-a]pyridin-6-ylacetone
|
|
C10H10N2O |
详情 |
详情
|
(VIII) |
11984 |
N-(Dimethoxymethyl)-N,N-dimethylamine;dimethylformamide dimethylacetal;1,1-dimethoxy-N,N-dimethylmethanamine; Dimethoxy-N,N-dimethylmethanamine; N,N-Dimethylformamide dimethyl acetal |
4637-24-5 |
C5H13NO2 |
详情 | 详情
|
(IX) |
12121 |
(Z)-4-(Dimethylamino)-3-imidazo[1,2-a]pyridin-6-yl-3-buten-2-one
|
|
C13H15N3O |
详情 |
详情
|
(X) |
12122 |
Cyanoacetamide; 2-Cyanoacetamide
|
107-91-5 |
C3H4N2O |
详情 | 详情
|
(XI) |
12123 |
5-Bromo-2-pyridinylamine; 5-Bromo-2-pyridinamine; 2-Amino-5-bromopyridine
|
1072-97-5 |
C5H5BrN2 |
详情 | 详情
|
(XII) |
12124 |
6-Bromoimidazo[1,2-a]pyridine
|
6188-23-4 |
C7H5BrN2 |
详情 | 详情
|
(XIII) |
12125 |
[2-Methoxy-1-(methoxycarbonyl)-2-oxoethyl]potassium
|
|
C5H7KO4 |
详情 |
详情
|
(XIV) |
12126 |
3-Imidazo[1,2-a]pyridin-6-yl-2,4-pentanedione
|
|
C12H12N2O2 |
详情 |
详情
|
(XV) |
12127 |
3-Chloro-2-methyl-1-propene; Isobutenyl chloride
|
563-47-3 |
C4H7Cl |
详情 | 详情
|
(XVI) |
12128 |
6-(2-Methyl-2-propenyl)imidazo[1,2-a]pyridine
|
|
C11H12N2 |
详情 |
详情
|
合成路线8
该中间体在本合成路线中的序号:
(VII) 1) The condensation of 6-bromoimidazo[1,2-a]-pyridine (I) with 2-(chloromethyl)propene (II) by means of Mg and ethyl bromide in THF gives 6-(2-methyl-2-propenyl)imidazo[1,2-a]pyridine (III), which is ozonolyzed with O3 yielding 1-(imidazo[1,2-a]-pyridin-6-yl)-2-propanone (IV). The condensation of (IV) with dimethylformamide dimethylketal (V) in hot DMF affords 4-(dimethylamino)-3-(imidazo[1,2-a]-pyridin-6-yl)-3-buten-2-one (IV), which is finally cyclized with 2-cyanoacetamide (VII) by means of sodium methoxide in hot DMF.
![](http://zy.yaozh.com/wmf/sch/13/13581302a.jpg)
【1】
Miyake, K.; Ohhara, H.; Suda, S.; Toshiaki, O.; Yamanaka, M. (Eisai Co., Ltd.); 5-(6-Imidazo[1,2-a]pyridyl)pyridine derivs.. EP 0199127; ES 8706146; ES 8708230; ES 8708231; ES 8801654; ES 8801655; JP 1986218589; US 4751227 .
|
【2】
Prous, J.; Castaner, J.; E-1020. Drugs Fut 1988, 13, 6, 514.
|
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) |
12124 |
6-Bromoimidazo[1,2-a]pyridine
|
6188-23-4 |
C7H5BrN2 |
详情 | 详情
|
(II) |
12127 |
3-Chloro-2-methyl-1-propene; Isobutenyl chloride
|
563-47-3 |
C4H7Cl |
详情 | 详情
|
(III) |
12128 |
6-(2-Methyl-2-propenyl)imidazo[1,2-a]pyridine
|
|
C11H12N2 |
详情 |
详情
|
(IV) |
12119 |
1-Imidazo[1,2-a]pyridin-6-ylacetone
|
|
C10H10N2O |
详情 |
详情
|
(V) |
11984 |
N-(Dimethoxymethyl)-N,N-dimethylamine;dimethylformamide dimethylacetal;1,1-dimethoxy-N,N-dimethylmethanamine; Dimethoxy-N,N-dimethylmethanamine; N,N-Dimethylformamide dimethyl acetal |
4637-24-5 |
C5H13NO2 |
详情 | 详情
|
(VI) |
12121 |
(Z)-4-(Dimethylamino)-3-imidazo[1,2-a]pyridin-6-yl-3-buten-2-one
|
|
C13H15N3O |
详情 |
详情
|
(VII) |
12122 |
Cyanoacetamide; 2-Cyanoacetamide
|
107-91-5 |
C3H4N2O |
详情 | 详情
|
合成路线9
该中间体在本合成路线中的序号:
(VII) 2) The condensation of imidazo[1,2-a]pyridine-6-carboxaldehyde (VIII) with nitroethane (IX) by means of butylamine in refluxing ethanol gives 6-(2-nitro-1-propenyl)imidazo[1,2-a]pyridine (X), which is treated with FeCl2 and concentrated HCl in refluxing ethanol to afford propanone (IV), already obtained.
