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【结 构 式】 
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【分子编号】37173 【品名】3-(dimethylamino)-1-propanol 【CA登记号】3179-63-3 |
【 分 子 式 】C5H13NO 【 分 子 量 】103.16436 【元素组成】C 58.21% H 12.7% N 13.58% O 15.51% |
合成路线1
该中间体在本合成路线中的序号：(XI)1) The acetylation of iminodibenzyl (I) with acetyl chloride (A) in refluxing toluene gives N-acetyl-iminodibenzyl (II), which by a Friedel-Kraft's reaction with methyl oxalyl chloride (B) and AlCl3 in CH2Cl2 or CS2 is converted to N-acetyl-3-(methyloxalyl)iminodibenzyl (III). The hydrolysis of (III) with NaOH in methanol-water yields N-acetyl-5-oxalyliminodibenzyl (IV), which by treatment with NaOH in water-ethanol at high temperature affords 3-oxalyliminodibenzyl (V). The reaction of (V) with hydroxylamine and acetic acid gives 3-hydroxylaminooxalyliminodibenzyl (VI), which by heating at 100 C in water is converted into 3-cyanoiminodibenzyl (VII). Finally, this compound is condensed with 3-(dimethylamino)propyl chloride (VIII) by means of NaH in DMF. 2) Compound (VII) can also be condensed with dimethylaminopropyl N,N-dimethylcarbamate (IX) by heating at 250 C. 3) The reaction of (VII) with phosgene gives N-chlorocarbonyl-3-cyanoiminodibenzyl (X), which is condensed with 3-dimethylaminopropanol (XI) to afford 3-cyanoiminodibenzyl-N-carboxylic acid 3-dimethylaminopropyl ester (XII). Finally, this compound is heated at 250 C under reduced pressure.
| 【1】 Dostert, P. (Hoffmann-La Roche, Inc.); 3-Cyano-N-(N,N-dimethylaminopropyl)-iminodibenzyl and salts thereof. US 4138482 . |
| 【2】 Blancafort, P.; Castaner, J.; Owen, R.T.; Serradell, M.N.; RO-11-2465. Drugs Fut 1981, 6, 1, 41. |
| 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) | 19273 | acetyl chloride | 75-36-5 | C2H3ClO | 详情 | 详情 |
| (B) | 26971 | 2-methoxy-2-oxoacetyl chloride | 5781-53-3 | C3H3ClO3 | 详情 | 详情 |
| (I) | 37165 | 10,11-dihydro-5H-dibenzo[b,f]azepine | 494-19-9 | C14H13N | 详情 | 详情 |
| (II) | 37166 | 1-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-1-ethanone | C16H15NO | 详情 | 详情 | |
| (III) | 37167 | methyl 2-(5-acetyl-10,11-dihydro-5H-dibenzo[b,f]azepin-3-yl)-2-oxoacetate | C19H17NO4 | 详情 | 详情 | |
| (IV) | 37168 | 2-(5-acetyl-10,11-dihydro-5H-dibenzo[b,f]azepin-3-yl)-2-oxoacetic acid | C18H15NO4 | 详情 | 详情 | |
| (V) | 37169 | 2-(10,11-dihydro-5H-dibenzo[b,f]azepin-3-yl)-2-oxoacetic acid | C16H13NO3 | 详情 | 详情 | |
| (VI) | 37170 | 2-(10,11-dihydro-5H-dibenzo[b,f]azepin-3-yl)-2-(hydroxyimino)acetic acid | C16H14N2O3 | 详情 | 详情 | |
| (VII) | 37171 | 10,11-dihydro-5H-dibenzo[b,f]azepine-3-carbonitrile | C15H12N2 | 详情 | 详情 | |
| (VIII) | 24581 | 3-(Dimethylamino)propyl chloride; 3-Chloro-N,N-dimethyl-1-propanamine | 5407-04-5 | C5H12ClN | 详情 | 详情 |
| (IX) | 37175 | 3-(dimethylamino)propyl dimethylcarbamate | C8H18N2O2 | 详情 | 详情 | |
| (X) | 37172 | 3-cyano-10,11-dihydro-5H-dibenzo[b,f]azepine-5-carbonyl chloride | C16H11ClN2O | 详情 | 详情 | |
| (XI) | 37173 | 3-(dimethylamino)-1-propanol | 3179-63-3 | C5H13NO | 详情 | 详情 |
| (XII) | 37174 | 3-(dimethylamino)propyl 3-cyano-10,11-dihydro-5H-dibenzo[b,f]azepine-5-carboxylate | C21H23N3O2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)N-Boc-L-Tyrosine methyl ester (I) was alkylated with either 3-(dimethylamino)-1-propanol (II) under Mitsunobu conditions or with N,N-dimethyl-3-chloropropylamine (III) in the presence of K2CO3 to afford N-Boc-L-4-(3-dimethylaminopropoxy)phenylalanine methyl ester (IV). Subsequent acidic cleavage of the N-Boc protecting group of (IV) gave amino ester (V). N-Tosyl-L-5,5-dimethylthiaproline (VII) was obtained by treatment of L-5,5-dimethylthiaproline (VI) with p-toluenesulfonyl chloride in the presence of NaOH. Acid (VII) was then coupled to amino ester (V) using EDC and HOBt to furnish amide (VIII). Finally, basic hydrolysis of the methyl ester group of (VIII) yielded the title compound.
