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【结 构 式】 
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【分子编号】10844 【品名】4-(Chloromethyl)pyridine 【CA登记号】10445-91-7 |
【 分 子 式 】C6H6ClN 【 分 子 量 】127.57308 【元素组成】C 56.49% H 4.74% Cl 27.79% N 10.98% |
合成路线1
该中间体在本合成路线中的序号：(II)The condensation of 5-chlorosalicyialdehyde (I) with 4-chloromethylpyridine (II) by means of K2CO3 / KI in hot DMF gives 5-chloro-2-[(4-pyridyl)methoxy]benzaldehyde (III), which is cyclized by heating at 300 C to afford 5-chloro-2-(4-pyridyl)benzofurane (IV). Quaternization of (IV) with methyl iodide in hot methanol yields 1-methyl-4-(5-chloro-2-benzofuranyl)pyridinium iodide (V), which is hydrogenated with NaBH4 in methanol giving 5-chloro-2-(1-methyl-1,2,3,6-tetrahydro-4-pyridyl)benzofurane (VI). Finally, this compound is hydrogenated further with H2 over PtO2 in methanol.
| 【1】 Bernasconi, R.; Schenker, K. (Novartis Corp.); Anti-depressant benzofuranyl piperidines. CH 592656; CH 605926; DE 2408476; FR 2219781; JP 49117474; JP 58004781; US 210655 . |
| 【2】 Castaner, J.; Serradell, M.N.; Sercloremine Hydrochloride. Drugs Fut 1986, 11, 2, 126. |
| 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) | 26408 | 5-chlorosalicylaldehyde; 5-chloro-2-hydroxybenzaldehyde | 635-93-8 | C7H5ClO2 | 详情 | 详情 |
| (II) | 10844 | 4-(Chloromethyl)pyridine | 10445-91-7 | C6H6ClN | 详情 | 详情 |
| (III) | 28844 | 5-chloro-2-(4-pyridinylmethoxy)benzaldehyde | C13H10ClNO2 | 详情 | 详情 | |
| (IV) | 28845 | 4-(5-chloro-1-benzofuran-2-yl)pyridine | C13H8ClNO | 详情 | 详情 | |
| (V) | 28846 | 4-(5-chloro-1-benzofuran-2-yl)-1-methylpyridinium iodide | C14H11ClINO | 详情 | 详情 | |
| (VI) | 28847 | 4-(5-chloro-1-benzofuran-2-yl)-1-methyl-1,2,3,6-tetrahydropyridine | C14H14ClNO | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(III)Bromination of 2-hydroxy-5-methoxybenzaldehyde (I) in acetic acid / sodium acetate mixture gives bromoaldehyde (II). Condensation to the benzofuranylpyridine (IV) is achieved by heating a solution of (II) and 4-(chloromethyl)pyridine hydrochloride (III) in polyethylene glycol-400 in the presence of potassium carbonate. Quaternization of (IV) with dimethylsulfate in dichloromethane affords (V), which upon reduction with sodium borohydride gives intermediate (VI). Reduction of (VI) with platinum on charcoal in methanol/HBr solution yields the N-methylpiperidine (VII). Degradation of the N-methyl group with ethylchloroformate in toluene affords the carbamate (VIII). Final treatment of (VIII) with potassium hydroxide in n-butanol yields the free base of brofaremine, which is converted to its hydrochloride salt by treatment with hydrochloric acid in methanol.
| 【1】 Schenker, K.; Bernasconi, R. (Novartis AG); Tetrahydropyridine and piperidine derivatives and processes for the preparation thereof. DE 2653147; ES 453582; FR 2332754; GB 1565055; JP 52065277 . |
| 【2】 Waldmeier, P.C.; Schilling, W.; Brofaremine Hydrochloride. Drugs Fut 1985, 10, 5, 371. |
| 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) | 29301 | 2-hydroxy-5-methoxybenzaldehyde | 672-13-9 | C8H8O3 | 详情 | 详情 |
| (II) | 29302 | 3-bromo-2-hydroxy-5-methoxybenzaldehyde | C8H7BrO3 | 详情 | 详情 | |
| (III) | 10844 | 4-(Chloromethyl)pyridine | 10445-91-7 | C6H6ClN | 详情 | 详情 |
| (IV) | 29303 | 4-(7-bromo-5-methoxy-1-benzofuran-2-yl)pyridine | C14H10BrNO2 | 详情 | 详情 | |
| (V) | 29304 | 4-(7-bromo-5-methoxy-1-benzofuran-2-yl)-1-methylpyridinium (sulfonatooxy)methane | C16H16BrNO6S | 详情 | 详情 | |