![](http://zy.yaozh.com/wmf/sch/13/13581303a.jpg)
【1】
Miyake, K.; Ohhara, H.; Suda, S.; Toshiaki, O.; Yamanaka, M. (Eisai Co., Ltd.); 5-(6-Imidazo[1,2-a]pyridyl)pyridine derivs.. EP 0199127; ES 8706146; ES 8708230; ES 8708231; ES 8801654; ES 8801655; JP 1986218589; US 4751227 .
|
【2】
Prous, J.; Castaner, J.; E-1020. Drugs Fut 1988, 13, 6, 514.
|
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) |
12119 |
1-Imidazo[1,2-a]pyridin-6-ylacetone
|
|
C10H10N2O |
详情 |
详情
|
(V) |
11984 |
N-(Dimethoxymethyl)-N,N-dimethylamine;dimethylformamide dimethylacetal;1,1-dimethoxy-N,N-dimethylmethanamine; Dimethoxy-N,N-dimethylmethanamine; N,N-Dimethylformamide dimethyl acetal |
4637-24-5 |
C5H13NO2 |
详情 | 详情
|
(VI) |
12121 |
(Z)-4-(Dimethylamino)-3-imidazo[1,2-a]pyridin-6-yl-3-buten-2-one
|
|
C13H15N3O |
详情 |
详情
|
(VII) |
12122 |
Cyanoacetamide; 2-Cyanoacetamide
|
107-91-5 |
C3H4N2O |
详情 | 详情
|
(VIII) |
12116 |
Imidazo[1,2-a]pyridine-6-carbaldehyde
|
|
C8H6N2O |
详情 |
详情
|
(IX) |
12117 |
Nitroethane; 1-Nitroethane
|
79-24-3 |
C2H5NO2 |
详情 | 详情
|
(X) |
12118 |
6-[(E)-2-Nitro-1-propenyl]imidazo[1,2-a]pyridine
|
|
C10H9N3O2 |
详情 |
详情
|
合成路线10
该中间体在本合成路线中的序号:
(II) Treatment of ethyl cyanoacetate derivative (I) with cyanoacetamide (II) in EtOH in the presence of NaOEt provides dicyano derivative (III), which is then converted into diimide (IV) by treatment with refluxing sulfuric acid. Alternatively, (IV) can also be obtained by reaction between cyclopentanone (V), cyanoacetamide (II) and piperidine by means of KOH or NaOH in H2O (or H2O/EtOH) to provide mononitrile derivative (VI), which is then refluxed with H2SO4. Double N-alkylation of compound (IV) with chloride (VII) by heating with NaH or alkaline carbonate in DMF yields dialkylated compound (VIII), which is reduced with LiAlH4 or Red-Al in refluxing THF/toluene to furnish the free base (IX). Finally, (IX) is converted into the desired dihydrochloride by treatment with HCl in isopropanol.
![](http://zy.yaozh.com/wmf/sch/14/14472201a.jpg)
【1】
McElvain, S.M.; Clemens, D.H.; Piperidine derivatives. XXX. 1,4-Dialkyl-4-arylpiperidines. J Am Chem Soc 1958, 80, 3915.
|
【2】
Thole, F.B.; Thorpe, J.F.; The formation and reactions of imino-compounds. Part XV. The production of imino-derivatives of piperidine leading to the formation of the betabeta-disubstituted glutaric acids. J Chem Soc 1911, 99, 422.
|
【3】
Schon, U.; et al.; Synthesis, pharmacological characterization, and quantitative structure-activity relationship analyses of 3,7,9,9-tetraalkylbispidines: Derivatives with specific bradycardic activity. J Med Chem 1998, 41, 3, 318.
|
【4】
Shon, U.; Hachmeister, B.; Kehrbach, W.; Kuhl, U.; Buschmann, G. (Kali-Chemie AG); New 3,7-diazabicylo[3.3.1]nonanes. DE 3234697; EP 0103833; JP 1993247039 .
|
【5】
Schon, U.; Heitmann, W.; Matzel, U. (Kali-Chemie AG); Medicament containing crystalline fumaric acid salts or 9,9-alkylen-3-7-diazabicyclononane cpds.. DE 4139763; EP 0550383; JP 1993247040 .
