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【结 构 式】 
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【分子编号】17531 【品名】(2S)-N-(2,6-dimethylphenyl)-2-piperidinecarboxamide 【CA登记号】 |
【 分 子 式 】C14H20N2O 【 分 子 量 】232.32568 【元素组成】C 72.38% H 8.68% N 12.06% O 6.89% |
合成路线1
该中间体在本合成路线中的序号：(V)Optical resolution of DL-pipecolinic acid (I) with (+)-tartaric acid gives L-pipecolinic acid (II), which is treated with PCl5 to obtain acil chloride (III). This compound is condensed with 2,5-dimethylaniline (IV) by means N-methylpirrolidine (NMP) to afford amide (V). Finally, amide (V) is alkylated with 1-bromopropane by means potassium carbonate (K2CO3) to yield Ropivacaine.
| 【1】 Sandeberg, R.V. (AstraZeneca plc); S-(-)-1-propyl-2',6'-pipecoloxylidide hydrochloride monohydrate, process for its preparation and pharmaceutical preparation containing it. EP 0239710; US 4870086 . |
| 【2】 T. af Ekenstam, B.; Bovin, C. (Alpharma Inc.); L-N-n-Propylpipecolic acid-2,6-xylidide and method for preparing the same. JP 1985502054; WO 8500599 . |
| 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) | 17532 | 2-piperidinecarboxylic acid; pipecolic acid | 535-75-1 | C6H11NO2 | 详情 | 详情 |
| (II) | 17380 | (2S)hexahydro-2-pyridinecarboxylic acid; (S)-pipecolic acid | 3105-95-1 | C6H11NO2 | 详情 | 详情 |
| (III) | 19499 | (2S)-2-piperidinecarbonyl chloride | C6H10ClNO | 详情 | 详情 | |
| (IV) | 17527 | 2,6-Xylidine; 2,6-Dimethylaniline; 2,6-Dimethylphenylamine | 87-62-7 | C8H11N | 详情 | 详情 |
| (V) | 17531 | (2S)-N-(2,6-dimethylphenyl)-2-piperidinecarboxamide | C14H20N2O | 详情 | 详情 | |
| (VI) | 19502 | Propyl bromide; 1-Bromopropane | 106-94-5 | C3H7Br | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(V)L-Picolinic acid (II) is protected with benzyl chloroformiate (VII) to afford compound (VIII), which is condensed with 2-methylaniline (IX) by means SOCl2/DMAP to yield amide (X). This compound (X) is methylated by treatment with palladium acetate (Pd(Oac)2) to obtain compound (XI), which is deprotected by means HBr to yield compound (V). Finally, this compound (V) is alkylated with 1-iodopropane by means potassium carbonate (K2CO3) to yield Ropivacaine.
| 【1】 Sandeberg, R.V. (AstraZeneca plc); S-(-)-1-propyl-2',6'-pipecoloxylidide hydrochloride monohydrate, process for its preparation and pharmaceutical preparation containing it. EP 0239710; US 4870086 . |
| 【2】 T. af Ekenstam, B.; Bovin, C. (Alpharma Inc.); L-N-n-Propylpipecolic acid-2,6-xylidide and method for preparing the same. JP 1985502054; WO 8500599 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 28758 | 1-iodopropane | 107-08-4 | C3H7I | 详情 | 详情 | |
| (II) | 17380 | (2S)hexahydro-2-pyridinecarboxylic acid; (S)-pipecolic acid | 3105-95-1 | C6H11NO2 | 详情 | 详情 |
| (V) | 17531 | (2S)-N-(2,6-dimethylphenyl)-2-piperidinecarboxamide | C14H20N2O | 详情 | 详情 | |
| (VII) | 10101 | Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene | 501-53-1 | C8H7ClO2 | 详情 | 详情 |
| (VIII) | 19504 | (2S)-1-[(benzyloxy)carbonyl]-2-piperidinecarboxylic acid | C14H17NO4 | 详情 | 详情 | |
| (IX) | 15511 | o-toluidine; 2-methylphenylamine;2-Methylaniline；2-Aminotoluene;1-Amino-2-methylbenzene;1-Methyl-2-aminobenzene; ortho-Toluidine | 95-53-4 | C7H9N | 详情 | 详情 |
| (X) | 19506 | benzyl (2S)-2-(2-toluidinocarbonyl)-1-piperidinecarboxylate | C21H24N2O3 | 详情 | 详情 | |
| (XI) | 19507 | benzyl (2S)-2-[(2,6-dimethylanilino)carbonyl]-1-piperidinecarboxylate | C22H26N2O3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(V)Compound (XII) is protected with benzyl chloroformiate (VII) to afford compound (XIII), which is condensed with 2,5-dimethylaniline (XIV) by means SOCl2/DMAP to yield amide (XIV). This compound (XIV) is deprotected by means trimethylsillyl chloride to yield compound (XV), which is hydrogenated by means Rh/Al2O3. Finally, this compound (V) is alkylated with 1-iodopropane by means potassium carbonate (K2CO3) to yield Ropivacaine.