| (VI) | 29305 | 4-(7-bromo-5-methoxy-1-benzofuran-2-yl)-1-methyl-1,2,3,6-tetrahydropyridine | C15H16BrNO2 | 详情 | 详情 | |
| (VII) | 29306 | 4-(7-bromo-5-methoxy-1-benzofuran-2-yl)-1-methylpiperidine | C15H18BrNO2 | 详情 | 详情 | |
| (VIII) | 29307 | ethyl 4-(7-bromo-5-methoxy-1-benzofuran-2-yl)-1-piperidinecarboxylate | C17H20BrNO4 | 详情 | 详情 | |
| (IX) | 11229 | 1-[(Chlorocarbonyl)oxy]ethane;ethyl carbonochloridate; Carbonchloridic acid ethyl ester;Ethyl chloroformate;Ethyl chlorocarbonate | 541-41-3 | C3H5ClO2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)1) The reaction of 4-(chloromethyl)pyridine (I) with KCN in refluxing methanol gives 2-(4-pyridyl)acetonitrile (II), which is alkylated with ethyl iodide and sodium hydride in DMF, yielding 2-(4-pyridyl)butyronitrile (III). The condensation of (III) with acrylonitrile (IV) by means of Triton B in tert-butanol affords 2-cyano-2-(4-pyridyl)hexanenitrile (V), which is finally cyclized with concentrated H2SO4 in refluxing acetic acid. 2) The alkylation of 2-(4-pyridyl)acetic acid ethyl ester (VI) with ethyl iodide and potassium tert-butoxide gives 2-(4-pyridyl)butanoic acid ethyl ester (VII), which is condensed with acrylamide (VIII) by means of potassium tert-butoxide, yielding 4-carbamoyl-2-ethyl-2-(4-pyridyl)butanoic acid ethyl ester (IX). Finally, this compound is cyclized in the presence of potassium tert-butoxide. 3) The condensation of ester (VI) with acrylonitrile (IV) in the presence of Triton B gives 4-cyano-2-(4-pyridyl)butanoic acid ethyl ester (X), which is alkylated with ethyl iodide and lithium diisopropylamide yielding 4-cyano-2-ethyl-2-(4-pyridyl)butanoic acid ethyl ester (XI). Finally, this compound is cyclized with concentrated H2SO4 in refluxing acetic acid.
| 【1】 Foster, A.B.; Jarman, M.; Taylor, G.N.; Kwan, C.-S. (Institute of Cancer Research); 2,6-Dioxopiperidine derivs., their preparation and pharmaceutical compsns. containing them. EP 0147121; GB 2151226; JP 1986500613; US 5071857; WO 8502618 . |
| 【2】 Markson, A.J.; Boss, A.M.; Clissold, D.W.; Thickitt, C.P.; Mann, J.; A concise synthesis of racemic pyridoglutethimide and its resolution using chiral stationary phase HPLC. Tetrahedron 1989, 45, 18, 6011. |
| 【3】 Jarman, M.; Griggs, L.J.; Wilman, D.E.V.; Rowlands, M.G.; Foster, A.B.; Leung, C.-S.; Analogues of 3-ethyl-3-(4-pyridyl)piperidine-2,6-dione as selective inhibitors of aromatase: Derivatives with variable 1-alkyl and 3-alkyl substituents. J Med Chem 1987, 30, 9, 1550. |
| 【4】 Sampson, P.; Taylor, G.N.; Leung, C.-S.; Rowlands, M.G.; Plevey, R.G.; Jarman, M.; Foster, A.B.; Analogues of animoglutethimide: Selective inhibition of aromatase. J Med Chem 1989, 28, 2, 200. |
| 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) | 10844 | 4-(Chloromethyl)pyridine | 10445-91-7 | C6H6ClN | 详情 | 详情 |
| (II) | 10845 | 2-(4-Pyridinyl)acetonitrile | C7H6N2 | 详情 | 详情 | |
| (III) | 10846 | 2-(4-Pyridinyl)butanenitrile | C9H10N2 | 详情 | 详情 | |
| (IV) | 10847 | Acrylonitrile | 107-13-1 | C3H3N | 详情 | 详情 |
| (V) | 10848 | 2-Ethyl-2-(4-pyridinyl)pentanedinitrile | C12H13N3 | 详情 | 详情 | |
| (VI) | 10849 | ethyl 2-(4-pyridinyl)acetate; Ethyl 4-pyridylacetate | 54401-85-3 | C9H11NO2 | 详情 | 详情 |
| (VII) | 10850 | ethyl 2-(4-pyridinyl)butanoate | C11H15NO2 | 详情 | 详情 | |
| (VIII) | 10851 | Acrylamide | 79-06-1 | C3H5NO | 详情 | 详情 |
