|
【结 构 式】 
|
【分子编号】24581 【品名】3-(Dimethylamino)propyl chloride; 3-Chloro-N,N-dimethyl-1-propanamine 【CA登记号】5407-04-5 |
【 分 子 式 】C5H12ClN 【 分 子 量 】121.60972 【元素组成】C 49.38% H 9.95% Cl 29.15% N 11.52% |
合成路线1
该中间体在本合成路线中的序号：(I)By condensation of 3-dimethylaminopropyl chloride (I) with thiourea (II) in refluxing ethanol.
| 【1】 Weetman, D.F.; Castaner, J.; Dimaprit. Drugs Fut 1978, 3, 4, 273. |
| 【2】 Kartinos, N.J. (Baxter International Inc.); Gamma-Dimethylaminopropyl isothiourea and acid addition salts thereof. US 3116327 . |
合成路线2
该中间体在本合成路线中的序号：(A)The reaction of 5-bromophthalide (I) with 4-fluorophenylmagnesium bromide (II) in ether gives 4-bromo-4'-fluoro-2-(hydroxymethyl)benzophenone (III), which is reduced with LiAlH4 or NaBH4 in ether to afford 4-bromo-4'-fluoro-2-(hydroxymethyl)benzhydrol (IV). The cyclization of (IV) with 60% H3PO4 or TsOH or H2SO4 at 100 C yields 5-bromo-1-(4-fluoropheny)phthalan (V), which by reaction with cuprous cyanide in refluxing DMF is converted into 1-(4-fluorophenyl)-5-phtalancarbonitrile (VI). Finally, this compound is condensed with 3-(dimethylamino)propyl chloride (A) by means of NaH in hot DMSO.
| 【1】 Bigler, A.J.; et al.; Quantitative structure-activity relationships in a series of selective 5-HT uptake inhibitors. Eur J Med Chem - Chim Ther 1977, 12, 3, 289-295. |
| 【2】 Bogeso, K.P.; Toft, A.S. (Kefalas A/S); Anti-depressive substituted 1-dimethylaminopropyl-1-phenyl phthalans. DE 2657013; FR 2338271; GB 1526331; JP 52105162; US 4136193 . |
| 【3】 Muddasani, P.R.; Nannapaneni, W.C. (Natco Pharma Ltd.); Process for the preparation of high purity citalopram and its pharmaceutically acceptable salts. WO 0416602 . |
| 【4】 Roberts, P.J.; Castaner, J.; Serradell, M.N.; Blancafort, P.; Citalopram. Drugs Fut 1979, 4, 6, 407. |
| 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) | 24581 | 3-(Dimethylamino)propyl chloride; 3-Chloro-N,N-dimethyl-1-propanamine | 5407-04-5 | C5H12ClN | 详情 | 详情 |
| (I) | 33229 | 5-bromophthalide; 5-bromo-2-benzofuran-1(3H)-one | 64169-34-2 | C8H5BrO2 | 详情 | 详情 |
| (II) | 13643 | 4-fluorophenyl magnesium bromide;Bromo(4-fluorophenyl)magnesium;bromo(p-fluorophenyl)Magnesium;p-Fluorophenylmagnesium bromide | 352-13-6 | C6H4BrFMg | 详情 | 详情 |
| (III) | 33230 | [4-Bromo-2-(hydroxymethyl)phenyl](4-fluorophenyl)methanone; 4-Bromo-4'-fluoro-2-(hydroxymethyl)benzophenone | C14H10BrFO2 | 详情 | 详情 | |
| (IV) | 33231 | 4-bromo-4'-fluoro-2-(hydroxymethyl)benzhydrol; [4-bromo-2-(hydroxymethyl)phenyl](4-fluorophenyl)methanol | C14H12BrFO2 | 详情 | 详情 | |
| (V) | 33232 | 5-bromo-1-(4-fluoropheny)phthalan; 5-bromo-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran | C14H10BrFO | 详情 | 详情 | |
| (VI) | 33233 | 1-(4-fluorophenyl)-5-phtalancarbonitrile; 1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-carbonitrile | C15H10FNO | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)The reaction of 1,2:5.6-di-O-isopropyliden-D-glucofuranose (I) with 3-chloro-N,N-dimethylaminopropane (II) by means of NaOH in refluxing dioxane gives 1,2:5,6-di-O-isopropylidene-3-O-[3'-(N,N-dimethylamino)propyl]-D-gluco-furanose (III), which is partially hydrolyzed with HCl in water.
