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【结 构 式】 
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【分子编号】35657 【品名】bromo(4-methylphenyl)magnesium 【CA登记号】4294-57-9 |
【 分 子 式 】C7H7BrMg 【 分 子 量 】195.34158 【元素组成】C 43.04% H 3.61% Br 40.9% Mg 12.44% |
合成路线1
该中间体在本合成路线中的序号：2-Methoxybenzoic acid (I) was protected as the oxazoline (II). Further coupling with tolylmagnesium bromide, followed by acid hydrolysis of the oxazoline provided the intermediate biphenyl carboxylic acid (III).
| 【1】 Hosogai, N.; Tanaka, H.; Tomita, M.; Ohkawa, T.; Hemmi, K.; Setoi, H.; Zenkoh, O.; Synthesis and characterization of orally active nonpeptide vasopressin V2 receptor antagonists. Chem Pharm Bull 1999, 47, 4, 501. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 35657 | bromo(4-methylphenyl)magnesium | 4294-57-9 | C7H7BrMg | 详情 | 详情 | |
| (I) | 13926 | 2-Methoxybenzoic acid; o-Methoxybenzoic Acid | 579-75-9 | C8H8O3 | 详情 | 详情 |
| (II) | 13927 | 2-(2-Methoxyphenyl)-4,4-dimethyl-2-oxazoline; 2-(2-Methoxyphenyl)-4,4-dimethyl-4,5-dihydro-1,3-oxazole; 2-(4,4-Dimethyl-4,5-dihydro-1,3-oxazol-2-yl)phenyl methyl ether | 57598-33-1 | C12H15NO2 | 详情 | 详情 |
| (III) | 16915 | 4'-methyl[1,1'-biphenyl]-2-carboxylic acid | 7148-03-0 | C14H12O2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)Addition of 4-tolylmagnesium bromide (II) to 2,3-pyridinedicarboxylic acid anhydride (I) afforded ketoacid (III). Subsequent condensation of (III) with diethyl bromomalonate (VII) in the presence of Et3N, followed by DBU-promoted cyclization produced the pyridine lactone (VI). In an alternative procedure, acid (III) was converted to acid chloride (IV) using SOCl2, and then condensed with diethyl hydroxymalonate (V) in the presence of NaH to give (VI). The tertiary alcohol group of (VI) was then dehydrated with HCl in AcOH to give (VIII). Acid chloride (IX), prepared by treatment of (VIII) with SOCl2, was coupled with 3,5-bis(trifluoromethyl)benzylamine (X) to furnish amide (XI). The tetrahydropyranyl-protected aminoalcohol (XIII) was obtained by reduction of nitrile (XII) with LiAlH4. Reaction of (XIII) with lactone (XI), followed by treatment with DBU, produced the 1,7-naphthyridine system (XIV). Acid-catalyzed deprotection of the tetrahydropyranyl group yielded alcohol (XV).
