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【结 构 式】 
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【分子编号】13070 【品名】L-Aspartic acid; (2S)-2-Aminobutanedioic acid 【CA登记号】56-84-8 |
【 分 子 式 】C4H7NO4 【 分 子 量 】133.10392 【元素组成】C 36.1% H 5.3% N 10.52% O 48.08% |
合成路线1
该中间体在本合成路线中的序号：(I)1) The reaction of L-aspartic acid (I) with NaNO2, NaBr and H2SO4 gives 2(S)-bromosuccinic acid (II), which is reduced with methyl sulfide borane complex in THF, yielding 2(S)-bromobutane-1,4-diol (III). The cyclization of (III) with Cs2CO3 in methylene chloride affords (R)-(2-hydroxyethyl)oxirane (IV), which is acylated with methanesulfonyl chloride to the corresponding mesylate (V). The cyclization of (V) with Na2S in acetonitrile/water gives 3(R)-hydroxythiolane (VI), which is acylated with p-toluenesulfonyl chloride, affording the corresponding tosylate (VII). The controlled oxidation of (VII) with potassium peroxymonosulfate (oxone) gives 3(R)-(p-toluenesulfonyloxy)thiolane-1(R)-oxide (VIII), which by reaction with potassium thioacetate in acetone is converted to 3(S)-(acetylthio)thiolane 1(R)-oxide (IX). The reaction of (IX) with NaOEt and CS2 in ethanol yields the trithiocarbonate (X), which is condensed with the chloroazetidinone (XI), yielding the trithiocarbonate ester (XII). The condensation of (XII) with 2-chloroallyloxalyl fluoride (XIII) by means of diisopropylethylamine in methylene chloride affords the substituted oxalamic ester (XIV), which is cyclized by means of triethyl phosphite in refluxing chloroform to the fully protected penem derivative (XV). The reaction of (XV) with tetrabutylammonium fluoride (TBAF) in THF eliminates the protecting tert-butyldimethylsilyl group, yielding the chloroallyl ester (XVI), which is treated with triphenylphosphine and sodium 2-ethylhexanoate in dichloromethane to obtain the corresponding sodium salt (XVII). Finally, this compound is treated with HCl in cool water.
| 【1】 Mealy, N.; Castaner, J.; Sulopenem. Drugs Fut 1996, 21, 7, 706. |
| 【2】 Volkmann, R.A. (Pfizer Inc.); Diastereomeric 5R,6S-6-(1R-hydroxyethyl)-2-(cis-1-oxo-3-thiolanylthio)-2-penem-3-carboxylic acids. JP 1995278137; US 5013729; WO 8808845 . |
| 【3】 Volkmann, R.A.; Kelbaugh, P.R.; Nason, D.M.; Jasys, V.J.; 2-Thioalkyl penems: An efficient synthesis of sulopenem, a (5R,6S)-6-(1(R)-hydroxyethyl)-2-[(cis-1-oxo-3-thiolanyl)thio]-2-penem antibacterial. J Org Chem 1992, 57, 16, 4352-61. |
| 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) | 13070 | L-Aspartic acid; (2S)-2-Aminobutanedioic acid | 56-84-8 | C4H7NO4 | 详情 | 详情 |
| (II) | 13071 | (S)-(-)-Bromosuccinic acid; (2S)-2-Bromobutanedioic acid | 20859-23-8 | C4H5BrO4 | 详情 | 详情 |
| (III) | 13072 | (2S)-2-Bromo-1,4-butanediol | C4H9BrO2 | 详情 | 详情 | |
| (IV) | 13073 | 2-[(2R)Oxiranyl]-1-ethanol | C4H8O2 | 详情 | 详情 | |
| (V) | 13074 | methyl 2-[(2R)oxiranyl]ethyl sulfite | C5H10O4S | 详情 | 详情 | |
| (VI) | 13075 | (3R)Tetrahydro-3-thiophenol | C4H8OS | 详情 | 详情 | |
| (VII) | 13076 | (3R)tetrahydro-3-thiophenyl 4-methylbenzenesulfonate | C11H14O3S2 | 详情 | 详情 | |
| (VIII) | 13077 | (3R)-1-oxotetrahydro-1H-1lambda(4)-thiophen-3-yl 4-methylbenzenesulfonate | C11H14O4S2 | 详情 | 详情 | |
| (IX) | 13078 | S-[(3S)-1-oxotetrahydro-1H-1lambda(4)-thiophen-3-yl] ethanethioate | C6H10O2S2 | 详情 | 详情 | |
| (X) | 13079 | Sodium (3S)-3-(carbodithioatosulfanyl)-1-oxotetrahydro-1H-1lambda(4)-thiophene | C5H7NaOS4 | 详情 | 详情 | |
