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【结 构 式】 
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【分子编号】15787 【品名】4-chlorobenzenesulfonyl chloride;4-chlorobenzene-1-sulfonyl chloride 【CA登记号】98-60-2 |
【 分 子 式 】C6H4Cl2O2S 【 分 子 量 】211.06796 【元素组成】C 34.14% H 1.91% Cl 33.59% O 15.16% S 15.19% |
合成路线1
该中间体在本合成路线中的序号：(VIII)1) The mesylation of (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid methyl ester (I) with mesyl chloride and triethylamine in dichloromethane gives the corresponding mesylate (II), which is treated with sodium benzoate in DMSO yielding the (2S,4S)-benzoate (III). The hydrolysis of (III) with K2CO3 in methanol affords (2S,4S)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid methyl ester (IV), which is mesylated with mesyl chloride and triethylamine as before giving the mesylate (V). The reaction of (V) with sodium azide in DMSO yields the corresponding (2S,4R)-azide (VI), which is reduced with H2 over Pd/C in methanol affording (2S,4R)-4-amino-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid methyl ester (VII). The acylation of (VII) with 4-chlorobenzenesulfonyl chloride (VIII) and triethylamine in dichloromethane gives the corresponding amide (IX), which is reduced with diisobutylaluminum hydride (DIBAL) in toluene/THF yielding the aldehyde (X). The Wittig condensation of aldehyde (X) with (4-carboxybutyl)triphenylphosphonium bromide (XI) by means of lithium bis(trimethylsilyl)amide (LBSA) in HMPT affords 6-[1-(tert-butoxycarbonyl)-4(R)-(4-chlorophenylsulfonamido)pyrrolidin-2(S)-yl]-5(Z)-hexenoic acid (XII), which is esterified and deprotected with methanol/HCl to give 6-[4(R)-(4-chlorophenylsulfonamido)pyrrolidin-2(S)-yl]-5(Z)-hexenoic acid methyl ester (XIII). The condensation of (XIII) with 3-(chloromethyl)pyridine (XIV) and triethylamine in refluxing THF yields 6-[4(R)-(4-chlorophenylsulfonamido)-1-(3-pyridylmethyl)pyrrolidin-2(S)-yl]-5(Z)-hexenoic acid methyl ester (XV), which is finally hydrolyzed with NaOH in methanol/water.
| 【1】 Graul, A.; Castaner, J.; KDI-792. Drugs Fut 1996, 21, 12, 1224. |
| 【2】 Setoi, H.; Sawada, A.; Tanaka, H.; Hashimoto, M. (Fujisawa Pharmaceutical Co., Ltd.); Pyrrolidine derivs. AU 8943753; EP 0367130; JP 1990152960; US 5130323; US 5264453; US 5514701 . |
| 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) | 15780 | 1-(tert-butyl) 2-methyl (2S,4S)-4-hydroxytetrahydro-1H-pyrrole-1,2-dicarboxylate;(2S,4S)-1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate | C11H19NO5 | 详情 | 详情 | |
| (II) | 15781 | 1-(tert-butyl) 2-methyl (2S,4R)-4-[(methylsulfonyl)oxy]tetrahydro-1H-pyrrole-1,2-dicarboxylate | C12H21NO7S | 详情 | 详情 | |
| (III) | 15782 | 1-(tert-butyl) 2-methyl (2S,4S)-4-(benzoyloxy)tetrahydro-1H-pyrrole-1,2-dicarboxylate | C18H23NO6 | 详情 | 详情 | |
| (IV) | 15783 | 1-(tert-butyl) 2-methyl (2S,4S)-4-hydroxytetrahydro-1H-pyrrole-1,2-dicarboxylate | C11H19NO5 | 详情 | 详情 | |
| (V) | 15784 | 1-(tert-butyl) 2-methyl (2S,4S)-4-[(methylsulfonyl)oxy]tetrahydro-1H-pyrrole-1,2-dicarboxylate | C12H21NO7S | 详情 | 详情 | |
| (VI) | 15785 | 1-(tert-butyl) 2-methyl (2S,4R)-4-azidotetrahydro-1H-pyrrole-1,2-dicarboxylate | C11H18N4O4 | 详情 | 详情 | |
| (VII) | 15786 | 1-(tert-butyl) 2-methyl (2S,4R)-4-aminotetrahydro-1H-pyrrole-1,2-dicarboxylate | C11H20N2O4 | 详情 | 详情 | |
| (VIII) | 15787 | 4-chlorobenzenesulfonyl chloride;4-chlorobenzene-1-sulfonyl chloride | 98-60-2 | C6H4Cl2O2S | 详情 | 详情 |
| (IX) | 15788 | 1-(tert-butyl) 2-methyl (2S,4R)-4-[[(4-chlorophenyl)sulfonyl]amino]tetrahydro-1H-pyrrole-1,2-dicarboxylate | C17H23ClN2O6S | 详情 | 详情 | |
| (X) | 15789 | tert-butyl (2S,4R)-4-[[(4-chlorophenyl)sulfonyl]amino]-2-formyltetrahydro-1H-pyrrole-1-carboxylate | C16H21ClN2O5S | 详情 | 详情 | |
| (XI) | 13616 | (4-Carboxybutyl)triphenylphosphonium bromide | 17814-85-6 | C23H24BrO2P | 详情 | 详情 |
| (XII) | 15791 | (Z)-6-((2S,4R)-1-(tert-butoxycarbonyl)-4-[[(4-chlorophenyl)sulfonyl]amino]tetrahydro-1H-pyrrol-2-yl)-5-hexenoic acid | C21H29ClN2O6S | 详情 | 详情 | |
| (XIII) | 15792 | methyl (Z)-6-((2S,4R)-4-[[(4-chlorophenyl)sulfonyl]amino]tetrahydro-1H-pyrrol-2-yl)-5-hexenoate | C17H23ClN2O4S | 详情 | 详情 | |
| (XIV) | 15793 | 3-(Chloromethyl)pyridine | 3099-31-8 | C6H6ClN | 详情 | 详情 |
| (XV) | 15794 | methyl (Z)-6-[(2S,4R)-4-[[(4-chlorophenyl)sulfonyl]amino]-1-(3-pyridinylmethyl)tetrahydro-1H-pyrrol-2-yl]-5-hexenoate | C23H28ClN3O4S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VIII)2) The esterification of trans-4-hydroxy-L-proline (XVI) with SOCl2 and methanol gives the methyl ester (XVII), which is condensed with 3-(methanesulfonyloxymethyl)pyridine (XVIII), obtained by treatment of 3-(hydroxymethyl)pyridine (XIX) with methanesulfonyl chloride, by means of triethylamine yielding trans-N-(3-pyridylmethyl)-4-hydroxy-L-proline methyl ester (XX). The treatment of (XX) with methanesulfonyl chloride affords the corresponding mesylate (XXI), which by reaction with LiCl in hot polyethylene glycol gives cis-4-chloro-N-(3-pyridylmethyl)-L-proline methyl ester (XXII). The reaction of (XXII) with sodium azide in DMSO yields the trans-4-azido derivative (XXIII), which is reduced with triphenylphosphine in hot ethyl acetate to the corresponding trans-4-amino compound (XXIV). The treatment of (XXIV) with 4-chlorophenylsulfonyl chloride (VIII) and triethylamine in ethyl acetate affords the sulfonamide (XXV), which is reduced with diisobutylaluminum hydride in toluene/dichloromethane giving (2S,4R)-4-(4-chlorophenylsulfonamido)-1-(3-pyridylmethyl)pyrrolidine-2-carbaldehyde (XXVI). Finally, this compound is submitted to a Wittig condensation with (4-carboxybutyl)triphenylphosphonium chloride (XXVII) and potassium tert-butoxide in THF.
