合成路线1
该中间体在本合成路线中的序号:
An improved procedure for the large-scale preparation of (R)-aminoglutethimide has been reported. Nucleophilic substitution of 1-chloro-4-nitrobenzene (I) with methyl cyanoacetate afforded the (nitrophenyl)cyanoacetate (II), which was alkylated with diethyl sulfate in the presence of Et3N, yielding (III). Hydrolysis and decarboxylation of the cyano ester (III) by means of K2CO3 in aqueous MeOH provided the arylbutyronitrile (IV). Subsequent Michael addition with methyl acrylate gave adduct (V). This was hydrolyzed to the cyano acid (VI), which was further resolved with (-)-cinchonidine, yielding the desired (R)-enantiomer (VII). Acid-catalyzed cyclization of (VII) in boiling toluene generated the glutarimide derivative (VIII). The nitro group of (VIII) was finally reduced to the title amino derivative by hydrogenation over Pd/C.
【1】
Bunegar, M.J.; et al.; Production of (R)-aminogluthimide: A new route from 1-chloro-4-nitrobenzene. Org Process Res Dev 1999, 3, 6, 442.
|
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
|
14156 |
methyl acrylate
|
96-33-3 |
C4H6O2 |
详情 | 详情
|
|
34458 |
Cyanoacetic acid methyl ester; methyl 2-cyanoacetate
|
105-34-0 |
C4H5NO2 |
详情 | 详情
|
(I) |
13909 |
1-Chloro-4-nitrobenzene; p-Nitrochlorobenzene
|
100-00-5 |
C6H4ClNO2 |
详情 | 详情
|
(II) |
34928 |
methyl 2-cyano-2-(4-nitrophenyl)acetate
|
|
C10H8N2O4 |
详情 |
详情
|
(III) |
34929 |
methyl 2-cyano-2-(4-nitrophenyl)butanoate
|
|
C12H12N2O4 |
详情 |
详情
|
(IV) |
34930 |
2-(4-nitrophenyl)butanenitrile
|
|
C10H10N2O2 |
详情 |
详情
|
(V) |
34931 |
methyl 4-cyano-4-(4-nitrophenyl)hexanoate
|
|
C14H16N2O4 |
详情 |
详情
|
(VI) |
34932 |
4-cyano-4-(4-nitrophenyl)hexanoic acid
|
|
C13H14N2O4 |
详情 |
详情
|
(VII) |
34933 |
(4R)-4-cyano-4-(4-nitrophenyl)hexanoic acid
|
|
C13H14N2O4 |
详情 |
详情
|
(VIII) |
34934 |
(3R)-3-ethyl-3-(4-nitrophenyl)-2,6-piperidinedione
|
|
C13H14N2O4 |
详情 |
详情
|
合成路线2
该中间体在本合成路线中的序号:
(II) The condensation of diethylgermanium dihydride (I) with methyl acrylate (II) gives diethyldi-(beta-carbomethoxyethyl)germane (III), which is cyclized by treatment with potassium tert-butoxide in refluxing toluene yielding carbomethoxy-4,4-diethyl-4-germacyclohexanone (IV). The decarboxylative hydrolysis of (IV) with refluxing 20% aqueous H2SO4 affords 4,4-diethyl-4-germacyclohexanone (V), which is condensed with ethyl cyanoacetate (VI) by means of ammonium acetate acetic acid in refluxing benzene giving ethyl alpha-cyano-alpha-(4,4-diethyl-4-germacyclohexylidene)acetate (VII). The treatment of (VII) with KCN in ethanol-water, and then with refluxing aqueous HCl yields 4,4-diethyl-4-germacyclohexane-1-carboxy-1-acetic acid (VIII), which is then converted into its cyclic anhydride (IX) by reaction with refluxing acetic anhydride. The reaction of (IX) with 3-dimethylaminopropylamine (X) at 180 C gives N-(3-dimethylaminopropyl)-2-aza-8,8-diethyl-8-germaspiro[4.5]decane-1,3-dione (XI), which is finally reduced with LiAlH4 in benzene-ether.
【1】
Rice, L.M.; US 3825546 .
|
【2】
Rice, L.M.; et al.; Spirans. XXII. Synthesis of 4,4-dialkyl-4-germacyclohexanone and 8,8-dialkyl-8-germaazaspiro[4,5]decanes. J Heterocycl Chem 1974, 11, 6, 1041-47.
|
【3】
Castaner, J.; Spirogermanium Hydrochloride. Drugs Fut 1980, 5, 3, 149.
|
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) |
39022 |
diethyl-lambda(2)-germane
|
|
C4H12Ge |
详情 |
详情
|
(II) |
14156 |
methyl acrylate
|
96-33-3 |
C4H6O2 |
详情 | 详情
|
(III) |
39023 |
methyl 3-[diethyl(3-methoxy-3-oxopropyl)germyl]propanoate
|
|
C12H24GeO4 |
详情 |
详情
|
(IV) |
39024 |
methyl 1,1-diethyl-4-oxo-3-germinanecarboxylate
|
|
C11H20GeO3 |
详情 |
详情
|
(V) |
39025 |
1,1-diethyl-4-germinanone
|
|
C9H18GeO |
详情 |
详情
|
(VI) |
11877 |
Cyanoacetic acid ethyl ester; Ethyl 2-cyanoacetate; Ethyl cyanoacetate; Ethyl isocyanacetate
|
105-56-6 |
C5H7NO2 |
详情 | 详情
|
(VII) |
39026 |
ethyl 2-cyano-2-(1,1-diethyl-4-germinanylidene)acetate
|
|
C14H23GeNO2 |
详情 |
详情
|
(VIII) |
39027 |
4-(carboxymethyl)-1,1-diethyl-4-germinanecarboxylic acid
|
|
C12H22GeO4 |
详情 |
详情
|
(IX) |
39028 |
8,8-diethyl-2-oxa-8-germaspiro[4.5]decane-1,3-dione
|
|
C12H20GeO3 |
详情 |
详情
|
(X) |
25248 |
N-(3-aminopropyl)-N,N-dimethylamine; N(1),N(1)-dimethyl-1,3-propanediamine
|
109-55-7 |
C5H14N2 |
详情 | 详情
|
(XI) |
39029 |
2-[3-(dimethylamino)propyl]-8,8-diethyl-2-aza-8-germaspiro[4.5]decane-1,3-dione
|
|
C17H32GeN2O2 |
详情 |
详情
|
合成路线3
该中间体在本合成路线中的序号:
(VI) The reaction of 1-methylcyclohexylmethanol (II) with 4-chloronitrobenzene (III) by means of NaH in hot DMSO gives 4-(1-methylcyclohexylmethoxylnitrobenzene (III), which is reduced with H2 over Pd/C in methanol yielding 4-(1-methylcyclohexylmethoxylaniline (IV). Diazotation of (IV) with NaNO2 and HCl in water affords a solution of the corresponding diazonium chloride (V), which is condensed with methyl acrylate (VI) by means of Cu2O affording methyl 2-chloro-3-[4-(1-methylcyclohexylmethoxyl)phenyl]propionate (VII). The cyclization of (VII) with thiourea (VIII) by means of sodium acetate in hot 2-methoxyethanol gives 2-imino-5-[4-(1-methylcyclohexylmethoxy)benzyl]thiazolidin-4-one (IX), which is finally hydrolyzed with HCl in refluxing 2-methoxyethanol - water.
【1】
Kawamatsu, Y.; Mizuno, K.; Sugiyama, Y.; Imamiya, E.; Fujita, T.; Sohda, T.; Studies on antidiabetic agents. II. Synthesis of 5-[4-(1-methylcyclohexylmethoxy)benzyl]thiazolidine-2,4-dione (ADD-3878) and its derivatives. Chem Pharm Bull 1982, 30, 10, 3580. |
【2】
Nohria, V.; Castaner, J.; Serradell, M.N.; Ciglitazone. Drugs Fut 1984, 9, 4, 258.
|
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) |
34173 |
(1-methylcyclohexyl)methanol
|
|
C8H16O |
详情 |
详情
|
(II) |
13909 |
1-Chloro-4-nitrobenzene; p-Nitrochlorobenzene
|
100-00-5 |
C6H4ClNO2 |
详情 | 详情
|
(III) |
34174 |
1-[(1-methylcyclohexyl)methoxy]-4-nitrobenzene; (1-methylcyclohexyl)methyl 4-nitrophenyl ether
|
|
C14H19NO3 |
详情 |
详情
|
(IV) |
34175 |
4-[(1-methylcyclohexyl)methoxy]phenylamine; 4-[(1-methylcyclohexyl)methoxy]aniline
|
|
C14H21NO |
详情 |
详情
|
(V) |
34176 |
4-[(1-methylcyclohexyl)methoxy]benzenediazonium chloride
|
|
C14H19ClN2O |
详情 |
详情
|
(VI) |
14156 |
methyl acrylate
|
96-33-3 |
C4H6O2 |
详情 | 详情
|
(VII) |
34177 |
methyl 2-chloro-3-[4-[(1-methylcyclohexyl)methoxy]phenyl]propanoate
|
|
C18H25ClO3 |
详情 |
详情
|
(VIII) |
10180 |
Thiourea
|
62-56-6 |
CH4N2S |
详情 | 详情
|
(IX) |
34178 |
2-imino-5-[4-[(1-methylcyclohexyl)methoxy]benzyl]-1,3-thiazolidin-4-one
|
|
C18H24N2O2S |
详情 |
详情
|
合成路线4
该中间体在本合成路线中的序号:
(VI) The condensation of 2-methyl-3-(1H-imidazol-1-ylmethyl)indole (III) with acrylonitrile (IV) by means of benzyltrimethylammonium hydroxide (B) in dioxane gives 1-(2-cyanoethyl)-2-methyl-3-(1H-imidazol-1-ylmethyl)indole (V), which is then hydrolyzed with KOH in water. The reaction of compound (III) with methyl acrylate (VI) in the same conditions as before gives 1-(2-methoxy-carbonylethyl)-2-methyl-3-(1H-imidazol-1-ylmethyl)indole (VII), which is also hydrolyzed. Compound (III) can be obtained from 2-methylindole (I).
【1】
Cross, P.E.; Dickinson, R.P.; Randall, M.J.; Parry, M.J.; K-38485, a novel, selective thromboxane synthetase inhibitor with prolonged activity in vivo. N Am Med Chem Symp 1982, 68.
|
【2】
Cross, P.E.; Dickinson, R.P. (Pfizer Inc.); Inhibition of thromboxane synthetase by 3-(1-imidazolylalkyl)indoles. NL 8001351 .
|
【3】
Serradell, M.N.; Castaner, J.; Blancafort, P.; Grau, M.; UK-38485. Drugs Fut 1983, 8, 11, 947.
|
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
(A) |
10255 |
Imidazole; 1H-Imidazole
|
288-32-4 |
C3H4N2 |
详情 | 详情
|
(B) |
36194 |
N,N,N-trimethyl(phenyl)methanaminium
|
4525-46-6 |
C10H16N |
详情 | 详情
|
(I) |
28747 |
2-methyl-1H-indole
|
95-20-5 |
C9H9N |
详情 | 详情
|
(II) |
36192 |
N,N-dimethyl-N-[(2-methyl-1H-indol-3-yl)methyl]amine; N,N-dimethyl(2-methyl-1H-indol-3-yl)methanamine
|
|
C12H16N2 |
详情 |
详情
|
(III) |
36193 |
3-(1H-imidazol-1-ylmethyl)-2-methyl-1H-indole
|
|
C13H13N3 |
详情 |
详情
|
(IV) |
10847 |
Acrylonitrile
|
107-13-1 |
C3H3N |
详情 | 详情
|
(V) |
36195 |
3-[3-(1H-imidazol-1-ylmethyl)-2-methyl-1H-indol-1-yl]propanenitrile
|
|
C16H16N4 |
详情 |
详情
|
(VI) |
14156 |
methyl acrylate
|
96-33-3 |
C4H6O2 |
详情 | 详情
|
(VII) |
36196 |
methyl 3-[3-(1H-imidazol-1-ylmethyl)-2-methyl-1H-indol-1-yl]propanoate
|
|
C17H19N3O2 |
详情 |
详情
|
合成路线5
该中间体在本合成路线中的序号:
(IV) 2) The condensation of (I) with methyl acrylate (IV) by means of Triton B as before gives methyl 3-(3,4-diphenylpyrazol-1-yl)propionate (V), which is saponified with KOH in refluxing methanol yielding the corresponding free acid (VI). The reaction of (VI) with SOCl2 in refluxing CHCl3 affords the acyl chloride (VII), which is treated with dimethylamine in THF to give N,N-dimethyl-3-(3,4-diphenylpyrazol-1-yl)propionamide (VIII). Finally, this compound is reduced with LiAlH4 in refluxing THF.
【1】
Bailey, D.M. (Sanofi-Synthelabo); 1-Amino-lower-alkyl-3,4-diphenyl-1H-pyrazoles. US 4182895 .
|
【2】
Prous, J.; Castaner, J.; Fezolamine fumarate. Drugs Fut 1988, 13, 10, 913.
|
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
(I) |
23190 |
3,4-diphenyl-1H-pyrazole
|
|
C15H12N2 |
详情 |
详情
|
(IV) |
14156 |
methyl acrylate
|
96-33-3 |
C4H6O2 |
详情 | 详情
|
(V) |
23194 |
methyl 3-(3,4-diphenyl-1H-pyrazol-1-yl)propanoate
|
|
C19H18N2O2 |
详情 |
详情
|
(VI) |
23195 |
3-(3,4-diphenyl-1H-pyrazol-1-yl)propionic acid
|
|
C18H16N2O2 |
详情 |
详情
|
(VII) |
23196 |
3-(3,4-diphenyl-1H-pyrazol-1-yl)propanoyl chloride
|
|
C18H15ClN2O |
详情 |
详情
|
(VIII) |
23197 |
3-(3,4-diphenyl-1H-pyrazol-1-yl)-N,N-dimethylpropanamide
|
|
C20H21N3O |
详情 |
详情
|
合成路线6
该中间体在本合成路线中的序号:
(III) 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.
【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:
(XV) Reaction of benzaldehyde (I) with dimethyl malonate (II) in refluxing toluene in the presence of piperidine and HOAc provides dimethyl benzylidene malonate (III), which is then hydrogenated over Pd/C to afford dimethyl benzyl malonate (IV). Reduction of (IV) with LiAlH4 in refluxing THF furnishes 2-benzyl-1,3-propanediol (V), which is then subjected to reaction with vinyl acetate (VI) by means of Novozym 435 enzyme to yield diacetate (VII). Enantioselective removal of one acetyl group from (VII) by treatment with Pseudomonas fluorescens Lipase in acetone/phosphate buffer (pH = 7) at 30 C gives 3-acetoxy-2(S)-benzyl-propanol (S)-(VIII), which is then oxidized by means of Jones reagent in acetone/isopropanol to provide carboxylic acid (R)-(IX). The hydrolysis of (IX) with LiOH in THF/H2O gives 2(R)-benzyl-3-hydroxypropanoic acid (R)-(X).
Alternatively, intermediate (X) can also be synthesized as follows: Condensation of benzaldehyde (I) with methyl acrylate (XV) by means of diaza-1,4-bicyclo[2.2.2.]octane affords methyl beta-hydroxy-alpha-methylene-benzenepropanoate (XVI), which is then subjected to hydrolysis with KOH in MeOH/H2O to yield carboxylic acid (XVII). Treatment of (XVII) with p-toluenesulfonic acid in refluxing HOAc gives (E)-2-(acetoxymethyl)-3-phenylpropionic acid (XVIII), which is finally converted into (X) by enantioselective hydrogenation in the presence of S-Binap and ruthenium catalyst [CodRu(all)2].
Derivative (R)-(X) is then converted into 3-(acetylsulfanyl)-2(S)-benzylpropionic acid (XI) by means of a Mitsunobu reaction with thioacetic acid, diisopropyl azodicarboxylate (DIAD) and triphenylphosphine (PPh3). Compound (XI) is then subjected to optical purification by formation and isolation of the corresponding salt with (-)-ephedrine and subsequent hydrolysis with HCl to furnish enantiomerically pure (S)-(XII). Finally, carboxylic acid (S)-(XII) is converted into ecadotril by its coupling with benzyl glycinate (XIV), either by means of Et3N, DCC and HOBt in CHCl3, or by first reaction with thionyl chloride to give acid chloride (S)-(XIII) and subsequent coupling with glycinate (XIV) by means of Et3N in CH2Cl2.
