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【结 构 式】 
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【分子编号】10039 【品名】(1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine 【CA登记号】3886-69-9 |
【 分 子 式 】C8H11N 【 分 子 量 】121.18208 【元素组成】C 79.29% H 9.15% N 11.56% |
合成路线1
该中间体在本合成路线中的序号：(II)A new synthesis of YM-12617-1, the active R-isomer of YM-12617, has been described: The reductocondensation of 1-(4-methoxyphenyl)-2-propanone (I) with R-1-phenylethylamine (II) gives regioselectively the secondary amine (III) as the HCl salt, which by sulfonation with chlorosulfonic acid and treatment with NH4OH yields (R,R)-2-methoxy-5-[2-(1-phenylethylamino)propyl]benzenesulfonamide (IV). Eliminating the protecting group by hydrogenation, the free amine hydrochloride (V) is obtained, which is finally submitted to a reductocondensation with 2-(2-ethoxyphenoxy)acetaldehyde (VI) by means of sodium borohydride in methanol, and treated with HCl in ether.
| 【1】 Hunden, D.C.; Wheller, W.J.; Schmiegel, K.K.; The synthesis of the 14C and 2H-isotopomers of (R)-N-[2-(2'-ethoxyphenoxy)-ethyl]-N-2-[3-(4'-methoxy-3'-sulfonamido)-phenyl]-propylamine hydrochloride, an alpha1-adrenoreceptor antagonist. J Label Compd Radiopharm 1989, 26, 2, 171. |
| 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) | 10038 | 4-Methoxyphenylacetone; 1-(4-Methoxyphenyl)acetone | 122-84-9 | C10H12O2 | 详情 | 详情 |
| (II) | 10039 | (1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine | 3886-69-9 | C8H11N | 详情 | 详情 |
| (III) | 10040 | (2R)-1-(4-Methoxyphenyl)-N-[(1R)-1-phenylethyl]-2-propanamine; N-[(1R)-2-(4-Methoxyphenyl)-1-methylethyl]-N-[(1R)-1-phenylethyl]amine | C18H23NO | 详情 | 详情 | |
| (IV) | 10041 | 2-Methoxy-5-((2R)-2-[[(1R)-1-phenylethyl]amino]propyl)benzenesulfonamide | C18H24N2O3S | 详情 | 详情 | |
| (V) | 10042 | 5-[(2R)-2-Aminopropyl]-2-methoxybenzenesulfonamide | 112101-81-2 | C10H16N2O3S | 详情 | 详情 |
| (VI) | 10043 | 2-(2-Ethoxyphenoxy)acetaldehyde | 103181-55-1 | C10H12O3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)The reaction of dl-l-phenylethylamine (I) with ethyl chloroacetate (II) by means of triethylamine in DMF gives dl-N-[(ethoxycarbonyl)methyl]-1-phenylethylamine (III), which is then treated with formic acid in refluxing xylene yielding dl-N-formyl-N-[(ethoxycarbonyl)methyl]-1-phenylethylamine (IV). The reaction of (IV) with sodium ethoxide and ethyl formate (A) in THF affords dl-N-formyl-N-[(ethoxycarbonyl)-2-hydroxyvinyl]-1-phenylethylamine (V), which, without purification, is treated with potassium thiocyanate and HCl in diisopropyl ether to give dl-l-(phenylethyl)-2-mercapto-5-ethoxycarbonylimidazole (VI). This product is finally treated with nitric acid and sodium nitrate at room temperature. The optical active drugs can be obtained starting the synthesis with the optically active amine (I).
| 【1】 Godefroi, E.F.; et al.; Imidazole carboxylates. BE 0662474; DE 1545988; FR 4499M; GB 1064531; US 3354173 . |
| 【2】 Roberts, P.J.; Castaner, J.; Etomidate. Drugs Fut 1976, 1, 10, 461. |
| 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) | 16602 | ethyl formate | 109-94-4 | C3H6O2 | 详情 | 详情 |
| (I) | 10039 | (1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine | 3886-69-9 | C8H11N | 详情 | 详情 |
| (II) | 16601 | ethyl chloroacetate; ethyl 2-chloroacetate | 105-39-5 | C4H7ClO2 | 详情 | 详情 |
| (III) | 34103 | ethyl 2-[[(1R)-1-phenylethyl]amino]acetate | C12H17NO2 | 详情 | 详情 | |
| (IV) | 34104 | ethyl 2-[formyl[(1R)-1-phenylethyl]amino]acetate | C13H17NO3 | 详情 | 详情 | |
| (V) | 34105 | ethyl (Z)-2-[formyl[(1R)-1-phenylethyl]amino]-3-hydroxy-2-propenoate | C14H17NO4 | 详情 | 详情 | |
| (VI) | 34106 | ethyl 1-[(1R)-1-phenylethyl]-2-sulfanyl-1H-imidazole-5-carboxylate | C14H16N2O2S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(IV)The synthesis of the two enantiomers of flosequinan has been described: The reaction of 7-fluoro-3-(methylsulfanyl)quinolin-4(1H)-one (I) with POCl3 in refluxing CHCl3 gives the corresponding chloroquinoline (II), which by oxidation with m-chloroperbenzoic acid (m-CPBA) in CHCl3/water yields 4-chloro-7-fluoro-3-(methylsulfinyl)quinoline (III). The condensation of (III) with (R)-1-phenylethylamine (IV) affords the secondary amine (V) as a diastereomeric mixture that is separated by fractional crystallization to afford the two diastereomers (VI)-(S) and (VI)-(R). Both compounds are treated with hot 1N HCl to afford (S)-4-amino-7-fluoro-3-(methylsulfinyl)quinoline (VII)-(S) and (R)-4-amino-7-fluoro-3-(methylsulfinyl)quinoline (VII)-(R), respectively. Finally, (VII)-(S) and (VII)-(R) are treated with methyl iodide in hot butanone to afford (S)-flosequinan and (R)-flosequinan, respectively.
| 【1】 Ohtani, T.; Kido, M.; Shimizu, T.; Matsubara, J.; Morita, S.; Ohtsubo, K.; Uchida, M.; Synthesis and absolute configuration of the enantiomers of 7-fluoro-1-methyl-3-(methylsulfinyl)-4(1H)-quinolinone (flosequinan). Chem Pharm Bull 1994, 42, 10, 2157. |
| 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)-(S) | 10814 | 7-Fluoro-3-(methylsulfinyl)-N-[(1R)-1-phenylethyl]-4-quinolinamine; N-[7-Fluoro-3-(methylsulfinyl)-4-quinolinyl]-N-[(1R)-1-phenylethyl]amine | C18H17FN2OS | 详情 | 详情 | |
| (VII)-(S) | 10815 | 7-Fluoro-3-(methylsulfinyl)-4-quinolinylamine; 7-Fluoro-3-(methylsulfinyl)-4-quinolinamine | C10H9FN2OS | 详情 | 详情 | |
| (VI)-(R) | 17617 | N-[7-fluoro-3-(methylsulfinyl)-4-quinolinyl]-N-[(1R)-1-phenylethyl]amine; 7-fluoro-3-(methylsulfinyl)-N-[(1R)-1-phenylethyl]-4-quinolinamine | C18H17FN2OS | 详情 | 详情 | |
| (VII)-(R) | 17618 | 7-fluoro-3-(methylsulfinyl)-4-quinolinamine; 7-fluoro-3-(methylsulfinyl)-4-quinolinylamine | C10H9FN2OS | 详情 | 详情 | |
| (I) | 10809 | 7-Fluoro-3-(methylsulfanyl)-4(1H)-quinolinone | C10H8FNOS | 详情 | 详情 | |
| (II) | 10810 | 4-Chloro-7-fluoro-3-quinolinyl methyl sulfide; 4-Chloro-7-fluoro-3-(methylsulfanyl)quinoline | C10H7ClFNS | 详情 | 详情 | |
| (III) | 10811 | 4-Chloro-7-fluoro-3-(methylsulfinyl)quinoline; 4-Chloro-7-fluoro-3-quinolinyl methyl sulfoxide | C10H7ClFNOS | 详情 | 详情 | |
| (IV) | 10039 | (1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine | 3886-69-9 | C8H11N | 详情 | 详情 |
| (V) | 10813 | 7-Fluoro-3-(methylsulfinyl)-N-[(1R)-1-phenylethyl]-4-quinolinamine; N-[7-Fluoro-3-(methylsulfinyl)-4-quinolinyl]-N-[(1R)-1-phenylethyl]amine | C18H17FN2OS | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(A)An alternative procedure involves hydrolysis of racemic ethyl 2-(2-oxopyrrolidin-1-yl)burytate (VI) with sodium hydroxide to give racemic 2-(2-oxopyrrolidin-1-yl)butyric acid (VII), which is resolved by fractional crystallization with (R)-(+)-alpha-methylbenzylamine in benzene, followed by acid-base treatment to give (S)-2-(2-oxopyrrolidin-1-yl)butyric acid (VIII). Compound (VIII) is finally treated with ethyl chloroformiate and ammonia in dichloromethane.
| 【1】 Cossement, E.; Motte, G.; Geerts, J.-P.; Gobert, J. (UCB SA); The preparation of S-alpha-ethyl-2-oxo-1-pyrrolidineacetamide. GB 2225322 . |
| 【2】 Castaner, J.; Prous, J.; Mealy, N.; Levetiracetam. Drugs Fut 1994, 19, 2, 111. |
| 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) | 10039 | (1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine | 3886-69-9 | C8H11N | 详情 | 详情 |
| (VI) | 11267 | ethyl 2-(2-oxo-1-pyrrolidinyl)butanoate | C10H17NO3 | 详情 | 详情 | |
| (VII) | 11268 | 2-(2-Oxo-1-pyrrolidinyl)butyric acid | 67118-31-4 | C8H13NO3 | 详情 | 详情 |
| (VIII) | 11269 | (2S)-2-(2-Oxo-1-pyrrolidinyl)butyric acid | 102849-49-0 | C8H13NO3 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(IV)The benzoylation of thiazolidine-4(R)-carboxylic acid (I) with benzoyl chloride (II) by means of NaOH in acetone water gives the corresponding N-benzoyl derivative (III), which is then condensed with alpha-(R)-methylbenzylamine (IV) by means of isobutyl chloroformate and triethylamine in dichloromethane.
| 【1】 Matsui, T.; Nagano, M.; KLitamura, K.; Shimizu, F. (Sankyo Co., Ltd.); Amino acid derivatives having anti-tumor activity and compositions containing them.. EP 0173441; ES 8703830; US 4904680 . |
| 【2】 Castaner, J.; Prous, J.; RS-0481. Drugs Fut 1988, 13, 7, 627. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 13423 | 1-[(Chlorocarbonyl)oxy]-2-methylpropane; Isobutyl chloroformate;isobutyl carbonochloridate | 543-27-1 | C5H9ClO2 | 详情 | 详情 | |
| (I) | 12899 | L-(-)-Thiazolidine-4-carboxylic acid; (4R)-1,3-Thiazolidine-4-carboxylic acid; (R)-(-)-Thiazolidine-4-carboxylic acid | 34592-47-7 | C4H7NO2S | 详情 | 详情 |
| (II) | 10463 | Benzoyl chloride | 98-88-4 | C7H5ClO | 详情 | 详情 |
| (III) | 22557 | (4R)-3-benzoyl-1,3-thiazolidine-4-carboxylic acid | C11H11NO3S | 详情 | 详情 | |
| (IV) | 10039 | (1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine | 3886-69-9 | C8H11N | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(XLI)5) The thermal rearrangement of 3-bromo-4,6-dimethyl-2-oxo-2H-pyran-5-carboxylic acid ethyl ester (XXXIX) with NaOH in refluxing water gives (rac)-trans-3-methylenecyclopropane-1,2-dicarboxylic acid (XL), which was submitted to optical resolution with (R)-alpha-methylbenzylamine (XLI) yielding, after crystallization, the corresponding (R,R)-enantiomeric salt (XLII). The decomposition of the salt and esterification of the free acid with trimethyl orthoformate affords (1R-trans)-3-methylenecyclopropane-1,2-dicarboxylic acid dimethyl ester (XLIII), which is reduced with LiAlH4 in THF to (1R-trans)-3-methylenecyclopropane-1,2-dimethanol (XLIV). The esterification of (XLIV) with benzoic anhydride and triethylamine in ethyl acetate affords the corresponding dibenzoate (XLV), which is epoxidized with m-chloroperbenzoic acid (MCPBA) in dichloromethane to afford the oxirane (XLVI). The isomerization of (XLVI) by means of LiI in ethyl acetate gives (2S-trans)-2,3-bis(benzoyloxymethyl)cyclobutanone (IX), which is reduced with lithium trisiamylborohydride in THF yielding [1S-(1alpha,2beta,3beta)]-3-hydroxycyclobutane-1,2-dimethanol 1,2-dibenzoate ester (X). The reaction of (X) with p-toluenesulfonyl chloride in pyridine affords the corresponding tosylate (XI), which is condensed with 6-O-benzylguanine (XII) by means of K2CO3 and 18-crown-6 in DMF yielding the substituted guanine (XIII). Finally, this compound is deprotected by treatment first with sodium methoxide in hot methanol, and then with 3N HCl.
| 【1】 Ireland, C.; Leeson, P.A.; Castaner, J.; Lobucavir. Drugs Fut 1997, 22, 4, 359. |
| 【2】 Godfrey, J.D. Jr.; Mueller, R.H.; Kissick, T.P.; Singh, J. (Bristol-Myers Squibb Co.); Process and intermediates for the preparation of an antiviral agent containing a cyclobutyl group. EP 0535448 . |
| 【3】 Godfrey, J.D. Jr.; Mueller, R.H.; Kissick, T.P.; Singh, J. (Bristol-Myers Squibb Co.); Process for the preparation of an antiviral agent. US 5525726 . |
| 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) | 14380 | [(1S,2S)-2-[(benzoyloxy)methyl]-4-oxocyclobutyl]methyl benzoate | C20H18O5 | 详情 | 详情 | |
| (X) | 14381 | [(1S,2S,4S)-2-[(benzoyloxy)methyl]-4-hydroxycyclobutyl]methyl benzoate | C20H20O5 | 详情 | 详情 | |
| (XI) | 14382 | ((1S,2S,3S)-2-[(benzoyloxy)methyl]-3-[[(4-methylphenyl)sulfonyl]oxy]cyclobutyl)methyl benzoate | C27H26O7S | 详情 | 详情 | |
| (XII) | 14383 | 6-(benzyloxy)-9H-purin-2-ylamine; 6-(benzyloxy)-9H-purin-2-amine | 19916-73-5 | C12H11N5O | 详情 | 详情 |
| (XIII) | 63903 | [(1R,2R,4S)-2-[2-amino-6-(benzyloxy)-9H-purin-9-yl]-4-(hydroxymethyl)cyclobutyl]methanol | C18H21N5O3 | 详情 | 详情 | |
| (XXXIX) | 14410 | ethyl 3-bromo-2-hydroxy-4,6-dimethyl-2H-pyran-5-carboxylate | C10H13BrO4 | 详情 | 详情 | |
| (XL) | 14411 | (1R,2R)-3-methylene-1,2-cyclopropanedicarboxylic acid | 499-02-5 | C6H6O4 | 详情 | 详情 |
| (XLI) | 10039 | (1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine | 3886-69-9 | C8H11N | 详情 | 详情 |
| (XLII) | 14412 | (R,R)-3-methylenecyclopropane-1,2-dicarboxylic acid (R)-1-phenylethylamine salt | C14H17NO4 | 详情 | 详情 | |
| (XLIII) | 14413 | dimethyl (1R,2R)-3-methylene-1,2-cyclopropanedicarboxylate | C8H10O4 | 详情 | 详情 | |
| (XLIV) | 14414 | [(1R,2R)-2-(hydroxymethyl)-3-methylenecyclopropyl]methanol | C6H10O2 | 详情 | 详情 | |
| (XLV) | 14415 | [(1R,2R)-2-[(benzoyloxy)methyl]-3-methylenecyclopropyl]methyl benzoate | C20H18O4 | 详情 | 详情 | |
| (XLVI) | 14416 | [(4S,5S)-5-[(benzoyloxy)methyl]-1-oxaspiro[2.2]pent-4-yl]methyl benzoate | C20H18O5 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(XIII)The chiral intermediate (1R,2S)-N-(tert-butoxycarbonyl)-2-fluorocyclopropylamine (III) is obtained as follows: 1) The cyclization of butadiene (IX) with dibromofluoromethane by means of BuONa, followed by oxidation with KMnO4, esterification with ethanol - sulfuric acid and reduction with tributyltin hydride gives 2-fluorocyclopropanecarboxylic acid ethyl ester as a cis/trans mixture (X), which is separated by crystallization. The cis-racemic-isomer (XI) is hydrolyzed with NaOH to the corresponding acid (XII), which is condensed with (R)-alpha-methylbenzylamine (XIII) by means of diphenyl chlorophosphate to give the mixture of diastereomers (XIV). This mixture is separated by crystallization, yielding pure (1S,2S)-2-fluoro-N-[alpha(R)-methylbenzyl]cyclopropanecarboxamide (XV), which is hydrolyzed with HCl to the corresponding free acid (XVI). Finally, this compound is converted into (III) by treatment with diphenylphosphoryl azide in refluxing tert-butanol.
| 【1】 Hayakawa, I.; Kimura, Y. (Daiichi Pharmaceutical Co., Ltd.); Optically active pyridone carboxylic acid derivs. AU 8933702; EP 0341493; JP 1990231475; JP 1995300416; JP 1999124367; JP 1999124380; US 5587386; US 5767127 . |
| 【2】 Castaner, J.; Graul, A.; Prous, J.; DU-6859. Drugs Fut 1994, 19, 9, 827. |
| 【3】 Sato, K.; Saito, T.; Hayakawa, I.; Sato, M.; Yafune, T.; Atarashi, S.; Une, T.; Kimura, Y.; Kawakami, K.; Design and structure-activity relationship of new N1-cis-2-fluorocyclopropyl quinolones. 31st. 31st Intersci Conf Antimicrob Agents Chemother (Sept 29-Oct 2, Chicago) 1991, Abst 1504. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIVa) | 15139 | (1S,2S)-2-fluoro-N-[(1R)-1-phenylethyl]cyclopropanecarboxamide | C12H14FNO | 详情 | 详情 | |
| (XIVb) | 63959 | (1S,2R)-2-fluoro-N-[(1R)-1-phenylethyl]cyclopropanecarboxamide | C12H14FNO | 详情 | 详情 | |
| (III) | 15127 | tert-butyl N-[(1R,2S)-2-fluorocyclopropyl]carbamate | 127199-16-0 | C8H14FNO2 | 详情 | 详情 |
| (IX) | 11579 | 1,3-Butadiene; Butadiene | 106-99-0 | C4H6 | 详情 | 详情 |
| (X) | 15134 | ethyl 2-fluorocyclopropanecarboxylate | C6H9FO2 | 详情 | 详情 | |
| (XI) | 63960 | cis-rac[ethyl (1S,2S)-2-fluorocyclopropanecarboxylate] | C6H9FO2 | 详情 | 详情 | |
| (XII) | 63958 | cis-rac(1S,2S)-2-fluorocyclopropanecarboxylic acid | C4H5FO2 | 详情 | 详情 | |
| (XIII) | 10039 | (1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine | 3886-69-9 | C8H11N | 详情 | 详情 |
| (XV) | 15139 | (1S,2S)-2-fluoro-N-[(1R)-1-phenylethyl]cyclopropanecarboxamide | C12H14FNO | 详情 | 详情 | |
| (XVI) | 15140 | (1S,2S)-2-fluorocyclopropanecarboxylic acid | C4H5FO2 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(XIII)b) The intermediate 7(S)-(tert-Butoxycarbonylamino)-5-azaspiro[2.4]heptane (VII) can also be obtained as follows: 1) The cyclopropanation of ethyl acetoacetate (XXXI) with 1,2-dibromoethane (XXXII) by means of K2CO3 in DMF gives 1-acetylcyclopropane-1-carboxylic acid ethyl ester (XXXIII), which is brominated with Br2 in ethanol yielding the bromoacetyl derivative (XXXIV). The cyclization of (XXXI) with (R)-alpha-methylbenzylamine (XIII) by means of triethylamine affords 5-[1(R)-phenylethyl]-5-azaspiro[2.4]heptane-4,7-dione (XXXV), which by reaction with hydroxylamine is converted into the monooxime (XXXVI). The reduction of (XXXVI) with H2 over RaNi in methanol affords 7-amino-5-[1(R)-phenylethyl]-5-azaspiro[2.4]heptan-4-one as a diastereomeric mixture (XXXVII) + (XXXVIII), which is separated by column chromatography. The reduction of the (7S)-isomer (XXXVIII) with LiAlH4 in THF gives 7(S)-amino-5-[1(R)-phenylethyl]-5-azaspiro[2.4]heptane (XXXIX), which is protected in the usual way to the tert-butoxycarbonyl derivative (XL). Finally, this compound is debenzylated to (VII) by hydrogenation with H2 over Pd/C in ethanol.