|
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) |
43191 |
ethyl 2-cyano-2-cyclopentylideneacetate
|
5407-83-0 |
C10H13NO2 |
详情 | 详情
|
(II) |
12122 |
Cyanoacetamide; 2-Cyanoacetamide
|
107-91-5 |
C3H4N2O |
详情 | 详情
|
(III) |
49455 |
7,9-Dioxo-8-azaspiro[4.5]decane-6,10-dicarbonitrile
|
|
C11H11N3O2 |
详情 |
详情
|
(IV) |
49456 |
|
|
C11H12N2O4 |
详情 |
详情
|
(V) |
15113 |
cyclopentanone
|
120-92-3 |
C5H8O |
详情 | 详情
|
(VI) |
49457 |
10-cyano-7-imino-9-oxo-8-azaspiro[4.5]decane-6-carboxamide
|
|
C11H14N4O2 |
详情 |
详情
|
(VII) |
29776 |
1-(chloromethyl)cyclopropane
|
5911-08-0 |
C4H7Cl |
详情 | 详情
|
(VIII) |
49458 |
|
|
C19H24N2O4 |
详情 |
详情
|
(IX) |
49459 |
|
|
C19H32N2 |
详情 |
详情
|
合成路线11
该中间体在本合成路线中的序号:
(I) 9-Amino-20(RS)-camptothecin is obtained as follows:
The cyclization of cyanoacetamide (I) with 2-ethoxy-4-oxo-2-pentenoic acid ethyl ester (II) by means of K2CO3 in hot DMF gives the intermediate pyridone (III), which without isolation is cyclized again with methyl acrylate (IV) in the same conditions affording the indolizinone (V). The treatment of (V) with concentrated HCl in refluxing acetic acid gives the indolizinedione (VI), which is treated with ethylene glycol and trimethylsilyl chloride in dichloromethane to yield the ethylene ketal (VII). The carboxylation of (VII) with diethyl carbonate and KH in refluxing toluene affords the acetic ester derivative (VIII), which is alkylated with ethyl iodide and potassium tert-butoxide in anhydrous DME to the corresponding butyric ester derivative (IX). The reductive acetylation of (IX) with H2 over RaNi in acetic anhydride gives the acetamide derivative (X), which is treated with NaNO2 in acetic acid to yield the corresponding N-nitroso compound (XI). Thermal degradation of (XI) in refluxing CCl4 affords the acetoxymethyl compound (XII), which is submitted to a oxidative cyclization with O2 in methanol/K2CO3 to give the tetracyclic ketal (XIII). Hydrolysis of the ketal group of (XIII) with 2N H2SO4 in hot DME yields the tricyclic triketone (XIV), which is further cyclized with 2-amino-6-nitrobenzaldehyde (XV) by heating at 160 C to afford 9-nitro-20(RS)-camptothecin (XVI). Finally, this compound is hydrogenated with H2 over Pd/C in ethanol.
The title product can also be obtained by direct cyclization of tricyclic triketone (XIV) with 2,6-diaminobenzaldehyde (XVII) in the same conditions.
![](http://zy.yaozh.com/wmf/sch/18/18476402a.jpg)
【1】
Sinai, B.K.; Palmer, K.H.; McPhail, A.T.; Sim, G.A.; Topoisomerase inhibitors. A review of their therapeutic potential in cancer. Drugs 1995, 49, 11-19.
|
【2】
Wall, M.E.; Wani, M. (Research Triangle Institute); Camptothecin analogs as potent inhibitors of colorectal cancer. EP 0497910; JP 1993508619; US 5106742; WO 9105556 .
|
【3】
Wall, M.E.; Wani, M.C.; Nicholas, A.W.; Manikumar, G. (Research Triangle Institute); Synthesis of camptothecin and analogs thereof. WO 9003169 .
|
【4】
Wall, M.E.; Wani, M.C.; Nicholas, A.W.; Manikumar, G. (Res. Triangle Inst.); Camptothecin and analogues thereof and pharmaceutical compsns and method using them. US 5122526 .
