合成路线1
该中间体在本合成路线中的序号:
(I) ABPP is a phenylpyrimidinone and as such is prepared in high yield by condensation of guanidine with ethyl benzoylacetate.
Ethyl benzoylacetate is commercially available and can also be prepared in high yield by condensation of dilithiomonoethylmalonate at 78 C with benzoyl chloride. Reaction of the resultant beta-ketoester with guanidine in refluxing ethanol affords its pyrimidinone in high yield. ABPP can be prepared from this pyrimidinone by bromination in acetic acid at room temperature. Similarly, iodine can be introduced at this step to afford the iodo analogue, AIPP. The overall yield of these pyrimidinones from monoethylmalonate is generally) 50%.
【1】
Fitzpatrick, F.A.; Wynalda, M.A.; High-perfomance liquid chromatographic determination of 5-halopyrimidinone interferon inducers. Anal Chem 1982, 17, 151.
|
【2】
Skulnick, H.I.; Stringfellow, D.A.; Wierenga, W.; Weed, S.D.; Antiviral and interferon induction stucture-activity relationship profile of 6-aryl-pyrimidines. Am Soc Microbiol 1980, 2, 1402-1404.
|
【3】
Brown, T.B.; Stevens, M.F.G.; Triazines and related products. XV. 2,4-Diaminopyrimidines and 2-aminopyrimidin-4(3H)-ones bearing 1,2,3-benzotriazinyl groups as potential dihydrofolic reductase inhibitors. J Chem Soc - Perkins Trans I 1975, 11, 1023-1028. |
【4】
Wierenga, W.; Skulnick, H.I.; J Org Chem 1979, 44, 310.
|
【5】
Stringfellow, D.A.; Eidson, E.E.; Wierenga, W.; Skulnick, H.I.; Renis, H.E.; Weed, S.D.; 5-Substituted 2-amino-6-phenyl-4(3H)-pyrimidinones. Antiviral- and interferon-inducing agents. J Med Chem 1980, 23, 3, 237-239.
|
【6】
Wierenga, W.; ABPP. Drugs Fut 1984, 9, 8, 567.
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中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
(I) |
15086 |
3-ethoxy-3-oxopropionic acid
|
1071-46-1 |
C5H8O4 |
详情 | 详情
|
(II) |
10004 |
Ethyl 3-oxo-3-phenylpropanoate; Benzoylacetic acid, ethyl ester
|
94-02-0 |
C11H12O3 |
详情 | 详情
|
(III) |
14790 |
Guanidine
|
113-00-8 |
CH5N3 |
详情 | 详情
|
(IV) |
30490 |
2-amino-6-phenyl-4(3H)-pyrimidinone
|
|
C10H9N3O |
详情 |
详情
|
合成路线2
该中间体在本合成路线中的序号:
(VI) The methylation of 1-bromo-2,4,5-trifluoro-3-(trimethylsilyl)benzene (I) with methyl trifluoromethylsulfonate (II) by means of diisopropylamine and butyllithium in THF gives 2-bromo-3,5,6-trifluoro-4-(trimethylsilyl)toluene (III), which is carbonated with butyllithium and CO2 in ether to yield 2,4,5-trifluoro-6-methyl-3-(trimethylsilyl)benzoic acid (IV). Elimination of the silyl group with CsF in acetonitrile affords the corresponding benzoic acid (V). The condensation of (V) with malonic acid monoethyl ester (VI) by means of oxalyl chloride and butyllithium in THF affords 3-(3,4,6-trifluoro-2-methylphenyl)-2-oxopropionic acid ethyl ester (VII), which by condensation with triethyl orthoformate in refluxing acetic anhydride is converted into the ethoxymethylene derivative (VIII). The cyclization of (VIII) with cyclopropylamine (IX) by means of sodium hydride in THF gives 1-cyclopropyl-6,7-difluoro-5-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester (X), which is hydrolyzed with refluxing 6N HCl to yield the corresponding free acid (XI) (1). Finally, this compound is condensed with 2-methylpiperazine (XII) by means of triethylamine in refluxing acetonitrile.
