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【结 构 式】 
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【分子编号】12450 【品名】Bromo(cyclopropyl)magnesium;cyclopropylmagnesium bromide;cyclopropylmagnesiumbromide 【CA登记号】23719-80-4 |
【 分 子 式 】C3H5BrMg 【 分 子 量 】145.2817 【元素组成】C 24.8% H 3.47% Br 55% Mg 16.73% |
合成路线1
该中间体在本合成路线中的序号：(IX)The synthesis of 5-hydroxytiagabine, a metabolite of tiagabine in humans, has been undertaken to confirm that it is present entirely as (E)- and (Z)-isomers of the tautomeric 5-oxo form: The bromination of 3-methylthiophene (I) with N-bromosuccinimide gives 2-bromo-3-methylthiophene (II), which is chlorinated with N-chlorosuccinimide to yield 2-bromo-5-chloro-3-methylthiophene (III). The reaction of (III) with Mg affords 5-chloro-3-methylthien-2-ylmagnesium bromide (IV), which is condensed with 3-methylthiophene-2-carboxaldehyde (V) (obtained from (II) by reaction with magnesium and dimethylformamide) to give the bisthienylmethanol (VI). The oxidation of (VI) with pyridinium chlorochromate (PCC) yields the bisthienyl ketone (VII), which is treated with sodium methoxide to afford the bis(2-thienyl)ketone (VIII). The Grignard reaction of (VIII) with cyclopropylmagnesium bromide (IX) gives the trisubstituted methanol (X), which is submitted to ring opening with trimethylsilyl bromide to afford the thiophenone (XI) as a mixture of the (E)- and (Z)-isomers. The condensation of (XI) with piperidine-3(R)-carboxylic acid ethyl ester (XII) by means of K2CO3 gives 1-[4-(3-methyl-5-oxo-2,5-dihydrothien-2-ylidene)-4-(3-methyl-2-thienyl) butyl]piperidine-3(R)-carboxylic acid ethyl ester (XIII) (also as a mixture of (E)- and (Z)-isomers). Finally, this compound is hydrolyzed to the free acid in HCl medium.
| 【1】 Thogersen, H.; Chorghade, M.S.; Lee, E.C.; Andersen, K.E.; Sorensen, P.O.; Lundt, B.F.; Begtrup, M.; Lau, J.; Petersen, H.; The synthesis of novel GABA uptake inhibitors. 2. Synthesis of 5-hdroxytiagabine, a human metabolite of the GABA reuptake inhibitor tiagabine. Tetrahedron 1994, 50, 29, 8699. |
| 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) | 12442 | 3-Methylthiophene | 616-44-4 | C5H6S | 详情 | 详情 |
| (II) | 12443 | 2-Bromo-3-methylthiophene | 14282-76-9 | C5H5BrS | 详情 | 详情 |
| (III) | 12444 | 2-Bromo-5-chloro-3-methylthiophene | C5H4BrClS | 详情 | 详情 | |
| (IV) | 12445 | Bromo(5-chloro-3-methyl-2-thienyl)magnesium | C5H4BrClMgS | 详情 | 详情 | |
| (V) | 12446 | 3-Methyl-2-thiophenecarboxaldehyde; 3-Methyl-2-thiophenecarbaldehyde | 5834-16-2 | C6H6OS | 详情 | 详情 |
| (VI) | 12447 | (5-Chloro-3-methyl-2-thienyl)(3-methyl-2-thienyl)methanol | C11H11ClOS2 | 详情 | 详情 | |
| (VII) | 12448 | (5-Chloro-3-methyl-2-thienyl)(3-methyl-2-thienyl)methanone | C11H9ClOS2 | 详情 | 详情 | |
| (VIII) | 12449 | (5-Methoxy-3-methyl-2-thienyl)(3-methyl-2-thienyl)methanone | C12H12O2S2 | 详情 | 详情 | |
| (IX) | 12450 | Bromo(cyclopropyl)magnesium;cyclopropylmagnesium bromide;cyclopropylmagnesiumbromide | 23719-80-4 | C3H5BrMg | 详情 | 详情 |
| (X) | 12451 | Cyclopropyl(5-methoxy-3-methyl-2-thienyl)(3-methyl-2-thienyl)methanol | C15H18O2S2 | 详情 | 详情 | |
| (XI) | 12452 | 5-[(E)-4-Bromo-1-(3-methyl-2-thienyl)butylidene]-4-methyl-2(5H)-thiophenone | C14H15BrOS2 | 详情 | 详情 | |
| (XII) | 12453 | ethyl (3R)hexahydro-3-pyridinecarboxylate | C8H15NO2 | 详情 | 详情 | |