【1】
Monteil, T.; et al.; New asymmetric synthesis of dexecadotril and ecadotril starting from a single precursor. Synth Commun 2001, 31, 2, 211.
|
【2】
Duhamel, P.; Duhamel, L.; Danvy, D.; Plaquevent, J.-C.; Giros, B.; Gros, C.; Schwartz, J.-C.; Lecomte, J.-M. (Societe Civile Bioprojet); Enantiomeric derivs. of amino acids, process for their preparation and their pharmaceutical applications. EP 0318377; FR 2623498; JP 1990000161; JP 1996059606; US 5296509; US 5331008 . |
【3】
Schwartz, J.-C.; Lecomte, J.-M. (Societe Civile Bioprojet); Novel pharmaceutical compsns. for the treatment of functional colophaties and their process of obtention. EP 0501870; JP 1993105627 .
|
【4】
Schwartz, J.-C.; Danvy, D.; Lecomte, J.-M.; Duhamel, P.; Duhamel, L.; Monteil, T. (Societe Civile Bioprojet); Method for the asymmetrical synthesis of S-acylated derivs. of 2-mercaptomethyl 3-phenyl propanoic acid, and use thereof for synthesising N-(mercaptoacyl)amino acid derivs.. WO 9729086 . |
【5】
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 .
|
【6】
Henry, J.C.; Genet, J.P.; Dellis, P.; Vidal, V.; Binay, P. (Fournier Industrie et Santé); Preparation of S- and R-isomers of 2-mercaptomethyl-3-aryl propanoic acid by asymmetric reduction of an aryl propenoic acid. FR 2772027 . |
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
(S)-(VIII) |
49464 |
(2S)-2-benzyl-3-hydroxypropyl acetate
|
|
C12H16O3 |
详情 |
详情
|
(R)-(IX) |
49465 |
(2R)-3-(acetoxy)-2-benzylpropionic acid
|
|
C12H14O4 |
详情 |
详情
|
(R)-(X) |
49466 |
(2R)-2-benzyl-3-hydroxypropionic acid
|
|
C10H12O3 |
详情 |
详情
|
(XI),(S)-(XII) |
49467 |
(2S)-3-(acetylsulfanyl)-2-benzylpropionic acid
|
|
C12H14O3S |
详情 |
详情
|
(I) |
10498 |
Benzaldehyde;Benzoic aldehyde;Phenylmethanal |
100-52-7 |
C7H6O |
详情 | 详情
|
(II) |
19373 |
dimethyl malonate;Methyl malonate;Propanedioic acid dimethyl ester |
108-59-8 |
C5H8O4 |
详情 | 详情
|
(III) |
49460 |
Dimethyl benzylidenemalonate
|
|
C12H12O4 |
详情 |
详情
|
(IV) |
49461 |
dimethyl 2-benzylmalonate
|
|
C12H14O4 |
详情 |
详情
|
(V) |
49462 |
2-Benzylpropane-1,3-diol
|
|
C10H14O2 |
详情 |
详情
|
(VI) |
24543 |
vinyl acetate
|
108-05-4 |
C4H6O2 |
详情 | 详情
|
(VII) |
49463 |
3-(acetoxy)-2-benzylpropyl acetate
|
|
C14H18O4 |
详情 |
详情
|
(XIII) |
49468 |
S-[(2R)-2-benzyl-3-chloro-3-oxopropyl] ethanethioate
|
|
C12H13ClO2S |
详情 |
详情
|
(XIV) |
49469 |
1-amino-3-phenylacetone
|
|
C9H11NO |
详情 |
详情
|
(XV) |
14156 |
methyl acrylate
|
96-33-3 |
C4H6O2 |
详情 | 详情
|
(XVI) |
49470 |
methyl 2-[hydroxy(phenyl)methyl]acrylate
|
|
C11H12O3 |
详情 |
详情
|
(XVII) |
49471 |
2-[hydroxy(phenyl)methyl]acrylic acid
|
|
C10H10O3 |
详情 |
详情
|
(XVIII) |
49472 |
(E)-2-[(acetoxy)methyl]-3-phenyl-2-propenoic acid
|
|
C12H12O4 |
详情 |
详情
|
合成路线8
该中间体在本合成路线中的序号:
(LIV) The title compound was also prepared using solid-phase methodology within a parallel synthesis protocol for the construction of a combinatorial library of vitamin D3 analogues. The A-ring synthon (LVIII) was synthesized as follows. Esterification of the previously reported alcohol intermediate (L) with pivaloyl chloride gave pivalate ester (LI). Acetonide hydrolysis in (LI) and then selective mono-silylation of the resultant diol (LII) yielded (LIII). Michael addition of ethyl acrylate (LIV) to the free hydroxyl group of (LIII) furnished ester (LV). Subsequently reduction of methyl ester (LV), with simultaneous reductive cleavage of the pivaloyl group in the presence of LiAlH4 led to diol (LVI). Chlorination of the allylic alcohol of (LVI) by means of N-chlorosuccinimide and dimethylsulfide, followed by silylation of the remaining hydroxyl group gave (LVII). Conversion of chloride (LVII) into the phosphine oxide (LVIII) was then performed using a similar procedure as that for intermediate (XXXII)
【1】
Hijikuro, I.; Doi, T.; Takahashi, T.; Parallel synthesis of a vitamin D3 library in the solid-phase. J Am Chem Soc 2001, 123, 16, 3716.
|
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
(L) |
59888 |
2-[(3aR,7R,7aS)-7-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethyl-4-methylenetetrahydro-1,3-benzodioxol-5(4H)-ylidene]-1-ethanol
|
|
C18H32O4Si |
详情 |
详情
|
(LI) |
59889 |
2-[(3aR,7R,7aS)-7-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethyl-4-methylenetetrahydro-1,3-benzodioxol-5(4H)-ylidene]ethyl pivalate
|
|
C23H40O5Si |
详情 |
详情
|
(LII) |
59890 |
2-((3R,4S,5R)-5-{[tert-butyl(dimethyl)silyl]oxy}-3,4-dihydroxy-2-methylenecyclohexylidene)ethyl pivalate
|
|
C20H36O5Si |
详情 |
详情
|
(LIII) |
59891 |
2-((3R,4R,5R)-3,5-bis{[tert-butyl(dimethyl)silyl]oxy}-4-hydroxy-2-methylenecyclohexylidene)ethyl pivalate
|
|
C26H50O5Si2 |
详情 |
详情
|
(LIV) |
14156 |
methyl acrylate
|
96-33-3 |
C4H6O2 |
详情 | 详情
|
(LV) |
59892 |
2-[(3R,4R,5R)-3,5-bis{[tert-butyl(dimethyl)silyl]oxy}-4-(3-methoxy-3-oxopropoxy)-2-methylenecyclohexylidene]ethyl pivalate
|
|
C30H56O7Si2 |
详情 |
详情
|
(LVI) |
59893 |
3-({(1R,2R,6R)-2,6-bis{[tert-butyl(dimethyl)silyl]oxy}-4-[(Z)-2-hydroxyethylidene]-3-methylenecyclohexyl}oxy)-1-propanol
|
|
C24H48O5Si2 |
详情 |
详情
|
(LVII) |
59894 |
tert-butyl({(1R,2R,3R)-3-{[tert-butyl(dimethyl)silyl]oxy}-2-(3-{[tert-butyl(dimethyl)silyl]oxy}propoxy)-5-[(Z)-2-chloroethylidene]-4-methylenecyclohexyl}oxy)dimethylsilane; (1R,2R,6R)-2,6-bis{[tert-butyl(dimethyl)silyl]oxy}-4-[(Z)-2-chloroethylidene]-3-methylenecyclohexyl 3-{[tert-butyl(dimethyl)silyl]oxy}propyl ether |
|
C30H61ClO4Si3 |
详情 |
详情
|
(LVIII) |
59895 |
2-[(3R,4R,5R)-3,5-bis{[tert-butyl(dimethyl)silyl]oxy}-4-(3-{[tert-butyl(dimethyl)silyl]oxy}propoxy)-2-methylenecyclohexylidene]ethyl(diphenyl)phosphine oxide; {2-[(3R,4R,5R)-3,5-bis{[tert-butyl(dimethyl)silyl]oxy}-4-(3-{[tert-butyl(dimethyl)silyl]oxy}propoxy)-2-methylenecyclohexylidene]ethyl}(oxo)diphenylphosphorane |
|
C42H71O5PSi3 |
详情 |
详情
|
合成路线9
该中间体在本合成路线中的序号:
(VIII) The synthesis of metabolites M-III, M-IV and M-V of pioglitazone has been reported:
a) Synthesis of metabolite M-IV: The reduction of 5-acetyl-2-methylpyridine (I) with NaBH4 in cooled ethanol gives the corresponding 1-hydroxyethyl derivative (II), which is protected with chloromethyl methyl ether and NaH in DMF yielding the methoxymethyl ether (III). The hydroxymethylation of (III) with aqueous formaldehyde at 150-60 C affords the ethanol (IV), which is condensed with 4-fluoronitrobenzene (V) by means of NaH in cooled DMF giving 5-[1-(methoxymethoxy)ethyl]-2-[2-(4-nitrophenoxy)ethyl]pyridine (VI). The reduction of the nitro group of (VI) with H2 over Pd/C in ethyl acetate yields the corresponding amino compound (VII), which is diazotized with NaNO2 in aqueous HBr and condensed with methyl acrylate (VIII) by means of Cu2O to afford the 2-bromopropionate derivative (IX). The cyclization of (IX) with thiourea (X) by means of sodium acetate in refluxing ethanol gives the intermediate iminothiazolidinone (XI), which without isolation, is treated with refluxing 2N HCl to give metabolite M-IV.
b) Synthesis of metabolite M-III: By oxidation of metabolite M-IV with the pyridine.sulfur trioxide complex in ethanol/dichloromethane/triethylamine
【1】
Momose, Y.; Sohda, T.; Meguro, K.; Hatanaka, C.; Ikeda, H.; Oi, S.; Studies on antidiabetic agents: Synthesis and biological activities of pioglitazone and related compounds. 11th Symp Med Chem (Dec 4-5, Tokushima) 1990, Abst P-11.
|
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
M-IV |
63861 |
5-(4-{2-[5-(1-hydroxyethyl)-2-pyridinyl]ethoxy}benzyl)-1,3-thiazolidine-2,4-dione
|
|
C19H20N2O4S |
详情 |
详情
|
M-III |
63862 |
5-{4-[2-(5-acetyl-2-piperidinyl)ethoxy]benzyl}-1,3-thiazolidine-2,4-dione
|
|
C19H24N2O4S |
详情 |
详情
|
(I) |
14149 |
1-(6-Methyl-3-pyridinyl)-1-ethanone
|
|
C8H9NO |
详情 |
详情
|
(II) |
14150 |
1-(6-Methyl-3-pyridinyl)-1-ethanol
|
|
C8H11NO |
详情 |
详情
|
(III) |
14151 |
5-[1-(Methoxymethoxy)ethyl]-2-methylpyridine; Methoxymethyl 1-(6-methyl-3-pyridinyl)ethyl ether
|
|
C10H15NO2 |
详情 |
详情
|
(IV) |
14152 |
2-[5-[1-(Methoxymethoxy)ethyl]-2-pyridinyl]-1-ethanol
|
|
C11H17NO3 |
详情 |
详情
|
(V) |
14153 |
4-Fluoronitrobenzene; 1-Fluoro-4-nitrobenzene
|
350-46-9 |
C6H4FNO2 |
详情 | 详情
|
(VI) |
14154 |
2-[5-[1-(Methoxymethoxy)ethyl]-2-pyridinyl]ethyl 4-nitrophenyl ether; 5-[1-(Methoxymethoxy)ethyl]-2-[2-(4-nitrophenoxy)ethyl]pyridine
|
|
C17H20N2O5 |
详情 |
详情
|
(VII) |
14155 |
4-(2-[5-[1-(Methoxymethoxy)ethyl]-2-pyridinyl]ethoxy)aniline; 4-(2-[5-[1-(Methoxymethoxy)ethyl]-2-pyridinyl]ethoxy)phenylamine
|
|
C17H22N2O3 |
详情 |
详情
|
(VIII) |
14156 |
methyl acrylate
|
96-33-3 |
C4H6O2 |
详情 | 详情
|
(IX) |
14157 |
methyl 2-bromo-3-[4-(2-[5-[1-(methoxymethoxy)ethyl]-2-pyridinyl]ethoxy)phenyl]propanoate
|
|
C21H26BrNO5 |
详情 |
详情
|
(X) |
10180 |
Thiourea
|
62-56-6 |
CH4N2S |
详情 | 详情
|
(XI) |
14159 |
2-Imino-5-[4-(2-[5-[1-(methoxymethoxy)ethyl]-2-pyridinyl]ethoxy)benzyl]-1,3-thiazolan-4-one
|
|
C21H25N3O4S |
详情 |
详情
|
合成路线10
该中间体在本合成路线中的序号:
(VIII) c) Synthesis of metabolite M-V: The reduction of 6-methylpyridine-3-carboxylic acid methyl ester (XII) with LiAlH4 in THF gives the corresponding hydroxymethyl derivative (XIII), which is protected with chloromethyl methyl ether as before yielding the methoxymethoxymethyl compound (XIV). Hydroxymethylation of (XIV) with formaldehyde as described affords the ethanol derivative (XV), which is condensed with 4-fluoronitrobenzene (V) as before giving 5-(hydroxymethyl)-2-[2-(4-nitrophenoxy)ethyl]pyridine (XVI). The deprotection of (XVI) with HCl in refluxing methanol yields the hydroxymethyl compound (XVII), which is treated with SOCl2 in refluxing chloroform to afford the chloromethyl compound (XVIII). The reaction of (XVIII) with KCN in hot DMF gives the corresponding cyanomethyl derivative (XIX), which by reduction of the NO2 group with H2 over Pd/C in ethyl acetate yields the amino derivative (XX). The diazotation of (XX) with NaNO2 in aqueous HBr followed by condensation with methyl acrylate as before affords the 2-bromopropionate (XXI), which is cyclized with thiourea (X) as reported to give iminothiazolidinone derivative (XXII). Finally, the hydrolysis of the cyano gives Metabolite M-V.
【1】
Momose, Y.; Sohda, T.; Meguro, K.; Hatanaka, C.; Ikeda, H.; Oi, S.; Studies on antidiabetic agents: Synthesis and biological activities of pioglitazone and related compounds. 11th Symp Med Chem (Dec 4-5, Tokushima) 1990, Abst P-11.
|
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
M-V |
63863 |
2-[6-(2-{4-[(2,4-dioxo-1,3-thiazolidin-5-yl)methyl]phenoxy}ethyl)-3-pyridinyl]acetic acid
|
|
C19H18N2O5S |
详情 |
详情
|
(V) |
14153 |
4-Fluoronitrobenzene; 1-Fluoro-4-nitrobenzene
|
350-46-9 |
C6H4FNO2 |
详情 | 详情
|
(VIII) |
14156 |
methyl acrylate
|
96-33-3 |
C4H6O2 |
详情 | 详情
|
(X) |
10180 |
Thiourea
|
62-56-6 |
CH4N2S |
详情 | 详情
|
(XII) |
14160 |
methyl 6-methylnicotinate
|
5470-70-2 |
C8H9NO2 |
详情 | 详情
|
(XIII) |
14161 |
(6-Methyl-3-pyridinyl)methanol
|
|
C7H9NO |
详情 |
详情
|
(XIV) |
14162 |
Methoxymethyl (6-methyl-3-pyridinyl)methyl ether; 5-[(Methoxymethoxy)methyl]-2-methylpyridine
|
|
C9H13NO2 |
详情 |
详情
|
(XV) |
14163 |
2-[5-[(Methoxymethoxy)methyl]-2-pyridinyl]-1-ethanol
|
|
C10H15NO3 |
详情 |
详情
|
(XVI) |
14164 |
5-[(Methoxymethoxy)methyl]-2-[2-(4-nitrophenoxy)ethyl]pyridine; 2-[5-[(Methoxymethoxy)methyl]-2-pyridinyl]ethyl 4-nitrophenyl ether
|
|
C16H18N2O5 |
详情 |
详情
|
(XVII) |
14165 |
[6-[2-(4-Nitrophenoxy)ethyl]-3-pyridinyl]methanol
|
|
C14H14N2O4 |
详情 |
详情
|
(XVIII) |
14166 |
2-[5-(Chloromethyl)-2-pyridinyl]ethyl 4-nitrophenyl ether; 5-(Chloromethyl)-2-[2-(4-nitrophenoxy)ethyl]pyridine
|
|
C14H13ClN2O3 |
详情 |
详情
|
(XIX) |
14167 |
2-[6-[2-(4-Nitrophenoxy)ethyl]-3-pyridinyl]acetonitrile
|
|
C15H13N3O3 |
详情 |
详情
|
(XX) |
14168 |
2-[6-[2-(4-Aminophenoxy)ethyl]-3-pyridinyl]acetonitrile
|
|
C15H15N3O |
详情 |
详情
|
(XXI) |
14169 |
methyl 2-bromo-3-(4-[2-[5-(cyanomethyl)-2-pyridinyl]ethoxy]phenyl)propanoate
|
|
C19H19BrN2O3 |
详情 |
详情
|
(XXII) |
14170 |
2-[6-(2-[4-[(2-Imino-4-oxo-1,3-thiazolan-5-yl)methyl]phenoxy]ethyl)-3-pyridinyl]acetonitrile
|
|
C19H18N4O2S |
详情 |
详情
|
合成路线11
该中间体在本合成路线中的序号:
(V) The condensation of 2-(5-ethyl-2-pyridyl)ethanol (I) with 4-fluoronitrobenzene (II) by means of NaH in DMF gives 4-[2-(5-ethyl-2-pyridyl)ethoxy]nitrobenzene (III), which is reduced with H2 over Pd/C in methanol to yield the corresponding aniline (IV). The reaction of (IV) with NaNO2/HBr and methyl acrylate (V) in acetone/methanol affords the 2-bromopropionate derivative (VI), which is cyclized with thiourea (VII) by means of NaOAc in refluxing ethanol to provide the 2-imino-4-thiazolidinone (VIII). Finally, this compound is hydrolyzed with refluxing 2N HCl.
【1】
Meguro, K.; Fujita, T. (Takeda Chemical Industries, Ltd.); Thiazolidinedione derivs., their production and use. EP 0193256; ES 8705886; JP 1986267580; US 4687777 .
|
【2】
Sohda, T.; Momose, Y.; Meguro, K.; Kawamatsu, Y.; Sugiyama, Y.; Ikeda, H.; Studies on antidiabetic agents. Synthesis and hypoglycemic activity of 5-[4-(pyridylalkoxy)benzyl]-2,4-thiazolidinediones. Arzneim-Forsch Drug Res 1990, 40, 1, 37.
|
【3】
Prous, J.; Castaner, J.; PIOGLITAZONE HYDROCHLORIDE < Prop INNM; USAN >. Drugs Fut 1990, 15, 11, 1080.
|
【4】
Meguro, K.; Momose, Y.; Sohda, T.; Oi, S.; Ikeda, H.; Hatanaka, C.; Studies on antidiabetic agents. X. Synthesis and biological activities of pioglitazone and related compounds. Chem Pharm Bull 1991, 39, 6, 1440-5.
|
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) |
14139 |
2-(5-Ethyl-2-pyridinyl)-1-ethanol
|
5223-06-3 |
C9H13NO |
详情 | 详情
|
(II) |
14153 |
4-Fluoronitrobenzene; 1-Fluoro-4-nitrobenzene
|
350-46-9 |
C6H4FNO2 |
详情 | 详情
|
(III) |
62867 |
5-ethyl-2-[2-(4-nitrophenoxy)ethyl]pyridine; 2-(5-ethyl-2-pyridinyl)ethyl 4-nitrophenyl ether
|
|
C15H16N2O3 |
详情 |
详情
|
(IV) |
62868 |
4-[2-(5-ethyl-2-pyridinyl)ethoxy]aniline; 4-[2-(5-ethyl-2-pyridinyl)ethoxy]phenylamine
|
|
C15H18N2O |
详情 |
详情
|
(V) |
14156 |
methyl acrylate
|
96-33-3 |
C4H6O2 |
详情 | 详情
|
(VI) |
62869 |
methyl 2-bromo-3-{4-[2-(5-ethyl-2-pyridinyl)ethoxy]phenyl}propanoate
|
|
C19H22BrNO3 |
详情 |
详情
|
(VII) |
10180 |
Thiourea
|
62-56-6 |
CH4N2S |
详情 | 详情
|
(VIII) |
62870 |
5-{4-[2-(5-ethyl-2-pyridinyl)ethoxy]benzyl}-2-imino-1,3-thiazolidin-4-one
|
|
C19H21N3O2S |
详情 |
详情
|
合成路线12
该中间体在本合成路线中的序号:
(IV) 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.
【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13
该中间体在本合成路线中的序号:
(II) By condensation of 4-(N-phenylpropionamido)piperidine-4-carboxylic acid methyl ester (I) with acrylic acid methyl ester (II) in hot acetonitrile.
