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【结 构 式】 
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【分子编号】21513 【品名】2-amino-2-methyl-1-propanol；Karl Fischer;2-Amino-2-methyl-propan-1-ol；2-amino-2-methyl-1-propanol 【CA登记号】124-68-5 |
【 分 子 式 】C4H11NO 【 分 子 量 】89.13748 【元素组成】C 53.9% H 12.44% N 15.71% O 17.95% |
合成路线1
该中间体在本合成路线中的序号：(III)A new method for the preparation of citalopram has been developed: The chlorination of 1-oxo-1,3-dihydroisobenzofuran-5-carboxylic acid (I) with refluxing SOCl2 gives the acyl chloride (II), which is condensed with 2-amino-2-methyl-1-propanol (III) in THF yielding the corresponding amide (IV). The cyclization of (IV) by means of SOCl2 affords the oxazoline (V), which is treated with 4-fluorophenylmagnesium bromide (VI) in THF giving the benzophenone (VII). This compound (VII), without isolation, is treated with 3-(dimethylamino)propylmagnesium chloride (VIII) in the same solvent, providing the cabinol (IX), which is cyclized by means of methanesulfonyl chloride and Et3N in CH2Cl2 yielding the isobenzofuran (X). Finally, this compound is treated with POCl3 in refluxing pyridine to generate the 5-cyano substituent of citalopram.
| 【1】 Dall'asta, L.; Casazza, U.; Petersen, H. (H. Lundbeck A/S); Method for the preparation of citalopram. WO 0023431 . |
| 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) | 37594 | 1-oxo-1,3-dihydro-2-benzofuran-5-carboxylic acid | C9H6O4 | 详情 | 详情 | |
| (II) | 37595 | 1-oxo-1,3-dihydro-2-benzofuran-5-carbonyl chloride | C9H5ClO3 | 详情 | 详情 | |
| (III) | 21513 | 2-amino-2-methyl-1-propanol；Karl Fischer;2-Amino-2-methyl-propan-1-ol；2-amino-2-methyl-1-propanol | 124-68-5 | C4H11NO | 详情 | 详情 |
| (IV) | 37596 | N-(2-hydroxy-1,1-dimethylethyl)-1-oxo-1,3-dihydro-2-benzofuran-5-carboxamide | C13H15NO4 | 详情 | 详情 | |
| (V) | 37597 | 5-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-2-benzofuran-1(3H)-one | C13H13NO3 | 详情 | 详情 | |
| (VI) | 13643 | 4-fluorophenyl magnesium bromide;Bromo(4-fluorophenyl)magnesium;bromo(p-fluorophenyl)Magnesium;p-Fluorophenylmagnesium bromide | 352-13-6 | C6H4BrFMg | 详情 | 详情 |
| (VII) | 37598 | [4-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-2-(hydroxymethyl)phenyl](4-fluorophenyl)methanone | C19H18FNO3 | 详情 | 详情 | |
| (VIII) | 12587 | Chloro[3-(dimethylamino)propyl]magnesium | C5H12ClMgN | 详情 | 详情 | |
| (IX) | 37599 | 4-(dimethylamino)-1-[4-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-2-(hydroxymethyl)phenyl]-1-(4-fluorophenyl)-1-butanol | C24H31FN2O3 | 详情 | 详情 | |
| (X) | 37600 | N-[3-[5-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-1-yl]propyl]-N,N-dimethylamine; 3-[5-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-1-yl]-N,N-dimethyl-1-propanamine | C24H29FN2O2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IV)The reaction of terephthalic acid (I) with trioxane and oleum at 140-150 C gives 1-oxo-1,3-dihydroisobenzofuran-5-carboxylic acid (II), which is treated with SOCl2 in refluxing toluene to yield the acyl chloride (III). The condensation of (III) with 2-hydroxy-1,1-dimethylethylamine (IV) in the same solvent affords the amide (V), which is cyclized by means of SOCl2 in dichloromethane to provide the oxazoline (VI). The Grignard condensation of (VI) with 4-fluorophenylmagnesium bromide (VII) in THF gives the benzophenone (VIII), which is submitted to a new Grignard condensation with 3-(dimethylamino)propylmagnesium bromide (IX) in the same solvent to yield the diol (X). Finally, this compound is treated with POCl3 or SOCl2 and POCl3 in hot pyridine to afford the target citalopram. Alternatively, the cleavage of the oxazoline ring of (X) with H2SO4 and then with NaOH gives the sodium carboxylate (XI), which is treated with SOCl2 in dichloromethane to yield the corresponding acyl chloride (XII). The reaction of (XII) with dry ammonia in the same solvent affords the carboxamide (XIII), which is finally dehydrated with POCl3 in refluxing acetonitrile to provide the target citalopram.