|
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) |
12122 |
Cyanoacetamide; 2-Cyanoacetamide
|
107-91-5 |
C3H4N2O |
详情 | 详情
|
(II) |
15636 |
ethyl (Z)-2-ethoxy-4-oxo-2-pentenoate
|
|
C9H14O4 |
详情 |
详情
|
(III) |
15637 |
ethyl 5-cyano-4-methyl-6-oxo-1,6-dihydro-2-pyridinecarboxylate
|
|
C10H10N2O3 |
详情 |
详情
|
(IV) |
14156 |
methyl acrylate
|
96-33-3 |
C4H6O2 |
详情 | 详情
|
(V) |
15639 |
methyl 6-cyano-1-hydroxy-7-methyl-5-oxo-3,5-dihydro-2-indolizinecarboxylate
|
|
C12H10N2O4 |
详情 |
详情
|
(VI) |
15640 |
7-methyl-1,5-dioxo-1,2,3,5-tetrahydro-6-indolizinecarbonitrile
|
|
C10H8N2O2 |
详情 |
详情
|
(VII) |
15641 |
7'-Methyl-5'-oxo-1',2',3',5'-tetrahydrospiro[1,3-dixolane-2,1'-indolizin]-6'-ylcarbonitrile
|
|
C12H12N2O3 |
详情 |
详情
|
(VIII) |
15642 |
2-[6'-Cyano-5'-oxo-1',2',3',5'-tetrahydrospiro[1,3-dixolane-2,1'-indolizin]-7'-yl]acetic acid ethyl ester
|
|
C15H16N2O5 |
详情 |
详情
|
(IX) |
15643 |
2-[6'-Cyano-5'-oxo-1',2',3',5'-tetrahydrospiro[1,3-dixolane-2,1'-indolizin]-7'-yl]butyric acid ethyl ester
|
|
C17H20N2O5 |
详情 |
详情
|
(X) |
15644 |
2-[6'-(Acetamidomethyl)-5'-oxo-1',2',3',5'-tetrahydrospiro[1,3-dixolane-2,1'-indolizin]-7'-yl]butyric acid ethyl ester
|
|
C19H26N2O6 |
详情 |
详情
|
(XI) |
15645 |
2-[6'-(N-Nitrosoacetamidomethyl)-5'-oxo-1',2',3',5'-tetrahydrospiro[1,3-dixolane-2,1'-indolizin]-7'-yl]butyric acid ethyl ester
|
|
C19H25N3O7 |
详情 |
详情
|
(XII) |
15646 |
2-[6'-(Acetoxymethyl)-5'-oxo-1',2',3',5'-tetrahydrospiro[1,3-dixolane-2,1'-indolizin]-7'-yl]butyric acid ethyl ester
|
|
C19H25NO7 |
详情 |
详情
|
(XIII) |
15647 |
4'-Ethyl-4'-hydroxy-3',4',6',7',8',10'-hexahydro-1'H-spiro[1,3-dioxole-2,6'-pyrano[3,4-f]indolizine]-3',10'-dione
|
|
C15H17NO6 |
详情 |
详情
|
(XIV) |
63309 |
(?-beta-methoxydiisopinocamphenylborane
|
85134-98-1 |
C13H13NO5 |
详情 | 详情
|
(XV) |
15649 |
2-amino-6-nitrobenzaldehyde
|
|
C7H6N2O3 |
详情 |
详情
|
(XVI) |
15650 |
4-ethyl-4-hydroxy-10-nitro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione
|
|
C20H15N3O6 |
详情 |
详情
|
(XVII) |
15651 |
2,6-diaminobenzaldehyde
|
|
C7H8N2O |
详情 |
详情
|
合成路线12
该中间体在本合成路线中的序号:
(XXXIII) 5) The condensation of 3-methylbutanal (XIX) with cyanoacetic acid ethyl ester (XXXII) or cyanoacetamide (XXXIII) by means of dipropylamine in refluxing hexane, followed by treatment with refluxing 6N HCl, gives 3-isobutylglutaric acid (XXXIV). This compound is converted into the corresponding anhydride (XXXV) by treatment with refluxing acetic anhydride. The reaction of the anhydride (XXXV) with NH4OH affords the glutaramic amide (XXXVI), which is submitted to optical resolution with (R)-(+)-1-phenylethylamine, yielding the (S)-enantiomer (XXXVII). Finally, this compound is submitted to a Hoffmann degradation with Br2/NaOH.
![](http://zy.yaozh.com/wmf/sch/19/19464405a.jpg)
【1】
Newhouse, B.J.; Ibrahim, P.; Burgess, L.E.; et al.; Potent selective nonpeptidic inhibitors of human lung tryptase. Proc Natl Acad Sci USA 1999, 96, 15, 8348.
|
【2】
Sobieray, D.M.; Hoekstra, M.S.; Schwindt, M.A.; et al.; Chemical development of CI-1008, an enantiomerically pure anticonvulsant. Org Process Res Dev 1997, 1, 1, 26.
|
【3】
Huckabee, B.K.; Sobieray, D.M. (Pfizer Inc.); Methods of making (S)-3-(aminomethyl)-5-methylhexanoic acid. WO 9638405 .