| (IX) | 10852 | ethyl 5-amino-2-ethyl-5-oxo-2-(4-pyridinyl)pentanoate | C14H20N2O3 | 详情 | 详情 | |
| (X) | 10853 | ethyl 4-cyano-2-(4-pyridinyl)butanoate | C12H14N2O2 | 详情 | 详情 | |
| (XI) | 10854 | ethyl 4-cyano-2-ethyl-2-(4-pyridinyl)butanoate | C14H18N2O2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)This compound can be prepared by several different ways: 1) The reaction ot 4-(chloromethyl)pyridine (I) with NaCN in toluene - water gives 4-(cyanomethyl)pyridine (II), which is condensed with methyl acrylate (III) yielding dimethyl 4-cyano 4-(4-pyridyl)pimelate (IV). The hydrolysis and decarboxylation of (IV) atfords 4-(4-pyridyl)pimelic acid (V), which is cyclized by means of potassium tert-butoxide giving 4-(4-pyridyl)cyclohexanone (VI). The acetylation of (VI) with acetic anhydride or acetylimidazole affords 2-acetyl(4-4 pyridyl)cyclohexanone (VII), which is finally cyclized with acetylacetamide (VIII) by means of dimethylamine. 2) The cyclization of (VII) with cyanoacetamide (IX) by means of piperidine gives 4-cyano-1-methyl-7-(4-pyridyl)-5,6,7,8-tetrahydro-3(2H)-isoquinolinone (X), which is finally treated with methyl magnesium iodide in ether. 3) The condensation of 4 bromopyridine (XI) and cyclohexanedione monoethyleneketal (XII) by means of butyllithium in THF gives 4-hydroxy-4-(4-pyridyil)cyclohexanone ethyleneketal (XIII), which is dehydrated by treatment with SOCl2 and then with NaOH to afford 4-(4-pyridyl)-3-cyclohexenone ethyleneketal (XIV). Finally, this compound is hydrolyzed with HCl and reduced with H2 over Pd/C in 0.5 N HCl yielding cyclohexanone (VII), already obtained.
| 【1】 Hirayama, M.; Ito, T.; Kitano, T.; Maruyama, M.; Otsuka, K.; Sannohe, K. (Mitsui Chemicals, Inc.); Isoquinoline derivs.. EP 0207500; US 4639521 . |
| 【2】 Fukazawa, N.; Kaiho, T.; Yamashita, H. (Mitsui Chemicals, Inc.); Process for preparing 4-acetyl isoquinolinone cpds. JP 1987187467; US 4814458 . |
| 【3】 Prous, J.; Castaner, J.; MS-857. Drugs Fut 1988, 13, 9, 831. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 10158 | Piperidine | 110-89-4 | C5H11N | 详情 | 详情 | |
| (I) | 10844 | 4-(Chloromethyl)pyridine | 10445-91-7 | C6H6ClN | 详情 | 详情 |
| (II) | 23556 | 2-(4-pyridinyl)acetonitrile | C7H6N2 | 详情 | 详情 | |
| (III) | 14156 | methyl acrylate | 96-33-3 | C4H6O2 | 详情 | 详情 |
| (IV) | 23558 | dimethyl 4-cyano-4-(4-pyridinyl)heptanedioate | C15H18N2O4 | 详情 | 详情 | |
| (V) | 23559 | 4-(4-pyridinyl)heptanedioic acid | C12H15NO4 | 详情 | 详情 | |
| (VI) | 23560 | 4-(4-pyridinyl)cyclohexanone | C11H13NO | 详情 | 详情 | |
| (VII) | 23561 | 2-acetyl-4-(4-pyridinyl)cyclohexanone | C13H15NO2 | 详情 | 详情 | |
| (VIII) | 23562 | 3-oxobutanamide | 5977-14-0 | C4H7NO2 | 详情 | 详情 |
| (IX) | 12122 | Cyanoacetamide; 2-Cyanoacetamide | 107-91-5 | C3H4N2O | 详情 | 详情 |
| (X) | 23564 | 1-methyl-3-oxo-7-(4-pyridinyl)-2,3,5,6,7,8-hexahydro-4-isoquinolinecarbonitrile | C16H15N3O | 详情 | 详情 | |
| (XI) | 23565 | 4-bromopyridine | 1120-87-2 | C5H4BrN | 详情 | 详情 |
| (XII) | 11377 | 1,4-Dioxaspiro[4.5]decan-8-one | 4746-97-8 | C8H12O3 | 详情 | 详情 |
| (XIII) | 23567 | 8-(4-pyridinyl)-1,4-dioxaspiro[4.5]decan-8-ol | C13H17NO3 | 详情 | 详情 | |
| (XIV) | 23568 | 4-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)pyridine | C13H15NO2 | 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 title compound was prepared by alkylation of anthrone (I) with 4-picolyl chloride (II) in the presence of an alkaline hydroxide and a phase-transfer catalyst.