| 【1】 Graul, A.; Castaner, J.; KDI-792. Drugs Fut 1996, 21, 12, 1224. |
| 【2】 Kagara, K.; Goto, S.; Yonishi, S.; Ikushima, M.; Baba, Y.; Horiai, H. (Fujisawa Pharmaceutical Co., Ltd.); Process for producing pyrrolidine deriv. and salt thereof. WO 9401400 . |
| 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) | 15787 | 4-chlorobenzenesulfonyl chloride;4-chlorobenzene-1-sulfonyl chloride | 98-60-2 | C6H4Cl2O2S | 详情 | 详情 |
| (XVI) | 14489 | (2S,4R)-4-hydroxytetrahydro-1H-pyrrole-2-carboxylic acid; L-Hydroxyproline | 51-35-4 | C5H9NO3 | 详情 | 详情 |
| (XVII) | 15796 | methyl (2S,4R)-4-hydroxytetrahydro-1H-pyrrole-2-carboxylate | C6H11NO3 | 详情 | 详情 | |
| (XVIII) | 15797 | 3-pyridinylmethyl methanesulfonate | C7H9NO3S | 详情 | 详情 | |
| (XIX) | 15798 | 3-Pyridinemethanol; 3-pyridinylmethanol | 100-55-0 | C6H7NO | 详情 | 详情 |
| (XX) | 15799 | methyl (2S,4R)-4-hydroxy-1-(3-pyridinylmethyl)tetrahydro-1H-pyrrole-2-carboxylate | C12H16N2O3 | 详情 | 详情 | |
| (XXI) | 15800 | methyl (2S,4R)-4-[(methylsulfonyl)oxy]-1-(3-pyridinylmethyl)tetrahydro-1H-pyrrole-2-carboxylate | C13H18N2O5S | 详情 | 详情 | |
| (XXII) | 15801 | methyl (2S,4S)-4-chloro-1-(3-pyridinylmethyl)tetrahydro-1H-pyrrole-2-carboxylate | C12H15ClN2O2 | 详情 | 详情 | |
| (XXIII) | 15802 | methyl (2S,4R)-4-azido-1-(3-pyridinylmethyl)tetrahydro-1H-pyrrole-2-carboxylate | C12H15N5O2 | 详情 | 详情 | |
| (XXIV) | 15803 | methyl (2S,4R)-4-amino-1-(3-pyridinylmethyl)tetrahydro-1H-pyrrole-2-carboxylate | C12H17N3O2 | 详情 | 详情 | |
| (XXV) | 15804 | methyl (2S,4R)-4-[[(4-chlorophenyl)sulfonyl]amino]-1-(3-pyridinylmethyl)tetrahydro-1H-pyrrole-2-carboxylate | C18H20ClN3O4S | 详情 | 详情 | |
| (XXVI) | 15805 | 4-chloro-N-[(3R,5S)-5-formyl-1-(3-pyridinylmethyl)tetrahydro-1H-pyrrol-3-yl]benzenesulfonamide | C17H18ClN3O3S | 详情 | 详情 | |
| (XXVII) | 28718 | (4-carboxybutyl)(triphenyl)phosphonium chloride | C23H24ClO2P | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XII)The reaction of 1,3,5-tribromobenzene (I) with 4-fluorobenzaldehyde (II) by means of BuLi in ethyl ether gives the benzhydrol (III), which is condensed with ethyl acrylate (IV) by means of palladium acetate and tri o-tolylphosphine in refluxing acetonitrile yielding the phenylenebisacrylate (V). The acetylation of (V) with acetic anhydride and DMAP in dichloromethane affords the acetate (VI), which is hydrogenated with H2 over Pd/C in ethyl acetate providing the bispropanoate (VII). Selective hydrolysis of (VII) with NaOH in ethanol gives the monoacid (VIII), which is treated with oxalyl chloride in dichloromethane yielding the monoacyl chloride (IX). The reaction of (IX) with NH4OH affords the corresponding amide (X), which is treated with NaOCl and NaOH to perform degradation of the amide group and simultaneous hydrolysis of the ester group providing the amino acid (XI). Finally, this compound is sulfonated with 4-chlorophenylsulfonyl chloride (XII) and NaOH.
| 【1】 Dack, K.N.; Dickinson, R.P.; Long, C.J.; Steele, J.; Thromboxane modulating agents. 4. Design and synthesis of 3-(2-[((4-chlorophenyl)sulfonyl)amino]ethyl)benzenepropanoic acid derivatives as potent thromboxane receptor antagonists. Bioorg Med Chem Lett 1998, 8, 16, 2061. |
| 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) | 26991 | 1,3,5-tribromobenzene | 626-39-1 | C6H3Br3 | 详情 | 详情 |
| (II) | 12337 | 4-fluorobenzaldehyde | 459-57-4 | C7H5FO | 详情 | 详情 |
| (III) | 26992 | (3,5-dibromophenyl)(4-fluorophenyl)methanol | C13H9Br2FO | 详情 | 详情 | |
| (IV) | 10164 | ethyl acrylate | 140-88-5 | C5H8O2 | 详情 | 详情 |
| (V) | 26993 | ethyl (E)-3-[3-[(E)-3-ethoxy-3-oxo-1-propenyl]-5-[(4-fluorophenyl)(hydroxy)methyl]phenyl]-2-propenoate | C23H23FO5 | 详情 | 详情 | |
| (VI) | 26994 | ethyl (E)-3-[3-[(acetoxy)(4-fluorophenyl)methyl]-5-[(E)-3-ethoxy-3-oxo-1-propenyl]phenyl]-2-propenoate | C25H25FO6 | 详情 | 详情 | |
| (VII) | 26995 | ethyl 3-[3-(3-ethoxy-3-oxopropyl)-5-(4-fluorobenzyl)phenyl]propanoate | C23H27FO4 | 详情 | 详情 | |
| (VIII) | 26996 | 3-[3-(3-ethoxy-3-oxopropyl)-5-(4-fluorobenzyl)phenyl]propionic acid | C21H23FO4 | 详情 | 详情 | |
| (IX) | 26997 | ethyl 3-[3-(3-chloro-3-oxopropyl)-5-(4-fluorobenzyl)phenyl]propanoate | C21H22ClFO3 | 详情 | 详情 | |
| (X) | 26998 | ethyl 3-[3-(3-amino-3-oxopropyl)-5-(4-fluorobenzyl)phenyl]propanoate | C21H24FNO3 | 详情 | 详情 | |
| (XI) | 26999 | 3-[3-(2-aminoethyl)-5-(4-fluorobenzyl)phenyl]propionic acid | C18H20FNO2 | 详情 | 详情 | |
| (XII) | 15787 | 4-chlorobenzenesulfonyl chloride;4-chlorobenzene-1-sulfonyl chloride | 98-60-2 | C6H4Cl2O2S | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XII)The reaction of monoacid (VIII) with diphenylphosphoryl azide and triethylamine in refluxing tert-butanol gives the tert-butoxycarbonyl aminoester (XIII), which is deprotected with trifluoroacetic acid to yield the aminoester (XIV). The sulfonation of (XIV) with 4-chlorophenylsulfonyl chloride (XII) and triethylamine in dichloromethane affords the sulfonamido ester (XV), which is finally hydrolyzed with NaOH in refluxing methanol.