| 【1】 Greenwood, A.K.; McHattie, D.; Rechka, J.A.; Hedger, P.C.M.; Gamble, M.P. (Resolution Chemicals Ltd.); Process for the preparation of citalopram. WO 0166536 . |
| 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) | 54025 | 1,4-Benzenedicarboxylic acid; Benzene-1,4-dicarboxylic acid; p-Benzenedicarboxylic acid; p-Phthalic acid; Terephthalic acid | 100-21-0 | C8H6O4 | 详情 | 详情 |
| (II) | 37594 | 1-oxo-1,3-dihydro-2-benzofuran-5-carboxylic acid | C9H6O4 | 详情 | 详情 | |
| (III) | 37595 | 1-oxo-1,3-dihydro-2-benzofuran-5-carbonyl chloride | C9H5ClO3 | 详情 | 详情 | |
| (IV) | 21513 | 2-amino-2-methyl-1-propanol；Karl Fischer;2-Amino-2-methyl-propan-1-ol；2-amino-2-methyl-1-propanol | 124-68-5 | C4H11NO | 详情 | 详情 |
| (V) | 37596 | N-(2-hydroxy-1,1-dimethylethyl)-1-oxo-1,3-dihydro-2-benzofuran-5-carboxamide | C13H15NO4 | 详情 | 详情 | |
| (VI) | 37597 | 5-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-2-benzofuran-1(3H)-one | C13H13NO3 | 详情 | 详情 | |
| (VII) | 13643 | 4-fluorophenyl magnesium bromide;Bromo(4-fluorophenyl)magnesium;bromo(p-fluorophenyl)Magnesium;p-Fluorophenylmagnesium bromide | 352-13-6 | C6H4BrFMg | 详情 | 详情 |
| (VIII) | 37598 | [4-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-2-(hydroxymethyl)phenyl](4-fluorophenyl)methanone | C19H18FNO3 | 详情 | 详情 | |
| (IX) | 37604 | bromo[3-(dimethylamino)propyl]magnesium | 120615-47-6 | C5H12BrMgN | 详情 | 详情 |
| (X) | 37599 | 4-(dimethylamino)-1-[4-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-2-(hydroxymethyl)phenyl]-1-(4-fluorophenyl)-1-butanol | C24H31FN2O3 | 详情 | 详情 | |
| (XI) | 55284 | sodium 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-carboxylate | C20H21FNNaO3 | 详情 | 详情 | |
| (XII) | 55285 | 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-carbonyl chloride | C20H21ClFNO2 | 详情 | 详情 | |
| (XIII) | 55286 | 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-carboxamide | C20H23FN2O2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)This compound can be prepared by two different ways: 1) The dehydration of 2-amino-2-methylpropranol (I) with H2SO4 at 170-200 C gives 2,2-dimethylazirine (II), which by reaction with methanol by means of boron trifluoride - methanol complex and fractional distillation affords 2-methoxy-2-methylpropylamine (III). The reaction of (III) with formic acid in acetic anhydride yields N-(2-methoxy-2-methylpropyl)formamide (IV), which by reaction with diphosgene (trichloromethyl chloroformate) and triethylamine in dichloromethane gives 2-methoxy-2-methylpropylisonitrile (MIBI) (V). Finally, this compound or its CuBF4 complex Cu(MIBI)4BF4 is treated with 99mTcO4 (VI) and sodium dithionite or formamide sulfinic acid respectively, in ethanol - water. 2) The methylation of methyl 2-hydroxyisobutylrate (VII) with NaH - methyl iodide in DMF - THF gives methyl 2-methoxy-2-methylpropanoate (VIII), which by reaction with ammonia is converted to the corresponding amide (IX). Finally, this compound is reduced with LiAlH4 in THF yielding the amine (III), already obtained.
