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【结 构 式】 
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【分子编号】52240 【品名】5-hydroxy-1-benzothiophene-3-carboxylic acid 【CA登记号】 |
【 分 子 式 】C9H6O3S 【 分 子 量 】194.21084 【元素组成】C 55.66% H 3.11% O 24.71% S 16.51% |
合成路线1
该中间体在本合成路线中的序号：(I)5-Hydroxybenzothiophene-3-carboxylic acid (I) was esterified with acetic anhydride in pyridine to afford the 5-acetoxy derivative (II). Treatment of (II) with thionyl chloride produced acid chloride (III), which was condensed with the previously reported bicyclic amine (IV), yielding amide (V). The ester groups of (V) were finally hydrolyzed under basic conditions to furnish the target compound.
| 【1】 Tsuri, T.; Honma, T.; Hiramatsu, Y.; Okada, T.; Hashizume, H.; Mitsumori, S.; Inagaki, M.; Arimura, A.; Yasui, K.; Asanuma, F.; Kishino, J.; Ohtani, M.; Bicyclo[2.2.1]heptane and 6,6-dimethylbicyclo[3.1.1]heptane derivatives: Orally active, potent, and selective prostaglandin D2 receptor antagonists. J Med Chem 1997, 40, 22, 3504. |
| 【2】 Arimura, A.; Honma, T.; Hiramatsu, Y. (Shionogi & Co. Ltd.); Benzothiophenecarboxamide derivs. and PGD2 antagonists comprising them. EP 0944614; JP 2000514824; US 6083974; WO 9825919 . |
| 【3】 Arimura, A. (Shionogi & Co. Ltd.); Remedies for itching containing PGD2 antagonists. EP 1084711; WO 9962555 . |
| 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) | 52240 | 5-hydroxy-1-benzothiophene-3-carboxylic acid | C9H6O3S | 详情 | 详情 | |
| (II) | 52241 | 5-(acetyloxy)-1-benzothiophene-3-carboxylic acid | C11H8O4S | 详情 | 详情 | |
| (III) | 52242 | 3-(chlorocarbonyl)-1-benzothiophen-5-yl acetate | C11H7ClO3S | 详情 | 详情 | |
| (IV) | 52243 | methyl (Z)-7-[(1R,2R,3S,5R)-2-amino-6,6-dimethylbicyclo[3.1.1]hept-3-yl]-5-heptenoate | C17H29NO2 | 详情 | 详情 | |
| (V) | 52244 | methyl 7-[2-({[5-(acetyloxy)-1-benzothiophen-3-yl]carbonyl}amino)-6,6-dimethylbicyclo[3.1.1]hept-3-yl]-5-heptenoate | C28H35NO5S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)In an alternative method, (-)-myrtenol (VI) was heated with triethyl orthoacetate to produce an intermediate allyl vinyl ether (VII), which underwent Claisen rearrangement to the unsaturated ester (VIII). Ozonization of the olefin (VIII), followed by reductive treatment with trimethyl phosphite, furnished ketone (IX). Conversion of ketone (IX) into the required amine (XI) was effected via previous formation of either the oxime (XII) or the O-methyl oxime (X). Simultaneous reduction of the O-methyl oxime and ester functions of (X) was carried out by using NaBH4 in the presence of AlCl3 or, alternatively, with sodium metal and n-propanol, to produce the desired (2R,3R)-amino alcohol (XI) as the major diastereoisomer. Isolation of (XI) from the reaction mixture was achieved through formation of the corresponding benzoate salt. Amino alcohol (XI) was also obtained by reduction of oxime (XII) with NaBH4 in the presence of either boron trifluoride ethearate or TiCl4. Optionally, (X) was reduced in a two-step process by first conversion to alcohol (XIII) and subsequent reduction of the oxime function. Acid chloride (XIV) was prepared from 5-hydroxybenzothiophene-3-carboxylic acid (I) by sulfonylation of the phenolic hydroxyl with benzenesulfonyl chloride, followed by treatment with SOCl2. Condensation of acid chloride (XIV) with amine (XI) produced the corresponding amide (XV). The alcohol function of (XV) was oxidized to aldehyde (XVI) using NaOCl in the presence of catalytic amounts of TEMPO and KBr. Then Wittig condensation of aldehyde (XVI) with (4-carboxybutyl)triphenylphosphonium bromide (XVII), followed by basic hydrolysis of the phenylsulfonyl protecting group, gave rise to the title compound.