| 【1】 Grant, F.S.; Dressen, D.B.; Dappen, M.S.; et al.; CT747: A very potent and highly selective small molecule inhibitor of VLA4 that is metabolically stable. 220th ACS Natl Meet (Aug 20 2000, Washington DC) 2000, Abst MEDI 135. |
| 【2】 Ashwell, S.; Konradi, A.W.; Lombardo, L.J.; Dappen, M.S.; Baudy, R.B.; Kreft, A.; Grant, F.S.; Sarantakis, D.; Pleiss, M.A.; Semko, C.M.; Dressen, D.B.; Thorsett, E.D. (American Home Products Corp.; Athena Neurosciences, Inc.); Substd. phenylalanine type cpds. which inhibit leukocyte adhesion mediated by VLA-4. WO 9906431 . |
| 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) | 19875 | methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-hydroxyphenyl)propanoate | 4326-36-7 | C15H21NO5 | 详情 | 详情 |
| (II) | 37173 | 3-(dimethylamino)-1-propanol | 3179-63-3 | C5H13NO | 详情 | 详情 |
| (III) | 24581 | 3-(Dimethylamino)propyl chloride; 3-Chloro-N,N-dimethyl-1-propanamine | 5407-04-5 | C5H12ClN | 详情 | 详情 |
| (IV) | 45680 | methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-[4-[3-(dimethylamino)propoxy]phenyl]propanoate | C20H32N2O5 | 详情 | 详情 | |
| (V) | 45681 | methyl (2S)-2-amino-3-[4-[3-(dimethylamino)propoxy]phenyl]propanoate | C15H24N2O3 | 详情 | 详情 | |
| (VI) | 34776 | (4R)-5,5-dimethyl-1,3-thiazolidine-4-carboxylic acid | 72778-00-8 | C6H11NO2S | 详情 | 详情 |
| (VII) | 45682 | (4R)-5,5-dimethyl-3-[(4-methylphenyl)sulfonyl]-1,3-thiazolidine-4-carboxylic acid | C13H17NO4S2 | 详情 | 详情 | |
| (VIII) | 45683 | methyl (2S)-3-[4-[3-(dimethylamino)propoxy]phenyl]-2-[([(4R)-5,5-dimethyl-3-[(4-methylphenyl)sulfonyl]-1,3-thiazolidin-4-yl]carbonyl)amino]propanoate | C28H39N3O6S2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VII)Acetylation of aniline (I) with acetic anhydride (Ac2O) in HOAc followed by reaction with mercurium acetate (Hg(OAc)2) and HClO4 in HOAc provides derivative (II), which is first subjected to dimerization by treatment with Cu and PdCl2 in pyridine and then nitrated by means of HNO3 in HOAc to afford substituted biphenyl (III). Hydrolysis of (III) with H2SO4 gives 4,4'-diamino-3,3'-dinitrobiphenyl (IV), which is converted into tetraaminobiphenyl (V) by hydrogenation over Raney-Ni in acetone. Mitsunobu reaction between p-hydroxybenzaldehyde (VI) and 3-dimethylamino propan-1-ol (VII) with PPh3 and DEAD in THF gives substituted benzaldehyde (VIII), which is finally cyclized with biphenyl derivative (V) by heating in nitrobenzene to furnish the target product.