| 【1】 Drummond, S.; Wilkerson, W.W.; Calabrese, J.C.; Earl, R.A.; Teleha, C.A.; Zaczek, R.; Voss, M.E.; Acetylcholine release enhancers related to linopirdine: A structure-activity relationship study. II. Eur J Med Chem 1996, 31, 4, 319. |
| 【2】 Earl, R.A.; Myers, M.J.; Nickolson, V.J. (DuPont Pharmaceuticals Co.); alpha,alpha-Disubstd. aromatics and heteroaromatics as cognition enhancers. EP 0311010; US 5173489 . |
合成路线6
该中间体在本合成路线中的序号：(XII)The reaction of tert-butoxycarbonyl-L-phenylalanine (I) with isobutyl chloroformate in THF gives the expected mixed anhydride which is treated with diazomethane and HCl yielding the corresponding chloromethyl ketone (II). The reduction of (II) with NaBH4 in THF affords the (S)-chlorohydrin (IV), which is treated with KOH in ethanol to obtain the chiral epoxide (V)(1,2). Ring opening of (V) with (±)(cis)-N-tert-butyl-4-(4-pyridylmethoxy)piperidine-2-carboxamide (VI) by a treatment with LiCl in refluxing ethanol gives a mixture of diastereomers that is separated by chromatography giving the pure isomer (VII). The reaction of (VII) with tert-butoxycarbonyl-L-valine (VIII) by treatment first with trifluoroacetic acid (TFA), and condesation by means of BOP ((benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate) and NMM (N-methylmorpholine) affords the expected condensation product (IX). Finally, this compound is condensed with quinoline-2-carboxylic acid (X) by means of BOP and NMM as before. 2) The piperidine (VI) has been obtained by condensation of (±)(cis)-N-(tert-butoxycarbonyl)-4-hydroxypiperidine-2-carboxamide (XI) with 4-(chloromethyl)pyridine (XII) by means of NaH in DMS, followed by hydrolysis with HCl.
| 【1】 Beaulieu, P.L.; et al.; Practical, stereoselective synthesis of palinavir, a potent HIV protease inhibitor. J Org Chem 1997, 62, 11, 3440. |
| 【2】 Gillard, J.; et al.; Preparation of (2S,4R)-4-hydroxypipecolic acid and derivatives. J Org Chem 1996, 61, 6, 2226. |
| 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) | 12874 | (2R)-2-[(tert-Butoxycarbonyl)amino]-3-phenylpropionic acid; N-alpha-t-BOC-L-Phenylalanine | 13734-34-4 | C14H19NO4 | 详情 | 详情 |
| (II) | 19727 | tert-butyl (1S)-1-benzyl-3-diazo-2-oxopropylcarbamate | C15H19N3O3 | 详情 | 详情 | |
| (III) | 19728 | tert-butyl (1S)-1-benzyl-3-chloro-2-oxopropylcarbamate | C15H20ClNO3 | 详情 | 详情 | |
| (IV) | 19729 | (1S,2S)-[3-chloro-2-hydroxy-1-benzylpropyl]carbamic acid, 1,1-dimethylethyl ether; tert-butyl (1S,2S)-1-benzyl-3-chloro-2-hydroxypropylcarbamate | 165727-45-7 | C15H22ClNO3 | 详情 | 详情 |
| (V) | 19730 | tert-butyl (1S)-1-[(2S)oxiranyl]-2-phenylethylcarbamate | 98737-29-2 | C15H21NO3 | 详情 | 详情 |
| (VI) | 19731 | (2S,4R)-N-(tert-butyl)-4-(4-pyridinylmethoxy)-2-piperidinecarboxamide | C16H25N3O2 | 详情 | 详情 | |
| (VII) | 19732 | tert-butyl (1S,2R)-1-benzyl-3-[(2S,4R)-2-[(tert-butylamino)carbonyl]-4-(4-pyridinylmethoxy)piperidinyl]-2-hydroxypropylcarbamate | C31H46N4O5 | 详情 | 详情 | |
| (VIII) | 19733 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutyric acid | C10H19NO4 | 详情 | 详情 | |
| (IX) | 19734 | tert-butyl (1S)-1-[([(1S,2R)-1-benzyl-3-[(2S,4R)-2-[(tert-butylamino)carbonyl]-4-(4-pyridinylmethoxy)piperidinyl]-2-hydroxypropyl]amino)carbonyl]-2-methylpropylcarbamate | C36H55N5O6 | 详情 | 详情 | |
| (X) | 14532 | 2-Quinolinecarboxylic acid; Quinaldic Acid | 93-10-7 | C10H7NO2 | 详情 | 详情 |
| (XI) | 19736 | tert-butyl (2S,4R)-2-[(tert-butylamino)carbonyl]-4-hydroxy-1-piperidinecarboxylate | C15H28N2O4 | 详情 | 详情 | |
| (XII) | 10844 | 4-(Chloromethyl)pyridine | 10445-91-7 | C6H6ClN | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(XII)The chiral piperidine (2S,4R)(VI) has been obtained as follows: The cyclization of 3-buten-1-ol (XXII) with (S)-1-phenylethylamine (XXIII) and glyoxylic acid (XXIV) by means of tosyl chloride in THF gives a mixture of the (2S,4R) and (2R,4S) lactones (XXV), which is resolved by fractional crystallyzation of their salts with the chiral camphorsulfonic acid (XXVI), followed by elimination of the acid with ammonia to afford (2S,4R)(XXVII). The reaction of lactone (XXVII) with isopropylmagnesium chloride and tert-butylamine in THF gives (2S,4R)-N-tert-butyl-4-hydroxy-1-(1(S)-phenylethyl)piperidine-2-carboxamide (XXVIII), which is debenzylated by hydrogenation and protected with tert-butoxycarbonyl anhydride yielding (2S,4R)-N-(tert-butoxycarbonyl)-4-hydroxypiperidine-2-carboxamide (2S,4R)(XI), which is finally condensed with 4-(chloromethyl)pyridine (XII) as before to obtain the chiral piperidine (2S,4R)(VI), already reported.