【1】
Feldman, P.L.; James, M.K.; Brackeen, M.F.; Johnson, M.R.; Leighton, H.J. (Glaxo Wellcome plc); N-Phenyl-N-(4-piperidinyl)amides useful as analgesics. EP 0383579; JP 1990300167; US 5019583 .
|
【2】
Robinson, C.; Castaner, J.; Remifentanil Hydrochloride. Drugs Fut 1994, 19, 12, 1088.
|
【3】
Johnson, M.R.; Lahey, A.P.; James, M.K.; Bilotta, J.M.; Feldman, P.L.; Lutz, M.W.; Brackeen, M.F.; Schuster, S.V.; Leighton, H.J.; Design, synthesis, and pharmacological evaluation of ultrashort- to long-acting opioid analgetics. J Med Chem 1991, 34, 7, 2202-8. |
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
(I) |
15668 |
methyl 4-(propionylanilino)-4-piperidinecarboxylate
|
|
C16H22N2O3 |
详情 |
详情
|
(II) |
14156 |
methyl acrylate
|
96-33-3 |
C4H6O2 |
详情 | 详情
|
合成路线14
该中间体在本合成路线中的序号:
(X) The reaction of 1-benzyl-4-piperidone (I) with aniline (II) and KCN in acetic acid gives the aminonitrile (III), which is treated with H2SO4 at room temperature to yield the carboxamide (IV). The hydrolysis of (IV) with refluxing aqueous HCl affords the carboxylic acid (V), which is esterified with Ms-OH and methanol to provide the methyl ester (VI). Acylation of the NH group of (VI) with propionic anhydride (VII) gives the propionamide (VIII), which is debenzylated with H2 over Pd/C to yield the piperidine (IX). Finally, this compound is condensed with methyl acrylate (XI) in acetonitrile to afford the target compound.
【1】
Killgore, J.K.; Jacob, M. (Mallinckrodt Medical Inc.); New methods for the syntheses of alfentanil, sufentanil and remifentanil. WO 0140184 .
|
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) |
15720 |
1-benzyltetrahydro-4(1H)-pyridinone; 1-Benzyl-4-piperidone; N-Benzyl-4-piperidone; 1-(benzyl)-4-piperidinone; 1-benzylpiperidin-4-one; 1-(benzyl)piperidin-4-one
|
3612-20-2 |
C12H15NO |
详情 | 详情
|
(II) |
12294 |
Aniline; Phenylamine
|
62-53-3 |
C6H7N |
详情 | 详情
|
(III) |
49674 |
4-Anilino-1-benzyl-4-cyanopiperidine
|
|
C19H21N3 |
详情 |
详情
|
(IV) |
49675 |
4-Anilino-1-benzylisonipecotamide
|
|
C19H23N3O |
详情 |
详情
|
(V) |
33884 |
4-anilino-1-benzyl-4-piperidinecarboxylic acid
|
|
C19H22N2O2 |
详情 |
详情
|
(VI) |
49676 |
methyl 4-anilino-1-benzyl-4-piperidinecarboxylate
|
|
C20H24N2O2 |
详情 |
详情
|
(VII) |
20095 |
propionic anhydride
|
123-62-6 |
C6H10O3 |
详情 | 详情
|
(VIII) |
49677 |
methyl 1-benzyl-4-(propionylanilino)-4-piperidinecarboxylate
|
|
C23H28N2O3 |
详情 |
详情
|
(IX) |
15668 |
methyl 4-(propionylanilino)-4-piperidinecarboxylate
|
|
C16H22N2O3 |
详情 |
详情
|
(X) |
14156 |
methyl acrylate
|
96-33-3 |
C4H6O2 |
详情 | 详情
|
合成路线15
该中间体在本合成路线中的序号:
(IV) The reaction of 3-cyclopentyloxy-4-methoxybenzaldehyde (I) with LiBr, trimethylsilyl chloride (TMS-Cl) and 1,1,3,3-tetramethyldisiloxane in acetonitrile gives the corresponding benzyl bromide (II), which by reaction with NaCN in DMF affords 2-(3-cyclopentyloxy-4-methoxyphenyl)acetonitrile (III). The condensation of (III) with methyl acrylate (IV) by means of Triton B in refluxing acetonitrile yields the 4-cyanopimelate (V), which is cyclized by means of NaH in refluxing DME, giving the 2-oxocyclohexanecarboxylic ester (VI). The decarboxylation of (VI) by means of NaCl in DMSO/water at 150 C yields the cyclohexanone (VII), which is condensed with 2-(trimethylsilyl)-1,3-dithiane (VIII) by means of BuLi in THF, affording the cyclohexylidene-dithiane (IX). The methanolysis of (IX) catalyzed by HgCl2 and HClO4 in refluxing methanol gives a mixture of the cis- and trans-4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexanecarboxylic acid methyl ester which is submitted to flash chromatography to obtain the cis-isomer (XII). Finally, this compound is hydrolyzed with KOH in methanol/THF/water.
【1】
Graul, A.; Castañer, J.; Silvestre, J.S.; SB-207499. Drugs Fut 1998, 23, 6, 607.
|
【2】
Christensen, S.B.; Forster, C.J.; Guider, A.; et al.; 1,4-Cyclohexanecarboxylates: Potent and selective inhibitors of phosphodiesterase 4 for the treatment of asthma. J Med Chem 1998, 41, 6, 821-35.
|
【3】
Bordas-Nagy, J.; Gorycki, P.; Webb, K.S. (SmithKline Beecham plc); Cyano cpds. and preparation thereof. JP 1997510213; WO 9524381 .
|
【4】
Christensen, S.B. IV (SmithKline Beecham plc); Cpds. useful for treating allergic and inflammatory diseases. EP 0633776; EP 0919544; JP 1995508508; US 5552438; US 5602157; WO 9319749 .
|
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) |
16510 |
3-(cyclopentyloxy)-4-methoxybenzaldehyde
|
|
C13H16O3 |
详情 |
详情
|
(II) |
16511 |
4-(bromomethyl)-2-(cyclopentyloxy)phenyl methyl ether; 4-(bromomethyl)-2-(cyclopentyloxy)-1-methoxybenzene
|
|
C13H17BrO2 |
详情 |
详情
|
(III) |
16512 |
2-[3-(cyclopentyloxy)-4-methoxyphenyl]acetonitrile
|
|
C14H17NO2 |
详情 |
详情
|
(IV) |
14156 |
methyl acrylate
|
96-33-3 |
C4H6O2 |
详情 | 详情
|
(V) |
16514 |
dimethyl 4-cyano-4-[3-(cyclopentyloxy)-4-methoxyphenyl]heptanedioate
|
|
C22H29NO6 |
详情 |
详情
|
(VI) |
16515 |
methyl 5-cyano-5-[3-(cyclopentyloxy)-4-methoxyphenyl]-2-oxocyclohexanecarboxylate
|
|
C21H25NO5 |
详情 |
详情
|
(VII) |
16516 |
1-[3-(cyclopentyloxy)-4-methoxyphenyl]-4-oxocyclohexanecarbonitrile
|
|
C19H23NO3 |
详情 |
详情
|
(VIII) |
16517 |
1,3-dithian-2-yl(trimethyl)silane; 2-Trimethylsilyl-1,3-dithiane
|
13411-42-2 |
C7H16S2Si |
详情 | 详情
|
(IX) |
16518 |
1-[3-(cyclopentyloxy)-4-methoxyphenyl]-4-(1,3-dithian-2-ylidene)cyclohexanecarbonitrile
|
|
C23H29NO2S2 |
详情 |
详情
|
(XII) |
16519 |
methyl 4-cyano-4-[3-(cyclopentyloxy)-4-methoxyphenyl]cyclohexanecarboxylate
|
|
C21H27NO4 |
详情 |
详情
|
合成路线16
该中间体在本合成路线中的序号:
LY246736 dihydrate is prepared in 12 steps from 1,3-dimethyl-4-piperidone (I) in 6.2% yield as depicted in Scheme 20754901a.
Piperidinol (II) can be prepared from (I) using standard methodology. Selective elimination to tetrahydropyridine (IV) is accomplished by the cis-thermal elimination of an ethyl carbonate (III) at 190 C in refluxing Decalin(R). This maintains the stereochemistry at C-3, following resolution of carbonate (III) with di-p-toluoyl-D-tartaric acid ((+)-DDTA), and also enables the trans-stereochemistry of the methyl groups to be established in the next step. Alkylation of the metalloenamine with dimethyl sulfate at -50 C proceeds both regio- and stereospecifically, giving the trans-3,4-dimethyl-gamma-alkylation product (V). Reduction of the enamine with NaBH4 and N,O-didealkylation with phenyl chloroformate followed by HBr/AcOH gives the chiral 3,4-dimethyl-4-arylpiperidine (VII). The benzyl group of the N-substituent is introduced via a nonselective benzylation of the Michael adduct dianion at -20 C followed by a highly efficient crystallization of the (3R,4R,alphaS)-hydrochloride (VIII) from methanol. The undesired diastereomer can be epimerized (LDA, H2O) and recycled to afford additional (VIII). Hydrolysis of the ester with NaOH, DCC coupling of the glycine ester, and hydrolysis of the ester with NaOH in ethanol/water completes the synthesis. The crystalline dihydrate (X) is isolated directly from the saponification reaction mixture upon neutralization with hydrochloric acid (overall yield 6.2% with one recycle of (3R,4R,alphaR)-isomer of (VIII).
【1】
Copley-Merriman, C.R.; Maki, J.; Barnett, C.J.; Synthesis of picenadol via metalloenamine alkylation methodology. J Org Chem 1989, 54, 4795-800.
|
【2】
Robey, R.L.; Evans, D.A.; Zimmerman, D.M.; Mitch, C.H.; Thomas, R.C.; Application of metalated enamines to alkaloid synthesis. An expedient approach to the synthesis of morphine-based analgesics. J Am Chem Soc 1980, 102, 5955-6.
|
【3】
Werner, J.A.; Cerbone, L.R.; Selective "cis-dehydration" of 3-methyl-4-piperidinols via thermal elimination of carbonates and its application in synthesis. 203rd ACS Natl Meet (April 5-10, San Francisco) 1992, Abst ORGN 409.
|
【4】
Prather, D.E.; Werner, J.A.; Wad, J.A.; Frank, S.A. (Eli Lilly and Company); Trisubstd.-piperidinyl-N-alkylcarboxylates as opioid antagonists. EP 0984004 .
|
【5】
Pohland, R.C.; Franklin, R.B.; Cantrell, B.E.; Means, J.R.; Leander, J.D.; Parli, C.J.; Francis, P.C.; Zimmerman, D.M.; Gidda, J.S.; Werner, J.A.; LY246736 Dihydrate. Drugs Fut 1994, 19, 12, 1078.
|
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
|
14156 |
methyl acrylate
|
96-33-3 |
C4H6O2 |
详情 | 详情
|
|
63423 |
3-bromophenyl isopropyl ether; 1-bromo-3-isopropoxybenzene
|
|
C9H11BrO |
详情 |
详情
|
(I) |
16614 |
1,3-dimethyltetrahydro-4(1H)-pyridinone; 1,3-Dimethyl-4-piperidone
|
4629-80-5 |
C7H13NO |
详情 | 详情
|
(II) |
16615 |
(3S,4R)-4-(3-isopropoxyphenyl)-1,3-dimethylhexahydro-4-pyridinol
|
|
C16H25NO2 |
详情 |
详情
|
(III) |
16616 |
ethyl (3S,4R)-4-(3-isopropoxyphenyl)-1,3-dimethylhexahydro-4-pyridinyl carbonate
|
|
C19H29NO4 |
详情 |
详情
|
(IV) |
16617 |
(3R)-4-(3-isopropoxyphenyl)-1,3-dimethyl-1,2,3,6-tetrahydropyridine; 3-[(3R)-1,3-dimethyl-1,2,3,6-tetrahydro-4-pyridinyl]phenyl isopropyl ether
|
|
C16H23NO |
详情 |
详情
|
(V) |
16618 |
(3R,4R)-4-(3-isopropoxyphenyl)-1,3,4-trimethylhexahydropyridine; isopropyl 3-[(3R,4R)-1,3,4-trimethylhexahydro-4-pyridinyl]phenyl ether
|
|
C17H27NO |
详情 |
详情
|
(VI) |
16618 |
(3R,4R)-4-(3-isopropoxyphenyl)-1,3,4-trimethylhexahydropyridine; isopropyl 3-[(3R,4R)-1,3,4-trimethylhexahydro-4-pyridinyl]phenyl ether
|
|
C17H27NO |
详情 |
详情
|
(VII) |
16620 |
3-[(3R,4R)-3,4-dimethylhexahydro-4-pyridinyl]phenol
|
119193-19-0 |
C13H19NO |
详情 | 详情
|
(VIII) |
16621 |
(3R,4R)-1-[(2S)-2-benzyl-3-methoxy-3-oxopropyl]-4-(3-hydroxyphenyl)-3,4-dimethylhexahydropyridinium chloride
|
|
C24H32ClNO3 |
详情 |
详情
|
(IX) |
16622 |
(2S)-2-benzyl-3-[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyltetrahydro-1(2H)-pyridiniumyl]propanoate hydrate |
|
C23H29NO3.H2O |
详情 |
详情
|
合成路线17
该中间体在本合成路线中的序号:
(XII) Michael addition of methyl acrylate (XII) to (3,4-dichlorophenyl)acetonitrile (XI) produced the cyano diester adduct (XIII). Catalytic hydrogenation of the cyano group of (XIII) over Raney nickel with concomitant intramolecular cyclization gave rise to the piperidinone (XIV). After basic hydrolysis of the methyl ester function of (XIV), the resultant piperidone propionic acid (XV) was reduced to piperidino alcohol (XVI) by means of borane in THF. Resolution of the racemic piperidine (XVI) employing (+)-camphorsulfonic acid provided the dextro enantiomer (XVII). After N-protection of (XVII) as the Boc derivative (XVIII), its primary alcohol was activated as the corresponding mesylate (XIX) with methanesulfonyl chloride and Et3N. Condensation between mesylate (XIX) and intermediate piperidine (X) in acetonitrile at 60 C, produced (XX). The title benzamido derivative was then obtained by acid-promoted Boc group cleavage in (XX), followed by acylation with benzoyl chloride.
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) |
59267 |
N-methyl-N-(4-phenyl-4-piperidinyl)acetamide
|
|
C14H20N2O |
详情 |
详情
|
(XI) |
26935 |
2-(3,4-dichlorophenyl)acetonitrile
|
3218-49-3 |
C8H5Cl2N |
详情 | 详情
|
(XII) |
14156 |
methyl acrylate
|
96-33-3 |
C4H6O2 |
详情 | 详情
|
(XIII) |
59268 |
dimethyl 4-cyano-4-(3,4-dichlorophenyl)heptanedioate
|
|
C16H17Cl2NO4 |
详情 |
详情
|
(XIV) |
59269 |
methyl 3-[3-(3,4-dichlorophenyl)-6-oxo-3-piperidinyl]propanoate
|
|
C15H17Cl2NO3 |
详情 |
详情
|
(XV) |
59270 |
3-[3-(3,4-dichlorophenyl)-6-oxo-3-piperidinyl]propanoic acid
|
|
C14H15Cl2NO3 |
详情 |
详情
|
(XVI) |
29465 |
3-[3-(3,4-dichlorophenyl)-3-piperidinyl]-1-propanol
|
|
C14H19Cl2NO |
详情 |
详情
|
(XVII) |
29466 |
3-[(3S)-3-(3,4-dichlorophenyl)piperidinyl]-1-propanol
|
|
C14H19Cl2NO |
详情 |
详情
|
(XVIII) |
59271 |
tert-butyl (3S)-3-(3,4-dichlorophenyl)-3-(3-hydroxypropyl)-1-piperidinecarboxylate
|
|
C19H27Cl2NO3 |
详情 |
详情
|
(XIX) |
59272 |
tert-butyl (3S)-3-(3,4-dichlorophenyl)-3-{3-[(methylsulfonyl)oxy]propyl}-1-piperidinecarboxylate
|
|
C20H29Cl2NO5S |
详情 |
详情
|
(XX) |
59273 |
tert-butyl (3R)-3-(3-{4-[acetyl(methyl)amino]-4-phenyl-1-piperidinyl}propyl)-3-(3,4-dichlorophenyl)-1-piperidinecarboxylate
|
|
C33H45Cl2N3O3 |
详情 |
详情
|
合成路线18
该中间体在本合成路线中的序号:
(XII) In a related synthesis, (3,4-dichlorophenyl)acetonitrile (XI) was alkylated with bromide (XXII) --prepared by protection of 3-bromopropanol (XXI) with dihydropyran-- to afford (XXIII). Subsequent Michael addition of methyl acrylate (XII) to (XXIII) in the presence of Triton B® gave the cyanoacid (XXIV). This was cyclized to the glutarimide (XXV) by refluxing in HOAc in the presence of H2SO4. Reduction of (XXV) using borane-dimethylsulfide complex produced the already reported racemic piperidinoalcohol (XVI). After acylation of the amine group of (XVI) with benzoyl chloride to yield (XXVI), its hydroxyl group was converted into the target mesylate precursor (XXVII) with methanesulfonyl chloride and Et3N.
