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【结 构 式】 
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【分子编号】10117 【品名】1-(2-Chloroethyl)piperidine; N-(2-Chloroethyl)piperidine 【CA登记号】1932-03-2 |
【 分 子 式 】C7H14ClN 【 分 子 量 】147.6476 【元素组成】C 56.94% H 9.56% Cl 24.01% N 9.49% |
合成路线1
该中间体在本合成路线中的序号：(III)The synthesis of radiolabeled raloxifene has been reported: The esterification of 3,5-dibromo-4-hydroxybenzoic acid (I) with methanol/HCl gives the corresponding methyl ester (II), which is condensed with 1-(2-chloroethyl)piperidine (III) by means of K2CO3 in DMF yielding 3,5-dibromo-4-[2-(1-piperidyl)ethoxy]benzoic acid methyl ester (IV). The hydrolysis of (IV) with NaOH in methanol affords the corresponding free acid (V), which by treatment of SOCl2 in toluene is converted to the acyl chloride (VI). The Friedel-Crafts condensation of (VI) with 6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene (VII) by means of AlCl3 in dichloromethane gives [3,5-dibromo-4-[2-(1-piperidinyl)ethoxy]phenyl]-[6-methoxy-2-(4-methoxy phenyl)benzo[b]thien-3-yl]methanone (VIII), which is demethylated with AlCl3 and ethylmercaptane to dibromoraloxifene (IX). Finally, this compound is submitted to hydrogenolysis with tritium over Pd/C in methanol.
| 【1】 Dodge, J.A.; Stocksdale, M.G.; Jones, C.D.; A chemical probe for the estrogen receptor: Synthesis of the H-3 isotopomer of raloxifene. J Label Compd Radiopharm 1995, 36, 1, 43. |
| 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) | 10115 | 3,5-Dibromo-4-hydroxybenzoic acid | 3337-62-0 | C7H4Br2O3 | 详情 | 详情 |
| (II) | 10116 | methyl 3,5-dibromo-4-hydroxybenzoate | 41727-47-3 | C8H6Br2O3 | 详情 | 详情 |
| (III) | 10117 | 1-(2-Chloroethyl)piperidine; N-(2-Chloroethyl)piperidine | 1932-03-2 | C7H14ClN | 详情 | 详情 |
| (IV) | 10118 | methyl 3,5-dibromo-4-(2-piperidinoethoxy)benzoate | C15H19Br2NO3 | 详情 | 详情 | |
| (V) | 10119 | 3,5-Dibromo-4-(2-piperidinoethoxy)benzoic acid | C14H17Br2NO3 | 详情 | 详情 | |
| (VI) | 10120 | 3,5-Dibromo-4-(2-piperidinoethoxy)benzoyl chloride | C14H16Br2ClNO2 | 详情 | 详情 | |
| (VII) | 10121 | 4-(6-Methoxy-1-benzothiophen-2-yl)phenyl methyl ether; 6-Methoxy-2-(4-methoxyphenyl)-1-benzothiophene | 63675-74-1 | C16H14O2S | 详情 | 详情 |
| (VIII) | 10122 | [3,5-Dibromo-4-[2-(1-piperidinyl)ethoxy]phenyl][6-methoxy-2-(4-methoxyphenyl)-1-benzothiophen-3-yl]methanone | C30H29Br2NO4S | 详情 | 详情 | |
| (IX) | 10123 | [3,5-Dibromo-4-[2-(1-piperidinyl)ethoxy]phenyl][6-hydroxy-2-(4-hydroxyphenyl)-1-benzothiophen-3-yl]methanone | C28H25Br2NO4S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)The condensation of 5-acetamido-4,7-dimethoxy-6-hydroxybenzofuran (I) with N-(2-chloroethyl)piperidine (II) by means of K2CO3 in refluxing acetone gives 5-acetamido-4,7-dimethoxy-6-[2-(N-piperidino)ethoxy]benzofuran (III), which is hydrolyzed with refluxing 2N HCl yielding 5-amino-4,7-dimethoxy-6-[2-(N-piperidino)ethoxy]benzofuran (IV). Finally, this compound is treated with methyl isocyanate (V) in hot toluene.
