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【结 构 式】 
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【分子编号】13244 【品名】alpha-Bromo-m-tolunitrile; 3-(Bromomethyl)benzonitrile 【CA登记号】28188-41-2 |
【 分 子 式 】C8H6BrN 【 分 子 量 】196.04638 【元素组成】C 49.01% H 3.08% Br 40.76% N 7.14% |
合成路线1
该中间体在本合成路线中的序号：(VI)The condensation of p-benzyloxyaniline (I) with 1-chloro-2-hydroxy-3-methoxypropane (II) in ethanol, followed by cyclization ot the resulting amino alcohol (III) with ethyl carbonate (A) in toluene in the presence of CH3ONa and debenzylation affords a phenolic 2-oxazolidinone (V), which is alkylated with m-cyanobenzyl bromide (VI) to give cimoxatone.
| 【1】 Ancher, J.F.; Bourgery, G.; Dostert, P.; Douzon, C.; Guerret, P.; Lacour, A.; Laglois, M.; Nouvelles oxazolidinones, oxazolidinethiones et pyrrilidinones, leur procédé de préparation et leur application en thérapeutique. FR 2428032; JP 55051064; JP 56167666 . |
| 【2】 Ancher, J.F.; Cimoxatone. Drugs Fut 1984, 9, 6, 412. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 17470 | diethyl carbonate; diethylcarbonate | 105-58-8 | C5H10O3 | 详情 | 详情 |
| (I) | 22460 | 4-(benzyloxy)aniline; 4-(benzyloxy)phenylamine | C13H13NO | 详情 | 详情 | |
| (II) | 34214 | 1-chloro-3-methoxy-2-propanol | 4151-97-7 | C4H9ClO2 | 详情 | 详情 |
| (III) | 34215 | 1-[4-(benzyloxy)anilino]-3-methoxy-2-propanol | C17H21NO3 | 详情 | 详情 | |
| (IV) | 28690 | (5R)-3-[4-(benzyloxy)phenyl]-5-(methoxymethyl)-1,3-oxazolidin-2-one | C18H19NO4 | 详情 | 详情 | |
| (V) | 28682 | (5R)-3-(4-hydroxyphenyl)-5-(methoxymethyl)-1,3-oxazolidin-2-one | C11H13NO4 | 详情 | 详情 | |
| (VI) | 13244 | alpha-Bromo-m-tolunitrile; 3-(Bromomethyl)benzonitrile | 28188-41-2 | C8H6BrN | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VII)A shorter synthetic pathway is through the condensation of the above chlorohydrin (II) with m-cyanobenzyloxyaniline (X), prepared by alkylation of p-nitrophenol (VIII) with m-cyanobenzyl bromide (VII) in the presence of KI and further reduction of the nitro group with Fe-NH4Cl, then cyclization with ethyl carbonate. Cimoxatone can also be obtained by opening glycidol (XI) with m-cyanobenzyloxyaniline (X) in ethanol under reflux, and cyclizing with ethyl carbonate (A) to obtain a 5-hydroxymethyl-2-oxazolidinone (XIII), which is methylated by CH3I under phase-transfer catalysis.