【1】
Ueda, H.; Miyamoto, H.; Yamashita, H.; Tone, H. (Otsuka Pharmaceutical Co., Ltd.); Benzoheterocyclic cpds. EP 0287951; EP 0565132; JP 1989230558; JP 1995138232; JP 1995165636; US 5563138; US 5591744 .
|
【2】
Castaner, J.; Prous, J.; OPC-17116. Drugs Fut 1992, 17, 4, 286.
|
【3】
Heifetz, C.L.; Johnson, J.; Hagen, S.E.; Domagala, J.M.; Synthesis and biological activity of 5-alkyl-1,7,8-trisubstituted-6-fluoroquinoline-3-carboxylic acids. J Med Chem 1991, 34, 3, 1155.
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中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
(I) |
15081 |
(3-bromo-2,5,6-trifluorophenyl)(trimethyl)silane
|
|
C9H10BrF3Si |
详情 |
详情
|
(II) |
15082 |
methyl(dioxo)(trifluoromethyl)-lambda(6)-sulfane; methyl trifluoromethyl sulfone
|
|
C2H3F3O2S |
详情 |
详情
|
(III) |
15083 |
(3-bromo-2,5,6-trifluoro-4-methylphenyl)(trimethyl)silane
|
|
C10H12BrF3Si |
详情 |
详情
|
(IV) |
15084 |
2,4,5-trifluoro-6-methyl-3-(trimethylsilyl)benzoic acid
|
|
C11H13F3O2Si |
详情 |
详情
|
(V) |
15085 |
3,4,6-trifluoro-2-methylbenzoic acid
|
|
C8H5F3O2 |
详情 |
详情
|
(VI) |
15086 |
3-ethoxy-3-oxopropionic acid
|
1071-46-1 |
C5H8O4 |
详情 | 详情
|
(VII) |
15087 |
ethyl 3-oxo-3-(3,4,6-trifluoro-2-methylphenyl)propanoate
|
|
C12H11F3O3 |
详情 |
详情
|
(VIII) |
15088 |
ethyl (Z)-3-ethoxy-2-(3,4,6-trifluoro-2-methylbenzoyl)-2-propenoate
|
|
C15H15F3O4 |
详情 |
详情
|
(IX) |
12263 |
Cyclopropylamine; Cyclopropanamine
|
765-30-0 |
C3H7N |
详情 | 详情
|
(X) |
15090 |
ethyl 1-cyclopropyl-6,7-difluoro-5-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylate
|
|
C16H15F2NO3 |
详情 |
详情
|
(XI) |
15091 |
1-cyclopropyl-6,7-difluoro-5-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid
|
|
C14H11F2NO3 |
详情 |
详情
|
(XII) |
12267 |
2-Methylpiperazine
|
109-07-9 |
C5H12N2 |
详情 | 详情
|
合成路线3
该中间体在本合成路线中的序号:
(X) The reduction of diethyl 2-phenylmalonate (I) with LiAlH4 in ethyl ether gives the expected diol (II), which is tosylated with tosyl chloride and pyridine yielding the ditosylate (III). The cyclization of (III) with diethyl malonate (IV) by means of NaH in dioxane affords the diethyl 3-phenylcyclobutane-1,1-dicarboxylate (V), which is saponified with KOH to the diacid (VI). The partial decarboxylation of (VI) by heating at 200 C provides 3-phenylcyclobutane-1-carboxylic acid (VII), which is esterified with phenacyl bromide to the corresponding phenacyl ester (VIII). The oxidation of (VIII) with ruthenium chloride and periodic acid gives cyclobutane-1,3-dicarboxylic acid monophenacyl ester (IX) as a 1:1 mixture of the cis and trans isomers. The condensation of (IX) with malonic acid monoethyl ester (X) by means of oxalyl chloride and BuLi in THF yields tyhe intermediate diester (XI), which is condensed with thioxanthen (XII) in acetic acid to provide the thioxanthenyl acetic ester (XIII). The decarboxylative hydrolysis of (XIII) with NaOH in ethanol gives the ketoacid (XIV), which is cyclized with KCN and ammonium carbonate in ethanol/water yielding the imidazolidinedione (XV). The hydrolysis of (XV) with NaOH affords the 3-[1-amino-1-carboxy-2-(9-thioxanthenyl)ethyl]cyclobutane-1-carboxylic acid (XVI) as a 2:1 mixture of the cis and trans racemates. Finally, this mixture is treated with L-lysine and crystallized to afford the pure target compound.