|
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
(XIX) |
26052 |
3-methylbutanal
|
590-86-3 |
C5H10O |
详情 | 详情
|
(XXXII) |
11877 |
Cyanoacetic acid ethyl ester; Ethyl 2-cyanoacetate; Ethyl cyanoacetate; Ethyl isocyanacetate
|
105-56-6 |
C5H7NO2 |
详情 | 详情
|
(XXXIII) |
12122 |
Cyanoacetamide; 2-Cyanoacetamide
|
107-91-5 |
C3H4N2O |
详情 | 详情
|
(XXXIV) |
26065 |
3-isobutylpentanedioic acid
|
|
C9H16O4 |
详情 |
详情
|
(XXXV) |
26066 |
4-isobutyldihydro-2H-pyran-2,6(3H)-dione
|
|
C9H14O3 |
详情 |
详情
|
(XXXVI) |
26067 |
3-(2-amino-2-oxoethyl)-5-methylhexanoic acid
|
|
C9H17NO3 |
详情 |
详情
|
(XXXVII) |
26068 |
(3R)-3-(2-amino-2-oxoethyl)-5-methylhexanoic acid
|
|
C9H17NO3 |
详情 |
详情
|
合成路线13
该中间体在本合成路线中的序号:
(II) The partial hydrolysis of malonodinitrile (I) with HCl in ethanol gives 2-cyanoacetamide (II), which is treated with ammonia in ethanol to yield 3,3-diaminopropenenitrile (III). Finally, this compound is cyclized with 2-bromo-1-(2-fluorophenyl)-1-propanone (IV) by means of TEA in ethanol.
![](http://zy.yaozh.com/wmf/sch/24/24670002a.jpg)
【1】
Tsuda, M.; et al.; Studies on potassium channel openers: Synthesis and pharmacological properties of novel pyrrole derivatives. 20th Symp Med Chem (Dec 6 2000, Tokyo) 2000, Abst 2P-24.
|
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) |
12061 |
Malononitrile
|
109-77-3 |
C3H2N2 |
详情 | 详情
|
(II) |
12122 |
Cyanoacetamide; 2-Cyanoacetamide
|
107-91-5 |
C3H4N2O |
详情 | 详情
|
(III) |
42081 |
3,3-diaminoacrylonitrile
|
|
C3H5N3 |
详情 |
详情
|
(IV) |
42082 |
2-bromo-1-(2-fluorophenyl)-1-propanone
|
|
C9H8BrFO |
详情 |
详情
|
合成路线14
该中间体在本合成路线中的序号:
(IV) The reaction of 3-methoxybenzoylacetone (I) with dimethylformamide dimethylacetal (II) gives the dimethylaminomethylene derivative (III), which is cyclized with 2-cyanoacetamide (IV) by means of sodium ethoxide in ethanol yielding the pyridinone (V). The condensation of (V) with dimethylformamide dimethylacetal (II) affords the dimethylaminovinylpyridinone (VI), which is cyclized by means of ammonium acetate in DMF providing the 1,6-naphthyridine (VII). The hydrolysis of the cyano group of (VII) with NaOH gives the corresponding carboxylic acid (VIII), which is finally cyclized with N-hydroxyacetamidine (IX) by means of carbonydimidazole (CDI).
![](http://zy.yaozh.com/wmf/sch/26/26780601a.jpg)
【1】
Odai, O.; et al.; Synthesis and pharmacological evaluation of novel 3-oxadiazolyl-1,6-naphthyridines as a new class of potential cognitive enhancers. 15th European Federation for Medicinal Chemistry International Symposium on Medicinal Chemistry (Sept 6 1998, Edinburgh) 1998, Abst P.256. |
【2】
Masumoto, K.; et al.; Structure-activity relationships and cognition-enhancing actions of novel 1,6-naphthyridine derivatives with benzodiazepine receptor inverse agonists activities. Symp Med Chem 1998, Abst 2-P-10.