| 【1】 Bergstein, P.L.; Subramanyam, V. (E.I. Du Pont de Nemours & Co.); Ether isonitriles and radilabeled complexes thereof. AU 8666842; EP 0233368; JP 87201363 . |
| 【2】 Williams, S.; Okada, R.D.; Gaffney, T.; Glover, D.; Myocardial kinetics of technetium-99m-hexakis-2-methoxy-2-methylpropyl-isonitrile. Circulation 1988, 77, 491. |
| 【3】 Carrell, S.A.; Robinson, C.P.; Prous, J.; Castaner, J.; TECHNETIUM [(99m)Tc] SESTAMIBI < Prop INN; BAN >. Drugs Fut 1989, 14, 12, 1169. |
| 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) | 21513 | 2-amino-2-methyl-1-propanol；Karl Fischer;2-Amino-2-methyl-propan-1-ol；2-amino-2-methyl-1-propanol | 124-68-5 | C4H11NO | 详情 | 详情 |
| (II) | 21514 | 2,2-dimethylaziridine | C4H9N | 详情 | 详情 | |
| (III) | 21515 | 2-methoxy-2-methyl-1-propanamine | C5H13NO | 详情 | 详情 | |
| (IV) | 21516 | 2-methoxy-2-methylpropylformamide | C6H13NO2 | 详情 | 详情 | |
| (V) | 21517 | 2-Methoxy-2-methylpropyl isocyanide | C6H11NO | 详情 | 详情 | |
| (VII) | 21518 | methyl 2-hydroxy-2-methylpropanoate | 2110-78-3 | C5H10O3 | 详情 | 详情 |
| (VIII) | 21519 | methyl 2-methoxy-2-methylpropanoate | C6H12O3 | 详情 | 详情 | |
| (IX) | 21520 | 2-methoxy-2-methylpropanamide | C5H11NO2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(III)The reaction of [benzene-U-13C]benzoic acid (I) with SOCl2 gives the corresponding acyl chloride (II), which is cyclized with the ethanolamine (III) to yield the oxazoline (IV).The chlorination of (IV) with sec-BuLi and hexachloroethane in toluene affords the 2-chlorophenyl derivative (V), which is methylated with MeI to provide the oxazolinium salt (VI). The reduction of (VI) with NaBH4 in ethanol yields the oxazolidine (VII), which is hydrolyzed with HCl to afford the labeled 2-chlorobenzaldehyde (VIII). The condensation of aldehyde (VIII) with the tetrahydrothienopyridine (IX) by means of acetone cyanohydrine in hot toluene affords the substituted acetonitrile (X), which is hydrolyzed to the substituted acetamide (XI) with HCl in methanol. Finally, this compound is treated with H2SO4 in refluxing methanol to afford the target labeled methyl ester as a racemic mixture.
| 【1】 Kashimura, S.; Kuwata, F.; Ishige, O.; Uyama, H.; Shono, T.; Yamaguchi, Y.; Formation of a novel acyl anion equivalent by the electroreduction of oxazolinium salts. Chem Lett 1987, 1511. |
| 【2】 Burgos, A.; Simpson, I.; Herbert, J.M.; Ortho-metalation/chlorination of benzoic acid derivatives: Preparation of [benzene-U-C-13]-rac-clopidogrel ([benzene-U-C-13]-rac-SR25990C). J Label Compd Radiopharm 2000, 43, 9, 891. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 63476 | methyl 2-(2-chlorophenyl)-2-[6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl]acetate | C16H16ClNO2S | 详情 | 详情 | ||
| 63477 | methyl 2-(2-chlorophenyl)-2-[6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl]acetate | C16H16ClNO2S | 详情 | 详情 | ||
| (I) | 10202 | Benzoic acid | 65-85-0 | C7H6O2 | 详情 | 详情 |
| (I) | 44623 | C7H6O2 | 详情 | 详情 | ||
| (II) | 10463 | Benzoyl chloride | 98-88-4 | C7H5ClO | 详情 | 详情 |
| (II) | 45137 | C7H5ClO | 详情 | 详情 | ||
| (III) | 21513 | 2-amino-2-methyl-1-propanol；Karl Fischer;2-Amino-2-methyl-propan-1-ol；2-amino-2-methyl-1-propanol | 124-68-5 | C4H11NO | 详情 | 详情 |
| (IV) | 44072 | 4,4-dimethyl-2-phenyl-4,5-dihydro-1,3-oxazole | 19312-06-2 | C11H13NO | 详情 | 详情 |
| (IV) | 45138 | C11H13NO | 详情 | 详情 | ||
| (V) | 44073 | 2-(2-chlorophenyl)-4,4-dimethyl-4,5-dihydro-1,3-oxazole | C11H12ClNO | 详情 | 详情 | |
| (V) | 45139 | C11H12ClNO | 详情 | 详情 | ||
| (VI) | 44074 | 2-(2-chlorophenyl)-3,4,4-trimethyl-4,5-dihydro-1,3-oxazol-3-ium iodide | C12H15ClINO | 详情 | 详情 | |
| (VI) | 45140 | C12H15ClINO | 详情 | 详情 | ||
| (VII) | 44075 | 2-(2-chlorophenyl)-3,4,4-trimethyl-1,3-oxazolidine | C12H16ClNO | 详情 | 详情 | |
| (VII) | 45141 | C12H16ClNO | 详情 | 详情 | ||
| (VIII) | 24114 | 2-chlorobenzaldehyde | 89-98-5 | C7H5ClO | 详情 | 详情 |
| (VIII) | 45142 | C7H5ClO | 详情 | 详情 | ||
| (IX) | 34011 | 4,5,6,7-tetrahydrothieno[3,2-c]pyridine | 54903-50-3 | C7H9NS | 详情 | 详情 |
| (X) | 44076 | 2-(2-chlorophenyl)-2-[6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl]acetonitrile | C15H13ClN2S | 详情 | 详情 | |
| (X) | 45143 | C15H13ClN2S | 详情 | 详情 | ||
| (XI) | 44077 | 2-(2-chlorophenyl)-2-[6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl]acetamide | C15H15ClN2OS | 详情 | 详情 | |
| (XI) | 45144 | C15H15ClN2OS | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(I)The title compound has been synthesized by two different methods. Condensation of 2-amino-2-methyl-1-propanol (I) with styrene oxide (II) provided the target amino diol.