【1】
Clark, B.P.; et al.; alpha-Substituted-cyclobutylglycine LY393675 potently antagonises group 1 metabotropic glutamate receptors. 15th European Federation for Medicinal Chemistry International Symposium on Medicinal Chemistry (Sept 6 1998, Edinburgh) 1998, Abst P.125. |
【2】
Clark, B.P.; Harris, J.R. (Eli Lilly and Company); Pharmaceutical acidic cpds.. EP 0837061; JP 1998120635; US 6054448 .
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中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
(A) |
10315 |
2-Bromo-1-phenyl-ethanone; 2-Bromo-1-phenyl-1-ethanone
|
70-11-1 |
C8H7BrO |
详情 | 详情
|
(I) |
26952 |
diethyl 2-phenylmalonate
|
83-13-6 |
C13H16O4 |
详情 | 详情
|
(II) |
24198 |
2-phenyl-1,3-propanediol
|
|
C9H12O2 |
详情 |
详情
|
(III) |
26953 |
3-[[(4-methylphenyl)sulfonyl]oxy]-2-phenylpropyl 4-methylbenzenesulfonate
|
|
C23H24O6S2 |
详情 |
详情
|
(IV) |
16829 |
Diethyl malonate
|
105-53-3 |
C7H12O4 |
详情 | 详情
|
(V) |
26954 |
diethyl 3-phenyl-1,1-cyclobutanedicarboxylate
|
|
C16H20O4 |
详情 |
详情
|
(VI) |
26955 |
3-phenyl-1,1-cyclobutanedicarboxylic acid
|
|
C12H12O4 |
详情 |
详情
|
(VII) |
26956 |
3-phenylcyclobutanecarboxylic acid
|
|
C11H12O2 |
详情 |
详情
|
(VIII) |
26957 |
2-oxo-2-phenylethyl 3-phenylcyclobutanecarboxylate
|
|
C19H18O3 |
详情 |
详情
|
(IX) |
26958 |
3-[(2-oxo-2-phenylethoxy)carbonyl]cyclobutanecarboxylic acid
|
|
C14H14O5 |
详情 |
详情
|
(X) |
15086 |
3-ethoxy-3-oxopropionic acid
|
1071-46-1 |
C5H8O4 |
详情 | 详情
|
(XI) |
26959 |
2-oxo-2-phenylethyl 3-(3-ethoxy-3-oxopropanoyl)cyclobutanecarboxylate
|
|
C18H20O6 |
详情 |
详情
|
(XII) |
26071 |
9H-thioxanthen-9-ol
|
|
C13H10OS |
详情 |
详情
|
(XIII) |
26960 |
2-oxo-2-phenylethyl 3-[3-ethoxy-3-oxo-2-(9H-thioxanthen-9-yl)propanoyl]cyclobutanecarboxylate
|
|
C31H28O6S |
详情 |
详情
|
(XIV) |
26961 |
3-[2-(9H-thioxanthen-9-yl)acetyl]cyclobutanecarboxylic acid
|
|
C20H18O3S |
详情 |
详情
|
(XV) |
26962 |
3-[2,5-dioxo-4-(9H-thioxanthen-9-ylmethyl)-4-imidazolidinyl]cyclobutanecarboxylic acid
|
|
C22H20N2O4S |
详情 |
详情
|
(XVI) |
26963 |
3-[1-amino-1-carboxy-2-(9H-thioxanthen-9-yl)ethyl]cyclobutanecarboxylic acid
|
|
C21H21NO4S |
详情 |
详情
|
合成路线4
该中间体在本合成路线中的序号:
Aromatic hydroxylation of 1-bromo-2,4-difluorobenzene (I) using tert-butyl hydroperoxide and LDA afforded phenol (II), which was methylated with iodomethane and K2CO3 to give methyl ether (III). The required benzoic acid (IV) was then obtained from (III) by lithium-bromine exchange with n-butyllithium, followed by carboxylation with CO2 gas at -70 C. Treatment of (IV) with oxalyl chloride and DMF gave acid chloride (V). This was condensed with the lithium salt of monoethyl malonate to yield, after acid decarboxylation, ketoester (VI). Subsequent condensation of (VI) with triethyl orthoformate in refluxing Ac2O provided methoxyacrylate (VII), and