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【结 构 式】 
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【分子编号】33922 【品名】1-(2-Chloroethyl)pyrrolidine; N-(2-Chloroethyl)pyrrolidine 【CA登记号】 |
【 分 子 式 】C6H12ClN 【 分 子 量 】133.62072 【元素组成】C 53.93% H 9.05% Cl 26.53% N 10.48% |
合成路线1
该中间体在本合成路线中的序号：(IX)The reaction of khellinone (I) with hydroxylamine in refluxing ethanol gives the corresponding oxime (II), which undergoes the Beckmann rearrangement in a saturated solution of gaseous HCl in acetic acid to afford the acetamido compound (III). Treatment of (III) with gaseous HCl in ethanol under reflux yields an aminophenol (VII), which is first reacted with methyl isocyanate (IX) in chloroform, then O-alkylated by pyrrolidinoethyl chloride (IV) in refluxing acetonitrile in the presence of K2CO3 to give carocainide as the free base. Alternatively, (III) can be alkylated by pyrrolidinoethyl chloride (IV), then refluxed in aqueous 2N HCl and the resulting amino compound (VI) reacted with methyl isocyanate (IX) in dry toluene. The hydrochloride can be prepared by treatment of the free base with HCl in methylene chloride-chlorotene.
| 【1】 Ancher, J.F.; Carocainide Hydrochloride. Drugs Fut 1984, 9, 6, 410. |
| 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) | 34142 | 1-(6-hydroxy-4,7-dimethoxy-1-benzofuran-5-yl)-1-ethanone | 484-51-5 | C12H12O5 | 详情 | 详情 |
| (II) | 34143 | 1-(6-hydroxy-4,7-dimethoxy-1-benzofuran-5-yl)-1-ethanone oxime | C12H13NO5 | 详情 | 详情 | |
| (III) | 34144 | N-(6-hydroxy-4,7-dimethoxy-1-benzofuran-5-yl)acetamide | C12H13NO5 | 详情 | 详情 | |
| (IV) | 11019 | (Methylimino)(oxo)methane; methyl isocyanate | C2H3NO | 详情 | 详情 | |
| (V) | 34145 | N-[4,7-dimethoxy-6-[2-(1-pyrrolidinyl)ethoxy]-1-benzofuran-5-yl]acetamide | C18H24N2O5 | 详情 | 详情 | |
| (VI) | 34146 | 4,7-dimethoxy-6-[2-(1-pyrrolidinyl)ethoxy]-1-benzofuran-5-ylamine; 4,7-dimethoxy-6-[2-(1-pyrrolidinyl)ethoxy]-1-benzofuran-5-amine | C16H22N2O4 | 详情 | 详情 | |
| (VII) | 34147 | 5-amino-4,7-dimethoxy-1-benzofuran-6-ol | C10H11NO4 | 详情 | 详情 | |
| (VIII) | 34148 | N-(6-hydroxy-4,7-dimethoxy-1-benzofuran-5-yl)-N'-methylurea | C12H14N2O5 | 详情 | 详情 | |
| (IX) | 33922 | 1-(2-Chloroethyl)pyrrolidine; N-(2-Chloroethyl)pyrrolidine | C6H12ClN | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(B)The Grignard reaction of cis-3-phenyl-4-p-acetoxyphenyl-7-methoxy-3,4-dihydrocoumarin (I) with methylmagnesium iodide (A) in THF gives erythro-2-methyl-3-phenyl4-(p-hydroxyphenyl)-4-(2-hydroxy-4-methoxyphenyl)-4-(2-hydroxy-4-methoxyphenyl)butan-2-ol (II), which is cyclized with PPA at 75-80 C yielding cis-2,2-dimethyl-3phenyl-4-p-hydroxyphenyl-7-methoxychroman (III). This compound can also be obtained by hydrogenation of 2,2-dimethyl-4-p-hydroxyphenyl-3-phenyl-7-methoxychromene (IV) with H2 over Pd/C in THF. The condensation of (III) with N-(2-chloroethyl)pyrrolidine (B) by means of K2CO3 in refluxing acetone affords 3,4-cis-2,2-dimethyl-3-phenyl-4-[p-(beta-pyrrolidinoethoxy)phenyl]-7-methoxychromane (V), which is finally isomerized with n-butyllithium in DMSO.
