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【结 构 式】 
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【分子编号】18060 【品名】4-Chloro-4-oxobutyric acid methyl ester; 3-Carbomethosypropionyl chloride; Methyl 4-chloro-4-oxobutanoate 【CA登记号】1490-25-1 |
【 分 子 式 】C5H7ClO3 【 分 子 量 】150.56148 【元素组成】C 39.89% H 4.69% Cl 23.55% O 31.88% |
合成路线1
该中间体在本合成路线中的序号：(IV)The cyclization of 2-(methylaminomethyl)aniline (I) with 1,1'-carbonyldiimidazole (II) in refluxing THF gives 3-methyl-1,2,3,4-tetrahydroquinazolin-2-one (III), which is condensed with methyl succinyl chloride (IV) by means of anhydrous AlCl3 in refluxing carbon disulfide to yield 6-[3-(methoxycarbonyl)propionyl]-3-methyl-1,2,3,4-tetrahydroquinazolin-2-one (V). Finally, this compound is cyclocondensed with hydrazine in refluxing ethanol.
| 【1】 Kuhla, D.E.; Campbell, H.F.; Studt, W.L.; Faith, W.C.; Molino, B.F. (Aventis Pharma SA); Benzodiazinone-pyridazinone and hydroxy-pyrazolyl cpds., cardiotonic compsns. including the same, and their uses. EP 0247177; JP 1988502030; US 4725686; WO 8703201 . |
| 【2】 Prous, J.; Castaner, J.; RGW-2938. Drugs Fut 1989, 14, 2, 132. |
| 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) | 20377 | 2-[(methylamino)methyl]aniline; N-(2-aminobenzyl)-N-methylamine | C8H12N2 | 详情 | 详情 | |
| (II) | 11353 | 1,1'-Carbonyldiimidazole; Di(1H-imidazol-1-yl)methanone; N,N-Carbonyldiimidazole; 1,1'-Carbonylbis(1H-imidazole) | 530-62-1 | C7H6N4O | 详情 | 详情 |
| (III) | 20379 | 3-methyl-3,4-dihydro-2(1H)-quinazolinone | 24365-65-9 | C9H10N2O | 详情 | 详情 |
| (IV) | 18060 | 4-Chloro-4-oxobutyric acid methyl ester; 3-Carbomethosypropionyl chloride; Methyl 4-chloro-4-oxobutanoate | 1490-25-1 | C5H7ClO3 | 详情 | 详情 |
| (V) | 20381 | methyl 4-(3-methyl-2-oxo-1,2,3,4-tetrahydro-6-quinazolinyl)-4-oxobutanoate | C14H16N2O4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XIV)Alternatively, the mono-methyl ester of succinic acid (XIII) was prepared by refluxing succinic anhydride (XII) with MeOH. Subsequent treatment of (XIII) with SOCl2 gave acid chloride (XIV). This was condensed with diazomethane to produce the diazo ketone (XV), which was further converted to the chloro ketone (XVI) by treatment with HCl. Condensation of chlorolevulinate (XVI) with succinimide (XVII) produced methyl delta-succinimidolevulinate (XVIII). Smooth acidic hydrolysis of the methyl ester group of (XVIII) led to the succinimido acid (XIX), which was further hydrolyzed to the succinamido acid (XX) under basic conditions. The title compound could be obtained by hydrolysis of either (XVIII), (XIX) or (XX) in refluxing 7N HCl.