| 【1】 Montoro, F.; Calatayud, J.; Vila-Coro, A.; De la Fuente, R. (Byk Elmu SA); Process for the preparation of ethyl-1-hydroxy-1-phenyl-2-(2-methyl-1-propanol)-amine, a new drug with antiinflammatory activity. ES 453351 . |
| 【2】 Staibano, G.; Fanelli, O. (Istituto Gentili SpA); Diethanolamine derivs.. GB 1336732 . |
合成路线6
该中间体在本合成路线中的序号：(I)Phenylglyoxylic acid (III) was converted to the corresponding acid chloride (IV) upon treatment with SOCl2. Subsequent coupling of (IV) with 2-amino-2-methyl-1-propanol (I) afforded amide (V). Reduction of the ketone and amide functions of (V) by means of LiAlH4 furnished the title compound.
| 【1】 Montoro, F.; Calatayud, J.; Luna, M. (Byk Elmu SA); 2-[N-(2-Hydroxy-1,1-dimethylethyl)amino]-1-phenylethanol which is useful, in particular, as an anti-inflammatory, and process for preparing it. CH 670823; FR 2573071; JP 1986143344 . |
| 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) | 21513 | 2-amino-2-methyl-1-propanol；Karl Fischer;2-Amino-2-methyl-propan-1-ol；2-amino-2-methyl-1-propanol | 124-68-5 | C4H11NO | 详情 | 详情 |
| (III) | 55589 | Benzoylformic acid; Phenylglyoxylic acid | 611-73-4 | C8H6O3 | 详情 | 详情 |
| (IV) | 55590 | 2-oxo-2-phenylacetyl chloride | C8H5ClO2 | 详情 | 详情 | |
| (V) | 55591 | N-(2-hydroxy-1,1-dimethylethyl)-2-oxo-2-phenylacetamide | C12H15NO3 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(XIV)The chlorination of 1-oxo-1,3-dihydroisobenzofuran-5-carboxylic acid (XII) with refluxing SOCl2 gives the acyl chloride (XIII), which is condensed with 2-amino-2-methyl-1-propanol (XIV) in THF to yield the corresponding amide (XV). The cyclization of (XV) by means of SOCl2 affords the oxazoline (XVI), which is treated with 4-fluorophenylmagnesium bromide (XVII) in THF to give the benzophenone (XVIII). This compound (XVIII), without isolation, is treated with 3-(dimethylamino)propylmagnesium chloride (XIX) in the same solvent to provide the carbinol (XX), which is submitted to optical resolution with (+)- or (-)-tartaric acid, or (+)- or (-)-camphor-10-sulfonic acid (CSA) to give the desired (S)-enantiomer (XXI). Cyclization of (XXI) by means of methanesulfonyl chloride and TEA in dichloromethane yields the chiral isobenzofuran (XXII), which is finally treated with POCl3 in refluxing pyridine.
| 【1】 Sorbera, L.A.; Martin, L.; Revel, L.; Castaner, J.; Escitalopram oxalate. Drugs Fut 2001, 26, 2, 115. |
| 【2】 Dall'asta, L.; Casazza, U.; Petersen, H. (H. Lundbeck A/S); Method for the preparation of citalopram. WO 0023431 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XII) | 37594 | 1-oxo-1,3-dihydro-2-benzofuran-5-carboxylic acid | C9H6O4 | 详情 | 详情 | |
| (XIII) | 37595 | 1-oxo-1,3-dihydro-2-benzofuran-5-carbonyl chloride | C9H5ClO3 | 详情 | 详情 | |
| (XIV) | 21513 | 2-amino-2-methyl-1-propanol；Karl Fischer;2-Amino-2-methyl-propan-1-ol；2-amino-2-methyl-1-propanol | 124-68-5 | C4H11NO | 详情 | 详情 |
| (XV) | 37596 | N-(2-hydroxy-1,1-dimethylethyl)-1-oxo-1,3-dihydro-2-benzofuran-5-carboxamide | C13H15NO4 | 详情 | 详情 | |
| (XVI) | 37597 | 5-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-2-benzofuran-1(3H)-one | C13H13NO3 | 详情 | 详情 | |
| (XVII) | 13643 | 4-fluorophenyl magnesium bromide;Bromo(4-fluorophenyl)magnesium;bromo(p-fluorophenyl)Magnesium;p-Fluorophenylmagnesium bromide | 352-13-6 | C6H4BrFMg | 详情 | 详情 |