|
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) |
25984 |
1-(3-methoxyphenyl)-1,3-butanedione
|
|
C11H12O3 |
详情 |
详情
|
(II) |
11984 |
N-(Dimethoxymethyl)-N,N-dimethylamine;dimethylformamide dimethylacetal;1,1-dimethoxy-N,N-dimethylmethanamine; Dimethoxy-N,N-dimethylmethanamine; N,N-Dimethylformamide dimethyl acetal |
4637-24-5 |
C5H13NO2 |
详情 | 详情
|
(III) |
25985 |
2-[(E)-(dimethylamino)methylidene]-1-(3-methoxyphenyl)-1,3-butanedione
|
|
C14H17NO3 |
详情 |
详情
|
(IV) |
12122 |
Cyanoacetamide; 2-Cyanoacetamide
|
107-91-5 |
C3H4N2O |
详情 | 详情
|
(V) |
25986 |
5-(3-methoxybenzoyl)-6-methyl-2-oxo-1,2-dihydro-3-pyridinecarbonitrile
|
|
C15H12N2O3 |
详情 |
详情
|
(VI) |
25987 |
6-[(E)-2-(dimethylamino)ethenyl]-5-(3-methoxybenzoyl)-2-oxo-1,2-dihydro-3-pyridinecarbonitrile
|
|
C18H17N3O3 |
详情 |
详情
|
(VII) |
25988 |
5-(3-methoxyphenyl)-2-oxo-1,2-dihydro[1,6]naphthyridine-3-carbonitrile
|
|
C16H11N3O2 |
详情 |
详情
|
(VIII) |
25989 |
5-(3-methoxyphenyl)-2-oxo-1,2-dihydro[1,6]naphthyridine-3-carboxylic acid
|
|
C16H12N2O4 |
详情 |
详情
|
(IX) |
25990 |
N-hydroxyethanimidamide
|
|
C2H6N2O |
详情 |
详情
|
合成路线15
该中间体在本合成路线中的序号:
Knoevenagel condensation of ketone (I) with ethyl cyanoacetate followed by Michael addition of cyanoacetamide to the resulting alpha-cyanocinnamate (IIa-b) yields cyclic imide (III). Hydrolysis and decarboxylation of (III) with H2SO4 gives diacid (IV), which is cyclized by means of hot H2SO4 to provide indanone (V). Treatment of (V) with oxalyl chloride in CH2Cl2 and catalytic DMF followed by addition of EtOH affords ethyl ester (VI), which is then converted into oxime (VII) by means of t-BuONO in Et2O and HCl. Hydrogenolysis of (VII) with H2 over Pd/C in HOAc/HCl provides alpha-amino derivative (VIII). By reacting (VIII) with ethyl oxalyl chloride (A), in CH2Cl2 in presence of Et3N, (IX) was obtained and then cyclized in presence of NH4OAc in refluxing HOAc to yield pyrazino derivative (X). Finally (X) is hydrolyzed with HCl in dioxane.
![](http://zy.yaozh.com/wmf/sch/27/27860701a.jpg)
【1】
Jimonet, P.; Ribeill, Y.; Bohme, A.; et al.; Indeno[1,2-b]pyrazin-2,3-diones: A new class of antagonists at the glycine site of the NMDA receptor with potent in vivo activity. J Med Chem 2000, 43, 12, 2371.
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【2】
Jimonet, P.; Ribeill, Y.; Audiau, F.; Aloup, J.-C.; Barreau, M.; Mignani, S.; Genevois-Borella, A.; Damour, D. (Aventis Pharma SA); 5H-Indeno[1,2-b]pyrazine-2,3-dione derivs., their preparation and medicinal products containing them. US 5922716; WO 9526342 . |
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
|
11877 |
Cyanoacetic acid ethyl ester; Ethyl 2-cyanoacetate; Ethyl cyanoacetate; Ethyl isocyanacetate
|
105-56-6 |
C5H7NO2 |
详情 | 详情
|
|
12122 |
Cyanoacetamide; 2-Cyanoacetamide
|
107-91-5 |
C3H4N2O |
详情 | 详情
|
(A) |
11043 |
Ethyl 2-chloro-2-oxoacetate; Ethyl oxalyl chloride
|
4755-77-5 |
C4H5ClO3 |
详情 | 详情
|
(IIa) |
41464 |
ethyl (Z)-3-(4-chlorophenyl)-2-cyano-2-butenoate
|
|
C13H12ClNO2 |
详情 |
详情
|
(IIb) |
41465 |
