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【结 构 式】

【分子编号】11045

【品名】6,7-Dihydro-1-benzothiophen-4(5H)-one; 4-Keto-4,5,6,7-tetrahydrothianaphthene; Tetrahydrobenzo(b)thiophene-4-one

【CA登记号】13414-95-4

【 分 子 式 】C8H8OS

【 分 子 量 】152.21692

【元素组成】C 63.13% H 5.3% O 10.51% S 21.07%

与该中间体有关的原料药合成路线共 4 条

合成路线1

该中间体在本合成路线中的序号:(II)

A new synthesis of [14C]-PD-117302 has been described: The Reformatsky condensation of 4,5,6,7-tetrahydrobenzo[b]thiophen-4-one (II) with methyl [1-14C]-bromoacetate (I) by means of Zn in reflux toluene gives a mixture of methyl [1-14C]-2-(4,5,6,7-tetrahydrobenzothiophen-4-ylidene)acete (III) and methyl [1-14C]-2-(6,7-dihdyrobenzothiophen-4-yl)acetate (IV) which, without separation, are treated with Pd/C and S in refluxing N-methylpyrrolidone to afford methyl [1-14C]-2-(benzothiophen-4-yl)acetate (V). The hydrolysis of (V) with methanolic KOH yields the corresponding acid (VI), which is treated with refluxing SOCl2 to give the acyl chloride (VII). Finally, this compound is condensed with trans-1-[2-(methylamino)cyclohexyl]pyrrolidine (VIII) in dichloromethane ethyl ether.

1 Huang, C.C.; Hicks, J.L.; Butler, D.E.; Hays, S.J.; Synthesis of carbon-14 labeled PD 117,302 and PD 126,212, potential new analgesic agents. J Label Compd Radiopharm 1990, 28, 1, 15.
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) 11044 methyl 2-bromo-2-methylpropanoate; methyl 2-bromo-2-methylpropionate 23426-63-3 C5H9BrO2 详情 详情
(I) 63069 methyl 2-bromo-2-methylpropanoate C5H9BrO2 详情 详情
(II) 11045 6,7-Dihydro-1-benzothiophen-4(5H)-one; 4-Keto-4,5,6,7-tetrahydrothianaphthene; Tetrahydrobenzo(b)thiophene-4-one 13414-95-4 C8H8OS 详情 详情
(III) 11046 methyl 2-[6,7-dihydro-1-benzothiophen-4(5H)-ylidene]acetate C11H12O2S 详情 详情
(III) 63070 methyl 2-[6,7-dihydro-1-benzothiophen-4(5H)-ylidene]acetate C11H12O2S 详情 详情
(IV) 11047 methyl 2-(6,7-dihydro-1-benzothiophen-4-yl)acetate C11H12O2S 详情 详情
(IV) 63071 methyl 2-(6,7-dihydro-1-benzothiophen-4-yl)acetate C11H12O2S 详情 详情
(V) 11048 methyl 2-(1-benzothiophen-4-yl)acetate C11H10O2S 详情 详情
(V) 63072 methyl 2-(1-benzothiophen-4-yl)acetate C11H10O2S 详情 详情
(VI) 11049 2-(1-Benzothiophen-4-yl)acetic acid C10H8O2S 详情 详情
(VI) 63073 2-(1-benzothiophen-4-yl)acetic acid C10H8O2S 详情 详情
(VII) 11050 2-(1-Benzothiophen-4-yl)acetyl chloride C10H7ClOS 详情 详情
(VII) 63074 2-(1-benzothiophen-4-yl)acetyl chloride C10H7ClOS 详情 详情
(VIII) 11051 (1S,2S)-N-Methyl-2-(1-pyrrolidinyl)cyclohexanamine; N-Methyl-N-[(1S,2S)-2-(1-pyrrolidinyl)cyclohexyl]amine C11H22N2 详情 详情

合成路线2

该中间体在本合成路线中的序号:(III)

This compound has been obtained by two different ways: 1) The reaction of 4-iodo-1-tritylimidazole (I) with ethylmagnesium bromide produced the Grignard reagent (II). Subsequent addition of (II) to 4,5,6,7-tetrahydrobenzo[b]thiophen-4-one (III) afforded the tertiary alcohol (IV). Finally, acidic treatment of (IV) with methanolic HCl effected both alcohol dehydration and trityl group cleavage to yield the title compound. 2) The reaction of 4-iodo-1-tritylimidazole (I) first with ethylmagnesium bromide to give the Grignard reagent (II) and then with either Bu3SnCl or ZnCl2 gave the respective tin- or zinc-organometallic reagents (V). 4,5,6,7-Tetrahydrobenzo[b]thiophen-4-one (III) was then converted to the corresponding enol triflate (VI) by means of LDA and N-phenyltrifluoromethanesulfonimide (1) or trifluoromethanesulfonic anhydride. Subsequent coupling of (VI) with organometallic (V) in the presence of a palladium catalyst and LiCl in dioxane furnished 4-(1-tritylimidazol-4-yl)-6,7-dihydrobenzo[b]thiophene (VII), which was finally treated with methanolic HCl to perform the cleavage of the trityl group and yield the target compound.