| 【1】 Tsuri, T.; Honma, T.; Hiramatsu, Y.; Okada, T.; Hashizume, H.; Mitsumori, S.; Inagaki, M.; Arimura, A.; Yasui, K.; Asanuma, F.; Kishino, J.; Ohtani, M.; Bicyclo[2.2.1]heptane and 6,6-dimethylbicyclo[3.1.1]heptane derivatives: Orally active, potent, and selective prostaglandin D2 receptor antagonists. J Med Chem 1997, 40, 22, 3504. |
| 【2】 Arimura, A.; Honma, T.; Hiramatsu, Y. (Shionogi & Co. Ltd.); Benzothiophenecarboxamide derivs. and PGD2 antagonists comprising them. EP 0944614; JP 2000514824; US 6083974; WO 9825919 . |
| 【3】 Arimura, A. (Shionogi & Co. Ltd.); Remedies for itching containing PGD2 antagonists. EP 1084711; WO 9962555 . |
| 【4】 Okada, T.; Honma, T.; Kakinuma, M.; Hiramatsu, Y. (Shionogi & Co. Ltd.); Process for producing benzothiophenecarboxylic acid amide derivs.. EP 1069123; WO 9950261 . |
| 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) | 52240 | 5-hydroxy-1-benzothiophene-3-carboxylic acid | C9H6O3S | 详情 | 详情 | |
| (VI) | 51423 | [(1R,5R)-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl]methanol | C10H16O | 详情 | 详情 | |
| (VII) | 52245 | (6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)methyl 1-(ethyloxy)ethenyl ether; 2-({[1-(ethyloxy)ethenyl]oxy}methyl)-6,6-dimethylbicyclo[3.1.1]hept-2-ene | C14H22O2 | 详情 | 详情 | |
| (VIII) | 52246 | ethyl 2-(6,6-dimethyl-2-methylidenebicyclo[3.1.1]hept-3-yl)acetate | C14H22O2 | 详情 | 详情 | |
| (IX) | 52247 | ethyl 2-(6,6-dimethyl-2-oxobicyclo[3.1.1]hept-3-yl)acetate | C13H20O3 | 详情 | 详情 | |
| (X) | 52248 | ethyl 2-{6,6-dimethyl-2-[(methyloxy)imino]bicyclo[3.1.1]hept-3-yl}acetate | C14H23NO3 | 详情 | 详情 | |
| (XI) | 52250 | 2-(2-amino-6,6-dimethylbicyclo[3.1.1]hept-3-yl)-1-ethanol | C11H21NO | 详情 | 详情 | |
| (XII) | 52251 | ethyl 2-[2-(hydroxyimino)-6,6-dimethylbicyclo[3.1.1]hept-3-yl]acetate | C13H21NO3 | 详情 | 详情 | |
| (XIII) | 52249 | 3-(2-hydroxyethyl)-6,6-dimethylbicyclo[3.1.1]heptan-2-one O-methyloxime | C12H21NO2 | 详情 | 详情 | |
| (XIV) | 52252 | 3-(chlorocarbonyl)-1-benzothiophen-5-yl benzenesulfonate | C15H9ClO4S2 | 详情 | 详情 | |
| (XV) | 52253 | 3-({[3-(2-hydroxyethyl)-6,6-dimethylbicyclo[3.1.1]hept-2-yl]amino}carbonyl)-1-benzothiophen-5-yl benzenesulfonate | C26H29NO5S2 | 详情 | 详情 | |
| (XVI) | 52254 | 3-({[6,6-dimethyl-3-(2-oxoethyl)bicyclo[3.1.1]hept-2-yl]amino}carbonyl)-1-benzothiophen-5-yl benzenesulfonate | C26H27NO5S2 | 详情 | 详情 | |
| (XVII) | 37404 | (3-carboxypropyl)(triphenyl)phosphonium bromide | 17857-14-6 | C22H22BrO2P | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(IX)The protected acid chloride (X) was prepared by several methods. Alkylation of 4-mercaptophenol (I) with propargyl bromide (II) gave thioether (III). The phenolic hydroxyl of (III) was subsequently protected as the sulfonate ester (IV) by treatment with benzenesulfonyl