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【结 构 式】 
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【分子编号】26779 【品名】1-butanesulfonyl chloride 【CA登记号】2386-60-9 |
【 分 子 式 】C4H9ClO2S 【 分 子 量 】156.63296 【元素组成】C 30.67% H 5.79% Cl 22.63% O 20.43% S 20.47% |
合成路线1
该中间体在本合成路线中的序号：(XIV)Acid (XI) was converted to the methyl ester (XII) by alkylation with iodomethane in the presence of Cs2CO3. After removal of the N-Cbz group of (XII) by catalytic hydrogenolysis, the resultant amine (XIII) was acylated by butanesulfonyl chloride (XIV) producing sulfonamide (XV). Saponification of the ester group of (XV) with LiOH gave acid (XVI). The N-Boc group of (XVI) was finally cleaved by treatment with HCl in EtOAc.
| 【1】 Egbertson, M.S.; Hartman, G.D.; Halczenko, W.; Laswell, W.L.; Duggan, M.E. (Merck & Co., Inc.); Novel sulfonamide fibrinogen receptor antagonists. WO 9319046 . |
| 【2】 Egbertson, M.S.; Laswell, W.L.; Hartman, G.D.; Duggan, M.E.; Halczenko, W. (Merck & Co., Inc.); Novel sulfonamide fibrinogen receptor antagonists. EP 0478363; EP 0743302; JP 1992288051; US 5292756 . |
| 【3】 Egbertson, M.S.; Chang, C.T.C.; Duggan, M.E.; et al.; Non-peptide fibrinogen receptor antagonists. 2. Optimization of a tyrosine template as a mimic for Arg-Gly-Asp. J Med Chem 1994, 37, 16, 2537. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XI) | 59544 | (2S)-2-{[(benzyloxy)carbonyl]amino}-3-(4-{4-[1-(tert-butoxycarbonyl)-4-piperidinyl]butoxy}phenyl)propanoic acid | C31H42N2O7 | 详情 | 详情 | |
| (XII) | 59545 | tert-butyl 4-{4-[4-((2S)-2-{[(benzyloxy)carbonyl]amino}-3-methoxy-3-oxopropyl)phenoxy]butyl}-1-piperidinecarboxylate | C32H44N2O7 | 详情 | 详情 | |
| (XIII) | 59546 | tert-butyl 4-(4-{4-[(2S)-2-amino-3-methoxy-3-oxopropyl]phenoxy}butyl)-1-piperidinecarboxylate | C24H38N2O5 | 详情 | 详情 | |
| (XIV) | 26779 | 1-butanesulfonyl chloride | 2386-60-9 | C4H9ClO2S | 详情 | 详情 |
| (XV) | 59547 | tert-butyl 4-[4-(4-{(2S)-2-[(butylsulfonyl)amino]-3-methoxy-3-oxopropyl}phenoxy)butyl]-1-piperidinecarboxylate | C28H46N2O7S | 详情 | 详情 | |
| (XVI) | 59548 | (2S)-3-(4-{4-[1-(tert-butoxycarbonyl)-4-piperidinyl]butoxy}phenyl)-2-[(butylsulfonyl)amino]propanoic acid | C27H44N2O7S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XIV)Intermediate (XI) was converted to the title compound by an alternative method, reported to provide a higher enantiomeric excess. Hydrogenolysis of the N-Cbz group of (XI) in the presence of Pd/C gave the aminoacid (XV). Subsequent acylation of (XV) with butanesulfonyl chloride (XIV) under Schotten-Baumann conditions furnished sulfonamide (XVI), which was then treated with HCl in EtOAc to remove the N-Boc protecting group.