| 【1】 Neuberger, A.; Scott, J.J.; The synhtesis of delta-succinamidolaevulic acid and related compounds. J Chem Soc 1954, 1820. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XII) | 11291 | Dihydro-2,5-furandione; Succinic anhydride | 108-30-5 | C4H4O3 | 详情 | 详情 |
| (XIII) | 55901 | Methyl hydrogen succinate; Succinic acid monomethyl ester; Monomethyl succinate | 3878-55-5 | C5H8O4 | 详情 | 详情 |
| (XIV) | 18060 | 4-Chloro-4-oxobutyric acid methyl ester; 3-Carbomethosypropionyl chloride; Methyl 4-chloro-4-oxobutanoate | 1490-25-1 | C5H7ClO3 | 详情 | 详情 |
| (XV) | 59148 | C6H8N2O3 | 详情 | 详情 | ||
| (XVI) | 59149 | methyl 5-chloro-4-oxopentanoate | C6H9ClO3 | 详情 | 详情 | |
| (XVII) | 22543 | 2,5-pyrrolidinedione | 123-56-8 | C4H5NO2 | 详情 | 详情 |
| (XVIII) | 59150 | methyl 5-(2,5-dioxo-1-pyrrolidinyl)-4-oxopentanoate | C10H13NO5 | 详情 | 详情 | |
| (XIX) | 59151 | 5-(2,5-Dioxopyrrolidin-1-yl)-4-oxopentanoic acid | C9H11NO5 | 详情 | 详情 | |
| (XX) | 59152 | 5-[(3-carboxypropanoyl)amino]-4-oxopentanoic acid | C9H13NO6 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XIV)The acylation of hippuric acid (LXI) with methyl succinyl chloride (XIV) in cold 4-picoline gave rise to the acyl oxazolinone (LXII). Subsequent acidic hydrolysis of (LXII) provided delta-aminolevulinic acid. In a related strategy, the lithio-dianion of ethyl hippurate (LXIII) was acylated with succinic anhydride (XII) producing the 2-amino-3-oxoadipic acid derivative (LXIV). Further hydrolysis and decarboxylation of (LXIV) under acidic conditions furnished the target compound.
| 【1】 Sidebottom, P.J.; Evans, D.A.; A simple route to alpha-aminoketones and related derivatives by dianion acylation reactions; an improved preparation of delta-aminolevulinic acid. J Chem Soc Chem Commun 1978, 753. |
| 【2】 Aronova, N.I.; Makhova, N.N.; Zavyalov, S.I.; Volkenshtein, J.B.; Kunitskaya, G.M.; Method of producing delta-aminolevulinic acid hydrochloride. US 3846490 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XII) | 11291 | Dihydro-2,5-furandione; Succinic anhydride | 108-30-5 | C4H4O3 | 详情 | 详情 |
| (XIV) | 18060 | 4-Chloro-4-oxobutyric acid methyl ester; 3-Carbomethosypropionyl chloride; Methyl 4-chloro-4-oxobutanoate | 1490-25-1 | C5H7ClO3 | 详情 | 详情 |
| (LXI) | 27236 | 2-(benzoylamino)acetic acid | 495-69-2 | C9H9NO3 | 详情 | 详情 |
| (LXII) | 59186 | methyl 4-oxo-4-(5-oxo-2-phenyl-4,5-dihydro-1,3-oxazol-4-yl)butanoate | C14H13NO5 | 详情 | 详情 | |
| (LXIII) | 59187 | Ethyl hippurate | C11H13NO3 | 详情 | 详情 | |
| (LXIV) | 59188 | 5-(benzoylamino)-6-ethoxy-4,6-dioxohexanoic acid | C15H17NO6 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XIV)Methoxy succinyl cyanide (LXV) was prepared by acylation of cuprous cyanide with methoxy succinyl chloride (XIV). Reduction of the acyl cyanide (XIV) by means of zinc dust in the presence of Ac2O produced the acetylamino ketone (LXVI). Subsequent hydrolysis of (LXVI) in aqueous HCl afforded the target aminoacid.
| 【1】 Anwar, S.; Pfaltz, A.; Synthesis of alpha-aminoketones via selective reduction of acyl cyanides. Tetrahedron Lett 1984, 25, 28, 2977. |
合成路线5
该中间体在本合成路线中的序号：(IX)Condensation of (4-methoxyphenyl)acetic acid (I) with anisole (II) in hot PPA produced ketone (III). Subsequent treatment of (III) with the Vilsmeier reagent afforded chloroaldehyde (IV). The required thiophene (VI) was then obtained by cyclization with ethyl mercaptoacetate (V) in the presence of NaOEt. After basic hydrolysis of the ester group of (VI), the resulting acid (VII) was decarboxylated by means of copper in quinoline at 180 C, yielding thiophene (VIII). Stannic chloride-promoted Friedel-Crafts acylation of (VIII) with 3-(methoxycarbonyl)propionyl chloride (IX) gave ketoester (X). The keto group of (X) was further reduced employing triethylsilane in trifluoroacetic acid to afford (XI). Hydrolysis of the methyl ester of (XI), followed by treatment with oxalyl chloride furnished acid chloride (XII). The title hydroxamic acid was then obtained by coupling of (XII) with O-(tert-butyldimethylsilyl)-N-methylhydroxylamine and subsequent acid-catalyzed desilylation.