chloride. The sulfide group of (IV) was then oxidized to the sulfoxide (V) by means of in situ generated performic acid. Rearrangement of the propargyl sulfoxide (V) in refluxing DME gave rise to the 3-(hydroxymethyl)benzothiophene (VI). Oxidation of alcohol (VI) to the corresponding aldehyde (VII) by means of NaOCl in the presence of TEMPO, followed by oxidation with sodium chlorite, furnished the carboxylic acid (VIII). Alternatively, the sulfonate acid (VIII) was obtained by acylation of the known 5-hydroxybenzothiophene-3-carboxylic acid (IX) with benzenesulfonyl chloride. Conversion of acid (VIII) into acid chloride (X) was effected by chlorination with SOCl2 in the presence of a catalytic amount of DMF.
| 【1】 Arimura, A.; Honma, T.; Hiramatsu, Y. (Shionogi & Co. Ltd.); Benzothiophenecarboxamide derivs. and PGD2 antagonists comprising them. EP 0944614; JP 2000514824; US 6083974; WO 9825919 . |
| 【2】 Okada, T.; Honma, T.; Kakinuma, M.; Hiramatsu, Y. (Shionogi & Co. Ltd.); Process for producing benzothiophenecarboxylic acid amide derivs.. EP 1069123; WO 9950261 . |
| 【3】 Hiramatsu, Y.; Honma, T. (Shionogi & Co. Ltd.); Process for producing 5-hydroxybenzo[b]thiophene-3-carboxylic acid derivs.. EP 1069122; WO 9950260 . |
| 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) | 22546 | 4-sulfanylphenol | 637-89-8 | C6H6OS | 详情 | 详情 |
| (II) | 11176 | 3-Bromopropyne; 3-Bromo-1-propyne | 106-96-7 | C3H3Br | 详情 | 详情 |
| (III) | 60664 | 4-(2-propynylsulfanyl)phenol | C9H8OS | 详情 | 详情 | |
| (IV) | 60655 | (2S)-2-methyl-5-((2R,3S)-2-methyl-3-{(2S,3E)-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-2-[(triethylsilyl)oxy]-3-butenyl}oxiranyl)pentyl triethylsilyl ether; 2-methyl-4-{(E,3S)-2-methyl-4-((2S,3R)-3-methyl-3-{(4S)-4-methyl-5-[(triethylsilyl)oxy]pentyl}oxiranyl)-3-[(triethylsilyl)oxy]-1-butenyl}-1,3-thiazole | C30H57NO3SSi2 | 详情 | 详情 | |
| (V) | 60666 | 4-(2-propynylsulfinyl)phenyl benzenesulfonate | C15H12O4S2 | 详情 | 详情 | |
| (VI) | 60667 | 3-(hydroxymethyl)-1-benzothiophen-5-yl benzenesulfonate | C15H12O4S2 | 详情 | 详情 | |
| (VII) | 60668 | 3-formyl-1-benzothiophen-5-yl benzenesulfonate | C15H10O4S2 | 详情 | 详情 | |
| (VIII) | 52696 | 5-[(phenylsulfonyl)oxy]-1-benzothiophene-3-carboxylic acid | C15H10O5S2 | 详情 | 详情 | |
| (IX) | 52240 | 5-hydroxy-1-benzothiophene-3-carboxylic acid | C9H6O3S | 详情 | 详情 | |
| (X) | 52252 | 3-(chlorocarbonyl)-1-benzothiophen-5-yl benzenesulfonate | C15H9ClO4S2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(IX)The O-acetyl protected acid chloride analogue (XV) was prepared as follows. Removal of the bezenesulfonyl protecting group of (VIII) by basic hydrolysis gave hydroxythiophene (IX), which was subsequently acetylated with Ac2O in pyridine, yielding (XIV). This was then chlorinated by means of SOCl2.