| 【1】 Bourgery, G.; Lacour, A.; Pourrias, B.; Bregeon, G.C. (Laboratoires Delalande); Novel aminoalkoxybenzofurans, their process of preparation and their therapeutic use. FR 2358143 . |
| 【2】 Serradell, M.N.; Castaner, J.; Blancafort, P.; Thorpe, P.J.; Murocainide. Drugs Fut 1983, 8, 8, 687. |
| 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) | 34144 | N-(6-hydroxy-4,7-dimethoxy-1-benzofuran-5-yl)acetamide | C12H13NO5 | 详情 | 详情 | |
| (II) | 10117 | 1-(2-Chloroethyl)piperidine; N-(2-Chloroethyl)piperidine | 1932-03-2 | C7H14ClN | 详情 | 详情 |
| (III) | 36164 | N-[4,7-dimethoxy-6-[2-(1-piperidinyl)ethoxy]-1-benzofuran-5-yl]acetamide | C19H26N2O5 | 详情 | 详情 | |
| (IV) | 36165 | 4,7-dimethoxy-6-[2-(1-piperidinyl)ethoxy]-1-benzofuran-5-amine; 4,7-dimethoxy-6-[2-(1-piperidinyl)ethoxy]-1-benzofuran-5-ylamine | C17H24N2O4 | 详情 | 详情 | |
| (V) | 11019 | (Methylimino)(oxo)methane; methyl isocyanate | C2H3NO | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(III)Friedel-Crafts condensation of 2-phenylpropionyl chloride (I) with ethylene in the presence of AlCl3 furnished 1-methyl-1,2,3,4-tetrahydronaphthalen-2-one (II) (1). Subsequent alkylation of the sodium enolate of (II) with N-(2-chloroethyl)piperidine (III) gave rise to the title compound.
| 【1】 Fusco, R.; Tenconi, F. (Pfizer Inc.); Novel 1,2,3,4-tetrahydronaphthalen-2-ones and a process for the preparation thereof. GB 1140990; US 3576811 . |
| 【2】 Tenconi, F.; Furfaro, S.; A process for the preparation of nepinalone. EP 0507001 . |
合成路线4
该中间体在本合成路线中的序号：(VII)Friedel-Crafts reaction between 4-hydroxyphenylacetic acid (I) and resorcinol (II) by means of BF3.Et2O provides trihydroxydeoxy benzoin (III), which is then protected with dihydropyran (IV) in the presence of TsOH to give the bis-THP ether (V). Knoevenagel reaction of (V) with 4-hydroxybenzaldehyde (VI) in the presence of piperidine in refluxing benzene, followed by alkylation with 1-(2-chloroethyl)piperidine (VII) in the presence of Cs2CO3 in refluxing acetone:H2O to yield chromanone (VIII). Alternatively, (VIII) can be synthesized by reaction of (V) with compound (IX) (obtained in turn from reaction between aldehyde (VI) and chloro derivative (VII) with K2CO3 in DMF) by means of piperidine in refluxing toluene, followed by treatment with NaOAc in refluxing MeOH. Chromanone (VIII) is then alkylated either with MeLi or with methylmagnesium bromide in THF and then dehydrated and deprotected in HOAc furnishing chromene (X). Racemic compound (X) is then resolved to afford enantiomer (XI) either by preparative chiral HPLC or by chemical resolution of the corresponding diastereomeric salt obtained by reaction with (+)-CSA in DMF/CH2Cl2, and treatment of the resulting salt with saturated K2CO3 . Finally, the target product is obtained by acylation of (XI) by reaction with pivaloyl chloride (XII) and Et3N in CH2Cl2.