ethyl (E)-3-(4-chlorophenyl)-2-cyano-2-butenoate
|
|
C13H12ClNO2 |
详情 |
详情
|
(I) |
12685 |
4-Chloroacetophenone; 1-(4-Chlorophenyl)-1-ethanone; p-Chloroacetophenone
|
99-91-2 |
C8H7ClO |
详情 | 详情
|
(III) |
41466 |
4-(4-chlorophenyl)-4-methyl-2,6-dioxo-3,5-piperidinedicarbonitrile
|
|
C14H10ClN3O2 |
详情 |
详情
|
(IV) |
41467 |
3-(4-chlorophenyl)-3-methylpentanedioic acid
|
|
C12H13ClO4 |
详情 |
详情
|
(V) |
41468 |
2-(5-chloro-1-methyl-3-oxo-2,3-dihydro-1H-inden-1-yl)acetic acid
|
|
C12H11ClO3 |
详情 |
详情
|
(VI) |
41469 |
ethyl 2-(5-chloro-1-methyl-3-oxo-2,3-dihydro-1H-inden-1-yl)acetate
|
|
C14H15ClO3 |
详情 |
详情
|
(VII) |
41470 |
ethyl 2-[5-chloro-2-(hydroxyimino)-1-methyl-3-oxo-1,3-dihydro-2H-inden-1-yl]acetate
|
|
C14H14ClNO4 |
详情 |
详情
|
(VIII) |
41471 |
ethyl 2-(2-amino-5-chloro-1-methyl-3-oxo-2,3-dihydro-1H-inden-1-yl)acetate
|
|
C14H16ClNO3 |
详情 |
详情
|
(IX) |
41472 |
ethyl 2-[[5-chloro-1-(2-ethoxy-2-oxoethyl)-1-methyl-3-oxo-2,3-dihydro-1H-inden-2-yl]amino]-2-oxoacetate
|
|
C18H20ClNO6 |
详情 |
详情
|
(X) |
41473 |
ethyl 2-(6-chloro-9-methyl-2,3-dioxo-2,3,4,9-tetrahydro-1H-indeno[1,2-b]pyrazin-9-yl)acetate
|
|
C16H15ClN2O4 |
详情 |
详情
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合成路线16
该中间体在本合成路线中的序号:
(II) Condensation of 3-methoxysalicylaldehyde (I) with cyanoacetamide (II) in the presence of piperidine gave rise to the carbamoyl iminochromene (III). Subsequent condensation of (III) with 3,4,5-trimethoxybenzaldehyde furnished the title compound.
![](http://zy.yaozh.com/wmf/sch/28/28187501a.jpg)
【1】
Perry, P.J.; McGown, A.T.; Pavlidis, V.H.; Hadfield, J.A.; Synthesis and anticancer activities of 4-oxobenzopyrano[2,3-d]pyrimidines. Anti-Cancer Drugs 1999, 10, 6, 591.
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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) |
12620 |
o-Vanillin; 2-Hydroxy-3-methoxybenzaldehyde
|
148-53-8 |
C8H8O3 |
详情 | 详情
|
(II) |
12122 |
Cyanoacetamide; 2-Cyanoacetamide
|
107-91-5 |
C3H4N2O |
详情 | 详情
|
(III) |
38139 |
2-imino-8-methoxy-2H-chromene-3-carboxamide
|
|
C11H10N2O3 |
详情 |
详情
|
(IV) |
11136 |
3,4,5-Trimethoxybenzaldehyde
|
86-81-7 |
C10H12O4 |
详情 | 详情
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合成路线17
该中间体在本合成路线中的序号:
(XXIV)
![](http://zy.yaozh.com/wmf/sch/26/26758011a.jpg)
【1】
Dorg H, Zhang ZL, Huang JH, et al. 2005. Practical synthesisi of an orally active renin inhibitory aliskiren. Tetrahedron Lett, 46(37): 6337~6340 |
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
(XXV) |
67017 |
2-cyano-2-methylpropanamide |
7505-93-3 |
C5H8N2O |
详情 | 详情
|
(I) |
18455 |
3-hydroxy-4-methoxybenzaldehyde; Isovanillin
|
621-59-0 |
C8H8O3 |
详情 | 详情
|
(II) |
67010 |
3-methoxypropyl methanesulfonate |
|
C5H12O4S |
详情 | 详情
|
(III) |
61620 |
4-Methoxy-3-(3-methoxypropoxy)benzaldehyde
|
172900-75-3 |
C12H16O4 |
详情 | 详情
|
(IV) |
28116 |
[4-methoxy-3-(3-methoxypropoxy)phenyl]methanol
|
172900-74-2 |
C12H18O4 |
详情 | 详情
|
(V) |
28117 |
3-[5-(bromomethyl)-2-methoxyphenoxy]propyl methyl ether
|
172900-73-1 |
C12H17BrO3 |
详情 | 详情
|
(VI) |
28131 |