| 【1】 Bolger, J.W.; Process for preparation of substituted 3,4-(diphenyl)chromans. US 3822287 . |
| 【2】 Bolger, J.W.; Procede de preparation de 3,4-(diphenyl)-chromanes substitues. DE 2329201; FR 2187777 . |
| 【3】 Suprabhat, R.; et al.; Antifertility agents. 12. Structure-activity relationship of 3,4-diphenylchromenes and -chromans. J Med Chem 1976, 19, 2, 276-279. |
| 【4】 Castaner, J.; Hillier, K.; Centchroman. Drugs Fut 1977, 2, 7, 441. |
| 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) | 20225 | iodo(methyl)magnesium | 917-64-6 | CH3IMg | 详情 | 详情 |
| (B) | 33922 | 1-(2-Chloroethyl)pyrrolidine; N-(2-Chloroethyl)pyrrolidine | C6H12ClN | 详情 | 详情 | |
| (I) | 33918 | 4-[(3S,4R)-7-methoxy-2-oxo-3-phenyl-3,4-dihydro-2H-chromen-4-yl]phenyl acetate | C24H20O5 | 详情 | 详情 | |
| (II) | 33919 | 2-[(1R,2S)-3-hydroxy-1-(4-hydroxyphenyl)-3-methyl-2-phenylbutyl]-5-methoxyphenol | C24H26O4 | 详情 | 详情 | |
| (III) | 33920 | 4-[(3S,4R)-7-methoxy-2,2-dimethyl-3-phenyl-3,4-dihydro-2H-chromen-4-yl]phenol | C24H24O3 | 详情 | 详情 | |
| (IV) | 33921 | 4-(7-methoxy-2,2-dimethyl-3-phenyl-2H-chromen-4-yl)phenol | C24H22O3 | 详情 | 详情 | |
| (V) | 33923 | (3S,4R)-2,2-dimethyl-3-phenyl-4-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]-3,4-dihydro-2H-chromen-7-yl methyl ether; 1-(2-[4-[(3S,4R)-7-methoxy-2,2-dimethyl-3-phenyl-3,4-dihydro-2H-chromen-4-yl]phenoxy]ethyl)pyrrolidine | C30H35NO3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(B)The Grignard reaction of trans-3-phenyl-4-p-acetoxyphenyl-7-methoxy-3,4-dihydrocoumarin (VI) with methylmagnesium iodide (A) in THF gives a mixture of cis-2,2-dimethyl-3-phenyl-4-p-hydroxy-phenyl-7-methoxychromane (VII) and threo-2-methyl-3-phenyl-4-(p-hydroxyphenyl)-4-(2-hydroxy-4-methoxyphenyl)butan-2-ol (VIII), which can be cyclized to (VII) with PPA at 75-80 C. Finally, (VII) is condensed with N-(2-chloroethyl)-pyrrolidine (B) by means of K2CO3 in refluxing acetone.
