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【结 构 式】 
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【分子编号】25639 【品名】4-methoxyphenylhydrosulfide; 4-methoxybenzenethiol 【CA登记号】34320-82-6 |
【 分 子 式 】C7H8OS 【 分 子 量 】140.20592 【元素组成】C 59.97% H 5.75% O 11.41% S 22.87% |
合成路线1
该中间体在本合成路线中的序号：(IV)Horner-Emmons condensation of 5-phenylpentanal (I) with phosphonate (II) in the presence of NaH yielded tert-butyl 7-phenyl-2-heptenoate (III). Subsequent Michael addition of 4-methoxythiophenol (IV) to (III) using a catalytic amount of BuLi provided thioether (V). After acid deprotection of the tert-butyl ester of (V) with TFA, the resulting carboxylic acid (VI) was converted to acid chloride (VII) and then condensed with O-(trimethylsilyl)hydroxylamine to produce hydroxamic acid (VIII). Finally, sulfide oxidation of (VIII) with Oxone furnished the target beta-sulfonylhydroxamic acid. Alternatively tet-butyl ester (III) can be hydrolyzed first to the free acid (IX) with TFA, and then condensed with thiophenol (IV) by means of piperidine to afford the previously described carboxylic acid (VI).
| 【1】 Burns, C.J.; Groneberg, R.D.; Morrissette, M.M.; et al.; Dual inhibition of phosphodiesterase 4 and matrix metalloproteinases by an (arylsulfonyl)hydroxamic acid template. J Med Chem 1999, 42, 4, 541. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 26091 | O-(trimethylsilyl)hydroxylamine; (aminooxy)(trimethyl)silane | 22737-36-6 | C3H11NOSi | 详情 | 详情 | |
| (I) | 25636 | 5-phenylpentanal | C11H14O | 详情 | 详情 | |
| (II) | 25637 | tert-butyl 2-(diethoxyphosphoryl)acetate | 6273-47-8 | C10H21O5P | 详情 | 详情 |
| (III) | 25638 | tert-butyl (E)-7-phenyl-2-heptenoate | C17H24O2 | 详情 | 详情 | |
| (IV) | 25639 | 4-methoxyphenylhydrosulfide; 4-methoxybenzenethiol | 34320-82-6 | C7H8OS | 详情 | 详情 |
| (V) | 25640 | tert-butyl 3-[(4-methoxyphenyl)sulfanyl]-7-phenylheptanoate | C24H32O3S | 详情 | 详情 | |
| (VI) | 25641 | 3-[(4-methoxyphenyl)sulfanyl]-7-phenylheptanoic acid | C20H24O3S | 详情 | 详情 | |
| (VII) | 25642 | 3-[(4-methoxyphenyl)sulfanyl]-7-phenylheptanoyl chloride | C20H23ClO2S | 详情 | 详情 | |
| (VIII) | 25643 | N-hydroxy-3-[(4-methoxyphenyl)sulfanyl]-7-phenylheptanamide | C20H25NO3S | 详情 | 详情 | |
| (IX) | 25644 | (E)-7-phenyl-2-heptenoic acid | C13H16O2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XVI)An alternative preparation of hydroxy acid (IX) has been reported. 4-Methoxythiophenol (XVI) was alkylated with propargyl benzenesulfonate (XVII) to produce the propargyl sulfide (XVIII), which was further oxidized to sulfoxide (XIX). Rearrangement of (XIX) as above, followed by sequential oxidation of the resultant benzothiophenemethanol (XX) with I2/TEMPO to aldehyde (XXI) and then with NaClO2/H2O2, furnished the carboxylic acid (XXII). Then, methyl ether cleavage by using BBr3 in toluene afforded (IX).