1 Martinez, R.P.; Baxter, M.; McDonnell, M.E.; Boyd, R.E.; Connelly, C.D.; Codd, E.E.; Lewis, M.E.; Reitz, A.B.; Jetter, M.C.; Ross, T.M.; Synthesis, alpha2 adrenergic receptor binding affinity and in vivo activity of certain imidazole-substituted bicyclic thiophenes. 217th ACS Natl Meet (March 21 1999, Anaheim) 1999, Abst MEDI 111.
2 Ross, T.M.; Martinez, R.P.; Jetter, M.C.; McDonnell, M.E.; Boyd, R.E.; Raffa, R.B.; Codd, E.E.; Reitz, A.B.; Lewis, M.A.; Connelly, C.D.; alpha2 Adrenoceptor agonists as potential analgesic agents.2. Discovery of 4-(4-imidazo)-1,3-dimethyl-6,7-dihydrothianaphthene as a high-affinity ligand for the alpha2D adrenergic receptor. J Med Chem 2000, 43, 7, 1423.
3 Jetter, M.C.; Baxter, E.W.; McDonnell, M.; Ross, T.M.; Reitz, A.B.; Boyd, R.E. (Ortho-McNeil Pharmaceutical, Inc.); 4-Thionaphthyl-1H-imidazoles with alpha-2-adrenergic activity. WO 9951593 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(Va) 30219 4-(tributylstannyl)-1-trityl-1H-imidazole C34H44N2Sn 详情 详情
(Vb) 30220 chloro(1-trityl-1H-imidazol-4-yl)magnesium C22H17ClMgN2 详情 详情
(I) 30216 4-iodo-1-trityl-1H-imidazole C22H17IN2 详情 详情
(II) 30217 bromo(1-trityl-1H-imidazol-4-yl)magnesium C22H17BrMgN2 详情 详情
(III) 11045 6,7-Dihydro-1-benzothiophen-4(5H)-one; 4-Keto-4,5,6,7-tetrahydrothianaphthene; Tetrahydrobenzo(b)thiophene-4-one 13414-95-4 C8H8OS 详情 详情
(IV) 30218 4-(1-trityl-1H-imidazol-4-yl)-4,5,6,7-tetrahydro-1-benzothiophen-4-ol C30H26N2OS 详情 详情
(VI) 30221 6,7-dihydro-1-benzothiophen-4-yl trifluoromethanesulfonate C9H7F3O3S2 详情 详情
(VII) 30222 4-(6,7-dihydro-1-benzothiophen-4-yl)-1-trityl-1H-imidazole C30H24N2S 详情 详情

合成路线3

该中间体在本合成路线中的序号:(I)

Tetrahydrobenzothiophene-4-one (I) was treated with hydroxylamine to afford oxime (IIa-b) as a mixture of syn and anti isomers, which were condensed with tosyl chloride yielding the oxime O-tosylate (IIIa-b). Beckmann rearrangement of (IIIa-b) in the presence of KOAc gave rise to lactam (IV), and subsequent reduction with borane provided thienoazepine (V). Condensation of (V) with 2-chloro-4-nitrobenzoyl chloride (VI) gave amide (VII). A 7-oxo group was introduced by oxidation of (VII) with KMnO4 in acetone-water. The resulting ketone (VIII) was treated with Bredereck’s reagent to afford the dimethylaminomethylene ketone (IX). Cyclization of (IX) with hydrazine produced the tricyclic compound (X). The nitro group of (X) was then reduced to amine (XI) using stannous chloride. Coupling of (XI) with 2-biphenylcarbonyl chloride (XII) furnished the diacylated derivative (XIII). Finally, selective monodeacylation of(XIII) with NaOH yielded the title compound.