| 【1】 Suprabhat, R.; et al.; Antifertility agents. 12. Structure-activity relationship of 3,4-diphenylchromenes and -chromans. J Med Chem 1976, 19, 2, 276-279. |
| 【2】 Castaner, J.; Hillier, K.; Centchroman. Drugs Fut 1977, 2, 7, 441. |
| 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) | 20225 | iodo(methyl)magnesium | 917-64-6 | CH3IMg | 详情 | 详情 |
| (B) | 33922 | 1-(2-Chloroethyl)pyrrolidine; N-(2-Chloroethyl)pyrrolidine | C6H12ClN | 详情 | 详情 | |
| (VI) | 33924 | 4-[(3R,4R)-7-methoxy-2-oxo-3-phenyl-3,4-dihydro-2H-chromen-4-yl]phenyl acetate | C24H20O5 | 详情 | 详情 | |
| (VII) | 33926 | 4-[(3R,4R)-7-methoxy-2,2-dimethyl-3-phenyl-3,4-dihydro-2H-chromen-4-yl]phenol | C24H24O3 | 详情 | 详情 | |
| (VIII) | 33925 | 2-[(1R,2R)-3-hydroxy-1-(4-hydroxyphenyl)-3-methyl-2-phenylbutyl]-5-methoxyphenol | C24H26O4 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(VII)The condensation beta-tetralone (I) with phenyl 4-methoxybenzoate (II) by means of NaNH2 in THF gives 3,4-dihydro-1-(4-methoxybenzoyl)-2(1H)-naphthalenone (III), which is then submitted to a Grignard reaction with 4-methoxyphenylmagnesium bromide (IV) in hot THF yielding 3,4-dihydro-2-(4-methoxyphenyl)-1-naphthyl-4-methoxyphenyl ketone (V). The cleavage of one methoxy group of (V) with sodium ethylmercaptide (A) in dry DMF affords 3,4-dihydro-2-(4-methoxyphenyl)-1-naphthyl-4-hydroxyphenyl ketone (VI), which is finally condensed with N-(2-chloroethyl)pyrrolidine (VII) by means of K2CO3 in refluxing 2-butanone.
| 【1】 Jones, C.D.; et al.; Synthesis and antiestrogenic activity of [3,4-dihydro-2-(4-methoxyphenyl)-1-naphthalenyl][4-[2-(1-pyrrolidinyl)ethoxyphenyl]methanone]methane sulfonic acid salt. J Med Chem 1979, 22, 8, 962-966. |
| 【2】 Castaner, J.; Hillier, K.; Trioxifene mesylate. Drugs Fut 1980, 5, 5, 259. |
| 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) | 39110 | Sodium 1-ethanethiolate; Sodium ethylmercaptide | 811-51-8 | C2H5NaS | 详情 | 详情 |
| (I) | 39106 | 3,4-Dihydro-2(1H)-naphthalenone; beta-Tetralone | 530-93-8 | C10H10O | 详情 | 详情 |
| (II) | 39107 | Phenyl 4-methoxybenzoate | C14H12O3 | 详情 | 详情 | |
| (III) | 39108 | 1-(4-Methoxybenzoyl)-3,4-dihydro-2(1H)-naphthalenone; 3,4-Dihydro-1-(4-methoxybenzoyl)-2(1H)-naphthalenone | C18H16O3 | 详情 | 详情 | |
| (IV) | 37674 | Bromo(4-methoxyphenyl)magnesium; 4-Methoxyphenylmagnesium bromide | 352-13-6 | C7H7BrMgO | 详情 | 详情 |
| (V) | 39109 | (4-Methoxyphenyl)[2-(4-methoxyphenyl)-3,4-dihydro-1-naphthalenyl]methanone; 3,4-Dihydro-2-(4-methoxyphenyl)-1-naphthyl-4-methoxyphenyl ketone | C25H22O3 | 详情 | 详情 | |
| (VI) | 39111 | (4-Hydroxyphenyl)[2-(4-methoxyphenyl)-3,4-dihydro-1-naphthalenyl]methanone; 3,4-Dihydro-2-(4-methoxyphenyl)-1-naphthyl-4-hydroxyphenyl ketone | C24H20O3 | 详情 | 详情 | |
| (VII) | 33922 | 1-(2-Chloroethyl)pyrrolidine; N-(2-Chloroethyl)pyrrolidine | C6H12ClN | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(VI)Coumarin (III) was prepared by condensation of benzophenone (I) with phenylacetic acid (II) in the presence of Ac2O and Et3N. Reduction of the lactone function of (III) with LiAlH4, followed by acidic treatment furnished diaryl chromene (IV). Subsequent hydrogenation of (IV) over Pd/C gave rise to the racemic cis chromane (V), which was O-alkylated with 1-(2-chloroethyl) pyrrolidine (VI) producing the corresponding (pyrrolidinyl)ethoxy derivative. Resolution by means of active ditoluoyl tartaric acid yielded the desired (-)-enantiomer (VII). Finally, cleavage of the methoxy group using pyridine hydrochloride at 150 C provided the title compound.