| 【1】 Wierzbicki, M.; Sauveur, F.; Bonnet, J.; Tordjman, C. (ADIR et Cie.); Thiophene cpds., process for their preparation and pharmaceutical compsns. containing them. EP 0728755; FR 2730996; JP 1996253470 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 40600 | tert-butyl(dimethyl)[(methylamino)oxy]silane; O-[tert-butyl(dimethyl)silyl]-N-methylhydroxylamine | C7H19NOSi | 详情 | 详情 | ||
| (I) | 34793 | 2-(4-methoxyphenyl)acetic acid; p-Methoxyphenyl formate; Homoanisic acid; p-Methyl benzyl formate; 4-methoxyphenylacetic acid; 4-methoxybenzeneacetic acid; p-methoxyphenylacetic acid | 104-01-8 | C9H10O3 | 详情 | 详情 |
| (II) | 23767 | Methoxybenzene; Methyl phenyl ether; Anisole | 100-66-3 | C7H8O | 详情 | 详情 |
| (III) | 22991 | 1,2-bis(4-methoxyphenyl)-1-ethanone | 120-44-5 | C16H16O3 | 详情 | 详情 |
| (IV) | 34794 | (E)-3-chloro-2,3-bis(4-methoxyphenyl)-2-propenal | C17H15ClO3 | 详情 | 详情 | |
| (V) | 23995 | ethyl 2-sulfanylacetate | 2713-34-0 | C4H8O2S | 详情 | 详情 |
| (VI) | 34795 | ethyl 4,5-bis(4-methoxyphenyl)-2-thiophenecarboxylate | C21H20O4S | 详情 | 详情 | |
| (VII) | 34796 | 4,5-bis(4-methoxyphenyl)-2-thiophenecarboxylic acid | C19H16O4S | 详情 | 详情 | |
| (VIII) | 34797 | 2,3-bis(4-methoxyphenyl)thiophene; 4-[2-(4-methoxyphenyl)-3-thienyl]phenyl methyl ether | C18H16O2S | 详情 | 详情 | |
| (IX) | 18060 | 4-Chloro-4-oxobutyric acid methyl ester; 3-Carbomethosypropionyl chloride; Methyl 4-chloro-4-oxobutanoate | 1490-25-1 | C5H7ClO3 | 详情 | 详情 |
| (X) | 34798 | methyl 4-[4,5-bis(4-methoxyphenyl)-2-thienyl]-4-oxobutanoate | C23H22O5S | 详情 | 详情 | |
| (XI) | 34799 | methyl 4-[4,5-bis(4-methoxyphenyl)-2-thienyl]butanoate | C23H24O4S | 详情 | 详情 | |
| (XII) | 34800 | 4-[4,5-bis(4-methoxyphenyl)-2-thienyl]butanoyl chloride | C22H21ClO3S | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(II)Title compound was obtained by acylation of 2-amino-3-chloro-1,4-naphthoquinone (I) with 3-carbomethoxypropionyl chloride (II) in the presence of dry HCl in refluxing toluene.
| 【1】 Kuo, S.-C.; et al.; Synthesis and cytotoxicity of 1,2-disubstituted naphth[2,3-d]imidazole-4,9-diones and related compounds. J Med Chem 1996, 39, 7, 1447-1451. |
合成路线7
该中间体在本合成路线中的序号：(XV)3-(Carbomethoxy)propionyl chloride (XV) is condensed with the chiral oxazolidine (XVI) to provide (XVII). Titanium-catalyzed Michael addition of acrylonitrile to the N-acyl oxazolidine (XVII) affords nitrile (XVIII), which is reduced to the primary amine (XIX) by catalytic hydrogenation in the presence of PtO2. Reductive alkylation of amine (XIX) with N-Boc-4-piperidone (XX) gives rise to the aminopiperidine (XXI). This is then cyclized to the piperidinyl piperidone (XXII) upon heating in acetonitrile. After alkaline hydrolysis of the methyl ester group of (XXII), coupling of the resultant acid (XXIII) with methylamine gives rise to the corresponding amide (XXIV). The N-Boc protecting group of (XXIV) is then removed by treatment with trifluoroacetic acid to furnish piperidine (XXV)