| 【1】 Beaulieu, P.L.; et al.; Practical, stereoselective synthesis of palinavir, a potent HIV protease inhibitor. J Org Chem 1997, 62, 11, 3440. |
| 【2】 Gillard, J.; et al.; Preparation of (2S,4R)-4-hydroxypipecolic acid and derivatives. J Org Chem 1996, 61, 6, 2226. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VI) | 19731 | (2S,4R)-N-(tert-butyl)-4-(4-pyridinylmethoxy)-2-piperidinecarboxamide | C16H25N3O2 | 详情 | 详情 | |
| (XI) | 19736 | tert-butyl (2S,4R)-2-[(tert-butylamino)carbonyl]-4-hydroxy-1-piperidinecarboxylate | C15H28N2O4 | 详情 | 详情 | |
| (XII) | 10844 | 4-(Chloromethyl)pyridine | 10445-91-7 | C6H6ClN | 详情 | 详情 |
| (XXII) | 19743 | 3-buten-1-ol | 627-27-0 | C4H8O | 详情 | 详情 |
| (XXIII) | 10039 | (1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine | 3886-69-9 | C8H11N | 详情 | 详情 |
| (XXIV) | 15618 | 2-Oxoacetic acid; Glyoxylic Acid | 298-12-4 | C2H2O3 | 详情 | 详情 |
| (XXV) | 19746 | 2-[(1S)-1-phenylethyl]-6-oxa-2-azabicyclo[3.2.1]octan-7-one | C14H17NO2 | 详情 | 详情 | |
| (XXVI) | 19747 | (3-bromo-1,7-dimethyl-2-oxobicyclo[2.2.1]hept-7-yl)methanesulfonic acid | C10H15BrO4S | 详情 | 详情 | |
| (XXVII) | 19748 | (1S,5R)-2-[(1S)-1-phenylethyl]-6-oxa-2-azabicyclo[3.2.1]octan-7-one | C14H17NO2 | 详情 | 详情 | |
| (XXVIII) | 19749 | (2S,4R)-N-(tert-butyl)-4-hydroxy-1-[(1S)-1-phenylethyl]-2-piperidinecarboxamide | C18H28N2O2 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(X)Hydrogenation of D-4-hydroxyphenyl glycine (I) over Raney-Ni in NaOH affords 4-hydroxycyclohexylglycine (II), which is condensed with sulfonyl chloride (III) in dioxane in the presence of Et3N to yield derivative (IV). Carboxylic acid (IV) is converted into benzyl ester (VI) by treatment with benzyl bromide (V) by means of N,N'-dicyclohexylamine (DCHA) in DMF and (VI) is then oxidized by treatment with NaBr, 2,2,6,6-tetramethyl-1-piperidinyloxy free radical (TEMPO) and NaClO2 in CH2Cl2/H2O to provide ketone (VII). Condensation of (VII) with n-propanol (VIII) by means of PhSiH3 and TFA gives a mixture of compounds from which trans-(IX) is cromatographically separated. Then ketone (IX) reacts with 4-picolyl chloride (X) and K2CO3 in DMF to furnish compound (XI). Hydrogenation of benzyl acetate (XI) over Pd/C in EtOH/HCl affords acetic acid derivative (XII), which is coupled to O-t-butylhydroxylamine hydrochloride by means of HOBt, N-methylmorpholine and N-[dimethylaminopropyl]-N'-ethylcarbodiimide hydrochloride (EDC·HCl) in CH2Cl2. Finally, removal of the t-Bu group with HCl (gas) in dichloroethane/EtOH yields the desired compound.