| 【1】 Bury, P.S.; et al.; Synthesis and pharmacological evaluation of novel cis-3,4-diaryl-hydroxychromanes as high affinity partial agonists for the estrogen receptor. Bioorg Med Chem 2002, 10, 1, 125. |
| 【2】 Jacobsen, P.; Treppendahl, S.; Stanley Bury, P.; Kanstrup, A.; Brown Christiansen, L. (Novo Nordisk A/S); Novel cis-3,4-chroman derivs. useful in the prevention or treatment of estrogen related diseases or syndromes. EP 0937060; WO 9818776 . |
| 【3】 Jacobsen, P.; Treppendahl, S.; Stanley Bury, P.; Kanstrup, A.; Brown Christiansen, L. (Novo Nordisk A/S); Novel (-)-enantiomers of cis-3,4-chroman derivs. useful in the prevention or treatment of estrogen related diseases or syndromes. EP 0937057; WO 9818771 . |
| 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) | 35211 | (2-hydroxy-4-methoxyphenyl)(4-hydroxyphenyl)methanone | C14H12O4 | 详情 | 详情 | |
| (II) | 16148 | Benzeneacetic acid; 2-Phenylacetic acid; Phenyl Acetic Acid | 103-82-2 | C8H8O2 | 详情 | 详情 |
| (III) | 35212 | 4-(7-methoxy-2-oxo-3-phenyl-2H-chromen-4-yl)phenyl acetate | C24H18O5 | 详情 | 详情 | |
| (IV) | 35213 | 4-(7-methoxy-3-phenyl-2H-chromen-4-yl)phenol | C22H18O3 | 详情 | 详情 | |
| (V) | 35214 | 4-[(3S,4R)-7-methoxy-3-phenyl-3,4-dihydro-2H-chromen-4-yl]phenol | C22H20O3 | 详情 | 详情 | |
| (VI) | 33922 | 1-(2-Chloroethyl)pyrrolidine; N-(2-Chloroethyl)pyrrolidine | C6H12ClN | 详情 | 详情 | |
| (VII) | 35215 | 1-(2-[4-[(3S,4R)-7-methoxy-3-phenyl-3,4-dihydro-2H-chromen-4-yl]phenoxy]ethyl)pyrrolidine; 4-[(3S,4R)-7-methoxy-3-phenyl-3,4-dihydro-2H-chromen-4-yl]phenyl 2-(1-pyrrolidinyl)ethyl ether | C28H31NO3 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(II)The title compound was prepared by alkylation of 4-phenylphenol (I) with 1-(2-chloroethyl)pyrrolidine.HCl (II) in the presence of NaH in hot DMF.
| 【1】 Penning, T.D.; Chandrakumar, N.S.; Chen, B.B.; et al.; Structure-activity relationship studies on 1-[2-(4-phenylphenoxy)ethyl]pyrrolidine (SC-22716), a potent inhibitor of leukotriene A4 (LTA4) hydrolase. J Med Chem 2000, 43, 3, 721. |
合成路线7
该中间体在本合成路线中的序号：(I)Diamine (II) was prepared by reaction of N-(2-chloroethyl)pyrrolidine hydrochloride (I) with ethylamine. Coupling of (II) with 3,4-dichlorophenylacetic acid (III) in the presence of DCC afforded amide (IV). The amide function of (IV) was finally reduced by means of aluminum hydride in THF to furnish the title diamine.