| 【1】 Caron, B.; Cloutier, J.; Gauthier, S.; (S)-(+)-4-[7-(2, 2-Dimethyl-1-oxopropoxy)-4-methyl-2-[4-[2-(1-piperidinyl)ethoxy]phenyl]-2H-1-benzopyran-3-yl]phenyl 2, 2-dimethylpropanoate (EM-800): A highly potent, specific, and orally active nonsteroidal antiestrogen. J Med Chem 1997, 40, 14, 2117. |
| 【2】 Labrie, F.; Merand, Y.; Gauthier, S. (Endorecherche Inc.); Benzopyran-containing cpds. and method for their use. EP 0811006; EP 1167364; JP 1999500133; WO 9626201 . |
| 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) | 18430 | 2-(4-Hydroxyphenyl)acetic acid; 4-Hydroxyphenylacetic acid | 156-38-7 | C8H8O3 | 详情 | 详情 |
| (II) | 10361 | 1,3-Dihydroxybenzene; m-Dihydroxybenzene; Resorcinol; Resorcin; 1,3-Benzenediol | 108-46-3 | C6H6O2 | 详情 | 详情 |
| (III) | 51229 | 1-(2,4-dihydroxyphenyl)-2-(4-hydroxyphenyl)-1-ethanone | C14H12O4 | 详情 | 详情 | |
| (IV) | 13684 | 3,4-Dihydro-2H-pyran;2,3-Dihydro-4H-pyran; 5,6-Dihydro-4H-pyran;Dihydropyran | 110-87-2 | C5H8O | 详情 | 详情 |
| (V) | 51230 | 1-[2-hydroxy-4-(tetrahydro-2H-pyran-2-yloxy)phenyl]-2-[4-(tetrahydro-2H-pyran-2-yloxy)phenyl]-1-ethanone | C24H28O6 | 详情 | 详情 | |
| (VI) | 13433 | 4-Hydroxybenzaldehyde; p-Hydroxybenzaldehyde | 123-08-0 | C7H6O2 | 详情 | 详情 |
| (VII) | 10117 | 1-(2-Chloroethyl)piperidine; N-(2-Chloroethyl)piperidine | 1932-03-2 | C7H14ClN | 详情 | 详情 |
| (VIII) | 51231 | 2-[4-[2-(1-piperidinyl)ethoxy]phenyl]-7-(tetrahydro-2H-pyran-2-yloxy)-3-[4-(tetrahydro-2H-pyran-2-yloxy)phenyl]-2,3-dihydro-4H-chromen-4-one | C38H45NO7 | 详情 | 详情 | |
| (IX) | 35795 | 4-[2-(1-piperidinyl)ethoxy]benzaldehyde | 26815-04-3 | C14H19NO2 | 详情 | 详情 |
| (X) | 51232 | 3-(4-hydroxyphenyl)-4-methyl-2-[4-[2-(1-piperidinyl)ethoxy]phenyl]-2H-chromen-7-ol | C29H31NO4 | 详情 | 详情 | |
| (XI) | 51233 | (2S)-3-(4-hydroxyphenyl)-4-methyl-2-[4-[2-(1-piperidinyl)ethoxy]phenyl]-2H-chromen-7-ol | C29H31NO4 | 详情 | 详情 | |
| (XII) | 13597 | 2,2-Dimethylpropanoyl chloride; Pivaloyl chloride | 3282-30-2 | C5H9ClO | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(II)Alkylation of ethyl 4-hydroxybenzoate (I) with 1-(2-chloroethyl)piperidine (II) provided adduct (III). After saponification of the ethyl ester group of (III), the resulting carboxylic acid (IV) was treated with oxalyl chloride to furnish the desired acid chloride (V).
| 【1】 Dantzig, A.H.; Grese, T.A.; Normal, B.H.; Palkowitz, A.D.; Sluka, J.P.; Starling, J.J. II; Winter, M.A. (Eli Lilly and Company); Methods for treating resistant tumors. EP 0773217; JP 2000500138; WO 9717069 . |
| 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) | 13492 | ethyl p-hydroxybenzoate; ethyl 4-hydroxybenzoate | 120-47-8 | C9H10O3 | 详情 | 详情 |
| (II) | 10117 | 1-(2-Chloroethyl)piperidine; N-(2-Chloroethyl)piperidine | 1932-03-2 | C7H14ClN | 详情 | 详情 |
| (III) | 36993 | ethyl 4-[2-(1-piperidinyl)ethoxy]benzoate | C16H23NO3 | 详情 | 详情 | |
| (IV) | 36994 | 4-[2-(1-piperidinyl)ethoxy]benzoic acid | C14H19NO3 | 详情 | 详情 | |
| (V) | 36995 | 4-[2-(1-piperidinyl)ethoxy]benzoyl chloride | C14H18ClNO2 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(IV)Reaction of benzothiazolone (I) with propionyl chloride in the presence of triethylamine in refluxing THF provided the N-propionyl derivative (II), which was subsequently rearranged by heating at 165 C with AlCl3 to give ketone (III). Alkylation of (III) with 1-(2-chloroethyl)piperidine and K2CO3 in hot DMF yielded (IV), which was finally reduced with triethylsilane in trifluoroacetic acid to the propyl derivative.