| 【1】 Neidle, S.; et al.; Symmetric bis-benzimidazoles: New sequence-selective DNA-binding molecules. Chem Commun (London) 1999, 10, 929. |
| 【2】 Kelland, L.R.; Opoku-Boahen, Y.; Mann, J.; Baron, A.; johansson, E.; Parkinson, G.; Neidle, S.; A new class of symmetric bisbenzimidazole-based DNA minor groove-binding agents showing antitumor activity. J Med Chem 2001, 44, 2, 138. |
| 【3】 Mann, J.; Neidle, S. (Institute of Cancer Research; Queen's University of Belfast; University of Reading); Bis-benzazoles and their use as antineoplastic agents. WO 0063180 . |
| 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) | 12294 | Aniline; Phenylamine | 62-53-3 | C6H7N | 详情 | 详情 |
| (II) | 47202 | C10H11HgNO3 | 详情 | 详情 | ||
| (III) | 47203 | N-[4'-(acetamido)-3,3'-dinitro[1,1'-biphenyl]-4-yl]acetamide | C16H14N4O6 | 详情 | 详情 | |
| (IV) | 47204 | 3,3'-dinitro[1,1'-biphenyl]-4,4'-diamine; 4'-amino-3,3'-dinitro[1,1'-biphenyl]-4-ylamine | 6271-79-0 | C12H10N4O4 | 详情 | 详情 |
| (V) | 47205 | 3',4,4'-triamino[1,1'-biphenyl]-3-ylamine; [1,1'-biphenyl]-3,3',4,4'-tetramine | 91-95-2 | C12H14N4 | 详情 | 详情 |
| (VI) | 13433 | 4-Hydroxybenzaldehyde; p-Hydroxybenzaldehyde | 123-08-0 | C7H6O2 | 详情 | 详情 |
| (VII) | 37173 | 3-(dimethylamino)-1-propanol | 3179-63-3 | C5H13NO | 详情 | 详情 |
| (VIII) | 47206 | 4-[3-(dimethylamino)propoxy]benzaldehyde | C12H17NO2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(II)Condensation of 1-benzyl-3-hydroxy-1H-pyrazole-5-carboxylic acid methyl ester (I) with 3-(dimethylamino)-1-propanol (II) by means of 1,1'-(azodicarbonyl)dipiperidine and tributylphosphine under Mitsunobu conditions afforded the dimethylaminopropyl ether (III). After basic hydrolysis of the methyl ester group of (III), the resultant carboxylic acid (IV) was coupled with 4-methoxyaniline (V) using HATU to furnish the title amide.
| 【1】 Brummel, D.G.; Budworth, J.; Selwood, D.L.; et al.; Synthesis and biological evaluation of novel pyrazoles and indazoles as activators of the nitric oxide receptor, soluble guanylate cyclase. J Med Chem 2001, 44, 1, 78. |
| 【2】 Glen, R.; Liu, Q.; Powell, K.; Reynolds, K.; Madge, D.; Kling, M.; Selwood, D.; Wishart, G. (University College London); Activators of soluble guanylate cyclase. WO 0027394 . |
| 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) | 47332 | methyl 1-benzyl-3-hydroxy-1H-pyrazole-5-carboxylate | C12H12N2O3 | 详情 | 详情 | |
| (II) | 37173 | 3-(dimethylamino)-1-propanol | 3179-63-3 | C5H13NO | 详情 | 详情 |
| (III) | 47333 | methyl 1-benzyl-3-[3-(dimethylamino)propoxy]-1H-pyrazole-5-carboxylate | C17H23N3O3 | 详情 | 详情 | |
| (IV) | 47334 | 1-benzyl-3-[3-(dimethylamino)propoxy]-1H-pyrazole-5-carboxylic acid | C16H21N3O3 | 详情 | 详情 | |
| (V) | 10478 | p-Anisidine; 4-Methoxyaniline; 4-Methoxyphenylamine | 104-94-9 | C7H9NO | 详情 | 详情 |