| 【1】 Hayakawa, I.; Kimura, Y. (Daiichi Pharmaceutical Co., Ltd.); Optically active pyridone carboxylic acid derivs. AU 8933702; EP 0341493; JP 1990231475; JP 1995300416; JP 1999124367; JP 1999124380; US 5587386; US 5767127 . |
| 【2】 Castaner, J.; Graul, A.; Prous, J.; DU-6859. Drugs Fut 1994, 19, 9, 827. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXXIX)) | 15177 | (7S)-5-[(1R)-1-phenylethyl]-5-azaspiro[2.4]heptan-7-amine; (7S)-5-[(1R)-1-phenylethyl]-5-azaspiro[2.4]hept-7-ylamine | C14H20N2 | 详情 | 详情 | |
| (VII) | 15131 | N-[(7S)-5-azaspiro[2.4]hept-7-yl]carbamic acid tert-butyl ester | 127199-45-5 | C11H20N2O2 | 详情 | 详情 |
| (XIII) | 10039 | (1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine | 3886-69-9 | C8H11N | 详情 | 详情 |
| (XXXI) | 11819 | ethyl acetoacetate; ethyl 3-oxobutanoate；Acetoacetic ester;Ethyl beta-ketobutyrate;ethyl 3-oxobutyrate | 141-97-9 | C6H10O3 | 详情 | 详情 |
| (XXXII) | 10252 | 1,2-Dibromoethane; Ethylene dibromide | 106-93-4 | C2H4Br2 | 详情 | 详情 |
| (XXXIII) | 15171 | ethyl 1-acetylcyclopropanecarboxylate | C8H12O3 | 详情 | 详情 | |
| (XXXIV) | 15172 | ethyl 1-(2-bromoacetyl)cyclopropanecarboxylate | C8H11BrO3 | 详情 | 详情 | |
| (XXXV) | 15173 | 5-[(1R)-1-phenylethyl]-5-azaspiro[2.4]heptane-4,7-dione | C14H15NO2 | 详情 | 详情 | |
| (XXXVI) | 15174 | 5-[(1R)-1-phenylethyl]-5-azaspiro[2.4]heptane-4,7-dione 7-oxime | C14H16N2O2 | 详情 | 详情 | |
| (XXXVII) | 15175 | (7R)-7-amino-5-[(1R)-1-phenylethyl]-5-azaspiro[2.4]heptan-4-one | C14H18N2O | 详情 | 详情 | |
| (XXXVIII) | 15176 | (7S)-7-amino-5-[(1R)-1-phenylethyl]-5-azaspiro[2.4]heptan-4-one | C14H18N2O | 详情 | 详情 | |
| (XL) | 15178 | N-[(7S)-5-[(1R)-1-phenylethyl]-5-azaspiro[2.4]hept-7-yl]carbamic acid | C15H20N2O2 | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(XIII)b) The intermediate 7(S)-(tert-Butoxycarbonylamino)-5-azaspiro[2.4]heptane (VII) can also be obtained as follows: 2) The reaction of 1-acetylcyclopropane-1-carboxylic acid ethyl ester (XXXIII) with (R)-alpha-methylbenzylamine (XIII) by means of NaOH and ethyl chloroformate gives the corresponding amide (XLI), which by reaction with ethylene glycol and p-toluenesulfonic acid is converted into the ethylene ketal (XLII). The bromination of (XLII) with Br2 in dioxane affords the bromomethyl dioxolane (XLIII), which is finally cyclized to 5-[1(R)-phenylethyl]-5-azaspiro[2.4]heptane-4,7-dione (XXXV), already obtained as an intermediate in the preceding synthesis.
| 【1】 Castaner, J.; Graul, A.; Prous, J.; DU-6859. Drugs Fut 1994, 19, 9, 827. |
| 【2】 Sato, K.; Saito, T.; Hayakawa, I.; Sato, M.; Yafune, T.; Atarashi, S.; Une, T.; Kimura, Y.; Kawakami, K.; Design and structure-activity relationship of new N1-cis-2-fluorocyclopropyl quinolones. 31st. 31st Intersci Conf Antimicrob Agents Chemother (Sept 29-Oct 2, Chicago) 1991, Abst 1504. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIII) | 10039 | (1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine | 3886-69-9 | C8H11N | 详情 | 详情 |
| (XXXIII) | 15171 | ethyl 1-acetylcyclopropanecarboxylate | C8H12O3 | 详情 | 详情 | |
| (XXXV) | 15173 | 5-[(1R)-1-phenylethyl]-5-azaspiro[2.4]heptane-4,7-dione | C14H15NO2 | 详情 | 详情 | |
| (XLI) | 15179 | 1-acetyl-N-[(1R)-1-phenylethyl]cyclopropanecarboxamide | C14H17NO2 | 详情 | 详情 | |
| (XLII) | 15180 | 1-(2-methyl-1,3-dioxolan-2-yl)-N-[(1R)-1-phenylethyl]cyclopropanecarboxamide | C16H21NO3 | 详情 | 详情 | |
| (XLIII) | 15181 | 1-[2-(bromomethyl)-1,3-dioxolan-2-yl]-N-[(1R)-1-phenylethyl]cyclopropanecarboxamide | C16H20BrNO3 | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(IV)A new synthesis of DU-6859 has been described: This compound is obtained by condensation of 8-chloro-6,7-difluoro-1-[2(S)-fluoro-1(R)-cyclopropyl]-4-oxo-1,4-dihydr oquinoline-3-carboxylic acid (I) with 7(S)-(tert-butoxycarbonylamino)-5-azaspiro[2.4]heptane (II) by means of triethylamine in refluxing acetonitrile, followed by deprotection with 35% aqueous HCl. The starting compounds (I) and (II) are obtained as follows: 1) The reaction of (+/-)-cis-2-fluorocyclopropane-1-carboxylic acid (III) with 1(R)-phenylethylamine (IV) by means of N,N'-carbonyldiimidazole (CDI) gives the corresponding amide (V) as a mixture of diastereomers, which is submitted to preparative HPLC yielding 2(S)-fluorocyclopropane-1(R)-carboxylic acid 1(R)-phenylethylamide (VI). Hydrolysis of (VI) with hot 35% HCl affords the corresponding free acid (VII), which by reaction with diphenyl phosphorazidate in tert-butanol is converted to 1(R)-(tert-butoxycarbonylamino)-2(S)-fluorocyclopropane (VIII). The deprotection of (VIII) with trifluoroacetic acid gives the corresponding free amine as trifluoroacetate (IX), which is condensed with 2-(3-chloro-2,4,5-trifluorobenzoyl)-3-ethoxyacrylic acid ethyl ester (X) by means of triethylamine in dichloromethane to yield the chiral 3-aminoacrylate (XI). The cyclization of (XI) by means of NaH in dioxane affords 8-chloro-6,7-difluoro-1-[2(S)-fluoro-1(R)-cyclopropyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester (XII), which is finally saponified to the desired acid (I) with hot 35% HCl.
| 【1】 Kimura, Y.; Atarashi, S.; Kawakami, K.; Hayakawa, I.; Sato, K.; (Fluorocyclopropyl)quinolones. 2. Synthesis and stereochemical structure-activity relationships of chiral 7-(7-amino-5-azaspiro[2.4]heptan-5-yl)-1-(2-fluorocyclopropyl)quinolone antibacterial agents. J Med Chem 1994, 37, 20, 3344. |
| 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) | 15130 | 8-chloro-6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid | 127199-27-3 | C13H7ClF3NO3 | 详情 | 详情 |
| (II) | 15193 | tert-butyl N-[(7S)-5-azaspiro[2.4]hept-7-yl]carbamate | C11H20N2O2 | 详情 | 详情 | |
| (III) | 15140 | (1S,2S)-2-fluorocyclopropanecarboxylic acid | C4H5FO2 | 详情 | 详情 | |
| (IV) | 10039 | (1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine | 3886-69-9 | C8H11N | 详情 | 详情 |
| (V) | 15139 | (1S,2S)-2-fluoro-N-[(1R)-1-phenylethyl]cyclopropanecarboxamide | C12H14FNO | 详情 | 详情 | |
| (VI) | 15139 | (1S,2S)-2-fluoro-N-[(1R)-1-phenylethyl]cyclopropanecarboxamide | C12H14FNO | 详情 | 详情 | |
| (VII) | 15140 | (1S,2S)-2-fluorocyclopropanecarboxylic acid | C4H5FO2 | 详情 | 详情 | |
| (VIII) | 15127 | tert-butyl N-[(1R,2S)-2-fluorocyclopropyl]carbamate | 127199-16-0 | C8H14FNO2 | 详情 | 详情 |
| (IX) | 15146 | (1R,2S)-2-Fluorocyclopropanamine; (1R,2S)-2-Fluorocyclopropylamine | C3H6FN | 详情 | 详情 | |
| (X) | 11682 | ethyl (Z)-2-(3-chloro-2,4,5-trifluorobenzoyl)-3-ethoxy-2-propenoate | C14H12ClF3O4 | 详情 | 详情 | |
| (XI) | 15190 | ethyl (E)-2-(3-chloro-4,5-difluorobenzoyl)-3-[[(1R,2S)-2-fluorocyclopropyl]amino]-2-propenoate | C15H13ClF3NO3 | 详情 | 详情 | |
| (XII) | 15129 | ethyl 8-chloro-6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-4-oxo-1,4-dihydro-3-quinolinecarboxylate | C15H11ClF3NO3 | 详情 | 详情 |
合成路线11
该中间体在本合成路线中的序号：(IV)2) The reaction of 1-acetylcyclopropane-1-carboxylic acid (XIII) with 1(R)-phenylethylamine (IV) by means of ethyl chloroformate and triethylamine gives the corresponding amide (XIV), which is treated with ethylene glycol and p-toluenesulfonic acid, yielding the dioxolane (XV). The bromination of (XV) with Br2 in dioxane affords the bromomethyl-dioxolane (XVI), which is cyclized by means of NaH in DMF to give 5-[1(R)-phenylethyl]-5-azaspiro[2.4]heptane-4,7-dione 7-ethyleneketal (XVII). Opening of the ketal ring with 1N HCl in refluxing acetone yields the free diketone (XVIII), which by reaction with hydroxylamine and triethylamine in ethanol affords the monooxime (XIX). The reduction of (XIX) with H2 over RaNi in methanol gives the aminoketone (XX) as a diastereomeric mixture, which is separated by column chromatography yielding 7(S)-amino-5-[1(R)-phenylethyl]-5-azaspiro[2.4]heptan-4-one (XXI). The reduction of (XXI) with LiAlH4 in THF affords the amine (XXII), which is protected with 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile in THF to give 7(S)-(tert-butoxycarbonylamino)-5-[1(R)-phenylethyl]-5-azaspiro[2.4]heptane (XXIII). Finally, this compound is hydrogenolyzed with H2 over Pd/C in ethanol, yielding the desired chiral spiro compound (II).
| 【1】 Kimura, Y.; Atarashi, S.; Kawakami, K.; Hayakawa, I.; Sato, K.; (Fluorocyclopropyl)quinolones. 2. Synthesis and stereochemical structure-activity relationships of chiral 7-(7-amino-5-azaspiro[2.4]heptan-5-yl)-1-(2-fluorocyclopropyl)quinolone antibacterial agents. J Med Chem 1994, 37, 20, 3344. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 15193 | tert-butyl N-[(7S)-5-azaspiro[2.4]hept-7-yl]carbamate | C11H20N2O2 | 详情 | 详情 | |
| (IV) | 10039 | (1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine | 3886-69-9 | C8H11N | 详情 | 详情 |
| (XIII) | 15194 | 1-acetylcyclopropanecarboxylic acid | C6H8O3 | 详情 | 详情 | |
| (XIV) | 15179 | 1-acetyl-N-[(1R)-1-phenylethyl]cyclopropanecarboxamide | C14H17NO2 | 详情 | 详情 | |
| (XV) | 15180 | 1-(2-methyl-1,3-dioxolan-2-yl)-N-[(1R)-1-phenylethyl]cyclopropanecarboxamide | C16H21NO3 | 详情 | 详情 | |
| (XVI) | 15181 | 1-[2-(bromomethyl)-1,3-dioxolan-2-yl]-N-[(1R)-1-phenylethyl]cyclopropanecarboxamide | C16H20BrNO3 | 详情 | 详情 | |
| (XVII) | 15198 | 10-[(1R)-1-phenylethyl]-5,8-dioxa-10-azadispiro[2.0.4.3]undecan-11-one | C16H19NO3 | 详情 | 详情 | |
| (XVIII) | 15173 | 5-[(1R)-1-phenylethyl]-5-azaspiro[2.4]heptane-4,7-dione | C14H15NO2 | 详情 | 详情 | |
| (XIX) | 15174 | 5-[(1R)-1-phenylethyl]-5-azaspiro[2.4]heptane-4,7-dione 7-oxime | C14H16N2O2 | 详情 | 详情 | |
| (XX) | 63961 | 7-amino-5-[(1R)-1-phenylethyl]-5-azaspiro[2.4]heptan-4-one | C14H18N2O | 详情 | 详情 | |
| (XXI) | 15176 | (7S)-7-amino-5-[(1R)-1-phenylethyl]-5-azaspiro[2.4]heptan-4-one | C14H18N2O | 详情 | 详情 | |
| (XXII) | 15177 | (7S)-5-[(1R)-1-phenylethyl]-5-azaspiro[2.4]heptan-7-amine; (7S)-5-[(1R)-1-phenylethyl]-5-azaspiro[2.4]hept-7-ylamine | C14H20N2 | 详情 | 详情 | |
| (XXIII) | 15204 | tert-butyl N-[(7S)-5-[(1R)-1-phenylethyl]-5-azaspiro[2.4]hept-7-yl]carbamate | C19H28N2O2 | 详情 | 详情 |
合成路线12
该中间体在本合成路线中的序号：(III)The reaction of 2-naphthalenethiol (I) with 2-methyleneglutaronitrile (II) followed by treatment first with concentrated hydrochloric acid and then with p-toluenesulfonic acid in methanol gives racemic acid, which is resolved into optically pure (R)-4-methoxycarbonyl-2-(2-naphthylthiomethyl)butyric acid (IV) by use of (R)-(+)-alpha-methylbenzylamine (III). The treatment of compound (IV), first with thionyl chloride and then with N-(3-methoxypropyl)-N-pentylamine (V), affords (R)-methyl 4-[N-(3-methoxypropyl)-N-pentylcarbamoyl]-5-(2-naphthylthio)pentanoate (VI). Oxidation of compound (VI) with m-chloroperbenzoic acid followed by treatment with 1N sodium hydroxide gives (R)-4-[N-(3-methoxypropyl)-N-pentylcarbamoyl]-5-(2-naphthylsulfonyl) pentanoic acid (VII), which is finally converted into KSG-504 by treatment with L-arginine.
| 【1】 Kitazawa, M.; Akahane, M.; Yamazaki, Y.; Kobayashi, M.; KSG-504. Drugs Fut 1995, 20, 5, 472. |
| 【2】 Kitazawa, M.; Akahane, M.; Nakano, Y.; Tsubaki, A.; Sato, K.; Ban, M.; Kobayashi, M. (Kissei Pharmaceutical Co., Ltd.); Napthylsulfonylalkanoic acid cpds. EP 0433064; JP 1991193756; JP 1991197453; JP 1992210956; US 5177069 . |
| 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) | 15234 | 2-Naphthalenethiol; 2-Naphthylhydrosulfide | 91-60-1 | C10H8S | 详情 | 详情 |
| (II) | 63962 | 2-methylenepentanedinitrile | C6H6N2 | 详情 | 详情 | |
| (III) | 10039 | (1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine | 3886-69-9 | C8H11N | 详情 | 详情 |
| (IV) | 15235 | (2R)-5-methoxy-2-[(2-naphthylsulfanyl)methyl]-5-oxopentanoic acid | C17H18O4S | 详情 | 详情 | |
| (V) | 12130 | N-(3-Methoxypropyl)-N-pentylamine; N-(3-Methoxypropyl)-1-pentanamine | C9H21NO | 详情 | 详情 | |
| (VI) | 15236 | methyl (4R)-5-[(3-methoxypropyl)(pentyl)amino]-4-[(2-naphthylsulfanyl)methyl]-5-oxopentanoate | C26H37NO4S | 详情 | 详情 | |
| (VII) | 15237 | (4R)-5-[(3-methoxypropyl)(pentyl)amino]-4-[(2-naphthylsulfonyl)methyl]-5-oxopentanoic acid | C25H35NO6S | 详情 | 详情 |
合成路线13
该中间体在本合成路线中的序号：(R-X)3) The reaction of 3-methyl-1-[2-(1-piperidinyl)phenyl]butan-1-imine (VI) with acetic acid, triphenylphosphine and CCl4 (or with acetic anhydride and NaHCO3) gives N-[3-methyl-2-(1-piperidinyl)phenyl]-1(Z)-butenyl]acetamide (VII), with some of the (E)-isomer. The stereoselective reduction of the (Z)-isomer (VII) with the chiral complex Ru(OAc)2[(S)-2,2'-bis(diphenylphosphino-1,1'-binaphthyl] (S-BINAP), triethylamine and titanium tetraisopropoxide in methanol/methylene chloride yields N-[3-methyl-1(S)-[2-(1-piperidinyl)phenyl]butyl]acetamide (VIII). The hydrolysis of the chiral amide (VIII) with refluxing concentrated HCl affords the chiral amine (S-I), which is then condensed with the phenylacetic acid (II) by means of triphenylphosphine as before (or with dicyclohexylcarbodiimide) to give the chiral amide-ester (S-III). Finally, this ester is hydrolyzed to repaglinide with NaOH in hot ethanol. 4) The reductocondensation of 3-methyl-1-[2-(1-piperidyl)-1-butanone (IX) with 1(S)-phenylethylamine (S-X) yields the (S)-chiral ketimine (XI), which is reduced with TiCl4 in toluene yielding the (S,S)-chiral secondary amine (S,S-XII). Finally, the 1(S)-phenylethyl group of (S,S-XII) is eliminated by hydrogenolysis with H2 over Pd/C in diluted aqueous HCl to afford the (S)-chiral amine (S-I), already obtained. 5) The condensation of 1(R)-phenylethylamine (R-X) with 2-(1-piperidinyl)benzaldehyde (XIII) gives the corresponding chiral (R)-aldimine (XIV), which is converted into the (S,R)-chiral secondary amine (S,R-XII) by a Grignard reaction with isobutyl bromide in THF. Finally, the 1(R)-phenylethyl group of (S,R-XII) is eliminated by hydrogenolysis as before to afford the previously obtained (S)-chiral amine (S-I).
| 【1】 Graul, A.; Castaner, J.; Repaglinide. Drugs Fut 1996, 21, 7, 694. |
| 【2】 Grell, W.; Greischel, A.; Zahn, G.; Mark, M.; Knorr, H.; Rupprecht, E.; Muller, U. (Dr. Karl Thomae GmbH); (S)(+)-2-(Ethoxy-4-[N-[1-(2-piperidinophenyl)-3-methyl-1-butyl] aminocarbonylmethyl]benzoic acid. EP 0589874; JP 1994508816; WO 9300337 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 22876 | bromo(isobutyl)magnesium | 926-62-5 | C4H9BrMg | 详情 | 详情 | |
| (R-X) | 10039 | (1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine | 3886-69-9 | C8H11N | 详情 | 详情 |
| (S,S-XII) | 15312 | (1S)-3-methyl-N-[(1S)-1-phenylethyl]-1-(2-piperidinophenyl)-1-butanamine; N-[(1S)-3-methyl-1-(2-piperidinophenyl)butyl]-N-[(1S)-1-phenylethyl]amine | C24H34N2 | 详情 | 详情 | |
| (S;R-XII) | 15313 | N-[(1S)-3-methyl-1-(2-piperidinophenyl)butyl]-N-[(1R)-1-phenylethyl]amine; (1S)-3-methyl-N-[(1R)-1-phenylethyl]-1-(2-piperidinophenyl)-1-butanamine | C24H34N2 | 详情 | 详情 | |
| (S-I) | 15315 | (1S)-3-methyl-1-(2-piperidinophenyl)butylamine; (1S)-3-methyl-1-(2-piperidinophenyl)-1-butanamine | C16H26N2 | 详情 | 详情 | |
| (S-III) | 15316 | ethyl 2-ethoxy-4-(2-[[(1S)-3-methyl-1-(2-piperidinophenyl)butyl]amino]-2-oxoethyl)benzoate | C29H40N2O4 | 详情 | 详情 | |
| (S-X) | 20042 | (1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine | C8H11N | 详情 | 详情 | |
| (II) | 15302 | ethyl 2-ethoxy-4-(2-[[3-methyl-1-(2-piperidinophenyl)butyl]amino]-2-oxoethyl)benzoate | C29H40N2O4 | 详情 | 详情 | |
| (VI) | 15305 | 3-methyl-1-(2-piperidinophenyl)-1-butanimine | C16H24N2 | 详情 | 详情 | |
| (VII) | 15306 | N-[(Z)-3-methyl-1-(2-piperidinophenyl)-1-butenyl]acetamide | C18H26N2O | 详情 | 详情 | |
| (VIII) | 15307 | N-[(1S)-3-methyl-1-(2-piperidinophenyl)butyl]acetamide | C18H28N2O | 详情 | 详情 | |
| (IX) | 15308 | 3-methyl-1-(2-piperidinophenyl)-1-butanone | C16H23NO | 详情 | 详情 | |
| (XI) | 15311 | N-[(E)-3-methyl-1-(2-piperidinophenyl)butylidene]-N-[(1S)-1-phenylethyl]amine; (1S)-N-[(E)-3-methyl-1-(2-piperidinophenyl)butylidene]-1-phenyl-1-ethanamine | C24H32N2 | 详情 | 详情 | |
| (XIII) | 15314 | 2-piperidinobenzaldehyde | C12H15NO | 详情 | 详情 | |
| (XIV) | 63965 | (1R)-1-phenyl-N-{(E)-[2-(1-piperidinyl)phenyl]methylidene}-1-ethanamine; N-[(1R)-1-phenylethyl]-N-{(E)-[2-(1-piperidinyl)phenyl]methylidene}amine | C20H24N2 | 详情 | 详情 |
合成路线14
该中间体在本合成路线中的序号：(XVII)1) The condensation of 2-(1,3-dixolan-2-yl)ethylamine (I) with ethyl 2-bromo-2-(4-fluorophenyl)acetate (II) by means of triethylamine in acetonitrile gives ethyl 2-[2-(1,3-dioxolan-2-yl)ethylamino]-2-(4-fluorophenyl)acetate (III), which is acylated with isobutyryl chloride (IV) and triethylamine in dichloromethane yielding the corresponding amide (V). Saponification of the ester (V) with NaOH in methanol/water affords the free acid (VI), which is cyclized with N,3-diphenylpropynamide (VII) [obtained in the reaction of 3-phenylpropynoic acid (VIII) with aniline (IX) by means of dicyclohexylcarbodiimide (DCC)] by heating at 90 C in acetic anhydride giving 1-[2-(1,3-dioxolan-2-yl)ethyl]-5-(4-fluorophenyl)-2-isopropyl-N,4-diphenylpyrrole-3-carboxamide (X). The hydrolysis of the dioxolane group of (X) with HCl yields the corresponding aldehyde (XI), which is condensed with methyl acetoacetate (XII) by means of NaH in THF affording 7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(N-phenylcarbamoyl)pyrrol-1-yl]-5-hydroxy-3-oxoheptanoic acid methyl ester (XIII). The reduction of the carbonyl group of (XIII) with tributylborane and NaBH4 in THF gives the (3R*,5R*)-dihydroxy ester (XIV), which is saponified with NaOH in water yielding the corresponding free acid (XV). The lactonization of (XV) by heating in refluxing toluene affords the (R*,R*)-lactone (XVI), which is submitted to optical resolution by reaction with (R)-1-phenylethylamine (XVII) followed by fractional crystallization thus obtaining the amide (XVII) as the pure (R,R,R)-enantiomer. The hydrolysis of the amide (XVIII) with NaOH, followed by heating in refluxing toluene gives the (R,R)-lactone (XIX), which is finally treated first with NaOH in methanol/water, and then with CaCl2 or calcium acetate.