| 【1】 de Costa, B.R.; et al.; Synthesis, characterization, and biological evaluation of a novel class of N-(arylethyl)-N-alkyl-2-(1-pyrrolidinyl)ethylamines: Structural requirements and binding affinity at the sigma receptor. J Med Chem 1992, 35, 1, 38. |
| 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) | 33922 | 1-(2-Chloroethyl)pyrrolidine; N-(2-Chloroethyl)pyrrolidine | C6H12ClN | 详情 | 详情 | |
| (II) | 47992 | N-ethyl-2-(1-pyrrolidinyl)-1-ethanamine; N-ethyl-N-[2-(1-pyrrolidinyl)ethyl]amine | C8H18N2 | 详情 | 详情 | |
| (III) | 30414 | 2-(3,4-dichlorophenyl)acetic acid；2-(3,4-Dichlorophenyl)acetic acid | 5807-30-7 | C8H6Cl2O2 | 详情 | 详情 |
| (IV) | 47993 | 2-(3,4-dichlorophenyl)-N-ethyl-N-[2-(1-pyrrolidinyl)ethyl]acetamide | C16H22Cl2N2O | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(V)The previously described 4-hydroxyphenyl chromane derivative (I) was converted to the 4-sulfanylphenyl analogue (IV) via the following sequence. Condensation of the sodium salt of phenol (I) with N,N-dimethylthiocarbamoyl chloride gave the O-aryl thiocarbamate (II), which underwent further thermal rearrangement to the S-aryl thiocarbamate (III) in diphenyl ether at 260 C. Reductive cleavage of thiocarbamate (III) using LiAlH4 gave rise to thiophenol (IV). Subsequent alkylation of (IV) with N-(2-chloroethyl)pyrrolidine (V) yielded thioether (VI). The methyl ether function of (VI) was then cleaved by heating with pyridine hydrochloride, and the resultant compound was finally isolated as the corresponding hydrochloride salt.
| 【1】 Christiansen, L.B.; Weckens, M.; Bury, P.S.; Gissel, B.; Hansen, B.S.; Thorpe, S.M.; Jacobsen,P.; Kanstrup, A.; Jorgensen, A.S.; Naerum, L.; Wasserman, K.; Synthesis and biological evaluation of novel thio-substituted chromanes as high-affinity partial agonists for the estrogen receptor. Bioorg Med Chem Lett 2002, 12, 1, 17. |
| 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) | 35214 | 4-[(3S,4R)-7-methoxy-3-phenyl-3,4-dihydro-2H-chromen-4-yl]phenol | C22H20O3 | 详情 | 详情 | |
| (II) | 59926 | O-{4-[(3S,4R)-7-methoxy-3-phenyl-3,4-dihydro-2H-chromen-4-yl]phenyl} dimethylcarbamothioate | C25H25NO3S | 详情 | 详情 | |
| (III) | 59927 | S-{4-[(3S,4R)-7-methoxy-3-phenyl-3,4-dihydro-2H-chromen-4-yl]phenyl} dimethylcarbamothioate | C25H25NO3S | 详情 | 详情 | |
| (IV) | 59928 | 4-[(3S,4R)-7-methoxy-3-phenyl-3,4-dihydro-2H-chromen-4-yl]benzenethiol; 4-[(3S,4R)-7-methoxy-3-phenyl-3,4-dihydro-2H-chromen-4-yl]phenylhydrosulfide | C22H20O2S | 详情 | 详情 | |
| (V) | 33922 | 1-(2-Chloroethyl)pyrrolidine; N-(2-Chloroethyl)pyrrolidine | C6H12ClN | 详情 | 详情 | |
| (VI) | 59929 | 1-[2-({4-[(3S,4R)-7-methoxy-3-phenyl-3,4-dihydro-2H-chromen-4-yl]phenyl}sulfanyl)ethyl]pyrrolidine; methyl (3S,4R)-3-phenyl-4-(4-{[2-(1-pyrrolidinyl)ethyl]sulfanyl}phenyl)-3,4-dihydro-2H-chromen-7-yl ether | C28H31NO2S | 详情 | 详情 |