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【结 构 式】 
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【分子编号】21391 【品名】D-aspartic acid; (2R)-2-aminobutanedioic acid 【CA登记号】1783-96-6 |
【 分 子 式 】C4H7NO4 【 分 子 量 】133.10392 【元素组成】C 36.1% H 5.3% N 10.52% O 48.08% |
合成路线1
该中间体在本合成路线中的序号：(I)3) The acylation of D-aspartic acid (I) with methyl chloroformate and NaOH in water yields N-(methoxycarbonyl)-D-aspartic acid (II), which is anhydrized with oxalyl chloride and DMF in isopropyl acetate giving the corresponding anhydride (III). The Friedel-Craft's condensation of (III) with 2-chloroanisole (IV) by means of AlCl3 in nitromethane - dichloromethane affords 3-(3-chloro-4-methoxybenzoyl)-N-(methoxycarbonyl)-D-alanine (V), which is reduced with H2 over Pd/C in aqueous acetic acid to the substituted amino acid (VI). The reaction of (VI) with PCl5 or oxalyl chloride yields the corresponding acyl chloride (VII), which is cyclized by means of FeCl3 in nitromethane-dichloromethane affording 7-methoxy-2(R)-(methoxycarbonylamino)-1-tetralone (VIII). The reduction of (VIII) with sodium bis(methoxyethoxy) aluminum hydride (BMAlH) in toluene gives the trans-aminoalcohol (IX), which is deprotected by treatment with NaOH in methanol - water yielding (2R-trans)-2-amino-1-hydroxy-7-methoxytetraline (X). The acylation of (X) with propionyl anhydride in methanol - water affords the amide (XI), which is reduced with BH3-dimethyl sulfide giving [2(R)-trans]-1-hydroxy-7-methoxy-2-(propylamino)tetraline (XII). The acylation of (XII) with chloroacetyl chloride in toluene - aqueous Na2CO3 affords the chloroacetamide (XIII), which is cyclized by means of NaOH and tetrabutylammonium chloride to give [4a(R)-trans]-9-methoxy-4-propyl-3,4,4a,5,6,10b-hexahydro-2H-naphth [1,2-b]-1,4-oxazin-3-one (XIV). The reduction of (XIV) with BMAlH as before gives the methylated product (XV), which is finally demethylated with BBr3 and cyclohexene in dichloromethane.
| 【1】 Melillo, D.G.; Mathre, D.J.; Larsen, R.D. (Merck & Co., Inc.); Chiral synthesis of (+)-trans-1a,2,3,4a,5,6-hexahydro-9-hydroxy-4-propyl-4H-naphth(1,2-b)- 1,4-oxazine. EP 0251547 . |
| 【2】 Prous, J.; Castaner, J.; NAXAGOLIDE HYDROCHLORIDE < Prop INNM; USAN >. Drugs Fut 1989, 14, 10, 951. |
| 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) | 21391 | D-aspartic acid; (2R)-2-aminobutanedioic acid | 1783-96-6 | C4H7NO4 | 详情 | 详情 |
| (II) | 21392 | (2R)-2-[(methoxycarbonyl)amino]butanedioic acid | C6H9NO6 | 详情 | 详情 | |
| (III) | 21393 | methyl (3R)-2,5-dioxotetrahydro-3-furanylcarbamate | C6H7NO5 | 详情 | 详情 | |
| (IV) | 21394 | 1-chloro-2-methoxybenzene | 766-51-8 | C7H7ClO | 详情 | 详情 |
| (V) | 21395 | (2R)-4-(3-chloro-4-methoxyphenyl)-2-[(methoxycarbonyl)amino]-4-oxobutyric acid | C13H14ClNO6 | 详情 | 详情 | |
| (VI) | 21396 | (2R)-2-[(methoxycarbonyl)amino]-4-(4-methoxyphenyl)butyric acid | C13H17NO5 | 详情 | 详情 | |
| (VII) | 21397 | methyl (1R)-1-(chlorocarbonyl)-3-(4-methoxyphenyl)propylcarbamate | C13H16ClNO4 | 详情 | 详情 | |