| 【1】 Carruthers, N.I.; Alaimo, C.A.; Shih, N.-Y.; Lavey, B.J.; Ting, P.C.; Reichard, G.A. (Schering Corp.); Substd. oximes as neurokinin antagonists. EP 1032561; WO 9926924 . |
| 【2】 Carruthers, N.I.; Reichard, G.A.; Shih, N.-Y.; Lavey, B.J.; Alaimo, C.A.; Ting, P.C. (Schering Corp.); Substd. oximes as neurokinin antagonists. US 6063926 . |
| 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) | 10847 | Acrylonitrile | 107-13-1 | C3H3N | 详情 | 详情 |
| (XV) | 18060 | 4-Chloro-4-oxobutyric acid methyl ester; 3-Carbomethosypropionyl chloride; Methyl 4-chloro-4-oxobutanoate | 1490-25-1 | C5H7ClO3 | 详情 | 详情 |
| (XVI) | 25351 | (4R)-4-benzyl-1,3-oxazolidin-2-one; (R)-(+)-4-benzyl-2-oxazolidinone | 102029-44-7 | C10H11NO2 | 详情 | 详情 |
| (XVII) | 61347 | methyl 4-[(4R)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-4-oxobutanoate | C15H17NO5 | 详情 | 详情 | |
| (XVIII) | 61348 | methyl (3R)-3-{[(4R)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl}-5-cyanopentanoate | C18H20N2O5 | 详情 | 详情 | |
| (XIX) | 61349 | methyl (3R)-6-amino-3-{[(4R)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl}hexanoate | C18H24N2O5 | 详情 | 详情 | |
| (XX) | 18620 | tert-butyl 4-oxo-1-piperidinecarboxylate;BOC-Piperidone;N-(tert-Butoxycarbonyl)-4-piperidone; N-Boc-4-piperidone | 79099-07-3 | C10H17NO3 | 详情 | 详情 |
| (XXI) | 61350 | tert-butyl 4-[((4R)-4-{[(4R)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl}-6-methoxy-6-oxohexyl)amino]-1-piperidinecarboxylate | C28H41N3O7 | 详情 | 详情 | |
| (XXII) | 61351 | C18H30N2O5 | 详情 | 详情 | ||
| (XXIII) | 61352 | C17H28N2O5 | 详情 | 详情 | ||
| (XXIV) | 61353 | C18H31N3O4 | 详情 | 详情 | ||
| (XXV) | 61354 | C13H23N3O2 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(A)Diazotization of the known aniline (I), followed by Sandmeyer reaction with CuCN and KCN afforded nitrile (II). Addition of hydrogen sulfide to (II) in the presence of Et3N in hot DMF led to the thioamide (III). Subsequent alkylation of (III) with methyl triflate gave the intermediate thioimidate (IV), and a further treatment of (IV) with hydrogen sulfide and pyridine provided dithioester (V). Displacement of the methylthio group of (V) by hydrazine yielded thiohydrazide (VI). This was cyclized to the required thiadiazole (VII) upon treatment with 3-carbomethoxypropionyl chloride (A) in refluxing THF. Aminolysis of the ester group of (VII) with methanolic ammonia at 100 C in a sealed vessel provided amide (VIII). This was finally dehydrated to the title nitrile using trifluoroacetic anhydride and pyridine.