| 【1】 Dickinson, R.P.; Dack, K.N.; Steele, J. (Pfizer Inc.); Benzenealkanoic acids for cardiovascular diseases. EP 0662950; JP 1996502046; US 5618941; WO 9406761 . |
| 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) | 26996 | 3-[3-(3-ethoxy-3-oxopropyl)-5-(4-fluorobenzyl)phenyl]propionic acid | C21H23FO4 | 详情 | 详情 | |
| (XII) | 15787 | 4-chlorobenzenesulfonyl chloride;4-chlorobenzene-1-sulfonyl chloride | 98-60-2 | C6H4Cl2O2S | 详情 | 详情 |
| (XIII) | 27000 | ethyl 3-[3-[2-[(tert-butoxycarbonyl)amino]ethyl]-5-(4-fluorobenzyl)phenyl]propanoate | C25H32FNO4 | 详情 | 详情 | |
| (XIV) | 27001 | ethyl 3-[3-(2-aminoethyl)-5-(4-fluorobenzyl)phenyl]propanoate | C20H24FNO2 | 详情 | 详情 | |
| (XV) | 27002 | ethyl 3-[3-(2-[[(4-chlorophenyl)sulfonyl]amino]ethyl)-5-(4-fluorobenzyl)phenyl]propanoate | C26H27ClFNO4S | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(XII)The reaction of 3-bromo-5-iodobenzoic acid (I) with SOCl2 gives the corresponding acyl chloride (II), which by a Friedel-Crafts condensation with fluorobenzene (II) by means of AlCl3 in refluxing dichloromethane yields the benzophenone (IV). The condensation of (IV) with ethyl acrylate (V) by means of palladium acetate and triethylamine in refluxing acetonitrile affords the cinnamic acid derivative (VI), which is condensed with N-vinylphthalimide (VII) by means of palladium acetate and diisopropylamine in refluxing xylene to provide the unsaturated adduct (VIII). The reduction of the carbonyl group of (VIII) with triethylsilane and TFA gives the diphenylmethane derivative (IX), which is hydrogenated with H2 over Pd/C in ethyl acetate to yield the saturated diphenylmethane derivative (X). Elimination of the phthalimido group of (X) with hydrazine affords (XI) with a primary amino group. that is sulfonated with 4-chlorophenylsulfonyl chloride (XII) and triethylamine in THF to provide the sulfonamide (XIII). Finally, the ester group of (XIII) is hydrolyzed with aqueous NaOH.
| 【1】 Waite, D.C.; Mason, C.P.; A scalable synthesis of the thromboxane receptor antagonist 3-(3-[2-(4-chlorobenzenesulfonamido)ethyl]-5-(4-fluorobenzyl)phenyl]propionic acid via a regioselective heck cross-coupling strategy. Org Process Res Dev 1998, 2, 2, 116. |
| 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) | 32745 | 3-bromo-5-iodobenzoic acid | 188815-32-9 | C7H4BrIO2 | 详情 | 详情 |
| (II) | 32746 | 3-bromo-5-iodobenzoyl chloride | C7H3BrClIO | 详情 | 详情 | |
| (III) | 17466 | Fluorobenzene | 462-06-6 | C6H5F | 详情 | 详情 |
| (IV) | 32747 | (3-bromo-5-iodophenyl)(4-fluorophenyl)methanone | C13H7BrFIO | 详情 | 详情 | |
| (V) | 10164 | ethyl acrylate | 140-88-5 | C5H8O2 | 详情 | 详情 |
| (VI) | 32748 | ethyl (E)-3-[3-bromo-5-(4-fluorobenzoyl)phenyl]-2-propenoate | C18H14BrFO3 | 详情 | 详情 | |
| (VII) | 32749 | 2-vinyl-1H-isoindole-1,3(2H)-dione | 3485-84-5 | C10H7NO2 | 详情 | 详情 |
| (VIII) | 32750 | ethyl (E)-3-[3-[(E)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethenyl]-5-(4-fluorobenzoyl)phenyl]-2-propenoate | C28H20FNO5 | 详情 | 详情 | |
| (IX) | 32751 | ethyl (E)-3-[3-[(E)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethenyl]-5-(4-fluorobenzyl)phenyl]-2-propenoate | C28H22FNO4 | 详情 | 详情 | |
| (X) | 32752 | ethyl 3-[3-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-5-(4-fluorobenzyl)phenyl]propanoate | C28H26FNO4 | 详情 | 详情 | |
| (XI) | 27001 | ethyl 3-[3-(2-aminoethyl)-5-(4-fluorobenzyl)phenyl]propanoate | C20H24FNO2 | 详情 | 详情 | |
| (XII) | 15787 | 4-chlorobenzenesulfonyl chloride;4-chlorobenzene-1-sulfonyl chloride | 98-60-2 | C6H4Cl2O2S | 详情 | 详情 |
| (XIII) | 27002 | ethyl 3-[3-(2-[[(4-chlorophenyl)sulfonyl]amino]ethyl)-5-(4-fluorobenzyl)phenyl]propanoate | C26H27ClFNO4S | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：As shown in Scheme 22341901a, TER-930180 was prepared from 3-(3-pyridyl)acrolein (I) and methyl 4-(cyanomethyl)cinnamate (II). The condensation of (I) and (II) with sodium methoxide yielded a mixture of diene isomers (III), which was then hydrogenated over Pd/C in dioxane, and then over Raney Nickel at 10 approx. 15 atm of H2 in ammoniac/methanol. The amine thus obtained (IV) was treated with 4-chlorobenzenesulfonyl chloride, followed by hydrolyzation with sodium hydroxide solution, yielding TER-930180. The starting materials (I) and (II) were obtained as follows: Reduction of methyl 3-(3-pyridyl)acrylate with DIBAL, and oxidation with manganese dioxide to yield 3-(3-pyridyl)acrolein (I). Bromination of methyl 4-methylcinnamate with NBS, and cyanization with potassium cyanide in the presence of PTC produced methyl 4-cyanomethylcinnamate (II).
