【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% |
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 |