| 【1】 Egbertson, M.S.; Chang, C.T.C.; Duggan, M.E.; et al.; Non-peptide fibrinogen receptor antagonists. 2. Optimization of a tyrosine template as a mimic for Arg-Gly-Asp. J Med Chem 1994, 37, 16, 2537. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XI) | 59544 | (2S)-2-{[(benzyloxy)carbonyl]amino}-3-(4-{4-[1-(tert-butoxycarbonyl)-4-piperidinyl]butoxy}phenyl)propanoic acid | C31H42N2O7 | 详情 | 详情 | |
| (XIV) | 26779 | 1-butanesulfonyl chloride | 2386-60-9 | C4H9ClO2S | 详情 | 详情 |
| (XV) | 59547 | tert-butyl 4-[4-(4-{(2S)-2-[(butylsulfonyl)amino]-3-methoxy-3-oxopropyl}phenoxy)butyl]-1-piperidinecarboxylate | C28H46N2O7S | 详情 | 详情 | |
| (XVI) | 59548 | (2S)-3-(4-{4-[1-(tert-butoxycarbonyl)-4-piperidinyl]butoxy}phenyl)-2-[(butylsulfonyl)amino]propanoic acid | C27H44N2O7S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XIV)Tyrosine methyl ester (XXIII) was acylated with butanesulfonyl chloride (XIV) in the presence of pyridine to produce sulfonamide (XXIV). Mitsunobu coupling of pyridinyl butanol (XX) with the phenolic compound (XXIV) furnished ether (XXV). Subsequent hydrolysis of the methyl ester group of (XXV) employing LiOH afforded acid (XXVI). The title piperidine compound was then obtained by catalytic hydrogenation of the pyridine ring of (XXVI) in the presence of Pd/C.
| 【1】 Chung, J.Y.L.; Zhao, D.; Hughes, D.L. (Merck & Co., Inc.); Process for preparing fibrinogen receptor antagonists. US 5312923; WO 9316994 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIV) | 26779 | 1-butanesulfonyl chloride | 2386-60-9 | C4H9ClO2S | 详情 | 详情 |
| (XX) | 59550 | 4-(4-pyridinyl)-1-butanol | C9H13NO | 详情 | 详情 | |
| (XXIII) | 21431 | methyl (2S)-2-amino-3-(4-hydroxyphenyl)propanoate | 1080-06-4 | C10H13NO3 | 详情 | 详情 |
| (XXIV) | 59552 | methyl (2S)-2-[(butylsulfonyl)amino]-3-(4-hydroxyphenyl)propanoate | C14H21NO5S | 详情 | 详情 | |
| (XXV) | 59553 | methyl (2S)-2-[(butylsulfonyl)amino]-3-{4-[4-(4-pyridinyl)butoxy]phenyl}propanoate | C23H32N2O5S | 详情 | 详情 | |
| (XXVI) | 59554 | (2S)-2-[(butylsulfonyl)amino]-3-{4-[4-(4-pyridinyl)butoxy]phenyl}propanoic acid | C22H30N2O5S | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XIV)In a variation of this process, L-tyrosine (XXVII) was initially protected as the bis-O-silylated derivative (XXVIII) employing N,O-bis(trimethylsilyl) trifluoroacetamide. Acylation of (XXVIII) with butanesulfonyl chloride (XIV), followed by hydrolysis of the silyl groups, gave rise to N-butanesulfonyl tyrosine (XXIX). The phenolic hydroxyl of (XXIX) was then alkylated by 4-(4-pyridinyl)butyl chloride (XXII) to produce ether (XXVI). Finally, hydrogenation of the pyridine ring furnished the target piperidine derivative, which was isolated as the corresponding hydrochloride salt.
| 【1】 Chung, J.Y.L.; Zhao, D.; Hughes, D.L. (Merck & Co., Inc.); Process for preparing fibrinogen receptor antagonists. WO 9316995 . |
| 【2】 Chung, J.Y.L.; Zhao, D.; Hughes, D.L.; Grabowski, E.E.; A practical synthesis of fibrinogen receptor antagonist MK-383 - Selective functionalization of (S)-tyrosine. Tetrahedron 1993, 49, 26, 5767. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIV) | 26779 | 1-butanesulfonyl chloride | 2386-60-9 | C4H9ClO2S | 详情 | 详情 |
| (XXII) | 59551 | 4-(4-chlorobutyl)pyridine | C9H12ClN | 详情 | 详情 | |
| (XXVI) | 59554 | (2S)-2-[(butylsulfonyl)amino]-3-{4-[4-(4-pyridinyl)butoxy]phenyl}propanoic acid | C22H30N2O5S | 详情 | 详情 | |
| (XXVII) | 48794 | (S)-(-)-Tyrosine; (S)-2-Amino-3-(4-hydroxyphenyl)propionic acid; 3-(4-Hydroxyphenyl)-L-alanine; L-(-)-Tyrosine; L-3-(4-Hydroxyphenyl)alanine; L-4-Hydroxy-17O-phenylalanine; L-beta-(p-Hydroxyphenyl)alanine; L-Hydroxy Phenyl Alanine; L-tyrosine | 60-18-4 | C9H11NO3 | 详情 | 详情 |
| (XXVIII) | 59555 | trimethylsilyl (2S)-2-amino-3-{4-[(trimethylsilyl)oxy]phenyl}propanoate | C15H27NO3Si2 | 详情 | 详情 | |
| (XXIX) | 59556 | (2S)-2-[(butylsulfonyl)amino]-3-(4-hydroxyphenyl)propanoic acid | C13H19NO5S | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(XII)1-Butanesulfonyl chloride (XII) was reacted with ammonia in acetonitrile, and the resulting sulfonamide (XIII) was then converted to the N-trimethylsilyl derivative (XIV). This was coupled with acid fluoride (XVII), (obtained from Boc-valine (XV) and cyanuric fluoride (XVI)), to provide Boc-valinesulfonamide (XVIII). The Boc group of (XVIII) was then removed by acid treatment to give (XIX). Finally, coupling of this chiral intermediate with the previously obtained racemic acid (XI) furnished the title compound as a 7:3 mixture of diastereoisomers.