further treatment with cyclopropylamine (VIII) furnished aminoacrylate (IX). Cyclization of (IX) by means of NaH in THF generated the quinolone system (X). Acid hydrolysis of the ethyl ester group of (X) gave quinolinecarboxylic acid (XI), which was converted to the boron difluoride complex (XII) by treatment with BF3-Et2O in hot THF. Displacement of the aromatic fluorine of (XII) with 3R-(1S-tert-butoxycarbonylaminoethyl)pyrrolidine (XIII) in the presence of DIEA, followed by boron complex cleavage with Et3N in EtOH provided the pyrrolidinylquinoline (XIV). Finally, the Boc protecting group of (XIV) was removed by hydrolysis with ethanolic HCl.
【1】
Hu, X.E.; Gray, J.L.; Almstead, J.-I.K.; Ledoussal, B. (The Procter & Gamble Co.); Antimicrobial quinolones, their compsns. and uses. EP 1015445; WO 9914214 .
|
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
|
15086 |
3-ethoxy-3-oxopropionic acid
|
1071-46-1 |
C5H8O4 |
详情 | 详情
|
(I) |
15488 |
1-bromo-2,4-difluorobenzene
|
348-57-2 |
C6H3BrF2 |
详情 | 详情
|
(II) |
34648 |
3-bromo-2,6-difluorophenol
|
221220-99-1 |
C6H3BrF2O |
详情 | 详情
|
(III) |
34649 |
3-bromo-2,6-difluorophenyl methyl ether; 1-bromo-2,4-difluoro-3-methoxybenzene
|
221221-00-7 |
C7H5BrF2O |
详情 | 详情
|
(IV) |
30621 |
2,4-difluoro-3-methoxybenzoic acid
|
178974-97-5 |
C8H6F2O3 |
详情 | 详情
|
(V) |
34650 |
2,4-difluoro-3-methoxybenzoyl chloride
|
|
C8H5ClF2O2 |
详情 |
详情
|
(VI) |
34651 |
ethyl 3-(2,4-difluoro-3-methoxyphenyl)-3-oxopropanoate
|
|
C12H12F2O4 |
详情 |
详情
|
(VII) |
34652 |
ethyl (Z)-2-(2,4-difluoro-3-methoxybenzoyl)-3-ethoxy-2-propenoate
|
|
C15H16F2O5 |
详情 |
详情
|
(VIII) |
12263 |
Cyclopropylamine; Cyclopropanamine
|
765-30-0 |
C3H7N |
详情 | 详情
|
(IX) |
34653 |
ethyl (Z)-3-(cyclopropylamino)-2-(2,4-difluoro-3-methoxybenzoyl)-2-propenoate
|
|
C16H17F2NO4 |
详情 |
详情
|
(X) |
34654 |
ethyl 1-cyclopropyl-7-fluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxylate
|
|
C16H16FNO4 |
详情 |
详情
|
(XI) |
34655 |
1-cyclopropyl-7-fluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid
|
221221-16-5 |
C14H12FNO4 |
详情 | 详情
|
(XII) |
34656 |
|
|
C14H11BF3NO4 |
详情 |
详情
|
(XIII) |
34657 |
tert-butyl (1S)-1-[(3R)pyrrolidinyl]ethylcarbamate
|
|
C11H22N2O2 |
详情 |
详情
|
(XIV) |
34658 |
7-((3R)-3-[(1S)-1-[(tert-butoxycarbonyl)amino]ethyl]pyrrolidinyl)-1-cyclopropyl-8-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid
|
|
C25H33N3O6 |
详情 |
详情
|
合成路线5
该中间体在本合成路线中的序号:
(I) Malonic acid monoethyl ester (I) is converted into beta-ketoester (III) by formation of the corresponding trimethylsilyl ester with TMSCl and pyridine in ether followed by deprotonation with n-BuLi and acylation with cyclopropanecarbonyl chloride (II) in DME. Treatment of (III) with refluxing N,N-dimethylformamide dimethyl acetal (IV) affords enamine (V).