| 【1】 Parker, D.T. (Novartis AG); alpha-Substd. arylsulphonamido hydroxamic acids as TNF-alpha and matrix metalloproteinase inhibitors. EP 0873312; JP 2000502088; US 5770624; WO 9722587 . |
| 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) | 31690 | (2R)-2-amino-2-(4-hydroxyphenyl)ethanoic acid; (2R)-2-(4-hydroxyphenyl)glycine; D-(-)-p-Hydroxyphenylglycine; (R)-2-amino-2-(4-hydroxyphenyl)acetic acid | 22818-40-2 | C8H9NO3 | 详情 | 详情 |
| (II) | 45921 | (2R)-2-amino-2-(4-hydroxycyclohexyl)ethanoic acid | C8H15NO3 | 详情 | 详情 | |
| (III) | 45922 | 4-ethoxybenzenesulfonyl chloride | C8H9ClO3S | 详情 | 详情 | |
| (IV) | 45923 | (2R)-2-[[(4-ethoxyphenyl)sulfonyl]amino]-2-(4-hydroxycyclohexyl)ethanoic acid | C16H23NO6S | 详情 | 详情 | |
| (V) | 12912 | 1-(Bromomethyl)benzene; Alpha-bromotoluene | 100-39-0 | C7H7Br | 详情 | 详情 |
| (VI) | 45924 | benzyl (2R)-2-[[(4-ethoxyphenyl)sulfonyl]amino]-2-(4-hydroxycyclohexyl)ethanoate | C23H29NO6S | 详情 | 详情 | |
| (VII) | 45925 | benzyl (2R)-2-[[(4-ethoxyphenyl)sulfonyl]amino]-2-(4-oxocyclohexyl)ethanoate | C23H27NO6S | 详情 | 详情 | |
| (VIII) | 29338 | 1-propanol | 71-23-8 | C3H8O | 详情 | 详情 |
| (IX) | 45926 | benzyl (2R)-2-[[(4-ethoxyphenyl)sulfonyl]amino]-2-(4-propoxycyclohexyl)ethanoate | C26H35NO6S | 详情 | 详情 | |
| (X) | 10844 | 4-(Chloromethyl)pyridine | 10445-91-7 | C6H6ClN | 详情 | 详情 |
| (XI) | 45927 | benzyl (2R)-2-[[(4-ethoxyphenyl)sulfonyl](4-pyridinylmethyl)amino]-2-(4-propoxycyclohexyl)ethanoate | C32H40N2O6S | 详情 | 详情 | |
| (XII) | 45928 | (2R)-2-[[(4-ethoxyphenyl)sulfonyl](4-pyridinylmethyl)amino]-2-(4-propoxycyclohexyl)ethanoic acid | C25H34N2O6S | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(X)Cyclization of 2,2-dichloroisobutyraldehyde (I) - obtained by reaction of isovaleraldehyde (II) with chlorine in DMF - with 2-benzyloxyacetaldehyde (III) - produced by reaction of 2-butene-1,4-diol (IV) with benzyl chloride by means of NaOH in water, followed by ozonolysis in MeOH and finally reduction with triphenylphosphine in ethyl acetate - and aqueous NH4OH in methanol gives the imidazole derivative (VI), which is iodinated with I2 and NaOH in dichloromethane to yield the 5-iodoimidaz-ole derivative (VII). Condensation of compound (VII) with bis(3,5-dichlorophenyl)disulfide (VIII) by means of LiH in DMSO affords the dichlorophenylsulfanyl imidazole (IX), which is alkylated with 4-(chloromethyl)pyridine (X) and K2CO3 in DMF to provide the fully substituted imidazole (XI). Debenzylation of compound (XI) with conc. HCl in refluxing ethanol gives the carbinol (XII), which is finally treated with trichloroacetyl isocyanate and triethylamine in methanol/water.
| 【1】 Sorbera, L.A.; Castañer, J.; Bayes, M.; Capravirine. Drugs Fut 2003, 28, 12, 1149. |
| 【2】 Sugita, K.; Makino, I.; Sugimoto, H.; et al.; Synthesis and biological activity of imidazole derivatives as a novel class of HIV-1 nonnucleoside reverse transcriptase inhibitors. Symp Med Chem 1999, Abst 2P-05. |
| 【3】 Aono, K.; Ichihashi, T.; Sugawara, T.; Hirano, K. (Shionogi & Co. Ltd.); Lymph-absorbable imidazole derivs.. EP 0893442; US 6054591; WO 9735843 . |
| 【4】 Sugimoto, H.; Fujiwara, T. (Shionogi & Co. Ltd.); Imidazole deriv.. EP 0786455; US 5910506; US 6147097; WO 9610019 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 40725 | 2,2,2-trichloroacetyl isocyanate | 3019-71-4 | C3Cl3NO2 | 详情 | 详情 | |
| (I) | 35840 | 2,2-dichloro-3-methylbutanal | C5H8Cl2O | 详情 | 详情 | |
| (II) | 26052 | 3-methylbutanal | 590-86-3 | C5H10O | 详情 | 详情 |
| (III) | 17346 | Benzyloxyacetaldehyde; 2-(Benzyloxy)acetaldehyde | 60656-87-3 | C9H10O2 | 详情 | 详情 |