| 【1】 Cai, D.; Larsen, R.; Journet, M.; Campos, K. (Merck & Co., Inc.); Process for the preparation of PGD2 antagonist. WO 0232892 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IX) | 52240 | 5-hydroxy-1-benzothiophene-3-carboxylic acid | C9H6O3S | 详情 | 详情 | |
| (XVI) | 25639 | 4-methoxyphenylhydrosulfide; 4-methoxybenzenethiol | 34320-82-6 | C7H8OS | 详情 | 详情 |
| (XVII) | 60672 | 2-propynyl benzenesulfonate | C9H8O3S | 详情 | 详情 | |
| (XVIII) | 60673 | 1-methoxy-4-(2-propynylsulfanyl)benzene; methyl 4-(2-propynylsulfanyl)phenyl ether | C10H10OS | 详情 | 详情 | |
| (XIX) | 60674 | (4-methoxyphenyl)(oxo)2-propynyl-lambda~4~-sulfane; 4-methoxyphenyl 2-propynyl sulfoxide | C10H10O2S | 详情 | 详情 | |
| (XX) | 60675 | (5-methoxy-1-benzothiophen-3-yl)methanol | C10H10O2S | 详情 | 详情 | |
| (XXI) | 60676 | 5-methoxy-1-benzothiophene-3-carbaldehyde | C10H8O2S | 详情 | 详情 | |
| (XXII) | 60677 | 5-methoxy-1-benzothiophene-3-carboxylic acid | C10H8O3S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(V)The reaction of 5-phenylpentanal (I) with triethyl 2-phosphonopropionate (II) by means of NaOEt in THF gives ethyl 2-methyl-7-phenyl-2(E)-heptenoate (III), which is hydrolyzed with NaOH in methanol/water to the corresponding free acid (IV). The reaction of (IV) with 4-methoxythiophenol (V) in hot piperidine affords 3-(4-methoxyphenylsulfanyl)-2-methyl-7-phenylheptanoic acid (VI), which by reaction first with oxalyl chloride, then with O-trimethylsilylhydroxylamine (VII) in dichloromethane, and finally with HCl is converted into the hydroxamic acid (VIII). Finally, this compound is oxidized with oxone in methanol/water to provide the target compound as mixture of diastereomeric racemates that is separated by reversed phase HPLC.
| 【1】 Groneberg, R.D.; Neuenschwander, K.W.; Djuric, S.W.; McGeehan, G.M.; Burns, C.J.; Condon, S.M.; Morrissette, M.M.; Salvino, J.M.; Scotese, A.C.; Ullrich, J.W. (Aventis Pharma SA); Substd. (aryl, heteroaryl, arylmethyl or heteroarylmethyl) hydroxamic acid cpds.. EP 0871439; JP 2000503012; WO 9724117 . |
| 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) | 25636 | 5-phenylpentanal | C11H14O | 详情 | 详情 | |
| (II) | 18816 | ethyl 2-(diethoxyphosphoryl)propanoate | 3699-66-9 | C9H19O5P | 详情 | 详情 |
| (III) | 26081 | ethyl (E)-2-methyl-7-phenyl-2-heptenoate | C16H22O2 | 详情 | 详情 | |
| (IV) | 26082 | (E)-2-methyl-7-phenyl-2-heptenoic acid | C14H18O2 | 详情 | 详情 | |
| (V) | 25639 | 4-methoxyphenylhydrosulfide; 4-methoxybenzenethiol | 34320-82-6 | C7H8OS | 详情 | 详情 |
| (VI) | 26083 | 3-[(4-methoxyphenyl)sulfanyl]-2-methyl-7-phenylheptanoic acid | C21H26O3S | 详情 | 详情 | |
| (VII) | 26091 | O-(trimethylsilyl)hydroxylamine; (aminooxy)(trimethyl)silane | 22737-36-6 | C3H11NOSi | 详情 | 详情 |
| (VIII) | 26084 | N-hydroxy-3-[(4-methoxyphenyl)sulfanyl]-2-methyl-7-phenylheptanamide | C21H27NO3S | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(VI)Hydroxyacid (III) was prepared by condensation of 5-phenylpentanal (I) with the dilithium anion of propionic acid (II). Cyclization of (III) upon treatment with dipyridyl disulfide and PPh3, and then with mercuric mesylate yielded an equimolar mixture of beta-lactones (IV) and (V), from which the desired cis isomer (IV) was isolated by flash chromatography. Subsequent ring opening of (IV) with the sodium salt of 4-methoxythiophenol (VI) provided carboxylic acid (VII). This was converted to acid the corresponding chloride by means of oxalyl chloride and then condensed with O-(trimethylsilyl)hydroxylamine to produce hydroxamic acid (VIII). Finally, sulfide oxidation of (VIII) with Oxone furnished the target sulfonylhydroxamic acid.