1 Mazandarani, H.; Coupet, J.; Dusza, J.P:; Chan, P.S.; Ru, X.; Delos Santos, E.G.; Albright, J.D.; The synthesis and vasopressin (AVP) antagonist activity of a novel series of N-aroyl-2,4,5,6-tetrahydropyrazolo[3,4-d]thieno[3,2-b]azepines. Bioorg Med Chem Lett 2000, 10, 8, 695.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IIa) 41567 (Z)-6,7-dihydro-1-benzothiophen-4(5H)-one oxime C8H9NOS 详情 详情
(IIb) 41568 (E)-6,7-dihydro-1-benzothiophen-4(5H)-one oxime C8H9NOS 详情 详情
(IIIa) 41569 (Z)-4-([[(4-methylphenyl)sulfonyl]oxy]imino)-6,7-dihydro-1-benzothiophene C15H15NO3S2 详情 详情
(IIIb) 41570 (E)-4-([[(4-methylphenyl)sulfonyl]oxy]imino)-4,5,6,7-tetrahydro-1-benzothiophene C15H15NO3S2 详情 详情
(I) 11045 6,7-Dihydro-1-benzothiophen-4(5H)-one; 4-Keto-4,5,6,7-tetrahydrothianaphthene; Tetrahydrobenzo(b)thiophene-4-one 13414-95-4 C8H8OS 详情 详情
(IV) 41571 4,6,7,8-tetrahydro-5H-thieno[3,2-b]azepin-5-one C8H9NOS 详情 详情
(V) 41572 5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepine 180340-57-2 C8H11NS 详情 详情
(VI) 26674 2-chloro-4-nitrobenzoyl chloride 7073-36-1 C7H3Cl2NO3 详情 详情
(VII) 41573 (2-chloro-4-nitrophenyl)(5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepin-4-yl)methanone C15H13ClN2O3S 详情 详情
(VIII) 41574 4-(2-chloro-4-nitrobenzoyl)-4,5,6,7-tetrahydro-8H-thieno[3,2-b]azepin-8-one C15H11ClN2O4S 详情 详情
(IX) 41575 4-(2-chloro-4-nitrobenzoyl)-7-[(E)-(dimethylamino)methylidene]-4,5,6,7-tetrahydro-8H-thieno[3,2-b]azepin-8-one C18H16ClN3O4S 详情 详情
(X) 41576 (2-chloro-4-nitrophenyl)[4,5-dihydropyrazolo[3,4-d]thieno[3,2-b]azepin-6(2H)-yl]methanone C16H11ClN4O3S 详情 详情
(XI) 41577 (4-amino-2-chlorophenyl)[4,5-dihydropyrazolo[3,4-d]thieno[3,2-b]azepin-6(2H)-yl]methanone C16H13ClN4OS 详情 详情
(XII) 18506 [1,1'-biphenyl]-2-carbonyl chloride C13H9ClO 详情 详情
(XIII) 41578 N-(4-[[2-([1,1'-biphenyl]-2-ylcarbonyl)-4,5-dihydropyrazolo[3,4-d]thieno[3,2-b]azepin-6(2H)-yl]carbonyl]-3-chlorophenyl)[1,1'-biphenyl]-2-carboxamide C42H29ClN4O3S 详情 详情

合成路线4

该中间体在本合成路线中的序号:(I)

Enamino ketone (II) was synthesized by treatment of benzothiophenone (I) with dimethylformamide dimethylacetal. Condensation of (II) with methyl cyanoacetate (III) led to the pyridone-fused tricyclic system (IV), which was further aromatized to (V) using 2,3-dichloro-5,6-dicyano-1,4-benzoquinone. Ester group hydrolysis in (V) under acidic conditions afforded acid (VI). This was finally decarboxylated in refluxing quinoline in the presence of copper powder.

1 Fossa, P.; et al.; Novel angular furo and thieno-quinolinones: Synthesis and preliminary photobiological studies. Bioorg Med Chem 2002, 10, 3, 743.
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) 11045 6,7-Dihydro-1-benzothiophen-4(5H)-one; 4-Keto-4,5,6,7-tetrahydrothianaphthene; Tetrahydrobenzo(b)thiophene-4-one 13414-95-4 C8H8OS 详情 详情
(II) 56091 5-[(E)-(dimethylamino)methylidene]-6,7-dihydro-1-benzothiophen-4(5H)-one C11H13NOS 详情 详情
(III) 34458 Cyanoacetic acid methyl ester; methyl 2-cyanoacetate 105-34-0 C4H5NO2 详情 详情
(IV) 56092 methyl 2-oxo-1,2,5,6-tetrahydrothieno[2,3-h]quinoline-3-carboxylate C13H11NO3S 详情 详情
(V) 56093 methyl 2-oxo-1,2-dihydrothieno[2,3-h]quinoline-3-carboxylate C13H9NO3S 详情 详情
(VI) 56094 2-oxo-1,2-dihydrothieno[2,3-h]quinoline-3-carboxylic acid C12H7NO3S 详情 详情
Extended Information