| (IV) | 36995 | 4-[2-(1-piperidinyl)ethoxy]benzoyl chloride | C14H18ClNO2 | 详情 | 详情 | |
| (V) | 63296 | 1-({[(Z)-4-(benzyloxy)-2-butenyl]oxy}methyl)benzene; benzyl (Z)-4-(benzyloxy)-2-butenyl ether | C18H20O2 | 详情 | 详情 | |
| (VI) | 35841 | benzyl (4-isopropyl-1H-imidazol-2-yl)methyl ether; 2-[(benzyloxy)methyl]-4-isopropyl-1H-imidazole | C14H18N2O | 详情 | 详情 | |
| (VII) | 35842 | 2-[(benzyloxy)methyl]-5-iodo-4-isopropyl-1H-imidazole; benzyl (5-iodo-4-isopropyl-1H-imidazol-2-yl)methyl ether | C14H17IN2O | 详情 | 详情 | |
| (VIII) | 35843 | bis(3,5-dichlorophenyl) disulfide; 1,3-dichloro-5-[(3,5-dichlorophenyl)disulfanyl]benzene | 137897-99-5 | C12H6Cl4S2 | 详情 | 详情 |
| (IX) | 35844 | benzyl [5-[(3,5-dichlorophenyl)sulfanyl]-4-isopropyl-1H-imidazol-2-yl]methyl ether; 2-[(benzyloxy)methyl]-5-[(3,5-dichlorophenyl)sulfanyl]-4-isopropyl-1H-imidazole | C20H20Cl2N2OS | 详情 | 详情 | |
| (X) | 10844 | 4-(Chloromethyl)pyridine | 10445-91-7 | C6H6ClN | 详情 | 详情 |
| (XI) | 35845 | 4-([2-[(benzyloxy)methyl]-5-[(3,5-dichlorophenyl)sulfanyl]-4-isopropyl-1H-imidazol-1-yl]methyl)pyridine; benzyl [5-[(3,5-dichlorophenyl)sulfanyl]-4-isopropyl-1-(4-pyridinylmethyl)-1H-imidazol-2-yl]methyl ether | C26H25Cl2N3OS | 详情 | 详情 | |
| (XII) | 35846 | [5-[(3,5-dichlorophenyl)sulfanyl]-4-isopropyl-1-(4-pyridinylmethyl)-1H-imidazol-2-yl]methanol | C19H19Cl2N3OS | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(X)The debenzylation of 2-(benzyloxymethyl)-5-(3,5-dichlorophenylsulfanyl)-4-isopropyl-1H-imidazole (IX) with hot aqueous HCl gives 5-(3,5-dichlorophenylsulfanyl)-4-isopropyl-1H-imidazole-2-methanol (XIII), which is condensed with chlorosulfonyl isocyanate in acetonitrile to yield carbamic acid 5-(3,5-dichlorophenylsulfanyl)-4-isopropyl-1H-imidazol-2-ylmethyl ester (XIV). Finally, this compound is alkylated with 4-(chloromethyl)pyridine (X) - obtained by reaction of 4-(hydroxymethyl)pyridine (XV) and SOCl2 in acetonitrile - by means of NaHCO3 in ethyl acetate/water.
| 【1】 Sorbera, L.A.; Castañer, J.; Bayes, M.; Capravirine. Drugs Fut 2003, 28, 12, 1149. |
| 【2】 Sugimoto, H.; Fujiwara, T. (Shionogi & Co. Ltd.); Imidazole deriv.. EP 0786455; US 5910506; US 6147097; WO 9610019 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IX) | 35844 | benzyl [5-[(3,5-dichlorophenyl)sulfanyl]-4-isopropyl-1H-imidazol-2-yl]methyl ether; 2-[(benzyloxy)methyl]-5-[(3,5-dichlorophenyl)sulfanyl]-4-isopropyl-1H-imidazole | C20H20Cl2N2OS | 详情 | 详情 | |
| (X) | 10844 | 4-(Chloromethyl)pyridine | 10445-91-7 | C6H6ClN | 详情 | 详情 |
| (XIII) | 63297 | {5-[(3,5-dichlorophenyl)sulfanyl]-4-isopropyl-1H-imidazol-2-yl}methanol | C13H14Cl2N2OS | 详情 | 详情 | |
| (XIV) | 63298 | {5-[(3,5-dichlorophenyl)sulfanyl]-4-isopropyl-1H-imidazol-2-yl}methyl carbamate | C14H15Cl2N3O2S | 详情 | 详情 | |
| (XV) | 32835 | 4-pyridinylmethanol | 586-95-8 | C6H7NO | 详情 | 详情 |
合成路线11
该中间体在本合成路线中的序号：(X)Alkylation of 2-(benzyloxymethyl)-4-isopropyl-1H-imidazole (VI) with 4-(chloromethyl)pyridine (X) by means of NaOH in toluene gives 2-(benzyloxymethyl)-4-isopropyl-1-(4-pyridylmethyl)-1H-imidazole (XVI), which is then condensed with 3,5-dichlorophenylsulfanyl chloride (XVII) - obtained by reaction of bis(3,5-dichlorophenyl)-disulfide (VIII) first with chlorine gas in CCl4 or toluene and then dried nitrogen gas - by means of triethylamine in toluene/water to afford 2-(benzyloxymethyl)-5-(3,5-dichlorophenylsulfanyl)-4-isopropyl-1-(4-pyridylmethyl)-1H-imidazole (XI). Debenzylation of compound (XI) by means of hot aqueous HCl provides the hydroxymethyl derivative (XII), which is finally esterified with chlorosulfonyl isocyanate in ethyl acetate.