| 【1】 Ucar, H.; et al.; Synthesis and anticonvulsant activity of 2(3H)-benzoxazolone and 2(3H)-benzothiazolone derivatives. J Med Chem 1998, 41, 7, 1138. |
| 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) | 18871 | 1,3-benzothiazol-2(3H)-one | 934-34-9 | C7H5NOS | 详情 | 详情 |
| (II) | 18872 | 3-propionyl-1,3-benzothiazol-2(3H)-one | C10H9NO2S | 详情 | 详情 | |
| (III) | 18873 | 6-propionyl-1,3-benzothiazol-2(3H)-one | C10H9NO2S | 详情 | 详情 | |
| (IV) | 10117 | 1-(2-Chloroethyl)piperidine; N-(2-Chloroethyl)piperidine | 1932-03-2 | C7H14ClN | 详情 | 详情 |
| (V) | 18875 | 3-[2-(1-piperidinyl)ethyl]-6-propionyl-1,3-benzothiazol-2(3H)-one | C17H22N2O2S | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(IV)Friedel Crafts condensation of benzothiophene (I) with p-fluorobenzoyl chloride (II) yielded the benzoyl benzothiophene (III). Then, substitution of the fluorine atom of (III) with 2-(1-piperidinyl)ethanethiol (VI) (obtained from b-chloroethylpiperidine (IV) and thiourea (V)), afforded sulfide (VII). Finally, deprotection of the methyl ethers of (VII) with BBr3 in cold 1,2-dichloroethane furnished the target compound.
| 【1】 Glasebrook, A.W.; Schmid, C.R.; Duke, K.M.; Sluka, J.P.; Novel nonsteroidal selective estrogen receptor modulators. Carbon and heteroatom replacement of oxygen in the ethoxypiperidine region of raloxifene. Bioorg Med Chem Lett 1999, 9, 4, 523. |
| 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) | 10121 | 4-(6-Methoxy-1-benzothiophen-2-yl)phenyl methyl ether; 6-Methoxy-2-(4-methoxyphenyl)-1-benzothiophene | 63675-74-1 | C16H14O2S | 详情 | 详情 |
| (II) | 17263 | 4-fluorobenzoyl chloride | 403-43-0 | C7H4ClFO | 详情 | 详情 |
| (III) | 21916 | (4-fluorophenyl)[6-methoxy-2-(4-methoxyphenyl)-1-benzothiophen-3-yl]methanone | C23H17FO3S | 详情 | 详情 | |
| (IV) | 10117 | 1-(2-Chloroethyl)piperidine; N-(2-Chloroethyl)piperidine | 1932-03-2 | C7H14ClN | 详情 | 详情 |
| (V) | 10180 | Thiourea | 62-56-6 | CH4N2S | 详情 | 详情 |
| (VI) | 21919 | 2-(1-piperidinyl)ethylhydrosulfide; 2-(1-piperidinyl)-1-ethanethiol | C7H15NS | 详情 | 详情 | |
| (VII) | 21920 | [6-methoxy-2-(4-methoxyphenyl)-1-benzothiophen-3-yl](4-[[2-(1-piperidinyl)ethyl]sulfanyl]phenyl)methanone | C30H31NO3S2 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(II)Alkylation of p-hydroxybenzaldehyde (I) with 1-(2-chloroethyl)piperidine (II) afforded 4-(2-piperidinylethoxy)benzaldehyde (III). Aldehyde function reduction using NaBH4 provided the benzylic alcohol (IV). Alternatively, alcohol (IV) can be obtained by reaction of 4-hydroxybenzyl alcohol (A) with 1-(2-chloroethyl)piperidine hydrochloride (II) by means of NaOH and benzyl triethylammonium bromide in toluene.The hydrochloride salt of (IV) was then treated with SOCl2 to furnish chloride (V).