| 【1】 Kasukawa, H.; Ohnishi, H.; TER-930180. Drugs Fut 1996, 21, 1, 33. |
| 【2】 Ohnishi, H.; Miyakoshi, M.; Isozaki, M.; Fujitake, M.; Mikami, N.; Yanoshita, R.; Akasofu, H.; Sugizaki, K.; Nakata, N. (Terumo Corp.); N-(3-Pyridylalkyl)sulfonamide deriv. and pharmaceutical preparation containing thereof. EP 0501876; JP 1992270265; JP 1993043546; JP 1993043547; US 5374641 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 15787 | 4-chlorobenzenesulfonyl chloride;4-chlorobenzene-1-sulfonyl chloride | 98-60-2 | C6H4Cl2O2S | 详情 | 详情 | |
| (I) | 16977 | (E)-3-(3-pyridinyl)-2-propenal | C8H7NO | 详情 | 详情 | |
| (II) | 16978 | methyl (E)-3-[4-(cyanomethyl)phenyl]-2-propenoate | C12H11NO2 | 详情 | 详情 | |
| (III) | 16979 | methyl (E)-3-[4-[(1Z,3E)-1-cyano-4-(3-pyridinyl)-1,3-butadienyl]phenyl]-2-propenoate | C20H16N2O2 | 详情 | 详情 | |
| (IV) | 16980 | methyl 3-[4-[1-cyano-4-(3-pyridinyl)butyl]phenyl]propanoate | C20H22N2O2 | 详情 | 详情 | |
| (V) | 16981 | methyl 3-[4-[1-(aminomethyl)-4-(3-pyridinyl)butyl]phenyl]propanoate | C20H26N2O2 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(IV)Reductive amination of 4,4-diethoxycyclohexanone (I) with benzylamine in the presence of sodium triacetoxyborohydride provided amino ketal (II). Subsequent benzyl group hydrogenolysis in (II) yielded the primary amine (III), which was acylated by 4-chlorobenzenesulfonyl chloride (IV) affording sulfonamide (V). Claisen condensation of ketone (V) with ethyl formate furnished the hydroxymethylene ketone (VI). This was subjected to a Wittig reaction with (methoxycarbonylmethylene)triphenylphosphorane to produce ester (VII). Intramolecular cyclization of (VII) under acidic conditions gave rise to the benzopyranone (VIII). Diels-Alder cycloaddition between methyl butynoate (IX) and benzopyranone (VIII) led to a mixture of two regioisomeric tetrahydronaphthalenes (X) and (XI). Reduction of this mixture of esters by means of LiAlH4 yielded the desired alcohol (XII) along with its regioisomer, which were further oxidized to the corresponding aldehydes employing 4-benzylpyridinium dichromate. Separation of the resultant mixture by column chromatography furnished the desired aldehyde (XIII).
| 【1】 Cimetière, B.; Dubuffet, T.; Muller, O.; Descombes, J.-J.; Simonet, S.; Verbeuren, T.J.; Laubie, M.; Lavielle, G.; Synthesis and biological evaluation of new tetrahydronaphthalene derivatives as thromboxane receptor antagonists. Bioorg Med Chem Lett 1998, 8, 11, 1375. |
| 【2】 Lavielle, G.; Dubuffet, T.; Muller, O.; Laubie, M.; Verbeuren, T.; Simonet, S.; Descombes, J.-J. (ADIR et Cie.); 1,2,3,4-Tetrahydronaphthalene, chroman and thiochroman derivs. as antithrombotic agents. CA 2118102; EP 0648741; FR 2711139; JP 1995188155 . |
| 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) | 19576 | 4,4-diethoxycyclohexanone | C10H18O3 | 详情 | 详情 | |
| (II) | 19577 | N-benzyl-4,4-diethoxycyclohexanamine; N-benzyl-N-(4,4-diethoxycyclohexyl)amine | C17H27NO2 | 详情 | 详情 | |
| (III) | 19578 | 4,4-diethoxycyclohexanamine; 4,4-diethoxycyclohexylamine | C10H21NO2 | 详情 | 详情 | |
| (IV) | 15787 | 4-chlorobenzenesulfonyl chloride;4-chlorobenzene-1-sulfonyl chloride | 98-60-2 | C6H4Cl2O2S | 详情 | 详情 |
| (V) | 19580 | 4-chloro-N-(4-oxocyclohexyl)benzenesulfonamide | C12H14ClNO3S | 详情 | 详情 | |
| (VI) | 19583 | 4-chloro-N-[3-[(Z)-hydroxymethylidene]-4-oxocyclohexyl]benzenesulfonamide | C13H14ClNO4S | 详情 | 详情 | |
| (VII) | 19585 | methyl 3-(5-[[(4-chlorophenyl)sulfonyl]amino]-2-oxocyclohexylidene)propanoate | C16H18ClNO5S | 详情 | 详情 | |
| (VIII) | 19586 | 4-chloro-N-(2-oxo-5,6,7,8-tetrahydro-2H-chromen-6-yl)benzenesulfonamide | C15H14ClNO4S | 详情 | 详情 | |
| (IX) | 51405 | 2-Butynoic acid methyl ester; Methyl 2-butynoate; Tetrolic acid methyl ester; Methyl tetrolate | 23326-27-4 | C5H6O2 | 详情 | 详情 |
| (X) | 58536 | methyl 6-{[(4-chlorophenyl)sulfonyl]amino}-1-methyl-5,6,7,8-tetrahydro-2-naphthalenecarboxylate | C19H20ClNO4S | 详情 | 详情 | |
| (XI) | 58537 | methyl 6-{[(4-chlorophenyl)sulfonyl]amino}-2-methyl-5,6,7,8-tetrahydro-1-naphthalenecarboxylate | C19H20ClNO4S | 详情 | 详情 | |
| (XII) | 58535 | ethyl 2-[7-(1H-imidazol-1-yl)-2,3-dioxo-3,4-dihydro-1(2H)-quinoxalinyl]acetate | C15H14N4O4 | 详情 | 详情 | |
| (XIII) | 58539 | 4-chloro-N-(5-formyl-6-methyl-1,2,3,4-tetrahydro-2-naphthalenyl)benzenesulfonamide | C18H18ClNO3S | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(IV)Curtius rearrangement of indanylacetic acid (I) using diphenylphosphoryl azide (DPPA) in the presence of benzyl alcohol afforded benzyl carbamate (II). Hydrogenolytic deprotection of (II) in the presence of palladium catalyst then provided amine (III), which was condensed with 4-chlorobenzenesulfonyl chloride (IV) to give sulfonamide (V). Subsequent Friedel Crafts reaction of (V) with ethyl a-chloro-a-(methylsulfanyl)acetate (VI) and SnCl4 furnished sulfide (VII), from which the methylthio group was removed by reductive treatment with Zn dust in AcOH yielding (VIII). Finally, alkaline hydrolysis of the indanylacetic ester (VIII) provided the title carboxylic acid, isolated as the corresponding sodium salt.