【1】
Giardina, G.A.M.; et al.; A reliable and efficient synthesis of SR 142801. Bioorg Med Chem Lett 1996, 6, 19, 2307.
|
【2】
Chen, H.G.; et al.; A practical and scalable synthesis of SR 142801, a tachykinin NK3 antagonist. Bioorg Med Chem Lett 1997, 7, 5, 555.
|
【3】
Grugni, M.; Rigolio, R.; Erhard, K.F. (GlaxoSmithKline Inc.; GlaxoSmithKline SpA); Process for the preparation of 3,3-disubstd. piperidines. WO 9805640 .
|
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
(XI) |
26935 |
2-(3,4-dichlorophenyl)acetonitrile
|
3218-49-3 |
C8H5Cl2N |
详情 | 详情
|
(XII) |
14156 |
methyl acrylate
|
96-33-3 |
C4H6O2 |
详情 | 详情
|
(XVI) |
29465 |
3-[3-(3,4-dichlorophenyl)-3-piperidinyl]-1-propanol
|
|
C14H19Cl2NO |
详情 |
详情
|
(XXI) |
12573 |
3-Bromo-1-propanol; 3-Bromopropanol
|
627-18-9 |
C3H7BrO |
详情 | 详情
|
(XXII) |
42252 |
3-bromopropyl tetrahydro-2H-pyran-2-yl ether; 2-(3-bromopropoxy)tetrahydro-2H-pyran
|
|
C8H15BrO2 |
详情 |
详情
|
(XXIII) |
59274 |
2-(3,4-dichlorophenyl)-5-(tetrahydro-2H-pyran-2-yloxy)pentanenitrile
|
|
C16H19Cl2NO2 |
详情 |
详情
|
(XXIV) |
59275 |
4-cyano-4-(3,4-dichlorophenyl)-7-(tetrahydro-2H-pyran-2-yloxy)heptanoic acid
|
|
C19H23Cl2NO4 |
详情 |
详情
|
(XXV) |
59276 |
3-[3-(3,4-dichlorophenyl)-2,6-dioxo-3-piperidinyl]propyl acetate
|
|
C16H17Cl2NO4 |
详情 |
详情
|
(XXVI) |
59277 |
[3-(3,4-dichlorophenyl)-3-(3-hydroxypropyl)-1-piperidinyl](phenyl)methanone
|
|
C21H23Cl2NO2 |
详情 |
详情
|
(XXVII) |
59278 |
3-[1-benzoyl-3-(3,4-dichlorophenyl)-3-piperidinyl]propyl methanesulfonate
|
|
C22H25Cl2NO4S |
详情 |
详情
|
合成路线19
该中间体在本合成路线中的序号:
(XIV) Tritium-labeled RS-25259-197 can be obtained by the reaction of methyl 4-bromophenylacetate (XI) with methyl chloroformate (XII) by means of lithium diisopropylamide (LDA) in THF, giving the malonic ester (XIII), which is condensed with methyl acrylate (XIV) by means of Na in methanol to yield the tricarboxylic ester (XV). The decarboxylative hydrolysis of (XV) first with NaOH and finally in acidic medium (HCl) affords 2-(4-bromophenyl)glutaric acid (XVI), which is cyclized with hot polyphosphoric acid (PPA) to give 6-bromo-4-oxo-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (XVII). The reduction of (XVII) with NaBH4 in isopropanol yields the corresponding hydroxy acid (XVIII), which is dehydrated with p-toluenesulfonic acid to the lactone (XIX). Isomerization of (XIX) with H3PO4 in THF affords 6-bromo-1,2-dihydronaphthalene-1-carboxylic acid (XX), which is condensed with quinuclidin-3(S)-ylamine (III) by means of dicyclohexylcarbodiimide (DCC) and hydroxybenzotriazole (HOBT) in acetonitrile to give the corresponding amide as a mixture of diastereomers that is resolved by chromatography and crystallization in order to obtain the (S,S)-isomer (XXI). The hydrogenation of (XXI) with tritium (3H2) and Pd/C in ethyl acetate affords (S,S)-N-(3-quinuclidinyl)-3,4,7-tri-3H-1,2,3,4-tetrahydronaphthalene-1-carboxamide (XXII), which is reduced with the complex borane.dimethylsulfide to the corresponding amine (XXIII). Finally, this compound is cyclized with trichloromethyl chloroformate (diphosgene) in refluxing toluene.
【1】
Graul, A.; Castañer, J.; RS-25259-197. Drugs Fut 1996, 21, 9, 906.
|
【2】
Gong, L.; Parnes, H.; Synthesis of the 3H-labelled 5-HT3 antagonist (RS-25259-197) at high specific activity. J Label Compd Radiopharm 1996, 38, 5, 425.
|
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) |
16984 |
(3S)-1-azabicyclo[2.2.2]octan-3-amine; 1-aza-Bicyclo[2.2.2]oct-3-ylamine; (3S)-1-azabicyclo[2.2.2]oct-3-ylamine
|
120570-05-0 |
C7H14N2 |
详情 | 详情
|
(XI) |
16992 |
methyl 2-(4-bromophenyl)acetate
|
41841-16-1 |
C9H9BrO2 |
详情 | 详情
|
(XII) |
16993 |
methyl chlorocarbonate;Carbonochloridic acid methyl ester;[(chlorocarbonyl)oxy]methane;methyl chloroformate |
79-22-1 |
C2H3ClO2 |
详情 | 详情
|
(XIII) |
16994 |
dimethyl 2-(4-bromophenyl)malonate
|
|
C11H11BrO4 |
详情 |
详情
|
(XIV) |
14156 |
methyl acrylate
|
96-33-3 |
C4H6O2 |
详情 | 详情
|
(XV) |
16996 |
trimethyl 1-(4-bromophenyl)-1,1,3-propanetricarboxylate
|
|
C15H17BrO6 |
详情 |
详情
|
(XVI) |
16997 |
2-(4-bromophenyl)pentanedioic acid
|
|
C11H11BrO4 |
详情 |
详情
|
(XVII) |
16998 |
6-bromo-4-oxo-1,2,3,4-tetrahydro-1-naphthalenecarboxylic acid
|
|
C11H9BrO3 |
详情 |
详情
|
(XVIII) |
16999 |
6-bromo-4-hydroxy-1,2,3,4-tetrahydro-1-naphthalenecarboxylic acid
|
|
C11H11BrO3 |
详情 |
详情
|
(XIX) |
17000 |
5-bromo-9-oxatricyclo[6.2.2.0(2,7)]dodeca-2,4,6-trien-10-one
|
|
C11H9BrO2 |
详情 |
详情
|
(XX) |
17001 |
6-bromo-1,2-dihydro-1-naphthalenecarboxylic acid
|
|
C11H9BrO2 |
详情 |
详情
|
(XXI) |
17002 |
(1S)-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-bromo-1,2-dihydro-1-naphthalenecarboxamide
|
|
C18H21BrN2O |
详情 |
详情
|
(XXII) |
17003 |
(1S)-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1,2,3,4-tetrahydro-1-naphthalenecarboxamide
|
|
C18H24N2O |
详情 |
详情
|
(XXII) |
45319 |
(1S)-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1,2,3,4-tetrahydro-1-naphthalenecarboxamide
|
|
C18H24N2O |
详情 |
详情
|
(XXIII) |
17004 |
(3S)-N-[(1S)-1,2,3,4-tetrahydro-1-naphthalenylmethyl]-1-azabicyclo[2.2.2]octan-3-amine; N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-N-[(1S)-1,2,3,4-tetrahydro-1-naphthalenylmethyl]amine
|
|
C18H26N2 |
详情 |
详情
|
(XXIII) |
45320 |
N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-N-[(1S)-1,2,3,4-tetrahydro-1-naphthalenylmethyl]amine; (3S)-N-[(1S)-1,2,3,4-tetrahydro-1-naphthalenylmethyl]-1-azabicyclo[2.2.2]octan-3-amine
|
|
C18H26N2 |
详情 |
详情
|
合成路线20
该中间体在本合成路线中的序号:
(II) The condensation of 5-methoxy-3-nitro-3,4-dihydro-2H-1-benzopyran (I) with methyl acrylate (II) by means of benzyltrimethylammonium methoxide in methanol gives the propionic ester (III), which is submitted to a reductive cyclization with H2 over RaNi in methanol yielding the racemic spiro compound (IV). Optical resolution of (IV) by means of (+)-1,1'-dinaphthyl-2,2'-diyl hydrogen phosphate [(+)-BNP] in methanol/dichloromethane affords (+)(R)-(V), which is finally condensed with 8-(4-bromobutyl)-8-azaspiro[4.5]decane-7,9-dione (VI) by means of triethylamine (TEA) in hot DMF.
【1】
Comoy, C.; et al.; 3-Amino-3,4-dihydro-2H-1-benzopyran derivatives as 5-HT1A receptor ligands and potential anxiolytic agents. 2. Synthesis and quantitative structure-activity relationship studies of spiro[pyrrolidine- and piperidine-2, 3'(2'H)-benzopyrans]. J Med Chem 1996, 39, 21, 4285. |
【2】
Guillaumet, G.; Podona, T.; Adam, G.; Guardiola, B.; Renard, P. (ADIR et Cie.); 3-Aminochromane spiro derivs., processes for their preparation and pharmaceutical compsns. containing them. EP 0564358; FR 2689509; JP 1994287190; JP 1995084471; US 5376661; US 5397783 . |
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) |
33124 |
methyl 3-nitro-3,4-dihydro-2H-chromen-5-yl ether; 5-methoxy-3-nitrochromane
|
|
C10H11NO4 |
详情 |
详情
|
(II) |
14156 |
methyl acrylate
|
96-33-3 |
C4H6O2 |
详情 | 详情
|
(III) |
33125 |
methyl 3-(5-methoxy-3-nitro-3,4-dihydro-2H-chromen-3-yl)propanoate
|
|
C14H17NO6 |
详情 |
详情
|
(IV) |
33126 |
5-Methoxy-3,4-dihydro-2H-spiro[1-benzopyran-3,2'-pyrrolidine]
|
|
C13H17NO2 |
详情 |
详情
|
(V) |
33127 |
(R)-5-Methoxy-3,4-dihydro-2H-spiro[1-benzopyran-3,2'-pyrrolidine]
|
|
C13H17NO2 |
详情 |
详情
|
(VI) |
29455 |
8-(4-bromobutyl)-8-azaspiro[4.5]decane-7,9-dione
|
|
C13H20BrNO2 |
详情 |
详情
|
合成路线21
该中间体在本合成路线中的序号:
(IV) The condensation of 3-amino-1-(2-fluorophenyl)-6-methoxyindolin-2-one (I) with isoquinolin-3-ylcarbonyl chloride (II) by means of NaHCO3 in chloroform/dichloromethane/water gives the corresponding amide (III), which is condensed with methyl acrylate (IV) by means of K2CO3 in acetone to yield the propionic ester derivative (V). Finally, the ester group of (V) is hydrolyzed with NaOH in ethanol to afford the target propionic acid derivative as a racemic compound.
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) |
52869 |
3-amino-1-(2-fluorophenyl)-6-methoxy-1,3-dihydro-2H-indol-2-one
|
|
C15H13FN2O2 |
详情 |
详情
|
(II) |
56739 |
3-isoquinolinecarboxylic acid
|
203626-75-9 |
C10H7NO2 |
详情 | 详情
|
(III) |
56742 |
N-[1-(2-fluorophenyl)-6-methoxy-2-oxo-2,3-dihydro-1H-indol-3-yl]-3-isoquinolinecarboxamide
|
|
C25H18FN3O3 |
详情 |
详情
|
(IV) |
14156 |
methyl acrylate
|
96-33-3 |
C4H6O2 |
详情 | 详情
|
(V) |
56743 |
methyl 3-{1-(2-fluorophenyl)-3-[(3-isoquinolinylcarbonyl)amino]-6-methoxy-2-oxo-2,3-dihydro-1H-indol-3-yl}propanoate
|
|
C29H24FN3O5 |
详情 |
详情
|
合成路线22
该中间体在本合成路线中的序号:
(B) Treatment of 3-nitro-7-hydroxyquinoline (I) with NaH and benzyl bromide (A) provides benzyloxyderivative (II), which is reduced with SnCl4 in HCl/EtOH to yield (III). Amine (III) is then converted into (IV) via the diazonium salt by treatment with NaNO2 in HCl followed by reaction with methyl acrylate (B) in presence of CuO. Cyclization of (IV) with thiourea in 2-methoxyethanol in presence of NaOAc affords imino-thiazolidinone (V), which is finally hydrolyzed with HCl and EtOH.
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
|
10180 |
Thiourea
|
62-56-6 |
CH4N2S |
详情 | 详情
|
(A) |
12912 |
1-(Bromomethyl)benzene; Alpha-bromotoluene
|
100-39-0 |
C7H7Br |
详情 | 详情
|
(B) |
14156 |
methyl acrylate
|
96-33-3 |
C4H6O2 |
详情 | 详情
|
(I) |
41511 |
3-nitro-7-quinolinol
|
|
C9H6N2O3 |
详情 |
详情
|
(II) |
41512 |
7-(benzyloxy)-3-nitroquinoline; benzyl 3-nitro-7-quinolinyl ether
|
|
C16H12N2O3 |
详情 |
详情
|
(III) |
41513 |
7-(benzyloxy)-3-quinolinamine; 7-(benzyloxy)-3-quinolinylamine
|
|
C16H14N2O |
详情 |
详情
|
(IV) |
41514 |
methyl 3-[7-(benzyloxy)-3-quinolinyl]-2-chloropropanoate
|
|
C20H18ClNO3 |
详情 |
详情
|
(V) |
41515 |
5-[[7-(benzyloxy)-3-quinolinyl]methyl]-2-imino-1,3-thiazolidin-4-one
|
|
C20H17N3O2S |
详情 |
详情
|
合成路线23
该中间体在本合成路线中的序号:
(II) The diazonium salt prepared from 3,4-methylenedioxyaniline (I) was coupled to methyl acrylate (II) in the presence of Cu2O and HBr to produce the 2-bromo-3-phenylpropionic ester (III). Subsequent displacement of the bromo group of (III) by alpha-mercaptopropionic acid (IV) gave sulfide (V). After conversion of (V) to the corresponding acid chloride with (COCl)2, intramolecular Friedel-Crafts cyclization in the presence of SnCl4 afforded the benzothiepinone (VI) as a mixture of cis and trans isomers. Further treatment of this mixture with sodium methoxide equilibrated the mixture to the more stable trans form (VII). Resolution of the racemic trans ester was achieved by basic hydrolysis, coupling to ethyl (R)-(-)-mandelate (VIII), and fractional crystallization of the desired diastereomer (IX) from EtOAc-hexane. Ester hydrolysis of (IX) under acidic conditions led to the chiral carboxylic acid (X), which was finally condensed with diethyl 4-aminobenzylphosphonate (XI) to furnish the title compound.
【1】
Oda, T.; et al.; Synthesis of novel 2-benzothiopyran and 3-benzothiepin derivatives and their stimulatory effect on bone formation. J Med Chem 1999, 42, 4, 751.
|
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) |
10984 |
1,3-Benzodioxol-5-amine; 1,3-Benzodioxol-5-ylamine.; 3,4-(Methylenedioxy)aniline
|
14268-66-7 |
C7H7NO2 |
详情 | 详情
|
(II) |
14156 |
methyl acrylate
|
96-33-3 |
C4H6O2 |
详情 | 详情
|
(III) |
24360 |
3-(1,3-Benzodioxol-5-yl)-2-bromopropionic acid methyl ester
|
|
C11H11BrO4 |
详情 |
详情
|
(IV) |
24361 |
2-sulfanylpropionic acid; 2-mercaptopropionic acid
|
57965-30-7 |
C3H6O2S |
详情 | 详情
|
(V) |
24362 |
2-[2-(1,3-Benzodioxol-5-yl)-1-(methoxycarbonyl)ethylsulfanyl]propionic acid
|
|
C14H16O6S |
详情 |
详情
|
(VI) |
24363 |
8-Methyl-9-oxo-5,6,8,9-tetrahydro-1,3-dioxolo[4,5-h][3]benzothiepine-6-carboxylic acid methyl ester
|
|
C14H14O5S |
详情 |
详情
|
(VII) |
24364 |
8(S)-Methyl-9-oxo-5,6,8,9-tetrahydro-1,3-dioxolo[4,5-h][3]benzothiepine-6(R)-carboxylic acid methyl ester
|
|
C14H14O5S |
详情 |
详情
|
(VIII) |
24365 |
2-Hydroxy-2-phenylacetic acid methyl ester
|
4358-87-6 |
C9H10O3 |
详情 | 详情
|
(IX) |
24366 |
8(S)-Methyl-9-oxo-5,6,8,9-tetrahydro-1,3-dioxolo[4,5-h][3]benzothiepine-6(R)-carboxylic acid 1(R)-(methoxycarbonyl)-1-benzyl ester
|
|
C22H20O7S |
详情 |
详情
|
(X) |
24367 |
8(S)-Methyl-9-oxo-5,6,8,9-tetrahydro-1,3-dioxolo[4,5-h][3]benzothiepine-6(R)-carboxylic acid
|
|
C13H12O5S |
详情 |
详情
|
(XI) |
24368 |
4-Aminobenzylphosphonic acid diethyl ester
|
20074-79-7 |
C11H18NO3P |
详情 | 详情
|
合成路线24
该中间体在本合成路线中的序号:
(IV) Total synthesis: Reaction of ethyl acetopyruvate (I) with triethyl orthoformate gives compound (II), which is then treated with cyanoacetamide to yield 3-cyano-4-methyl-6-(carbethoxy)-2(1H)-pyridone (III). The reaction of (III) with methyl acrylate (A) gives compound (IV), which is sequentially submitted to decarboxylation, ketalization and treatment with diethylcarbonate, giving the functionalized tetrahydroindolizine (V). Ethylation of (V) followed by reduction in the presence of acetic anhydride gives the amide (VI), which is reacted with sodium nitrite, refluxed in CCl4, hydrolyzed and acidified to give the tricyclic compound (VII). The DIBAL reduction of (VII) and subsequent elimination of the hydroxyl group gives the cyclic enol ether (VIII). Asymmetric dihydroxylation of compound (VIII) with (DHQD)2PHAL, K2OsO4 and K3Fe(CN)6 in t-BuOH gives the diol (IX). The oxidation and deketalization of compound (IX) gives (S)-hydroxylactone (X). Finally, Friedlander condensation of the lactone (X) with 3-[N-isopropyl-N-(carbobenzyloxy)amino]-1-(2-aminophenyl)propan-1-one (B) followed by deprotection gives CKD-602.
【1】
Hong, C.I.; Kim, J.K.; Ahn, S.K.; CKD-602. Drugs Fut 2000, 25, 12, 1243.
|
【2】
Kim, J.M.; Jew, S.; Kim, M.G.; Kim, H.-J.; Hah, J.M.; Ok, K.; Cho, Y.; Enantioselective synthesis of 20(S)-camptothecin using sharpless catalytic asymmetric dihydroxylation. Tetrahedron Asymmetry 1995, 6, 6, 1245.
|
【3】
Jew, S.-S.; Kim, H.-J.; Kim, M.G.; et al.; Synthesis and antitumor activity of 7-substituted 20(RS)-camptothecin analogues. Bioorg Med Chem Lett 1996, 6, 7, 845.
|
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) |
42500 |
ethyl 2,4-dioxopentanoate
|
615-79-2 |
C7H10O4 |
详情 | 详情
|
(II) |
42501 |
ethyl (Z)-4-ethoxy-2-oxo-3-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) |
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
|
(VII) |
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
|
(VIII) |
42502 |
|
|
C15H17NO5 |
详情 |
详情
|
(IX) |
42503 |
|
|
C15H17NO4 |
详情 |
详情
|
(X) |
42504 |
|
|
C15H19NO6 |
详情 |
详情
|
(XI) |
10841 |
(4S)-4-Ethyl-4-hydroxy-7,8-dihydro-1H-pyrano[3,4-f]indolizine-3,6,10(4H)-trione
|
|
C13H13NO5 |
详情 |
详情
|
(XII) |
42505 |
benzyl 3-(2-aminophenyl)-3-oxopropyl(isopropyl)carbamate
|
|
C20H24N2O3 |
详情 |
详情
|
合成路线25
该中间体在本合成路线中的序号:
(IX) 2) An alternative method starting from aniline (VII) employed the Meerwein arylation of methyl acrylate (IX) with the intermediate diazonium salt (VIII) in the presence of cuprous oxide. The resulting bromoester (X) was cyclized with thiourea (XI) in Et2O, followed by hydrolysis with HCl in sulfolane to afford (XIII). Finally, acid (XIII) was coupled to benzylamine (V) in the presence of (EtO)2POCN and Et3N.