| 【1】 Graul, A.; Castaner, J.; Atorvastatin Calcium. Drugs Fut 1997, 22, 9, 956. |
| 【2】 Roth, B.D.; Blankley, C.J.; Chucholowski, A.W.; Ferguson, E.; Hoefle, M.L.; Ortwine, D.F.; Newton, R.S.; Sekerke, C.S.; Sliskovic, D.R.; Stratton, C.D.; Wilson, M.W.; Inhibitors of cholesterol biosynthesis. 3. Tetrahydro-4-hydroxy-6-[2-(1H-pyrrol-1-yl)ethyl]-2H-pyran-2-one inhibitors of HMG-CoA reductase. 2. Effects of introducing substituents at positions three and four of the pyrrole nucleus. J Med Chem 1991, 34, 1, 357-66. |
| 【3】 Roth, B.D. (Pfizer Inc.); Trans-6-[2-(3- or 4-carboxamido-substd. pyrrol-1-yl)alkyl]-4-hydroxypyran-2-one inhibitors of cholesterol synthesis. EP 0247633; US 4681893 . |
| 【4】 Roth, B.D. (Pfizer Inc.); (R-(R*R*)-2-(4-Fluorophenyl)-beta,delta-dihydroxy-5-(1-methylethyl-3 -phenyl-4-[(phenylamino)-carbonyl]-1H-pyrrole-1-heptanoic acid, its lactone form and salts thereo. EP 0409281; JP 1991058967; US 5273995 . |
| 【5】 Mills, N.; Muhammad, N.A.; Weiss, J.; Nesbitt, R.U. (Pfizer Inc.); Stable oral CI-981 formulation and process for preparing same. EP 0680320; JP 1996505640; US 5686104; WO 9416693 . |
| 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) | 15376 | 2-(1,3-dioxolan-2-yl)ethylamine; 2-(1,3-dioxolan-2-yl)-1-ethanamine | 5754-35-8 | C5H11NO2 | 详情 | 详情 |
| (II) | 15377 | ethyl 2-bromo-2-(4-fluorophenyl)acetate | 712-52-7 | C10H10BrFO2 | 详情 | 详情 |
| (III) | 15378 | ethyl 2-[[2-(1,3-dioxolan-2-yl)ethyl]amino]-2-(4-fluorophenyl)acetate | C15H20FNO4 | 详情 | 详情 | |
| (IV) | 14932 | isobutyryl chloride; 2-methylpropanoyl chloride | 79-30-1 | C4H7ClO | 详情 | 详情 |
| (V) | 15380 | ethyl 2-[[2-(1,3-dioxolan-2-yl)ethyl](isobutyryl)amino]-2-(4-fluorophenyl)acetate | C19H26FNO5 | 详情 | 详情 | |
| (VI) | 15381 | 2-[[2-(1,3-dioxolan-2-yl)ethyl](isobutyryl)amino]-2-(4-fluorophenyl)acetic acid | C17H22FNO5 | 详情 | 详情 | |
| (VII) | 15382 | N,3-diphenyl-2-propynamide | C15H11NO | 详情 | 详情 | |
| (VIII) | 15383 | 3-phenyl-2-propynoic acid; Phenylpropiolic acid | 637-44-5 | C9H6O2 | 详情 | 详情 |
| (IX) | 12294 | Aniline; Phenylamine | 62-53-3 | C6H7N | 详情 | 详情 |
| (X) | 15385 | 1-[2-(1,3-dioxolan-2-yl)ethyl]-5-(4-fluorophenyl)-2-isopropyl-N,4-diphenyl-1H-pyrrole-3-carboxamide | C31H31FN2O3 | 详情 | 详情 | |
| (XI) | 15386 | 5-(4-fluorophenyl)-2-isopropyl-1-(3-oxopropyl)-N,4-diphenyl-1H-pyrrole-3-carboxamide | C29H27FN2O2 | 详情 | 详情 | |
| (XII) | 11791 | methyl 3-oxobutanoate; Methyl acetoacetate | 105-45-3 | C5H8O3 | 详情 | 详情 |
| (XIII) | 15388 | methyl 7-[3-(anilinocarbonyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-1-yl]-5-hydroxy-3-oxoheptanoate | C34H35FN2O5 | 详情 | 详情 | |
| (XIV) | 15389 | methyl (3R,5R)-7-[3-(anilinocarbonyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-1-yl]-3,5-dihydroxyheptanoate | C34H37FN2O5 | 详情 | 详情 | |
| (XV) | 15390 | (3R,5R)-7-[3-(anilinocarbonyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-1-yl]-3,5-dihydroxyheptanoic acid | C33H35FN2O5 | 详情 | 详情 | |
| (XVI) | 15391 | 5-(4-fluorophenyl)-1-[2-[(2R,4R)-4-hydroxy-6-oxotetrahydro-2H-pyran-2-yl]ethyl]-2-isopropyl-N,4-diphenyl-1H-pyrrole-3-carboxamide | C33H33FN2O4 | 详情 | 详情 | |
| (XVII) | 10039 | (1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine | 3886-69-9 | C8H11N | 详情 | 详情 |
| (XVIII) | 15393 | 1-((3R,5R)-3,5-dihydroxy-7-oxo-7-[[(1R)-1-phenylethyl]amino]heptyl)-5-(4-fluorophenyl)-2-isopropyl-N,4-diphenyl-1H-pyrrole-3-carboxamide | C41H44FN3O4 | 详情 | 详情 | |
| (XIX) | 15391 | 5-(4-fluorophenyl)-1-[2-[(2R,4R)-4-hydroxy-6-oxotetrahydro-2H-pyran-2-yl]ethyl]-2-isopropyl-N,4-diphenyl-1H-pyrrole-3-carboxamide | C33H33FN2O4 | 详情 | 详情 |
合成路线15
该中间体在本合成路线中的序号：(VII)The condensation of dimethyl succinate (I) with benzaldehyde (II) by means of NaOMe in refluxing methanol followed by hydrolysis with NaOH in methanol/water gives 2-benzylidenesuccinic acid (III). Compound (III) is treated with refluxing Ac2O, yielding the corresponding anhydride (IV), which by reaction with cis-perhydroisoindole (V) in toluene affords the monoamide (VI). This amide is reduced with H2 over a chiral Rhodium catalyst and treated with (R)-1-phenylethylamine (VII) to provide the chiral salt (VIII) as a single diastereomer isolated by crystallization. Finally, this salt is treated first with aqueous NH4OH and then with aqueous CaCl2.
| 【1】 Castaner, R.M.; Sorbera, L.A.; Leeson, P.A.; Castaner, J.; Mitiglinide Calcium Hydrate. Drugs Fut 2000, 25, 10, 1034. |
| 【2】 Lecouve, J.-P.; Souvie, J.-C.; Fugier, C. (ADIR et Cie.); Method for preparing a substd. perhydroisoindole. FR 2765578; US 6133454; WO 9901430 . |
| 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) | 41056 | dimethyl succinate | 106-65-0 | C6H10O4 | 详情 | 详情 |
| (II) | 10498 | Benzaldehyde;Benzoic aldehyde;Phenylmethanal | 100-52-7 | C7H6O | 详情 | 详情 |
| (III) | 41057 | 2-[(Z)-benzylidene]succinic acid | C11H10O4 | 详情 | 详情 | |
| (IV) | 41058 | 3-[(Z)-benzylidene]-2,5(4H)-furandione | C11H8O3 | 详情 | 详情 | |
| (V) | 41059 | (3aR,7aS)octahydro-1H-isoindole | C8H15N | 详情 | 详情 | |
| (VI) | 41060 | (Z)-2-[2-[(3aR,7aS)octahydro-2H-isoindol-2-yl]-2-oxoethyl]-3-phenyl-2-propenoic acid | C19H23NO3 | 详情 | 详情 | |
| (VII) | 10039 | (1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine | 3886-69-9 | C8H11N | 详情 | 详情 |
| (VIII) | 41061 | (1R)-1-phenyl-1-ethanaminium (2S)-4-[(3aR,7aS)octahydro-2H-isoindol-2-yl]-2-benzyl-4-oxobutanoate | C27H36N2O3 | 详情 | 详情 |
合成路线16
该中间体在本合成路线中的序号：(VII)The condensation of diethyl succinate (IX) with benzaldehyde (II) gives 2-benzylidenesuccinic acid (III), which is treated with refluxing Ac2O to yield the corresponding anhydride (IV). Reaction of (IV) with cis-perhydroisoindole (V) in toluene affords the monoamide (VI), which is reduced with H2 over Pd/C in ethanol to provide the racemic benzylsuccinamic acid (X). Esterification of (X) with (S)-N-benzylmandelamide (XI) by means of DCC and DMAP in dichloromethane gives a mixture of diastereomeric esters, which were separated by column chromatography on silica gel to provide the desired diastereomer (XII). The hydrolysis of (XII) with NaOH in methanol yields the chiral acid (XIII), which is finally treated first with NaOH and then with CaCl2 in water. The preceding optical resolution of racemic acid (X) can also be performed with (R)-1-phenylethylamine (VII) or (R)-1-(1-naphthyl)ethylamine (XIV) by fractional crystallization of the corresponding diastereomeric salts and treatment with 2N HCl.
| 【1】 Castaner, R.M.; Sorbera, L.A.; Leeson, P.A.; Castaner, J.; Mitiglinide Calcium Hydrate. Drugs Fut 2000, 25, 10, 1034. |
| 【2】 Yamaguchi, T.; et al.; Preparation of optically active succinic acid derivatives. I. Optical resolution of 2-benzyl-3-(cis-hexahydroisoindolin-2-ylcarbonyl)propionic acid. Chem Pharm Bull 1997, 45, 9, 1518. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 10498 | Benzaldehyde;Benzoic aldehyde;Phenylmethanal | 100-52-7 | C7H6O | 详情 | 详情 |
| (III) | 41057 | 2-[(Z)-benzylidene]succinic acid | C11H10O4 | 详情 | 详情 | |
| (IV) | 41058 | 3-[(Z)-benzylidene]-2,5(4H)-furandione | C11H8O3 | 详情 | 详情 | |
| (V) | 41059 | (3aR,7aS)octahydro-1H-isoindole | C8H15N | 详情 | 详情 | |
| (VI) | 41060 | (Z)-2-[2-[(3aR,7aS)octahydro-2H-isoindol-2-yl]-2-oxoethyl]-3-phenyl-2-propenoic acid | C19H23NO3 | 详情 | 详情 | |
| (VII) | 10039 | (1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine | 3886-69-9 | C8H11N | 详情 | 详情 |
| (IX) | 12313 | diethyl succinate | 123-25-1 | C8H14O4 | 详情 | 详情 |
| (X) | 41062 | 4-[(3aR,7aS)octahydro-2H-isoindol-2-yl]-2-benzyl-4-oxobutyric acid | C19H25NO3 | 详情 | 详情 | |
| (XI) | 41063 | (2S)-N-benzyl-2-hydroxy-2-phenylethanamide | C15H15NO2 | 详情 | 详情 | |
| (XII) | 41065 | (1S)-2-(benzylamino)-2-oxo-1-phenylethyl (2S)-4-[(3aR,7aS)octahydro-2H-isoindol-2-yl]-2-benzyl-4-oxobutanoate | C34H38N2O4 | 详情 | 详情 | |
| (XIII) | 41064 | (2S)-4-[(3aR,7aS)octahydro-2H-isoindol-2-yl]-2-benzyl-4-oxobutyric acid | C19H25NO3 | 详情 | 详情 | |
| (XIV) | 17443 | (1R)-1-(1-naphthyl)ethylamine; (1R)-1-(1-naphthyl)-1-ethanamine | 3886-70-2 | C12H13N | 详情 | 详情 |
合成路线17
该中间体在本合成路线中的序号：(VII)The optical resolution of racemic 2-benzylsuccinic acid (XV) using the chiral amines (R)-1-phenylethylamine (VII), (R)-1-(1-naphthyl)ethylamine (XIV) or (S)-1-phenyl-2-(4-tolyl)ethylamine (XVI) is carried out by fractional crystallization of the corresponding diastereomeric salts and treatment with 2N HCl, providing the desired enantiomer 2(S)-benzylsuccinic acid (XVII). Reaction of (XVII) with SOCl2 gives the corresponding acyl chloride (XVIII), which is treated with 4-nitrophenol (XIX) and TEA in dichloromethane to yield the activated diester (XX). The regioselective reaction of (XX) with cis-perhydroisoindole (V) in dichloromethane affords the monoamide (XXI), which by reaction with HCl and methanol provides the corresponding methyl ester (XXII). This ester is hydrolyzed with NaOH to the previously described chiral succinamic acid (XIII), which is finally converted into its calcium salt.
| 【1】 Castaner, R.M.; Sorbera, L.A.; Leeson, P.A.; Castaner, J.; Mitiglinide Calcium Hydrate. Drugs Fut 2000, 25, 10, 1034. |
| 【2】 Mukaiyama, Y.; Hokari, H.; Kamijo, T.; Yanagi, T.; Yamaguchi, T.; Yamamoto, I.; Preparation of optically active succinic acid derivatives. II. Efficient and practical synthesis of KAD-1229. Chem Pharm Bull 1998, 46, 2, 337-340. |
| 【3】 Yamaguchi, T.; et al.; Synthesis of KAD-1229, a succinic acid derivative with optical activity. 118th Annu Meet Pharmaceut Soc Jpn (March 31 1998, Kyoto) 1998, Abst 31(XP)9-9. |
| 【4】 Yamaguchi, T.; Kamijo, T.; Yanagi, T. (Kissei Pharmaceutical Co., Ltd.); Process for producing optically active benzylsuccinic acid and intermediate therefor. WO 9832727 . |
| 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) | 41059 | (3aR,7aS)octahydro-1H-isoindole | C8H15N | 详情 | 详情 | |
| (VII) | 10039 | (1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine | 3886-69-9 | C8H11N | 详情 | 详情 |
| (XIII) | 41064 | (2S)-4-[(3aR,7aS)octahydro-2H-isoindol-2-yl]-2-benzyl-4-oxobutyric acid | C19H25NO3 | 详情 | 详情 | |
| (XIV) | 17443 | (1R)-1-(1-naphthyl)ethylamine; (1R)-1-(1-naphthyl)-1-ethanamine | 3886-70-2 | C12H13N | 详情 | 详情 |
| (XV) | 41066 | 2-benzylsuccinic acid | C11H12O4 | 详情 | 详情 | |
| (XVI) | 41067 | (1S)-2-(4-methylphenyl)-1-phenylethylamine; (1S)-2-(4-methylphenyl)-1-phenyl-1-ethanamine | 30339-30-1 | C15H17N | 详情 | 详情 |
| (XVII) | 41068 | (2S)-2-benzylbutanedioic acid | C11H12O4 | 详情 | 详情 | |
| (XVIII) | 41069 | (2S)-2-benzylbutanedioyl dichloride | C11H10Cl2O2 | 详情 | 详情 | |
| (XIX) | 11236 | 4-Nitrophenol; p-Nitrophenol | 100-02-7 | C6H5NO3 | 详情 | 详情 |
| (XX) | 41070 | bis(4-nitrophenyl) (2S)-2-benzylbutanedioate | C23H18N2O8 | 详情 | 详情 | |
| (XXI) | 41071 | 4-nitrophenyl (2S)-4-[(3aR,7aS)octahydro-2H-isoindol-2-yl]-2-benzyl-4-oxobutanoate | C25H28N2O5 | 详情 | 详情 | |
| (XXII) | 41072 | methyl (2S)-4-[(3aR,7aS)octahydro-2H-isoindol-2-yl]-2-benzyl-4-oxobutanoate | C20H27NO3 | 详情 | 详情 |
合成路线18
该中间体在本合成路线中的序号：(IV)Partial hydrolysis of cyclobutane-1,1-dicarboxylic acid diethyl ester (I) with one equivalent of hydroethanolic KOH produced monocarboxylic acid (II). This was converted to the mixed anhydride (III) by treatment with ethyl chloroformate and triethylamine, and subsequently condensed with (R)-1-phenyl-ethylamine (IV) to give amide (V). Hydrolysis of the remaining ester group of (V) with NaOH gave carboxylic acid (VI), from which the corresponding acid chloride (VII) was obtained by treatment with SOCl2. Further reaction of (VII) with methyllithium and CuI afforded methyl ketone (VIII). After protection of the carbonyl group of (VIII) as the ethylene ketal (IX), bromination in dioxan yielded bromide (X). Then, cyclization of (X) with NaH in DMF gave the spirocyclobutylpyrrolidine (XI). The ketal group of (XI) was then deprotected with p-toluenesulfonic acid in aqueous AcOH to afford pyrrolidinedione (XII), which was transformed to oxime (XIII) by treatment with hydroxylamine in EtOH. Catalytic hydrogenation of the oxime (XIII) yielded a diastereomeric mixture of amines (XIV) that were separated by column chromatography. The desired isomer was reduced with LiAlH4 to diamine (XV), and subsequently treated with 2-(tert--butoxycarbonyl)oxymino-2-phenylacetonitrile (BOC-ON) to afford the tert-butyl carbamate (XVI).
| 【1】 Kawakami, K.; Ararashi, S.; Kimura, Y.; Takemura, M.; Hayakawa, I.; Synthesis and antibacterial activity of novel pyridobenzoxazine analogues. Chem Pharm Bull 1998, 46, 11, 1710. |
| 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) | 19375 | diethyl 1,1-cyclobutanedicarboxylate | 3779-29-1 | C10H16O4 | 详情 | 详情 |
| (II) | 19376 | 1-(ethoxycarbonyl)cyclobutanecarboxylic acid | C8H12O4 | 详情 | 详情 | |
| (III) | 19377 | Cyclobutane-1,1-dicarboxylic acid ethyl ester ethoxycarbonyl anhydride | C11H16O6 | 详情 | 详情 | |
| (IV) | 10039 | (1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine | 3886-69-9 | C8H11N | 详情 | 详情 |
| (V) | 19379 | ethyl 1-([[(1R)-1-phenylethyl]amino]carbonyl)cyclobutanecarboxylate | C16H21NO3 | 详情 | 详情 | |
| (VI) | 19380 | 1-([[(1R)-1-phenylethyl]amino]carbonyl)cyclobutanecarboxylic acid | C14H17NO3 | 详情 | 详情 | |
| (VII) | 19381 | 1-([[(1R)-1-phenylethyl]amino]carbonyl)cyclobutanecarbonyl chloride | C14H16ClNO2 | 详情 | 详情 | |
| (VIII) | 19382 | 1-acetyl-N-[(1R)-1-phenylethyl]cyclobutanecarboxamide | C15H19NO2 | 详情 | 详情 | |
| (IX) | 19383 | 1-(2-methyl-1,3-dioxolan-2-yl)-N-[(1R)-1-phenylethyl]cyclobutanecarboxamide | C17H23NO3 | 详情 | 详情 | |
| (X) | 19384 | 1-[2-(bromomethyl)-1,3-dioxolan-2-yl]-N-[(1R)-1-phenylethyl]cyclobutanecarboxamide | C17H22BrNO3 | 详情 | 详情 | |
| (XI) | 19385 | 11-[(1R)-1-phenylethyl]-6,9-dioxa-11-azadispiro[3.0.4.3]dodecan-12-one | C17H21NO3 | 详情 | 详情 | |
| (XII) | 19386 | 6-[(1R)-1-phenylethyl]-6-azaspiro[3.4]octane-5,8-dione | C15H17NO2 | 详情 | 详情 | |
| (XIII) | 19387 | 6-[(1R)-1-phenylethyl]-6-azaspiro[3.4]octane-5,8-dione 8-oxime | C15H18N2O2 | 详情 | 详情 | |
| (XIV) | 19388 | 8-amino-6-[(1R)-1-phenylethyl]-6-azaspiro[3.4]octan-5-one | C15H20N2O | 详情 | 详情 | |
| (XV) | 19389 | (8S)-6-[(1R)-1-phenylethyl]-6-azaspiro[3.4]oct-8-ylamine; (8S)-6-[(1R)-1-phenylethyl]-6-azaspiro[3.4]octan-8-amine | C15H22N2 | 详情 | 详情 | |
| (XVI) | 19390 | tert-butyl (8S)-6-[(1R)-1-phenylethyl]-6-azaspiro[3.4]oct-8-ylcarbamate | C20H30N2O2 | 详情 | 详情 |
合成路线19
该中间体在本合成路线中的序号：1) The condensation of S-acetyl-N-(benzyloxycarbonyl)-L-homocysteine (I) with 6-hydroxy-L-norleucine methyl ester (II) by means of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (WSC) and hydroxybenzotriazole (HOBT) in dichloromethane gives the corresponding dipeptide (III), which is oxidized with oxalyl chloride in dichloromethane, yielding the aldehyde (IV). The cyclization of (IV) by means of sodium methoxide and trifluoroacetic acid affords the perhydro-pyridothiazepinone (V), which is deprotected with trimethylsilyl iodide (TMS-I) in dichloromethane to give (VI) with a free amino group (1). The acylation of (VI) with 2(S)-(acetylsulfanyl)-3-phenylpropionic acid (VII) by means of (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP) in dichloromethane yields the corresponding amide (VIII), which is finally deprotected with NaOH in methanol and treated with HCl. 2) The intermediates S-acetyl-N-(benzyloxycarbonyl)-L-homocysteine (I) and 6-hydroxy-L-norleucine (II) have been obtained as follows: 2a) The protection of 3-aminotetrahydrothiophen-2-one (IX) with N-(benzyloxycarbonyloxy)succinimide gives the expected carbamate (X), which is treated first with KOH and then with acetic anhydride, yielding S-acetyl-N-(benzyloxycarbonyl)-DL-homocysteine (XI). Finally, this compound is submitted to optical resolution with (S)-alpha-methylbenzylamine to afford intermediate (I). 2b) The alkylation of acetamidomalonic acid diethyl ester (XII) with 4-acetoxybutyl bromide (XIII) by means of NaH in DMF gives the alkylated ester (XIV), which by a decarboxylative saponification yields 6-acetoxy-DL-norleucine (XV). Optical resolution of (XV) by means of porcine kidney acylase/LiOH in water affords pure 6-hydroxy-L-norleucine (XVI), which is finally esterified with methanol/HCl to intermediate (II).
