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【结 构 式】 
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【分子编号】48447 【品名】Di-tert-butyl iminodicarboxylate; Iminodicarboxylic acid di-tert-butyl ester 【CA登记号】51779-32-9 |
【 分 子 式 】C10H19NO4 【 分 子 量 】217.2652 【元素组成】C 55.28% H 8.81% N 6.45% O 29.46% |
合成路线1
该中间体在本合成路线中的序号：(II)The condensation of bromoketone (I) with di-tert-butyl iminodicarboxylate (II) by means of Cs2CO3 in acetonitrile gives the adduct (III), which is monodecarboxylated by reaction with TFA in dichloromethane to yield the carbamate (IV). The asymmetric reduction of the ketonic group of (IV) by means of BH3 and a chiral oxazaborole catalyst affords the (R)-alcohol (V), which is cyclized by means of NaH in DMF to provide the chiral oxazolidinone (VI). The alkylation of (VI) with 6-(4-phenylbutoxy)hexyl bromide (VII) by means of NaH in THF gives the alkylated oxazolidinone (VIII), which is treated with Tms-OK in THF to cleave the oxazolidinone ring, yielding the aminoalcohol (IX). Finally, the acetonide ring of (IX) is cleaved by means of AcOH in methanol to provide salmeterol.
| 【1】 Coe, D.M.; Perciaccante, R.; Procopiou, P.A.; Potassium trimethylsilanolate induced cleavage of 1,3-oxazolidin-2 and 5-ones, and application to the synthesis of (R)-salmeterol. Org Biomol Chem 2003, 1, 7, 1106. |
| 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) | 52359 | 2-bromo-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1-ethanone | C12H13BrO3 | 详情 | 详情 | |
| (II) | 48447 | Di-tert-butyl iminodicarboxylate; Iminodicarboxylic acid di-tert-butyl ester | 51779-32-9 | C10H19NO4 | 详情 | 详情 |
| (III) | 64766 | 6-{2-[bis(tert-butoxycarbonyl)amino]acetyl}-2,2-dimethyl-4H-1,3-benzodioxine | C22H31NO7 | 详情 | 详情 | |
| (IV) | 64767 | tert-butyl 2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxoethylcarbamate | C17H23NO5 | 详情 | 详情 | |
| (V) | 64768 | tert-butyl (2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethylcarbamate | C17H25NO5 | 详情 | 详情 | |
| (VI) | 64769 | (5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one | C13H15NO4 | 详情 | 详情 | |
| (VII) | 31479 | 1-[4-[(6-bromohexyl)oxy]butyl]benzene; 6-bromohexyl-4-phenylbutyl ether; 6-Bromohexyloxybutylbenzene | 94749-73-2 | C16H25BrO | 详情 | 详情 |
| (VIII) | 64770 | (5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-3-[6-(4-phenylbutoxy)hexyl]-1,3-oxazolidin-2-one | C29H39NO5 | 详情 | 详情 | |
| (IX) | 52679 | (1R)-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-{[6-(4-phenylbutoxy)hexyl]amino}-1-ethanol | C28H41NO4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XVI)Reaction of 4-cyanobenzyl bromide (I) with bis(tert-butoxycarbonyl)imine (XVI) by means of NaH in THF gives the protected benzylamine (XVII), which is treated with hydroxylamine and Na2CO3 in ethanol/water to yield the N-hydroxybenzamidine (XVIII). Reduction of compound (XVIII) with H2 over Pd/C in HOAc/Ac2O affords the protected benzamidine (XIX), which is treated with benzyl chloroformate and NaOH in THF in order to obtain the fully protected compound (XX). Selective deprotection of (XX) with HCl gives 4-(benzyloxycarbonylamidino)benzylamine (V), which is condensed with the protected azetidine-2-carboxylic acid (XXI) to afford the corresponding amide (XXII). Boc-deprotection of (XXII) provides azetidine (XXIII), which is condensed with N-Boc-(R)-cyclohexylglycine (VII) to give the protected dipeptide (XI). Boc-deprotection of (XI) affords intermediate (XII), which is condensed with benzyl 2-bromoacetate (XIV) to give the melagatran precursor (XV). Finally, this compound is debenzylated by hydrogenation with H2 over Pd/C as before.