【1】
Nomura, M.; et al.; (3-Substituted benzyl)thiazolidine-2,4-diones as structurally new antihyperglycemic agents. Bioorg Med Chem Lett 1999, 9, 4, 533.
|
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
|
42235 |
Diethyl phosphorocyanidate; Diethyl cyanophosphonate; Cyanophosphonic acid diethyl ester; Diethyl phosphoryl cyanide; DEPC
|
2942-58-7 |
C5H10NO3P |
详情 | 详情
|
(V) |
21925 |
[4-(trifluoromethyl)phenyl]methanamine; 4-(trifluoromethyl)benzylamine
|
3300-51-4 |
C8H8F3N |
详情 | 详情
|
(VII) |
21927 |
methyl 5-amino-2-methoxybenzoate
|
|
C9H11NO3 |
详情 |
详情
|
(VIII) |
21928 |
methyl 5-(1lambda(5)-diazynyl)-2-methoxybenzoate
|
|
C9H10N2O3 |
详情 |
详情
|
(IX) |
14156 |
methyl acrylate
|
96-33-3 |
C4H6O2 |
详情 | 详情
|
(X) |
21930 |
methyl 5-(2-bromo-3-methoxy-3-oxopropyl)-2-methoxybenzoate
|
|
C13H15BrO5 |
详情 |
详情
|
(XI) |
10180 |
Thiourea
|
62-56-6 |
CH4N2S |
详情 | 详情
|
(XII) |
21932 |
methyl 5-[(2-imino-4-oxo-1,3-thiazolidin-5-yl)methyl]-2-methoxybenzoate
|
|
C13H14N2O4S |
详情 |
详情
|
(XIII) |
21933 |
5-[(2,4-dioxo-1,3-thiazolidin-5-yl)methyl]-2-methoxybenzoic acid
|
|
C12H11NO5S |
详情 |
详情
|
合成路线26
该中间体在本合成路线中的序号:
Diazotization of 4,4'-diaminodiphenylmethane (I) with NaNO2 and HCl, followed by copper-catalyzed coupling with methyl acrylate afforded the alpha,alpha'-dichloro diester (II). Subsequent cyclization of (II) with thiourea (III) in refluxing EtOH produced the bis(iminothiazolidinone) (IV). Finally, acid hydrolysis of (IV) yielded the title compound.
【1】
Niigata, K.; Takahashi, T.; Iwaoka, K.; Yoneda, T.; Noshiro, O.; Koike, R. (Yamanouchi Pharmaceutical Co., Ltd.); Bisheterocyclic cpd.. EP 0533933; JP 1992511153; WO 9200967 .
|
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
|
14156 |
methyl acrylate
|
96-33-3 |
C4H6O2 |
详情 | 详情
|
(I) |
36325 |
4-(4-aminobenzyl)phenylamine; 4-(4-aminobenzyl)aniline
|
101-77-9 |
C13H14N2 |
详情 | 详情
|
(II) |
36324 |
methyl 2-chloro-3-[4-[4-(2-chloro-3-methoxy-3-oxopropyl)benzyl]phenyl]propanoate
|
|
C21H22Cl2O4 |
详情 |
详情
|
(III) |
10180 |
Thiourea
|
62-56-6 |
CH4N2S |
详情 | 详情
|
(IV) |
36326 |
2-imino-5-(4-[4-[(2-imino-4-oxo-1,3-thiazolidin-5-yl)methyl]benzyl]benzyl)-1,3-thiazolidin-4-one
|
|
C21H20N4O2S2 |
详情 |
详情
|
合成路线27
该中间体在本合成路线中的序号:
(II) Palladium-catalyzed coupling of 4-bromobenzophenone (I) with methyl acrylate (II) afforded 4-benzoylcinnamic ester (III), which was hydrolyzed to acid (IV) with NaOH. Condensation with taxane derivative (V) in the presence of DCC and DMAP then provided the target ester.
【1】
Bernacki, R.J.; Ojima, I. (State University of New York, Albany); Taxoid reversal agents for drug-resistance in cancer chemotherapy and pharmaceutical compsns. thereof. EP 0966456; US 5811452; WO 9830553 .
|
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) |
18447 |
(4-bromophenyl)(phenyl)methanone
|
90-90-4 |
C13H9BrO |
详情 | 详情
|
(II) |
14156 |
methyl acrylate
|
96-33-3 |
C4H6O2 |
详情 | 详情
|
(III) |
18449 |
methyl (E)-3-(4-benzoylphenyl)-2-propenoate
|
|
C17H14O3 |
详情 |
详情
|
(IV) |
18450 |
(E)-3-(4-benzoylphenyl)-2-propenoic acid
|
|
C16H12O3 |
详情 |
详情
|
(V) |
18451 |
(1S,2S,4S,7R,9S,10S,12R,15R,16S)-4,12,15-tris(acetoxy)-9-hydroxy-10,14,20,20-tetramethyl-11,18-dioxo-6,17,19-trioxapentacyclo[11.6.1.0(1,16).0(3,10).0(4,7)]icos-13-en-2-yl benzoate
|
|
C34H38O14 |
详情 |
详情
|
合成路线28
该中间体在本合成路线中的序号:
(II) Addition of methyl acrylate (II) to 4-fluorophenethylamine (I) afforded diester (III). Dieckmann cyclization of (III) gave the carbomethoxy piperidone (IV), which was decarbomethoxylated to (V) under acidic conditions.
【1】
Kimura, T.; Takahashi, K.; Matsunaga, M.; Kawano, K.; Kubota, A.; Kitazawa, N.; Okabe, T.; Ueno, K.; Komatsu, M.; Sasaki, A. (Eisai Co., Ltd.); 1,4-Substd. cyclic amine derivs.. EP 0976732; WO 9843956 .
|
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) |
45818 |
2-(4-fluorophenyl)-1-ethanamine; 4-fluorophenethylamine
|
|
C8H10FN |
详情 |
详情
|
(II) |
14156 |
methyl acrylate
|
96-33-3 |
C4H6O2 |
详情 | 详情
|
(III) |
45819 |
methyl 3-[(4-fluorophenethyl)(3-methoxy-3-oxopropyl)amino]propanoate
|
|
C16H22FNO4 |
详情 |
详情
|
(IV) |
45820 |
methyl 1-(4-fluorophenethyl)-4-oxo-3-piperidinecarboxylate
|
|
C15H18FNO3 |
详情 |
详情
|
(V) |
45821 |
1-(4-fluorophenethyl)-4-piperidinone
|
|
C13H16FNO |
详情 |
详情
|
合成路线29
该中间体在本合成路线中的序号:
(IV) The reaction of 2-chloropyrimidine (I) with NaOMe in methanol gives 2-methoxypyrimidine (II), which is iodinated with N-iodosuccinimide (NIS) and trifluoroacetic anhydride in refluxing THF to yield 5-iodo-2-methoxypyrimidine (III). The condensation of (III) with methyl acrylate (IV) by means of Pd(OAc)2, K2CO3 and Bu4NCl at 120 C affords 3-(2-methoxypyrimidin-5-yl)acrylic acid methyl ester (V), which is hydrolyzed with KOH in methanol to provide the free acid (VI). The esterification of (VI) with p-nitrophenol (VII) by means of DCC and DMAP in dichloromethane gives the activate ester (VIII). The condensation of (VIII) with the tetracyclic ketone (IX) (obtained by treatment of the dimeric ketonic compound (X) with NaOMe in methanol) affords the adduct (XI), which is treated with HBr in acetonitrile to open the cyclopropane ring and provide the bromomethyl compound (XII). The aromatization of (XII) with p-nitrophenyl chloroformate (XIII) and TEA in dichloromethane affords the activated carbonate ester (XIV), which is finally treated with 1-methylpiperazine (XV) to furnish the target carbamate.
【1】
Nagamura, S.; et al.; Synthesis and antitumor activity of duocarmycin derivatives: Modification of affinity moiety to DNA minor groove. 218th ACS Natl Meet (Aug 22 1999, New Orleans) 1999, Abst MEDI 206.
|
【2】
Saito, H.; Nagamura, S.; Amishiro, N.; Kobayashi, E.; Gomi, K.; New water-soluble duocarmycin derivatives: Synthesis and antitumor activity of A-ring pyrrole compounds bearing beta-heteroarylacryloyl groups. J Med Chem 1999, 42, 4, 669.
|
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) |
11191 |
2-Chloropyrimidine
|
1722-12-9 |
C4H3ClN2 |
详情 | 详情
|
(II) |
38398 |
methyl 2-pyrimidinyl ether; 2-methoxypyrimidine
|
|
C5H6N2O |
详情 |
详情
|
(III) |
38394 |
5-iodo-2-methoxypyrimidine; 5-iodo-2-pyrimidinyl methyl ether
|
|
C5H5IN2O |
详情 |
详情
|
(IV) |
14156 |
methyl acrylate
|
96-33-3 |
C4H6O2 |
详情 | 详情
|
(V) |
38395 |
methyl (E)-3-(2-methoxy-5-pyrimidinyl)-2-propenoate
|
|
C9H10N2O3 |
详情 |
详情
|
(VI) |
38396 |
(E)-3-(2-methoxy-5-pyrimidinyl)-2-propenoic acid
|
|
C8H8N2O3 |
详情 |
详情
|
(VII) |
11236 |
4-Nitrophenol; p-Nitrophenol
|
100-02-7 |
C6H5NO3 |
详情 | 详情
|
(VIII) |
38397 |
4-nitrophenyl (E)-3-(2-methoxy-5-pyrimidinyl)-2-propenoate
|
|
C14H11N3O5 |
详情 |
详情
|
(IX) |
38365 |
methyl (3bR,4aS)-2-methyl-8-oxo-1,4,4a,5,6,8-hexahydrocyclopropa[c]pyrrolo[3,2-e]indole-3-carboxylate
|
|
C14H14N2O3 |
详情 |
详情
|
(X) |
38366 |
methyl (2R,3bR,4aS)-2-methyl-3,8-dioxo-6-[(5,6,7-trimethoxy-1H-indol-2-yl)carbonyl]-1,2,3,4,4a,5,6,8-octahydrocyclopropa[c]pyrrolo[3,2-e]indole-2-carboxylate
|
|
C26H25N3O8 |
详情 |
详情
|
(XI) |
38399 |
methyl (3bR,4aS)-6-[(E)-3-(2-methoxy-5-pyrimidinyl)-2-propenoyl]-2-methyl-8-oxo-1,4,4a,5,6,8-hexahydrocyclopropa[c]pyrrolo[3,2-e]indole-3-carboxylate
|
|
C22H20N4O5 |
详情 |
详情
|
(XII) |
38400 |
methyl (8S)-8-(bromomethyl)-6-[(E)-3-(2-methoxy-5-pyrimidinyl)-2-propenoyl]-2-methyl-4-oxo-3,4,6,7,8,8a-hexahydropyrrolo[3,2-e]indole-1-carboxylate
|
|
C22H21BrN4O5 |
详情 |
详情
|
(XIII) |
16605 |
4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene
|
7693-46-1 |
C7H4ClNO4 |
详情 | 详情
|
(XIV) |
38401 |
methyl (8S)-8-(bromomethyl)-6-[(E)-3-(2-methoxy-5-pyrimidinyl)-2-propenoyl]-2-methyl-4-[[(4-nitrophenoxy)carbonyl]oxy]-3,6,7,8-tetrahydropyrrolo[3,2-e]indole-1-carboxylate
|
|
C29H24BrN5O9 |
详情 |
详情
|
(XV) |
10061 |
1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine
|
109-01-3 |
C5H12N2 |
详情 | 详情
|
合成路线30
该中间体在本合成路线中的序号:
(II) Palladium-catalyzed coupling of 4-bromobenzaldehyde (I) with methyl acrylate (II) furnished methyl 4-formylcinnamate (III). After aldehyde protection as the ethylene acetal (IV), ester group reduction using DIBAL in cold CH2Cl2 gave rise to the cinnamyl alcohol (V). O-Alkylation of (V) with ethyl iodide in the presence of NaH produced the corresponding ethyl ether (VI). The acetal protecting group of (VI) was then hydrolyzed with HCl to yield aldehyde (VII).
【2】
Zhang, C.; Mjalli, A.M.M. (Ontogen Corp.); Imidazole derivs. as MDR modulators. EP 0999835; US 5840721; WO 9902155 .
|
【1】
Dixon, R.; Zhang, C.; Sarshar, S.; Mjalli, A.M.M.; Rodarte, J.C.; Moran, E.J.; Benbatoul, K.D.; Krane, S.; 2,4,5-Trisubstituted imidazoles: Novel nontoxic modulators of P-glycoprotein mediated multidrug resistance. Part 2. Bioorg Med Chem Lett 2000, 10, 23, 2603. |
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) |
22231 |
4-Bromobenzaldehyde
|
1122-91-4 |
C7H5BrO |
详情 | 详情
|
(II) |
14156 |
methyl acrylate
|
96-33-3 |
C4H6O2 |
详情 | 详情
|
(III) |
46515 |
methyl (E)-3-(4-formylphenyl)-2-propenoate
|
7560-50-1 |
C11H10O3 |
详情 | 详情
|
(IV) |
46516 |
methyl (E)-3-[4-(1,3-dioxolan-2-yl)phenyl]-2-propenoate
|
|
C13H14O4 |
详情 |
详情
|
(V) |
46517 |
(E)-3-[4-(1,3-dioxolan-2-yl)phenyl]-2-propen-1-ol
|
|
C12H14O3 |
详情 |
详情
|
(VI) |
46518 |
(E)-3-[4-(1,3-dioxolan-2-yl)phenyl]-2-propenyl ethyl ether; 2-[4-[(E)-3-ethoxy-1-propenyl]phenyl]-1,3-dioxolane
|
|
C14H18O3 |
详情 |
详情
|
(VII) |
46519 |
4-[(E)-3-ethoxy-1-propenyl]benzaldehyde
|
|
C12H14O2 |
详情 |
详情
|
合成路线31
该中间体在本合成路线中的序号:
The benzylation of 4-C-(hydroxymethyl)-1,2-isopropylidene-alpha-D-ribofuranose (I) with benzyl bromide and NaH in DMF gives the 3,5-di-O-benzyl derivative (II), which is treated with I2, imidazole and triphenylphosphine in refluxing toluene/acetonitrile yielding the iodomethyl derivative (III). The deiodination of (III) with tributyltin hydride and AIBN in hot toluene affords the 4-C-methyl compound (IV), which is treated with acetic anhydride and H2SO4 in acetic acid to give the 1,2-di-O-acetyl derivative (V). The condensation of (V) with uracil (VI) by means of TMS-OTf yields the uridine derivative (VII), which is deprotected first by deacetylation with ammonia and then by debenzylation with H2 over Pd/C affording the 4'-C-methyl-uridine (VIII). The reaction of (VIII) with acetyl bromide in refluxing acetonitrile gives the acetylated 2'-bromo derivative (IX), which is debrominated with tributyltin hydride and AIBN in hot toluene yielding 3',5'-O-diacetyl-2'-deoxy-4'-C-methyl-uridine (X). The iodination of (X) with I2 and ceric ammonium nitrate (CAN) affords the 5-iodo derivative (XI), which is condensed with methyl acrylate by means of Pd(OAc)2 and triphenylphosphine in dioxane giving the methoxycarbonylvinyl derivative (XII). The hydrolysis of (XII) with NaOH in methanol yields 5-(2(E)-carboxyvinyl)-2'-deoxy-4'-C-methyl-uridine (XIII), which is finally submitted to a decarboxylative bromination with N-bromosuccinimide ans KHCO3 in DMF.
【1】
Waga, T.; et al.; Synthesis of 4'-C-methylnucleosides. Biosci Biotech Biochem 1993, 57, 9, 1433-38.
|
【2】
Waga, T.; et al.; Synthesis and biological evaluation of 4'-C-methylnucleosides. Nucleosides Nucleotides 1996, 15, 1-3, 287-304.
|
【3】
Machida, H.; Kitano, K.; Miura, S.; Synthesis of novel 4'-C-methyl-pyrimidine nucleosides and their biological activities. Bioorg Med Chem Lett 1999, 9, 6, 827.
|
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
|
12912 |
1-(Bromomethyl)benzene; Alpha-bromotoluene
|
100-39-0 |
C7H7Br |
详情 | 详情
|
|
14156 |
methyl acrylate
|
96-33-3 |
C4H6O2 |
详情 | 详情
|
(I) |
30916 |
[(3aR,6S,6aR)-6-(benzyloxy)-5-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl]methanol
|
|
C16H22O6 |
详情 |
详情
|
(II) |
30917 |
[(3aR,5S,6S,6aR)-6-(benzyloxy)-5-[(benzyloxy)methyl]-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl]methanol
|
|
C23H28O6 |
详情 |
详情
|
(III) |
30918 |
(3aR,5S,6S,6aR)-6-(benzyloxy)-5-[(benzyloxy)methyl]-5-(iodomethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole; [(3aR,5S,6S,6aR)-6-(benzyloxy)-5-(iodomethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl]methyl benzyl ether
|
|
C23H27IO5 |
详情 |
详情
|
(IV) |
30919 |
(3aR,5S,6S,6aR)-5-[(benzyloxy)methyl]-2,2,5-trimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-yl benzyl ether; (3aR,5S,6S,6aR)-6-(benzyloxy)-5-[(benzyloxy)methyl]-2,2,5-trimethyltetrahydrofuro[2,3-d][1,3]dioxole
|
|
C23H28O5 |
详情 |
详情
|
(V) |
30920 |
(2S,3R,4S,5S)-2-(acetoxy)-4-(benzyloxy)-5-[(benzyloxy)methyl]-5-methyltetrahydro-3-furanyl acetate
|
|
C24H28O7 |
详情 |
详情
|
(VI) |
30921 |
2,4(1H,3H)-pyrimidinedione; Uracil
|
66-22-8 |
C4H4N2O2 |
详情 | 详情
|
(VII) |
30922 |
(2R,3R,4S,5S)-4-(benzyloxy)-5-[(benzyloxy)methyl]-2-[2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]-5-methyltetrahydro-3-furanyl acetate
|
|
C26H28N2O7 |
详情 |
详情
|
(VIII) |
30923 |
1-[(2R,3R,4S,5S)-3,4-dihydroxy-5-(hydroxymethyl)-5-methyltetrahydro-2-furanyl]-2,4(1H,3H)-pyrimidinedione
|
|
C10H14N2O6 |
详情 |
详情
|
(IX) |
30924 |
[(2S,3R,4R,5R)-3-(acetoxy)-4-bromo-5-[2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]-2-methyltetrahydro-2-furanyl]methyl acetate
|
|
C14H17BrN2O7 |
详情 |
详情
|
(X) |
30925 |
[(2S,3S,5R)-3-(acetoxy)-5-[2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]-2-methyltetrahydro-2-furanyl]methyl acetate
|
|
C14H18N2O7 |
详情 |
详情
|
(XI) |
30926 |
[(2S,3S,5R)-3-(acetoxy)-5-[5-iodo-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]-2-methyltetrahydro-2-furanyl]methyl acetate
|
|
C14H17IN2O7 |
详情 |
详情
|
(XII) |
30927 |
methyl (E)-3-(1-[(2R,4S,5S)-4-(acetoxy)-5-[(acetoxy)methyl]-5-methyltetrahydro-2-furanyl]-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)-2-propenoate
|
|
C18H22N2O9 |
详情 |
详情
|
(XIII) |
30928 |
(E)-3-[1-[(2R,4S,5S)-4-hydroxy-5-(hydroxymethyl)-5-methyltetrahydro-2-furanyl]-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]-2-propenoic acid
|
|
C13H16N2O7 |
详情 |
详情
|
合成路线32
该中间体在本合成路线中的序号:
(IV) The reaction of 2-chloropyrimidine (I) with NaOMe in methanol gives 2-methoxypyrimidine (II), which is iodinated with N-iodosuccinimide (NIS) and trifluoroacetic anhydride in refluxing THF to yield 5-iodo-2-methoxypyrimidine (III). The condensation of (III) with methyl acrylate (IV) by means of Pd(OAc)2, K2CO3 and Bu4NCl at 120 C affords 3-(2-methoxypyrimidin-5-yl)acrylic acid methyl ester (V), which is hydrolyzed with KOH in methanol to provide the free acid (VI). The esterification of (VI) with p-nitrophenol (VII) by means of DCC and DMAP in dichloromethane gives the activate ester (VIII). Finally, the condensation of (VIII) with the tetracyclic ketone (IX) (obtained by treatment of the dimeric ketonic compound (X) with NaOMe in methanol) affords the target compound.