| 【1】 Gordon, P. (Boston Life Sciences, Inc.); Method of enhancing learning and/or memory in warm blooded animals. US 3965262 . |
| 【2】 Hopkins, S.J.; Serradell, M.N.; Castaner, J.; Therafectin. Drugs Fut 1985, 10, 4, 301. |
| 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) | 29141 | (3aR,5S,6S,6aR)-5-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol | 582-52-5 | C12H20O6 | 详情 | 详情 |
| (II) | 24581 | 3-(Dimethylamino)propyl chloride; 3-Chloro-N,N-dimethyl-1-propanamine | 5407-04-5 | C5H12ClN | 详情 | 详情 |
| (III) | 29142 | 3-([(3aR,5S,6S,6aR)-5-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-yl]oxy)-N,N-dimethyl-1-propanamine | C17H31NO6 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(VIII)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5
该中间体在本合成路线中的序号：(VIII)The reaction of 3-bromoiminodibenzyl (XIII) with 3-(dimethylamino)propyl chloride (VIII) at 100 C gives N-(3-dimethylaminopropyl)-3-bromoiminodibenzyl (XIV), which is treated with cuprous cyanide in refluxing DMF.
| 【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 |
|---|---|---|---|---|---|---|
| (VIII) | 24581 | 3-(Dimethylamino)propyl chloride; 3-Chloro-N,N-dimethyl-1-propanamine | 5407-04-5 | C5H12ClN | 详情 | 详情 |
| (XIII) | 37176 | 3-bromo-10,11-dihydro-5H-dibenzo[b,f]azepine | C14H12BrN | 详情 | 详情 | |
| (XIV) | 37177 | N-[3-(3-bromo-10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)propyl]-N,N-dimethylamine; 3-(3-bromo-10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-N,N-dimethyl-1-propanamine | C19H23BrN2 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(II)By condensation of 1,5-diphenyl-1-pentanol (I) with 3-(dimethylamino)propyl chloride (II) by means of NaH in refluxing toluene, followed by a treatment with citric acid.
| 【1】 Ono, K.; Kawakami, H.; Katsube, J. (Sumitomo Pharmaceuticals Co., Ltd.); Diphenylalkanoether and diphenylalkanone oximeether derivatives. EP 0017217; US 4388469; US 4426394; US 4482573; US 4620036 . |
| 【2】 Castaner, J.; Prous, J.; SM-3163. Drugs Fut 1986, 11, 12, 1046. |
| 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) | 24580 | 1,5-diphenyl-1-pentanol | C17H20O | 详情 | 详情 | |
| (II) | 24581 | 3-(Dimethylamino)propyl chloride; 3-Chloro-N,N-dimethyl-1-propanamine | 5407-04-5 | C5H12ClN | 详情 | 详情 |
| (III) | 24582 | 3-[(1,5-diphenylpentyl)oxy]-N,N-dimethyl-1-propanamine | C22H31NO | 详情 | 详情 | |
| (IV) | 13856 | 2-Hydroxy-1,2,3-propanetricarboxylic acid; Citric acid | 77-92-9 | C6H8O7 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(IV)Addition of methylmagnesium iodide to nitrile (I), followed by hydrolytic treatment, provided ketone (II), which was brominated in CHCl3-MeOH to give bromomethyl ketone (III). Alkylation of thiourea (V) with 3-(dimethylamino)propyl chloride (IV) produced S-alkyl isothiourea (VI). After hydrolysis of (VI) with NaOEt, the intermediate thiol (VII) was condensed with bromoketone (III) to yield the required thioether, which was finally converted to the citrate salt.