| 【1】 T. af Ekenstam, B.; Bovin, C. (Alpharma Inc.); L-N-n-Propylpipecolic acid-2,6-xylidide and method for preparing the same. JP 1985502054; WO 8500599 . |
| 【2】 Sandeberg, R.V. (AstraZeneca plc); S-(-)-1-propyl-2',6'-pipecoloxylidide hydrochloride monohydrate, process for its preparation and pharmaceutical preparation containing it. EP 0239710; US 4870086 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 28758 | 1-iodopropane | 107-08-4 | C3H7I | 详情 | 详情 | |
| (IV) | 17527 | 2,6-Xylidine; 2,6-Dimethylaniline; 2,6-Dimethylphenylamine | 87-62-7 | C8H11N | 详情 | 详情 |
| (V) | 17531 | (2S)-N-(2,6-dimethylphenyl)-2-piperidinecarboxamide | C14H20N2O | 详情 | 详情 | |
| (VII) | 10101 | Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene | 501-53-1 | C8H7ClO2 | 详情 | 详情 |
| (XII) | 19508 | (2S)-1,2,3,4-tetrahydro-2-pyridinecarboxylic acid | C6H9NO2 | 详情 | 详情 | |
| (XIII) | 19509 | (2S)-1-[(benzyloxy)carbonyl]-1,2,3,4-tetrahydro-2-pyridinecarboxylic acid | C14H15NO4 | 详情 | 详情 | |
| (XIV) | 19510 | benzyl (2S)-2-[(2,6-dimethylanilino)carbonyl]-3,4-dihydro-1(2H)-pyridinecarboxylate | C22H24N2O3 | 详情 | 详情 | |
| (XV) | 19511 | (2S)-N-(2,6-dimethylphenyl)-1,2,3,4-tetrahydro-2-pyridinecarboxamide | C14H18N2O | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(V)1) The optical resolution of pipecolic acid (I) with (+)-tartaric acid in water-ethanol gives L-pipecolic acid (II), which by reaction with Cl5P in acetyl chloride is converted to the acyl chloride (III). The condensation of (III) with 2,6-xylidine (IV) by means of N-methylpyrrolidone (NMP) in acetone affords L-pipecolic acid 2,6-xylidide (V), which is finally alkylated with propyl bromide (VI) and K2CO3 in hot isopropanol.
| 【1】 T. af Ekenstam, B.; Bovin, C. (Astra Lakemedel AB); L-N-n-Propylpipecolic acid 2,6-xylidide. US 4695576 . |
| 【2】 Prous, J.; Castaner, J.; ROPIVACAINE HYDROCHLORIDE < Rec INNM >. Drugs Fut 1989, 14, 8, 767. |
| 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) | 17532 | 2-piperidinecarboxylic acid; pipecolic acid | 535-75-1 | C6H11NO2 | 详情 | 详情 |
| (II) | 17380 | (2S)hexahydro-2-pyridinecarboxylic acid; (S)-pipecolic acid | 3105-95-1 | C6H11NO2 | 详情 | 详情 |
| (III) | 19499 | (2S)-2-piperidinecarbonyl chloride | C6H10ClNO | 详情 | 详情 | |
| (IV) | 17527 | 2,6-Xylidine; 2,6-Dimethylaniline; 2,6-Dimethylphenylamine | 87-62-7 | C8H11N | 详情 | 详情 |
| (V) | 17531 | (2S)-N-(2,6-dimethylphenyl)-2-piperidinecarboxamide | C14H20N2O | 详情 | 详情 | |
| (VI) | 19502 | Propyl bromide; 1-Bromopropane | 106-94-5 | C3H7Br | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(V)2) The protection of L-pipecolic acid (II) with benzyl chloroformate (VII) gives the benzyloxycarbonyl compound (VIII), which is condensed with o-toluidine (IX) by means of SOCl2 and dimethylaminopyridine (DMAP) yielding the amide (X). The methylation of (X) with methyl iodide and palladium diacetate in acetic acid affords the 2,6-xylidide (XI), which is deprotected with HBr in acetic acid to give L-pipecolic acid 2,6-xylidide (V). Finally, this compound is alkylated with propyl iodide and K2CO3 in acetonitrile.