【1】
Saito, H.; Nagamura, S.; Amishiro, N.; Kobayashi, E.; Gomi, K.; New water-soluble duocarmycin derivatives: Synthesis and antitumor activity of A-ring pyrrole compounds bearing beta-heteroarylacryloyl groups. J Med Chem 1999, 42, 4, 669.
|
【2】
Nagamura, S.; et al.; Synthesis and antitumor activity of duocarmycin derivatives: Modification of affinity moiety to DNA minor groove. 218th ACS Natl Meet (Aug 22 1999, New Orleans) 1999, Abst MEDI 206.
|
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) |
11191 |
2-Chloropyrimidine
|
1722-12-9 |
C4H3ClN2 |
详情 | 详情
|
(II) |
38398 |
methyl 2-pyrimidinyl ether; 2-methoxypyrimidine
|
|
C5H6N2O |
详情 |
详情
|
(III) |
38394 |
5-iodo-2-methoxypyrimidine; 5-iodo-2-pyrimidinyl methyl ether
|
|
C5H5IN2O |
详情 |
详情
|
(IV) |
14156 |
methyl acrylate
|
96-33-3 |
C4H6O2 |
详情 | 详情
|
(V) |
38395 |
methyl (E)-3-(2-methoxy-5-pyrimidinyl)-2-propenoate
|
|
C9H10N2O3 |
详情 |
详情
|
(VI) |
38396 |
(E)-3-(2-methoxy-5-pyrimidinyl)-2-propenoic acid
|
|
C8H8N2O3 |
详情 |
详情
|
(VII) |
11236 |
4-Nitrophenol; p-Nitrophenol
|
100-02-7 |
C6H5NO3 |
详情 | 详情
|
(VIII) |
38397 |
4-nitrophenyl (E)-3-(2-methoxy-5-pyrimidinyl)-2-propenoate
|
|
C14H11N3O5 |
详情 |
详情
|
(IX) |
38365 |
methyl (3bR,4aS)-2-methyl-8-oxo-1,4,4a,5,6,8-hexahydrocyclopropa[c]pyrrolo[3,2-e]indole-3-carboxylate
|
|
C14H14N2O3 |
详情 |
详情
|
(X) |
38366 |
methyl (2R,3bR,4aS)-2-methyl-3,8-dioxo-6-[(5,6,7-trimethoxy-1H-indol-2-yl)carbonyl]-1,2,3,4,4a,5,6,8-octahydrocyclopropa[c]pyrrolo[3,2-e]indole-2-carboxylate
|
|
C26H25N3O8 |
详情 |
详情
|
合成路线33
该中间体在本合成路线中的序号:
(IX) Heck coupling between 4-bromobenzophenone (VIII) and methyl acrylate (IX) in the presence of palladium diacetate gave the unsaturated ester (X). Subsequent basic hydrolysis of the methyl ester group of (X) yielded p-benzoylcinnamic acid (XI). The title compound was then obtained by the coupling of acid (XI) with the precursor baccatin (VII) in the presence of EDC and DMAP.
【1】
Strum, M.; et al.; Synthesis and SAR of new taxane reversal agents. 221st ACS Natl Meet (April 1 2001, San Diego) 2001, Abst MEDI 131.
|
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
(VII) |
51205 |
(1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12,15-tris(acetoxy)-1,9-dihydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl 3-methoxybenzoate
|
|
C34H42O13 |
详情 |
详情
|
(VIII) |
18447 |
(4-bromophenyl)(phenyl)methanone
|
90-90-4 |
C13H9BrO |
详情 | 详情
|
(IX) |
14156 |
methyl acrylate
|
96-33-3 |
C4H6O2 |
详情 | 详情
|
(X) |
18449 |
methyl (E)-3-(4-benzoylphenyl)-2-propenoate
|
|
C17H14O3 |
详情 |
详情
|
(XI) |
18450 |
(E)-3-(4-benzoylphenyl)-2-propenoic acid
|
|
C16H12O3 |
详情 |
详情
|
合成路线34
该中间体在本合成路线中的序号:
(II) Conjugate addition of methyl acrylate (II) to 3-methoxybenzaldehyde (I) under reversion of reactivity conditions in the presence of KCN produced the keto ester (III). The Wolff-Kishner reduction of the keto group caused simultaneous ester hydrolysis, yielding acid (IV), which was further cyclized to the tetralone (V) employing hot polyphosphoric acid. Mannich reaction of ketone (V) with N-benzyl methylamine and paraformaldehyde furnished amino ketone (VI). To this was added phenylmagnesium bromide (VII), yielding amino alcohol (VIII), which was subsequently dehydrated to (IX) by means of trifluoroacetic acid. Catalytic hydrogenation of the olefin double bond of (IX) with simultaneous N-benzyl group hydrogenolysis gave the secondary amine (X). This was then alkylated with ethyl bromoacetate, producing the substituted glycine ester (XI), which was finally hydrolyzed by means of LiOH.
【1】
Jaap, D.R.; Gilfillan, R.; Gibson, S.G.; Thorn, S.N. (Akzo Nobel N.V.); Aminomethylcarboxylic acid derivs.. EP 1100769; WO 0007978 .
|
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) |
20589 |
3-methoxybenzaldehyde; m-Anisaldehyde
|
591-31-1 |
C8H8O2 |
详情 | 详情
|
(II) |
14156 |
methyl acrylate
|
96-33-3 |
C4H6O2 |
详情 | 详情
|
(III) |
51352 |
methyl 4-(3-methoxyphenyl)-4-oxobutanoate
|
|
C12H14O4 |
详情 |
详情
|
(IV) |
51353 |
4-(3-methoxyphenyl)butyric acid
|
|
C11H14O3 |
详情 |
详情
|
(V) |
17594 |
6-methoxy-3,4-dihydro-1(2H)-naphthalenone; 6-Methoxytetralone; 6-Methoxy-1-tetralone; 3,4-dihydro-6-methoxy-1(2H)-naphthalenone
|
1078-19-9 |
C11H12O2 |
详情 | 详情
|
(VI) |
51354 |
2-[[benzyl(methyl)amino]methyl]-6-methoxy-3,4-dihydro-1(2H)-naphthalenone
|
|
C20H23NO2 |
详情 |
详情
|
(VII) |
17616 |
bromo(phenyl)magnesium; Phenyl Magnesium Bromide
|
100-58-3 |
C6H5BrMg |
详情 | 详情
|
(VIII) |
51355 |
2-[[benzyl(methyl)amino]methyl]-6-methoxy-1-phenyl-1,2,3,4-tetrahydro-1-naphthalenol
|
|
C26H29NO2 |
详情 |
详情
|
(IX) |
51356 |
N-benzyl(6-methoxy-1-phenyl-3,4-dihydro-2-naphthalenyl)-N-methylmethanamine; N-benzyl-N-[(6-methoxy-1-phenyl-3,4-dihydro-2-naphthalenyl)methyl]-N-methylamine
|
|
C26H27NO |
详情 |
详情
|
(X) |
51357 |
[(1S,2R)-6-methoxy-1-phenyl-1,2,3,4-tetrahydro-2-naphthalenyl]-N-methylmethanamine; N-[[(1S,2R)-6-methoxy-1-phenyl-1,2,3,4-tetrahydro-2-naphthalenyl]methyl]-N-methylamine
|
|
C19H23NO |
详情 |
详情
|
(XI) |
51358 |
ethyl 2-[[[(1S,2R)-6-methoxy-1-phenyl-1,2,3,4-tetrahydro-2-naphthalenyl]methyl](methyl)amino]acetate
|
|
C23H29NO3 |
详情 |
详情
|
合成路线35
该中间体在本合成路线中的序号:
(IV) The esterification of 4-formylcinnamic acid (I) with methanol and HCl gives the methyl ester (II), which can be obtained by Heck coupling of 4-bromobenzaldehyde (III) with methyl acrylate (IV). The reductocondensation of (II) with tryptamine (V) by means of NaBH(OAc)3 in dichloroethane yields the secondary amine (VI), which is alkylated with 2-(tert-butyldimethylsilyloxy)ethyl bromide (VII) by means of DIEA in DMSO to afford the tertiary amine (VIII). The reaction of the methyl ester group of (VIII) with KOH and hydroxylamine in methanol provides the silylated hydroxamic acid (IX), which is finally deprotected with TFA in water.
【1】
Perez, L.B.; Remiszewski, S.; Sambucetti, L.; et al.; Discovery and SAR of NVP-LAQ824, a novel histone deacetylase inhibitor with in vitro and in vivo antitumor activity. Proc Am Assoc Cancer Res 2002, 43, Abst 3671.
|
【2】
Bair, K.W.; Versace, R.W.; Green, M.A.; Remiszewski, S.W.; Perez, L.B.; Sambucetti, L.; Sharma, S.K. (Novartis AG; Novartis-Erfindungen VmbH); Deacetylase inhibitors. WO 0222577 .
|
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) |
55571 |
4-Formylcinnamic acid
|
23359-08-2 |
C10H8O3 |
详情 | 详情
|
(II) |
46515 |
methyl (E)-3-(4-formylphenyl)-2-propenoate
|
7560-50-1 |
C11H10O3 |
详情 | 详情
|
(III) |
22231 |
4-Bromobenzaldehyde
|
1122-91-4 |
C7H5BrO |
详情 | 详情
|
(IV) |
14156 |
methyl acrylate
|
96-33-3 |
C4H6O2 |
详情 | 详情
|
(V) |
40537 |
Tryptamine; 2-(1H-Indol-3-yl)-1-ethanamine; 2-(1H-Indol-3-yl)ethylamine
|
61-54-1 |
C10H12N2 |
详情 | 详情
|
(VI) |
55572 |
methyl 3-[4-({[2-(1H-indol-3-yl)ethyl]amino}methyl)phenyl]-2-propenoate
|
|
C21H22N2O2 |
详情 |
详情
|
(VII) |
55573 |
2-Bromoethoxy-t-butyldimethylsilane
|
86864-60-0 |
C8H19BrOSi |
详情 | 详情
|
(VIII) |
55574 |
|
|
C29H40N2O3Si |
详情 |
详情
|
(IX) |
55575 |
3-[4-({(2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}ethyl)[2-(1H-indol-3-yl)ethyl]amino}methyl)phenyl]-N-hydroxy-2-propenamide
|
|
C28H39N3O3Si |
详情 |
详情
|
合成路线36
该中间体在本合成路线中的序号:
(XIII) In a related method, electrophilic bromination of 2,3-dichlorophenol (XI) gave (XII). Heck reaction of bromide (XII) with methyl acrylate (XIII) produced the cinnamic acid derivative (XIV). Sulfonylation of the phenolic hydroxyl of (XIV) with trifluoromethanesulfonic anhydride in pyridine furnished the aryl triflate (XV). This was coupled with the silyl sulfide intermediate (II) in the presence of CsF to produce the diaryl sulfide (XVI). After methyl ester (XVI) hydrolysis, the resultant cinnamic acid (VIII) was coupled with methyl isonipecotate (XVII) to furnish amide (XVIII). The title compound was then obtained by methyl ester (XVIII) hydrolysis with LiOH, followed by treatment with methanolic NaOH.
【1】
Jae, H.-S.; Pei, Z.; Staeger, M.A.; Gunawardana, I.W.; Winn, M.; Freeman, J.C.; Liu, G.; Link, J.; Boyd, S.A.; Zhu, G.-D.; Von Geldern, T.W.; Xin, Z.; Lynch, J.K.; Wang, S. (Abbott Laboratories Inc.); Cell adhesion-inhibiting antiinflammatory and immune-suppressive cpds.. WO 0059880 . |
【2】
Lynch, J.K.; Link, J.; Zhu, G.-D.; Boyd, S.A.; Winn, M.; Pei, Z.; Gunawardana, I.W.; Liu, G.; Xin, Z.; Jae, H.-S.; Freeman, J.C.; Von Geldern, T.; Staeger, M.A. (Abbott Laboratories Inc.); Cell adhesion-inhibiting antiinflammatory and immune-suppressive cpds.. US 6110922; WO 0039081 . |
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
(II) |
53020 |
1-methyl-5-[(triisopropylsilyl)sulfanyl]-1H-indole; 1-methyl-1H-indol-5-yl triisopropylsilyl sulfide
|
n/a |
C18H29NSSi |
详情 | 详情
|
(VIII) |
53023 |
(E)-3-{2,3-dichloro-4-[(1-methyl-1H-indol-5-yl)sulfanyl]phenyl}-2-propenoic acid
|
n/a |
C18H13Cl2NO2S |
详情 | 详情
|
(XI) |
53025 |
2,3-Dichlorophenol
|
576-24-9 |
C6H4Cl2O |
详情 | 详情
|
(XII) |
53026 |
4-bromo-2,3-dichlorophenol
|
n/a |
C6H3BrCl2O |
详情 | 详情
|
(XIII) |
14156 |
methyl acrylate
|
96-33-3 |
C4H6O2 |
详情 | 详情
|
(XIV) |
53027 |
methyl (E)-3-(2,3-dichloro-4-hydroxyphenyl)-2-propenoate
|
n/a |
C10H8Cl2O3 |
详情 | 详情
|
(XV) |
53028 |
methyl (E)-3-(2,3-dichloro-4-{[(trifluoromethyl)sulfonyl]oxy}phenyl)-2-propenoate
|
n/a |
C11H7Cl2F3O5S |
详情 | 详情
|
(XVI) |
53029 |
methyl (E)-3-{2,3-dichloro-4-[(1-methyl-1H-indol-5-yl)sulfanyl]phenyl}-2-propenoate
|
n/a |
C19H15Cl2NO2S |
详情 | 详情
|
(XVII) |
38418 |
methyl 4-piperidinecarboxylate; Isonipecotic acid methyl ester; 4-piperidinecarboxylic acid methyl ester
|
2971-79-1 |
C7H13NO2 |
详情 | 详情
|
(XVIII) |
53030 |
methyl 1-((E)-3-{2,3-dichloro-4-[(1-methyl-1H-indol-5-yl)sulfanyl]phenyl}-2-propenoyl)-4-piperidinecarboxylate
|
n/a |
C25H24Cl2N2O3S |
详情 | 详情
|
合成路线37
该中间体在本合成路线中的序号:
(IX) Condensation of acetaldehyde with methyl acrylate (VIII) under Bayliss-Hillmann conditions gave rise to the allylic alcohol (IX). Bromination of (IX) using N-bromosuccinimide and dimethyl sulfide proceeded with rearrangement to the allyl bromide (X). This was then coupled with aldehyde (VII) in the presence of metallic tin and catalytic amounts of HOAc to produce, after acid-catalyzed cyclization, the target methylene butyrolactone derivative.
【1】
Gonzalez, A.G.; et al.; Synthesis and antiproliferative activity of a new compound containing an alpha-methylene-gamma-lactone group. J Med Chem 2002, 45, 12, 2358.
|
【2】
Bermejo Barrera, J.; Hernandez Silva, M.; Alvarez de Mon, M.; Pivel Ranieri, J.P. (CSIC (Consejo Superior de Investigaciones Cientificas)); Derivs. of p-hydroxy phenyl propionic acid as antiproliferative agents. ES 2160093; WO 0172733 .
|
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
(VIII) |
56437 |
3-(4-methoxyphenyl)propanal
|
|
C10H12O2 |
详情 |
详情
|
(IX) |
14156 |
methyl acrylate
|
96-33-3 |
C4H6O2 |
详情 | 详情
|
(X) |
56438 |
Methyl 3-hydroxy-2-methylenebutyrate
|
|
C6H10O3 |
详情 |
详情
|
(XI) |
30136 |
methyl (Z)-2-(bromomethyl)-2-butenoate
|
|
C6H9BrO2 |
详情 |
详情
|
合成路线38
该中间体在本合成路线中的序号:
(VIII) Michael addition of methyl acrylate (VIII) to methyl phenylacetate (VII) in the presence of NaH produces the intermediate triester (IX) which, under the reaction conditions, undergoes Dieckmann cyclization to the cyclohexanone diester (X). Hydrolysis and decarboxylation of keto diester (X) leads to keto acid (XI). This is then subjected to Curtius rearrangement in the presence of diphenylphosphoryl azide (DPPA) to yield, after acidic hydrolysis of the intermediate isocyanate, the amino cyclohexanone (XII). Acylation of amine (XII) by acid chloride (VI) then gives amide (XIII).