| 【1】 Iwakuma, T.; Kurimoto, T.; Yoshida, K.; Shinozaki, K.; Sato, R.; Sato, H.; Synthesis and thromboxane A2 antagonistic activity of indane derivatives. Bioorg Med Chem Lett 1999, 9, 3, 401. |
| 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) | 21721 | 2-(2,3-dihydro-1H-inden-2-yl)acetic acid | 37868-26-1 | C11H12O2 | 详情 | 详情 |
| (II) | 21722 | benzyl 2,3-dihydro-1H-inden-2-ylmethylcarbamate | C18H19NO2 | 详情 | 详情 | |
| (III) | 21723 | 2,3-dihydro-1H-inden-2-ylmethylamine; 2,3-dihydro-1H-inden-2-ylmethanamine | C10H13N | 详情 | 详情 | |
| (IV) | 15787 | 4-chlorobenzenesulfonyl chloride;4-chlorobenzene-1-sulfonyl chloride | 98-60-2 | C6H4Cl2O2S | 详情 | 详情 |
| (V) | 21725 | 4-chloro-N-(2,3-dihydro-1H-inden-2-ylmethyl)benzenesulfonamide | C16H16ClNO2S | 详情 | 详情 | |
| (VI) | 21726 | ethyl 2-chloro-2-(methylsulfanyl)acetate | C5H9ClO2S | 详情 | 详情 | |
| (VII) | 21727 | ethyl 2-[2-([[(4-chlorophenyl)sulfonyl]amino]methyl)-2,3-dihydro-1H-inden-5-yl]-2-(methylsulfanyl)acetate | C21H24ClNO4S2 | 详情 | 详情 | |
| (VIII) | 21728 | ethyl 2-[2-([[(4-chlorophenyl)sulfonyl]amino]methyl)-2,3-dihydro-1H-inden-5-yl]acetate | C20H22ClNO4S | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(VII)A new synthesis of Sch-56592 has been described: The reaction of (S)-ethyl lactate (I) with pyrrolidine (II) gives 1-[(S)-lactoyl]pyrrolidine (III), which is benzylated as usual with benzyl chloride yielding the benzyl ether (IV). The reaction of (IV) with ethylmagnesium bromide in THF affords 2(S)-benzyloxy-3-pentanone (V), which is reduced with LiBH4 in dimethoxyethane giving 2(S)-benzyloxy-3(RS)-pentanol (VI). The reaction of (VI) with 4-chlorobenzenesulfonyl chloride (VII) yields the corresponding sulfonate (VIII), which is treated with hydrazine in ethanol to afford a diastereomeric mixture of hydrazines that is resolved with L-dibenzoyltartaric acid giving the (S,S)-enantiomer (IX). The formylation of (IX) with refluxing ethyl formate yields the chiral formyl hydrazide (X), which is cyclized with N-[4-[4-[4-(trimethylsilyloxy)phenyl]piperazin-1-yl]phenyl]carbamic acid phenyl ester (XI) affording the triazolone (XII). Finally, this compound is condensed with the chiral tetrahydrofuran derivative (XIII) by means of NaOH in DMSO, and debenzylated by hydrogenation with H2 over Pd/C in formic acid
| 【1】 Andrews, D.R.; Gala, D.; Gosteli, J.; Guenter, F.; Leong, W.; Mergelsberg, I.; Sudhakar, A. (Schering Corp.); Process for the preparation of triazolones. WO 9633178 . |
| 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) | 16659 | ethyl (2S)-2-hydroxypropanoate; (S)-ethyl lactate | 687-47-8 | C5H10O3 | 详情 | 详情 |
| (II) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 |
| (III) | 17099 | (2S)-2-hydroxy-1-(1-pyrrolidinyl)-1-propanone | C7H13NO2 | 详情 | 详情 | |
| (IV) | 17100 | (2S)-2-(benzyloxy)-1-(1-pyrrolidinyl)-1-propanone | 122151-32-0 | C14H19NO2 | 详情 | 详情 |
| (V) | 17101 | (2S)-2-(benzyloxy)-3-pentanone | C12H16O2 | 详情 | 详情 | |
| (VI) | 17102 | (2S)-2-(benzyloxy)-3-pentanol | C12H18O2 | 详情 | 详情 | |
| (VII) | 15787 | 4-chlorobenzenesulfonyl chloride;4-chlorobenzene-1-sulfonyl chloride | 98-60-2 | C6H4Cl2O2S | 详情 | 详情 |
| (VIII) | 17104 | (2S)-2-(benzyloxy)-1-ethylpropyl 4-chlorobenzenesulfonate | C18H21ClO4S | 详情 | 详情 | |
| (IX) | 17105 | 1-[(1S,2S)-2-(benzyloxy)-1-ethylpropyl]hydrazine; benzyl (1S,2S)-2-hydrazino-1-methylbutyl ether | C12H20N2O | 详情 | 详情 | |
| (X) | 17106 | N'-[(1S,2S)-2-(benzyloxy)-1-ethylpropyl]formic hydrazide | C13H20N2O2 | 详情 | 详情 | |
| (XI) | 17107 | phenyl 4-(4-[4-[(trimethylsilyl)methyl]phenyl]-1-piperazinyl)phenylcarbamate | C27H33N3O2Si | 详情 | 详情 | |
| (XII) | 17108 | 2-[(1S,2S)-2-(benzyloxy)-1-ethylpropyl]-4-[4-[4-(4-hydroxyphenyl)-1-piperazinyl]phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one | C30H35N5O3 | 详情 | 详情 | |
| (XIII) | 17109 | [(3S,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methyl 4-chlorobenzenesulfonate | C20H18ClF2N3O4S | 详情 | 详情 | |
| (XIV) | 17110 | 4-[4-(4-aminophenyl)piperazino]phenol; 1-(4-Aminophenyl)-4-(4-hydroxyphenyl)piperazine; 1-(4-Hydroxyphenyl)-4-(4-aminophenyl)piperazine | 74853-08-0 | C16H19N3O | 详情 | 详情 |
| (XV) | 17111 | phenyl N-[4-[4-(4-hydroxyphenyl)piperazino]phenyl]carbamate | C23H23N3O3 | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：Reaction of 2-(1,3-dioxol-5-yl)acetic acid (XXI) with pivaloyl chloride and TEA gives the corresponding anhydride (XXII), which is condensed with the chiral oxazolidinone (XXIII) by means of n-BuLi in THF to yield the amide (XXIV). Condensation of (XXIV) with 2-bromoacetic acid tert-butyl ester (XXV) by means of NaHMDS in THF affords the adduct (XXVI). Elimination of the chiral auxiliary of (XXVI) by means of LiOOH in THF/water provides the chiral succinic acid hemiester (XXVII) (93% ee), which is selectively reduced with BH3THF complex to give the 4-hydroxysuccinate (XXVIII). Reaction of succinate (XXVIII) with 4-chlorophenylsulfonyl chloride, TEA and DMAP in dichloromethane yields the sulfonate (XXIX), which is condensed with 