| 【1】 Tanaka, T.; Kawada, M.; Ishichi, Y.; Kamo, I.; Ishimaru, T.; Fujishima, A.; Ikeura, Y.; Natsugari, H.; Doi, T.; Kasahara, F.; Axially chiral 1,7-naphthyridine-6-carboxamide derivatives as orally active tachykinin NK1 receptor antagonists: Synthesis, antagonistic activity, and effects on bladder functions. J Med Chem 1999, 42, 19, 3982. |
| 【2】 Natsugari, H.; Ishimaru, T.; Doi, T.; Ikeura, Y.; Kimura, C. (Takeda Chemical Industries, Ltd.); Cyclic cpds., their production and use as tachykinin receptor antagonists. CA 2172421; EP 0733632; JP 1997263585; JP 1997263587; US 5786352 . |
| 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) | 17247 | furo[3,4-b]pyridine-5,7-dione; 2,3-Pyridinedicarboxylic anhydride | 699-98-9 | C7H3NO3 | 详情 | 详情 |
| (II) | 35657 | bromo(4-methylphenyl)magnesium | 4294-57-9 | C7H7BrMg | 详情 | 详情 |
| (III) | 35643 | 3-(4-methylbenzoyl)-2-pyridinecarboxylic acid | C14H11NO3 | 详情 | 详情 | |
| (IV) | 35644 | 3-(4-methylbenzoyl)-2-pyridinecarbonyl chloride | C14H10ClNO2 | 详情 | 详情 | |
| (V) | 35645 | diethyl tartronate | C7H12O5 | 详情 | 详情 | |
| (VI) | 35646 | diethyl 5-hydroxy-5-(4-methylphenyl)-8-oxo-5,8-dihydro-6H-pyrano[3,4-b]pyridine-6,6-dicarboxylate | C21H21NO7 | 详情 | 详情 | |
| (VII) | 35647 | diethyl 2-bromomalonate | 685-87-0 | C7H11BrO4 | 详情 | 详情 |
| (VIII) | 35648 | 5-(4-methylphenyl)-8-oxo-8H-pyrano[3,4-b]pyridine-6-carboxylic acid | C16H11NO4 | 详情 | 详情 | |
| (IX) | 35649 | 5-(4-methylphenyl)-8-oxo-8H-pyrano[3,4-b]pyridine-6-carbonyl chloride | C16H10ClNO3 | 详情 | 详情 | |
| (X) | 35650 | [3,5-bis(trifluoromethyl)phenyl]methanamine; 3,5-bis(trifluoromethyl)benzylamine | 85068-29-7 | C9H7F6N | 详情 | 详情 |
| (XI) | 35651 | N-[3,5-bis(trifluoromethyl)benzyl]-5-(4-methylphenyl)-8-oxo-8H-pyrano[3,4-b]pyridine-6-carboxamide | C25H16F6N2O3 | 详情 | 详情 | |
| (XII) | 35652 | (3R)-3-methyl-4-(tetrahydro-2H-pyran-2-yloxy)butanenitrile | C10H17NO2 | 详情 | 详情 | |
| (XIII) | 35653 | (3R)-3-methyl-4-(tetrahydro-2H-pyran-2-yloxy)butylamine; (3R)-3-methyl-4-(tetrahydro-2H-pyran-2-yloxy)-1-butanamine | C10H21NO2 | 详情 | 详情 | |
| (XIV) | 35654 | N-[3,5-bis(trifluoromethyl)benzyl]-5-(4-methylphenyl)-7-[(3R)-3-methyl-4-(tetrahydro-2H-pyran-2-yloxy)butyl]-8-oxo-7,8-dihydro[1,7]naphthyridine-6-carboxamide | C35H35F6N3O4 | 详情 | 详情 | |
| (XV) | 35655 | N-[3,5-bis(trifluoromethyl)benzyl]-7-[(3R)-4-hydroxy-3-methylbutyl]-5-(4-methylphenyl)-8-oxo-7,8-dihydro[1,7]naphthyridine-6-carboxamide | C30H27F6N3O3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)Conjugate addition of tolylmagnesium bromide (II) to ecgonidine methyl ester (I) provided the 3-beta-tolyl tropane derivative (III). N-Dealkylation of (III) to produce the nortropane analogue (V) was carried out via acylation with trichloroethyl chloroformate, followed by reductive cleavage of the resultant trichloroethyl carbamate (IV) with Zn and HOAc. Alkylation of the secondary amine (V) with propargyl bromide (VI) afforded the corresponding propargyl amine (VII). Subsequent hydrostannylation of the propargyl group furnished the desired (E)-stannylpropenyl compound (VIII) along with the corresponding (Z)-isomer. In an improved procedure, amine (V) was alkylated with (E)-3-chloro-1-(tributylstannyl)-1-propene (IX) to yield pure (VIII). Finally, the title vinyl iodide was obtained by iododestannylation of (VIII) employing iodine in cold CHCl3.