【1】
Elliott, J.M.; Castro Pineiro, J.L.; Swain, C.J.; Hollingworth, G.J.; Dinnell, K.; Shaw, D.E. (Merck Sharp & Dohme Ltd.); Cyclohexane derivs. and their use as therapeutic agents. WO 0187838 .
|
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
(VI) |
57084 |
2-[3,5-bis(trifluoromethyl)phenyl]propanoyl chloride
|
|
C11H7ClF6O |
详情 |
详情
|
(VII) |
32831 |
methyl 2-phenylacetate
|
101-41-7 |
C9H10O2 |
详情 | 详情
|
(VIII) |
14156 |
methyl acrylate
|
96-33-3 |
C4H6O2 |
详情 | 详情
|
(IX) |
57085 |
trimethyl 3-phenyl-1,3,5-pentanetricarboxylate
|
|
C17H22O6 |
详情 |
详情
|
(X) |
57086 |
dimethyl 4-oxo-1-phenyl-1,3-cyclohexanedicarboxylate
|
|
C16H18O5 |
详情 |
详情
|
(XI) |
57087 |
4-oxo-1-phenylcyclohexanecarboxylic acid
|
|
C13H14O3 |
详情 |
详情
|
(XII) |
57088 |
4-amino-4-phenylcyclohexanone
|
|
C12H15NO |
详情 |
详情
|
(XIII) |
57089 |
2-[3,5-bis(trifluoromethyl)phenyl]-N-(4-oxo-1-phenylcyclohexyl)propanamide
|
|
C23H21F6NO2 |
详情 |
详情
|
合成路线39
该中间体在本合成路线中的序号:
(II) The Baylis-Hillman reaction between N-Boc-alaninal (I) and methyl acrylate (II) in the presence of DABCO yields the allylic alcohol adduct (III). Subsequent Mitsunobu coupling with acetic acid leads to the rearranged allylic acetate (IV). Acidic Boc group cleavage in (IV) then gives the amino ester intermediate (V).
【1】
Zhu, S.; et al.; Synthesis and in vitro studies of novel pyrimidinyl peptidomimetics as potential antimalarial therapeutic agents. J Med Chem 2002, 45, 16, 3491.
|
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) |
59029 |
tert-butyl (1S)-1-methyl-2-oxoethylcarbamate
|
|
C8H15NO3 |
详情 |
详情
|
(II) |
14156 |
methyl acrylate
|
96-33-3 |
C4H6O2 |
详情 | 详情
|
(III) |
59026 |
methyl 2-{(2S)-2-[(tert-butoxycarbonyl)amino]-1-hydroxypropyl}acrylate
|
|
C12H21NO5 |
详情 |
详情
|
(IV) |
59027 |
methyl (E,4S)-2-[(acetyloxy)methyl]-4-[(tert-butoxycarbonyl)amino]-2-pentenoate
|
|
C14H23NO6 |
详情 |
详情
|
(V) |
59028 |
methyl (E,4S)-2-[(acetyloxy)methyl]-4-amino-2-pentenoate
|
|
C9H15NO4 |
详情 |
详情
|
合成路线40
该中间体在本合成路线中的序号:
(IV) Friedel-Crafts condensation of 4'-bromobiphenyl-4-ol (I) with 1-adamantanol (II) affords the adamantanylbiphenyl derivative (III). This is then subjected to Heck coupling with methyl acrylate (IV) to produce the biphenylyl acrylate (V). Finally, basic hydrolysis of ester (V) leads to the title carboxylic acid.
【1】
Cincinelli, R.; Dallavalle, S.; Merlini, L.; Penco, S.; Pisano, C.; Carminati, P.; Giannini, G.; Vesci, L.; Gaetano, C.; Illy, B.; Zuco, V.; Supino, R.; Zunino, F.; A novel atypical retinoid endowed with proapoptotic and antitumor activity. J Med Chem 2003, 46, 6, 909. |
【2】
Penco, S.; Merlini, L.; Giannini, G.; Vesci, L.; Pisano, C.; Dallavalle, S. (Sigma-Tau Industrie Farmaceutiche Riunite SpA); Retinoid derivs. with antiangiogenic, antitumoral and proapoptotic activities. WO 0311808 .
|
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) |
48853 |
4-(4-Bromophenyl)phenol; 4-(4'-Bromophenyl)phenol; 4-Bromo-4'-hydroxybiphenyl
|
29558-77-8 |
C12H9BrO |
详情 | 详情
|
(II) |
52642 |
1-Adamantanol; 1-Hydroxyadamantane; Tricyclo[3.3.1.1]decan-1-ol
|
768-95-6 |
C10H16O |
详情 | 详情
|
(III) |
63330 |
4'-bromo-3-tricyclo[3.3.1.1~3,7~]dec-1-yl[1,1'-biphenyl]-4-ol
|
|
C22H23BrO |
详情 |
详情
|
(IV) |
14156 |
methyl acrylate
|
96-33-3 |
C4H6O2 |
详情 | 详情
|
(V) |
63331 |
methyl 3-(4'-hydroxy-3'-tricyclo[3.3.1.1~3,7~]dec-1-yl[1,1'-biphenyl]-4-yl)-2-propenoate
|
|
C26H28O3 |
详情 |
详情
|
合成路线41
该中间体在本合成路线中的序号:
(XVII) A different protection strategy involves masking the ring nitrogens as amide groups. Methyl acrylate (XVII) is reacted with neat ethylenediamine (XVIII) to yield the aminopropionamide derivative (XIX), which is then cyclized with dimethyl malonate (XX), producing the trioxocyclam (XXI). After condensation of (XXI) with p-dibromoxylene (IIIa), the resulting hexaoxo bis-cyclam (XXII) is reduced to the title compound employing borane-dimethyl sulfide complex in refluxing THF (10). Alternatively, protection of the linear tetraamine (XXIII) with pyruvic aldehyde (XXIV) generates the tricyclic bisaminal (XXV) along with its minor isomer (XXVI). The crude mixture of bis-aminals (XXV) and (XXVI) is then cyclized to (XXVIII) with 1,3-dibromopropane (XXVII) and K2CO3. After condensation of (XXVIII) with dibromide (IIIa), the resulting bis-ammonium dimer (XXIX) is hydrolyzed to the title compound upon heating with 3M NaOH (11). Scheme 3.
【10】
Achmatowicz, M., Hegedus, L.S. Direct synthesis of 1,1’-[1,4-phenylenebis(methylene)]-bis-1,4,8,11-tetraazacyclotetradecane octahydrochloride (AMD 3100) without the use of protecting groups. J Org Chem 2003, 68(16): 6435-6. |
【11】
Boschetti, F., Denat, F., Espinosa, E., Tabard, A., Dory, Y., Guilard, R. Regioselective N-functionalization of tetraazacycloalkanes. J Org Chem 2005, 70(18): 7042-53. |
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
(IIIa) |
18697 |
1,4-bis(bromomethyl)benzene
|
623-24-5 |
C8H8Br2 |
详情 | 详情
|
(XVII) |
14156 |
methyl acrylate
|
96-33-3 |
C4H6O2 |
详情 | 详情
|
(XVIII) |
14754 |
ethylenediamine;1,2-Diaminoethane;ethane-1,2-diamine;1,2-Ethanediamine |
107-15-3 |
C2H8N2 |
详情 | 详情
|
(XIX) |
65221 |
|
|
C7H18N4O |
详情 | 详情
|
(XX) |
19373 |
dimethyl malonate;Methyl malonate;Propanedioic acid dimethyl ester |
108-59-8 |
C5H8O4 |
详情 | 详情
|
(XXI) |
65222 |
|
|
C10H18N4O3 |
详情 | 详情
|
(XXII) |
65223 |
|
|
C28H42N8O6 |
详情 | 详情
|
(XXIII) |
53968 |
1,4,8,11-Tetraazaundecane; 3,7-Diaza-1,9-nonanediamine; N,N'-Bis(2-aminoethyl)-1,3-propanediamine; N,N[-Bis(2-aminoethyl)-1,3-propanediamine
|
4741-99-5 |
C7H20N4 |
详情 | 详情
|
(XXIV) |
25598 |
2-oxopropanal
|
78-98-8 |
C3H4O2 |
详情 | 详情
|
(XXV) |
65224 |
|
|
C10H20N4 |
详情 | 详情
|
(XXVI) |
65225 |
|
|
C10H20N4 |
详情 | 详情
|
(XXVII) |
12581 |
1,3-Dibromopropane
|
109-64-8 |
C3H6Br2 |
详情 | 详情
|
(XXVIII) |
65526 |
|
|
C26H37O7P |
详情 | 详情
|
(XXIX) |
65227 |
|
|
C34H54Br2N8 |
详情 | 详情
|
合成路线42
该中间体在本合成路线中的序号:
(VI)
【1】
R4jendra GL, Pang NG, Maya JS, et al. 2004. Improved process for preparation of thiazolidinedione derivatives. W0 2004024059 |
【2】
Sohda T, Momose Y, Meguro K, et al. 1990. Studies on antidiabetic agents Synthesis and hypoglycemic activity of 5-[4-(pyridylaIkoxy) benzyl]-2,4-thiazolidinediones. Arzneim-Forsch, 40: 37~42 |
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) |
62866 |
2-(5-ethyl-2-pyridinyl)ethyl methanesulfonate
|
|
C10H15NO3S |
详情 |
详情
|
(II) |
11236 |
4-Nitrophenol; p-Nitrophenol
|
100-02-7 |
C6H5NO3 |
详情 | 详情
|
(III) |
62867 |
5-ethyl-2-[2-(4-nitrophenoxy)ethyl]pyridine; 2-(5-ethyl-2-pyridinyl)ethyl 4-nitrophenyl ether
|
|
C15H16N2O3 |
详情 |
详情
|
(IV) |
62868 |
4-[2-(5-ethyl-2-pyridinyl)ethoxy]aniline; 4-[2-(5-ethyl-2-pyridinyl)ethoxy]phenylamine
|
|
C15H18N2O |
详情 |
详情
|
(V) |
66597 |
4-(2-(5-ethylpyridin-2-yl)ethoxy)benzenediazonium |
|
C15H16N3O |
详情 | 详情
|
(VI) |
14156 |
methyl acrylate
|
96-33-3 |
C4H6O2 |
详情 | 详情
|
(VII) |
66598 |
methyl 3-(4-(2-(5-ethylpyridin-2-yl)ethoxy)phenyl)propanoate |
|
C19H23NO3 |
详情 | 详情
|
合成路线43
该中间体在本合成路线中的序号:
(V)
【1】
Li L, Tian QS, Wei WT, et al. 2003. Process for preparation of alvimopan and intermediates. 发明专利申请公开说明书, CN 1827598(Tianjiu Taipu Medicine Science and Technology Development Co, Ltd, Peop Rep China) |
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) |
16618 |
(3R,4R)-4-(3-isopropoxyphenyl)-1,3,4-trimethylhexahydropyridine; isopropyl 3-[(3R,4R)-1,3,4-trimethylhexahydro-4-pyridinyl]phenyl ether
|
|
C17H27NO |
详情 |
详情
|
(II) |
67026 |
(3R,4R)-phenyl 4-(3-isopropoxyphenyl)-3,4-dimethylpiperidine-1-carboxylate |
|
C23H29NO3 |
详情 | 详情
|
(III) |
16620 |
3-[(3R,4R)-3,4-dimethylhexahydro-4-pyridinyl]phenol
|
119193-19-0 |
C13H19NO |
详情 | 详情
|
(IV) |
10498 |
Benzaldehyde;Benzoic aldehyde;Phenylmethanal |
100-52-7 |
C7H6O |
详情 | 详情
|
(V) |
14156 |
methyl acrylate
|
96-33-3 |
C4H6O2 |
详情 | 详情
|
(VI) |
49470 |
methyl 2-[hydroxy(phenyl)methyl]acrylate
|
|
C11H12O3 |
详情 |
详情
|
(VII) |
49475 |
methyl (E)-2-[(acetoxy)methyl]-3-phenyl-2-propenoate
|
|
C13H14O4 |
详情 |
详情
|
(VIII) |
49476 |
(E)-2-(hydroxymethyl)-3-phenyl-2-propenoic acid
|
|
C10H10O3 |
详情 |
详情
|
(IX) |
49480 |
2-benzyl-3-hydroxypropionic acid
|
|
C10H12O3 |
详情 |
详情
|
(X) |
49481 |
(2S)-2-benzyl-3-hydroxypropionic acid
|
|
C10H12O3 |
详情 |
详情
|
(XI) |
13601 |
benzyl 2-aminoacetate; Glycine benzyl ester hydrochloride
|
1738-68-7 |
C9H11NO2 |
详情 | 详情
|
(XII) |
49477 |
benzyl 2-[[(2S)-2-benzyl-3-hydroxypropanoyl]amino]acetate
|
|
C19H21NO4 |
详情 |
详情
|
(XIII) |
49478 |
benzyl 2-([(2S)-2-benzyl-3-[(methylsulfonyl)oxy]propanoyl]amino)acetate
|
|
C20H23NO6S |
详情 |
详情
|
(XIV) |
49479 |
benzyl 2-[[(2S)-2-benzyl-3-bromopropanoyl]amino]acetate
|
|
C19H20BrNO3 |
详情 |
详情
|
(XV) |
67027 |
benzyl 2-(2-benzyl-3-(4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl)propanamido)acetate |
|
C32H38N2O4 |
详情 | 详情
|
合成路线44
该中间体在本合成路线中的序号:
(XXVIIb) Jones oxidation of 2-fluoro-4-methyl-1-nitrobenzene (XVIII) with CrO3 and H2SO4, followed by acetylation with Ac2O in AcOH yields the gemdiacetate (XIX), which by deacetylation with HCl in AcOH at 115 °C provides 3-fluoro-4-nitrobenzaldehyde (XX). Horner-Wadsworth-Emmons reaction of aldehyde (XX) with ethyl (diethoxyphosphoryl)acetate (XXI) using NaH in THF affords the unsaturated ester (XXII), which by fluoride substitution with methylamine (XXIII) in DMSO provides the nitro-aniline derivative (XXIVa) . Alternatively, condensation of 2,4-dichloro-1-nitrobenzene (XXV) with methylamine (XXIII) using Et3N in DMSO or THF yields 5-chloro-N-methyl-2-nitroaniline (XXVI), which is then subjected to Heck coupling with ethyl acrylate (XXVIIa), methyl acrylate (XXVIIb) or butyl acrylate (XXVIIa) in the presence of Pd(OAc)2, LiCl and DIEA in DMAc at 110 °C , or Pd2dba3, t-Bu3P and (c-Hex)2NMe at 110 °C to give the corresponding arylacrylates (XXIVa), (XXIVb) or (XXIVc). Reduction of the nitro group in compounds (XXIVa), (XXIVb) or (XXIVc) by means of SnCl2.2H2O in EtOH at 80 °C , H2 over Raney-Ni in toluene/MeOH or Na2S2O4 and K2CO3 in EtOH/H2O produces the corresponding diaminophenylacrylates (XXVIIIa) , (XXVIIIb) or (XXVIIIc) , which are finally condensed with 1-aminocyclo-butanecarboxylic acid hydrochloride (XXIX) in CH2Cl2 to provide the benzimidazole intermediates (IIIa) , (IIIb) or (XXX), the free base of intermediate (II) .
Similarly, intermediate (II) can be obtained by condensation of the diaminophenylacrylate (XXVIIIc) with N-Boc-1-aminocyclobutanecarboxylic acid (XXXI) using DCC in toluene, followed by N-deprotection and cyclization of the resulting amino amide (XXXII) with HCl in BuOH at 75 °C .
【1】
Boecher, W., Haefner, C., Kukolj, G. (Boehringer Ingelheim Pharma GmbH & Co. KG). Combination therapy for treating HCV infection. CN 103228278, EP 2621495, JP 2013540112, KR 2013116245, US 2012135949, WO 2012041771. |
【2】
Brickl, R.-S., Chen, S., Chung, J. et al. (Boehringer Ingelheim Pharma GmbH & Co. KG). Solid state forms of a potent HCV inhibitor. CN 103153987, EP 2621921, JP 2013543495, KR 2013108326, US 2012122887, US 8598183, US 2014057928, WO 2012044520. |
【3】
Mensa, F., Nehmiz, G. (Boehringer Ingelheim Pharma GmbH & Co. KG). Oral combination therapy for treating HCV infection in specific patient subgenotype populations. WO 2013147749. |
【4】
Mensa, F. (Boehringer Ingelheim Pharma GmbH & Co. KG). Oral combination therapy for treating HCV infection in specific patient sub-population. WO 2013147750. |
【5】
LaPlante, S.R., Boes, M., Brochu, C. et al. Conformation-based restrictions and scaffold replacements in the design of hepatitis C virus polymerase inhibitors. Discovery of deleobuvir (BI 207127). J Med Chem 2014, 57(5): 1845-54. |
【6】
Tsantrizos, Y.S., Chabot, C., Beaulieu, P. et al. (Boehringer Ingelheim Pharma GmbH & Co. KG). Viral polymerase inhibitors. CN 102911161, CN 103304541, CN 103319464, CN 103333162, EP 1718608, EP 2626354, JP 2007523094, JP 2010195818, JP 2010280740, KR 2012091276, US 2005222236, US 8030309, WO 2005080388. |
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
(XXIVa) |
67786 |
(E)-ethyl 3-(3-(methylamino)-4-nitrophenyl)acrylate |
|
C12H14N2O4 |
详情 | 详情
|
(XXIVb) |
67787 |
(E)-methyl 3-(3-(methylamino)-4-nitrophenyl)acrylate |
|
C11H12N2O4 |
详情 | 详情
|
(XXIVc) |
67788 |
(E)-butyl 3-(3-(methylamino)-4-nitrophenyl)acrylate |
|
C14H18N2O4 |
详情 | 详情
|
(XXVIIa) |
10164 |
ethyl acrylate
|
140-88-5 |
C5H8O2 |
详情 | 详情
|
(XXVIIb) |
14156 |
methyl acrylate
|
96-33-3 |
C4H6O2 |
详情 | 详情
|
(XXVIIc) |
67789 |
butyl acrylate |
|
C7H12O2 |
详情 | 详情
|
(XXVIIIa) |
67791 |
(E)-ethyl 3-(4-amino-3-(methylamino)phenyl)acrylate |
|
C12H16N2O2 |
详情 | 详情
|
(XXVIIIb) |
67792 |
(E)-methyl 3-(4-amino-3-(methylamino)phenyl)acrylate |
|
C11H14N2O2 |
详情 | 详情
|
(XXVIIIc) |
67790 |
(E)-butyl 3-(4-amino-3-(methylamino)phenyl)acrylate |
|
C14H20N2O2 |
详情 |
详情
|
(IIIa) |
67765 |
(E)-methyl 3-(2-(1-aminocyclobutyl)-1-methyl-1H-benzo[d]imidazol-6-yl)acrylate |
|
C16H19N3O2 |
详情 | 详情
|
(IIIb) |
67766 |
(E)-ethyl 3-(2-(1-aminocyclobutyl)-1-methyl-1H-benzo[d]imidazol-6-yl)acrylate |
|
C17H21N3O2 |
详情 | 详情
|
(II) |
67764 |
(E)-butyl 3-(2-(1-aminocyclobutyl)-1-methyl-1H-benzo[d]imidazol-6-yl)acrylate dihydrochloride |
|
C19H25N3O2.2HCl |
详情 | 详情
|
(XVIII) |
39366 |
2-fluoro-4-methyl-1-nitrobenzene
|
446-34-4 |
C7H6FNO2 |
详情 | 详情
|
(XIX) |
67783 |
(3-fluoro-4-nitrophenyl)methylene diacetate |
|
C11H10FNO6 |
详情 | 详情
|
(XX) |
67784 |
3-fluoro-4-nitrobenzaldehyde |
|
C7H4FNO3 |
详情 | 详情
|
(XXI) |
10019 |
Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate
|
867-13-0 |
C8H17O5P |
详情 | 详情
|
(XXII) |
67785 |
(E)-ethyl 3-(3-fluoro-4-nitrophenyl)acrylate |
|
C11H10FNO4 |
详情 | 详情
|
(XXIII) |
11021 |
Methanamine; Methylamine
|
74-89-5 |
CH5N |
详情 | 详情
|
(XXV) |
21787 |
2,4-dichloro-1-nitrobenzene
|
611-06-3 |
C6H3Cl2NO2 |
详情 | 详情
|
(XXVI) |
46715 |
5-chloro-N-methyl-2-nitroaniline; N-(5-chloro-2-nitrophenyl)-N-methylamine
|
35966-84-8 |
C7H7ClN2O2 |
详情 | 详情
|
(XXIX) |
67793 |
1-aminocyclo-butanecarboxylic acid
hydrochloride |
98071-16-0 |
C5H9NO2.HCl |
详情 | 详情
|
(XXX) |
67794 |
(E)-butyl 3-(2-(1-aminocyclobutyl)-1-methyl-1H-benzo[d]imidazol-6-yl)acrylate |
|
C19H25N3O2 |
详情 | 详情
|
(XXXI) |
67795 |
1-((tert-butoxycarbonyl)amino)cyclobutanecarboxylic acid |
|
C10H17NO4 |
详情 | 详情
|
(XXXII) |
67796 |
(E)-butyl 3-(4-amino-3-(1-((tert-butoxycarbonyl)amino)-N-methylcyclobutanecarboxamido)phenyl)acrylate |
|
C24H35N3O5 |
详情 | 详情
|
合成路线45
该中间体在本合成路线中的序号:
(II) Heck coupling of 2-bromo-6-fluoroaniline (I) with methyl acrylate (II) by means of Pd(oAc)2, (o-tol)3P and Et3n in refluxing acetonitrile yields the (E)-cinnamate (III), which is then treated with PPh3 in the presence of CCl4 and Et3n in acetonitrile to give the iminophosphorane (IV). Compound (IV) is then condensed with 2-methoxy-5-(trifluoromethyl) phenyl isocyanate (V) [prepared by treatment of 2-methoxy-5-(trifluoromethyl)aniline (VI) with diphosgene in the presence of proton sponge] in CH2Cl2 to provide the carbodiimide (VII). Cyclocondensation of carbodiimide (VII) with 1-(3-methoxyphenyl)-piperazine (VIII) in the presence of Sio2 in refluxing CH2Cl2 affords the 3,4-dihydroquinazoline derivative (IX) (1), which is then subjected to ester hydrolysis with naoH in H2o/dioxane to produce the racemic carboxylic acid (X) . Finally, racemate (X) is resolved through chiral HPLC .