| 【1】 Robl, J.A.; Sun, C.-Q.; Stevenson, J.; et al.; Dual metalloprotease inhibitors: Mercaptoacetyl-based fused heterocyclic dipeptide mimetics as inhibitors of angiotensin-converting enzyme and neutral endopeptidase. J Med Chem 1997, 40, 11, 1570. |
| 【2】 Graul, A.; Castañer, J.; Leeson, P.; Omapatrilat. Drugs Fut 1999, 24, 3, 269. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 10039 | (1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine | 3886-69-9 | C8H11N | 详情 | 详情 | |
| (I) | 22487 | (2S)-4-(acetylsulfanyl)-2-[[(benzyloxy)carbonyl]amino]butyric acid | C14H17NO5S | 详情 | 详情 | |
| (II) | 22488 | methyl (2S)-2-amino-6-hydroxyhexanoate | C7H15NO3 | 详情 | 详情 | |
| (III) | 22489 | methyl (2S)-2-[((2S)-4-(acetylsulfanyl)-2-[[(benzyloxy)carbonyl]amino]butanoyl)amino]-6-hydroxyhexanoate | C21H30N2O7S | 详情 | 详情 | |
| (IV) | 22490 | methyl (2S)-2-[((2S)-4-(acetylsulfanyl)-2-[[(benzyloxy)carbonyl]amino]butanoyl)amino]-6-oxohexanoate | C21H28N2O7S | 详情 | 详情 | |
| (V) | 22491 | methyl (4S,7S,10aS)-4-[[(benzyloxy)carbonyl]amino]-5-oxooctahydro-7H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate | C19H24N2O5S | 详情 | 详情 | |
| (VI) | 22492 | methyl (4S,7S,10aS)-4-amino-5-oxooctahydro-7H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate | C11H18N2O3S | 详情 | 详情 | |
| (VII) | 22493 | (2S)-2-(acetylsulfanyl)-3-phenylpropionic acid | C11H12O3S | 详情 | 详情 | |
| (VIII) | 22494 | methyl (4S,7S,10aS)-4-[[(2S)-2-(acetylsulfanyl)-3-phenylpropanoyl]amino]-5-oxooctahydro-7H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate | C22H28N2O5S2 | 详情 | 详情 | |
| (IX) | 22495 | 3-aminodihydro-2(3H)-thiophenone | 10593-85-8 | C4H7NOS | 详情 | 详情 |
| (X) | 22496 | benzyl 2-oxotetrahydro-3-thiophenylcarbamate | C12H13NO3S | 详情 | 详情 | |
| (XI) | 22497 | acetyl-N-[(benzyloxy)carbonyl]homocysteine | C14H17NO5S | 详情 | 详情 | |
| (XII) | 16710 | Diethyl 2-(acetamido)malonate; Diethyl acetamidomalonate | 1068-90-2 | C9H15NO5 | 详情 | 详情 |
| (XIII) | 22499 | 4-bromobutyl acetate | C6H11BrO2 | 详情 | 详情 | |
| (XIV) | 22500 | diethyl 2-(acetamido)-2-[4-(acetoxy)butyl]malonate | C15H25NO7 | 详情 | 详情 | |
| (XV) | 22501 | 6-(acetoxy)norleucine | C8H15NO4 | 详情 | 详情 | |
| (XVI) | 22502 | (2S)-2-amino-6-hydroxyhexanoic acid | 6033-32-5 | C6H13NO3 | 详情 | 详情 |
合成路线20
该中间体在本合成路线中的序号：The isoquinoline intermediate (IX) has been synthesized as follows: The reduction of methyl 3,5-dimethoxybenzoate (I) with LiAlH4 gives the benzyl alcohol (II), which is treated with Swern oxidant to yield the benzaldehyde (III). The treatment of (III) with the sequence outlined in the scheme the chiral secondary amine is obtained. The cyclization of (IV) with ammonium formate catalyzed by Pd, followed by a treatment with acetic anhydride and POCl3 afforded the dihydroisoquinoline (V), which is reduced with LiAlH4 to the tetrahydro derivative (VI). Cleavage of the methoxy groups of (VI) with BBr3 affords the dihydroxycompound (VII), which is benzylated with benzyl bromide and Cs2CO3 providing the fully benzylated tetrahydroisoquinoline (VIII). Finally, this compound is iodinated with I2 and Ag2SO4 furnishing the desired isoquinoline intermediate (IX).
| 【1】 Hoye, T.R.; et al.; Total synthesis of michellamines A-C, korupensamines A-D, and ancistrobrevine B. J Org Chem 1999, 64, 19, 7184. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 10039 | (1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine | 3886-69-9 | C8H11N | 详情 | 详情 | |
| 12912 | 1-(Bromomethyl)benzene; Alpha-bromotoluene | 100-39-0 | C7H7Br | 详情 | 详情 | |
| 40727 | 2-phenyl-2-propanamine; 1-methyl-1-phenylethylamine | 585-32-0 | C9H13N | 详情 | 详情 | |
| (I) | 37841 | methyl 3,5-dimethoxybenzoate | 2150-37-0 | C10H12O4 | 详情 | 详情 |
| (II) | 35424 | (3,5-dimethoxyphenyl)methanol | 705-76-0 | C9H12O3 | 详情 | 详情 |
| (III) | 21720 | 3,5-dimethoxybenzaldehyde | 7311-34-4 | C9H10O3 | 详情 | 详情 |
| (IV) | 37842 | (2R)-1-(3,5-dimethoxyphenyl)-N-(1-methyl-1-phenylethyl)-2-propanamine; N-[(1R)-2-(3,5-dimethoxyphenyl)-1-methylethyl]-N-(1-methyl-1-phenylethyl)amine | C20H27NO2 | 详情 | 详情 | |
| (V) | 37843 | (3R)-6-methoxy-1,3-dimethyl-3,4-dihydro-8-isoquinolinyl methyl ether; (3R)-6,8-dimethoxy-1,3-dimethyl-3,4-dihydroisoquinoline | C13H17NO2 | 详情 | 详情 | |
| (VI) | 37844 | (1R,3R)-6-methoxy-1,3-dimethyl-1,2,3,4-tetrahydro-8-isoquinolinyl methyl ether; (1R,3R)-6,8-dimethoxy-1,3-dimethyl-1,2,3,4-tetrahydroisoquinoline | C13H19NO2 | 详情 | 详情 | |
| (VII) | 37845 | (1R,3R)-1,3-dimethyl-1,2,3,4-tetrahydro-6,8-isoquinolinediol | C11H15NO2 | 详情 | 详情 | |
| (VIII) | 37846 | benzyl (1R,3R)-2-benzyl-6-(benzyloxy)-1,3-dimethyl-1,2,3,4-tetrahydro-8-isoquinolinyl ether; (1R,3R)-2-benzyl-6,8-bis(benzyloxy)-1,3-dimethyl-1,2,3,4-tetrahydroisoquinoline | C32H33NO2 | 详情 | 详情 | |
| (IX) | 37847 | benzyl (1R,3R)-2-benzyl-6-(benzyloxy)-5-iodo-1,3-dimethyl-1,2,3,4-tetrahydro-8-isoquinolinyl ether; (1R,3R)-2-benzyl-6,8-bis(benzyloxy)-5-iodo-1,3-dimethyl-1,2,3,4-tetrahydroisoquinoline | C32H32INO2 | 详情 | 详情 |
合成路线21
该中间体在本合成路线中的序号：(VIII)The reaction of uniformly 14C-labeled phenol (I) with acetylenedicarboxylic acid dimethyl ester (II) gives the adduct (III), which is reduced with ammonium formate and Pd/C to yield the 2-phenoxysuccinic acid dimethyl ester (IV). The hydrolysis of (IV) in acidic medium (HCl) affords the succinic acid derivative (V), which is cyclized by means of P2O5 to provide 4-oxo-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid (VI). The reduction of (VI) by means of Ph3SiH and TFA gives 3,4-dihydro-2H-1-benzopyran-2-carboxylic acid (VII), which is condensed with 1(R)-phenylethylamine (VIII) by means of CDI to yield the corresponding amide (IX) as a diastereomeric mixture. The reduction of (IX) by means of NaAlH2(OC2H4OMe)2 affords the secondary amine (X), also as a diastereomeric mixture, which is resolved by chromatography. The desired isomer (XI) is condensed with the butyl bromide derivative (XII) by means of NaHCO3 and KI to provide the tertiary amine (XIII), which is finally debenzylated by hydrogenation with H2 over Pd/C to furnish the target labeled Repinotan.
| 【1】 Seidel, D.; et al.; Synthesis of [14C]-labelled repinotan hydrochloride and its major metabolite M-6. J Label Compd Radiopharm 2002, 45, 13, 1115. |
| 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) | 23540 | Phenol | 108-95-2 | C6H6O | 详情 | 详情 |
| (II) | 24551 | Dimethyl acetylenedicarboxylate; Dimethyl 2-butynedioate;Acetylenedicarboxylic acid dimethyl ester | 762-42-5 | C6H6O4 | 详情 | 详情 |
| (III) | 62010 | dimethyl (E)-2-phenoxy-2-butenedioate | C12H12O5 | 详情 | 详情 | |
| (IV) | 62011 | dimethyl 2-phenoxysuccinate | C12H14O5 | 详情 | 详情 | |
| (V) | 62012 | 2-phenoxysuccinic acid | C10H10O5 | 详情 | 详情 | |
| (VI) | 62013 | 4-oxo-2-chromanecarboxylic acid | C10H8O4 | 详情 | 详情 | |
| (VII) | 17037 | 2-chromanecarboxylic acid | C10H10O3 | 详情 | 详情 | |
| (VIII) | 10039 | (1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine | 3886-69-9 | C8H11N | 详情 | 详情 |
| (IX) | 17040 | (2R)-N-[(1S)-1-phenylethyl]-3,4-dihydro-2H-chromene-2-carboxamide | C18H19NO2 | 详情 | 详情 | |
| (X) | 17041 | (1S)-N-[(2R)-3,4-dihydro-2H-chromen-2-ylmethyl]-1-phenyl-1-ethanamine; N-[(2R)-3,4-dihydro-2H-chromen-2-ylmethyl]-N-[(1S)-1-phenylethyl]amine | C18H21NO | 详情 | 详情 | |
| (XI) | 62014 | (1R)-N-[(2R)-3,4-dihydro-2H-chromen-2-ylmethyl]-1-phenyl-1-ethanamine; N-[(2R)-3,4-dihydro-2H-chromen-2-ylmethyl]-N-[(1R)-1-phenylethyl]amine | C18H21NO | 详情 | 详情 | |
| (XII) | 17043 | 2-(4-bromobutyl)-1H-1,2-benzisothiazole-1,1,3(2H)-trione | C11H12BrNO3S | 详情 | 详情 | |
| (XIII) | 62015 | 2-(4-{[(2R)-3,4-dihydro-2H-chromen-2-ylmethyl][(1R)-1-phenylethyl]amino}butyl)-1H-1,2-benzisothiazole-1,1,3(2H)-trione | C29H32N2O4S | 详情 | 详情 |
合成路线22
该中间体在本合成路线中的序号：(XXIII)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23
该中间体在本合成路线中的序号：(XXVIII)The preferred synthetic route began with the Friedel-Crafts acylation of benzodioxol (XXXVII) by means of butyric anhydride and BF3. The resultant butyrophenone (XIII) was then condensed with (R)-1-phenylethylamine (XXXVII), using TiCl4 as the dehydrating reagent, to afford the E-imine (XXXIX) as the major isomer. Catalytic hydrogenation of imine (XXXIX) in the presence of Raney-Ni furnished the desired amine (XL). The chiral auxiliary was then removed by hydrogenolysis over Pd/C to yield amine (XVII).
| 【1】 Storace, L.; et al.; An efficient large-scale process for the human leukocyte elastase inhibitor, DMP 777. Org Process Res Dev 2002, 6, 1, 54. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIII) | 53629 | 1-(1,3-benzodioxol-5-yl)-1-butanone | 63740-97-6 | C11H12O3 | 详情 | 详情 |
| (XVII) | 53631 | (1R)-1-(1,3-benzodioxol-5-yl)-1-butanamine; (1R)-1-(1,3-benzodioxol-5-yl)butylamine | n/a | C11H15NO2 | 详情 | 详情 |
| (XXVIII) | 10039 | (1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine | 3886-69-9 | C8H11N | 详情 | 详情 |
| (XXXVII) | 50641 | 1,3-Dioxaindane; 1,3-Benzodioxole; methylenedioxybenzene; 1,2-methylenedioxybenzene; catechol methylene ether | 274-09-9 | C7H6O2 | 详情 | 详情 |
| (XXXIX) | 53649 | (1R)-N-[(E)-1-(1,3-benzodioxol-5-yl)butylidene]-1-phenyl-1-ethanamine; N-[(E)-1-(1,3-benzodioxol-5-yl)butylidene]-N-[(1R)-1-phenylethyl]amine | n/a | C19H21NO2 | 详情 | 详情 |
| (XL) | 53650 | N-[(1R)-1-(1,3-benzodioxol-5-yl)butyl]-N-[(1R)-1-phenylethyl]amine; (1R)-1-(1,3-benzodioxol-5-yl)-N-[(1R)-1-phenylethyl]-1-butanamine | n/a | C19H23NO2 | 详情 | 详情 |
合成路线24
该中间体在本合成路线中的序号：(VIII)The reaction of trifluoroacetoacetic acid ethyl ester (I) with (?)-isoborneol (II) at 130 C gives the corresponding isobornyl ester (III), which is condensed with cyclohexane-1,3-dione (IV) and 3-cyanobenzaldehyde (V) by means of ammonium acetate in refluxing ethanol to yield the octahydroquinolone (VI). The hydrolysis of the ester group of (VI), with simultaneous dehydration by means of TsOH in refluxing toluene affords 4-(3-cyanophenyl)-5-oxo-2-(trifluoromethyl)-1,4,5,6,7,8-hexahydroquinoline-3-carboxylic acid (VII) as a racemic mixture. Optical resolution of (VII) through the diastereomeric salt with 1(S)-phenylethylamine (VIII) in toluene/butanol provides the desired isomer (IX), which is finally decarboxylated in N-methyl-2-pyrrolidone at 210 C to furnish the target hexahydroquinolone.
| 【1】 Ashworth, I.; Hopes, P.; Levin, D.; Patel, I.; Salloo, R.; An asymmetric synthesis of a 4-substituted-1,4-dihydropyridine. Tetrahedron Lett 2002, 43, 28, 4931. |
| 【2】 Warawa, J.E.; Ohnmacht, C.J. Jr.; Trainor, D.A.; Hulsizer, J.M. (AstraZeneca plc); Quinolone deriv. for treatment of urinary incontinence. EP 0755382; JP 1997512254; WO 9528388 . |
| 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) | 62025 | propyl 4,4,4-trifluoro-3-oxobutanoate | C7H9F3O3 | 详情 | 详情 | |
| (II) | 62026 | (1R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ol | C10H18O | 详情 | 详情 | |
| (III) | 62027 | (1R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl 4,4,4-trifluoro-3-oxobutanoate | C14H19F3O3 | 详情 | 详情 | |
| (IV) | 11244 | 1,3-Cyclohexanedione | 504-02-9 | C6H8O2 | 详情 | 详情 |
| (V) | 13245 | 3-Formylbenzonitrile; 3-Cyanobenzaldehyde | 24964-64-5 | C8H5NO | 详情 | 详情 |
| (VI) | 62028 | (1R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl 4-(3-cyanophenyl)-2-hydroxy-5-oxo-2-(trifluoromethyl)-1,2,3,4,5,6,7,8-octahydro-3-quinolinecarboxylate | C28H31F3N2O4 | 详情 | 详情 | |
| (VII) | 62029 | 4-(3-cyanophenyl)-5-oxo-2-(trifluoromethyl)-1,4,5,6,7,8-hexahydro-3-quinolinecarboxylic acid | C18H13F3N2O3 | 详情 | 详情 | |
| (VIII) | 10039 | (1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine | 3886-69-9 | C8H11N | 详情 | 详情 |
| (IX) | 62030 | (4S)-4-(3-cyanophenyl)-5-oxo-2-(trifluoromethyl)-1,4,5,6,7,8-hexahydro-3-quinolinecarboxylic acid | C18H13F3N2O3 | 详情 | 详情 |
合成路线25
该中间体在本合成路线中的序号：(V)The condensation of 3-cyanobenzaldehyde (I) with trifluoroacetone (II) in piperidine gives 3-(4,4,4-trifluoro-3-oxo-2-butenyl)benzonitrile (III). The condensation of cyclohexane-1,3-dione (IV) with 1(R)-phenylethylamine (V) in refluxing toluene or THF yields the secondary enamine (VI), which is condensed with benzonitrile (III) by means of Tms-Cl in hot acetonitrile to afford the chiral adduct (VII). The cyclization of (VII) by means of NH3 in hot acetonitrile provides the chiral octahydroquinolone (VIII), which is finally dehydrated by means of TFA, MsOH, TsOH or HCl in refluxing acetonitrile to give the target hexahydroquinolone.
| 【1】 Patel, I.; Hopes, P. (AstraZeneca AB); Process for synthesis of alpha,beta-unsaturated ketones. WO 0210103 . |
| 【2】 Patel, I.; Ashworth, I.; Levin, D. (AstraZeneca AB); Process for asymmetric synthesis of substd. 1,4-dihydropyridines. WO 0210134 . |
| 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) | 13245 | 3-Formylbenzonitrile; 3-Cyanobenzaldehyde | 24964-64-5 | C8H5NO | 详情 | 详情 |
| (II) | 35450 | 3,3-dibromo-1,1,1-trifluoroacetone | 431-67-4 | C3HBr2F3O | 详情 | 详情 |
| (III) | 62031 | 3-[(E)-4,4,4-trifluoro-3-oxo-1-butenyl]benzonitrile | C11H6F3NO | 详情 | 详情 | |
| (IV) | 11244 | 1,3-Cyclohexanedione | 504-02-9 | C6H8O2 | 详情 | 详情 |
| (V) | 10039 | (1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine | 3886-69-9 | C8H11N | 详情 | 详情 |
| (VI) | 62032 | 3-{[(1R)-1-phenylethyl]amino}-2-cyclohexen-1-one | C14H17NO | 详情 | 详情 | |
| (VII) | 62033 | 3-[(1S)-4,4-dimethyl-3-oxo-1-(6-oxo-2-{[(1R)-1-phenylethyl]amino}-1-cyclohexen-1-yl)pentyl]benzonitrile | C28H32N2O2 | 详情 | 详情 | |
| (VIII) | 62034 | 3-[(4S)-2-hydroxy-5-oxo-2-(trifluoromethyl)-1,2,3,4,5,6,7,8-octahydro-4-quinolinyl]benzonitrile | C17H15F3N2O2 | 详情 | 详情 |
合成路线26
该中间体在本合成路线中的序号：(II)The reaction of 6-bromo-1,2,3,4-tetrahydronaphthalen-2-one (I) with 1(R)-phenylethylamine (II) by means of p-toluenesulfonic acid in refluxing toluene gives the enamine (III), which is methylated with lithium diisopropylamide and methyl iodide in THF yielding the 1-methyldihydronaphthalene (IV). The cyclization of (IV) with acryloyl chloride (V) in toluene affords the benzoquinoline derivative (VI), which is treated with triethylsilane and trifluoroacetic acid to eliminate the chiral auxiliar giving intermediate (VII). The methylation of (VII) with methyllithium in THF yields the N-methyl benzoquinoline (VIII), which is treated with N,N'-diisopropylthiuram disulfide (IX) and tert-butyllithium to afford the thiol derivative (X). Finally, this compound is condensed with 2-chloro-4-ethylbenzo thiazole (XI) by means of K2CO3 in hot DMF.