| 【1】 Emond, P.; et al.; Synthesis and ligand bindin of nortropane derivatives: N-substituted 2beta-carbomethoxy-3beta-(4'-iodophenyl)nortropane and N-(3-iodotrop-(2E)-enyl)-2beta-carbomethoxy-3beta-(3',4'-disubstituted phenyl)nortropane. New high-affinity and selective compounds. J Med Chem 1997, 40, 9, 1366. |
| 【2】 Mauclaire, L.; Edmond, P.; Guilloteau, D.; Besnard, J.-C.; Frangin, Y. (CIS Bio International); Tropane derivs. useable in particular for in vivo detection of dopamine transporters. EP 0901491; JP 2000510141; US 6180083; WO 9743285 . |
| 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) | 21118 | methyl (1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene-2-carboxylate | C10H15NO2 | 详情 | 详情 | |
| (II) | 35657 | bromo(4-methylphenyl)magnesium | 4294-57-9 | C7H7BrMg | 详情 | 详情 |
| (III) | 50267 | methyl (1R,2S,3S,5S)-8-methyl-3-(4-methylphenyl)-8-azabicyclo[3.2.1]octane-2-carboxylate | C17H23NO2 | 详情 | 详情 | |
| (IV) | 50993 | 2-methyl 8-(2,2,2-trichloroethyl) (1R,2S,3S,5S)-3-(4-methylphenyl)-8-azabicyclo[3.2.1]octane-2,8-dicarboxylate | C19H22Cl3NO4 | 详情 | 详情 | |
| (V) | 50994 | methyl (1R,2S,3S,5S)-3-(4-methylphenyl)-8-azabicyclo[3.2.1]octane-2-carboxylate | C16H21NO2 | 详情 | 详情 | |
| (VI) | 11176 | 3-Bromopropyne; 3-Bromo-1-propyne | 106-96-7 | C3H3Br | 详情 | 详情 |
| (VII) | 50995 | tributyl[(E)-3-chloro-1-propenyl]stannane | C15H31ClSn | 详情 | 详情 | |
| (VIII) | 50996 | methyl (1R,2S,3S,5S)-3-(4-methylphenyl)-8-(2-propynyl)-8-azabicyclo[3.2.1]octane-2-carboxylate | C19H23NO2 | 详情 | 详情 | |
| (IX) | 50997 | methyl (1R,2S,3S,5S)-3-(4-methylphenyl)-8-[(E)-3-(tributylstannyl)-2-propenyl]-8-azabicyclo[3.2.1]octane-2-carboxylate | C31H51NO2Sn | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(V)Treatment of 3-oxo-6-phenylcyclohex-1-ene-1-carboxylic acid (I) with methyl iodide and DBU afforded methyl ester (II). Subsequent cycloaddition of (II) with N-n-butoxymethyl-N-(trimethylsilyl)methyl benzylamine (III) in the presence of trifluoroacetic acid gave the octahydroisoindole (IV). Addition of p-tolylmagnesium bromide (V) to the keto group of (IV) produced carbinol (VI), which was converted to the tetracyclic system (VII) by intramolecular cyclization in the presence of trifluoromethanesulfonic acid. Cleavage of the N-benzyl of (VII) group to give (VIII) was effected by transfer hydrogenation with ammonium formate and Pd/C. On the other hand, condensation of (2-methoxyphenyl)acetic acid (IX) with bis(dimethylamino)methane, followed by treatment with acetic anhydride generated the 2-arylpropenoic acid (X), which was converted to acid chloride (XI) employing oxalyl chloride and a catalytic amount of DMF. Coupling of acid chloride (XI) with the tetracyclic amine (VIII) yielded the corresponding amide (XII). The methyl ester group of (XII) was finally hydrolyzed with NaOH to the title carboxylic acid.