| (XVIII) | 37598 | [4-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-2-(hydroxymethyl)phenyl](4-fluorophenyl)methanone | C19H18FNO3 | 详情 | 详情 | |
| (XIX) | 12587 | Chloro[3-(dimethylamino)propyl]magnesium | C5H12ClMgN | 详情 | 详情 | |
| (XX) | 37599 | 4-(dimethylamino)-1-[4-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-2-(hydroxymethyl)phenyl]-1-(4-fluorophenyl)-1-butanol | C24H31FN2O3 | 详情 | 详情 | |
| (XXI) | 44337 | (1S)-4-(dimethylamino)-1-[4-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-2-(hydroxymethyl)phenyl]-1-(4-fluorophenyl)-1-butanol | C24H31FN2O3 | 详情 | 详情 | |
| (XXII) | 44338 | N-[3-[(1S)-5-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-1-yl]propyl]-N,N-dimethylamine; 3-[(1S)-5-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-1-yl]-N,N-dimethyl-1-propanamine | C24H29FN2O2 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(L)The iodophenyl propionic acid (XLVIII) was protected as the oxazoline (LII) via activation as the corresponding acid chloride (XLIX), which was condensed with 2-amino-2-methylpropanol (L) to yield amide (LI). Subsequent cyclization of hydroxy amide (LI) by treatment with phosphorus oxychloride led to oxazoline (LII). Palladium coupling between aryl iodide (LII) and the Grignard reagent (VIII) provided the biaryl adduct (LIII). The oxazoline (LIII) was then hydrolyzed to (IX) with sulfuric acid and AcOH
| 【2】 Arai, H.; Tanaka, K.; Watanabe, I.; Kodama, T.; Hirano, H.; Abe, N.; Nakabayashi, M. (Toyama Chemical Co., Ltd.); Novel 2-[4-(3-methyl-2-thienyl)phenyl]propionic acid and pharmaceutically acceptable salt thereof and method for treating symptoms of inflammation and pain. US 4230719 . |
| 【1】 Kodama, T.; Nakabayashi, M.; Watanabe, I.; Hirano, Y.; Abe, N.; Tanaka, K.; Arai, H. (Toyama Chemical Co., Ltd.); 2-[4-(3-Methyl-2-thienyl)phenyl]propionic acid derivs. and its non-toxic salts. DE 2850485; JP 1981049376 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIII) | 36973 | bromo(3-methyl-2-thienyl)magnesium | C5H5BrMgS | 详情 | 详情 | |
| (IX) | 62687 | 2-[4-(3-methyl-2-thienyl)phenyl]propanoic acid | C14H14O2S | 详情 | 详情 | |
| (XLVIII) | 62718 | 2-(4-iodophenyl)propanoic acid | C9H9IO2 | 详情 | 详情 | |
| (XLIX) | 62719 | 2-(4-iodophenyl)propanoyl chloride | C9H8ClIO | 详情 | 详情 | |
| (L) | 21513 | 2-amino-2-methyl-1-propanol；Karl Fischer;2-Amino-2-methyl-propan-1-ol；2-amino-2-methyl-1-propanol | 124-68-5 | C4H11NO | 详情 | 详情 |
| (LI) | 62720 | N-(2-hydroxy-1,1-dimethylethyl)-2-(4-iodophenyl)propanamide | C13H18INO2 | 详情 | 详情 | |
| (LII) | 62721 | 2-[1-(4-iodophenyl)ethyl]-4,4-dimethyl-4,5-dihydro-1,3-oxazole | C13H16INO | 详情 | 详情 | |
| (LIII) | 62722 | 4,4-dimethyl-2-{1-[4-(3-methyl-2-thienyl)phenyl]ethyl}-4,5-dihydro-1,3-oxazole | C18H21NOS | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(II)A different synthetic strategy requires the precursor phthalide derivative (V), which is prepared by two related ways. 3,4,5-Trimethoxybenzoyl chloride (I) is condensed with 2-amino-2-methyl-1-propanol (II), and the resultant hydroxy amide is further cyclized with SOCl2 to the oxazoline (III). Lithiation of (III), followed by addition to veratraldehyde (IV) and acidic oxazoline hydrolysis, leads to the target lactone (V). Alternatively, isobenzofuranone (V) is obtained by direct condensation between trimethoxybenzoic acid (VI) and veratraldehyde (IV) in the presence of polyphosphoric acid.