Quinoline-5-amine (VI) is first subjected to diazotation by treatment with NaNO2 in H2O/HCl, reduced with SnCl2.2H2O in HCl and isolated as the corresponding dihydrochloride salt (VII) by treatment with HCl.
Condensation of enamine (V) with hydrazine (VII) in the presence of Et3N in refluxing EtOH yields pyrazole ester (VIII), which is converted into acylguanidine (X) either by direct heating with guanidine (IX) in EtOH or by first transformation into the corresponding carboxylic acid (XI) by saponification with NaOH in refluxing MeOH, followed by treatment with refluxing thionyl chloride and reaction with guanidine hydrochloride (XII) under Schotten-Baumann conditions in refluxing THF/NaOH. Finally, treatment of the free base (X) with HCl in THF allows isolation of the corresponding monohydrochloride-monohydrate salt .
【1】
Wester, R.T.; Allen, M.C.; Guzman-Perez, A.; et al.; Discovery of zoniporide: A potent and selective sodium-hydrogen exchanger type 1 (NHE-1) inhibitor with high aqueous solubility. Bioorg Med Chem Lett 2001, 11, 6, 803.
|
【2】
Guzman-Perez, A.; Ruggeri, R.B.; Wester, R.T.; Hamanaka, E.S.; Mularski, C.J. (Pfizer Inc.); N-[(Substd. five-membered di- or triaza diunsaturated ring)carbonyl] guanidine derivs. for the treatment of ischemia. EP 1056729; WO 9943663 .
|
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
(IX),(XII) |
14790 |
Guanidine
|
113-00-8 |
CH5N3 |
详情 | 详情
|
(I) |
15086 |
3-ethoxy-3-oxopropionic acid
|
1071-46-1 |
C5H8O4 |
详情 | 详情
|
(II) |
14061 |
Cyclopropanecarbonyl chloride; Cyclopropanecarboxylic acid chloride
|
4023-34-1 |
C4H5ClO |
详情 | 详情
|
(III) |
15949 |
3-Cyclopropyl-3-oxo-propionic acid ethyl ester; ethyl 3-cyclopropyl-3-oxopropanoate
|
24922-02-9 |
C8H12O3 |
详情 | 详情
|
(IV) |
11984 |
N-(Dimethoxymethyl)-N,N-dimethylamine;dimethylformamide dimethylacetal;1,1-dimethoxy-N,N-dimethylmethanamine; Dimethoxy-N,N-dimethylmethanamine; N,N-Dimethylformamide dimethyl acetal |
4637-24-5 |
C5H13NO2 |
详情 | 详情
|
(V) |
48913 |
ethyl (Z)-3-amino-2-(cyclopropylcarbonyl)-2-propenoate
|
|
C9H13NO3 |
详情 |
详情
|
(VI) |
26799 |
5-Aminoquinoline; 5-quinolinamine
|
611-34-7 |
C9H8N2 |
详情 | 详情
|
(VII) |
48914 |
5-hydrazinoquinoline
|
|
C9H9N3 |
详情 |
详情
|
(VIII) |
48915 |
ethyl 5-cyclopropyl-1-(5-quinolinyl)-1H-pyrazole-4-carboxylate
|
|
C18H17N3O2 |
详情 |
详情
|
(X) |
48917 |
N''-[[5-cyclopropyl-1-(5-quinolinyl)-1H-pyrazol-4-yl]carbonyl]guanidine
|
|
C17H16N6O |
详情 |
详情
|
(XI) |
48916 |
5-cyclopropyl-1-(5-quinolinyl)-1H-pyrazole-4-carboxylic acid
|
|
C16H13N3O2 |
详情 |
详情
|
合成路线6
该中间体在本合成路线中的序号:
(A) Metalation of 1-bromo-2,4-difluorobenzene (I) by means of LDA, followed by treatment with tert-butyl hydroperoxide gave rise to phenol (II), which was further converted to methyl ether (III) by alkylation with iodomethane and K2CO3. Lithium halogen exchange of (III) with n-butyllithium, and subsequent quenching with CO2 produced 3-methoxy-2,4-difluorobenzoic acid (IV). After activation of (IV) as the acid chloride (V), condensation with the lithium derivative of monoethyl malonate (A) led to the benzoyl acetate ester (VI). The benzoyl ethoxyacrylate (VII), obtained by condensation of ketoester (VI) with triethyl orthoformate, was then