| 【1】 Brennan, J.; et al.; Selective thiomethylation of benzo[f]quinolinone dianions facilitates production of a type I/II 5-alpha-reductase inhibitor (LY320236). 216th ACS Natl Meet (Aug. 23-27, Boston) 1998, Abst ORGN 151. |
| 【2】 Audia, J.E.; Haehl, K.L.; Kress, T.J.; McQuaid, L.A.; Neubauer, B.L.; Rocco, V.P.; Wepsiec, J.P. (Eli Lilly and Company); 5alpha-Reductase inhibitors. CA 2158609; EP 0703221; JP 1996225533; WO 9609046 . |
| 【3】 Audia, J.E.; Neubauer, B.L. (Eli Lilly and Company); Benzoquinolin-3-ones to inhibit bone loss. EP 0742010; JP 1999511739; US 5550134; WO 9635422 . |
| 【4】 Audia, J.E.; Neubauer, B.L. (Eli Lilly and Company); Use of benzoquinolin-3-ones for the treatment and prevention of prostatic cancer. CA 2172211; EP 0733365; JP 1996277220 . |
| 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) | 28584 | 6-bromo-3,4-dihydro-2(1H)-naphthalenone | 4133-35-1 | C10H9BrO | 详情 | 详情 |
| (II) | 10039 | (1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine | 3886-69-9 | C8H11N | 详情 | 详情 |
| (III) | 28585 | 6-bromo-N-[(1R)-1-phenylethyl]-3,4-dihydro-2-naphthalenamine | C18H18BrN | 详情 | 详情 | |
| (IV) | 28586 | N-(6-bromo-1-methyl-3,4-dihydro-2-naphthalenyl)-N-[(1R)-1-phenylethyl]amine | C19H20BrN | 详情 | 详情 | |
| (V) | 11577 | Acryloyl chloride; Acrylyl chloride;2-Propenoyl chloride | 814-68-6 | C3H3ClO | 详情 | 详情 |
| (VI) | 28587 | (10bR)-8-bromo-10b-methyl-4-[(1R)-1-phenylethyl]-1,4,6,10b-tetrahydrobenzo[f]quinolin-3(2H)-one | C22H22BrNO | 详情 | 详情 | |
| (VII) | 28588 | (4aR,10bR)-8-bromo-10b-methyl-1,4,4a,5,6,10b-hexahydrobenzo[f]quinolin-3(2H)-one | C14H16BrNO | 详情 | 详情 | |
| (VIII) | 28589 | (4aR,10bR)-8-bromo-4,10b-dimethyl-1,4,4a,5,6,10b-hexahydrobenzo[f]quinolin-3(2H)-one | C15H18BrNO | 详情 | 详情 | |
| (IX) | 28590 | 2-[([[(isopropylamino)carbothioyl]disulfanyl]carbothioyl)amino]propane | C8H16N2S4 | 详情 | 详情 | |
| (X) | 28591 | (4aR,10bR)-4,10b-dimethyl-8-sulfanyl-1,4,4a,5,6,10b-hexahydrobenzo[f]quinolin-3(2H)-one | C15H19NOS | 详情 | 详情 | |
| (XI) | 28592 | 2-chloro-4-ethyl-1,3-benzothiazole | C9H8ClNS | 详情 | 详情 |
合成路线27
该中间体在本合成路线中的序号：(VI)The reaction of 6-bromo-1,2,3,4-tetrahydronaphthalen-2-one (I) with 1,3-bis(trimethylsilyloxy)propane (II) by means of trimethylsilyl trifluoromethanesulfonate in THF gives the propylene ketal (III), which is treated with dimethyldisulfide and BuLi in THF yielding the methylsulfanyl derivative (IV). The hydrolysis of (IV) by means of HCl in THF affords 6-(methylsulfanyl)-1,2,3,4-tetrahydronaphthalen-2-one (V), which is condensed with 1(R)-phenyl ethylamine (VI) by means of p-toluenesulfonic acid in refluxing toluene giving the enamine (VII). The methylation of (VII) with lithium diisopropylamide and methyl iodide in THF yields the 1-methyldihydronaphthalene (VIII), which is cyclized with acryloyl anhydride (IX) in toluene affording the benzoquinoline derivative (X). The treatment of (X) with triethylsilane and trifluoroacetic acid to eliminate the chiral auxiliar gives intermediate (XI), which is methylated with methyllithium in THF yielding the N-methylbenzoquinoline (XII). The oxidation of (XII) with m-chloroperbenzoic acid (MCPBA) in dichloromethane affords the corresponding methylsulfinyl derivative (XIII), which by reaction with trifluoroacetic anhydride provides the trifluoroacetoxymethylsulfanyl derivative (XIV). Finally, this compound is condensed with 2-chloro-4-ethylbenzothiazole (XV) by means of tetrabutylammonium bisulfate (BNS) and NaBH4 in toluene/water.
| 【1】 Udodong, U.E.; Brennan, J.; Doecke, C.W.; Heath, P.C.; Patterson, L.E.; Weigel, L.O. (Eli Lilly and Company); Synthesis of benzo[f]quinolinones. WO 9818757 . |
| 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) | 28584 | 6-bromo-3,4-dihydro-2(1H)-naphthalenone | 4133-35-1 | C10H9BrO | 详情 | 详情 |
| (II) | 28593 | trimethyl[5-(trimethylsilyl)pentyl]silane | C11H28Si2 | 详情 | 详情 | |
| (III) | 28594 | 6'-Bromo-1',2',3',4'-tetrahydrospiro[1,3-dioxane-2,2'-naphthalene] | C13H15BrO2 | 详情 | 详情 | |
| (IV) | 28595 | 6'-(Methylsulfanyl)-1',2',3',4'-tetrahydrospiro[1,3-dioxane-2,2'-naphthalene] | C14H18O2S | 详情 | 详情 | |
| (V) | 28596 | 6-(methylsulfanyl)-3,4-dihydro-2(1H)-naphthalenone | C11H12OS | 详情 | 详情 | |
| (VI) | 10039 | (1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine | 3886-69-9 | C8H11N | 详情 | 详情 |
| (VII) | 28598 | 6-(methylsulfanyl)-N-[(1R)-1-phenylethyl]-3,4-dihydro-2-naphthalenamine | C19H21NS | 详情 | 详情 | |
| (VIII) | 28599 | 1-methyl-6-(methylsulfanyl)-N-[(1R)-1-phenylethyl]-3,4-dihydro-2-naphthalenamine | C20H23NS | 详情 | 详情 | |
| (IX) | 28600 | acrylic anhydride | C6H6O3 | 详情 | 详情 | |
| (X) | 28601 | (10bR)-10b-methyl-8-(methylsulfanyl)-4-[(1R)-1-phenylethyl]-1,4,6,10b-tetrahydrobenzo[f]quinolin-3(2H)-one | C23H25NOS | 详情 | 详情 | |
| (XI) | 28602 | (4aR,10bR)-10b-methyl-8-(methylsulfanyl)-1,4,4a,5,6,10b-hexahydrobenzo[f]quinolin-3(2H)-one | C15H19NOS | 详情 | 详情 | |
| (XII) | 28603 | (4aR,10bR)-4,10b-dimethyl-8-(methylsulfanyl)-1,4,4a,5,6,10b-hexahydrobenzo[f]quinolin-3(2H)-one | C16H21NOS | 详情 | 详情 | |
| (XIII) | 28604 | (4aR,10bR)-4,10b-dimethyl-8-(methylsulfinyl)-1,4,4a,5,6,10b-hexahydrobenzo[f]quinolin-3(2H)-one | C16H21NO2S | 详情 | 详情 | |
| (XIV) | 28605 | [[(4aR,10bR)-4,10b-dimethyl-3-oxo-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-8-yl]sulfanyl]methyl 2,2,2-trifluoroacetate | C18H20F3NO3S | 详情 | 详情 | |
| (XV) | 28592 | 2-chloro-4-ethyl-1,3-benzothiazole | C9H8ClNS | 详情 | 详情 | |
| (XVI) | 28597 | 2-[4-(methylsulfanyl)phenyl]acetic acid | C9H10O2S | 详情 | 详情 | |
| (XVII) | 25755 | 2-[4-(methylsulfanyl)phenyl]acetyl chloride | C9H9ClOS | 详情 | 详情 | |
| (XVIII) | 28363 | ethylene | 9002-88-4 | C2H4 | 详情 | 详情 |
| (XIX) | 28589 | (4aR,10bR)-8-bromo-4,10b-dimethyl-1,4,4a,5,6,10b-hexahydrobenzo[f]quinolin-3(2H)-one | C15H18BrNO | 详情 | 详情 |
合成路线28
该中间体在本合成路线中的序号：(XXXV)The intermediate cyclopentanecarboxylic ester (XII) has been obtained as follows: The reaction of 2-oxaspiro[4.4]nonane-1,3-dione (XXVI) with the chiral auxiliary 4(S)-isopropyloxazolidin-2-one (XXVII) by means of BuLi in THF gives the addition product (XXVIII), which is protected as the benzyl ester (XXIX) with benzylbromide and DBU. The regioselective azidation of (XXIX) with 2,4,6-triisopropylbenzenesulfonyl azide and potassium bis(trimethylsilyl)amide affords the (S)-azide (XXX), which is treated with H2O2 in THF/water to eliminate chiral auxiliary and providing 2(S)-azido-2-[1-(benzyloxycarbonyl)cyclopentyl]acetic acid (XXXI). Condensation of (XXXI) with 1(R)-ethyl-2,2-dimethylpropylamine (XXXII) by means of HBTU in dichloromethane gives the corresponding amide (XXXIII), which is finally reduced at the azido group with SnCl2 in methanol to afford the target intermediate (XII). The intermediate 1(R)-ethyl-2,2-dimethylpropylamine (XXXII) has been obtained as follows: The reaction of 2,2-dimethyl-3-pentanone (XXXIV) with the chiral auxiliary 1(R)-phenylethylamine (XXXV) by means of TiCl4 in benzene gives N-(1(R)-ethyl-2,2-dimethylpropyl)-N-(1(R)-phenylethyl)amine (XXXVI), which is then hydrogenated with H2 over Pd/C in methanol to eliminate the chiral auxiliary and obtain the target amine (XXXII).
| 【1】 Gauthier, J.-A.; Moss, N. (Bio-Mega, Inc.; Boehringer Ingelheim GmbH); Herpes ribonucleotide reductase inhibitors. EP 0837845; JP 1999508246; US 5672586; WO 9700855 . |
| 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) | 27151 | benzyl 1-((1S)-1-amino-2-[[(1R)-1-ethyl-2,2-dimethylpropyl]amino]-2-oxoethyl)cyclopentanecarboxylate | C22H34N2O3 | 详情 | 详情 | |
| (XXVI) | 27158 | 2-oxaspiro[4.4]nonane-1,3-dione | C8H10O3 | 详情 | 详情 | |
| (XXVII) | 12867 | (4S)-4-Isopropyl-1,3-oxazolidin-2-one; (R)-4-Isopropyl-2-oxazolidinone | 17016-83-0 | C6H11NO2 | 详情 | 详情 |
| (XXVIII) | 27159 | 1-[2-[(4S)-4-isopropyl-2-oxo-1,3-oxazolidin-3-yl]-2-oxoethyl]cyclopentanecarboxylic acid | C14H21NO5 | 详情 | 详情 | |
| (XXIX) | 27160 | benzyl 1-[2-[(4S)-4-isopropyl-2-oxo-1,3-oxazolidin-3-yl]-2-oxoethyl]cyclopentanecarboxylate | C21H27NO5 | 详情 | 详情 | |
| (XXX) | 27161 | benzyl 1-[(1S)-1-azido-2-[(4S)-4-isopropyl-2-oxo-1,3-oxazolidin-3-yl]-2-oxoethyl]cyclopentanecarboxylate | C21H26N4O5 | 详情 | 详情 | |
| (XXXI) | 27162 | (2S)-2-azido-2-[1-[(benzyloxy)carbonyl]cyclopentyl]ethanoic acid | C15H17N3O4 | 详情 | 详情 | |
| (XXXII) | 27163 | (1R)-1-ethyl-2,2-dimethylpropylamine | C7H17N | 详情 | 详情 | |
| (XXXIII) | 27164 | benzyl 1-((1S)-1-azido-2-[[(1R)-1-ethyl-2,2-dimethylpropyl]amino]-2-oxoethyl)cyclopentanecarboxylate | C22H32N4O3 | 详情 | 详情 | |
| (XXXIV) | 27165 | 2,2-dimethyl-3-pentanone | 564-04-5 | C7H14O | 详情 | 详情 |
| (XXXV) | 10039 | (1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine | 3886-69-9 | C8H11N | 详情 | 详情 |
| (XXXVI) | 27166 | (3R)-2,2-dimethyl-N-[(1R)-1-phenylethyl]-3-pentanamine | C15H25N | 详情 | 详情 |
合成路线29
该中间体在本合成路线中的序号：(XII)Ethoxycarbonylpiperidone (I) was converted into enol triflate (II), and this was coupled with either phenylboronic acid or phenyl trimethylstannane using Pd catalysts to give 4-phenyltetrahydro-pyridine (III). Subsequent double bond hydrogenation produced a racemic mixture of cis piperidines (IV) and (V), from which several routes were used to synthesize the chiral title compounds. Removal of BOC protecting groups with HCl in EtOAc gave racemic (VI), which was alkylated with bromide (VII) in the presence of diisopropylethylamine to afford racemic (VIII). The enantiomers of (VIII) were separated utilizing chiral HPLC on a Chiralcel OD column, yielding the (-)(S,S) compound (XV, 247751) and the (+)(R,R) compound (XIV, 247752). Alternatively, racemic piperidine (VI) could be separated using a Chiralcel OD column into enantiomers (-)(S,S) (IX) and (+)(R,R) (X), which were separately alkylated with bromide (VII) to furnish (XV) and (XIV), respectively. Resolution of the racemic mixture (IV) and (V) was also achieved by hydrolysis to the racemic acids (XI) with LiOH under controlled conditions, followed by treatment with (S)-a-methylbenzylamine (XII) and crystallization of the resulting salt (XIII), whose absolute configuration was determined by X-ray diffraction. Liberation of the (S,S) acid, followed by BOC removal and esterification with an ethanolic solution of HCl then provided ester (IX), which could be alkylated with bromide (VII) to afford (XV).
| 【1】 Patane, M.A.; DiPardo, R.M.; Price, R.P.; Chang, R.S.; Ransom, R.W.; O'Malley, S.S.; Di Salvo, J.; Bock, M.G.; Selective alpha-1a adrenergic receptor antagonists. Effects of pharmacophore regio- and stereochemistry on potency and selectivity. Bioorg Med Chem Lett 1998, 8, 18, 2495. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 16593 | Phenylboronic acid；Benzeneboronic acid;Phenylboron dihydroxide | 98-80-6 | C6H7BO2 | 详情 | 详情 | |
| 63323 | trimethyl(phenyl)stannane | C9H14Sn | 详情 | 详情 | ||
| (I) | 18394 | 1-(tert-butyl) 3-ethyl 4-oxo-1,3-piperidinedicarboxylate | C13H21NO5 | 详情 | 详情 | |
| (II) | 18395 | 1-(tert-butyl) 3-ethyl 4-[[(trifluoromethyl)sulfonyl]oxy]-5,6-dihydro-1,3(2H)-pyridinedicarboxylate | C14H20F3NO7S | 详情 | 详情 | |
| (III) | 18396 | 1-(tert-butyl) 3-ethyl 4-phenyl-5,6-dihydro-1,3(2H)-pyridinedicarboxylate | C19H25NO4 | 详情 | 详情 | |
| (IV) | 18397 | 1-(tert-butyl) 3-ethyl (3S,4S)-4-phenyl-1,3-piperidinedicarboxylate | C19H27NO4 | 详情 | 详情 | |
| (V) | 18398 | 1-(tert-butyl) 3-ethyl (3R,4R)-4-phenyl-1,3-piperidinedicarboxylate | C19H27NO4 | 详情 | 详情 | |
| (VI) | 18399 | ethyl 4-phenyl-3-piperidinecarboxylate | C14H19NO2 | 详情 | 详情 | |
| (VII) | 18400 | 2-(4-bromobutyl)-5-chloro-1H-1,2-benzisothiazole-1,1,3(2H)-trione | C11H11BrClNO3S | 详情 | 详情 | |
| (VIII) | 18401 | ethyl 1-[4-(5-chloro-1,1,3-trioxo-1,3-dihydro-2H-1,2-benzisothiazol-2-yl)butyl]-4-phenyl-3-piperidinecarboxylate | C25H29ClN2O5S | 详情 | 详情 | |
| (IX) | 18402 | ethyl (3S,4S)-4-phenyl-3-piperidinecarboxylate | C14H19NO2 | 详情 | 详情 | |
| (X) | 18403 | ethyl (3R,4R)-4-phenyl-3-piperidinecarboxylate | C14H19NO2 | 详情 | 详情 | |
| (XI) | 18404 | 1-(tert-butoxycarbonyl)-4-phenyl-3-piperidinecarboxylic acid | C17H23NO4 | 详情 | 详情 | |
| (XII) | 10039 | (1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine | 3886-69-9 | C8H11N | 详情 | 详情 |
| (XIII) | 18406 | (1S)-1-phenyl-1-ethanaminium | C8H12N | 详情 | 详情 | |
| (XIV) | 18407 | ethyl (3R,4R)-1-[4-(5-chloro-1,1,3-trioxo-1,3-dihydro-2H-1,2-benzisothiazol-2-yl)butyl]-4-phenyl-3-piperidinecarboxylate | C25H29ClN2O5S | 详情 | 详情 | |
| (XV) | 18408 | ethyl (3S,4S)-1-[4-(5-chloro-1,1,3-trioxo-1,3-dihydro-2H-1,2-benzisothiazol-2-yl)butyl]-4-phenyl-3-piperidinecarboxylate | C25H29ClN2O5S | 详情 | 详情 |
合成路线30
该中间体在本合成路线中的序号：(XII)Ethoxycarbonylpiperidone (I) was converted into enol triflate (II), and this was coupled with either phenylboronic acid or phenyl trimethylstannane using Pd catalysts to give 4-phenyltetrahydro-pyridine (III). Subsequent double bond hydrogenation produced a racemic mixture of cis piperidines (IV) and (V), from which several routes were used to synthesize the chiral title compounds. Removal of BOC protecting groups with HCl in EtOAc gave racemic (VI), which was alkylated with bromide (VII) in the presence of diisopropylethylamine to afford racemic (VIII). The enantiomers of (VIII) were separated utilizing chiral HPLC on a Chiralcel OD column, yielding the (-)(S,S) compound (XV, 247751) and the (+)(R,R) compound (XIV, 247752). Alternatively, racemic piperidine (VI) could be separated using a Chiralcel OD column into enantiomers (-)(S,S) (IX) and (+)(R,R) (X), which were separately alkylated with bromide (VII) to furnish (XV) and (XIV), respectively. Resolution of the racemic mixture (IV) and (V) was also achieved by hydrolysis to the racemic acids (XI) with LiOH under controlled conditions, followed by treatment with (S)-a-methylbenzylamine (XII) and crystallization of the resulting salt (XIII), whose absolute configuration was determined by X-ray diffraction. Liberation of the (S,S) acid, followed by BOC removal and esterification with an ethanolic solution of HCl then provided ester (IX), which could be alkylated with bromide (VII) to afford (XV).
| 【1】 Patane, M.A.; DiPardo, R.M.; Price, R.P.; Chang, R.S.; Ransom, R.W.; O'Malley, S.S.; Di Salvo, J.; Bock, M.G.; Selective alpha-1a adrenergic receptor antagonists. Effects of pharmacophore regio- and stereochemistry on potency and selectivity. Bioorg Med Chem Lett 1998, 8, 18, 2495. |
| 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) | 18394 | 1-(tert-butyl) 3-ethyl 4-oxo-1,3-piperidinedicarboxylate | C13H21NO5 | 详情 | 详情 | |
| (II) | 18395 | 1-(tert-butyl) 3-ethyl 4-[[(trifluoromethyl)sulfonyl]oxy]-5,6-dihydro-1,3(2H)-pyridinedicarboxylate | C14H20F3NO7S | 详情 | 详情 | |
| (III) | 18396 | 1-(tert-butyl) 3-ethyl 4-phenyl-5,6-dihydro-1,3(2H)-pyridinedicarboxylate | C19H25NO4 | 详情 | 详情 | |
| (IV) | 18397 | 1-(tert-butyl) 3-ethyl (3S,4S)-4-phenyl-1,3-piperidinedicarboxylate | C19H27NO4 | 详情 | 详情 | |
| (V) | 18398 | 1-(tert-butyl) 3-ethyl (3R,4R)-4-phenyl-1,3-piperidinedicarboxylate | C19H27NO4 | 详情 | 详情 | |
| (VI) | 18399 | ethyl 4-phenyl-3-piperidinecarboxylate | C14H19NO2 | 详情 | 详情 | |
| (VII) | 18400 | 2-(4-bromobutyl)-5-chloro-1H-1,2-benzisothiazole-1,1,3(2H)-trione | C11H11BrClNO3S | 详情 | 详情 | |
| (VIII) | 18401 | ethyl 1-[4-(5-chloro-1,1,3-trioxo-1,3-dihydro-2H-1,2-benzisothiazol-2-yl)butyl]-4-phenyl-3-piperidinecarboxylate | C25H29ClN2O5S | 详情 | 详情 | |
| (IX) | 18402 | ethyl (3S,4S)-4-phenyl-3-piperidinecarboxylate | C14H19NO2 | 详情 | 详情 | |
| (X) | 18403 | ethyl (3R,4R)-4-phenyl-3-piperidinecarboxylate | C14H19NO2 | 详情 | 详情 | |
| (XI) | 18404 | 1-(tert-butoxycarbonyl)-4-phenyl-3-piperidinecarboxylic acid | C17H23NO4 | 详情 | 详情 | |
| (XII) | 10039 | (1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine | 3886-69-9 | C8H11N | 详情 | 详情 |
| (XIII) | 18406 | (1S)-1-phenyl-1-ethanaminium | C8H12N | 详情 | 详情 | |
| (XIV) | 18407 | ethyl (3R,4R)-1-[4-(5-chloro-1,1,3-trioxo-1,3-dihydro-2H-1,2-benzisothiazol-2-yl)butyl]-4-phenyl-3-piperidinecarboxylate | C25H29ClN2O5S | 详情 | 详情 | |
| (XV) | 18408 | ethyl (3S,4S)-1-[4-(5-chloro-1,1,3-trioxo-1,3-dihydro-2H-1,2-benzisothiazol-2-yl)butyl]-4-phenyl-3-piperidinecarboxylate | C25H29ClN2O5S | 详情 | 详情 |
合成路线31
该中间体在本合成路线中的序号：(VI)The cyclization of 4-methoxyphenacyl bromide (I) with 2-amidinoacetic acid ethyl ester (II) by means of sodium ethoxide in ethanol gives 2-amino-5-(4-methoxyphenyl)-1H-pyrrole-3-carboxylic acid ethyl ester (III), which is cyclized with formamide in DMF at 150 C to yield the pyrrolopyrimidine (IV). The reaction of the OH group of (IV) with POCl3 at 150 C affords the corresponding chloro derivative (V), which is condensed with 1(R)-phenylethylamine (VI) in refluxing butanol to provide the adduct (VII). Finally, this compound is demethylated by means of BBr3 in dichloromethane to furnish the target pyrrolopyrimidine.