| 【1】 Burns, C.J.; Groneberg, R.D.; Morrissette, M.M.; et al.; Dual inhibition of phosphodiesterase 4 and matrix metalloproteinases by an (arylsulfonyl)hydroxamic acid template. J Med Chem 1999, 42, 4, 541. |
| 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) | 25636 | 5-phenylpentanal | C11H14O | 详情 | 详情 | |
| (II) | 26085 | 2-Lithiopropionic acid lithium salt | C3H4Li2O2 | 详情 | 详情 | |
| (III) | 26086 | 3-hydroxy-2-methyl-7-phenylheptanoic acid | C14H20O3 | 详情 | 详情 | |
| (IV) | 26087 | (3S,4R)-3-methyl-4-(4-phenylbutyl)-2-oxetanone | C14H18O2 | 详情 | 详情 | |
| (V) | 26088 | (3R,4R)-3-methyl-4-(4-phenylbutyl)-2-oxetanone | C14H18O2 | 详情 | 详情 | |
| (VI) | 25639 | 4-methoxyphenylhydrosulfide; 4-methoxybenzenethiol | 34320-82-6 | C7H8OS | 详情 | 详情 |
| (VII) | 26089 | (2S,3R)-3-[(4-methoxyphenyl)sulfanyl]-2-methyl-7-phenylheptanoic acid | C21H26O3S | 详情 | 详情 | |
| (VIII) | 26090 | (2S,3R)-N-hydroxy-3-[(4-methoxyphenyl)sulfanyl]-2-methyl-7-phenylheptanamide | C21H27NO3S | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(IV)The reaction of L-glutamic acid di tert-butyl ester (I) with 4-nitrophenyl chloroformate (II) by means of triethylamine in dichloromethane gives the corresponding carbamate (III), which is treated with 4-methoxythiophenol (IV) in dichloromethane to afford the thiocarbamate (V). Finally, this compound is treated with HCl.
| 【1】 Browne, P.J.; Burke, P.J.; Eno-Amooquaye, E.A.; Khan, T.H.; Osborn, H.M.I.; Searle, F.; Novel inhibitors of carboxypeptidase G2 (CPG2): Potential use in antibody-directed enzyme prodrug therapy. J Med Chem 1999, 42, 6, 951. |
| 【2】 Khan, T. (Aepact Ltd.); Drug therapy. WO 9720580 . |
| 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) | 29471 | di(tert-butyl) (2S)-2-aminopentanedioate | C13H25NO4 | 详情 | 详情 | |
| (II) | 16605 | 4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene | 7693-46-1 | C7H4ClNO4 | 详情 | 详情 |
| (III) | 29472 | di(tert-butyl) (2S)-2-[[(4-nitrophenoxy)carbonyl]amino]pentanedioate | C20H28N2O8 | 详情 | 详情 | |
| (IV) | 25639 | 4-methoxyphenylhydrosulfide; 4-methoxybenzenethiol | 34320-82-6 | C7H8OS | 详情 | 详情 |
| (V) | 29473 | di(tert-butyl) (2S)-2-([[(4-methoxyphenyl)sulfanyl]carbonyl]amino)pentanedioate | C21H31NO6S | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(I)Addition of 3-methyl-2-butenoic acid (II) to 4-methoxythiophenol (I) in the presence of piperidine at 105 C afforded adduct (III). After conversion of (III) to the corresponding acid chloride (IV) with oxalyl chloride, Friedel-Crafts cyclization using SnCl4 produced thiochromanone (V). Cleavage of the methyl ether of (V) by means of BBr3 gave phenol (VI), which was converted to triflate (VII) with trifluoromethanesulfonic anhydride in pyridine. Coupling of (VII) with trimethylsilyl acetylene (VIII) using a palladium catalyst provided (IX). Subsequent desilylation of (IX) with K2CO3 in MeOH, followed by palladium-catalyzed coupling of the resulting alkyne with ethyl 4-iodobenzoate (X) afforded the diaryl acetylene (XI). Introduction of the 4-aryl group in (XI) was achieved by conversion of (XI) to vinyl triflate (XIII) upon treatment of the sodium enolate with the bis-triflimide reagent (XII), and further condensation with 4-ethyl-phenylzinc chloride (XIV) yielding (XV). Finally, basic hydrolysis of the ethyl ester (XV) furnished the target carboxylic acid.
