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【结 构 式】 
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【分子编号】33455 【品名】2-chloro-1-ethanamine; 2-chloroethylamine 【CA登记号】 |
【 分 子 式 】C2H6ClN 【 分 子 量 】79.52908 【元素组成】C 30.21% H 7.6% Cl 44.58% N 17.61% |
合成路线1
该中间体在本合成路线中的序号：(B)Compound can be prepared in three different ways all starting from p-trifluoromethyl-5-methoxy-valerophenone (I): 1) By condensation of (I) with 2-aminooxyethylamine dihydrochloride in refluxing pyridine ethanol (C). 2) The reaction of (I) with hydroxylamine as usual yields the corresponding oxime (II), which is then condensed with 2-chloroethylamine (B) by means of KOH in DMF. 3) The reaction of the oxime (II) with Li and ethylene oxide (A) in absolute ethanol affords the O-(2-hydroxyethyl)oxime (III), which is esterified with mesyl chloride by means of triethylamine in methylene chloride giving the O-(2-mesyloxyethyl)oxime (IV). Finally, this compound is treated with NH3 in methanol at 100 C in a pressure vessel.
| 【1】 Welle, H.B.A.; Claassen, V.; Oxime ethers having anti-depressive activity. DE 2610886; FR 2304336; GB 1535226; JP 51125345; NL 7503310; US 4085225 . |
| 【2】 Thorpe, P.J.; Castaner, J.; Fluvoxamine. Drugs Fut 1978, 3, 4, 288. |
| 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) | 10393 | Oxirane; Ethylene oxide | 75-21-8 | C2H4O | 详情 | 详情 |
| (B) | 33455 | 2-chloro-1-ethanamine; 2-chloroethylamine | C2H6ClN | 详情 | 详情 | |
| (I) | 33451 | 5-methoxy-1-[4-(trifluoromethyl)phenyl]-1-pentanone | C13H15F3O2 | 详情 | 详情 | |
| (II) | 33452 | 5-methoxy-1-[4-(trifluoromethyl)phenyl]-1-pentanone oxime | C13H16F3NO2 | 详情 | 详情 | |
| (III) | 33453 | 5-methoxy-1-[4-(trifluoromethyl)phenyl]-1-pentanone O-(2-hydroxyethyl)oxime | C15H20F3NO3 | 详情 | 详情 | |
| (IV) | 33454 | 2-[([(E)-5-methoxy-1-[4-(trifluoromethyl)phenyl]pentylidene]amino)oxy]ethyl methanesulfonate | C16H22F3NO5S | 详情 | 详情 | |
| (C) | 21003 | 2-(aminooxy)-1-ethanamine; 2-(aminooxy)ethylamine | C2H8N2O | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)Condensation of the chiral 2-chloro-3-(alpha-methylbenzyl)tetrahydro-2H-1,3,2-oxaazaphosphorine 2-oxide (I) with 2-chloroethylamine (II) afforded the 2-(chloroethylamino) derivative (III). The chiral auxiliary group of (III) was then removed by catalytic hydrogenation with H2 over -Pd/C yielding (R)-2-(2-chloroethylamino)tetrahydro-2H-1,3,2-oxaazaphosphorine 2-oxide (IV). Acylation of (IV) with bromoacetyl bromide (V) in the presence of triethylamine hydrobromide furnished bromoacetamide (VI). The amide carbonyl group of (VI) was finally reduced by treatment with NaBH4 and BF3·Et2O.
| 【1】 Kinas, R.W.; Stec, W.J.; Kusnierczyk, H.; Misiura, K.; radzikowski, C.; (S)-(-)-Bromofosfamide (CBM-11): Synthesis and antitumor activity and cytotoxicity in mice. Anti-Cancer Drugs 2001, 12, 5, 453. |
| 【2】 Kutner, A.; Grynkiewicz, G.; Stec, W.J.; Radzikowski, C.; Szelejeswki, W.; Kinas, R.; Misiura, K.; Grodner, J.; Kusnierczyk, H.; Pilichowska, S.; Process for the production of the derivs. of 1,3,2-oxazaphosphorinane. EP 0295576 . |
| 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) | 56222 | 2-chloro-3-[(1S)-1-phenylethyl]-1,3,2lambda~5~-oxazaphosphinan-2-one | C11H15ClNO2P | 详情 | 详情 | |
| (II) | 33455 | 2-chloro-1-ethanamine; 2-chloroethylamine | C2H6ClN | 详情 | 详情 | |
| (III) | 56223 | 2-[(2-chloroethyl)amino]-3-[(1S)-1-phenylethyl]-1,3,2lambda~5~-oxazaphosphinan-2-one | C13H20ClN2O2P | 详情 | 详情 | |
| (IV) | 56224 | 2-[(2-chloroethyl)amino]-1,3,2lambda~5~-oxazaphosphinan-2-one | C5H12ClN2O2P | 详情 | 详情 | |
| (V) | 14005 | 2-Bromoacetyl bromide; Bromoacetyl bromide | 598-21-0 | C2H2Br2O | 详情 | 详情 |
| (VI) | 56225 | 3-(2-bromoacetyl)-2-[(2-chloroethyl)amino]-1,3,2lambda~5~-oxazaphosphinan-2-one | C7H13BrClN2O3P | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：The reaction of 6-cyclohexyl-3,4-dihydro-2H-carbazol-1-one (I) with 2-dibenzylaminoethyl chloride by means of phase transfer catalysis using benzyltriethylammonium chloride and sodium hydroxide in chlorobenzene gives 6-cyclohexyl-9-[2-(dibenzylamino)ethyl-3,4-dihydro-2H-carbazol-1-one (II), which is reduced with H2 over palladium bis(acetonylacetonate) and carbon to give tetrindol.