| 【1】 Silvestre, J.S.; Sorbera, L.A.; Castaner, J.; Pipendoxifene. Drugs Fut 2002, 27, 10, 942. |
| 【2】 Vid, G.; Potoski, J.R.; Raveendranath, P.; Zeldis, J.; Ren, J. (American Home Products Corp.); Novel aryloxy-alkyl-dialkylamines. EP 1025077; WO 9919293 . |
| 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) | 29474 | 4-(hydroxymethyl)phenol; 4-hydroxyphenylmethanol 4-hydroxybenzenemethanol; 4-Hydroxybenzyl alcohol | 623-05-2 | C7H8O2 | 详情 | 详情 |
| (I) | 13433 | 4-Hydroxybenzaldehyde; p-Hydroxybenzaldehyde | 123-08-0 | C7H6O2 | 详情 | 详情 |
| (II) | 10117 | 1-(2-Chloroethyl)piperidine; N-(2-Chloroethyl)piperidine | 1932-03-2 | C7H14ClN | 详情 | 详情 |
| (III) | 35795 | 4-[2-(1-piperidinyl)ethoxy]benzaldehyde | 26815-04-3 | C14H19NO2 | 详情 | 详情 |
| (IV) | 35796 | [4-[2-(1-piperidinyl)ethoxy]phenyl]methanol | C14H21NO2 | 详情 | 详情 | |
| (V) | 46522 | 1-[2-[4-(chloromethyl)phenoxy]ethyl]piperidine; 4-(chloromethyl)phenyl 2-(1-piperidinyl)ethyl ether | C14H20ClNO | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(XII)The hydrolysis of 2-(dimethylamino)-6-methoxybenzo[b]thiophene (I) with HCl in refluxing THF gives 6-methoxybenzo[b]thiophen-2(3H)-one (II), which is condensed with 4-methoxybenzaldehyde (III) by means of piperidine in methanol yielding the 3-benzylidene derivative (IV). The rearrangement of (IV) with the same catalyst and solvent affords trans-6-methoxy-2-(4-methoxyphenyl)-2,3-dihydrobenzo[b]thiophene-3-carboxylic acid methyl ester (V), which is hydrolyzed with NaOH in methanol to the corresponding acid (VI). The reaction of (VI) with SOCl2 in dichloromethane gives the acyl chloride (VII), which is condensed with N,O-dimethylhydroxylamine by means of triethylamine in dichloromethane providing the N-methoxy-N-methylamide (VIII). The condensation of (VIII) with the Grignard reagent (IX) in THF affords the dimethyl ether of the target compound (X), which is finally demethylated with AlCl3 and propanethiol in dichloromethane. The intermediate Grignard reagent (IX) has been obtained by condensation of 4-bromophenol (XI) with 1-(2-chloroethyl)piperidine (XII) by means of K2CO3 in hot DMF to give 1-[2-(4-bromophenoxy)ethyl]piperidine (XIII), which is then treated with magnesium in THF to afford (IX).
| 【1】 Stephenson, G.A.; Glasebrook, A.L.; Schmid, C.R.; Misner, J.W.; Synthesis and biological activity of trans-2,3-dihydroraloxifene. Bioorg Med Chem Lett 1999, 9, 8, 1137. |
| 【2】 Glasebrook, A.L.; Schmid, C.R.; Stephenson, G.A.; Misner, J.W.; Synthesis and biological activity of dihydroraloxifene. 217th ACS Natl Meet (March 21 1999, Anaheim) 1999, Abst MEDI 072. |
| 【3】 Misner, J.W.; Schmid, C.R. (Eli Lilly and Company); Intermediates and processes for preparing benzo[b]thiophenes. EP 0979076; WO 9848793 . |
| 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) | 30906 | N-(6-methoxy-1-benzothiophen-2-yl)-N,N-dimethylamine; 6-methoxy-N,N-dimethyl-1-benzothiophen-2-amine | C11H13NOS | 详情 | 详情 | |
| (II) | 30907 | 6-methoxy-1-benzothiophen-2(3H)-one | C9H8O2S | 详情 | 详情 | |
| (III) | 27251 | 4-methoxybenzaldehyde; Anisicaldehyde; p-anisaldehyde | 123-11-5 | C8H8O2 | 详情 | 详情 |