| (VIII) | 21398 | methyl (2R)-7-methoxy-1-oxo-1,2,3,4-tetrahydro-2-naphthalenylcarbamate | C13H15NO4 | 详情 | 详情 | |
| (IX) | 21399 | methyl (1R,2R)-1-hydroxy-7-methoxy-1,2,3,4-tetrahydro-2-naphthalenylcarbamate | C13H17NO4 | 详情 | 详情 | |
| (X) | 21400 | (1R,2R)-2-amino-7-methoxy-1,2,3,4-tetrahydro-1-naphthalenol | C11H15NO2 | 详情 | 详情 | |
| (XI) | 21388 | N-[(1R,2R)-1-hydroxy-7-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl]propanamide | C14H19NO3 | 详情 | 详情 | |
| (XII) | 21389 | (1R,2R)-7-methoxy-2-(propylamino)-1,2,3,4-tetrahydro-1-naphthalenol | C14H21NO2 | 详情 | 详情 | |
| (XIII) | 21403 | 2-chloro-N-[(1R,2R)-1-hydroxy-7-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl]-N-propylacetamide | C16H22ClNO3 | 详情 | 详情 | |
| (XIV) | 21390 | (4aR,10bR)-9-methoxy-4-propyl-4a,5,6,10b-tetrahydro-2H-naphtho[1,2-b][1,4]oxazin-3(4H)-one | C16H21NO3 | 详情 | 详情 | |
| (XV) | 21381 | (4aR,10bR)-4-propyl-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazin-9-yl methyl ether | C16H23NO2 | 详情 | 详情 | |
| (C) | 11296 | 2-Chloroacetyl chloride; Chloroacetic chloride | 79-04-9 | C2H2Cl2O | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(B)Acylation of Meldrum's acid (I) with propionyl chloride (II) in the presence of pyridine gave propionyl derivative (III). Subsequent ring opening of (III) with ethanethiol (IV), followed by decarboxylation provided S-ethyl 3-oxothiovalerate (V). Propyl 3-amino-3-phenyl-2-propenoate (VII) was prepared by reaction of benzoylacetate (VI) with ammonium acetate in refluxing ethanol. Then, Hantzsch condensation of ketothioester (V), beta-enaminoester (VII), and butyraldehyde (VIII) in EtOH at 80 C in a sealed tube furnished the dihydropyridine (IX). Finally, oxidation of (IX) using chloranil (X) in boiling THF gave the target pyridine.
| 【1】 Li, A.-H.; Moro, S.; Melman, N.; Ji, X.D.; Jacobson, K.A.; Structure-activity relationships and molecular mod. J Med Chem 1998, 41, 17, 3186. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (B) | 21391 | D-aspartic acid; (2R)-2-aminobutanedioic acid | 1783-96-6 | C4H7NO4 | 详情 | 详情 |
| (I) | 14738 | Meldrum's acid; 2,2-dimethyl-1,3-dioxane-4,6-dione；Malonic acid cyclic isopropylidene ester | 2033-24-1 | C6H8O4 | 详情 | 详情 |
| (II) | 15967 | propanoyl chloride; propionyl chloride | 79-03-8 | C3H5ClO | 详情 | 详情 |
| (III) | 23689 | 2,2-dimethyl-5-propionyl-1,3-dioxane-4,6-dione | C9H12O5 | 详情 | 详情 | |
| (IV) | 23712 | 1-ethanethiol; ethylhydrosulfide | 75-08-1 | C2H6S | 详情 | 详情 |
| (V) | 23696 | S-ethyl 3-oxopentanethioate | C7H12O2S | 详情 | 详情 | |
| (VI) | 23692 | propyl 3-oxo-3-phenylpropanoate | C12H14O3 | 详情 | 详情 | |
| (VII) | 23693 | propyl (E)-3-amino-3-phenyl-2-propenoate | C12H15NO2 | 详情 | 详情 | |
| (VIII) | 23694 | butyraldehyde | 123-72-8 | C4H8O | 详情 | 详情 |
| (IX) | 23695 | propyl 6-ethyl-5-[(ethylsulfanyl)carbonyl]-2-phenyl-4-propyl-1,4-dihydro-3-pyridinecarboxylate | C23H31NO3S | 详情 | 详情 |