| 【1】 Hiramatsu, Y.; Honma, T. (Shionogi & Co. Ltd.); Process for producing 5-hydroxybenzo[b]thiophene-3-carboxylic acid derivs.. EP 1069122; WO 9950260 . |
| 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) | 52696 | 5-[(phenylsulfonyl)oxy]-1-benzothiophene-3-carboxylic acid | C15H10O5S2 | 详情 | 详情 | |
| (IX) | 52240 | 5-hydroxy-1-benzothiophene-3-carboxylic acid | C9H6O3S | 详情 | 详情 | |
| (XIV) | 52241 | 5-(acetyloxy)-1-benzothiophene-3-carboxylic acid | C11H8O4S | 详情 | 详情 | |
| (XV) | 52242 | 3-(chlorocarbonyl)-1-benzothiophen-5-yl acetate | C11H7ClO3S | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(IX)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6
该中间体在本合成路线中的序号：(IX)Coupling of amino ester (XLIV) with carboxylic acid (IX) by means of EDC and HOBt produced the corresponding amide ester (XLV). In a related procedure, the analogous amino methyl ester (XLVI) was coupled with acid chloride (XV) to yield amide (XLVII). The title compound was then obtained by hydrolysis of the ethyl ester (XLV) with LiOH or by NaOH hydrolysis of diester (XLVII).
| 【1】 Tsuri, T.; Honma, T.; Hiramatsu, Y.; Okada, T.; Hashizume, H.; Mitsumori, S.; Inagaki, M.; Arimura, A.; Yasui, K.; Asanuma, F.; Kishino, J.; Ohtani, M.; Bicyclo[2.2.1]heptane and 6,6-dimethylbicyclo[3.1.1]heptane derivatives: Orally active, potent, and selective prostaglandin D2 receptor antagonists. J Med Chem 1997, 40, 22, 3504. |
| 【2】 Arimura, A.; Honma, T.; Hiramatsu, Y. (Shionogi & Co. Ltd.); Benzothiophenecarboxamide derivs. and PGD2 antagonists comprising them. EP 0944614; JP 2000514824; US 6083974; WO 9825919 . |
| 【3】 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 | |
| (XV) | 52242 | 3-(chlorocarbonyl)-1-benzothiophen-5-yl acetate | C11H7ClO3S | 详情 | 详情 | |
| (XLIV) | 60688 | ethyl (Z)-7-[(1R,2R,3S,5R)-2-amino-6,6-dimethylbicyclo[3.1.1]hept-3-yl]-5-heptenoate | C18H31NO2 | 详情 | 详情 | |
| (XLV) | 60689 | ethyl (Z)-7-((1R,2R,3S,5R)-2-{[(5-hydroxy-1-benzothiophen-3-yl)carbonyl]amino}-6,6-dimethylbicyclo[3.1.1]hept-3-yl)-5-heptenoate | C27H35NO4S | 详情 | 详情 | |
| (XLVI) | 52243 | methyl (Z)-7-[(1R,2R,3S,5R)-2-amino-6,6-dimethylbicyclo[3.1.1]hept-3-yl]-5-heptenoate | C17H29NO2 | 详情 | 详情 | |
| (XLVII) | 52244 | methyl 7-[2-({[5-(acetyloxy)-1-benzothiophen-3-yl]carbonyl}amino)-6,6-dimethylbicyclo[3.1.1]hept-3-yl]-5-heptenoate | C28H35NO5S | 详情 | 详情 |