| 【1】 Prous, J.; Castaner, J.; ROPIVACAINE HYDROCHLORIDE < Rec INNM >. Drugs Fut 1989, 14, 8, 767. |
| 【2】 Sahlberg, C.; Synthesis of carbon-14 labelled ropivacaine, a local anaesthetic agent. J Label Compd Radiopharm 1987, 24, 5, 529. |
| 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) | 17380 | (2S)hexahydro-2-pyridinecarboxylic acid; (S)-pipecolic acid | 3105-95-1 | C6H11NO2 | 详情 | 详情 |
| (V) | 17531 | (2S)-N-(2,6-dimethylphenyl)-2-piperidinecarboxamide | C14H20N2O | 详情 | 详情 | |
| (VI) | 19502 | Propyl bromide; 1-Bromopropane | 106-94-5 | C3H7Br | 详情 | 详情 |
| (VII) | 10101 | Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene | 501-53-1 | C8H7ClO2 | 详情 | 详情 |
| (VIII) | 19504 | (2S)-1-[(benzyloxy)carbonyl]-2-piperidinecarboxylic acid | C14H17NO4 | 详情 | 详情 | |
| (IX) | 15511 | o-toluidine; 2-methylphenylamine;2-Methylaniline；2-Aminotoluene;1-Amino-2-methylbenzene;1-Methyl-2-aminobenzene; ortho-Toluidine | 95-53-4 | C7H9N | 详情 | 详情 |
| (X) | 19506 | benzyl (2S)-2-(2-toluidinocarbonyl)-1-piperidinecarboxylate | C21H24N2O3 | 详情 | 详情 | |
| (XI) | 19507 | benzyl (2S)-2-[(2,6-dimethylanilino)carbonyl]-1-piperidinecarboxylate | C22H26N2O3 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(V)3) The protection of 1,2,3,6-tetrahydropyridine-2(S)-carboxylic acid (XII) with benzyl chloroformate (VII) gives the benzyloxycarbonyl derivative (XIII), which is condensed with 2,6-xylidine (IV) with SOCl2 and DMAP as before yielding the amide (XIV). Deprotection of (XIV) with iodotrimethylsilane in dichloromethane affords N-(2,6-dimethylphenyl)-1,2,3,6-tetrahydropyridine-2(S)-carboxamide (XV), which is reduced with H2 over Rh/Al2O3 in DMF giving the saturated amide (V). Finally, this compound is alkylated with propyl iodide and K2CO3 as before.