| 【1】 Traxler, P.; Bold, G.; Brill, W.K.-D.; Frei, J. (Novartis AG); Pyrrolopyrimidines and processes for the preparation thereof. EP 0836605; JP 1999508570; US 6140332; WO 9702266 . |
| 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) | 21991 | 2-Methoxyphenacyl bromide; 2-bromo-1-(4-methoxyphenyl)-1-ethanone | 2632-13-5 | C9H9BrO2 | 详情 | 详情 |
| (II) | 54308 | ethyl 3-amino-3-iminopropanoate | 50551-10-5 | C5H10N2O2 | 详情 | 详情 |
| (III) | 54309 | ethyl 2-amino-5-(4-methoxyphenyl)-1H-pyrrole-3-carboxylate | n/a | C14H16N2O3 | 详情 | 详情 |
| (IV) | 54310 | 6-(4-methoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ol | n/a | C13H11N3O2 | 详情 | 详情 |
| (V) | 54311 | 4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl methyl ether; 4-chloro-6-(4-methoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine | n/a | C13H10ClN3O | 详情 | 详情 |
| (VI) | 10039 | (1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine | 3886-69-9 | C8H11N | 详情 | 详情 |
| (VII) | 54312 | N-[6-(4-methoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-N-[(1R)-1-phenylethyl]amine; 6-(4-methoxyphenyl)-N-[(1R)-1-phenylethyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine | n/a | C21H20N4O | 详情 | 详情 |
合成路线32
该中间体在本合成路线中的序号：(XI)The Knoevenagel condensation between benzyl propionylacetate (V) and 2,4-difluorobenzaldehyde (VI) afforded the benzylidene derivative (VII), which was cyclized with O-methylisourea hemisulfate (VIII), yielding the dihydropyrimidine (IX). This compound, upon reaction with 4-nitrophenyl chloroformate, regioselectively produced the carbamate ester (X). Resolution of the enantiomers of (X) was achieved by condensation with the chiral auxiliary (S)-(-)-alpha-methylbenzylamine (XI) to obtain a mixture of diastereomeric amides, which were separated by flash chromatography. The alpha-methylbenzylaminocarbonyl moiety was then removed from the desired diastereomer (+)-(XII) by treatment with DBU, and the resulting chiral dihydropyridine was again condensed with 4-nitrophenyl chloroformate to give (+)-(X). Coupling of the chiral carbamate (+)-(X) with amine (IV) provided adduct (XIII), which on treatment with aqueous HCl gave the dihydropyrimidinone (XIV). After catalytic hydrogenolysis of the benzyl ester of (XIV), the resulting acid was converted to the title amide by reaction with ammonia in the presence of EDC and DMAP.
| 【1】 Marzabadi, M.R.; Murali Dhar, T.G.; Nagarathnam, D.; et al.; Design and synthesis of novel alpha1a adrenoceptor-selective antagonists. 2. Approaches to eliminate opioid agonist metabolites via modification of linker and 4-methoxycarbonyl-4-phenylpiperidine moiety. J Med Chem 1999, 42, 23, 4778. |
| 【2】 Lagu, B.; Nagarathnam, D.; Miao, S.W.; et al.; Design and synthesis of novel alpha1a adrenoceptor-selective antagonists. 1. Structure-activity relationship in dihydropyrimidinones. J Med Chem 1999, 42, 23, 4764. |
| 【3】 Wong, W.C.; Lagu, B.; Nagarathnam, D.; Marzabadi, M.R.; Gluchowski, C. (Synaptic Pharmaceutical Corp.); Dihydropyrimidines and uses thereof. EP 1021185; JP 2000506904; WO 9742956 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IV) | 43079 | 1-(3-aminopropyl)-4-phenyl-4-piperidinecarbonitrile | C15H21N3 | 详情 | 详情 | |
| (V) | 43080 | benzyl 3-oxopentanoate | 4949-45-5 | C12H14O3 | 详情 | 详情 |
| (VI) | 26654 | 3,4-difluorobenzaldehyde | 34036-07-2 | C7H4F2O | 详情 | 详情 |
| (VII) | 43081 | benzyl (Z)-3-(2,4-difluorophenyl)-2-propionyl-2-propenoate | C19H16F2O3 | 详情 | 详情 | |
| (VIII) | 26657 | O-methyl isourea; [Amino(imino)methoxy]methane | 52328-05-9 | C2H6N2O | 详情 | 详情 |
| (IX) | 43082 | benzyl 6-(2,4-difluorophenyl)-4-ethyl-2-methoxy-1,6-dihydro-5-pyrimidinecarboxylate | C21H20F2N2O3 | 详情 | 详情 | |
| (X) | 43084 | 5-benzyl 1-(4-nitrophenyl) 6-(2,4-difluorophenyl)-4-ethyl-2-methoxy-1,5(6H)-pyrimidinedicarboxylate | C28H23F2N3O7 | 详情 | 详情 | |
| (XI) | 10039 | (1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine | 3886-69-9 | C8H11N | 详情 | 详情 |
| (XII) | 43083 | benzyl 6-(2,4-difluorophenyl)-4-ethyl-2-methoxy-1-([[(1R)-1-phenylethyl]amino]carbonyl)-1,6-dihydro-5-pyrimidinecarboxylate | C30H29F2N3O4 | 详情 | 详情 | |
| (XIII) | 43085 | benzyl 1-([[3-(4-cyano-4-phenyl-1-piperidinyl)propyl]amino]carbonyl)-6-(2,4-difluorophenyl)-4-ethyl-2-methoxy-1,6-dihydro-5-pyrimidinecarboxylate | C37H39F2N5O4 | 详情 | 详情 | |
| (XIV) | 43086 | benzyl 3-([[3-(4-cyano-4-phenyl-1-piperidinyl)propyl]amino]carbonyl)-4-(2,4-difluorophenyl)-6-ethyl-2-oxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate | C36H37F2N5O4 | 详情 | 详情 |
合成路线33
该中间体在本合成路线中的序号：(A)The cyclopropanation of ethyl acetoacetate (I) with 1,2-dibromoethane and K2CO3 in DMF, followed by hydrolysis with NaOH gives 1-acetylcyclopropane-1-carboxylic acid (II), which is condensed with 1(R)-phenylethylamine (A) by means of butyl chloroformate in dichloromethane yielding the chiral amide (III). The protection of the acetyl group with ethylene glycol and p-toluenesulfonic acid affords the cyclic acetal (IV), which is brominated with Br2 in dioxane to give the bromomethyl compound (V). The cyclization of (V) by means of NaH in THF affords the spirocyclopropane derivative (VI), which is deprotected with HCl providing the spiro pyrrolidinedione (VII). The reaction of (VII) with hydroxylamine affords the oxime (VIII), which is reduced with H2 over RaNi in methanol and crystallized with l-tartaric acid to give the desired chiral 7(R)-amino-5-(1(R)-phenylethyl)-5-azaspiro[2.4]heptan-4-one (IX). The reduction of the ketonic group of (IX) with LiAlH4 yields the chiral amine (X), which is protected with tert-butoxycarbonyl anhydride to the carbamate (XI). The hydrogenation of (XI) with H 2 over Pd/C affords the spiropyrrolidine (XII) with its NH group free, which is condensed with the quinolizine (XIII) by means of triethylamine in DMF providing intermediate (XIV). Finally, this compound is deprotected and hydrolyzed to the target compound with LiOH in ethanol.
| 【1】 Armiger, Y.L.; Chu, D.T.W.; Fung, A.K.L.; et al.; The discovery of A-165753 and A-170568, two potent broad-spectrum antimicrobial agents. 38th Intersci Conf Antimicrob Agents Chemother (Sept 24 1998, San Diego) 1998, Abst F-86. |
| 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) | 10039 | (1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine | 3886-69-9 | C8H11N | 详情 | 详情 |
| (I) | 11819 | ethyl acetoacetate; ethyl 3-oxobutanoate；Acetoacetic ester;Ethyl beta-ketobutyrate;ethyl 3-oxobutyrate | 141-97-9 | C6H10O3 | 详情 | 详情 |
| (II) | 15194 | 1-acetylcyclopropanecarboxylic acid | C6H8O3 | 详情 | 详情 | |
| (III) | 15179 | 1-acetyl-N-[(1R)-1-phenylethyl]cyclopropanecarboxamide | C14H17NO2 | 详情 | 详情 | |
| (IV) | 15180 | 1-(2-methyl-1,3-dioxolan-2-yl)-N-[(1R)-1-phenylethyl]cyclopropanecarboxamide | C16H21NO3 | 详情 | 详情 | |
| (V) | 15181 | 1-[2-(bromomethyl)-1,3-dioxolan-2-yl]-N-[(1R)-1-phenylethyl]cyclopropanecarboxamide | C16H20BrNO3 | 详情 | 详情 | |
| (VI) | 15198 | 10-[(1R)-1-phenylethyl]-5,8-dioxa-10-azadispiro[2.0.4.3]undecan-11-one | C16H19NO3 | 详情 | 详情 | |
| (VII) | 15173 | 5-[(1R)-1-phenylethyl]-5-azaspiro[2.4]heptane-4,7-dione | C14H15NO2 | 详情 | 详情 | |
| (VIII) | 15174 | 5-[(1R)-1-phenylethyl]-5-azaspiro[2.4]heptane-4,7-dione 7-oxime | C14H16N2O2 | 详情 | 详情 | |
| (IX) | 15176 | (7S)-7-amino-5-[(1R)-1-phenylethyl]-5-azaspiro[2.4]heptan-4-one | C14H18N2O | 详情 | 详情 | |
| (X) | 15177 | (7S)-5-[(1R)-1-phenylethyl]-5-azaspiro[2.4]heptan-7-amine; (7S)-5-[(1R)-1-phenylethyl]-5-azaspiro[2.4]hept-7-ylamine | C14H20N2 | 详情 | 详情 | |
| (XI) | 15204 | tert-butyl N-[(7S)-5-[(1R)-1-phenylethyl]-5-azaspiro[2.4]hept-7-yl]carbamate | C19H28N2O2 | 详情 | 详情 | |
| (XII) | 15193 | tert-butyl N-[(7S)-5-azaspiro[2.4]hept-7-yl]carbamate | C11H20N2O2 | 详情 | 详情 | |
| (XIII) | 16831 | ethyl 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate | C16H15ClFNO3 | 详情 | 详情 | |
| (XIV) | 26950 | ethyl 8-[(7S)-7-[(tert-butoxycarbonyl)amino]-5-azaspiro[2.4]hept-5-yl]-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate | C27H34FN3O5 | 详情 | 详情 |
合成路线34
该中间体在本合成路线中的序号：(A)The cyclopropanation of ethyl acetoacetate (I) with 1,2-dibromoethane and K2CO3 in DMF, followed by hydrolysis with NaOH gives 1-acetylcyclopropane-1-carboxylic acid (II), which is condensed with 1(R)-phenylethylamine (A) by means of butyl chloroformate in dichloromethane yielding the chiral amide (III). The protection of the acetyl group with ethylene glycol and p-toluenesulfonic acid affords the cyclic acetal (IV), which is brominated with Br2 in dioxane to give the bromomethyl compound (V). The cyclization of (V) by means of NaH in THF affords the spirocyclopropane derivative (VI), which is deprotected with HCl providing the spiro pyrrolidinedione (VII). The reaction of (VII) with hydroxylamine affords the oxime (VIII), which is reduced with H2 over RaNi in methanol and crystallized with l-tartaric acid to give the desired chiral 7(R)-amino-5-(1(R)-phenylethyl)-5-azaspiro[2.4]heptan-4-one (IX). The reduction of the ketonic group of (IX) with LiAlH4 yields the chiral amine (X), which is protected with tert-butoxycarbonyl anhydride to the carbamate (XI). The hydrogenation of (XI) with H 2 over Pd/C affords the spiropyrrolidine (XII) with its NH group free, which is condensed with the quinolizine (XIII) by means of triethylamine in DMF providing intermediate (XIV). This compound is methylated by means of methyl iodide and sodium bis(trimethylsilyl)amide yielding the methylamino derivative (XV), which is finally deprotected and hydrolyzed to the target compound with LiOH in ethanol.
| 【1】 Armiger, Y.L.; Chu, D.T.W.; Fung, A.K.L.; et al.; The discovery of A-165753 and A-170568, two potent broad-spectrum antimicrobial agents. 38th Intersci Conf Antimicrob Agents Chemother (Sept 24 1998, San Diego) 1998, Abst F-86. |
| 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) | 10039 | (1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine | 3886-69-9 | C8H11N | 详情 | 详情 |
| (I) | 11819 | ethyl acetoacetate; ethyl 3-oxobutanoate；Acetoacetic ester;Ethyl beta-ketobutyrate;ethyl 3-oxobutyrate | 141-97-9 | C6H10O3 | 详情 | 详情 |
| (II) | 15194 | 1-acetylcyclopropanecarboxylic acid | C6H8O3 | 详情 | 详情 | |
| (III) | 15179 | 1-acetyl-N-[(1R)-1-phenylethyl]cyclopropanecarboxamide | C14H17NO2 | 详情 | 详情 | |
| (IV) | 15180 | 1-(2-methyl-1,3-dioxolan-2-yl)-N-[(1R)-1-phenylethyl]cyclopropanecarboxamide | C16H21NO3 | 详情 | 详情 | |
| (V) | 15181 | 1-[2-(bromomethyl)-1,3-dioxolan-2-yl]-N-[(1R)-1-phenylethyl]cyclopropanecarboxamide | C16H20BrNO3 | 详情 | 详情 | |
| (VI) | 15198 | 10-[(1R)-1-phenylethyl]-5,8-dioxa-10-azadispiro[2.0.4.3]undecan-11-one | C16H19NO3 | 详情 | 详情 | |
| (VII) | 15173 | 5-[(1R)-1-phenylethyl]-5-azaspiro[2.4]heptane-4,7-dione | C14H15NO2 | 详情 | 详情 | |
| (VIII) | 15174 | 5-[(1R)-1-phenylethyl]-5-azaspiro[2.4]heptane-4,7-dione 7-oxime | C14H16N2O2 | 详情 | 详情 | |
| (IX) | 15176 | (7S)-7-amino-5-[(1R)-1-phenylethyl]-5-azaspiro[2.4]heptan-4-one | C14H18N2O | 详情 | 详情 | |
| (X) | 15177 | (7S)-5-[(1R)-1-phenylethyl]-5-azaspiro[2.4]heptan-7-amine; (7S)-5-[(1R)-1-phenylethyl]-5-azaspiro[2.4]hept-7-ylamine | C14H20N2 | 详情 | 详情 | |
| (XI) | 15204 | tert-butyl N-[(7S)-5-[(1R)-1-phenylethyl]-5-azaspiro[2.4]hept-7-yl]carbamate | C19H28N2O2 | 详情 | 详情 | |
| (XII) | 15193 | tert-butyl N-[(7S)-5-azaspiro[2.4]hept-7-yl]carbamate | C11H20N2O2 | 详情 | 详情 | |
| (XIII) | 16831 | ethyl 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate | C16H15ClFNO3 | 详情 | 详情 | |
| (XIV) | 26950 | ethyl 8-[(7S)-7-[(tert-butoxycarbonyl)amino]-5-azaspiro[2.4]hept-5-yl]-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate | C27H34FN3O5 | 详情 | 详情 | |
| (XV) | 26951 | ethyl 8-[(7S)-7-[(tert-butoxycarbonyl)(methyl)amino]-5-azaspiro[2.4]hept-5-yl]-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate | C28H36FN3O5 | 详情 | 详情 |
合成路线35
该中间体在本合成路线中的序号：(IX)Basic hydrolysis of cis-4-methylenecyclopentane-1,2-dicarboxylic acid diethyl ester (I) with LiOH gives the free acid (II), which by refluxing with propionic anhydride yields the cyclic anhydride (III). Rearrangement using trimethylsilyl azide in dioxane at 80 C produces the oxazinedione (IV), which is hydrolyzed to (±)-cis-2-amino-4-methylenecyclopentane-1-carboxylic acid ethyl ester (V) by means of acetyl chloride in EtOH. Further hydrolysis of ester (V) with aqueous HCl provides the racemic amino acid (VI), which is coupled with N-(9-fluorenylmethoxycarbonyl)succinimide (VII) to afford the Fmoc-amino acid (VIII). Racemic (VIII) is resolved by treatment with (+)-(R)-1-phenylethylamine (IX) and crystallization of the resulting salt (X) in EtOH/methyl tert-butyl ether. Finally, acidification of salt (X) and extraction of the (1R,2S)-free acid, followed by removal of the Fmoc group with liquid ammonia, provides PLD-118 isolated as its hydrochloride salt.
| 【1】 Sorbera, L.A.; Castañer, J.; Bozzo, J.; PLD-118. Drugs Fut 2002, 27, 11, 1049. |
| 【2】 Mittendorf, J.; Kunisch, F.; Matzke, M.; Militzer, H.-C.; Endermann, R.; Metzger, K.G.; Bremm, K.-D.; Plempel, M. (Bayer AG); Cyclopentane- and pentene-beta-amino-acids. DE 4217776; EP 0571870; JP 1994056751 . |
| 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) | 27275 | diethyl (1R,2S)-4-methylene-1,2-cyclopentanedicarboxylate | C12H18O4 | 详情 | 详情 | |
| (II) | 27276 | (1R,2S)-4-methylene-1,2-cyclopentanedicarboxylic acid | C8H10O4 | 详情 | 详情 | |
| (III) | 56629 | (3aR,6aS)-5-methylenetetrahydro-1H-cyclopenta[c]furan-1,3(3aH)-dione | C8H8O3 | 详情 | 详情 | |
| (IV) | 56630 | (4aR,7aS)-6-methylenehexahydrocyclopenta[d][1,3]oxazine-2,4-dione | C8H9NO3 | 详情 | 详情 | |
| (V) | 27279 | ethyl (1R,2S)-2-amino-4-methylenecyclopentanecarboxylate | C9H15NO2 | 详情 | 详情 | |
| (VI) | 27280 | (1R,2S)-2-amino-4-methylenecyclopentanecarboxylic acid | C7H11NO2 | 详情 | 详情 | |
| (VII) | 21011 | 1-[[(9H-fluoren-9-ylmethoxy)carbonyl]oxy]-2,5-pyrrolidinedione | 82911-69-1 | C19H15NO5 | 详情 | 详情 |
| (VIII) | 27281 | (1R,2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-4-methylenecyclopentanecarboxylic acid | C22H21NO4 | 详情 | 详情 | |
| (IX) | 10039 | (1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine | 3886-69-9 | C8H11N | 详情 | 详情 |
| (X) | 27282 | (1R)-1-phenyl-1-ethanaminium (1R,2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-4-methylenecyclopentanecarboxylate | C30H32N2O4 | 详情 | 详情 |
合成路线36
该中间体在本合成路线中的序号：(II)The condensation of itaconic acid (I) with (R)-1-phenylethylamine (II) produced a mixture of diastereomeric pyrrolidinones (III). The desired isomer (IV) was then isolated after conversion to the corresponding methyl ester. Introduction of the fluorine atom to give (VI) was achieved by either treatment with diethylaminosulfur trifluoride (DAST) or via conversion to the corresponding mesylate and further displacement by tetrabutylammonium fluoride. Hydroxylation of the lithium enolate of (VI) by means of O2 and (EtO)3P afforded the trans-3-hydroxy-4-(fluoromethyl)pyrrolidinone (VII). This was converted to mesylate (VIII) and subsequently displaced by NaN3 to provide the cis azide (IX). Hydrogenation of the azido group of (IX) over Pd/C in the presence of di-tert-butyl dicarbonate produced the Boc-protected amine (X). The pyrrolidinone ring was then reduced to pyrrolidine (XI) with borane in THF, and further hydrogenation over Pd/C at 50 C removed the alpha-methylbenzyl group, yielding (XII). Optionally, acid deprotection of the Boc group of (XII) provided intermediate (XIII).
| 【1】 Takahaski, H.; et al.; DC-756: A new methoxyquinolone: Synthesis and in vitro activity of 7-(3-amino-4-substituted-pyrrolidin-1-yl) derivatives. 38th Intersci Conf Antimicrob Agents Chemother (Sept 24 1998, San Diego) 1998, Abst F-73. |
| 【2】 Takeda, T.; Kimura, K.; Ohki, H.; Takahashi, H.; Miyauchi, R.; Takemura, M. (Daiichi Pharmaceutical Co., Ltd.); Cis-substd. fluoromethylpyrrolidine derivs.. EP 0995744; WO 9858923 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IIIa) | 36288 | (3R)-5-oxo-1-[(1R)-1-phenylethyl]-3-pyrrolidinecarboxylic acid | C13H15NO3 | 详情 | 详情 | |
| (IIIb) | 36289 | (3S)-5-oxo-1-[(1R)-1-phenylethyl]-3-pyrrolidinecarboxylic acid | C13H15NO3 | 详情 | 详情 | |
| (I) | 27493 | 2-methylenesuccinic acid | 97-65-4 | C5H6O4 | 详情 | 详情 |
| (II) | 10039 | (1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine | 3886-69-9 | C8H11N | 详情 | 详情 |
| (IV) | 36290 | methyl (3R)-5-oxo-1-[(1R)-1-phenylethyl]-3-pyrrolidinecarboxylate | C14H17NO3 | 详情 | 详情 | |
| (V) | 36291 | (4R)-4-(hydroxymethyl)-1-[(1R)-1-phenylethyl]-2-pyrrolidinone | C13H17NO2 | 详情 | 详情 | |
| (VI) | 36292 | (4R)-4-(fluoromethyl)-1-[(1R)-1-phenylethyl]-2-pyrrolidinone | C13H16FNO | 详情 | 详情 | |
| (VII) | 36293 | (3R,4S)-4-(fluoromethyl)-3-hydroxy-1-[(1R)-1-phenylethyl]-2-pyrrolidinone | C13H16FNO2 | 详情 | 详情 | |
| (VIII) | 36294 | (3R,4S)-4-(fluoromethyl)-2-oxo-1-[(1R)-1-phenylethyl]pyrrolidinyl methanesulfonate | C14H18FNO4S | 详情 | 详情 | |
| (IX) | 36295 | (3S,4S)-3-azido-4-(fluoromethyl)-1-[(1R)-1-phenylethyl]-2-pyrrolidinone | C13H15FN4O | 详情 | 详情 | |
| (X) | 36296 | tert-butyl (3S,4S)-4-(fluoromethyl)-2-oxo-1-[(1R)-1-phenylethyl]pyrrolidinylcarbamate | C18H25FN2O3 | 详情 | 详情 | |
| (XI) | 36297 | tert-butyl (3S,4S)-4-(fluoromethyl)-1-[(1R)-1-phenylethyl]pyrrolidinylcarbamate | C18H27FN2O2 | 详情 | 详情 | |
| (XII) | 36298 | tert-butyl (3S,4S)-4-(fluoromethyl)pyrrolidinylcarbamate | C10H19FN2O2 | 详情 | 详情 | |
| (XIII) | 36299 | (3S,4S)-4-(fluoromethyl)-3-pyrrolidinamine; (3S,4S)-4-(fluoromethyl)pyrrolidinylamine | C5H11FN2 | 详情 | 详情 |
合成路线37
该中间体在本合成路线中的序号：(VI)The condensation of 2-methoxypyridine-3-amine (I) with ethyl 2-(ethoxymethylene)-3-oxohexanoate (II) by heating at 120-30 C gives the aminoacrylate ewster (III), which is cyclized by heating in refluxing diphenyl ether to yield the naphthyridinone (IV). The reaction of (IV) with methanesulfonyl chloride and triethylamine in dichloromethane affords the methanesulfonyloxy naphthyridine (V), which is finally condensed with (R)-1-phenylethylamine (VI) in refluxing acetonitrile.