| 【1】 Harris, P.J.; Heal, D.J. (The Boots Company plc); 1-Arylcycloalkyl sulphides, sulphoxides and sulphones for the treatment of depression, anxiety and Parkinson's disease. EP 0715620; JP 1996510222; US 5652271; WO 9426704 . |
| 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) | 27478 | 1-(3,4-dichlorophenyl)cyclobutanecarbonitrile | C11H9Cl2N | 详情 | 详情 | |
| (II) | 27479 | 1-[1-(3,4-dichlorophenyl)cyclobutyl]-1-ethanone | C12H12Cl2O | 详情 | 详情 | |
| (III) | 27480 | 2-bromo-1-[1-(3,4-dichlorophenyl)cyclobutyl]-1-ethanone | C12H11BrCl2O | 详情 | 详情 | |
| (IV) | 24581 | 3-(Dimethylamino)propyl chloride; 3-Chloro-N,N-dimethyl-1-propanamine | 5407-04-5 | C5H12ClN | 详情 | 详情 |
| (V) | 10180 | Thiourea | 62-56-6 | CH4N2S | 详情 | 详情 |
| (VI) | 27481 | 1-[[amino(imino)methyl]sulfanyl]-3-(dimethylamino)propane | C6H15N3S | 详情 | 详情 | |
| (VII) | 27482 | N,N-Dimethyl-N-(3-sulfanylpropyl)amine sodium salt | C5H12NNaS | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(VII)Condensation of 7-hydroxy-5-methoxy-4-methylcoumarin (I) with 2-chlorocyclohexanone (II) by means of K2CO3 in refluxing acetone affords derivative (III), which is then cyclized by means of refluxing NaOH to provide compound (IV). Oxidation of (IV) by means of DDQ in refluxing benzene furnishes angelicine (V), whose methoxy group is then hydrolyzed with HI and acetic anhydride in refluxing HOAc to yield compound (VI). Finally, the desired product is obtained by coupling of (VI) with 3-chloro-N,N'-dimethylpropylamine (VII) by means of Williamson's reaction using NaH and NaI in refluxing DMF or using K2CO3 and HMPA in refluxing acetone.
| 【1】 Santana, L.; Gia, O.; Dalla Via, L.; Uriarte, E.; A new benzoangelicin with strong photobiological activity. Bioorg Med Chem Lett 2000, 10, 2, 135. |
| 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) | 47132 | 7-hydroxy-5-methoxy-4-methyl-2H-chromen-2-one | C11H10O4 | 详情 | 详情 | |
| (II) | 17985 | 2-Chlorocyclohexanone | 822-87-7 | C6H9ClO | 详情 | 详情 |
| (III) | 47133 | 5-methoxy-4-methyl-7-[(2-oxocyclohexyl)oxy]-2H-chromen-2-one | C17H18O5 | 详情 | 详情 | |
| (IV) | 47134 | 5-methoxy-4-methyl-8,9,10,11-tetrahydro-2H-[1]benzofuro[2,3-h]chromen-2-one | C17H16O4 | 详情 | 详情 | |
| (V) | 47135 | 5-methoxy-4-methyl-2H-[1]benzofuro[2,3-h]chromen-2-one | C17H12O4 | 详情 | 详情 | |
| (VI) | 47136 | 5-hydroxy-4-methyl-2H-[1]benzofuro[2,3-h]chromen-2-one | C16H10O4 | 详情 | 详情 | |
| (VII) | 24581 | 3-(Dimethylamino)propyl chloride; 3-Chloro-N,N-dimethyl-1-propanamine | 5407-04-5 | C5H12ClN | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(III)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 |