In an alternative procedure, chlorination of the dihydroquinazolinone derivative (XI) with PoCl3 and DBU in refluxing chlorobenzene, followed by coupling of the resulting 2-chloro-3,4-dihydroquinazoline (XII) with 1-(3-methoxyphenyl)piperazine (VIII) in the presence of DBU in refluxing dioxane produces the 3,4-dihydroquinazoline derivative (IX). Resolution of the racemic ester (IX) using di-p-toluoyl-D-tartaric acid in EtoAc provides the corresponding (S)-enantiomer (XIII), which is finally hydrolyzed with naoH in H2O/dioxane .
【1】
Wunberg, T., Jeske, M., Lampe, T. et al. (Bayer HealthCare AG). Substituted dihydrochinazolines having antiviral properties. DE 10319612, EP 1622880, JP 2006525249, US 2005065160, US 7196086, US 2007191387, Wo 2004096778. |
【2】
Goossen, K., Kuhn, o., Berwe, M., Krueger, J., Militzer, H.-C. (Bayer HealthCare AG). Method for producing dihydroquinazolines. Cn 101863843, DE 10227517, EP 1893587, JP 2008543797, US 2009221822, US 8084604, US 2012130072, US 8372972, Wo 2006133822. |
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) |
68030 |
2-bromo-6-fluoroaniline |
65896-11-9 |
C6H5BrFN |
详情 | 详情
|
(II) |
14156 |
methyl acrylate
|
96-33-3 |
C4H6O2 |
详情 | 详情
|
(III) |
68031 |
(E)-methyl 3-(2-amino-3-fluorophenyl)acrylate |
|
C10H10FNO2 |
详情 | 详情
|
(IV) |
68032 |
(E)-methyl 3-(3-fluoro-2-((triphenylphosphoranylidene)amino)phenyl)acrylate |
|
C28H23FNO2P |
详情 | 详情
|
(V) |
68033 |
2-methoxy-5-(trifluoromethyl)phenyl isocyanate |
16588-75-3 |
C9H6F3NO2 |
详情 | 详情
|
(VI) |
27669 |
2-methoxy-5-(trifluoromethyl)aniline
|
349-65-5 |
C8H8F3NO |
详情 | 详情
|
(VII) |
68034 |
(E)-methyl 3-(3-fluoro-2-((((2-methoxy-4-(trifluoromethyl)phenyl)imino)methylene)amino)phenyl)acrylate |
|
C19H14F4N2O3 |
详情 | 详情
|
(VIII) |
14853 |
methyl 3-piperazinophenyl ether; 1-(3-methoxyphenyl)piperazine
|
16015-71-7 |
C11H16N2O |
详情 | 详情
|
(IX) |
68035 |
methyl 2-(8-fluoro-3-(2-methoxy-5-(trifluoromethyl)phenyl)-2-(4-(3-methoxyphenyl)piperazin-1-yl)-3,4-dihydroquinazolin-4-yl)acetate |
|
C30H30F4N4O4 |
详情 | 详情
|
(X) |
68036 |
2-(8-fluoro-3-(2-methoxy-5-(trifluoromethyl)phenyl)-2-(4-(3-methoxyphenyl)piperazin-1-yl)-3,4-dihydroquinazolin-4-yl)acetic acid |
|
C29H28F4N4O4 |
详情 | 详情
|
(XI) |
68037 |
methyl 2-(8-fluoro-3-(2-methoxy-5-(trifluoromethyl)phenyl)-2-oxo-1,2,3,4-tetrahydroquinazolin-4-yl)acetate |
|
C19H16F4N2O4 |
详情 | 详情
|
(XII) |
68038 |
methyl 2-(2-chloro-8-fluoro-3-(2-methoxy-5-(trifluoromethyl)phenyl)-3,4-dihydroquinazolin-4-yl)acetate |
|
C19H15ClF4N2O3 |
详情 | 详情
|
(XIII) |
68039 |
(S)-methyl 2-(8-fluoro-3-(2-methoxy-5-(trifluoromethyl)phenyl)-2-(4-(3-methoxyphenyl)piperazin-1-yl)-3,4-dihydroquinazolin-4-yl)acetate |
|
C30H30F4N4O4 |
详情 | 详情
|
合成路线46
该中间体在本合成路线中的序号:
(II) Condensation of 2-fluoroaniline (XIV) or 2-bromo-6-fluoroaniline (I) with 2-methoxy-5-(trifluoromethyl)phenyl isocyanate (V) in refluxing acetonitrile yields the corresponding diaryl ureas (XV) or (XVI), respec-tively. The N-(2-Fluorophenyl)urea derivative (XV) is then condensed with methyl acrylate (II) by means of Pd(OAc)2 and H2S2O7 in AcoH to give the corresponding (E)-cinnamate (XVII), which finally undergoes intramolecular Michael addition in the presence of DBU in refluxing acetone .
Alternatively, intermediate (XI) is obtained by Heck coupling of aryl bromide (XVI) with methyl acrylate (II) in the presence of Pd(MeCn)2Cl2, (o-tol)3P and Et3n in isobutyronitrile at 90-102 °C .
【1】
Goossen, K., Kuhn, o., Berwe, M., Krueger, J., Militzer, H.-C. (Bayer HealthCare AG). Method for producing dihydroquinazolines. Cn 101863843, DE 10227517, EP 1893587, JP 2008543797, US 2009221822, US 8084604, US 2012130072, US 8372972, Wo 2006133822. |
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) |
68030 |
2-bromo-6-fluoroaniline |
65896-11-9 |
C6H5BrFN |
详情 | 详情
|
(II) |
14156 |
methyl acrylate
|
96-33-3 |
C4H6O2 |
详情 | 详情
|
(V) |
68033 |
2-methoxy-5-(trifluoromethyl)phenyl isocyanate |
16588-75-3 |
C9H6F3NO2 |
详情 | 详情
|
(XI) |
68037 |
methyl 2-(8-fluoro-3-(2-methoxy-5-(trifluoromethyl)phenyl)-2-oxo-1,2,3,4-tetrahydroquinazolin-4-yl)acetate |
|
C19H16F4N2O4 |
详情 | 详情
|
(XIV) |
22296 |
2-fluorophenylamine; 2-fluoroaniline
|
348-54-9 |
C6H6FN |
详情 | 详情
|
(XV) |
68040 |
1-(2-fluorophenyl)-3-(2-methoxy-5-(trifluoromethyl)phenyl)urea |
|
C15H12F4N2O2 |
详情 | 详情
|
(XVI) |
68041 |
1-(2-bromo-6-fluorophenyl)-3-(2-methoxy-5-(trifluoromethyl)phenyl)urea |
|
C15H11BrF4N2O2 |
详情 | 详情
|
(XVII) |
68042 |
(E)-methyl 3-(3-fluoro-2-(3-(2-methoxy-5-(trifluoromethyl)phenyl)ureido)phenyl)acrylate |
|
C19H16F4N2O4 |
详情 | 详情
|
合成路线47
该中间体在本合成路线中的序号:
(XIV) The tetracyclic aldehyde (I) is prepared as follows. Heck coupling of 3-bromo-3-cyclohexen-1-one ethylene ketal (XIII) with methyl acrylate (XIV) in the presence of PdCl2(PPh3)2 and Et3N in DMF at 75 °C gives the dienoate ester (XV), which is hydrolyzed to the corresponding carboxylic acid (XVI) using NaOH in THF/MeOH. Subsequent DCC-mediated coupling of acid (XVI) with alcohol (XVII) in the presence of 4-pyrrolidinopyridine (4-Ppy) in CH2Cl2 affords the triene ester (XVIII). Intramolecular Diels–Alder reaction in triene (XVIII) by heating in xylene at 215 °C results in a tetracyclic intermediate, which undergoes epimerization at C9a by means of DBU in THF to provide the cis-lactone (XIX). The benzyl ester group of (XIX) is then removed by catalytic hydrogenolysis over Pd/C in EtOAc, and subsequent diastereoselective hydrogenation of the internal double bond over PtO2 in EtOAc affords the tetracyclic carboxylic acid (XX). Finally,chlorination of acid (XX) with SOCl2 in toluene at 180 °C followed by reduction of the resulting acid chloride with Bu3SnH in the presence of Pd(PPh3)4 in toluene yields the key aldehyde (I) .
Hydroxy ester (XVII) is obtained by protection of 2(R)-butynol (XXI) as the corresponding tetrahydropyranyl ether (XXII) with DHP in the presence of p-TsOH. Subsequent deprotonation of the terminal alkyne in compound (XXII) by means of BuLi and treatment with PhCH2OCOCl in THF at –78 °C followed by acidic THP group hydrolysis yields benzyl ester (XXIII), which is finally submitted to partial reduction of the triple bond by hydrogenation over Lindlar catalyst in THF .
【2】
Chackalamannil, S., Asberom, T., Xia, Y., Doller, D., Clasby, M.C.,Czarniecki, M.F. Thrombin receptor antagonists. US 6063847. |
【1】
Clasby, M.C., Chackalamannil, S., Czarniecki, M. et al. Metabolism-based identification of a potent thrombin receptor antagonist. J Med Chem 2007, 50(1): 129-38. |
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
(XXXII) |
68728 |
(R,E)-4-hydroxy-N,N-diphenylpent-2-enamide;4(R)-hydroxy-N,Ndiphenyl-2-pentenamide |
|
C17H17NO2 |
详情 | 详情
|
(I) |
68713 |
(1'R,3a'R,4a'R,8a'R,9a'S)-1'-methyl-3'-
oxodecahydro-1'H-spiro[[1,3]dioxolane-2,6'-naphtho
[2,3-c]furan]-9'-carbaldehyde |
|
C16H22O5 |
详情 | 详情
|
(IX) |
68708 |
(3S,3aS,4R,4aS,7S,8aS,9aS)-7-amino-3-methyl-1-oxododecahydronaphtho[2,3-c]furan-4-carboxylic acid |
|
C14H21NO4 |
详情 | 详情
|
(XIII) |
68714 |
3-bromo-3-cyclohexen-1-one ethylene ketal;7-bromo-1,4-Dioxaspiro[4.5]dec-7-ene |
81036-84-2 |
C8H11BrO2 |
详情 | 详情
|
(XIV) |
14156 |
methyl acrylate
|
96-33-3 |
C4H6O2 |
详情 | 详情
|
(XV) |
68715 |
(E)-methyl 3-(1,4-dioxaspiro[4.5]dec-7-en-7-yl)acrylate |
|
C12H16O4 |
详情 | 详情
|
(XVI) |
68716 |
(E)-3-(1,4-dioxaspiro[4.5]dec-7-en-7-yl)acrylic acid |
|
C11H14O4 |
详情 | 详情
|
(XVI) |
68716 |
(E)-3-(1,4-dioxaspiro[4.5]dec-7-en-7-yl)acrylic acid |
|
C11H14O4 |
详情 | 详情
|
(XVII) |
68717 |
(R,E)-benzyl 4-hydroxypent-2-enoate |
|
C12H14O3 |
详情 | 详情
|
(XVIII) |
68718 |
(R,Z)-benzyl 4-(((E)-3-(1,4-dioxaspiro[4.5]dec-7-en-7-yl)acryloyl)oxy)pent-2-enoate |
|
C23H26O6 |
详情 | 详情
|
(XIX) |
68721 |
(1'R,3a'R,8a'R,9'S,9a'S)-benzyl 1'-methyl-3'-oxo-3',3a',5',7',8',8a',9',9a'-octahydro-1'H-spiro[[1,3]dioxolane-2,6'-naphtho[2,3-c]furan]-9'-carboxylate |
|
C23H28O6 |
详情 | 详情
|
(XX) |
68722 |
(1'R,3a'R,8a'R,9'S,9a'S)-1'-methyl-3'-oxodecahydro-1'H-spiro[[1,3]dioxolane-2,6'-naphtho[2,3-c]furan]-9'-carboxylic acid |
|
C16H22O6 |
详情 | 详情
|
(XXI) |
68719 |
2(R)-butynol;(R)-but-3-yn-2-ol |
42969-65-3 |
C4H6O |
详情 | 详情
|
(XXI) |
68719 |
2(R)-butynol;(R)-but-3-yn-2-ol |
42969-65-3 |
C4H6O |
详情 | 详情
|
(XXII) |
68720 |
2-((R)-but-3-yn-2-yloxy)tetrahydro-2H-pyran |
|
C9H14O2 |
详情 | 详情
|
(XXIII) |
68723 |
(R)-benzyl 4-hydroxypent-2-ynoate |
|
C12H12O3 |
详情 | 详情
|
(XXIII) |
68723 |
(R)-benzyl 4-hydroxypent-2-ynoate |
|
C12H12O3 |
详情 | 详情
|
(XXVIII) |
68724 |
(R)-(but-3-yn-2-yloxy)trimethylsilane |
|
C7H14OSi |
详情 | 详情
|
(XXIX) |
68725 |
1-(diphenylcarbamoyl)imidazole;N,N-diphenyl-1H-imidazole-1-carboxamide |
|
C16H13N3O |
详情 | 详情
|
(XXX) |
68726 |
(R)-4-hydroxy-N,N-diphenylpent-2-ynamide;4(R)-hydroxy-N,N-diphenyl-2-pentynamide;4-hydroxy-N,N-diphenyl-(4R)-2-Pentynamide |
899809-61-1 |
C17H15NO2 |
详情 | 详情
|
(XXXI) |
68727 |
4-hydroxy-N,N-diphenyl-2-pentynamide |
|
C17H15NO2 |
详情 | 详情
|
(XXXIII) |
68729 |
(E)-(R,Z)-5-(diphenylamino)-5-oxopent-3-en-2-yl 3-(1,4-dioxaspiro[4.5]dec-7-en-7-yl)acrylate |
|
C28H29NO5 |
详情 | 详情
|
(XXXIV) |
68730 |
(1'R,3a'R,8a'R,9'S,9a'S)-1'-methyl-3'-oxo-N,N-diphenyl-3',3a',5',7',8',8a',9',9a'-octahydro-1'H-spiro[[1,3]dioxolane-2,6'-naphtho[2,3-c]furan]-9'-carboxamide |
|
C28H29NO5 |
详情 | 详情
|
(XXXV) |
68731 |
(1'R,3a'R,4a'R,8a'R,9'S,9a'S)-1'-methyl-3'-oxo-N,N-diphenyldecahydro-1'H-spiro[[1,3]dioxolane-2,6'-naphtho[2,3-c]furan]-9'-carboxamide |
|
C28H31NO5 |
详情 | 详情
|
(XXXVI) |
68732 |
(3S,3aS,4R,4aS,8aS,9aS)-3-methyl-1,7-dioxododecahydronaphtho[2,3-c]furan-4-carboxylic acid |
|
C14H18O5 |
详情 | 详情
|
(XXXVII) |
68733 |
(E)-3-(5-nitrocyclohex-1-en-1-yl)acrylic acid;3-(5-nitro-1-cyclohexenyl)-2-propenoic acid |
|
C9H11NO4 |
详情 | 详情
|
(XXXVIII) |
68735 |
(4R)-benzyl 4-(((E)-3-(5-nitrocyclohex-1-en-1-yl)acryloyl)oxy)pent-2-ynoate |
|
C21H21NO6 |
详情 | 详情
|
(XXXIX) |
68734 |
(4R)-benzyl 4-(((E)-3-(5-nitrocyclohex-1-en-1-yl)acryloyl)oxy)pent-2-enoate |
|
C21H23NO6 |
详情 | 详情
|
(XL) |
68736 |
(3S,3aS,4R,4aS,7R,9aS)-benzyl 3-methyl-7-nitro-1-oxo-1,3,3a,4,4a,5,6,7,8,9a-decahydronaphtho[2,3-c]furan-4-carboxylate |
|
C21H23NO6 |
详情 | 详情
|