| 【1】 Mori, S.; et al.; Convergent synthesis of S-8921, a new potent hypocholesterolemic arylnapththalene lignan analog. Tetrahedron Lett 1999, 40, 6, 1165. |
| 【2】 Mori, S.; Takechi, S.; Kida, S. (Shionogi & Co. Ltd.); Process for producing lignan cpd.. EP 0646570; WO 9424087 . |
| 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) | 13571 | 3,4,5Ttrimethoxybenzoyl chloride | 4521-61-3 | C10H11ClO4 | 详情 | 详情 |
| (II) | 21513 | 2-amino-2-methyl-1-propanol；Karl Fischer;2-Amino-2-methyl-propan-1-ol；2-amino-2-methyl-1-propanol | 124-68-5 | C4H11NO | 详情 | 详情 |
| (III) | 57442 | 4-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-2,6-dimethoxyphenyl methyl ether; 4,4-dimethyl-2-(3,4,5-trimethoxyphenyl)-4,5-dihydro-1,3-oxazole | C14H19NO4 | 详情 | 详情 | |
| (IV) | 18304 | 3,4-Dimethoxybenzaldehyde; Veratraldehyde | 120-14-9 | C9H10O3 | 详情 | 详情 |
| (V) | 57443 | 3-(3,4-dimethoxyphenyl)-4,5,6-trimethoxy-2-benzofuran-1(3H)-one | C19H20O7 | 详情 | 详情 | |
| (VI) | 32225 | 3,4,5-trimethoxybenzoic acid | 118-41-2 | C10H12O5 | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(IV)Alkylation of methyl 3,5-dihydroxybenzoate (I) with benzyl bromide in the presence of NaH gave dibenzyl ether (II). Subsequent basic hydrolysis of the ester function of (II) provided carboxylic acid (III). This was protected as the oxazoline (VI) via conversion into acid chloride with SOCl2, followed by coupling with 2-amino-2-methyl-1-propanol (IV), and then cyclization of the hydroxy amide (V) with SOCl2. After lithiation of (VI) with n-BuLi at -78 C, the 2-benzyl substituent was introduced by treatment with benzyl bromide to afford (VII). Quaternization of (VII) with boiling CH3I provided iminium salt (VIII), which was reduced with NaBH4 and then hydrolyzed to aldehyde (IX). Hydantoin (X) was then prepared from (IX) under Bucherer-Bergs conditions in the presence of KCN and (NH4)2CO3. Finally, hydrogenolytic cleavage of the O-benzyl groups, of (X) yielded (XI), which by basic hydrolysis of the hydantoin ring provided the title amino acid.
| 【1】 Baker, S.R.; et al.; Synthesis and pharmacological evaluation of benzamides as selective 5-HT4 receptor agonists. 15th European Federation for Medicinal Chemistry International Symposium on Medicinal Chemistry (Sept 6 1998, Edinburgh) 1998, Abs P 270. |
| 【2】 Baker, S.R.; Clark, B.P.; Goldsworthy, J.; Harris, J.R. (Eli Lilly and Company); Derivs. of phenylglycine and use thereof as pharmaceuticals. EP 0807621; JP 1998067723; US 5863947 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 12912 | 1-(Bromomethyl)benzene; Alpha-bromotoluene | 100-39-0 | C7H7Br | 详情 | 详情 | |
| (I) | 25155 | methyl 3,5-dihydroxybenzoate | 2150-44-9 | C8H8O4 | 详情 | 详情 |
| (II) | 25156 | methyl 3,5-bis(benzyloxy)benzoate | C22H20O4 | 详情 | 详情 | |
| (III) | 25157 | 3,5-bis(benzyloxy)benzoic acid | 28917-43-3 | C21H18O4 | 详情 | 详情 |
| (IV) | 21513 | 2-amino-2-methyl-1-propanol；Karl Fischer;2-Amino-2-methyl-propan-1-ol；2-amino-2-methyl-1-propanol | 124-68-5 | C4H11NO | 详情 | 详情 |
| (V) | 25158 | 3,5-bis(benzyloxy)-N-(2-hydroxy-1,1-dimethylethyl)benzamide | C25H27NO4 | 详情 | 详情 | |
| (VI) | 25159 | benzyl 3-(benzyloxy)-5-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)phenyl ether | C25H25NO3 | 详情 | 详情 | |
| (VII) | 25160 | 2-[2-benzyl-3,5-bis(benzyloxy)phenyl]-4,4-dimethyl-4,5-dihydro-1,3-oxazole | C32H31NO3 | 详情 | 详情 | |
| (VIII) | 25161 | 2-[2-benzyl-3,5-bis(benzyloxy)phenyl]-3,4,4-trimethyl-4,5-dihydro-1,3-oxazol-3-ium iodide | C33H34INO3 | 详情 | 详情 | |
| (IX) | 25162 | 2-benzyl-3,5-bis(benzyloxy)benzaldehyde | C28H24O3 | 详情 | 详情 | |
| (X) | 25163 | 5-[2-benzyl-3,5-bis(benzyloxy)phenyl]-2,4-imidazolidinedione | C30H26N2O4 | 详情 | 详情 | |
| (XI) | 25164 | 5-(2-benzyl-3,5-dihydroxyphenyl)-2,4-imidazolidinedione | C16H14N2O4 | 详情 | 详情 |
合成路线11
该中间体在本合成路线中的序号：(V)N-Protection of 2-methylalanine with Boc2O, optionally in the presence of NaHCO3, in THF/H2O yields N-Boc-2-methylalanine (II) , which is then methylated with Me3SiCHN2 in MeOH/THF or with MeI using KHCO3 in DMF to give the methyl ester (III) . Reduction of the ester (III) by means of LiBH4 in THF /EtOH affords the primary alcohol (IV) , which can also be prepared from 2-amino-2-methyl-1-propanol (V) by N-protection with Boc2O in CH2Cl2 . After conversion of alcohol (IV) to the corresponding mesylate (VI) with MsCl and Et3N in CH2Cl2, N-deprotection with HCl in dioxane provides amine (VII), which by reaction with Na2SO3 in H2O yields the aminosulfonic acid (VIII) . Finally, compound (VIII) is N-chlorinated using trichloroisocyanuric acid , Cl2 , HOCl or NaOCl/HCl .