| 【1】 Ancher, J.F.; Bourgery, G.; Dostert, P.; Douzon, C.; Guerret, P.; Lacour, A.; Laglois, M.; Nouvelles oxazolidinones, oxazolidinethiones et pyrrilidinones, leur procédé de préparation et leur application en thérapeutique. FR 2428032; JP 55051064; JP 56167666 . |
| 【2】 Ancher, J.F.; Cimoxatone. Drugs Fut 1984, 9, 6, 412. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 17470 | diethyl carbonate; diethylcarbonate | 105-58-8 | C5H10O3 | 详情 | 详情 |
| (II) | 34214 | 1-chloro-3-methoxy-2-propanol | 4151-97-7 | C4H9ClO2 | 详情 | 详情 |
| (VII) | 13244 | alpha-Bromo-m-tolunitrile; 3-(Bromomethyl)benzonitrile | 28188-41-2 | C8H6BrN | 详情 | 详情 |
| (VIII) | 11236 | 4-Nitrophenol; p-Nitrophenol | 100-02-7 | C6H5NO3 | 详情 | 详情 |
| (IX) | 34216 | 3-[(4-nitrophenoxy)methyl]benzonitrile | C14H10N2O3 | 详情 | 详情 | |
| (X) | 34217 | 3-[(4-aminophenoxy)methyl]benzonitrile | C14H12N2O | 详情 | 详情 | |
| (XI) | 29648 | 2-oxiranylmethanol | 556-52-5 | C3H6O2 | 详情 | 详情 |
| (XII) | 34218 | 3-([4-[(2,3-dihydroxypropyl)amino]phenoxy]methyl)benzonitrile | C17H18N2O3 | 详情 | 详情 | |
| (XIII) | 34219 | 3-([4-[5-(hydroxymethyl)-2-oxo-1,3-oxazolidin-3-yl]phenoxy]methyl)benzonitrile | C18H16N2O4 | 详情 | 详情 | |
| (XIV) | 34220 | 3-([4-[(2-hydroxy-3-methoxypropyl)amino]phenoxy]methyl)benzonitrile | C18H20N2O3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)Free radical bromination of 3-tolunitrile gives 3-cyanobenzyl bromide, which is oxidized with hexamine/acetic acid to 3-cyanobenzaldehyde. A Knoevenagel reaction with malonic acid then gives 3-cyanocinnamic acid, which is reduced to the alcohol via the acid chloride. The tetrazole ring is formed by reaction of the alcohol with sodium azide and triethylamine hydrogen chloride in dimethyl acetamide. This tetrazole group is then protected using trityl chloride and triethylamine in dichloromethane. The key chiral epoxidation is conducted using tert-butyl hydroperoxide and catalytic quantities of diisopropyl L-tartrate and titanium (IV) isopropoxide. A Swern oxidation then gives the aldehyde, which is homolagated to the trans-alpha,beta-unsaturated aldehyde using the formyl methylene ylid. This aldehyde is then reacted at -100 C with the ylid formed from n-decylphosphonium bromide and sodium bis(trimethylsilyl)amide in THF. A base catalyzed Sn2 reaction between the diene epoxide and methyl 3-thiopropionate in methanol gives the protected analogue of LY-170680. Finally, the protecting groups are removed using acid ion exchange resin followed by base hydrolysis in methanol/water. After chromatography LY-170680 is crystallized from acetone/hexane.
| 【1】 Wishart, G.; Baker, S.R.; Lucas, R.; Boot, J.R.; Sulukast. Drugs Fut 1991, 16, 5, 432. |
| 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) | 13243 | m-Tolunitrile; 3-Methylbenzonitrile | 620-22-4 | C8H7N | 详情 | 详情 |
| (II) | 13244 | alpha-Bromo-m-tolunitrile; 3-(Bromomethyl)benzonitrile | 28188-41-2 | C8H6BrN | 详情 | 详情 |
| (III) | 13245 | 3-Formylbenzonitrile; 3-Cyanobenzaldehyde | 24964-64-5 | C8H5NO | 详情 | 详情 |
| (IV) | 13246 | (E)-3-(3-Cyanophenyl)-2-propenoic acid | C10H7NO2 | 详情 | 详情 | |
| (V) | 13247 | (E)-3-(3-Cyanophenyl)-2-propenoyl chloride | C10H6ClNO | 详情 | 详情 | |
| (VI) | 13248 | 3-[(E)-3-Hydroxy-1-propenyl]benzonitrile | C10H9NO | 详情 | 详情 | |
| (VII) | 13249 | (E)-3-[3-(1H-1,2,3,4-Tetraazol-5-yl)phenyl]-2-propen-1-ol | C10H10N4O | 详情 | 详情 | |