| 【1】 Dereu, N.; Sounigo-Thompson, F.; Commercon, A.; Martin, J.-P.; Bourzat, J.-D.; Capet, M.; Cheve, M.; Mailliet, P. (Aventis Pharma SA); Farnesyl transferase inhibitors. EP 0948483; WO 9829390 . |
| 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) | 37784 | 3-oxo-6-phenyl-1-cyclohexene-1-carboxylic acid | C13H12O3 | 详情 | 详情 | |
| (II) | 37785 | methyl 3-oxo-6-phenyl-1-cyclohexene-1-carboxylate | C14H14O3 | 详情 | 详情 | |
| (III) | 19702 | N-benzyl-N-(butoxymethyl)-N-[(trimethylsilyl)methyl]amine; N-(butoxymethyl)(phenyl)-N-[(trimethylsilyl)methyl]methanamine | C16H29NOSi | 详情 | 详情 | |
| (IV) | 37786 | methyl (4R,7aS)-2-benzyl-7-oxo-4-phenyloctahydro-3aH-isoindole-3a-carboxylate | C23H25NO3 | 详情 | 详情 | |
| (V) | 35657 | bromo(4-methylphenyl)magnesium | 4294-57-9 | C7H7BrMg | 详情 | 详情 |
| (VI) | 37787 | methyl (4R,7R,7aS)-2-benzyl-7-hydroxy-7-(4-methylphenyl)-4-phenyloctahydro-3aH-isoindole-3a-carboxylate | C30H33NO3 | 详情 | 详情 | |
| (VII) | 37788 | methyl (1R,8R,9S,13S)-11-benzyl-1-(4-methylphenyl)-11-azatetracyclo[6.5.2.0(2,7).0(9,13)]pentadeca-2,4,6-triene-9-carboxylate | C30H31NO2 | 详情 | 详情 | |
| (VIII) | 37789 | methyl (1R,8R,9S,13S)-1-(4-methylphenyl)-11-azatetracyclo[6.5.2.0(2,7).0(9,13)]pentadeca-2,4,6-triene-9-carboxylate | C23H25NO2 | 详情 | 详情 | |
| (IX) | 19706 | 2-(2-methoxyphenyl)acetic acid | 93-25-4 | C9H10O3 | 详情 | 详情 |
| (X) | 37790 | 2-(2-methoxyphenyl)acrylic acid | C10H10O3 | 详情 | 详情 | |
| (XI) | 37791 | 2-(2-methoxyphenyl)acryloyl chloride | C10H9ClO2 | 详情 | 详情 | |
| (XII) | 37792 | methyl (1R,8R,9S,13S)-11-[2-(2-methoxyphenyl)acryloyl]-1-(4-methylphenyl)-11-azatetracyclo[6.5.2.0(2,7).0(9,13)]pentadeca-2,4,6-triene-9-carboxylate | C33H33NO4 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(II)The reaction of anhydroecgonine methyl ester (I) with 4-methylphenylmagnesium bromide (II) in ethyl ether gives 3beta-(4-methylphenyl)tropane-2beta-carboxylic acid methyl ester (III), which is demethylated by reaction with 2,2,2-trichloroethyl chloroformate (IV) yielding the carbamate (V), followed by reduction with Zn/AcOH to afford the nortropane derivative (VI). The alkylation of (VI) with the tributylstannane (VII), TEA and iodine in ethanol provides the adduct (VIII), which is finally brominated with NBS in THF.