| 【1】 Sakaki, J.; Murata, T.; Yuumoto, Y.; Nakamura, I.; Frueh, T.; Pitterna, T.; Iwasaki, G.; Oda, K.; Yamamura, T.; Hayakawa, K.; Discovery of IRL 3461: A novel and potent endothelin antagonist with balanced ETA/ETB affinity. Bioorg Med Chem Lett 1998, 8, 16, 2241. |
| 【2】 Fruh, T.; Pitterna, T.; Murata, T.; Svensson, L.D.; Yuumoto, Y.; Sakaki, J. (Novartis Japan KK); Antagonists of endothelin receptors. EP 0753004; JP 1997510720; US 5703106; WO 9526360 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XI) | 26778 | N-(3,5-dimethylbenzoyl)-4-(5-isoxazolyl)-N-methylphenylalanine | C22H22N2O4 | 详情 | 详情 | |
| (XII) | 26779 | 1-butanesulfonyl chloride | 2386-60-9 | C4H9ClO2S | 详情 | 详情 |
| (XIII) | 26780 | 1-butanesulfonamide | C4H11NO2S | 详情 | 详情 | |
| (XIV) | 26781 | N-(trimethylsilyl)-1-butanesulfonamide | C7H19NO2SSi | 详情 | 详情 | |
| (XV) | 19733 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutyric acid | C10H19NO4 | 详情 | 详情 | |
| (XVI) | 26782 | Cyanuric fluoride; 2,4,6-trifluoro-1,3,5-triazine | 675-14-9 | C3F3N3 | 详情 | 详情 |
| (XVII) | 26783 | tert-butyl (1S)-1-(fluorocarbonyl)-2-methylpropylcarbamate | C10H18FNO3 | 详情 | 详情 | |
| (XVIII) | 26784 | tert-butyl (1S)-1-[[(butylsulfonyl)amino]carbonyl]-2-methylpropylcarbamate | C14H28N2O5S | 详情 | 详情 | |
| (XIX) | 26785 | N-[(2S)-2-amino-3-methylbutanoyl]-1-butanesulfonamide | C9H20N2O3S | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(XII)1-Butanesulfonyl chloride (XII) was reacted with ammonia in acetonitrile, and the resulting sulfonamide (XIII) was then converted to the N-trimethylsilyl derivative (XIV). This compound was coupled with acid fluoride (XVII), (obtained from Boc-valine (XV) and cyanuric fluoride (XVI)), to provide Boc-valinesulfonamide (XVIII). The Boc group of (XVIII) was then removed by acid treatment to give (XIX). Coupling of this chiral intermediate (XIX) with racemic acid (XI) in a biphasic solvent system, with partial isomerization of acid (XI), furnished the amide (XX) as a 12:1 diastereomeric mixture. The major D,L diastereoisomer was then isolated either by preparative HPLC or by recrystallization from isopropanol.
