|
【结 构 式】 
|
【分子编号】52252 【品名】3-(chlorocarbonyl)-1-benzothiophen-5-yl benzenesulfonate 【CA登记号】 |
【 分 子 式 】C15H9ClO4S2 【 分 子 量 】352.81876 【元素组成】C 51.06% H 2.57% Cl 10.05% O 18.14% S 18.18% |
合成路线1
该中间体在本合成路线中的序号：(XIV)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2
该中间体在本合成路线中的序号：(X)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3
该中间体在本合成路线中的序号：(X)In a different method, after protection of 5-hydroxybenzothiophene (XI) as the benzenesulfonate ester (XII), Friedel-Crafts acylation with acetyl chloride and AlCl3 gave ketone (XIII). Haloform reaction on the methyl ketone (XIII) produced the carboxylic acid (VIII), which was further converted to acid chloride (X) by treatment with SOCl2 as above.
| 【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 | |
| (X) | 52252 | 3-(chlorocarbonyl)-1-benzothiophen-5-yl benzenesulfonate | C15H9ClO4S2 | 详情 | 详情 | |
| (XI) | 60669 | 1-benzothiophen-5-ol | C8H6OS | 详情 | 详情 | |
| (XII) | 60670 | 1-benzothiophen-5-yl benzenesulfonate | C14H10O3S2 | 详情 | 详情 | |
| (XIII) | 60671 | 3-acetyl-1-benzothiophen-5-yl benzenesulfonate | C16H12O4S2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(X)Amino alcohol (XXVIII) was acylated with acid chloride (X) under Schotten-Baumann conditions to afford amide (XXX). Subsequent conversion of the primary alcohol (XXX) to aldehyde (XXXI) was accomplished by either Swern oxidation or by treatment with NaOCl in the presence of 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO). Wittig condensation of aldehyde (XXXI) with the ylide generated from (4-carboxybutyl)triphenylphosphonium bromide (XXXII) in the presence of potassium tert-butoxide furnished the Z-olefin (XXXIII). Finally, basic hydrolysis of the benzenesulfonyl protecting group of (XXXIII) yielded the title compound.
| 【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 . |
| 【4】 Cai, D.; Larsen, R.; Journet, M.; Campos, K. (Merck & Co., Inc.); Process for the preparation of PGD2 antagonist. WO 0232892 . |
| 【5】 Hiramatsu, Y.; Honma, T.; Mitsumori, S. (Shionogi & Co. Ltd.); Novel process for producing bicyclic amino alcohol. EP 1193243; WO 0102334 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (X) | 52252 | 3-(chlorocarbonyl)-1-benzothiophen-5-yl benzenesulfonate | C15H9ClO4S2 | 详情 | 详情 | |
| (XXVIII) | 52250 | 2-(2-amino-6,6-dimethylbicyclo[3.1.1]hept-3-yl)-1-ethanol | C11H21NO | 详情 | 详情 | |
| (XXX) | 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 | |
| (XXXI) | 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 | |
| (XXXII) | 23582 | (4-carboxybutyl)(triphenyl)phosphonium | C23H24O2P | 详情 | 详情 | |
| (XXXIII) | 52697 | (Z)-7-{(1R,2R,3S,5R)-6,6-dimethyl-2-[({5-[(phenylsulfonyl)oxy]-1-benzothiophen-3-yl}carbonyl)amino]bicyclo[3.1.1]hept-3-yl}-5-heptenoic acid | C31H35NO6S2 | 详情 | 详情 |