4-methoxybenzaldoxime (XXX) by means of Cs2CO3 in hot acetonitrile to afford the oxime ether (XXXI). Transesterification of the tert-butyl ester of (XXXI) with trimethyl orthoformate and p-toluenesulfonic acid in hot methanol provides the methyl ester (XXXII), which is cyclized by means of trimethylsilyl triflate and tributylamine in dichloroethane to afford a 9:1 diastereomeric mixture of perhydro-1,2-oxazines (XXXIII) and (XXXIV) which is easily separated. The reductive N-O-bond cleavage of the major oxazine diastereomer (XXXIII) by means of Zn/HOAc or H2 over Pd/C gives the trisubstituted 4-aminobutanol (XXXV), which is cyclized by means of CBr4, PPh3 and TEA to yield chiral pyrrolidine (XXXVI) (4). Finally, pyrrolidine (XXXVI) is alkylated with N,N-dibutyl-2-bromoacetamide (XIII) followed by ester hydrolysis as before.
| 【1】 Leeson, P.; Castañer, R.M.; Sorbera, L.A.; Castañer, J.; Atrasentan. Drugs Fut 2001, 26, 10, 939. |
| 【2】 McLaughlin, M.A.; Wittenberger, S.J.; Preparation of endothelin antagonist ABT-627. Tetrahedron Lett 1999, 40, 7175. |
| 【3】 Winn, M.; et al.; 2,4-Diarylpyrrolidine-3-carboxylic acids-potent ETA selective endothelin receptor antagonists. 1. Discovery of A-127722. J Med Chem 1996, 39, 5, 1039. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 15787 | 4-chlorobenzenesulfonyl chloride;4-chlorobenzene-1-sulfonyl chloride | 98-60-2 | C6H4Cl2O2S | 详情 | 详情 | |
| (XIII) | 20685 | 2-Bromo-N,N-dibutylacetamide; N,N-Dibutylbromoacetamide | C10H20BrNO | 详情 | 详情 | |
| (XXI) | 18117 | 2-(1,3-benzodioxol-5-yl)acetic acid; 3,4-(Methylenedioxy)phenylacetic acid | 2861-28-1 | C9H8O4 | 详情 | 详情 |
| (XXII) | 48688 | 1,3-benzodioxol-5-ylacetic 1,1-dimethylpropionic anhydride | C14H16O5 | 详情 | 详情 | |
| (XXIII) | 12867 | (4S)-4-Isopropyl-1,3-oxazolidin-2-one; (R)-4-Isopropyl-2-oxazolidinone | 17016-83-0 | C6H11NO2 | 详情 | 详情 |
| (XXIV) | 48689 | (4S)-3-[2-(1,3-benzodioxol-5-yl)acetyl]-4-isopropyl-1,3-oxazolidin-2-one | C15H17NO5 | 详情 | 详情 | |
| (XXV) | 17430 | 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate | 5292-43-3 | C6H11BrO2 | 详情 | 详情 |
| (XXVI) | 48690 | tert-butyl (3S)-3-(1,3-benzodioxol-5-yl)-4-[(4S)-4-isopropyl-2-oxo-1,3-oxazolidin-3-yl]-4-oxobutanoate | C21H27NO7 | 详情 | 详情 | |
| (XXVII) | 48691 | (2S)-2-(1,3-benzodioxol-5-yl)-4-(tert-butoxy)-4-oxobutyric acid | C15H18O6 | 详情 | 详情 | |
| (XXVIII) | 48692 | tert-butyl (3S)-3-(1,3-benzodioxol-5-yl)-4-hydroxybutanoate | C15H20O5 | 详情 | 详情 | |
| (XXIX) | 48693 | tert-butyl (3S)-3-(1,3-benzodioxol-5-yl)-4-[[(4-chlorophenyl)sulfonyl]oxy]butanoate | C21H23ClO7S | 详情 | 详情 | |
| (XXX) | 48694 | 4-methoxybenzaldehyde oxime | C8H9NO2 | 详情 | 详情 | |
| (XXXI) | 48695 | tert-butyl (3S)-3-(1,3-benzodioxol-5-yl)-4-([[(E)-(4-methoxyphenyl)methylidene]amino]oxy)butanoate | C23H27NO6 | 详情 | 详情 | |
| (XXXII) | 48696 | methyl (3S)-3-(1,3-benzodioxol-5-yl)-4-([[(E)-(4-methoxyphenyl)methylidene]amino]oxy)butanoate | C20H21NO6 | 详情 | 详情 | |
| (XXXIII) | 48697 | methyl (3R,4R,5S)-5-(1,3-benzodioxol-5-yl)-3-(4-methoxyphenyl)-1,2-oxazinane-4-carboxylate | C20H21NO6 | 详情 | 详情 | |
| (XXXIV) | 48698 | methyl (3S,5S)-5-(1,3-benzodioxol-5-yl)-3-(4-methoxyphenyl)-1,2-oxazinane-4-carboxylate | C20H21NO6 | 详情 | 详情 | |
| (XXXV) | 48699 | methyl (2R,3S)-2-[(R)-amino(4-methoxyphenyl)methyl]-3-(1,3-benzodioxol-5-yl)-4-hydroxybutanoate | C20H23NO6 | 详情 | 详情 | |
| (XXXVI) | 48700 | methyl (2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-2-(4-methoxyphenyl)-3-pyrrolidinecarboxylate | C20H21NO5 | 详情 | 详情 |
合成路线11
该中间体在本合成路线中的序号：(IV)The intermediate 4-(4-chlorophenylsulfonyl)aminocyclohexanone (V) was prepared by two synthetic ways: 1) Reductive condensation of 4,4-diethoxycyclohexanone (I) with benzylamine in the presence of sodium triacetoxyborohydride and AcOH provided the benzylcyclohexylamine (II). Further hydrogenolysis of the N-benzyl group of (III) in the presence of Pd/C and oxalic acid yielded cyclohexylamine (III) as the oxalate salt. Sulfonamide (V) was then obtained by condensation with 4-chlorophenylsulfonyl chloride (IV), followed by hydrolysis of the diethyl acetal with aqueous HCl. 2) Alternatively, treatment of trans-4-aminocyclohexanol hydrochloride (VI) with sulfonyl chloride (IV) in the presence of Et3N provided the sulfonamide (VII), which was subsequently oxidized with chromic anhydride and H2SO4 to the target ketone (V). 3) Condensation of this intermediate with ethyl formate in the presence of NaH produced the hydroxymethylene cyclohexanone (VIII), which was submitted to a Wittig reaction with phosphorane (IX) to give the cyclohexylidenpropanoic ester (X). Cyclization of this compound using anhydrous p-toluenesulfonic acid in refluxing toluene furnished pyranone (XI), which by subsequent bromination in acetic acid yielded the 3-bromopyranone (XII) (1). The key tetrahydronaphthalene system (XIV) was then obtained by Diels-Alder reaction with refluxing methyl hexynoate (XIII) with concomitant decarboxylation. The ester function of (XIV) was reduced to alcohol (XV) with LiAlH4.