| 【2】 Hervé, Y.; Fournier, J.; De Nanteuil, G.; Leborgne, F.; Verbeuren, T.J.; Lila, C.; Gloanec, P.; Cadet, L.; Large scale preparation of protected 4-aminomethylbenzamidine. Application to the synthesis of the thrombin inhibitor melagatran. Synth Commun 1998, 28, 23, 4419. |
| 【1】 Bayes, M.; Silvestre, J.S.; Sorbera, L.A.; Castaner, J.; Melagatran and Ximelagatran. Drugs Fut 2001, 26, 12, 1155. |
| 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) | 14200 | 4-(Bromomethyl)benzonitrile; alpha-Bromo-p-tolunitrile | 17201-43-3 | C8H6BrN | 详情 | 详情 |
| (V) | 50386 | benzyl [4-(aminomethyl)phenyl](imino)methylcarbamate | C16H17N3O2 | 详情 | 详情 | |
| (VII) | 35619 | (2S)-2-[(tert-butoxycarbonyl)amino]-2-cyclohexylethanoic acid | C13H23NO4 | 详情 | 详情 | |
| (XI) | 50376 | benzyl [4-([[((2S)-1-[(2R)-2-[(tert-butoxycarbonyl)amino]-2-cyclohexylethanoyl]azetidinyl)carbonyl]amino]methyl)phenyl](imino)methylcarbamate | C33H43N5O6 | 详情 | 详情 | |
| (XII) | 50390 | benzyl (4-[[([(2S)-1-[(2R)-2-amino-2-cyclohexylethanoyl]azetidinyl]carbonyl)amino]methyl]phenyl)(imino)methylcarbamate | C28H35N5O4 | 详情 | 详情 | |
| (XIV) | 12869 | benzyl 2-bromoacetate | 5437-45-6 | C9H9BrO2 | 详情 | 详情 |
| (XV) | 50392 | benzyl 2-[((1R)-2-[(2S)-2-[([4-[[[(benzyloxy)carbonyl]amino](imino)methyl]benzyl]amino)carbonyl]azetidinyl]-1-cyclohexyl-2-oxoethyl)amino]acetate | C37H43N5O6 | 详情 | 详情 | |
| (XVI) | 48447 | Di-tert-butyl iminodicarboxylate; Iminodicarboxylic acid di-tert-butyl ester | 51779-32-9 | C10H19NO4 | 详情 | 详情 |
| (XVII) | 50393 | 1-[[bis(tert-butoxycarbonyl)amino]methyl]-4-cyanobenzene | C18H24N2O4 | 详情 | 详情 | |
| (XVIII) | 50394 | 1-[amino(hydroxyimino)methyl]-4-[[bis(tert-butoxycarbonyl)amino]methyl]benzene | C18H27N3O5 | 详情 | 详情 | |
| (XIX) | 50395 | 1-[amino(imino)methyl]-4-[[bis(tert-butoxycarbonyl)amino]methyl]benzene | C18H27N3O4 | 详情 | 详情 | |
| (XX) | 50396 | 1-[[[(benzyloxy)carbonyl]amino](imino)methyl]-4-[[bis(tert-butoxycarbonyl)amino]methyl]benzene | C26H33N3O6 | 详情 | 详情 | |
| (XXI) | 26205 | (2S)-1-(tert-butoxycarbonyl)-2-azetidinecarboxylic acid | C9H15NO4 | 详情 | 详情 | |
| (XXII) | 50397 | tert-butyl (2S)-2-[([4-[[[(benzyloxy)carbonyl]amino](imino)methyl]benzyl]amino)carbonyl]-1-azetidinecarboxylate | C25H30N4O5 | 详情 | 详情 | |