| 【1】 Sohn, S.K.; Chang, M.S.; Kim, S.G.; Chung, K.J.; Kang, D.P.; Kim, Y.H.; Kang, B.G.; Choi, W.S.; Seo, K.H.; Yoo, H.Y.; Paek, J.H. (Yung-Jin Pharmaceutical Co., Ltd.); 4-Amino-3-acylnaphthyridine derivs.. WO 9703074 . |
| 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) | 25075 | 2-methoxy-3-pyridinamine | C6H8N2O | 详情 | 详情 | |
| (II) | 12517 | ethyl (E)-2-butyryl-3-ethoxy-2-propenoate | C11H18O4 | 详情 | 详情 | |
| (III) | 25076 | ethyl (Z)-2-butyryl-3-[(2-methoxy-3-pyridinyl)amino]-2-propenoate | C15H20N2O4 | 详情 | 详情 | |
| (IV) | 25077 | 3-butyryl-8-methoxy[1,7]naphthyridin-4(1H)-one | C13H14N2O3 | 详情 | 详情 | |
| (V) | 25078 | 8-methoxy-4-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]-3-(1-propylvinyl)[1,7]naphthyridine | C17H22N2O2S | 详情 | 详情 | |
| (VI) | 10039 | (1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine | 3886-69-9 | C8H11N | 详情 | 详情 |
合成路线38
该中间体在本合成路线中的序号：(II)Formation of the diastereoisomeric salts with (R)-alpha-methylbenzylamine (II), followed by crystallization from methanol/toluene, provided the desired (R)-phenylpropionic acid salt (III) in good enantiomeric purity, which was further enriched in the desired enantiomer by recrystallization from the same solvent. The chiral carboxylic acid was then liberated from the recrystallized methylbenzylamine salt (III) by acidification with HCl in a water/heptane two-phase system.
| 【1】 Coe, P.F.; Hardy, R.; Hirst, A.; O'Donnell, H.O. (The Boots Company plc); Process for preparing substantially pure enantiomers of phenylpropionic acids. WO 9412460 . |
合成路线39
该中间体在本合成路线中的序号：(II)Synthesis of the tricyclic ketone intermediate (VI): Optical resolution of racemic bicyclo[3.2.0]hept-2-en-6-one (I) by reaction with SO2 and (+)-a-methylbenzylamine (II) yields a mixture of diastereomeric salts of the a-hydroxysulfonic acid with the chiral amine (II), which are separated by crystallization. Treatment of the purified salt (III) with aqueous Na2CO3 results in the pure enantiomer ()-(I). Reaction of ()-(I) with 1,3-dibromo-5,5-dimethylhydantoin (DBDMH) in acetone/water affords the bromohydrin (IV), which is treated with TBDMS-Cl and imidazole to provide the silyl ether (V). Finally, reaction of the protected bromohydrin (V) with potassium tert-butoxide in toluene gives the target tricyclic ketone intermediate (VI).
| 【1】 Boulton, L.T.; Brick, D.; Fox, M.E.; et al.; Synthesis of the potent antiglaucoma agent, travoprost. Org Process Res Dev 2002, 6, 2, 138. |
| 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) | 24421 | (1S,5R)bicyclo[3.2.0]hept-2-en-6-one | C7H8O | 详情 | 详情 | |
| (rac)-(I) | 53261 | bicyclo[3.2.0]hept-2-en-6-one | 13173-09-6 | C7H8O | 详情 | 详情 |
| (II) | 10039 | (1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine | 3886-69-9 | C8H11N | 详情 | 详情 |
| (III) | 53267 | Butanoic acid; Butyric acid; N-Butanic acid; N-Butanoic acid; n-Butyric acid; N-Ethylacetic acid; N-Propanecarboxylic acid; N-Propylformic acid | 107-92-6 | C4H8O2 | 详情 | 详情 |
| (IV) | 53258 | (1R,2S,3S,5R)-2-bromo-3-hydroxybicyclo[3.2.0]heptan-6-one | n/a | C7H9BrO2 | 详情 | 详情 |
| (V) | 53259 | (1R,2S,3S,5R)-2-bromo-3-{[tert-butyl(dimethyl)silyl]oxy}bicyclo[3.2.0]heptan-6-one | n/a | C13H23BrO2Si | 详情 | 详情 |
| (VI) | 53260 | (1R,3S,5R)-3-{[tert-butyl(dimethyl)silyl]oxy}tricyclo[3.2.0.0~2,7~]heptan-6-one | n/a | C13H22O2Si | 详情 | 详情 |
合成路线40
该中间体在本合成路线中的序号：(I)The alkylation of (R)-alpha-methylbenzylamine (I) with methyl bromoacetate (II) gave aminoacetate (III). This was coupled with protected histidine (IV) by means of HATU as the coupling agent, yielding the protected dipeptide (V). Subsequent saponification of (V) using LiOH gave acid (VI). beta,beta-Dimethyl-phenethylamine (IX) was prepared by alkylation of phenylacetonitrile (VII) with iodomethane and NaH, followed by hydrogenation of the resulting dimethylated compound (VIII) in the presence of Raney Nickel. Coupling of amine (IX) with dipeptide (VI) provided the corresponding amide (X). The trityl protecting group of (X) was finally removed by treatment with trifluoroacetic acid.
| 【1】 Doherty, A.M.; Quin, J. III; Kaltenbronn, J.S.; Leonard, D.M.; McNamara, D.J. (Pfizer Inc.); Functionalized alkyl and alkenyl side chain derivs. of glycinamides as farnesyl transferase inhibitors. WO 9955725 . |
| 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) | 10039 | (1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine | 3886-69-9 | C8H11N | 详情 | 详情 |
| (II) | 12309 | methyl 2-bromoacetate; methyl bromoacetate | 96-32-2 | C3H5BrO2 | 详情 | 详情 |
| (III) | 34626 | methyl 2-[[(1R)-1-phenylethyl]amino]acetate | C11H15NO2 | 详情 | 详情 | |
| (IV) | 34627 | (2S)-2-[[(benzyloxy)carbonyl]amino]-3-(1-trityl-1H-imidazol-4-yl)propionic acid | C33H29N3O4 | 详情 | 详情 | |
| (V) | 34628 | methyl 2-[[(2S)-2-[[(benzyloxy)carbonyl]amino]-3-(1-trityl-1H-imidazol-4-yl)propanoyl][(1R)-1-phenylethyl]amino]acetate | C44H42N4O5 | 详情 | 详情 | |
| (VI) | 34629 | 2-[[(2S)-2-[[(benzyloxy)carbonyl]amino]-3-(1-trityl-1H-imidazol-4-yl)propanoyl][(1R)-1-phenylethyl]amino]acetic acid | C43H40N4O5 | 详情 | 详情 | |
| (VII) | 17046 | Phenylacetonitrile; 2-phenylacetonitrile; Benzyl cyanide | 140-29-4 | C8H7N | 详情 | 详情 |
| (VIII) | 34630 | 2-methyl-2-phenylpropanenitrile | C10H11N | 详情 | 详情 | |
| (IX) | 34631 | 2-methyl-2-phenylpropylamine; 2-methyl-2-phenyl-1-propanamine | C10H15N | 详情 | 详情 | |
| (X) | 34632 | benzyl (1S)-2-[[2-[(2-methyl-2-phenylpropyl)amino]-2-oxoethyl][(1R)-1-phenylethyl]amino]-2-oxo-1-[(1-trityl-1H-imidazol-4-yl)methyl]ethylcarbamate | C53H53N5O4 | 详情 | 详情 |
合成路线41
该中间体在本合成路线中的序号：(XVIII)Coupling of ethyl phenylsulfinylfluoro acetate (I) with bromo derivative (II) by means of NaH in DMF yields ethyl hexenoate (III), which is then oxidized by means of Jones reagent in acetone to provide 5-carboxy pentenoate derivative (IV). Alternatively, compound (IV) can be obtained as follows: eduction of gamma-butyrolactone (V) in THF with aluminum diisobutylhydride in toluene affords gamma-butyrolactol (VI), which is treated with ethyl (diethoxyphosphoryl)fluoroacetate (VII) and sodium bis(trimethylsilyl)amide in THF to provide an isomeric mixture of hexenoates (VIII). O-Protection of (VIII) by means of tert-butyldiphenylchlorosilane and imidazole in DMF followed by chromatographic separation of the geometrical isomers furnishes hexenoate (Z)-(IX), which is finally oxidized with Jones reagent in acetone. Conversion of carboxylic acid (IV) into bicycle (±)-(X) is then performed by first reaction with oxalyl chloride in refluxing hexane to form the corresponding acid chloride, followed by treatment with diazomethane in ether and subsequent reaction with cooper(II) bis(N-tert-butylsalicylaldiimidate) in refluxing benzene. Treatment of oxobicycle (±)-(X) with LiHMDS and chlorotrimethylsilane in THF followed by reaction with palladium acetate in acetonitrile gives 6-fluoro-2-oxobicyclo[3.1.0]hex-3-en-6-carboxylate (±)-(XI), from which epoxide (±)-(XII) is obtained by reaction in toluene with tert-butyl hydroxyperoxide (TBHP) and benzyltrimethylammoniumhydroxide (Triton B) in MeOH or EtOH. Epoxide reduction of (±)-(XII) using diphenyl diselenide (PhSe)2 and sodium borohydride in the presence of HOAc in EtOH, or by means of (PhSe)2, N-acetyl-L-cysteine and sodium tetraborate decahydrate in H2O:EtOH, yields hydroxy derivative (±)-(XIII), which is converted into ethylenedithio derivative (±)-(XV) by first protection of the hydroxyl group with tert-butyldimethylsilyl chloride in DMF in the presence of imidazole, followed by thioketalization with 1,2-ethanedithiol (XIV) and boron trifluoride-diethylether complex in CHCl3 (with subsequent TBS group removal during work-up). Oxidation of the hydroxyl group of (±)-(XV) with DMSO and dicyclohexylcarbodiimide (DCC) in the presence of pyridine and TFA gives ketone (±)-(XVI), which is then hydrolyzed with NaOH in EtOH and subjected to reaction with KCN and ammonium carbonate (Bucherer-Bergs conditions) to yield hydantoin (±)-(XVII). Coupling of (±)-(XVII) with (R)-(+)-1-phenylethylamine using EDC-HCl and HOBt followed by chromatographic separation of the two resulting diastereomers furnishes (1R,2S,5R,6S)-(XIX), which is finally converted into the desired product after hydrolysis with H2SO4.
| 【4】 Kumagai, T.; Sakagami, K.; Nakazato, A.; Tomisawa, K. (Taisho Pharmaceutical Co., Ltd.); 6-Fluorobicyclo[3.1.0]hexane derivs.. EP 1110943; JP 2000336071; WO 0012464 . |
| 【1】 Nakazato, A.; et al.; Synthesis, SAR, and biological activities of potent and selective group II mGluR agonists, novel 2-amino-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivatives. 220th ACS Natl Meet (Aug 20 2000, Washington DC) 2000, Abst MEDI 104. |
| 【2】 Nakazato, A.; et al.; Synthesis, SARs, and pharmacological characterization of 2-amino-3 or 6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylix acid derivatives as potent, selective, and orally active group II metabotropic glutamate receptor agonists. J Med Chem 2000, 43, 25, 4893. |
| 【3】 Yoshikawa, R.; Kumagai, T.; Suzuki, Y.; Nakazato, A.; Sakagami, K.; Chaki, S.; Okuyama, S.; Synthesis SAR and biological activities of potent and selective group II metabotropic glutamate receptor antagonists, novel 2-amino-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivatives. 16th Int Symp Med Chem (Sept 18 2000, Bologna) 2000, Abst PB-104. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (rac)-(XIV) | 27313 | 1,2-ethanedithiol | 540-63-6 | C2H6S2 | 详情 | 详情 |
| (rac)-(X) | 49005 | ethyl (rac)-(1S*,5S*,6S*)-6-fluoro-2-oxobicyclo[3.1.0]hexane-6-carboxylate | C9H11FO3 | 详情 | 详情 | |
| (rac)-(XI) | 49006 | ethyl (rac)-(1S*,5S*,6S*)-6-fluoro-4-oxobicyclo[3.1.0]hex-2-ene-6-carboxylate | C9H9FO3 | 详情 | 详情 | |
| (rac)-(XII) | 49007 | ethyl (rac)-(1R*,2S*,4S*,6S*,7S*)-7-fluoro-5-oxo-3-oxatricyclo[4.1.0.0(2,4)]heptane-7-carboxylate | C9H9FO4 | 详情 | 详情 | |
| (rac)-(XIII) | 49008 | ethyl (rac)-(1R*,2R*,5S*,6S*)-6-fluoro-2-hydroxy-4-oxobicyclo[3.1.0]hexane-6-carboxylate | C9H11FO4 | 详情 | 详情 | |
| (rac)-(XV) | 49009 | C11H15FO3S2 | 详情 | 详情 | ||
| (rac)-(XVI) | 49010 | C11H13FO3S2 | 详情 | 详情 | ||
| (rac)-(XVII) | 49011 | C11H11FN2O4S2 | 详情 | 详情 | ||
| (VIIIa) | 49014 | ethyl (Z)-2-fluoro-6-hydroxy-2-hexenoate | C8H13FO3 | 详情 | 详情 | |
| (VIIIIb) | 49015 | ethyl (E)-2-fluoro-6-hydroxy-2-hexenoate | C8H13FO3 | 详情 | 详情 | |
| (I) | 49002 | ethyl 2-fluoro-2-(phenylsulfinyl)acetate | C10H11FO3S | 详情 | 详情 | |
| (II) | 29460 | 2-(4-bromobutoxy)tetrahydro-2H-pyran; 4-bromobutyl tetrahydro-2H-pyran-2-yl ether | C9H17BrO2 | 详情 | 详情 | |
| (III) | 49003 | ethyl (Z)-2-fluoro-6-(tetrahydro-2H-pyran-2-yloxy)-2-hexenoate | C13H21FO4 | 详情 | 详情 | |
| (IV) | 49004 | (Z)-6-ethoxy-5-fluoro-6-oxo-4-hexenoic acid | C8H11FO4 | 详情 | 详情 | |
| (V) | 20576 | dihydro-2(3H)-furanone | 96-48-0 | C4H6O2 | 详情 | 详情 |
| (VI) | 49013 | tetrahydro-2-furanol | C4H8O2 | 详情 | 详情 | |
| (VII) | 18192 | ethyl 2-(diethoxyphosphoryl)-2-fluoroacetate | 2356-16-3 | C8H16FO5P | 详情 | 详情 |
| (IX) | 49016 | ethyl (Z)-6-[[tert-butyl(diphenyl)silyl]oxy]-2-fluoro-2-hexenoate | C24H31FO3Si | 详情 | 详情 | |
| (XVIII) | 10039 | (1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine | 3886-69-9 | C8H11N | 详情 | 详情 |
| (XIX) | 49012 | C19H20FN3O3S2 | 详情 | 详情 |
合成路线42
该中间体在本合成路线中的序号：(XVIII)Alternatively, intermediate (1R,2S,5R,6S)-(XIX) can also be obtained by first separation of the isomeric mixture (±)-(X) by chiral HPLC to provide isomer (+)-(X), which is then subjected to the same process described for (±)-(X) in Scheme 28677701a to furnish the desired compound (1R,2S,5R,6S)-(XIX).
| 【2】 Kumagai, T.; Sakagami, K.; Nakazato, A.; Tomisawa, K. (Taisho Pharmaceutical Co., Ltd.); 6-Fluorobicyclo[3.1.0]hexane derivs.. EP 1110943; JP 2000336071; WO 0012464 . |
| 【1】 Nakazato, A.; et al.; Synthesis, SAR, and biological activities of potent and selective group II mGluR agonists, novel 2-amino-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivatives. 220th ACS Natl Meet (Aug 20 2000, Washington DC) 2000, Abst MEDI 104. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (rac)-(X) | 49005 | ethyl (rac)-(1S*,5S*,6S*)-6-fluoro-2-oxobicyclo[3.1.0]hexane-6-carboxylate | C9H11FO3 | 详情 | 详情 | |
| (+)-(X) | 49017 | ethyl (+)-(1S,5S,6S)-6-fluoro-2-oxobicyclo[3.1.0]hexane-6-carboxylate | C9H11FO3 | 详情 | 详情 | |
| (+)-(XI) | 49018 | ethyl (+)-(1S,5S,6S)-6-fluoro-4-oxobicyclo[3.1.0]hex-2-ene-6-carboxylate | C9H9FO3 | 详情 | 详情 | |
| (-)-(XII) | 49019 | ethyl (-)-(1R,2S,4S,6S,7S)-7-fluoro-5-oxo-3-oxatricyclo[4.1.0.0(2,4)]heptane-7-carboxylate | C9H9FO4 | 详情 | 详情 | |
| (-)-(XIII) | 49020 | ethyl (-)-(1R,2R,5S,6S)-6-fluoro-2-hydroxy-4-oxobicyclo[3.1.0]hexane-6-carboxylate | C9H11FO4 | 详情 | 详情 | |
| (-)-(XV) | 49021 | C11H15FO3S2 | 详情 | 详情 | ||
| (-)-(XVI) | 49022 | C11H13FO3S2 | 详情 | 详情 | ||
| (R,S,R,S)(XVII) | 49023 | C11H11FN2O4S2 | 详情 | 详情 | ||
| (XIV) | 27313 | 1,2-ethanedithiol | 540-63-6 | C2H6S2 | 详情 | 详情 |
| (XVIII) | 10039 | (1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine | 3886-69-9 | C8H11N | 详情 | 详情 |
| (XIX) | 49012 | C19H20FN3O3S2 | 详情 | 详情 |
合成路线43
该中间体在本合成路线中的序号：(XXII)Methyl 4-methoxyacetoacetate (XIV) was transesterified with 3-hydroxypropionitrile (XV) at 180 C to yield the 2-cyanoethyl ester (XVI). Subsequent condensation between 3,4-difluorobenzaldehyde (XVII) and ketoester (XVI) in the presence of piperidine acetate furnished the benzylidene derivative (XVIII), which was cyclized with O-methylisourea hemisulfate (XIX) to produce the racemic pyrimidine (XX). Resolution of (XX) was achieved via conversion to the 4-nitrophenyl carbamate (XXI), which was then condensed with (R)-1-phenylethylamine (XXII) to afford a separable mixture of diastereoisomeric amides. The desired isomer (XXIII) was treated with DBU in hot toluene to give the (+)-pyrimidine (XXIV). This was again converted to the corresponding 4-nitrophenyl carbamate (XXV) by reaction with 4-nitrophenyl chloroformate and DMAP.
| 【1】 Wong, W.C.; Lagu, B.; Nagarathnam, D.; Marzabadi, M.R.; Gluchowski, C. (Synaptic Pharmaceutical Corp.); Dihydropyrimidines and uses thereof. EP 1021185; JP 2000506904; WO 9742956 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIV) | 26655 | methyl 4-methoxy-3-oxobutanoate;Methyl 4-methoxyacetoacetate;Methyl 4-methoxy-3-oxo-butanoate | 41051-15-4 | C6H10O4 | 详情 | 详情 |
| (XV) | 14029 | Ethylene cyanohydrin; ECN; 3-Hydroxypropanenitrile | 109-78-4 | C3H5NO | 详情 | 详情 |
| (XVI) | 48390 | 2-cyanoethyl 4-methoxy-3-oxobutanoate | C8H11NO4 | 详情 | 详情 | |
| (XVII) | 26654 | 3,4-difluorobenzaldehyde | 34036-07-2 | C7H4F2O | 详情 | 详情 |
| (XVIII) | 48391 | 2-cyanoethyl (Z)-3-(3,4-difluorophenyl)-2-(2-methoxyacetyl)-2-propenoate | C15H13F2NO4 | 详情 | 详情 | |
| (XIX) | 26657 | O-methyl isourea; [Amino(imino)methoxy]methane | 52328-05-9 | C2H6N2O | 详情 | 详情 |
| (XX) | 48392 | 2-cyanoethyl 6-(3,4-difluorophenyl)-2-methoxy-4-(methoxymethyl)-1,6-dihydro-5-pyrimidinecarboxylate | C17H17F2N3O4 | 详情 | 详情 | |
| (XXI) | 48393 | 5-(2-cyanoethyl) 1-(4-nitrophenyl) 6-(3,4-difluorophenyl)-2-methoxy-4-(methoxymethyl)-1,5(6H)-pyrimidinedicarboxylate | C24H20F2N4O8 | 详情 | 详情 | |
| (XXII) | 10039 | (1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine | 3886-69-9 | C8H11N | 详情 | 详情 |
| (XXIII) | 48394 | 2-cyanoethyl (6S)-6-(3,4-difluorophenyl)-2-methoxy-4-(methoxymethyl)-1-([[(1R)-1-phenylethyl]amino]carbonyl)-1,6-dihydro-5-pyrimidinecarboxylate | C26H26F2N4O5 | 详情 | 详情 | |
| (XXIV) | 48395 | 2-cyanoethyl (6S)-6-(3,4-difluorophenyl)-2-methoxy-4-(methoxymethyl)-1,6-dihydro-5-pyrimidinecarboxylate | C17H17F2N3O4 | 详情 | 详情 | |
| (XXV) | 48396 | 5-(2-cyanoethyl) 1-(4-nitrophenyl) (6S)-6-(3,4-difluorophenyl)-2-methoxy-4-(methoxymethyl)-1,5(6H)-pyrimidinedicarboxylate | C24H20F2N4O8 | 详情 | 详情 |
合成路线44
该中间体在本合成路线中的序号：(IV)Condensation of 2-amino-5-bromopyridine (I) with thiocarbonyl diimidazole (II) gave rise to thioimidazolide (III), which was then condensed with (R)-1-phenylethylamine (IV) to yield the title thiourea.