The aminosulfonic acid (VIII) can also be prepared by the following two strategies: Condensation of acetone (IX) with t-BuSONH2 by means of Ti(OEt)4 gives the N-sulfinylimine (X), which is then coupled with ethyl methanesulfonate (XI) in the presence of BuLi and HMPA in THF to produce the propanesulfonate derivative (XII). Finally, hydrolysis of the sulfonate ester (XII) with LiOH in THF/MeOH/H2O, followed by removal of the sulfinyl protecting group with HCl in MeOH furnishes aminosulfonic acid (VIII) .
Reduction of 2-hydroxy-2-methylpropanenitrile (XIII) by means of LiAlH4 yields 1-amino-2-methylpropan-2-ol (XIV), which is then Nprotected with Boc2O to give N-Boc-1-amino-2-methylpropan-2-ol (XV). Mesylation of the alcohol (XV) with MsCl using Et3N in CH2Cl2 and subsequent N-deprotection of the resulting mesylate (XVI) with HCl in dioxane affords the amino mesylate (XVII). Finally, substitution of the tertiary mesylate (XVII) with Na2SO3 occurs with rearrangement of the primary amino group generating aminosulfonic acid (VIII) .
| 【1】 Shiau, T.P., Houchin, A., Nair, S., Xu, P., Low, E., Najafi, R., Jain, R. Stieglitz rearrangement of N,N-dichloro-beta,beta-disubstituted taurines under mild aqueous conditions. Bioorg Med Chem Lett 2009, 19(4): 1110-4. |
| 【2】 Braghiroli, D., DiBella, M. New methods for the preparation of 2-amino-2-methylpropanesulfonic acid. Tetrahedron Lett 1996, 37(40): 7319-. |
| 【3】 Ilson, B.E. et al. Effect of a new synthetic hexapetide to selectively stimulate growth hormone release in healthy human subjects. J Clin Endocrinol Metab 1989, 69(1): 212. |
| 【4】 Wang, L., Khosrovi, B., Najafi, R. N-Chloro-2,2-dimethyltaurines: A new class of remarkably stable N-chlorotaurines. Tetrahedron Lett 2008, 49(14): 2193-5. |
| 【5】 Debabov, D. NVC-422, a novel n-chlorotaurine derivative as topical antimicrobial. Drug Discov Chem 2010, Abst. |
| 【6】 Najafi, R., Wang, L., Bassiri, M., Yang, J. (NovaBay Pharmaceuticals, Inc.). N,N-Dihalogenated amino acids and derivatives. CA 2535926, EP 1656095, JP 2007502826, US 2005065115, US 7462361, WO 2005020896. |
| 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) | 31173 | 2-methylalanine；2-Aminoisobutyric acid;2-Amino-2-methylpropionic acid;alpha-Aminoisobutyric acid | 62-57-7 | C4H9NO2 | 详情 | 详情 |
| (II) | 18471 | N-(tert-butoxycarbonyl)-2-methylalanine | 30992-29-1 | C9H17NO4 | 详情 | 详情 |
| (III) | 68833 | methyl 2-((tert-butoxycarbonyl)amino)-2-methylpropanoate | C10H19NO4 | 详情 | 详情 | |
| (IV) | 68834 | tert-butyl (1-hydroxy-2-methylpropan-2-yl)carbamate;tert-ButylN-(2-hydroxy-1,1-dimethylethyl)carbamate;tert-Butyl(2-hydroxy-1,1-dimethylethyl)carbamate;1,1-Dimethylethyl(2-hydroxy-1,1-dimethylethyl)carbamate;(2-Hydroxy-1,1-dimethylethyl)carbamicacid tert-butyl ester | 102520-97-8 | C9H19NO3 | 详情 | 详情 |
| (V) | 21513 | 2-amino-2-methyl-1-propanol；Karl Fischer;2-Amino-2-methyl-propan-1-ol；2-amino-2-methyl-1-propanol | 124-68-5 | C4H11NO | 详情 | 详情 |
| (VI) | 68835 | 2-((tert-butoxycarbonyl)amino)-2-methylpropyl methanesulfonate | C10H21NO5S | 详情 | 详情 | |
| (VII) | 68836 | 2-amino-2-methylpropyl methanesulfonate hydrochloride | C5H13NO3S.HCl | 详情 | 详情 | |