| (XIII) | 12454 | ethyl (3R)-1-[4-[3-methyl-5-oxo-2(5H)-thiophenylidene]-4-(3-methyl-2-thienyl)butyl]hexahydro-3-pyridinecarboxylate | C22H29NO3S2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(V)This compound has been obtained by two different ways: 1) The Grignard condensation of 3-methylthiophene-2-carbaldehyde (I) with 3-methylthiophen-2-ylmagnesium bromide (II) in ethyl ether gives the carbinol (III), which is oxidized with MnO2 in dichloromethane yielding the corresponding ketone (IV). A new Grignard condensation of (IV) with cyclopropylmagnesium bromide (V) in THF affords the carbinol (VI), which is dehydrated with simultaneous cyclopropane ring opening by means of HBr or TMS-Br in acetic acid giving 4,4-bis(3-methyl-2-thienyl)-3-butenyl bromide (VII).The condensation of (VII) with piperidine-2(R)-carboxylic acid ethyl ester (VIII) by means of K2CO3 and KI in acetone yields the ethyl ester (IX) of the target compound, which is finally hydrolyzed with NaOH in ethanol. 2) The reaction of 2-bromo-3-methylthiophene (X) with BuLi in ethyl ether gives the corresponding lithium derivative (XI), which is condensed with ethyl 4-bromobutyrate (XII) in the same solvent to afford the previously reported 4,4-bis(3-methyl-2-thienyl)-3-butenyl bromide (VII).
| 【1】 Braestrup, C.; Gronvald, F.C. (Novo Nordisk A/S); Amino acid derivs.. AU 8661336; EP 0236342; ES 8800927; JP 1987503172; US 5010090; WO 8700171 . |
| 【2】 Andersen, K.E.; et al.; The synthesis of novel GABA uptake inhibitors. 1. Elucidation of the structure-activity studies leading to the choice of (R)-1-[4, 4-bis(3-methyl-2-thienyl)-3-butenyl]-3-piperidinecarboxylic acid (tiagabine) as an anticonvulsant drug candidate. J Med Chem 1993, 36, 12, 1716. |
| 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) | 12446 | 3-Methyl-2-thiophenecarboxaldehyde; 3-Methyl-2-thiophenecarbaldehyde | 5834-16-2 | C6H6OS | 详情 | 详情 |
| (II) | 36973 | bromo(3-methyl-2-thienyl)magnesium | C5H5BrMgS | 详情 | 详情 | |
| (III) | 36974 | bis(3-methyl-2-thienyl)methanol | C11H12OS2 | 详情 | 详情 | |
| (IV) | 36975 | bis(3-methyl-2-thienyl)methanone | C11H10OS2 | 详情 | 详情 | |
| (V) | 12450 | Bromo(cyclopropyl)magnesium;cyclopropylmagnesium bromide;cyclopropylmagnesiumbromide | 23719-80-4 | C3H5BrMg | 详情 | 详情 |
| (VI) | 36976 | cyclopropyl[bis(3-methyl-2-thienyl)]methanol | C14H16OS2 | 详情 | 详情 | |
| (VII) | 36977 | 2-[4-bromo-1-(3-methyl-2-thienyl)-1-butenyl]-3-methylthiophene | C14H15BrS2 | 详情 | 详情 | |
| (VIII) | 12453 | ethyl (3R)hexahydro-3-pyridinecarboxylate | C8H15NO2 | 详情 | 详情 | |
| (IX) | 36978 | ethyl (3R)-1-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]-3-piperidinecarboxylate | C22H29NO2S2 | 详情 | 详情 | |
| (X) | 12443 | 2-Bromo-3-methylthiophene | 14282-76-9 | C5H5BrS | 详情 | 详情 |
| (XI) | 36979 | (3-methyl-2-thienyl)lithium | C5H5LiS | 详情 | 详情 | |
| (XII) | 11263 | ethyl 4-bromobutanoate; Ethyl 4-bromobutyrate | 2969-81-5 | C6H11BrO2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)Addition of cyclopropylmagnesium bromide (II) to dibenzocycloheptanone (I) afforded the carbinol adduct (III), which was further rearranged to the bromopropylidene derivative (IV) upon treatment with bromotrimethylsilane. Alkylation of ethyl (R)-nipecotate (V) with bromide (IV) gave the tertiary amine (VI). The ethyl ester group of (VI) was finally hydrolyzed under basic conditions to furnish the corresponding carboxylic acid.