| 【1】 Ford, C.W.; Gadwood, R.C.; Thomasco, L.M.; Weaver, E.A.Zurenko, G.E.; Synthesis and antibacterial activity of azolylphenyl oxazolidinones having 1,3,4-thiadiazolyl C-rings. 39th Intersci Conf Antimicrob Agents Chemother (Sept 26 1999, San Francisco) 1999, Abst F571. |
| 【2】 Gadwood, R.C.; Thomasco, L.M.; Anderson, D.J. (Pharmacia Corp.); Thiadiazolyl and oxadiazolyl phenyl oxazolidinone antibacterial agents. EP 0994874; WO 9902525 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 27344 | hydrazine | 302-01-2 | H4N2 | 详情 | 详情 | |
| (A) | 18060 | 4-Chloro-4-oxobutyric acid methyl ester; 3-Carbomethosypropionyl chloride; Methyl 4-chloro-4-oxobutanoate | 1490-25-1 | C5H7ClO3 | 详情 | 详情 |
| (I) | 28504 | N-[[(5S)-3-(4-amino-3-fluorophenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl]acetamide | C12H14FN3O3 | 详情 | 详情 | |
| (II) | 28555 | N-[[(5S)-3-(4-cyano-3-fluorophenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl]acetamide | C13H12FN3O3 | 详情 | 详情 | |
| (III) | 28556 | N-([(5S)-3-[4-(aminocarbothioyl)-3-fluorophenyl]-2-oxo-1,3-oxazolidin-5-yl]methyl)acetamide | C13H14FN3O3S | 详情 | 详情 | |
| (IV) | 32980 | methyl 4-[(5S)-5-[(acetamido)methyl]-2-oxo-1,3-oxazolidin-3-yl]-2-fluorobenzenecarbimidothioate | C14H16FN3O3S | 详情 | 详情 | |
| (V) | 32981 | methyl 4-[(5S)-5-[(acetamido)methyl]-2-oxo-1,3-oxazolidin-3-yl]-2-fluorobenzenecarbodithioate | C14H15FN2O3S2 | 详情 | 详情 | |
| (VI) | 32982 | N-([(5S)-3-[3-fluoro-4-(hydrazinocarbothioyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl]methyl)acetamide | C13H15FN4O3S | 详情 | 详情 | |
| (VII) | 32983 | methyl 3-[5-(4-[(5S)-5-[(acetamido)methyl]-2-oxo-1,3-oxazolidin-3-yl]-2-fluorophenyl)-1,3,4-thiadiazol-2-yl]propanoate | C18H19FN4O5S | 详情 | 详情 | |
| (VIII) | 32984 | 3-[5-(4-[(5S)-5-[(acetamido)methyl]-2-oxo-1,3-oxazolidin-3-yl]-2-fluorophenyl)-1,3,4-thiadiazol-2-yl]propanamide | C17H18FN5O4S | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(II)The condensation of 4-nitrobenzenesulfonamide (I) with 4-chloro-4-oxobutyric acid methyl ester (II) in refluxing pyridine gives 4-(4-nitrobenzenesulfonamido)-4-oxobutyric acid methyl ester (III), which is reduced with Fe and NH4Cl in methanol/water to yield the corresponding 4-amino derivative (IV). The diazotization of (IV) with NaNO2 and HCl affords the diazonium salt (V), which is condensed with 2-hydroxybenzoic acid (VI) to provide the azo compound (VII). Finally, this compound is hydrolyzed with NaOH to the target succinamic acid derivative.
| 【1】 Riggs-Sauthier, J.A.; Malson, E.; Harris, M.; Myung, S.; Liddle, R.; Ekwuribe, N.; Synthesis and activity of novel 5-aminosalicylic acid (5-ASA)-containing prodrugs for the treatment of inflammatory bowel disease. 224th ACS Natl Meet (Aug 18 2002, Boston) 2002, Abst MEDI 305. |
| 【2】 Ekwuribe, N.N.; Malson, E.; Riggs-Sauthier, J. (Nobex Corp.); 5-ASA derivs. having anti-inflammatory and antibiotic activity and methods of treating diseases therewith. US 6458776; WO 0218330 . |
| 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) | 55807 | 4-Nitrobenzenesulfonamide; p-Nitrobenzenesulfonamide | 6325-93-5 | C6H6N2O4S | 详情 | 详情 |
| (II) | 18060 | 4-Chloro-4-oxobutyric acid methyl ester; 3-Carbomethosypropionyl chloride; Methyl 4-chloro-4-oxobutanoate | 1490-25-1 | C5H7ClO3 | 详情 | 详情 |
| (III) | 55808 | methyl 4-{[(4-nitrophenyl)sulfonyl]amino}-4-oxobutanoate | C11H12N2O7S | 详情 | 详情 | |
| (IV) | 55809 | methyl 4-{[(4-aminophenyl)sulfonyl]amino}-4-oxobutanoate | C11H14N2O5S | 详情 | 详情 | |
| (V) | 55810 | 4-{[(4-methoxy-4-oxobutanoyl)amino]sulfonyl}benzenediazonium chloride | C11H12ClN3O5S | 详情 | 详情 | |
| (VI) | 15240 | 2-Hydroxybenzoic acid; Salicylic acid | 69-72-7 | C7H6O3 | 详情 | 详情 |
| (VII) | 55811 | 2-hydroxy-5-[(E)-2-(4-{[(4-methoxy-4-oxobutanoyl)amino]sulfonyl}phenyl)diazenyl]benzoic acid | C18H17N3O8S | 详情 | 详情 |