| (VIII) | 68837 | 2-amino-2-methylpropyl hydrogen sulfate | C4H11NO4S | 详情 | 详情 | |
| (IX) | 23199 | 2-Propanone; Acetone; beta-ketopropane; chevron acetone;propan-2-one； Dimethyl formaldehyde; Dimethyl ketone; dimethylketal; Ketone propane; Methyl ketone; Propanone; Pyroacetic acid; Pyroacetic ether | 67-64-1 | C3H6O | 详情 | 详情 |
| (X) | 68838 | 2-methyl-N-(propan-2-ylidene)propane-2-sulfinamide | C7H15NOS | 详情 | 详情 | |
| (XI) | 48097 | ethyl methanesulfonate；ethylmesylate;ethyl methanesulphonate；O-ethylmethylsulfonate | 62-50-0 | C3H8O3S | 详情 | 详情 |
| (XII) | 68839 | ethyl 2-(1,1-dimethylethylsulfinamido)-2-methylpropane-1-sulfonate | C10H23NO4S2 | 详情 | 详情 | |
| (XIII) | 18029 | Acetone cyanohydrin; 2-Hydroxy-2-methylpropanenitrile; 2-Hydroxy-2-methylpropionitrile; 2-Hydroxyisobutyronitrile; 2-Methyllactonitrile; alpha-Hydroxyisobutyronitrile | 75-86-5 | C4H7NO | 详情 | 详情 |
| (XIV) | 25008 | 1-amino-2-methylpropan-2-ol;1-amino-2-methyl-2-propanol;1,1-Dimethylethanolamine;2-Amino-a,a-dimethylethanol;2-Hydroxy-2-methyl-1-propylamine;2-Hydroxyisobutylamine;2-Methyl-2-hydroxypropylamine;3-Amino-2-methyl-2-propanol | 2854-16-2 | C4H11NO | 详情 | 详情 |
| (XV) | 68840 | tert-butyl (2-hydroxy-2-methylpropyl)carbamate;(2-hydroxy-2-methylpropyl)-1,1-dimethylethyl ester Carbamicacid;N-(2-hydroxy-2-methylpropyl)-1,1-dimethylethyl ester Carbamic acid | 183059-24-7 | C9H19NO3 | 详情 | 详情 |
| (XVI) | 68841 | 1-((tert-butoxycarbonyl)amino)-2-methylpropan-2-yl methanesulfonate | C10H21NO5S | 详情 | 详情 | |
| (XVII) | 68842 | 1-amino-2-methylpropan-2-yl methanesulfonate hydrochloride | C5H13NO3S.HCl | 详情 | 详情 |
合成路线12
该中间体在本合成路线中的序号：(VIII)Oxazoline intermediate (V) can also be prepared by condensation of ethyl 2-[4-(2-hydroxyethyl)phenyl]-2-methylpropionate (VII) with 2-amino-2-methyl-1-propanol (VIII) by means of t-BuOK in CH2Cl2, followed by cyclization with SOCl2 in acetonitrile to give the oxazoline (IX), which is then condensed with 1-(2-ethoxyethyl)-2-(4-piperidyl)benzimidazole (X) in the presence of Na2CO3 in refluxing MeOH .
| 【1】 Lee, C.-H., Khoo, J.-H., Kwon, K.-C., Ju, H. (Yuhan Corp.). Process for preparation of 2-methyl-2’-phenylpropionic acid derivatives and novel intermediate compounds. WO 2009102155. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (V) | 54968 | 2-[2-(1-{4-[1-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-1-methylethyl]phenethyl}-4-piperidinyl)-1H-benzimidazol-1-yl]ethyl ethyl ether; 2-(1-{4-[1-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-1-methylethyl]phenethyl}-4-piperidinyl)-1-(2-ethoxyethyl)-1H-benzimidazole | C32H44N4O2 | 详情 | 详情 | |
| (VII) | 69010 | ethyl 2-[4-(2-hydroxyethyl)phenyl]-2-methylpropionate | C14H20O3 | 详情 | 详情 | |
| (VIII) | 21513 | 2-amino-2-methyl-1-propanol；Karl Fischer;2-Amino-2-methyl-propan-1-ol；2-amino-2-methyl-1-propanol | 124-68-5 | C4H11NO | 详情 | 详情 |
| (IX) | 69011 | 2-(2-(4-(2-chloroethyl)phenyl)propan-2-yl)-4,4-dimethyl-4,5-dihydrooxazole | C16H22ClNO | 详情 | 详情 | |
| (X) | 69012 | 1-(2-ethoxyethyl)-2-(4-piperidyl)benzimidazole;1-(2-ethoxyethyl)-2-(piperidin-4-yl)-1H-benzo[d]imidazole | C16H23N3O | 详情 | 详情 |