| (XI) | 13080 | (3S,4R)-3-((1R)-1-[[tert-Butyl(dimethyl)silyl]oxy]ethyl)-4-chloro-2-azetidinone | C11H22ClNO2Si | 详情 | 详情 | |
| (XII) | 13081 | (2R,3S)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetidinyl (3S)-1-oxotetrahydro-1H-1lambda(4)-thiophen-3-yl carbonotrithioate | C16H29NO3S4Si | 详情 | 详情 | |
| (XIII) | 13082 | 2-[(2-Chloro-2-propenyl)oxy]-2-oxoacetyl fluoride | C5H4ClFO3 | 详情 | 详情 | |
| (XIV) | 13083 | 2-chloro-2-propenyl 2-[(3S,4R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-2-oxo-4-[([[(3S)-1-oxotetrahydro-1H-1lambda(4)-thiophen-3-yl]sulfanyl]carbothioyl)sulfanyl]azetidinyl]-2-oxoacetate | C21H32ClNO6S4Si | 详情 | 详情 | |
| (XV) | 13084 | 2-chloro-2-propenyl (5R,6S)-6-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-7-oxo-3-[[(3S)-1-oxotetrahydro-1H-1lambda(4)-thiophen-3-yl]sulfanyl]-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C21H32ClNO5S3Si | 详情 | 详情 | |
| (XVI) | 13085 | (5R,6S)-2-[1-[(2-Chloro-2-propenyl)oxy]vinyl]-6-[(1R)-1-hydroxyethyl]-3-[[(3S)-1-oxotetrahydro-1H-1lambda(4)-thiophen-3-yl]sulfanyl]-4-thia-1-azabicyclo[3.2.0]hept-2-en-7-one | C16H20ClNO4S3 | 详情 | 详情 | |
| (XVII) | 13086 | sodium (5R,6S)-6-[(1R)-1-hydroxyethyl]-7-oxo-3-[[(3S)-1-oxotetrahydro-1H-1lambda(4)-thiophen-3-yl]sulfanyl]-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C12H14NNaO5S3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：A general synthesis of this entire class of thrombin inhibitors has been published recently. An alternative synthesis for the preparation of napsagatran is outlined in Scheme 21319301a: L-Aspartic acid is sulfonated with naphthalenesulfochloride to give the sulfonamide (I). Reaction of (I) with formaldehyde leads to the oxazolinone (II), which is reacted with N-cyclopropylglycine ethyl ester (III) to afford the aspartate (IV). Condensation of (IV) with the guanidine (IX) and saponification of the ethyl ester group provides napsagatran. For the preparation of the guanidine (IX), picolylamine is hydrogenated to give the racemic 3-aminomethyl-piperidine, from which the desired enantiomer (V) is isolated as dibenzoyltartrate by crystallization. Reaction of piperidine (V) with acetoacetate affords the protected piperidine (VI), which is amidinated with amidinotriazole (VII) to give the protected guanidine (VIII). Deprotection of (VIII) with hydrochloric acid provides the enantiomerically pure guanidine (IX) as dihydrochloride.
| 【1】 Banner, D.W.; Hilpert, K.; Ackermann, J.; et al.; Design and synthesis of potent and highly selective thrombin inhibitors. J Med Chem 1994, 37, 23, 3889-901. |
| 【2】 Gast, A.; Kirchhofer, D.; Soukup. M.; Roux, S.; Ackermann, J.; Hilpert, K.; Tschopp, T.B.; Schmid, G.; Napsagatran. Drugs Fut 1995, 20, 5, 476. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 12263 | Cyclopropylamine; Cyclopropanamine | 765-30-0 | C3H7N | 详情 | 详情 | |
| 13070 | L-Aspartic acid; (2S)-2-Aminobutanedioic acid | 56-84-8 | C4H7NO4 | 详情 | 详情 | |
| 16640 | Ethyl 2-bromoacetate; Ethyl bromoacetate | 105-36-2 | C4H7BrO2 | 详情 | 详情 | |
| 18731 | 3-pyridinylmethanamine; 3-pyridinylmethylamine | 3731-52-0 | C6H8N2 | 详情 | 详情 | |
| (I) | 16803 | (2S)-2-[(2-naphthylsulfonyl)amino]butanedioic acid | C14H13NO6S | 详情 | 详情 | |
| (II) | 16804 | 2-[(4S)-3-(2-naphthylsulfonyl)-5-oxo-1,3-oxazolan-4-yl]acetic acid | C15H13NO6S | 详情 | 详情 | |
| (III) | 16805 | ethyl 2-(cyclopropylamino)acetate | C7H13NO2 | 详情 | 详情 | |
| (IV) | 16806 | (3S)-4-[cyclopropyl(2-ethoxy-2-oxoethyl)amino]-3-[(2-naphthylsulfonyl)amino]-4-oxobutyric acid | C21H24N2O7S | 详情 | 详情 | |