| (IV) | 30908 | 6-methoxy-3-[(Z)-(4-methoxyphenyl)methylidene]-1-benzothiophen-2-one | C17H14O3S | 详情 | 详情 | |
| (V) | 30909 | methyl (2R,3S)-6-methoxy-2-(4-methoxyphenyl)-2,3-dihydro-1-benzothiophene-3-carboxylate | C18H18O4S | 详情 | 详情 | |
| (VI) | 30910 | (2R,3S)-6-methoxy-2-(4-methoxyphenyl)-2,3-dihydro-1-benzothiophene-3-carboxylic acid | C17H16O4S | 详情 | 详情 | |
| (VII) | 30911 | (2R,3R)-6-methoxy-2-(4-methoxyphenyl)-2,3-dihydro-1-benzothiophene-3-carbonyl chloride | C17H15ClO3S | 详情 | 详情 | |
| (VIII) | 30912 | (2R,3S)-N,6-dimethoxy-2-(4-methoxyphenyl)-N-methyl-2,3-dihydro-1-benzothiophene-3-carboxamide | C19H21NO4S | 详情 | 详情 | |
| (IX) | 30913 | bromo[4-[2-(1-piperidinyl)ethoxy]phenyl]magnesium | C13H18BrMgNO | 详情 | 详情 | |
| (X) | 30914 | [(2R,3S)-6-methoxy-2-(4-methoxyphenyl)-2,3-dihydro-1-benzothiophen-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone | C30H33NO4S | 详情 | 详情 | |
| (XI) | 25313 | 4-bromophenol | 106-41-2 | C6H5BrO | 详情 | 详情 |
| (XII) | 10117 | 1-(2-Chloroethyl)piperidine; N-(2-Chloroethyl)piperidine | 1932-03-2 | C7H14ClN | 详情 | 详情 |
| (XIII) | 30915 | 4-bromophenyl 2-(1-piperidinyl)ethyl ether; 1-[2-(4-bromophenoxy)ethyl]piperidine | C13H18BrNO | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(II)Alkylation of 4-hydroxybenzaldehyde (I) with 1-(2-chloroethyl)piperidine hydrochloride (II) in the presence of K2CO3 yielded (piperidinylethoxy)benzaldehyde (III), which was further reduced to the benzylic alcohol (IV) with methanolic NaBH4. Coupling of (IV) with thioacetic acid according to the Mitsunobu procedure yielded thioacetate ester (V), which was converted to the corresponding thiol (VI) by reductive cleavage of the thioester group with LiAlH4.
| 【1】 Leblanc, G.; Noël, P.; Poirier, D.; Labrie, F.; Breton, E.; Luu-The, V.; Tremblay, M.R.; Spironolactone-related inhibitors of type II 17beta-hydroxysteroid dehydrogenase: Chemical synthesis, receptor binding affinities, and proliferative/antiproliferative activities. Bioorg Med Chem 1999, 7, 6, 1013. |
| 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) | 13433 | 4-Hydroxybenzaldehyde; p-Hydroxybenzaldehyde | 123-08-0 | C7H6O2 | 详情 | 详情 |
| (II) | 10117 | 1-(2-Chloroethyl)piperidine; N-(2-Chloroethyl)piperidine | 1932-03-2 | C7H14ClN | 详情 | 详情 |
| (III) | 35795 | 4-[2-(1-piperidinyl)ethoxy]benzaldehyde | 26815-04-3 | C14H19NO2 | 详情 | 详情 |
| (IV) | 35796 | [4-[2-(1-piperidinyl)ethoxy]phenyl]methanol | C14H21NO2 | 详情 | 详情 | |
| (V) | 35797 | S-[4-[2-(1-piperidinyl)ethoxy]benzyl] ethanethioate | C16H23NO2S | 详情 | 详情 | |
| (VI) | 35798 | 4-[2-(1-piperidinyl)ethoxy]benzylhydrosulfide; [4-[2-(1-piperidinyl)ethoxy]phenyl]methanethiol | C14H21NOS | 详情 | 详情 |
合成路线11
该中间体在本合成路线中的序号：(II)2-Amino-3-hydroxypyridine (I) is alkylated with N-(2-chloroethyl)piperidine (II) under phase transfer conditions to provide ether (III). Subsequent cyclization of aminopyridine (III) with bis-trichlorophenyl malonate (IV) in refluxing acetone leads to the pyridopyrimidine (V). This is finally condensed with the N-(bromomethyl)saccharin derivative (VI) to furnish the title compound.