| 【1】 Glushkov, R.G.; Mashkovsky, M.D.; Andrejeva, N.I.; Tetrindole. Drugs Fut 1997, 22, 12, 1333. |
| 【2】 Glushkov, R.G.; Design of new synthetic drugs: State of the art and prospects. Vestn Russ Acad Med Sci 1994, 11, 31-5. |
合成路线4
该中间体在本合成路线中的序号：(VI)Treatment of 2,5-dihydroxybenzoic acid (I) with dimethyl sulfate and K2CO3 afforded methyl 2-hydroxy-5-methoxybenzoate (II). Condensation of (II) with dimethylthiocarbamoyl chloride gave the O-aryl thiocarbamate (III), which underwent thermal rearrangement to the S-aryl isomer (IV) upon heating at 265 C in diphenyl ether. Subsequent hydrolysis of the thiocarbamate group of (IV) furnished the desired thiophenol compound (V). Cyclization of the mercapto ester (V) with 2-chloroethylamine (VI) gave rise to the benzothiazepinone (VII), which was further reduced to the benzothiazepine (VIII) using LiAlH4. Acylation of (VIII) with acryloyl chloride (IX) provided the acrylamide (X). Finally, Michael addition of 4-benzylpiperidine (XI) to acrylamide (X) yielded the title compound.
| 【1】 Kaneko, N.; Oosawa, T.; Sakai, T.; Oota, H. (Kirin Brewery Co., Ltd.); 1,4-Benzothiazepine derivs.. EP 0565721; US 5416066; WO 9212148 . |
| 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) | 60415 | 2,5-dihydroxybenzoic acid | C7H6O4 | 详情 | 详情 | |
| (II) | 60416 | methyl 2-hydroxy-5-methoxybenzoate | C9H10O4 | 详情 | 详情 | |
| (III) | 60417 | methyl 2-{[(dimethylamino)carbothioyl]oxy}-5-methoxybenzoate | C12H15NO4S | 详情 | 详情 | |
| (IV) | 60418 | methyl 2-{[(dimethylamino)carbonyl]sulfanyl}-5-methoxybenzoate | C12H15NO4S | 详情 | 详情 | |
| (V) | 13887 | methyl 5-methoxy-2-sulfanylbenzoate | C9H10O3S | 详情 | 详情 | |
| (VI) | 33455 | 2-chloro-1-ethanamine; 2-chloroethylamine | C2H6ClN | 详情 | 详情 | |
| (VII) | 60419 | 7-methoxy-3,4-dihydro-1,4-benzothiazepin-5(2H)-one | C10H11NO2S | 详情 | 详情 | |
| (VIII) | 60420 | 7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine; methyl 2,3,4,5-tetrahydro-1,4-benzothiazepin-7-yl ether | C10H13NOS | 详情 | 详情 | |
| (IX) | 11577 | Acryloyl chloride; Acrylyl chloride;2-Propenoyl chloride | 814-68-6 | C3H3ClO | 详情 | 详情 |
| (X) | 60421 | 1-[7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl]-2-propen-1-one | C13H15NO2S | 详情 | 详情 | |
| (XI) | 26225 | 4-benzylpiperidine | 31252-42-3 | C12H17N | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(II)By alkylation of 2-chloro-3-(2-chloroethyl)perhydro-1,3,2-oxaazaphosphorine (I) with 2-chloroethylamine (II) by means of TEA in dichloromethane.
| 【1】 Arnold, H.; et al. (Asta Medica AG); Verfahren zur Herstellung von neuen N-substituierten Amiden und Esteramiden der Phosphosaure und Thiophosphosaure. DE 1645921 . |
合成路线6
该中间体在本合成路线中的序号：(III)The reaction of beta-chloroethylamine (III) with ammonium thiocyanate (B) gives beta-aminoethylthiocyanate (IV), which is alkylated with alpha,beta-dichloroethylbenzene (V) in hot benzene yielding the secondary amine (VI). The cyclization of (VI) in hot aqueous NaOH affords racemic levamisole, which is finally resolved in its optical isomers through the d-10-camphorsulfonate or N-benzene (or p-toluene)sulfonyl-L-(+)-glutamic salt.