| (V) | 16807 | (3S)hexahydro-3-pyridinylmethylamine; (3S)hexahydro-3-pyridinylmethanamine | C6H14N2 | 详情 | 详情 | |
| (VI) | 16808 | methyl (Z)-3-[[(3R)hexahydro-3-pyridinylmethyl]amino]-2-butenoate | C11H20N2O2 | 详情 | 详情 | |
| (VII) | 16809 | 1H-1,2,4-triazole-1-carboximidamide hydrochloride | C3H6ClN5 | 详情 | 详情 | |
| (VIII) | 16810 | methyl (Z)-3-[([(3S)-1-[amino(imino)methyl]piperidinyl]methyl)amino]-2-butenoate hydrochloride | C12H23ClN4O2 | 详情 | 详情 | |
| (IX) | 16811 | (3S)-3-(aminomethyl)-1-piperidinecarboximidamide | C7H16N4 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)Reaction of L-aspartic acid (I) with trifluoroacetic acid and trifluoroacetic anhydride afforded N-trifluoroacetyl-L-aspartic anhydride (II). Then, Friedel-Crafts acylation of 1,3-difluorobenzene (III) with this anhydride in the presence of AlCl3 gave ketone (IV). The reduction of the carbonyl group of (IV) was effected by catalytic hydrogenation in the presence of Pearlman's catalyst, and the resulting phenylbutyric acid (V) was converted to acid chloride on treatment with PCl5 in cold dichloromethane, and subsequently cyclized by addition of AlCl3 to yield tetralone (VI). Hydrogenolysis of (VI) in the presence of Pearlman's catalyst gave tetrahydronaphthalene (VII), and further hydrolysis of trifluoroacetamide with LiOH yielded (S)-5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl amine (VIII). Imidazole ring was then constructed by treatment of this amine with 1,3-dihydroxyacetone (IX) and potassium thiocyanate in acidic medium, and the hydroxyl group of the resulting X was substituted by a formamido group by either heating in formamide at 175 C or with ammonium formate. Finally, formamide (XI) was hydrolyzed in refluxing isopropanolic HCl.
| 【1】 Martinez, G.R.; Repke, D.B.; Teitelbaum, P.J.; Walker, K.A.M.; Gooding, O.W.; Whiting, R.L.; Bansal, R.P.; Muehldorf, A.V. (Syntex (USA), Inc.); Benzocycloalkylazolethione derivs.. JP 1997512269; US 5438150; WO 9529165 . |
| 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) | 13070 | L-Aspartic acid; (2S)-2-Aminobutanedioic acid | 56-84-8 | C4H7NO4 | 详情 | 详情 |
| (II) | 18410 | N-[(3S)-2,5-dioxotetrahydro-3-furanyl]-2,2,2-trifluoroacetamide | 777-33-3 | C6H4F3NO4 | 详情 | 详情 |
| (III) | 13095 | m-Difluorobenzene; 1,3-Difluorobenzene | 372-18-9 | C6H4F2 | 详情 | 详情 |
| (IV) | 18412 | (2S)-4-(2,4-difluorophenyl)-4-oxo-2-[(2,2,2-trifluoroacetyl)amino]butyric acid | C12H8F5NO4 | 详情 | 详情 | |
| (V) | 18413 | (2S)-4-(2,4-difluorophenyl)-2-[(2,2,2-trifluoroacetyl)amino]butyric acid | C12H10F5NO3 | 详情 | 详情 | |
| (VI) | 18414 | N-[(2S)-5,7-difluoro-1-oxo-1,2,3,4-tetrahydro-2-naphthalenyl]-2,2,2-trifluoroacetamide | C12H8F5NO2 | 详情 | 详情 | |
| (VII) | 18415 | N-[(2S)-5,7-difluoro-1,2,3,4-tetrahydro-2-naphthalenyl]-2,2,2-trifluoroacetamide | C12H10F5NO | 详情 | 详情 | |
| (VIII) | 18416 | (2S)-5,7-difluoro-1,2,3,4-tetrahydro-2-naphthalenylamine; (2S)-5,7-difluoro-1,2,3,4-tetrahydro-2-naphthalenamine | C10H11F2N | 详情 | 详情 | |
| (IX) | 14575 | Dihydroxyacetone; 1,3-dihydroxyacetone | 96-26-4 | C3H6O3 | 详情 | 详情 |
| (X) | 18418 | 1-[(2S)-5,7-difluoro-1,2,3,4-tetrahydro-2-naphthalenyl]-5-(hydroxymethyl)-1,3-dihydro-2H-imidazole-2-thione | C14H14F2N2OS | 详情 | 详情 | |
| (XI) | 18419 | [3-[(2S)-5,7-difluoro-1,2,3,4-tetrahydro-2-naphthalenyl]-2-thioxo-2,3-dihydro-1H-imidazol-4-yl]methylformamide | C15H15F2N3OS | 详情 | 详情 |