| (VIII) | 13250 | (E)-3-[3-(2-trityl-2H-1,2,3,4-Tetraazol-5-yl)phenyl]-2-propen-1-ol | C29H24N4O | 详情 | 详情 | |
| (IX) | 13251 | [(2S,3S)-3-[3-(2-trityl-2H-1,2,3,4-Tetraazol-5-yl)phenyl]oxiranyl]methanol | C29H24N4O2 | 详情 | 详情 | |
| (X) | 13252 | (2R,3S)-3-[3-(2-trityl-2H-1,2,3,4-Tetraazol-5-yl)phenyl]-2-oxiranecarbaldehyde | C29H22N4O2 | 详情 | 详情 | |
| (XI) | 55468 | 2-(triphenylphosphoranylidene)acetaldehyde | C20H17OP | 详情 | 详情 | |
| (XII) | 13253 | (E)-3-[(2S,3S)-3-[3-(2-trityl-2H-1,2,3,4-Tetraazol-5-yl)phenyl]oxiranyl]-2-propenal | C31H24N4O2 | 详情 | 详情 | |
| (XIII) | 13254 | 5-(3-[(2S,3S)-3-[(1E,3Z)-1,3-Tridecadienyl]oxiranyl]phenyl)-2-trityl-2H-1,2,3,4-tetraazole | C41H44N4O | 详情 | 详情 | |
| (XIV) | 13255 | methyl 3-[((1R,2E,4Z)-1-[(S)-hydroxy[3-(2-trityl-2H-1,2,3,4-tetraazol-5-yl)phenyl]methyl]-2,4-tetradecadienyl)sulfanyl]propanoate | C45H52N4O3S | 详情 | 详情 | |
| (XV) | 13256 | methyl 3-[((1R,2E,4Z)-1-[(S)-hydroxy[3-(1H-1,2,3,4-tetraazol-5-yl)phenyl]methyl]-2,4-tetradecadienyl)sulfanyl]propanoate | C26H38N4O3S | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(VII)N-Boc-4-Hydroxypiperidine (I) was converted to the mesylate (II) with methanesulfonyl chloride and pyridine. Then, alkylation of 3-methyl-4-phenylpyrazole (III) with (II) in the presence of NaH yielded a mixture of regioisomeric pyrazoles (IV) and (V), which were separated using flash chromatography. The required isomer (IV) was subsequently treated with HCl in Et2O to remove the Boc protecting group. The resulting piperidine (VI) was finally alkylated with 3-(bromomethyl)benzonitrile (VII) to afford the title compound.
| 【1】 Bonner, K.; Jones, E.A.; Moore, K.W.; et al.; 4-N-Linked-heterocyclic piperidine derivatives with high affinity and selectivity for human dopamine D4 receptors. Bioorg Med Chem Lett 1999, 9, 9, 1285. |
| 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) | 18625 | tert-butyl 4-hydroxy-1-piperidinecarboxylate | C10H19NO3 | 详情 | 详情 | |
| (II) | 25308 | tert-butyl 4-[(methylsulfonyl)oxy]-1-piperidinecarboxylate | C11H21NO5S | 详情 | 详情 | |
| (III) | 25309 | 3-methyl-4-phenyl-1H-pyrazole | 3566-44-7 | C10H10N2 | 详情 | 详情 |
| (IV) | 25310 | tert-butyl 4-(5-methyl-4-phenyl-1H-pyrazol-1-yl)-1-piperidinecarboxylate | C20H27N3O2 | 详情 | 详情 | |
| (V) | 25311 | tert-butyl 4-(3-methyl-4-phenyl-1H-pyrazol-1-yl)-1-piperidinecarboxylate | C20H27N3O2 | 详情 | 详情 | |
| (VI) | 25312 | 4-(5-methyl-4-phenyl-1H-pyrazol-1-yl)piperidine | C15H19N3 | 详情 | 详情 | |
| (VII) | 13244 | alpha-Bromo-m-tolunitrile; 3-(Bromomethyl)benzonitrile | 28188-41-2 | C8H6BrN | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(XIII)Aminopiperidine (I) was alkylated with 2-bromopropiophenone (VII), and the resulting unstable aminoketone (VIII) was treated with benzoyl isocyanate to produce the benzoyl urea (IX). Cyclization of (IX), followed by benzoyl group cleavage upon treatment with methanolic NaOMe gave the hydroxy imidazolinone (X). This was dehydrated to the imidazolone (V) by means of trifluoroacetic acid. The intermediate (V) was debenzylated to (XII) by reaction with 1-chloroethyl chloroformate, followed by treatment of the resulting (1-chloroethyl) carbamate (XI) with boiling MeOH. The debenzylated piperidine (XII) was finally alkylated with alpha-bromo-m-tolunitrile (XIII) to give the target m-cyanobenzyl derivative.