| 【1】 Hermecz, I.; Kapui, Z.; Arányi, P.; Bátori, S.; Varga, M.; Dessilla, S.; Lévai, F.; Mikus, E.; Pascal, M.; Simonot, B.; Urbán Szabó, K.; Vasváriné Debreczy, L.; T. Nagy, L. (Sanofi-Synthélabo); Saccharin derivs. as orally active elastase inhibitors. WO 0144245 . |
| 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) | 37086 | 2-amino-3-pyridinol; 2-Amino-3-hydroxypyridine | 16867-03-1 | C5H6N2O | 详情 | 详情 |
| (II) | 10117 | 1-(2-Chloroethyl)piperidine; N-(2-Chloroethyl)piperidine | 1932-03-2 | C7H14ClN | 详情 | 详情 |
| (III) | 62082 | 3-[2-(1-piperidinyl)ethoxy]-2-pyridinamine; 3-[2-(1-piperidinyl)ethoxy]-2-pyridinylamine | C12H19N3O | 详情 | 详情 | |
| (IV) | 12956 | bis(2,4,6-trichlorophenyl) malonate | C15H6Cl6O4 | 详情 | 详情 | |
| (V) | 62083 | 2-hydroxy-9-[2-(1-piperidinyl)ethoxy]-4H-pyrido[1,2-a]pyrimidin-4-one | C15H19N3O3 | 详情 | 详情 | |
| (VI) | 62084 | 2-(bromomethyl)-4-isopropyl-6-methoxy-1H-1,2-benzisothiazole-1,1,3(2H)-trione | C12H14BrNO4S | 详情 | 详情 |
合成路线12
该中间体在本合成路线中的序号：(VII)Friedel-Crafts acylation of 3-methoxyphenol (I) with 4-hydroxyphenylacetic acid (II) in the presence of ZnCl2 and POCl3 furnished ketone (III), which was subsequently protected with triisopropylsilyl chloride and Et3N to yield the mono-silyl ether (IV). Coumarin (VI) was then synthesized by condensation of hydroxy ketone (IV) with phenylacetyl chloride (V) in the presence of K2CO3. Alkylation of the phenolic hydroxyl group of (VI) with N-(2-chloroethyl)piperidine (VII) gave the piperidinylethyl ether (VIII). Finally, selective methyl ether hydrolysis using HBr in refluxing HOAc led to the title compound.
| 【1】 Bhagwat, S.S.; McKie, J.A.; Khammungkhune, S. (Signal Pharmaceuticals, Inc.); Cpds. and methods for modulation of estrogen receptors. WO 0149673 . |
| 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) | 22389 | 3-Methoxyphenol | 150-19-6 | C7H8O2 | 详情 | 详情 |
| (II) | 18430 | 2-(4-Hydroxyphenyl)acetic acid; 4-Hydroxyphenylacetic acid | 156-38-7 | C8H8O3 | 详情 | 详情 |
| (III) | 56078 | 1-(2-hydroxy-4-methoxyphenyl)-2-(4-hydroxyphenyl)-1-ethanone | C15H14O4 | 详情 | 详情 | |
| (IV) | 56079 | 1-(2-hydroxy-4-methoxyphenyl)-2-{4-[(triisopropyl-lambda~4~-sulfanyl)oxy]phenyl}-1-ethanone | C24H34O4S | 详情 | 详情 | |
| (V) | 25890 | 2-phenylacetyl chloride；Phenylacetyl chloride;Phenacetyl chloride;Benzeneacetyl chloride | 103-80-0 | C8H7ClO | 详情 | 详情 |
| (VI) | 56080 | 4-(4-hydroxybenzyl)-7-methoxy-3-phenyl-2H-chromen-2-one | C23H18O4 | 详情 | 详情 | |
| (VII) | 10117 | 1-(2-Chloroethyl)piperidine; N-(2-Chloroethyl)piperidine | 1932-03-2 | C7H14ClN | 详情 | 详情 |
| (VIII) | 56081 | 7-methoxy-3-phenyl-4-{4-[2-(1-piperidinyl)ethoxy]benzyl}-2H-chromen-2-one | C30H31NO4 | 详情 | 详情 |
合成路线13
该中间体在本合成路线中的序号：(IX)The title compound is synthesized starting from the natural isoflavone formononetin (I). Esterification of (I) with pivaloyl chloride (II) affords pivalate (III). Catalytic hydrogenation of (III) in the presence of Pd/BaSO4 leads to the chromane derivative (IV). The Grignard reagent (VI), prepared from 4-(benzyloxy)benzyl chloride (V), is then condensed with ketone (IV) to furnish the tertiary alcohol (VII). The O-benzyl protecting group of (VII) is then removed by catalytic hydrogenolysis to afford phenol (VIII). Alkylation of (VIII) with N-(2-chloroethyl)piperidine (IX) and K2CO3, with simultaneous pivalate ester hydrolysis, leads to the piperidylethyl ether (X). The tertiary alcohol of (X) is finally dehydrated by means of HCl in acetonitrile to provide the target compound (1,2).