| 【1】 Andersen, K.E.; Olsen, U.B.; Petersen, H.; Grønvald, F.C.; Sonnewald, U.; Jørgensen, T.K.; Andersen, H.S. (Novo Nordisk A/S); Novel heterocyclic cpds.. US 5595989; US 5668129; US 5688788; US 5693649; US 5712292; US 5721254; US 5795888; US 6043239; WO 9518793 . |
| 【2】 Olsen, U.B. (Novo Nordisk A/S); Novel method. JP 1999507947; WO 9722338 . |
| 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) | 40123 | 10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-one; Dibenzosuberone | 1210-35-1 | C15H12O | 详情 | 详情 |
| (II) | 12450 | Bromo(cyclopropyl)magnesium;cyclopropylmagnesium bromide;cyclopropylmagnesiumbromide | 23719-80-4 | C3H5BrMg | 详情 | 详情 |
| (III) | 52138 | 5-cyclopropyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ol | C18H18O | 详情 | 详情 | |
| (IV) | 52139 | 5-(3-bromopropylidene)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene | C18H17Br | 详情 | 详情 | |
| (V) | 35224 | ethyl (3S)-3-piperidinecarboxylate | C8H15NO2 | 详情 | 详情 | |
| (VI) | 52140 | ethyl (3R)-1-[3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)propyl]-3-piperidinecarboxylate | C26H31NO2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(D)The Grignard reaction of dibenzo[a,d]cyclohepta-1,4,6-triene-5-one (I) with cyclopropyl magnesium bromide (D) in THF gives 5-hydroxy-5-cyclopropyldibenzo[a,d]cyclohepta-1,4,6-triene (V), which is then treated with HBr in acetic acid to yield 5-(3-bromopropylidene)dibenzo[a,d]cyclohepta-1,4,6-triene (VI). Finally, (VI) is treated with dimethylamine (B) in benzene at 95 C. The hydroxycompound (V), obtained as before, is treated with HClO4 in dioxane to yield 5-(3-hydroxypropylidene)dibenzo[a,d]cyclohepta-1,4,6-triene (VII), which is then treated with p-toluenesulfonyl chloride in pyridine to afford the tosyl derivate (VIII). Finally, (VIII) is treated with dimethylamine (B) in benzene at 100 C.
| 【1】 Roberts, P.J.; Castañer, J.; Cyclobenzaprine. Drugs Fut 1977, 2, 5, 299. |
| 【2】 Hoffsommer, R.D. Jr.; et al.; Nouveaux derives de dibenzocycloheptenes et leur preparation. BE 0631012 . |
| 【3】 Wendler, N.L.; Dibenzocycloheptenes. BE 0633316 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (D) | 12450 | Bromo(cyclopropyl)magnesium;cyclopropylmagnesium bromide;cyclopropylmagnesiumbromide | 23719-80-4 | C3H5BrMg | 详情 | 详情 |
| (B) | 19443 | N-methylmethanamine; N,N-dimethylamine | 124-40-3 | C2H7N | 详情 | 详情 |
| (I) | 29151 | 5H-dibenzo[a,d]cyclohepten-5-one; Dibenzosuberenone | 2222-33-5 | C15H10O | 详情 | 详情 |
| (V) | 40129 | 5-cyclopropyl-5H-dibenzo[a,d]cyclohepten-5-ol | C18H16O | 详情 | 详情 | |
| (VI) | 40130 | 5-(3-bromopropylidene)-5H-dibenzo[a,d]cycloheptene | C18H15Br | 详情 | 详情 | |
| (VII) | 40131 | 3-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-propanol | C18H16O | 详情 | 详情 | |
| (VIII) | 40132 | 3-(5H-dibenzo[a,d]cyclohepten-5-ylidene)propyl 4-methylbenzenesulfonate | C25H22O3S | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(XVII)Oxidation of (4-cyclopropyl-1-naphthyl)methanol (XI) by means of MnO2 in CH2Cl2 yields 4-cyclopropyl-1-naphthaldehyde (XII), which is then treated with NH2OH·HCl or (NH2OH)2SO4 in the presence of NaOMe (generated from Na in MeOH) to give 4-cyclopropyl-1-naphthaldehyde oxime (XIII). Bromination of oxime (XIII) with NBS in acetonitrile provides the corresponding oximidoyl bromide (XIV), which is finally treated with CS(NH2)2 in the presence of Et3N in THF (I) .