| 【1】 Prous, J.; Castaner, J.; ROPIVACAINE HYDROCHLORIDE < Rec INNM >. Drugs Fut 1989, 14, 8, 767. |
| 【2】 Gawell, L.; Synthesis of tritium labelled ropivacaine - A new potential local anaesthetic. J Label Compd Radiopharm 1987, 24, 5, 521. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IV) | 17527 | 2,6-Xylidine; 2,6-Dimethylaniline; 2,6-Dimethylphenylamine | 87-62-7 | C8H11N | 详情 | 详情 |
| (V) | 17531 | (2S)-N-(2,6-dimethylphenyl)-2-piperidinecarboxamide | C14H20N2O | 详情 | 详情 | |
| (VI) | 19502 | Propyl bromide; 1-Bromopropane | 106-94-5 | C3H7Br | 详情 | 详情 |
| (VII) | 10101 | Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene | 501-53-1 | C8H7ClO2 | 详情 | 详情 |
| (XII) | 19508 | (2S)-1,2,3,4-tetrahydro-2-pyridinecarboxylic acid | C6H9NO2 | 详情 | 详情 | |
| (XIII) | 19509 | (2S)-1-[(benzyloxy)carbonyl]-1,2,3,4-tetrahydro-2-pyridinecarboxylic acid | C14H15NO4 | 详情 | 详情 | |
| (XIV) | 19510 | benzyl (2S)-2-[(2,6-dimethylanilino)carbonyl]-3,4-dihydro-1(2H)-pyridinecarboxylate | C22H24N2O3 | 详情 | 详情 | |
| (XV) | 19511 | (2S)-N-(2,6-dimethylphenyl)-1,2,3,4-tetrahydro-2-pyridinecarboxamide | C14H18N2O | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(VII)Levobupivacaine has been obtained by two different ways: 1) The deamination of N-benzoyloxycarbonyl-L-lysine (I) with NaNO2/acetic acid gives 6-acetoxy-2(S)-(benzyl-oxycarbonylamino)hexanoic acid (II), which is amidated with 2,6-dimethylaniline (III) and dicyclohexylcarbodiimide (DCC) to the expected amide (IV). The deacetylation of (IV) with K2CO3 in methanol affords compound (V), which is tosylated as usual with tosyl chloride giving intermediate (VI), which is stereospecifically cyclized by means of K2CO3 in ethanol yielding N-(2,6-dimethyl-phenyl)piperidine-2 (S)-carboxamide (VII). Finally, this compound is alkylated with butyl bromide and K2CO3 or by reductoalkylation with butyraldehyde. 2) The amidation of piperidine-2-carboxylic acid (VIII) with 2,6-dimethylaniline (III) by means of SOCl2 in toluene gives the corresponding amide (IX), which is alkylated with butyl bromide as before yielding racemic bupivacaine (X) (3). This compound is then submitted to optical resolution by treatment with (S,S)-()-tartaric acid followed by crystallization of the resulting tartrate and acidification with HCl in isopropanol.
| 【1】 Dyer, U.; Hutton, G.; Adger, B.; Woods, M.; Stereospecific synthesis of the anaesthetic levobupivacaine. Tetrahedron Lett 1996, 37, 35, 6399-402. |
| 【2】 Skead, B.M.; Langston, M. (Celltech Chiroscience plc); Crystallization of levobupicavaine and analogues thereof. WO 9612699 . |
| 【3】 Hutton, G.E. (Celltech Chiroscience plc); The manufacture of levo-bupivacaine and analogues thereof from L-lysine. WO 9611181 . |
| 【4】 Frampton, G.A.C.; Zavareh, H.S. (Celltech Chiroscience plc); Progress for preparing levobupivacaine and analogues thereof. WO 9612700 . |
| 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) | 17525 | (2S)-6-amino-2-[[(benzyloxy)carbonyl]amino]hexanoic acid | C14H20N2O4 | 详情 | 详情 | |
| (II) | 17526 | (2S)-6-(acetoxy)-2-[[(benzyloxy)carbonyl]amino]hexanoic acid | C16H21NO6 | 详情 | 详情 | |
| (III) | 17527 | 2,6-Xylidine; 2,6-Dimethylaniline; 2,6-Dimethylphenylamine | 87-62-7 | C8H11N | 详情 | 详情 |
| (IV) | 17528 | (5S)-5-[[(benzyloxy)carbonyl]amino]-6-(2,6-dimethylanilino)-6-oxohexyl acetate | C24H30N2O5 | 详情 | 详情 | |
| (V) | 17529 | benzyl (1S)-1-[(2,6-dimethylanilino)carbonyl]-5-hydroxypentylcarbamate | C22H28N2O4 | 详情 | 详情 | |
| (VI) | 17530 | (5S)-5-[[(benzyloxy)carbonyl]amino]-6-(2,6-dimethylanilino)-6-oxohexyl 4-methylbenzenesulfonate | C29H34N2O6S | 详情 | 详情 | |
| (VII) | 17531 | (2S)-N-(2,6-dimethylphenyl)-2-piperidinecarboxamide | C14H20N2O | 详情 | 详情 | |
| (VIII) | 17532 | 2-piperidinecarboxylic acid; pipecolic acid | 535-75-1 | C6H11NO2 | 详情 | 详情 |
| (IX) | 17533 | N-(2,6-dimethylphenyl)-2-piperidinecarboxamide | C14H20N2O | 详情 | 详情 | |
| (X) | 17534 | 1-butyl-N-(2,6-dimethylphenyl)-2-piperidinecarboxamide | 2180-92-9 | C18H28N2O | 详情 | 详情 |