| 【1】 Ghirardi, S.; Armani, E.; Amari, G.; Delcanale, M.; Civelli, M.; Caruso, P.; Galbiati, E.; Synthesis and pharmacological activity of CHF 4227, one of the most potent in vitro and in vivo SERMs till new discovered. Drugs Fut 2002, 27, Suppl. A. |
| 【2】 Delcanale, M.; Civelli, M.; Armani, E.; Amari, G.; Galbiati, E. (Chiesi Farmaceutici SpA); 2H-1-Benzopyran derivs., processes for their preparation and pharmaceutical compsns. thereof. EP 1229036; EP 1281710; EP 1355906; WO 0259113 . |
| 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) | 65118 | 7-hydroxy-3-(4-methoxyphenyl)-4H-chromen-4-one | C16H12O4 | 详情 | 详情 | |
| (II) | 13597 | 2,2-Dimethylpropanoyl chloride; Pivaloyl chloride | 3282-30-2 | C5H9ClO | 详情 | 详情 |
| (III) | 65119 | 3-(4-methoxyphenyl)-4-oxo-4H-chromen-7-yl pivalate | C21H20O5 | 详情 | 详情 | |
| (IV) | 65120 | 3-(4-methoxyphenyl)-4-oxo-3,4-dihydro-2H-chromen-7-yl pivalate | C21H22O5 | 详情 | 详情 | |
| (V) | 65125 | 1-(benzyloxy)-4-(chloromethyl)benzene; benzyl 4-(chloromethyl)phenyl ether | C14H13ClO | 详情 | 详情 | |
| (VI) | 65124 | [4-(benzyloxy)benzyl](chloro)magnesium | C14H13ClMgO | 详情 | 详情 | |
| (VII) | 65121 | 4-[4-(benzyloxy)benzyl]-4-hydroxy-3-(4-methoxyphenyl)-3,4-dihydro-2H-chromen-7-yl pivalate | C35H36O6 | 详情 | 详情 | |
| (VIII) | 65122 | 4-hydroxy-4-(4-hydroxybenzyl)-3-(4-methoxyphenyl)-3,4-dihydro-2H-chromen-7-yl pivalate | C28H30O6 | 详情 | 详情 | |
| (IX) | 10117 | 1-(2-Chloroethyl)piperidine; N-(2-Chloroethyl)piperidine | 1932-03-2 | C7H14ClN | 详情 | 详情 |
| (X) | 65123 | 3-(4-methoxyphenyl)-4-{4-[2-(1-piperidinyl)ethoxy]benzyl}-4,7-chromanediol | C30H35NO5 | 详情 | 详情 |
合成路线14
该中间体在本合成路线中的序号：(II)Alkylation of 4-amino-3-nitrophenol (I) with 1-(2-chloroethyl)piperidine (II) provides ether (III). Subsequent nitro group reduction in (III) to afford diamine (IV) is performed by means of zinc powder in AcOH. Coupling of diamine (IV) with 2-chloroquinoline-3-carboxylic acid (V) furnishes amide (VI). Then, intramolecular cyclization of amino amide (VI) with Burgess reagent, followed by hydrolysis in boiling 6 M HCl gives rise to the title benzimidazolyl quinolinone.
| 【1】 Hungate, R.W.; Fraley, M.E.; Hambaugh, S.R. (Merck & Co., Inc.); Tyrosine kinase inhibitors. JP 2003512353; US 6479512; WO 0128993 . |
| 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) | 61945 | 4-amino-3-nitrophenol | C6H6N2O3 | 详情 | 详情 | |
| (II) | 10117 | 1-(2-Chloroethyl)piperidine; N-(2-Chloroethyl)piperidine | 1932-03-2 | C7H14ClN | 详情 | 详情 |
| (III) | 61946 | 2-nitro-4-[2-(1-piperidinyl)ethoxy]aniline; 2-nitro-4-[2-(1-piperidinyl)ethoxy]phenylamine | C13H19N3O3 | 详情 | 详情 | |
| (IV) | 61947 | 2-amino-4-[2-(1-piperidinyl)ethoxy]phenylamine; 4-[2-(1-piperidinyl)ethoxy]-1,2-benzenediamine | C13H21N3O | 详情 | 详情 | |
| (V) | 61948 | 2-chloro-3-quinolinecarboxylic acid | C10H6ClNO2 | 详情 | 详情 | |
| (VI) | 61949 | N-{2-amino-4-[2-(1-piperidinyl)ethoxy]phenyl}-2-chloro-3-quinolinecarboxamide | C23H25ClN4O2 | 详情 | 详情 |