Chlorination of oxime (XIII) using 1,3-dichloro-5,5-dimethylhydantoin (DDH) or trichloroisocyanuric acid (TCCA) in acetonitrile affords 4-cyclopropyl-N-hydroxynaphthalene-1-carboximidoyl chloride (XV), which is then treated with CS(NH2)2 or CH3CSNH2 in the presence of Et3N in THF .
Coupling of 1-bromonaphthalene (XVI) with cyclopropylmagnesium bromide (XVII) in the presence of NiCl2(dppp) in THF gives 1-cyclopropylnaphthalene (XVIII), which is then nitrated with NaNO2 at 0 °C to produce 1-cyclopropyl-4-nitronaphthalene (XIX). Reduction of the nitronaphthalene derivative (XIX) by means of H2 over Pd/C in EtOH yields 4-cyclopropyl-1-naphthylamine (XX), which is finally treated with CSCl2 and DIEA in CH2Cl2 at 0 °C .
| 【1】 Miner, J., Quart, B.D., Girardet, J.-L. (Ardea Biosciences, Inc.). Treatment of gout. WO 201116852. |
| 【2】 Quart, B.D., Girardet, J.-L., Gunic, E., Yeh, L.-T. (Ardea Biosciences, Inc.).Novel compounds and composition and methods of use. CA 2706858, CN 01918377, EP 2217577, JP 2011504935, KR 2010085195, US 2009197825, US 2011268801, WO 009070740. |
| 【3】 Zamansky, I., Galvin, G., Girardet, J.-L. (Ardea Biosciences, Inc.). Polymorphic, crystalline and mesophase forms of sodium 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate, and uses thereof. WO 2011085009. |
| 【4】 Liu, X., Hong, D., Wu, X. (Taizhou Hwasun Pharm. & Chem. Co., Ltd.). Method for preparing 4-cyclopropyl-1-isothiocyanonaphthalene and intermediate 4-cyclopropyl-1-naphthaldehyde oxime/halide. CN 102040546. |
| 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) | 68901 | 4-cyclopropyl-1-naphthyl isothiocyanate | 878671-95-5 | C14H11NS | 详情 | 详情 |
| (XI) | 68910 | (4-cyclopropyl-1-naphthyl)methanol | C14H14O | 详情 | 详情 | |
| (XII) | 68911 | 4-cyclopropyl-1-naphthaldehyde | C14H12O | 详情 | 详情 | |
| (XIII) | 68912 | (Z)-4-cyclopropyl-1-naphthaldehyde oxime;4-cyclopropyl-1-naphthaldehyde oxime | C14H13NO | 详情 | 详情 | |
| (XIV) | 68914 | (E)-4-cyclopropyl-N-hydroxy-1-naphthimidoyl bromide | C14H12BrNO | 详情 | 详情 | |
| (XV) | 68913 | 4-cyclopropyl-N-hydroxynaphthalene-1-carboximidoyl chloride;(E)-4-cyclopropyl-N-hydroxy-1-naphthimidoyl chloride | C14H12ClNO | 详情 | 详情 | |
| (XVI) | 10105 | 1-Bromonaphthalene | 90-11-9 | C10H7Br | 详情 | 详情 |
| (XVII) | 12450 | Bromo(cyclopropyl)magnesium;cyclopropylmagnesium bromide;cyclopropylmagnesiumbromide | 23719-80-4 | C3H5BrMg | 详情 | 详情 |
| (XVIII) | 68915 | 1-cyclopropylnaphthalene | 25033-19-6 | C13H12 | 详情 | 详情 |
| (XIX) | 68916 | 1-cyclopropyl-4-nitronaphthalene | C13H11NO2 | 详情 | 详情 | |
| (XX) | 68917 | 4-cyclopropyl-1-naphthylamine | 878671-94-4 | C13H13N | 详情 | 详情 |