reacted with cyclopropylamine (VIII) to afford enamine (IX). This was cyclized to the quinolone compound (X) upon treatment with NaH in THF. Acidic hydrolysis of ester (X) gave a keto acid, which was subsequently converted to the boron chelate (XI) by treatment with boron trifluoride etherate. Fluoride displacement of quinolone (XI) with the amino piperidine (XII) produced the piperidino quinolone (XIII). The boron difluoride complex of (XIII) was finally removed by means of triethylamine in boiling EtOH.
【1】
Hu, X.E.; Gray, J.L.; Almstead, J.-I.K.; Ledoussal, B. (The Procter & Gamble Co.); Antimicrobial quinolones, their compsns. and uses. EP 1015445; WO 9914214 .
|
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) |
15086 |
3-ethoxy-3-oxopropionic acid
|
1071-46-1 |
C5H8O4 |
详情 | 详情
|
(I) |
15488 |
1-bromo-2,4-difluorobenzene
|
348-57-2 |
C6H3BrF2 |
详情 | 详情
|
(II) |
34648 |
3-bromo-2,6-difluorophenol
|
221220-99-1 |
C6H3BrF2O |
详情 | 详情
|
(III) |
34649 |
3-bromo-2,6-difluorophenyl methyl ether; 1-bromo-2,4-difluoro-3-methoxybenzene
|
221221-00-7 |
C7H5BrF2O |
详情 | 详情
|
(IV) |
30621 |
2,4-difluoro-3-methoxybenzoic acid
|
178974-97-5 |
C8H6F2O3 |
详情 | 详情
|
(V) |
34650 |
2,4-difluoro-3-methoxybenzoyl chloride
|
|
C8H5ClF2O2 |
详情 |
详情
|
(VI) |
34651 |
ethyl 3-(2,4-difluoro-3-methoxyphenyl)-3-oxopropanoate
|
|
C12H12F2O4 |
详情 |
详情
|
(VII) |
34652 |
ethyl (Z)-2-(2,4-difluoro-3-methoxybenzoyl)-3-ethoxy-2-propenoate
|
|
C15H16F2O5 |
详情 |
详情
|
(VIII) |
12263 |
Cyclopropylamine; Cyclopropanamine
|
765-30-0 |
C3H7N |
详情 | 详情
|
(IX) |
34653 |
ethyl (Z)-3-(cyclopropylamino)-2-(2,4-difluoro-3-methoxybenzoyl)-2-propenoate
|
|
C16H17F2NO4 |
详情 |
详情
|
(X) |
34654 |
ethyl 1-cyclopropyl-7-fluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxylate
|
|
C16H16FNO4 |
详情 |
详情
|
(XI) |
59792 |
1-cyclopropyl-3-{[(difluoroboryl)oxy]carbonyl}-7-fluoro-8-methoxy-4(1H)-quinolinone
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C14H11BF3NO4 |
详情 |
详情
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(XII) |
59793 |
(3S,4R)-4-ethyl-3-piperidinamine; (3S,4R)-4-ethylpiperidinylamine
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C7H16N2 |
详情 |
详情
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(XIII) |
59794 |
7-[(3S,4R)-3-amino-4-ethylpiperidinyl]-1-cyclopropyl-3-{[(difluoroboryl)oxy]carbonyl}-8-methoxy-4(1H)-quinolinone
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C21H26BF2N3O4 |
详情 |
详情
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合成路线7
该中间体在本合成路线中的序号:
(VIII) The reaction of 1,3-benzodioxol-5-ylmethylamine (I) with acryloyl chloride (II) by means of TEA gives the acrylamide (III), which is reductocondensed with perhydroazepine (IV) by means of LiAlH4 or BH3/THF in THF to yield the secondary amine (V). Finally this compound is condensed with 5-chloro-3-(3,5-difluorophenyl)isoxazole (VI) by means of BuLi in diethyl ether to afford the target tertiary amine.
The intermediate 5-chloro-3-(3,5-difluorophenyl)isoxazole (VI) has been obtained by two related ways: The condensation of 3.5-difluorobenzoyl chloride (VII) with malonic acid monoethyl ester (VIII) by means of BuLi gives 2-(3,5-difluorobenzoyl)acetic acid ethyl ester (IX), which is cyclized with hydroxylamine in HOAc to yield 3-(3,5-difluorophenyl)isoxazol-5-ol (X). Finally this compound is treated with POCl3 to afford the desired 5-chloro-3-(3,5-difluorophenyl)isoxazole (VI) intermediate.