| 【1】 Mao, C.; Venkatachalam, T.K.; Uckun, F.M.; Sudbeck, E.A.; Stereochemistry of halopyridyl and thiazolyl thiourea compounds is a major determinant of their potency as nonnucleoside inhibitors of HIV-1 reverse transcriptase. Bioorg Med Chem Lett 2000, 10, 18, 2071. |
| 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) | 12123 | 5-Bromo-2-pyridinylamine; 5-Bromo-2-pyridinamine; 2-Amino-5-bromopyridine | 1072-97-5 | C5H5BrN2 | 详情 | 详情 |
| (II) | 11990 | Di(1H-imidazol-1-yl)methanethione; 1,1'-Thiocarbonyldiimidazole | 6160-65-2 | C7H6N4S | 详情 | 详情 |
| (III) | 24645 | N-(5-bromo-2-pyridinyl)-1H-imidazole-1-carbothioamide | C9H7BrN4S | 详情 | 详情 | |
| (IV) | 10039 | (1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine | 3886-69-9 | C8H11N | 详情 | 详情 |
合成路线45
该中间体在本合成路线中的序号：(II)Coupling of N-Boc-L-tert-leucine (I) with (R)-1-phenylethylamine (II) using EDC and HOBt gave amide (III) which, after acid cleavage of the N-Boc group, provided amino amide (IV). Acylation of amine (IV) with (R)-2-allylsuccinic acid 4-tert-butyl ester (V) afforded the diamide (VI). Biphenylyl bromide (IX) was prepared by the Suzuki coupling between 5-bromo-2-iodotoluene (VII) and phenylboronic acid (VIII). The biaryl group was then introduced via Heck reaction of biphenylyl bromide (IX) with olefin (VI), yielding adduct (X). Subsequent hydrogenation of the olefin double bond of (X) over Pd/C afforded (XI). Carboxylic acid (XII) was then obtained by trifluoroacetic acid-promoted cleavage of the tert-butyl ester group of (XI). Conversion of (XII) to the title hydroxamic acid was then achieved by coupling of carboxylic acid (XII) with O-allylhydroxylamine (XIII), followed by O-allyl group cleavage in the presence of ammonium formate and palladium catalyst.
| 【1】 Fray, M.J.; et al.; Discovery of potent and selective succinyl hydroxamate inhibitors of matrix metalloprotease-3 (stromelysin-1). 13th Noordwijkerhout-Camerino Symp Trends Drug Res (May 6 2001, Noordwijkerhout) 2001, Abst P8. |
| 【2】 Fray, M.J.; Dickinson, R.P.; Discovery of potent and selective succinyl hydroxamate inhibitors of matrix metalloprotease-3 (stromelysin-1). Bioorg Med Chem Lett 2001, 11, 4, 571. |
| 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) | 22251 | (2S)-2-[(tert-butoxycarbonyl)amino]-3,3-dimethylbutyric acid;2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoic acid;N-(tert-butoxycarbonyl)-3-methyl-L-valine | 62965-35-9 | C11H21NO4 | 详情 | 详情 |
| (II) | 10039 | (1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine | 3886-69-9 | C8H11N | 详情 | 详情 |
| (III) | 49186 | tert-butyl (1S)-2,2-dimethyl-1-([[(1R)-1-phenylethyl]amino]carbonyl)propylcarbamate | C19H30N2O3 | 详情 | 详情 | |
| (IV) | 49187 | (2S)-2-amino-3,3-dimethyl-N-[(1R)-1-phenylethyl]butanamide | C14H22N2O | 详情 | 详情 | |
| (V) | 49188 | (2R)-2-[2-(tert-butoxy)-2-oxoethyl]-4-pentenoic acid | C11H18O4 | 详情 | 详情 | |
| (VI) | 49189 | tert-butyl (3R)-3-([[(1S)-2,2-dimethyl-1-([[(1R)-1-phenylethyl]amino]carbonyl)propyl]amino]carbonyl)-5-hexenoate | C25H38N2O4 | 详情 | 详情 | |
| (VII) | 49190 | 1-Bromo-4-iodo-5-methylbenzene; 5-Bromo-2-iodotoluene | C7H6BrI | 详情 | 详情 | |
| (VIII) | 16593 | Phenylboronic acid；Benzeneboronic acid;Phenylboron dihydroxide | 98-80-6 | C6H7BO2 | 详情 | 详情 |
| (IX) | 49191 | 4-bromo-2-methyl-1,1'-biphenyl | C13H11Br | 详情 | 详情 | |
| (X) | 49192 | tert-butyl (3R,5E)-3-([[(1S)-2,2-dimethyl-1-([[(1R)-1-phenylethyl]amino]carbonyl)propyl]amino]carbonyl)-6-(2-methyl[1,1'-biphenyl]-4-yl)-5-hexenoate | C38H48N2O4 | 详情 | 详情 | |
| (XI) | 49193 | tert-butyl (3R)-3-([[(1S)-2,2-dimethyl-1-([[(1R)-1-phenylethyl]amino]carbonyl)propyl]amino]carbonyl)-6-(2-methyl[1,1'-biphenyl]-4-yl)hexanoate | C38H50N2O4 | 详情 | 详情 | |
| (XII) | 49194 | (3R)-3-([[(1S)-2,2-dimethyl-1-([[(1R)-1-phenylethyl]amino]carbonyl)propyl]amino]carbonyl)-6-(2-methyl[1,1'-biphenyl]-4-yl)hexanoic acid | C34H42N2O4 | 详情 | 详情 | |
| (XIII) | 49195 | 3-(aminooxy)-1-propene; O-allylhydroxylamine | C3H7NO | 详情 | 详情 |
合成路线46
该中间体在本合成路线中的序号：Reaction of (S)-2-aminobutyramide (I) with ethyl 4-bromobutyrate (II) in the presence of triethylamine in toluene gives ethyl (S)-4-[1-(carbamoyl)propylamino]butyrate (III), which is cyclized in toluene by means of 2-hydroxypyridine. Compound (I) can also be condensed with 4-chlorobutyryl chloride (IV) either directly in the presence of tetrabutylammonium bromide (TBAB) in dichloromethane, followed by in situ treatment with potassium hydroxide, or via the isolation of intermediate (S)-N-[1-(carbamoyl)propyl]-4-chlorobutyramide (V). An alternative procedure involves hydrolysis of racemic ethyl 2-(2-oxopyrrolidin-1-yl)butyrate (VI) with sodium hydroxide to give racemic 2-(2-oxopyrrolidin-1-yl)butyric acid (VII), which is resolved by fractional crystallization with (R)-(+)-alpha-methylbenzylamine in benzene, followed by acid-base treatment to give (S)-2-(2-oxopyrrolidin-1-yl)butyric acid (VIII). Compound (VIII) is finally treated with ethyl chloroformiate and ammonia in dichloromethane. A third procedure involves Ni-Raney desulfurization of (S)-4-(methylthio)-2-(2-oxopyrrolidin-1-yl)butyramide (XI), prepared from (S)-2-amino-4-(methylthio)butyramide (IX) by reaction with 4-chlorobutyryl chloride (IV). Compound (XI) can also be obtained by treatment of (IX) with ethyl 4-bromobutyrate (II) to give ethyl (S)-4-[1-(carbamoyl)-3-(methylthio)propylamino]butyrate (X), which is cyclized in toluene by means of 2-hydroxypyridine.
| 【1】 Gobert, J.; Geerts, J.-P.; Bodson, G. (UCB SA); (S)-alpha-Ethyl-2-oxopyrrolidineacetamide. AU 8542530; EP 0162036; ES 8608485; ES 8704893; US 4696943; US 4837223 . |
| 【2】 Cossement, E.; Motte, G.; Geerts, J.-P.; Gobert, J. (UCB SA); The preparation of S-alpha-ethyl-2-oxo-1-pyrrolidineacetamide. GB 2225322 . |
| 【3】 Castaner, J.; Prous, J.; Mealy, N.; Levetiracetam. Drugs Fut 1994, 19, 2, 111. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 10039 | (1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine | 3886-69-9 | C8H11N | 详情 | 详情 | |
| (VII)-rac | 11268 | 2-(2-Oxo-1-pyrrolidinyl)butyric acid | 67118-31-4 | C8H13NO3 | 详情 | 详情 |
| (I) | 11262 | (2S)-2-Aminobutanamide | C4H10N2O | 详情 | 详情 | |
| (II) | 11263 | ethyl 4-bromobutanoate; Ethyl 4-bromobutyrate | 2969-81-5 | C6H11BrO2 | 详情 | 详情 |
| (III) | 11264 | ethyl 4-[[(1S)-1-(aminocarbonyl)propyl]amino]butanoate | C10H20N2O3 | 详情 | 详情 | |
| (IV) | 11265 | 4-Chlorobutanoyl chloride; 4-Chlorobutyric acid chloride | 4635-59-0 | C4H6Cl2O | 详情 | 详情 |
| (V) | 11266 | (2S)-2-[(4-Chlorobutanoyl)amino]butanamide | C8H15ClN2O2 | 详情 | 详情 | |
| (VI) | 11267 | ethyl 2-(2-oxo-1-pyrrolidinyl)butanoate | C10H17NO3 | 详情 | 详情 | |
| (VIII) | 11269 | (2S)-2-(2-Oxo-1-pyrrolidinyl)butyric acid | 102849-49-0 | C8H13NO3 | 详情 | 详情 |
| (IX) | 11270 | (2S)-2-Amino-4-(methylsulfanyl)butanamide | C5H12N2OS | 详情 | 详情 | |
| (X) | 11271 | ethyl 4-[[(1S)-1-(aminocarbonyl)-3-(methylsulfanyl)propyl]amino]butanoate | C11H22N2O3S | 详情 | 详情 | |
| (XI) | 11272 | (2S)-4-(Methylsulfanyl)-2-(2-oxo-1-pyrrolidinyl)butanamide | C9H16N2O2S | 详情 | 详情 |
合成路线47
该中间体在本合成路线中的序号：(II)Resolution of racemic cis-ketoacid (I) by precipitation with (R)-(+)-alpha-methylbenzylamine (II) in EtOH, followed by recrystallization of the corresponding salt from EtOH and final acidic treatment, allows isolation of (+)-ketoacid (IV). Finally, cyclization of (IV) with 2-adamantylhydrazine (V) gives rise to the title phthalazinone.
| 【1】 Van der Mey, M.; et al.; Novel selective phosphodiesterase (PDE4) inhibitors. 4. Resolution, absolute configuration, and PDE4 inhibitory activity of cis- tetra- and cis-hexahydrophthalazinones. J Med Chem 2002, 45, 12, 2526. |
| 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) | 61861 | 6-(3,4-dimethoxybenzoyl)-3-cyclohexene-1-carboxylic acid | C16H18O5 | 详情 | 详情 | |
| (II) | 10039 | (1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine | 3886-69-9 | C8H11N | 详情 | 详情 |
| (III) | 61862 | (1S,6R)-6-(3,4-dimethoxybenzoyl)-3-cyclohexene-1-carboxylic acid | C16H18O5 | 详情 | 详情 | |
| (IV) | 61864 | (1R,6S)-6-(3,4-dimethoxybenzoyl)-3-cyclohexene-1-carboxylic acid | C16H18O5 | 详情 | 详情 | |
| (V) | 61863 | 1-(2-adamantyl)hydrazine | C10H18N2 | 详情 | 详情 |
合成路线48
该中间体在本合成路线中的序号：(XXXII)The pyrrolo-oxazine fragments, the free base (II) or the Boc-protected (V) can be synthesized as follows. Butene-1,4-diol (XXIV) is subjected to either of the two following alternative procedures: 1) treatment with mesyl chloride in the presence of Et3N in CH2Cl2 and subsequent reaction with tosylamine, NaOH and tetrabutylammonium hydrogensulfate (TBAHS) in toluene/water at 40 °C (1, 2); or 2) chlorination with thionyl chloride followed by treatment with tosylamide by means of NaH in DMF (3) to afford 1-tosyl-2,5-dihydro-1H-pyrrole (XXV). Compound (XXV) is then epoxidated with meta-chloroperbenzoic acid (mCPBA) in refluxing dichloromethane to yield cis-N-tosyl-6-oxa-3-azabicyclo[3.1.0]hexane (XXVI) (1-3). Desymmetrization of intermediate (XXVI) is carried out by condensation with ethanolamine (XXVII) in refluxing dichloromethane to yield the racemic N-alkylated pyrrolidine derivative rac-(XXVIII), which by reaction with tosyl chloride in pyridine/THF at –10 °C affords the tosylate rac-(XXIX). Cyclization of the racemic (XXIX) by means of NaOH in THF/methanol at 0-3 °C gives the racemic pyrrolo-oxazine rac-(XXX), from which the desired enantiomer (4aS,7aS)-octahydropyrrolo[3,4-b][1,4]oxazine (XXX) is separated by chiral chromatography. Finally, compound (XXX) is detosylated by means of HBr/AcOH and anisole at 60 °C and the resulting dihydrobromide salt (XXXI) is treated with potassium hydroxide in isopropanol to afford the free base intermediate (II) (1). Scheme 3.
In an improved method for intermediate (II), compound (XXVI) is desymmetrized by coupling with (R)-phenylethylamine (XXXII) in water (2, 3), resulting in a mixture of diastereomers that is resolved by crystallization (2) or chromatography (3). The desired isomer (XXXIII) is N-acylated with chloroacetyl chloride (XXXIV) by means of triethylamine (2) or DIEA in THF (3) to afford the N-chloroacetyl amine (XXXV), which then cyclizes in the presence of sodium hydroxide (2) or potassium tert-butoxide in dichloromethane (3). The resulting bicyclic lactam (XXXVI) is reduced with LiAlH4 in THF (3) or NaBH4 in the presence of BF3.THF complex (2) to give the pyrrolooxazine derivative (XXXVII) (2, 3), which is detosylated by treatment with HCl and subsequently with NaOH, yielding the free amine (XXXVIII). Finally, compound (XXXVIII) is subjected to hydrogenolysis over Pd/C in methanol to afford the target (4aS,7aS)-octahydropyrrolo[3,4-b][1,4]oxazine (II) (2). Scheme 3.
The Boc-protected compound (V) is obtained by subjecting N-alkylated derivative (XXXVII) to hydrogenolysis over Pd/C in methanol followed by treatment with tert-butoxycarbonyl anhydride in dichloromethane. The resulting fully protected intermediate (XXXIX) is finally detosylated with sodium naphthalenide (3). Scheme 3.
| 【1】 Matzke, M., Petersen, U., Schenke, T. et al. (Bayer Healthcare AG). Use of 7-(2-oxa-5,8-diazabicyclo[4.3.0]non-8-yl)-quinolone carboxylic acid and naphthyridon carboxylic acid derivatives for the treatment of Helicobacter pylori infections and associated gastroduodenal diseases. CA 2274894, DE 19652239, EP 0946176, JP 200351781, JP 2000514825, US 6133260, US 6432948, WO 1998026779. |
| 【2】 Wohlert, S.E., Jaetsch, T., Gallenkamp, B. et al. New fluoroquinolone finafloxacin HCI (FIN): Route of synthesis, physicochemical characteristics and activity under neutral and acid conditions. 48th Annu Intersci Conf Antimicrob Agents Chemother (ICAAC) Infect Dis Soc Am (IDSA) Annu Meet (Oct 25-28, Washington, D.C.) 2008, Abst F1-2036. |
| 【3】 Hong, J., Zhang, Z., Lei, H. et al. A novel approach to finafloxacin hydrochloride (BAY35-3377). Tetrahedron Lett 2009, 50(21): 2525-8. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 65947 | (4aS,7aS)-octahydropyrrolo[3,4-b][1,4]oxazine | C6H12N2O | 详情 | 详情 | |
| (V) | 65950 | C11H20N2O3 | 详情 | 详情 | ||
| (XXIV) | 36965 | (Z)-2-butene-1,4-diol | 6117-80-2 | C4H8O2 | 详情 | 详情 |
| (XXV) | 65968 | 1-(Toluene-4-sulfonyl)-2,5-dihydro-1H-pyrrole; 1-(p-Tolylsulfonyl)-3-pyrroline; 1-(4-Methylphenylsulfonyl)-2,5-dihydropyrrole; 2,5-Dihydro-1-[(4-methylphenyl)sulfonyl]-1H-pyrrole | 16851-72-2 | C11H13NO2S | 详情 | 详情 |
| (XXVI) | 65969 | 3-Tosyl-6-oxa-3-azabicyclo[3.1.0]hexane | 159555-66-5 | C11H13NO3S | 详情 | 详情 |
| (XXVII) | 10259 | Ethanol amine;Ethanolamine;2-Aminoethanol; 2-Amino-1-ethanol；2-Aminoethyl alcohol | 141-43-5 | C2H7NO | 详情 | 详情 |
| (XXVIII) | 65970 | 2,5-Dihydro-3-hydroxy-4-[(2-hydroxyethyl)amino]-1-[(4-methylphenyl)sulfonyl]-1H-pyrrole | C13H20NO4S | 详情 | 详情 | |
| (XXIX) | 65971 | C20H26NO6S2 | 详情 | 详情 | ||
| (XXX) | 65972 | C20H24N2O5S2 | 详情 | 详情 | ||
| (XXXI) | 65973 | (4aS,7aS)-octahydropyrrolo[3,4-b][1,4]oxazine dihydrobromide | C6H12N2O.2HBr | 详情 | 详情 | |
| (XXXII) | 10039 | (1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine | 3886-69-9 | C8H11N | 详情 | 详情 |
| (XXXIII) | 65974 | C19H24N2O3S | 详情 | 详情 | ||
| (XXXIV) | 11296 | 2-Chloroacetyl chloride; Chloroacetic chloride | 79-04-9 | C2H2Cl2O | 详情 | 详情 |
| (XXXV) | 65975 | C21H25ClN2O4S | 详情 | 详情 | ||
| (XXXVI) | 65976 | C21H24N2O4S | 详情 | 详情 | ||
| (XXXVII) | 65977 | C21H26N2O3S | 详情 | 详情 | ||
| (XXXVIII) | 65978 | C14H20N2O | 详情 | 详情 | ||
| (XXXIX) | 65979 | C18H26N2O5S | 详情 | 详情 |
合成路线49
该中间体在本合成路线中的序号：(XLV)
| 【1】 Zhao MM, McNamara JM, Ho GJ, et aL 2002. Practical aaymmetric synthesis of aprepitant,apotmt Human NK-1 receptor anUylonist, viaa stereoselective lewis acid-catalyzed trans aoetalization rraction- J Org Chem, 67 (19)t 6743~6747 |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| （XLIV) | 13188 | ethyl 3-chloro-3-oxopropanoate; 2-Ethoxycarbonylacetyl chloride; Ethyl malonyl chloride | 36239-09-5 | C5H7ClO3 | 详情 | 详情 |
| （XLVI） | 66104 | 2-oxo-2-((1-phenylethyl)amino)acetic acid | C10H11NO3 | 详情 | 详情 | |
| （XLVII） | 11972 | (1R)-3-(Methylamino)-1-phenyl-1-propanol; (R)-3-Hydroxy-N-methyl-3-phenyl propylamine | 42142-52-9 | C10H15NO | 详情 | 详情 |
| （XLVIII） | 66105 | 3-(4-fluorophenyl)-4-((S)-1-phenylethyl)morpholin-2-one hydrochloride | C18H19FClNO2 | 详情 | 详情 | |
| （XLIX） | 66106 | 3-(4-fluorophenyl)-4-((R)-1-phenylethyl)morpholin-2-ol | C18H20FNO2 | 详情 | 详情 | |
| （L） | 66107 | (2S)-3-(4-fluorophenyl)-4-((S)-1-phenylethyl)morpholin-2-yl 2,2,2-trichloroacetimidate | C20H20FCl3N2O2 | 详情 | 详情 | |
| （LI） | 66108 | (R)-1-(3,5-(trifluoromethyl)phenyl)ethanol | C10H8F6O | 详情 | 详情 | |
| （LII） | 66109 | (3R)-2-(1-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(4-fluorophenyl)-4-((R)-1-phenylethyl)morpholine | C28H26F7NO2 | 详情 | 详情 | |
| （XLI） | 66101 | (2R)-2-(1-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(4-fluorophenyl)morpholine | C20H18F7NO2 | 详情 | 详情 | |
| （LIII） | 66110 | 6-(1-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-5-(4-fluorophenyl)-3,6-dihydro-2H-1,4-oxazine | C20H16F7NO2 | 详情 | 详情 | |
| （LIV） | 66111 | 2-(1-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(4-fluorophenyl)morpholine hydrochloride | C20H19ClF7NO2 | 详情 | 详情 | |
| (X) | 18999 | 4-Fluorophenylacetic acid; 2-(4-Fluorophenyl)acetic acid | 405-50-5 | C8H7FO2 | 详情 | 详情 |
| (XXVI) | 44196 | 5-(chloromethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one | C3H4ClN3O | 详情 | 详情 | |
| (XLIII) | 66103 | 1-(4-fluorophenyl)-2,2-dihydroxyethanone | C8H7FO3 | 详情 | 详情 | |
| (XLV) | 10039 | (1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine | 3886-69-9 | C8H11N | 详情 | 详情 |