(4S)-4-benzyl-3-(3-methylbutanoyl)-1,3-oxazolidin-2-one
|
|
C15H19NO3 |
详情 |
详情
|
(VII) |
28118 |
(4S)-4-benzyl-3-[(2R)-2-[4-methoxy-3-(3-methoxypropoxy)benzyl]-3-methylbutanoyl]-1,3-oxazolidin-2-one
|
|
C27H35NO6 |
详情 |
详情
|
(VIII) |
28119 |
(2R)-2-[4-methoxy-3-(3-methoxypropoxy)benzyl]-3-methylbutyric acid
|
|
C17H26O5 |
详情 |
详情
|
(IX) |
50573 |
(2R)-2-[4-methoxy-3-(3-methoxypropoxy)benzyl]-3-methyl-1-butanol
|
|
C17H28O4 |
详情 |
详情
|
(X) |
28120 |
3-[5-[(2R)-2-(bromomethyl)-3-methylbutyl]-2-methoxyphenoxy]propyl methyl ether
|
172900-69-5 |
C17H27BrO3 |
详情 | 详情
|
(XI) |
67009 |
(S)-3,6-diethoxy-2-isopropyl-2,5-dihydropyrazine |
134870-62-5 |
C11H20N2O2 |
详情 | 详情
|
(XII) |
67011 |
3,6-diethoxy-2-isopropyl-5-(2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-3-methylbutyl)-2,5-dihydropyrazine |
|
C28H46N2O5 |
详情 | 详情
|
(XIII) |
67012 |
ethyl 2-amino-4-(4-methoxy-3-(3-methoxypropoxy)benzyl)-5-methylhexanoate |
|
C21H35NO5 |
详情 | 详情
|
(XIV) |
28122 |
methyl (2S,4S)-2-[(tert-butoxycarbonyl)amino]-4-[4-methoxy-3-(3-methoxypropoxy)benzyl]-5-methylhexanoate
|
|
C25H41NO7 |
详情 |
详情
|
(XV) |
67013 |
tert-butyl (1-hydroxy-4-(4-methoxy-3-(3-methoxypropoxy)benzyl)-5-methylhexan-2-yl)carbamate |
|
C24H41NO6 |
详情 | 详情
|
(XVI) |
28123 |
tert-butyl (1S,3S)-1-formyl-3-[4-methoxy-3-(3-methoxypropoxy)benzyl]-4-methylpentylcarbamate
|
|
C24H39NO6 |
详情 |
详情
|
(XVII) |
18710 |
Benzyl alcohol; Phenylmethanol
|
100-51-6 |
C7H8O |
详情 | 详情
|
(XVIII) |
14560 |
Benzyl chloromethyl ether; 1-[(chloromethoxy)methyl]benzene
|
3587-60-8 |
C8H9ClO |
详情 | 详情
|
(XIX) |
23285 |
(4R)-4-benzyl-3-(3-methylbutanoyl)-1,3-oxazolidin-2-one
|
|
C15H19NO3 |
详情 |
详情
|
(XX) |
67014 |
4-benzyl-3-(2-((benzyloxy)methyl)-3-methylbutanoyl)oxazolidin-2-one |
|
C23H27NO4 |
详情 | 详情
|
(XXI) |
67015 |
(R)-2-((benzyloxy)methyl)-3-methylbutanoic acid |
|
C13H18O3 |
详情 | 详情
|
(XXII) |
67016 |
2-((benzyloxy)methyl)-3-methylbutan-1-ol |
|
C13H20O2 |
详情 | 详情
|
(XXIII) |
66991 |
(R)-((2-(bromomethyl)-3-methylbutoxy)methyl)benzene |
|
C13H19BrO |
详情 | 详情
|
(XXIV) |
12122 |
Cyanoacetamide; 2-Cyanoacetamide
|
107-91-5 |
C3H4N2O |
详情 | 详情
|
(XXVI) |
67018 |
benzyl (3-amino-2,2-dimethyl-3-oxopropyl)carbamate |
|
C13H18N2O3 |
详情 | 详情
|
(XXVII) |
28129 |
3-amino-2,2-dimethylpropanamide
|
324763-51-1 |
C5H12N2O |
详情 | 详情
|
(XXVIII) |
28125 |
tert-butyl (1S,4S)-4-[(benzyloxy)methyl]-2-hydroxy-1-[(2S)-2-[4-methoxy-3-(3-methoxypropoxy)benzyl]-3-methylbutyl]-5-methylhexylcarbamate
|
|
C37H59NO7 |
详情 |
详情
|
(XXIX) |
67019 |
tert-butyl (6-hydroxy-8-(hydroxymethyl)-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-2,9-dimethyldecan-5-yl)carbamate |
|
C30H53NO7 |
详情 | 详情
|
(XXX) |
67004 |
tert-butyl (1-(4-isopropyl-5-oxotetrahydrofuran-2-yl)-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-4-methylpentyl)carbamate |
|
C30H49NO7 |
详情 | 详情
|
(XXXI) |
67020 |
tert-butyl (8-((1-amino-2-methyl-1-oxopropan-2-yl)carbamoyl)-6-hydroxy-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-2,9-dimethyldecan-5-yl)carbamate |
|
C34H59N3O8 |
详情 | 详情
|