| 【1】 Cimetière, B.; Dubuffet, T.; Landras, C.; Descombes, J.J.; Simonet, S.; Verbeuren, T.J.; Lavielle, G.; New tetrahydronaphthalene derivatives as combined thromboxane receptor antagonists and thromboxane synthase inhibitors. Bioorg Med Chem Lett 1998, 8, 11, 1381. |
| 【2】 Lavielle, G.; Dubuffet, T.; Muller, O.; Laubie, M.; Verbeuren, T.; Simonet, S.; Descombes, J.-J. (ADIR et Cie.); 1,2,3,4-Tetrahydronaphthalene, chroman and thiochroman derivs. as antithrombotic agents. CA 2118102; EP 0648741; FR 2711139; JP 1995188155 . |
| 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) | 19576 | 4,4-diethoxycyclohexanone | C10H18O3 | 详情 | 详情 | |
| (II) | 19577 | N-benzyl-4,4-diethoxycyclohexanamine; N-benzyl-N-(4,4-diethoxycyclohexyl)amine | C17H27NO2 | 详情 | 详情 | |
| (III) | 19578 | 4,4-diethoxycyclohexanamine; 4,4-diethoxycyclohexylamine | C10H21NO2 | 详情 | 详情 | |
| (IV) | 15787 | 4-chlorobenzenesulfonyl chloride;4-chlorobenzene-1-sulfonyl chloride | 98-60-2 | C6H4Cl2O2S | 详情 | 详情 |
| (V) | 19580 | 4-chloro-N-(4-oxocyclohexyl)benzenesulfonamide | C12H14ClNO3S | 详情 | 详情 | |
| (VI) | 19581 | trans-4-Aminocyclohexanol；trans-4-Amino-1-cyclohexanol;trans-4-Amino-1-cyclohexanol; | 27489-62-9 | C6H13NO | 详情 | 详情 |
| (VII) | 19582 | 4-chloro-N-(4-hydroxycyclohexyl)benzenesulfonamide | C12H16ClNO3S | 详情 | 详情 | |
| (VIII) | 19583 | 4-chloro-N-[3-[(Z)-hydroxymethylidene]-4-oxocyclohexyl]benzenesulfonamide | C13H14ClNO4S | 详情 | 详情 | |
| (IX) | 14689 | Methyl (triphenylphosphoranylidene)acetate; (methoxycarbonylmethylene)triphenylphosphorane；Methyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate | 2605-67-6 | C21H19O2P | 详情 | 详情 |
| (X) | 19585 | methyl 3-(5-[[(4-chlorophenyl)sulfonyl]amino]-2-oxocyclohexylidene)propanoate | C16H18ClNO5S | 详情 | 详情 | |
| (XI) | 19586 | 4-chloro-N-(2-oxo-5,6,7,8-tetrahydro-2H-chromen-6-yl)benzenesulfonamide | C15H14ClNO4S | 详情 | 详情 | |
| (XII) | 19587 | N-(3-bromo-2-oxo-5,6,7,8-tetrahydro-2H-chromen-6-yl)-4-chlorobenzenesulfonamide | C15H13BrClNO4S | 详情 | 详情 | |
| (XIII) | 19609 | methyl 2-hexynoate | 18937-79-6 | C7H10O2 | 详情 | 详情 |
| (XIV) | 19610 | methyl 3-bromo-6-[[(4-chlorophenyl)sulfonyl]amino]-2-propyl-5,6,7,8-tetrahydro-1-naphthalenecarboxylate | C21H23BrClNO4S | 详情 | 详情 | |
| (XV) | 19611 | N-[7-bromo-5-(hydroxymethyl)-6-propyl-1,2,3,4-tetrahydro-2-naphthalenyl]-4-chlorobenzenesulfonamide | C20H23BrClNO3S | 详情 | 详情 |
合成路线12
该中间体在本合成路线中的序号：(II)The reaction of the chiral benzyl alcohol (I) with 4-chlorobenzenesulfonyl chloride (II) and DABCO in toluene gives the sulfonate (III), which is condensed with the monoprotected piperazine (IV) by means of K2CO3 in hot toluene/acetonitrile to yield the adduct (V). The deprotection of (V) by means of hot aqueous HCl affords the piperazine derivative (VI), which is condensed with the acyl piperidine (VII) --obtained by condensation of 4,6-dimethylpyrimidine-5-carboxylic acid (VIII) with 4-piperidone (IX) --by means of acetone cyanohydrin or NaCN/AcOH to provide the cyano adduct (X). Finally, this compound is treated with AlMe3 and Me-MgCl in THF/toluene to yield the target compound.