| 【1】 Bullock, M.W.; DE 1645975 . |
| 【2】 Dick, P.R.; Rombi, M.; FR 2183313 . |
| 【3】 Castañer, J.; Hopkins, S.J.; Blancafort, P.; Serradell, M.N.; Levamisole hydrochloride. Drugs Fut 1979, 4, 6, 420. |
| 【4】 US 3579530 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (B) | 39499 | ammonium thiocyanate | 1762-95-4 | CH4N2S | 详情 | 详情 |
| (rac)-(XII) | 39503 | 6-phenyl-2,3,5,6-tetrahydroimidazo[2,1-b][1,3]thiazole | C11H12N2S | 详情 | 详情 | |
| (III) | 33455 | 2-chloro-1-ethanamine; 2-chloroethylamine | C2H6ClN | 详情 | 详情 | |
| (IV) | 39500 | 2-amino-1-ethanesulfenyl cyanide | C3H6N2S | 详情 | 详情 | |
| (V) | 39501 | 1-(1,2-dichloroethyl)benzene | 1074-11-9 | C8H8Cl2 | 详情 | 详情 |
| (VI) | 39502 | 2-[(2-chloro-2-phenylethyl)amino]-1-ethanesulfenyl cyanide | C11H13ClN2S | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(V)It can be prepared in several different ways: 1) By condensation of (I) with ethanolamine (II) by means of triethylamine in dioxane that gives 2-(2-hydroxyethylamino)-3-(2-chloroethyl)tetrahydro-2H-1,3,2-oxazaphosphorine-2-oxide (III), which is then esterified with methanesulfonyl chloride and triethylamine in dioxane. (1,2) 2) By condensation of 2-chloro-3-(2-chloroethyl)tetrahydro-2H-1,3,2-oxazaphosphorine-2-oxide (I) with 2-(methylsulfonyloxy)ethylamine by means of triethylamine (IV) in CH2Cl2. (1,2) 3) By condensation of (I) with 2-chloroethylamine (V) by means of triethylamine in CH2Cl2 that gives 2-(2-chloroethylamino)-3-(2-chloroethyl)tetrahydro-2H-1,3,2-oxazaphosphorine-2-oxide (VI), which is then transformed into the ester by means of silver methanesulfonate in refluxing acetonitrile. (1,2) 4) By cyclization at N-(3-hydroxypropyl)-2-chloroethylamine (VII) with N-(2-methylsulfonyl-oxyethyl)dichlorophosphoramide (VIII) by means of triethylamine in CH2Cl2. (1,2) 5) By mesylation of 2-(ethyleneimino)-3-(2-chloroethyl)tetrahydro-2H-1,3,2-oxaza-phosphorine-2-oxide (IX) with methanesulfonic acid in ethyl ether. (1,2)
| 【1】 (Asta-Werke A.G.); FR 2125595 . |
| 【2】 Arnold, H.; et al. (Asta-Werke A.G.); DE 2107936 . |
| 【3】 Castaner, J.; Hillier, K.; Sufosfamide. Drugs Fut 1977, 2, 5, 339. |
| 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) | 40966 | 2-chloro-3-(2-chloroethyl)-1,3,2lambda(5)-oxazaphosphinan-2-one | C5H10Cl2NO2P | 详情 | 详情 | |
| (II) | 10259 | Ethanol amine;Ethanolamine;2-Aminoethanol; 2-Amino-1-ethanol；2-Aminoethyl alcohol | 141-43-5 | C2H7NO | 详情 | 详情 |
| (III) | 60926 | 3-(2-chloroethyl)-2-[(2-hydroxyethyl)amino]-1,3,2lambda~5~-oxazaphosphinan-2-one | C7H16ClN2O3P | 详情 | 详情 | |
| (IV) | 60931 | 2-aminoethyl methanesulfonate | C3H9NO3S | 详情 | 详情 | |
| (V) | 33455 | 2-chloro-1-ethanamine; 2-chloroethylamine | C2H6ClN | 详情 | 详情 | |
| (VI) | 60927 | 3-(2-chloroethyl)-2-[(2-chloroethyl)amino]-1,3,2lambda~5~-oxazaphosphinan-2-one | C7H15Cl2N2O2P | 详情 | 详情 | |
| (VII) | 60930 | 3-[(2-chloroethyl)amino]-1-propanol | C5H12ClNO | 详情 | 详情 | |
| (VIII) | 60929 | 2-[(dichlorophosphoryl)amino]ethyl methanesulfonate | C3H8Cl2NO4PS | 详情 | 详情 | |
| (IX) | 60928 | 2-(1-aziridinyl)-3-(2-chloroethyl)-1,3,2lambda~5~-oxazaphosphinan-2-one | C7H14ClN2O2P | 详情 | 详情 |