| 【1】 Carling, R.W.; Moyes, C.R.; Moore, K.W.; et al.; 1-(3-Cyanobenzylpiperidin-4-yl)-5-methyl-4-phenyl-1, 3-dihydroimidazol-2-one: A selective high-affinity antagonist for the human dopamine D(4) receptor with excellent selectivity over ion channels. J Med Chem 1999, 42, 14, 2706. |
| 【2】 Carling, W.R.; Moore, K.W. (Merck Sharp & Dohme Ltd.); Imidazolone and oxazolone derivs. as dopamine antagonists. EP 0719264; JP 1997504272; US 5698573; WO 9507904 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 22014 | 1-chloro-1-[(chlorocarbonyl)oxy]ethane | 50893-53-3 | C3H4Cl2O2 | 详情 | 详情 | |
| 40601 | benzoyl isocyanate | 4461-33-0 | C8H5NO2 | 详情 | 详情 | |
| (I) | 34808 | 1-Benzyl-4-piperidinylamine; 1-Benzyl-4-piperidinamine; 4-Amino-1-benzylpiperidine | 50541-93-0 | C12H18N2 | 详情 | 详情 |
| (V) | 34812 | 1-(1-benzyl-4-piperidinyl)-5-methyl-4-phenyl-1,3-dihydro-2H-imidazol-2-one | C22H25N3O | 详情 | 详情 | |
| (VII) | 34814 | 2-bromo-1-phenyl-1-propanone | 2114-00-3 | C9H9BrO | 详情 | 详情 |
| (VIII) | 34815 | 2-[(1-benzyl-4-piperidinyl)amino]-1-phenyl-1-propanone | C21H26N2O | 详情 | 详情 | |
| (IX) | 34816 | N'-benzoyl-N-(1-benzyl-4-piperidinyl)-N-(1-methyl-2-oxo-2-phenylethyl)urea | C29H31N3O3 | 详情 | 详情 | |
| (X) | 34817 | 1-(1-benzyl-4-piperidinyl)-4-hydroxy-5-methyl-4-phenyl-2-imidazolidinone | C22H27N3O2 | 详情 | 详情 | |
| (XI) | 34818 | 1-chloroethyl 4-(5-methyl-2-oxo-4-phenyl-2,3-dihydro-1H-imidazol-1-yl)-1-piperidinecarboxylate | C18H22ClN3O3 | 详情 | 详情 | |
| (XII) | 34819 | 5-methyl-4-phenyl-1-(4-piperidinyl)-1,3-dihydro-2H-imidazol-2-one | C15H19N3O | 详情 | 详情 | |
| (XIII) | 13244 | alpha-Bromo-m-tolunitrile; 3-(Bromomethyl)benzonitrile | 28188-41-2 | C8H6BrN | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(VIII)Protection of methyl (R)-3-aminobutyrate (VI) with di-tert-butyl dicarbonate provided the Boc derivative (VII), which was alkylated with 3-cyanobenzyl bromide (VIII) in the presence of lithium bis(trimethylsilyl)amide at -78 C to afford adduct (IX). Acid deprotection of the Boc group of (IX) yielded amino ester (X). Alternatively, (X) was obtained by protection of methyl 3-aminobutyrate (VI) with benzyl chloroformate, followed by alkylation with 3-cyanobenzyl bromide to give (XI). The carbobenzoxy group of (XI) was then deprotected by hydrogenation over Pd/C. Coupling of amino ester (X) with acid chloride (V) gave rise to amide (XII). Conversion of (XII) to the required amidine was then achieved by treatment with methanolic HCl, followed by reaction of the resulting imidate with ammonia in boiling MeOH. The title compound was isolated after conversion to the trifluoroacetate salt.