| (XXIII) | 50398 | benzyl [4-([[(2S)azetidinylcarbonyl]amino]methyl)phenyl](imino)methylcarbamate | C20H22N4O3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VIII)Treatment of diamino compound (I) with oxalic acid (II) in refluxing HCl provides tetrahydroquinoxalindione derivative (III), which is then converted into dichloro compound (IV) by reaction with refluxing POCl3. Treatment of (IV) with Na in refluxing MeOH affords dimethoxy quinoxaline (V), which is then brominated by reaction with NBS and AIBN in refluxing CCl4 to give bromomethyl derivative (VI). Nitration of (VI) by reaction with isopropyl nitrate in H2SO4 yields nitro derivative (VII), which is then converted into protected amino methyl derivative (IX) by reaction with di-tert-butyl-iminocarboxylate (VIII) and cesium carbonate in DMF. Removal of the Boc groups of (IX) by means of TFA gives aminomethyl derivative (X), which is then converted into phosphonic dimethyl ester (XII) by first treatment with formaline in EtOH followed by reaction with dimethyl phosphonate (XI), Et3N and trimethylsilyl chloride (TMSCl) in CHCl3. Finally, treatment of (XII) with trimethylsilyl bromide (TMSBr) in CH2Cl2 obtains the desired product.
| 【1】 Acklin, P.; Allgeier, H.; Auberson, Y.; Ofner, S.; Veenstra, S.J. (Novartis AG); Substd. aminoalkane phosphonic acids. EP 0934326; US 6117873; WO 9817672 . |
| 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) | 48441 | 2,3-Diaminotoluene; o-Tolylenediamine | 2687-25-4 | C7H10N2 | 详情 | 详情 |
| (II) | 15713 | Oxalic acid | 144-62-7 | C2H2O4 | 详情 | 详情 |
| (III) | 48442 | 5-methyl-1,4-dihydro-2,3-quinoxalinedione | C9H8N2O2 | 详情 | 详情 | |
| (IV) | 48443 | 2,3-dichloro-5-methylquinoxaline | C9H6Cl2N2 | 详情 | 详情 | |
| (V) | 48444 | 2,3-dimethoxy-5-methylquinoxaline; 3-methoxy-5-methyl-2-quinoxalinyl methyl ether | C11H12N2O2 | 详情 | 详情 | |
| (VI) | 48445 | 5-(bromomethyl)-3-methoxy-2-quinoxalinyl methyl ether; 5-(bromomethyl)-2,3-dimethoxyquinoxaline | C11H11BrN2O2 | 详情 | 详情 | |
| (VII) | 48446 | 5-(bromomethyl)-3-methoxy-7-nitro-2-quinoxalinyl methyl ether; 5-(bromomethyl)-2,3-dimethoxy-7-nitroquinoxaline | C11H10BrN3O4 | 详情 | 详情 | |
| (VIII) | 48447 | Di-tert-butyl iminodicarboxylate; Iminodicarboxylic acid di-tert-butyl ester | 51779-32-9 | C10H19NO4 | 详情 | 详情 |
| (IX) | 48448 | 5-[[bis(tert-butoxycarbonyl)amino]methyl]-2,3-dimethoxy-7-nitroquinoxaline | C21H28N4O8 | 详情 | 详情 | |
| (X) | 48449 | (2,3-dimethoxy-7-nitro-5-quinoxalinyl)methanamine; (2,3-dimethoxy-7-nitro-5-quinoxalinyl)methylamine | C11H12N4O4 | 详情 | 详情 | |
| (XI) | 32359 | dimethyl phosphonate | 868-85-9 | C2H7O3P | 详情 | 详情 |
| (XII) | 48450 | dimethyl [[(2,3-dimethoxy-7-nitro-5-quinoxalinyl)methyl]amino]methylphosphonate | C14H19N4O7P | 详情 | 详情 |