| 【1】 Sorbera, L.A.; Castañer, J.; Bayes, M.; Capravirine. Drugs Fut 2003, 28, 12, 1149. |
| 【2】 Kabaki, M.; Hajima, M.; Hozumi, Y. (Shionogi & Co. Ltd.); Process for producing imidazole derivs.. EP 0949249; US 6057448; WO 9829395 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VI) | 35841 | benzyl (4-isopropyl-1H-imidazol-2-yl)methyl ether; 2-[(benzyloxy)methyl]-4-isopropyl-1H-imidazole | C14H18N2O | 详情 | 详情 | |
| (X) | 10844 | 4-(Chloromethyl)pyridine | 10445-91-7 | C6H6ClN | 详情 | 详情 |
| (XI) | 35845 | 4-([2-[(benzyloxy)methyl]-5-[(3,5-dichlorophenyl)sulfanyl]-4-isopropyl-1H-imidazol-1-yl]methyl)pyridine; benzyl [5-[(3,5-dichlorophenyl)sulfanyl]-4-isopropyl-1-(4-pyridinylmethyl)-1H-imidazol-2-yl]methyl ether | C26H25Cl2N3OS | 详情 | 详情 | |
| (XII) | 35846 | [5-[(3,5-dichlorophenyl)sulfanyl]-4-isopropyl-1-(4-pyridinylmethyl)-1H-imidazol-2-yl]methanol | C19H19Cl2N3OS | 详情 | 详情 | |
| (XV) | 35843 | bis(3,5-dichlorophenyl) disulfide; 1,3-dichloro-5-[(3,5-dichlorophenyl)disulfanyl]benzene | 137897-99-5 | C12H6Cl4S2 | 详情 | 详情 |
| (XVI) | 63299 | benzyl [4-isopropyl-1-(4-pyridinylmethyl)-1H-imidazol-2-yl]methyl ether; 4-({2-[(benzyloxy)methyl]-4-isopropyl-1H-imidazol-1-yl}methyl)pyridine | C20H23N3O | 详情 | 详情 | |
| (XVII) | 63000 | methyl 6-[3-(1-adamantyl)-5-bromo-4-methoxyphenyl]-5-bromo-2-naphthoate; methyl 6-[3-(1-adamantyl)-5-bromo-4-methoxyphenyl]-5-bromo-2-naphthoate | C29H28Br2O3 | 详情 | 详情 |
合成路线12
该中间体在本合成路线中的序号：(II)The alkylation of 2-fluoro-4-hydroxybenzonitrile (I) with 4-picolyl chloride (II) afforded ether (III). This was coupled with (R,S)-2-hydroxy-2-(2-methylphenyl)acetic acid (IV) in the presence of NaH in DMSO to produce the racemic adduct (V). Resolution of (V) was then achieved by fractional crystallization of the diastereoisomeric salts with (-)-ephedrine to furnish the desired (S)-enantiomer, which was finally isolated as the corresponding sodium salt.
| 【1】 Astles, P.C.; Brown, T.J.; Halley, F.; et al.; Selective ETA antagonists. 5. Discovery and structure-activity relationships of phenoxyphenylacetic acid derivatives. J Med Chem 2000, 43, 5, 900. |
| 【2】 Porter, B.; Astles, P.C.; Bridge, A.W.; McLay, I.M.; Van Sickle, A.P.; Walsh, R.J.A.; McCarthy, C.; Morley, A.D.; Halley, F.; Harris, N.V.; Majid, T.N.; Smith, C. (Rhône-Poulenc Rorer Ltd.); Substd. phenyl cpds. as endothelin antagonists. US 6048893; US 6124343; WO 9622978 . |
| 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) | 20094 | 2,4-dihydroxybenzaldehyde | 95-01-2 | C7H6O3 | 详情 | 详情 |
| (II) | 10844 | 4-(Chloromethyl)pyridine | 10445-91-7 | C6H6ClN | 详情 | 详情 |
| (III) | 38985 | 2-fluoro-4-(4-pyridinylmethoxy)benzonitrile | C13H9FN2O | 详情 | 详情 | |
| (IV) | 38977 | 2-hydroxy-2-(2-methylphenyl)acetic acid | C9H10O3 | 详情 | 详情 | |
| (V) | 38986 | 2-[2-cyano-5-(4-pyridinylmethoxy)phenoxy]-2-(2-methylphenyl)acetic acid | C22H18N2O4 | 详情 | 详情 |