| 【1】 Gong, Y.; Guertin, K.R.; McGarry, D.G.; Pauls, H.W.; Klein, S.I.; Spada, A.P. (Aventis Pharmaceuticals, Inc.); Substd. N-[(aminoiminomethyl or aminomethyl)phenyl]propyl amides. CA 2264556; EP 0931060; WO 9900356 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 10101 | Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene | 501-53-1 | C8H7ClO2 | 详情 | 详情 | |
| (V) | 38455 | 3',4'-dimethoxy[1,1'-biphenyl]-4-carbonyl chloride | C15H13ClO3 | 详情 | 详情 | |
| (VI) | 38456 | methyl (3R)-3-aminobutanoate | C5H11NO2 | 详情 | 详情 | |
| (VII) | 38457 | methyl (3R)-3-[(tert-butoxycarbonyl)amino]butanoate | C10H19NO4 | 详情 | 详情 | |
| (VIII) | 13244 | alpha-Bromo-m-tolunitrile; 3-(Bromomethyl)benzonitrile | 28188-41-2 | C8H6BrN | 详情 | 详情 |
| (IX) | 38458 | methyl (2R,3R)-3-[(tert-butoxycarbonyl)amino]-2-(3-cyanobenzyl)butanoate | C18H24N2O4 | 详情 | 详情 | |
| (X) | 38459 | methyl (2R,3R)-3-amino-2-(3-cyanobenzyl)butanoate | C13H16N2O2 | 详情 | 详情 | |
| (XI) | 38460 | methyl (2R,3R)-3-[[(benzyloxy)carbonyl]amino]-2-(3-cyanobenzyl)butanoate | C21H22N2O4 | 详情 | 详情 | |
| (XII) | 38461 | methyl (2R,3R)-2-(3-cyanobenzyl)-3-[[(3',4'-dimethoxy[1,1'-biphenyl]-4-yl)carbonyl]amino]butanoate | C28H28N2O5 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(III)Methyl (R)-3-aminobutyrate (I) is protected as the N-Boc derivative (II) using di-tert-butyl dicarbonate. Diastereoselective alkylation of the lithium enolate of (II) with 3-cyanobenzyl bromide (III) yields adduct (IV). Deprotection of (IV) is then effected by treatment with trifluoroacetic acid, to afford amino ester (V). Alternatively, aminobutyrate (I) is protected as the N-(benzyloxycarbonyl) derivative (VI), which is then alkylated with 3-cyanobenzyl bromide (III) to give (VII). Catalytic hydrogenolysis of (VII) in the presence of Pd/C yields the target intermediate (V).
| 【1】 Guertin, K.R.; Klein, S.I.; Spada, A.P. (Aventis Pharma SA); Substd. N-[(aminoiminomethyl or aminomethyl)phenyl]propyl amides. EP 0906094; JP 2000502710; US 6080767; WO 9724118 . |
| 【2】 Gong, Y.; Guertin, K.R.; McGarry, D.G.; Pauls, H.W.; Klein, S.I.; Spada, A.P. (Aventis Pharmaceuticals, Inc.); Substd. N-[(aminoiminomethyl or aminomethyl)phenyl]propyl amides. CA 2264556; EP 0931060; WO 9900356 . |
| 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) | 38456 | methyl (3R)-3-aminobutanoate | C5H11NO2 | 详情 | 详情 | |
| (II) | 38457 | methyl (3R)-3-[(tert-butoxycarbonyl)amino]butanoate | C10H19NO4 | 详情 | 详情 | |
| (III) | 13244 | alpha-Bromo-m-tolunitrile; 3-(Bromomethyl)benzonitrile | 28188-41-2 | C8H6BrN | 详情 | 详情 |
| (IV) | 38458 | methyl (2R,3R)-3-[(tert-butoxycarbonyl)amino]-2-(3-cyanobenzyl)butanoate | C18H24N2O4 | 详情 | 详情 | |
| (V) | 38459 | methyl (2R,3R)-3-amino-2-(3-cyanobenzyl)butanoate | C13H16N2O2 | 详情 | 详情 | |
| (VI) | 58216 | methyl (3R)-3-{[(benzyloxy)carbonyl]amino}butanoate | C13H17NO4 | 详情 | 详情 | |
| (VII) | 38460 | methyl (2R,3R)-3-[[(benzyloxy)carbonyl]amino]-2-(3-cyanobenzyl)butanoate | C21H22N2O4 | 详情 | 详情 |