Alternatively, the reaction of 3,5-difluoroacetophenone (XI) with diethyl carbonate (XII) by means of NaH yields also the already reported intermediate 2-(3,5-difluorobenzoyl)acetic acid ethyl ester (IX)
【1】
Nantermet, P.G.; et al.; Discovery of a nonpeptide small molecule antagonist of the human platelet thrombin receptor (PAR-1). Bioorg Med Chem Lett 2002, 12, 3, 319.
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【2】
Freidinger, R.M.; Selnick, H.G.; Connolly, T.; Barrow, J.C.; Nantermet, P.G. (Merck & Co., Inc.); Isoxazole thrombin receptor antagonists. GB 2356198 .
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中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
(I) |
33669 |
1,3-benzodioxol-5-ylmethylamine; 1,3-benzodioxol-5-ylmethanamine; 3,4-Methylendioxybenzylamine
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2620-50-0 |
C8H9NO2 |
详情 | 详情
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(II) |
11577 |
Acryloyl chloride; Acrylyl chloride;2-Propenoyl chloride |
814-68-6 |
C3H3ClO |
详情 | 详情
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(III) |
56910 |
N-(1,3-benzodioxol-5-ylmethyl)acrylamide
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C11H11NO3 |
详情 |
详情
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(IV) |
18672 |
azepane
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111-49-9 |
C6H13N |
详情 | 详情
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(V) |
56911 |
3-(1-azepanyl)-N-(1,3-benzodioxol-5-ylmethyl)-1-propanamine; N-[3-(1-azepanyl)propyl]-N-(1,3-benzodioxol-5-ylmethyl)amine
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C17H26N2O2 |
详情 |
详情
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(VI) |
56912 |
5-chloro-3-(3,5-difluorophenyl)isoxazole
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C9H4ClF2NO |
详情 |
详情
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(VII) |
56913 |
3,5-Difluorobenzoyl chloride
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129714-97-2 |
C7H3ClF2O |
详情 | 详情
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(VIII) |
15086 |
3-ethoxy-3-oxopropionic acid
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1071-46-1 |
C5H8O4 |
详情 | 详情
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(IX) |
56914 |
ethyl 3-(3,5-difluorophenyl)-3-oxopropanoate
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C11H10F2O3 |
详情 |
详情
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(X) |
56915 |
3-(3,5-difluorophenyl)-5-isoxazolol
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C9H5F2NO2 |
详情 |
详情
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(XI) |
56916 |
3,5-Difluoroacetophenone
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123577-99-1 |
C8H6F2O |
详情 | 详情
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(XII) |
17470 |
diethyl carbonate; diethylcarbonate
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105-58-8 |
C5H10O3 |
详情 | 详情
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合成路线8
该中间体在本合成路线中的序号:
(XXVIII) In an alternative route to the quinolone precursor (XX), deprotonation of 2,4-difluorobromobenzene (XXIII) with LDA in THF followed by addition of tert-butyl hydroperoxide gives 3-bromo-2,6-difluorophenol (XXIV), which is converted to the corresponding methyl ether (XXV) by treatment with iodomethane and K2CO3. Metalation of the aryl bromide (XXV) with butyl lithium in cold diethyl ether and subsequent addition of CO2 gas leads to 3-methoxy-2,4-difluorobenzoic acid (XXVI). After chlorination of acid (XXVI) with oxalyl chloride and catalytic DMF, the obtained acid chloride (XXVII) is condensed with monoethyl malonate (XXVIII) in the presence of butyl lithium in THF at –50 °C to yield the 2-(benzoyl)acetate (XVII). Subsequent reaction of keto ester (XVII) with triethyl orthoformate in boiling Ac2O provides the enol ether (XXIX), which is then condensed with cyclopropylamine (XIX) in EtOH to give the key enamine (XX) (3). Scheme 3.
【3】
Ledoussal, B., Hu, X.E., Gray, J.L., Almstead, J.-I.K. (The Procter & Gamble Co.). Antimicrobial quinolones, their compositions and uses. CA 2303389, EP 1015445, JP 2001516756, US 6329391, US 6387928, WO 1999014214. |
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
(XVII) |
34651 |
ethyl 3-(2,4-difluoro-3-methoxyphenyl)-3-oxopropanoate
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C12H12F2O4 |
详情 |
详情
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(XIX) |
12263 |
Cyclopropylamine; Cyclopropanamine
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765-30-0 |
C3H7N |
详情 | 详情
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(XX) |
34653 |
ethyl (Z)-3-(cyclopropylamino)-2-(2,4-difluoro-3-methoxybenzoyl)-2-propenoate
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C16H17F2NO4 |
详情 |
详情
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(XXIII) |
15488 |
1-bromo-2,4-difluorobenzene
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348-57-2 |
C6H3BrF2 |
详情 | 详情
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(XXIV) |
34648 |
3-bromo-2,6-difluorophenol
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221220-99-1 |
C6H3BrF2O |
详情 | 详情
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(XXV) |
34649 |
3-bromo-2,6-difluorophenyl methyl ether; 1-bromo-2,4-difluoro-3-methoxybenzene
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221221-00-7 |
C7H5BrF2O |
详情 | 详情
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(XXVI) |
30621 |
2,4-difluoro-3-methoxybenzoic acid
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178974-97-5 |
C8H6F2O3 |
详情 | 详情
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(XXVII) |
34650 |
2,4-difluoro-3-methoxybenzoyl chloride
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C8H5ClF2O2 |
详情 |
详情
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(XXVIII) |
15086 |
3-ethoxy-3-oxopropionic acid
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1071-46-1 |
C5H8O4 |
详情 | 详情
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(XXIX) |
34652 |
ethyl (Z)-2-(2,4-difluoro-3-methoxybenzoyl)-3-ethoxy-2-propenoate
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C15H16F2O5 |
详情 |
详情
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