| 【1】 Clarke, R.L.; et al.; Compounds affecting the central nervous system. 4. 3beta-Phenyltropane-2-carboxylic esters and analogs. J Med Chem 1973, 16, 1, 1260-67. |
| 【2】 Carroll, F.I.; Gao, Y.; Rahman, M.A.; Abraham, P.; Parham, K.; Lewin, A.H.; Boja, J.W.; Kuhar, M.J.; Synthesis, ligand binding, QSAR, and CoMFA study of 3beta-(p-substitutedphenyl)tropane-2beta-carboxylic acid methyl esters. J Med Chem 1991, 34, 9, 2719. |
| 【3】 Helfenbein, J.; et al.; Synthesis of (E)-N-(3-bromoprop-2-enyl)-2 beta-carbomethoxy-3 beta-(4 '-tolyl) nortropane (PE2Br) and radiolabelling of [Br-76]PE2Br: A potential ligand for exploration of the dopamine transporter by PET. J Label Compd Radiopharm 1999, 42, 6, 581. |
| 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) | 40516 | methyl (1R,5R)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene-2-carboxylate | C10H15NO2 | 详情 | 详情 | |
| (II) | 35657 | bromo(4-methylphenyl)magnesium | 4294-57-9 | C7H7BrMg | 详情 | 详情 |
| (III) | 40517 | methyl (1R,2S,3S,5R)-8-methyl-3-(4-methylphenyl)-8-azabicyclo[3.2.1]octane-2-carboxylate | C17H23NO2 | 详情 | 详情 | |
| (IV) | 13664 | 1,1,1-Trichloro-2-[(chlorocarbonyl)oxy]ethane; 2,2,2-Trichloroethyl chloroformate | 17341-93-4 | C3H2Cl4O2 | 详情 | 详情 |
| (V) | 40518 | 2-methyl 8-(2,2,2-trichloroethyl) (1R,2S,3S,5R)-3-(4-methylphenyl)-8-azabicyclo[3.2.1]octane-2,8-dicarboxylate | C19H22Cl3NO4 | 详情 | 详情 | |
| (VI) | 40519 | methyl (1R,2S,3S,5R)-3-(4-methylphenyl)-8-azabicyclo[3.2.1]octane-2-carboxylate | C16H21NO2 | 详情 | 详情 | |
| (VII) | 40520 | tributyl[(E)-3-chloro-2-propenyl]stannane | C15H31ClSn | 详情 | 详情 | |
| (VIII) | 40521 | methyl (1R,2S,3S,5R)-3-(4-methylphenyl)-8-[(E)-3-(tributylstannyl)-1-propenyl]-8-azabicyclo[3.2.1]octane-2-carboxylate | C31H51NO2Sn | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(II)Conjugate addition of 4-tolylmagnesium bromide (II) to anhydroecgonine methyl ester (I) afforded regioselectively the 2-beta-carbomethoxy-3-beta-aryl tropane (III). Hydrolysis of the ester function of (III) in aqueous dioxan gave the corresponding acid (IV). Treatment of (IV) with POCl3 yielded the acid chloride (V), which was condensed with 1,3-propanediol monomesylate (VI), yielding ester (VII). Finally, nucleophilic displacement of the mesylate group of (VII) with tetrabutylammonium fluoride in refluxing THF afforded the title fluoropropyl ester.
| 【1】 Gu, X.-H.; et al.; Synthesis and biological evaluation of a series of novel N- or O-fluoroalkyl derivatives of tropane: Potential positron emission tomography (PET) imaging agents for the dopamine transporter. Bioorg Med Chem Lett 2001, 11, 23, 3049. |
| 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) | 21118 | methyl (1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene-2-carboxylate | C10H15NO2 | 详情 | 详情 | |
| (II) | 35657 | bromo(4-methylphenyl)magnesium | 4294-57-9 | C7H7BrMg | 详情 | 详情 |
| (III) | 50267 | methyl (1R,2S,3S,5S)-8-methyl-3-(4-methylphenyl)-8-azabicyclo[3.2.1]octane-2-carboxylate | C17H23NO2 | 详情 | 详情 | |
| (IV) | 50268 | (1R,2S,3S,5S)-8-methyl-3-(4-methylphenyl)-8-azabicyclo[3.2.1]octane-2-carboxylic acid | C16H21NO2 | 详情 | 详情 | |
| (V) | 50269 | (1R,2S,3S,5S)-8-methyl-3-(4-methylphenyl)-8-azabicyclo[3.2.1]octane-2-carbonyl chloride | C16H20ClNO | 详情 | 详情 | |
| (VI) | 50262 | 3-hydroxypropyl methanesulfonate | C4H10O4S | 详情 | 详情 | |
| (VII) | 50270 | 3-[(methylsulfonyl)oxy]propyl (1R,2S,3S,5S)-8-methyl-3-(4-methylphenyl)-8-azabicyclo[3.2.1]octane-2-carboxylate | C20H29NO5S | 详情 | 详情 |