| 【1】 Gala, D.; Leong, W.; Jones, A.D.; Shi, X.; Chen, M.; D'sa, B.A.; Zhu, M.; Xiao, T.; Tang, S.; Goodman, A.J.; Nielsen, C.M.; Lee, G.M.; Gamboa, J.A. (Schering Corp.); Synthesis of piperidine and piperazine cpds. as CCR5 antagonists. WO 0384950 . |
| 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) | 64951 | (1S)-2-methoxy-1-[4-(trifluoromethyl)phenyl]-1-ethanol | C10H11F3O2 | 详情 | 详情 | |
| (II) | 15787 | 4-chlorobenzenesulfonyl chloride;4-chlorobenzene-1-sulfonyl chloride | 98-60-2 | C6H4Cl2O2S | 详情 | 详情 |
| (III) | 64952 | (1S)-2-methoxy-1-[4-(trifluoromethyl)phenyl]ethyl 4-chlorobenzenesulfonate | C16H14ClF3O4S | 详情 | 详情 | |
| (IV) | 50647 | benzyl (3R)-3-methyl-1-piperazinecarboxylate | C13H18N2O2 | 详情 | 详情 | |
| (V) | 64953 | benzyl (3S)-4-{(1R)-2-methoxy-1-[4-(trifluoromethyl)phenyl]ethyl}-3-methyl-1-piperazinecarboxylate | C23H27F3N2O3 | 详情 | 详情 | |
| (VI) | 64946 | 2-methyl-1-{2-(methyloxy)-1-[4-(trifluoromethyl)phenyl]ethyl}piperazine; methyl 2-(2-methyl-1-piperazinyl)-2-[4-(trifluoromethyl)phenyl]ethyl ether | C15H21F3N2O | 详情 | 详情 | |
| (VII) | 64954 | 1-[(4,6-dimethyl-5-pyrimidinyl)carbonyl]-4-piperidinone | C12H15N3O2 | 详情 | 详情 | |
| (VIII) | 64955 | 4,6-dimethyl-5-pyrimidinecarboxylic acid | C7H8N2O2 | 详情 | 详情 | |
| (IX) | 27115 | 4-piperidinone | 40064-34-4 | C5H9NO | 详情 | 详情 |
| (X) | 64956 | 1-[(4,6-dimethyl-5-pyrimidinyl)carbonyl]-4-((3S)-4-{(1R)-2-methoxy-1-[4-(trifluoromethyl)phenyl]ethyl}-3-methylpiperazinyl)-4-piperidinecarbonitrile | C28H35F3N6O2 | 详情 | 详情 |
合成路线13
该中间体在本合成路线中的序号：(VIIIb)Chlorination of (S)-naproxen (I) with SOCl2 by means of Et3N in cyclohexane at 60 °C affords the acyl chloride (II) , which is condensed with 4-hydroxybutyl nitrate (III) in CH2Cl2 at 40 °C directly or after pretreatment of nitrate (III) with K2CO3 in CH2Cl2 or toluene, or CaCO3 or CaAl2Si2O8 in CH2Cl2 .
By treatment of (S)-naproxen (I) with KHCO3 in DMF followed by condensation with either 4-nitrooxybutyl tosylate (IVa) or 4-bromobutyl nitrate (IVb) in the presence of KI .
Esterification of (S)-naproxen (I) with 1,4-butanediol (V) in the presence of H2SO4 or NaHSO4·H2O in toluene at 80 °C gives (S)-naproxen 4-hydroxybutyl ester (VI), which is then converted to: a) the mesylate (VII) by mesylation with MsCl by means of Et3N or Nmethylmorpholine (NMM) in toluene; b) the tosylate (IXa) by reaction with tosyl chloride (VIIIa) by means of either DMAP and Et3N in toluene or NMM in EtOAc; and c) the chlorobenzenesulfonate (IXb) by treatment with 4-chlorobenzenesulfonyl chloride (VIIIb) by means of NMM in acetonitrile. Finally, esters (VII), (IXa) and (IXb) are nitrated with NaNO3 or LiNO3 in the presence or absence of Bu4NNO3 or Bu4NHSO4 in various solvents, such as N-methylpyrrolidone (NMP), sulfolane and tetramethylurea, among others .
| 【1】 Hack, A., Weingartner, G., Kramer, M. (NicOX SA). Process for preparing 1,4-butanediol mononitrate. WO 2009000723. |
| 【2】 Benedini, F., Tarquini, A., Castaldi, G., Oldani, E. (NicOX SA). Process for the preparation of naproxene nitroxyalkylesters. CA 2380116, EP 1200386, EP 1384707, JP 2003506425, US 2005119339, US 6700011, US 7238829, WO 2001010814. |
| 【3】 Del Soldato, P., Santus, G., Benedini, F. (NicOX SA). Process for preparing nitrooxyderivative of naproxen. CA 2497187, EP 1532098, JP 2005536558, US 2006173005, US 7199258, WO2004020384. |
| 【4】 Belli, A., Cannata, V., Villa, M., Hedberg, M., Westermark, A., Fonduca, T. (AstraZeneca AB). New process. CA 2465697, EP 1451140, JP 2005510557, US 2005234123, WO 2003045896. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IVa) | 69254 | 4-(nitrooxy)butyl 4-methylbenzenesulfonate | C11H15NO6S | 详情 | 详情 | |
| (IVb) | 69255 | 4-bromobutyl nitrate;4-Nitrooxybutyl bromide;4-bromo-1-Butanol nitrate | 146563-40-8 | C4H8BrNO3 | 详情 | 详情 |
| (VIIIa) | 13975 | p-Toluenesulfonyl chloride;p-tosyl chloride;Toluene-4-sulfonyl chloride;4-Toluene sulfochloride;tosyl chloride; 4-Methylbenzenesulfonyl chloride | 98-59-9 | C7H7ClO2S | 详情 | 详情 |
| (VIIIb) | 15787 | 4-chlorobenzenesulfonyl chloride;4-chlorobenzene-1-sulfonyl chloride | 98-60-2 | C6H4Cl2O2S | 详情 | 详情 |
| (IXa) | 69258 | (S)-4-(tosyloxy)butyl 2-(6-methoxynaphthalen-2-yl)propanoate | C25H28O6S | 详情 | 详情 | |
| (IXb) | 69259 | (S)-4-(((4-chlorophenyl)sulfonyl)oxy)butyl 2-(6-methoxynaphthalen-2-yl)propanoate | C24H25ClO6S | 详情 | 详情 | |
| (I) | 30839 | (2S)-2-(6-methoxy-2-naphthyl)propionic acid;(S)-naproxen;(S)-6-Methoxy-alpha-methyl-2-naphthaleneacetic acid | 22204-53-1 | C14H14O3 | 详情 | 详情 |
| (II) | 69252 | (S)-2-(6-methoxynaphthalen-2-yl)propanoyl chloride | C14H13ClO2 | 详情 | 详情 | |
| (III) | 69253 | 4-hydroxybutyl nitrate | C4H9NO4 | 详情 | 详情 | |
| (V) | 43160 | 1,4-butanediol;1,4-Dihydroxybutane;1,4-Butylene glycol;Tetramethylene glycol | 110-63-4 | C4H10O2 | 详情 | 详情 |
| (VI) | 69256 | (S)-4-hydroxybutyl 2-(6-methoxynaphthalen-2-yl)propanoate | C18H22O4 | 详情 | 详情 | |
| (VII) | 69257 | (S)-4-((methylsulfonyl)oxy)butyl 2-(6-methoxynaphthalen-2-yl)propanoate | C19H24O6S | 详情 | 详情 |