| 【1】 Sakaki, J.; Murata, T.; Yuumoto, Y.; Nakamura, I.; Hayakawa, K.; Stereoselective synthesis of a novel and bifunctional endothelin antagonist, IRL 3630. Bioorg Med Chem Lett 1998, 8, 16, 2247. |
| 【2】 Sakaki, J.; Murata, T.; Yuumoto, Y.; Nakamura, I.; Okada, T. (Novartis Japan KK); Antagonists of endothelin receptors. JP 1999512702; WO 9711960 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XI) | 26778 | N-(3,5-dimethylbenzoyl)-4-(5-isoxazolyl)-N-methylphenylalanine | C22H22N2O4 | 详情 | 详情 | |
| (XII) | 26779 | 1-butanesulfonyl chloride | 2386-60-9 | C4H9ClO2S | 详情 | 详情 |
| (XIII) | 26780 | 1-butanesulfonamide | C4H11NO2S | 详情 | 详情 | |
| (XIV) | 26781 | N-(trimethylsilyl)-1-butanesulfonamide | C7H19NO2SSi | 详情 | 详情 | |
| (XV) | 19733 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutyric acid | C10H19NO4 | 详情 | 详情 | |
| (XVI) | 26782 | Cyanuric fluoride; 2,4,6-trifluoro-1,3,5-triazine | 675-14-9 | C3F3N3 | 详情 | 详情 |
| (XVII) | 26783 | tert-butyl (1S)-1-(fluorocarbonyl)-2-methylpropylcarbamate | C10H18FNO3 | 详情 | 详情 | |
| (XVIII) | 26784 | tert-butyl (1S)-1-[[(butylsulfonyl)amino]carbonyl]-2-methylpropylcarbamate | C14H28N2O5S | 详情 | 详情 | |
| (XIX) | 26785 | N-[(2S)-2-amino-3-methylbutanoyl]-1-butanesulfonamide | C9H20N2O3S | 详情 | 详情 | |
| (XX) | 26786 | N-[2-[((1S)-1-[[(butylsulfonyl)amino]carbonyl]-2-methylpropyl)amino]-1-[4-(5-isoxazolyl)benzyl]-2-oxoethyl]-N,3,5-trimethylbenzamide | C31H40N4O6S | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(VII)The reduction of 4-hydroxyindane-2-carboxylic acid ethyl ester (I) by means of LiAlH4 in THF gives the hydroxymethyl derivative (II), which is condensed with 3-fluoronitrobenzene (III) by means of K2CO3 in DMF to yield the diaryl ether (IV). The reduction of the nitro group of (IV) by means of H2 over Pd/C in THF/methanol affords the aniline derivative (V), which is treated with NaNO2 and H2SO4 and heated at 100 C to provide the phenol (VI). The condensation of (VI) with 4,4,4-trifluorobutylsulfonyl chloride (VII) by means of t-BuOK in THF leads to the racemic sulfonate (VIII), which is finally submitted to optical resolution by preparative chiral HPLC over Chiracel OD to furnish the target (R)-enantiomer.
| 【1】 Raddatz, S.; De Vry, J.-M.-V.; Mohrs, K.-H.; Dressel, J.; Matzke, M.; Mittendorf, J.; Mauler, F.; Schuhmacher, J.; Friedl, A.; Horvath, E.; Jork, R.; Keldenich, J.; Franz, J.; Spreyer, P.; Vöhringer, V.; Rock, M.-H. (Bayer AG); Aryl sulfonamides and analogues thereof and their use in the treatment of neurodegenerative diseases. DE 19740785; EP 0966436; JP 2001515470; US 2002072529; US 6262112; US 6573278; WO 9837061 . |
| 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) | 60546 | ethyl 4-hydroxy-2-indanecarboxylate | C12H14O3 | 详情 | 详情 | |
| (II) | 60547 | 2-(hydroxymethyl)-4-indanol | C10H12O2 | 详情 | 详情 | |
| (III) | 55147 | di(tert-butyl) (2R,4S,5R)-5-{(1R)-1-(acetylamino)-2-[(triisopropylsilyl)oxy]ethyl}-4-[(Z)-1-propenyl]-1,2-pyrrolidinedicarboxylate | C30H56N2O6Si | 详情 | 详情 | |
| (IV) | 60548 | [4-(3-nitrophenoxy)-2,3-dihydro-1H-inden-2-yl]methanol | C16H15NO4 | 详情 | 详情 | |
| (V) | 60549 | [4-(3-aminophenoxy)-2,3-dihydro-1H-inden-2-yl]methanol | C16H17NO2 | 详情 | 详情 | |