| 【1】 Standeven, A.M.; Escobar, M.; Wang, L.; Johnson, A.T.; Chandraratna, R.A.S.; Synthesis and biological activity of high-affinity retinoic acid receptor antagonists. Bioorg Med Chem 1999, 7, 1321. |
| 【2】 Klein, E.S.; Chandraratna, R.A.; Teng, M.; Duong, T.T.; Gillett, S.J.; Beard, R.L.; Vuligonda, V.; Johnson, A.T.; Standeven, A.M.; Nagpal, S. (Allergan, Inc.); Benzopyran and benzothiopyran derivs. having retinoid antagonist-like activity. WO 9933821 . |
| 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) | 25639 | 4-methoxyphenylhydrosulfide; 4-methoxybenzenethiol | 34320-82-6 | C7H8OS | 详情 | 详情 |
| (II) | 34677 | 3-methyl-2-butenoic acid | 541-47-9 | C5H8O2 | 详情 | 详情 |
| (III) | 34678 | 3-[(4-methoxyphenyl)sulfanyl]-3-methylbutyric acid | C12H16O3S | 详情 | 详情 | |
| (IV) | 34679 | 3-[(4-methoxyphenyl)sulfanyl]-3-methylbutanoyl chloride | C12H15ClO2S | 详情 | 详情 | |
| (V) | 34680 | 6-methoxy-2,2-dimethyl-2,3-dihydro-4H-thiochromen-4-one | C12H14O2S | 详情 | 详情 | |
| (VI) | 34681 | 6-hydroxy-2,2-dimethyl-2,3-dihydro-4H-thiochromen-4-one | C11H12O2S | 详情 | 详情 | |
| (VII) | 34682 | 2,2-dimethyl-4-oxo-3,4-dihydro-2H-thiochromen-6-yl trifluoromethanesulfonate | C12H11F3O4S2 | 详情 | 详情 | |
| (VIII) | 23897 | ethynyl(trimethyl)silane；trimethylsilyl acetylene | 1066-54-2 | C5H10Si | 详情 | 详情 |
| (IX) | 34683 | 2,2-dimethyl-6-[2-(trimethylsilyl)ethynyl]-2,3-dihydro-4H-thiochromen-4-one | C16H20OSSi | 详情 | 详情 | |
| (X) | 23796 | ethyl 4-iodobenzoate | 51934-41-9 | C9H9IO2 | 详情 | 详情 |
| (XI) | 34684 | ethyl 4-[2-(2,2-dimethyl-4-oxo-3,4-dihydro-2H-thiochromen-6-yl)ethynyl]benzoate | C22H20O3S | 详情 | 详情 | |
| (XII) | 34685 | N-(5-chloro-2-pyridinyl)(trifluoro)-N-[(trifluoromethyl)sulfonyl]methanesulfonamide | 145100-51-2 | C7H3ClF6N2O4S2 | 详情 | 详情 |
| (XIII) | 34686 | ethyl 4-[2-(2,2-dimethyl-4-[[(trifluoromethyl)sulfonyl]oxy]-2H-thiochromen-6-yl)ethynyl]benzoate | C23H19F3O5S2 | 详情 | 详情 | |
| (XIV) | 34687 | chloro(4-ethylphenyl)zinc | C8H9ClZn | 详情 | 详情 | |
| (XV) | 34688 | ethyl 4-[2-[4-(4-ethylphenyl)-2,2-dimethyl-2H-thiochromen-6-yl]ethynyl]benzoate | C30H28O2S | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(VII)Phosphonate (III) was prepared by the Michaelis-Arbuzov reaction by heating a mixture of 2-chloroethyl chloromethyl ether (I) and tris(2,2,2-trifluoroethyl)phosphite (II) at 160 C. The chloroethoxy derivative (III) was then converted to the corresponding iodide (IV) by treatment with NaI under Finkelstein reaction conditions. Alkylation of 2-amino-6-chloropurine (V) with iodide (IV) in the presence of DBU furnished the phosphonyl purine (VI). The 6-chloro group of (VI) was finally displaced with p-methoxythiophenol (VII) in hot DMF, yielding the target thioether.
| 【1】 Ubasawa, M.; Kamiya, N.; Takashima, H.; Yuasa, S.; Ueda, N.; Sekiya, K. (Mitsubishi Chemical Corp.); Phosphonate nucleotide cpds.. EP 0785208; US 5840716 . |
| 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) | 36041 | 2-chloroethyl chloromethyl ether; 1-chloro-2-(chloromethoxy)ethane | 1462-33-5 | C3H6Cl2O | 详情 | 详情 |
| (II) | 52499 | Tris(2,2,2-trifluoroethyl)phosphite | C6H6F9O3P | 详情 | 详情 | |
| (III) | 52500 | bis(2,2,2-trifluoroethyl) [(2-chloroethyl)oxy]methylphosphonate | C7H10ClF6O4P | 详情 | 详情 | |
| (IV) | 52501 | bis(2,2,2-trifluoroethyl) [(2-iodoethyl)oxy]methylphosphonate | C7H10F6IO4P | 详情 | 详情 | |
| (V) | 11644 | 6-Chloro-9H-purin-2-amine; 6-Chloro-9H-purin-2-ylamine; 2-Amino-6-chloropurine | 10310-21-1 | C5H4ClN5 | 详情 | 详情 |
| (VI) | 52502 | bis(2,2,2-trifluoroethyl) {[2-(2-amino-6-chloro-9H-purin-9-yl)ethyl]oxy}methylphosphonate | C12H13ClF6N5O4P | 详情 | 详情 | |
| (VII) | 25639 | 4-methoxyphenylhydrosulfide; 4-methoxybenzenethiol | 34320-82-6 | C7H8OS | 详情 | 详情 |