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【结 构 式】 
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【药物名称】S-5751 【化学名称】(1R,2R,3S,5S)-7-[2-(5-Hydroxybenzothiophen-3-ylcarboxamido)-6,6-dimethylbicyclo[3.1.1]hept-3-yl]-5(Z)-heptenoic acid 【CA登记号】209268-36-0, 209268-44-0 (E-isomer), 209272-21-9 (enantiomer), 209268-37-1 (Na salt) 【 分 子 式 】C25H31NO4S 【 分 子 量 】441.59412 |
【开发单位】Shionogi (Originator) 【药理作用】Antiallergy/Antiasthmatic Drugs, Asthma Therapy, RESPIRATORY DRUGS, Prostanoid DP Antagonists |
合成路线1
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
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
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
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5
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6
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7
The precursor amino alcohol (XXVIII) was prepared by the following synthetic routes. Claisen orthoester rearrangement of (-)-myrtenol (XXIII) with triethyl orthoacetate at 165-195 C afforded the gamma,delta-unsaturated ester (XXIV). Subsequent ozonolysis of the exocyclic double bond gave rise to keto ester (XXV). Alternatively, keto ester (XXV) was obtained as the major diastereoisomer by alkylation of the lithium enolate of (R)-(+)-nopinone (XXVI) with ethyl bromoacetate in the presence of 1,3-dimethyl-2-imidazolidinone (DMI). Ketone (XXV) was either converted to oxime (XXVI) or to O-methyl oxime (XXVII) by treatment with hydroxylamine or O-methyl hydroxylamine, respectively. Reduction of the hydroxyimino and ester groups of (XXVI) to the key amino alcohol intermediate (XXVIII) was performed by using the combination LiAlH4/AlCl3 or with NaBH4 in the presence of several Lewis acids. The O-methyl oxime (XXVII) was directly reduced to amino alcohol (XXVIII) employing NaBH4 in the presence of boron trifluoride etherate or AlCl3 or, alternatively, with sodium metal in n-propanol. Optionally, the oxime ester (XXVII) was converted to (XXVIII) in a two step procedure, by first reduction of the ester group to alcohol (XXIX) with sodium bis(2-methoxyethoxy)aluminium hydride, and then reduction of the O-methyl oxime with sodium in n-propanol.
| 【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】 Hiramatsu, Y.; Honma, T.; Mitsumori, S. (Shionogi & Co. Ltd.); Novel process for producing bicyclic amino alcohol. EP 1193243; WO 0102334 . |
| 【3】 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 |
|---|---|---|---|---|---|---|
| (B) | 16640 | Ethyl 2-bromoacetate; Ethyl bromoacetate | 105-36-2 | C4H7BrO2 | 详情 | 详情 |
| (A) | 60678 | (1R,5S)-6,6-dimethylbicyclo[3.1.1]heptan-2-one | C9H14O | 详情 | 详情 | |
| (XXIII) | 51423 | [(1R,5R)-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl]methanol | C10H16O | 详情 | 详情 | |
| (XXIV) | 52246 | ethyl 2-(6,6-dimethyl-2-methylidenebicyclo[3.1.1]hept-3-yl)acetate | C14H22O2 | 详情 | 详情 | |
| (XXV) | 52247 | ethyl 2-(6,6-dimethyl-2-oxobicyclo[3.1.1]hept-3-yl)acetate | C13H20O3 | 详情 | 详情 | |
| (XXVI) | 52251 | ethyl 2-[2-(hydroxyimino)-6,6-dimethylbicyclo[3.1.1]hept-3-yl]acetate | C13H21NO3 | 详情 | 详情 | |
| (XXVII) | 52246 | ethyl 2-(6,6-dimethyl-2-methylidenebicyclo[3.1.1]hept-3-yl)acetate | C14H22O2 | 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 | |
| (XXIX) | 60679 | (1R,3R,5R)-3-(2-hydroxyethyl)-6,6-dimethylbicyclo[3.1.1]heptan-2-one O-methyloxime | C12H21NO2 | 详情 | 详情 |
合成路线8
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 |
合成路线9
In a further method, the lithium acetylide of 2-(propargyloxy)tetrahydropyran (XXXIV) was alkylated with 1-bromo-3-chloropropane (XXXV) to afford chloride (XXXVI). Displacement of the Cl atom of (XXXVI) with NaCN yielded nitrile (XXXVII), which was further hydrolyzed to carboxylic acid (XXXVIII) under basic conditions. Esterification of (XXXVIII) with concomitant tetrahydropyranyl group cleavage in ethanolic H2SO4 gave hydroxy ester (XXXIX). Conversion of (XXXIX) to the corresponding mesylate, followed by treatment with KI, provided ethyl 7-iodo-5-heptynoate (XL). (R)-(+)-nopinone (XXVI) was then alkylated with the propargyl iodide (XL) in the presence of LDA to afford (XLI). Conversion of (XLI) to oxime (XLII), followed by reduction with TiCl3 and BH3•t-BuNH2, provided amino ester (XLIII). Then, partial hydrogenation of the triple bond of (XLIII) over Lindlar catalyst furnished the precursor aminoalkene ester (XLIV).
| 【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 |
|---|---|---|---|---|---|---|
| (XXVI) | 60678 | (1R,5S)-6,6-dimethylbicyclo[3.1.1]heptan-2-one | C9H14O | 详情 | 详情 | |
| (XXXIV) | 43835 | 2-propynyl tetrahydro-2H-pyran-2-yl ether; 2-(2-propynyloxy)tetrahydro-2H-pyran | 6089-04-9 | C8H12O2 | 详情 | 详情 |
| (XXXV) | 10358 | 1-Bromo-3-chloropropane | 109-70-6 | C3H6BrCl | 详情 | 详情 |
| (XXXVI) | 60680 | 2-[(6-chloro-2-hexynyl)oxy]tetrahydro-2H-pyran; 6-chloro-2-hexynyl tetrahydro-2H-pyran-2-yl ether | C11H17ClO2 | 详情 | 详情 | |
| (XXXVII) | 60681 | 7-(tetrahydro-2H-pyran-2-yloxy)-5-heptynenitrile | C12H17NO2 | 详情 | 详情 | |
| (XXXVIII) | 60682 | 7-(tetrahydro-2H-pyran-2-yloxy)-5-heptynoic acid | C12H18O4 | 详情 | 详情 | |
| (XXXIX) | 60683 | ethyl 7-hydroxy-5-heptynoate | C9H14O3 | 详情 | 详情 | |
| (XL) | 60684 | ethyl 7-iodo-5-heptynoate | C9H13IO2 | 详情 | 详情 | |
| (XLI) | 60685 | ethyl 7-[(1R,3R,5R)-6,6-dimethyl-2-oxobicyclo[3.1.1]hept-3-yl]-5-heptynoate | C18H26O3 | 详情 | 详情 | |
| (XLII) | 60686 | ethyl 7-[(1R,3R,5R)-2-(hydroxyimino)-6,6-dimethylbicyclo[3.1.1]hept-3-yl]-5-heptynoate | C18H27NO3 | 详情 | 详情 | |
| (XLIII) | 60687 | ethyl 7-[(1R,2R,3R,5R)-2-amino-6,6-dimethylbicyclo[3.1.1]hept-3-yl]-5-heptynoate | C18H29NO2 | 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 |
合成路线10
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 |