| (VI) | 60550 | 3-{[2-(hydroxymethyl)-2,3-dihydro-1H-inden-4-yl]oxy}phenol | C16H16O3 | 详情 | 详情 | |
| (VII) | 26779 | 1-butanesulfonyl chloride | 2386-60-9 | C4H9ClO2S | 详情 | 详情 |
| (VIII) | 60551 | 3-{[2-(hydroxymethyl)-2,3-dihydro-1H-inden-4-yl]oxy}phenyl 4,4,4-trifluoro-1-butanesulfonate | C20H21F3O5S | 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 condensation of 2,3-dimethylphenol (I) with 3-bromoanisole (II) by means of K2CO3 and CuO in pyridine gives the diaryl ether (III), which is demethylated by means of HBr in refluxing acetic acid to yield the phenol (IV). The condensation of (IV) with 4,4,4-trifluorobutylsulfonyl chloride (V) by means of t-BuOK in THF affords the sulfonate (VI), which is brominated by means of NBS in refluxing CCl4 to provide the bis(bromomethyl)compound (VII). The cyclization of (VII) with dimethyl malonate (VIII) by means of K2CO3 in refluxing butanone furnishes the indane-dicarboxylate (IX), which is hydrolyzed and monodecarboxylated by means of HBr in refluxing acetic acid/water to give the indane-carboxylic acid (X). The reduction of the CO2H group of (X) by means of BH3/Me2S in THF yields the racemic hydroxymethyl derivative (XI), which is finally submitted to optical resolution by means of chiral preparative HPLC over Chiracel OD to provide the target (R)-enantiomer.
| 【1】 Dressel, J.; Matzke, M.; Mittendorf, J.; De Vry, J.-M.V.; Mauler, F.; Friedl, A.; Horvath, E.; Keldenich, J.; Franz, J.; Spreyer, P.; Vöhringer, V.; Rock, M.-H.; Schumacher, J. (Bayer AG); Novel aryl sulphonamide amino acid esters and analogues. CA 2341028; DE 19837627; EP 1105371; US 6545050; WO 0010968 . |
| 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) | 60555 | 4,4,4-trifluorobutyl methanesulfonate | C5H9F3O3S | 详情 | 详情 | |
| (A) | 60556 | 4,4,4-trifluoro-1-butanol | C4H7F3O | 详情 | 详情 | |
| (I) | 40074 | 2,3-dimethylphenol | 526-75-0 | C8H10O | 详情 | 详情 |
| (II) | 35983 | m-bromoanisole; 1-Bromo-3-methoxybenzene; 3-Bromoanisole; 3-Bromophenyl methyl ether | 2398-37-0 | C7H7BrO | 详情 | 详情 |
| (III) | 60552 | 3-(2,3-dimethylphenoxy)phenyl methyl ether; 1-(3-methoxyphenoxy)-2,3-dimethylbenzene | C15H16O2 | 详情 | 详情 | |
| (IV) | 60553 | 3-(2,3-dimethylphenoxy)phenol | C14H14O2 | 详情 | 详情 | |
| (V) | 26779 | 1-butanesulfonyl chloride | 2386-60-9 | C4H9ClO2S | 详情 | 详情 |
| (VI) | 60557 | 3-(2,3-dimethylphenoxy)phenyl 4,4,4-trifluoro-1-butanesulfonate | C18H19F3O4S | 详情 | 详情 | |
| (VII) | 60558 | 3-[2,3-bis(bromomethyl)phenoxy]phenyl 4,4,4-trifluoro-1-butanesulfonate | C18H17Br2F3O4S | 详情 | 详情 | |
| (VIII) | 19373 | dimethyl malonate；Methyl malonate;Propanedioic acid dimethyl ester | 108-59-8 | C5H8O4 | 详情 | 详情 |
| (IX) | 60559 | dimethyl 4-(3-{[(4,4,4-trifluorobutyl)sulfonyl]oxy}phenoxy)-1,3-dihydro-2H-indene-2,2-dicarboxylate | C23H23F3O8S | 详情 | 详情 | |
| (X) | 60560 | 4-(3-{[(4,4,4-trifluorobutyl)sulfonyl]oxy}phenoxy)-2-indanecarboxylic acid | C20H19F3O6S | 详情 | 详情 | |
| (XI) | 60551 | 3-{[2-(hydroxymethyl)-2,3-dihydro-1H-inden-4-yl]oxy}phenyl 4,4,4-trifluoro-1-butanesulfonate | C20H21F3O5S | 详情 | 详情 | |
| (C) | 60554 | 4,4,4-trifluoro-1-butanesulfenyl cyanide | C5H6F3NS | 详情 | 详情 |