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【结 构 式】 
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【分子编号】21381 【品名】(4aR,10bR)-4-propyl-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazin-9-yl methyl ether 【CA登记号】 |
【 分 子 式 】C16H23NO2 【 分 子 量 】261.36416 【元素组成】C 73.53% H 8.87% N 5.36% O 12.24% |
合成路线1
该中间体在本合成路线中的序号：(VI)1) The acylation of 2-amino-7-methoxy-1-tetralone (I) with chloroacetyl chloride in ethyl acetate - water by means of NaHCO3 gives the corresponding chloroacetamido derivative (II), which is reduced with NaBH4 in ethanol - CHCl3 to trans-2-(chloroacetamido)-7-methoxy-1,2,3,4-tetrahydronaphthalen-1-ol (III). The cyclization of (III) by means of NaH in DMF yields the oxazinone (IV), which is reduced with LiAlH4 in refluxing THF to trans-9-methoxy-3,4,4a,5,6,10b-hexahydro-2H-naphth[1,2-b]-1,4-oxazine (V). The alkylation of (V) with propyl bromide by means of K2CO3 in DMF gives the N-propyl derivative (VI), which is finally demethylated by means of pyridine hydrochloride at 200 C.
| 【1】 Jones, J.H.; McClure, D.E.; Grenda, V.J. (Merck & Co., Inc.); Hexahydronaphth(1,2-b)-1,4-oxazines, process for their preparation and pharmaceutical formulation containing them. EP 0080115 . |
| 【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 |
|---|---|---|---|---|---|---|
| 11296 | 2-Chloroacetyl chloride; Chloroacetic chloride | 79-04-9 | C2H2Cl2O | 详情 | 详情 | |
| 19502 | Propyl bromide; 1-Bromopropane | 106-94-5 | C3H7Br | 详情 | 详情 | |
| (I) | 21376 | 2-amino-7-methoxy-3,4-dihydro-1(2H)-naphthalenone | C11H13NO2 | 详情 | 详情 | |
| (II) | 21377 | 2-chloro-N-(7-methoxy-1-oxo-1,2,3,4-tetrahydro-2-naphthalenyl)acetamide | C13H14ClNO3 | 详情 | 详情 | |
| (III) | 21378 | 2-chloro-N-[(1R,2R)-1-hydroxy-7-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl]acetamide | C13H16ClNO3 | 详情 | 详情 | |
| (IV) | 21379 | (4aR,10bR)-9-methoxy-4a,5,6,10b-tetrahydro-2H-naphtho[1,2-b][1,4]oxazin-3(4H)-one | C13H15NO3 | 详情 | 详情 | |
| (V) | 21380 | (4aR,10bR)-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazin-9-yl methyl ether | C13H17NO2 | 详情 | 详情 | |
| (VI) | 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 |
合成路线2
该中间体在本合成路线中的序号：(VI)2) The reaction of 7-methoxy-1-tetralone (VII) with isopentyl nitrite and potassium tert-butoxide in ethanol - ether gives 7-methoxy-2-oxyimino-1-tetralone (VIII), which by reduction with H2 over Pd/C in THF and acylation with propanoyl chloride is converted to 7-methoxy-2-propionamido-1-tetralone (IX). The reduction of (IX) with NaBH4 in ethanol yields the alcohol (X), which by further reduction with LiAlH4 in THF affords trans-7-methoxy-2-(proylamino)-1,2,3,4-tetrahydronaphthalen-1-ol (XI). The cyclization of (XI) with chloroacetyl chloride by means of NaH in THF - acetonitrile gives trans-9-methoxy-4-propyl-3,4,4a,5,6,10b-hexahydro-2H-naphth[1,2-b]-1,4-oxazin-3-one (XII), which is reduced with LiAlH4 in THF to compound (VI), already obtained.
| 【1】 Jones, J.H.; McClure, D.E.; Grenda, V.J. (Merck & Co., Inc.); Hexahydronaphth(1,2-b)-1,4-oxazines, process for their preparation and pharmaceutical formulation containing them. EP 0080115 . |
| 【2】 Williams, M.; Jones, J.H.; Randall, W.C.; Clineschmidt, B.V.; Martin, G.E.; Lumma, P.K.; Hirshfield, J.M.; Anderson, P.S.; McClure, D.E.; Lundell, G.F.; Baldwin, J.J.; Smith, G.; Synthesis of 4-substituted 2H-naphth[1,2-b]-1,4-oxazines, a new class of dopamine agonists. J Med Chem 1984, 27, 12, 1607. |
| 【3】 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 |
|---|---|---|---|---|---|---|
| (B) | 15967 | propanoyl chloride; propionyl chloride | 79-03-8 | C3H5ClO | 详情 | 详情 |
| (A) | 21382 | 1-nitropentane | 1002-16-0 | C5H11NO2 | 详情 | 详情 |
| (VI) | 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 | |
| (VII) | 21385 | 7-methoxy-3,4-dihydro-1(2H)-naphthalenone | 6836-19-7 | C11H12O2 | 详情 | 详情 |
| (VIII) | 21386 | 7-methoxy-3,4-dihydro-1,2-naphthalenedione 2-oxime | C11H11NO3 | 详情 | 详情 | |
| (IX) | 21387 | N-(7-methoxy-1-oxo-1,2,3,4-tetrahydro-2-naphthalenyl)propanamide | C14H17NO3 | 详情 | 详情 | |
| (X) | 21388 | N-[(1R,2R)-1-hydroxy-7-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl]propanamide | C14H19NO3 | 详情 | 详情 | |
| (XI) | 21389 | (1R,2R)-7-methoxy-2-(propylamino)-1,2,3,4-tetrahydro-1-naphthalenol | C14H21NO2 | 详情 | 详情 | |
| (XII) | 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 | |
| (C) | 11296 | 2-Chloroacetyl chloride; Chloroacetic chloride | 79-04-9 | C2H2Cl2O | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XV)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4
该中间体在本合成路线中的序号：(IX)Nitrosation of 7-methoxy-2-tetralone (I) using isoamyl nitrite and potassium tert-butoxide provided the oximino ketone (II). Catalytic hydrogenation of the oxime function of (II) in the presence of propionic anhydride gave rise to the propionamide (III). Ketone reduction by means of NaBH4 produced a mixture of cis- and trans-hydroxy amides from which the pure trans-isomer (IV) was isolated after two recrystallizations from EtOAc. The amide function of (IV) was subsequently reduced with LiAlH-4 to the N-propyl amine (V). Acylation of amino alcohol (V) with chloroacetyl chloride (VI) afforded the corresponding chloroacetamido alcohol (VII), which was further cyclized to compound (VIII) upon treatment with NaH. The lactam carbonyl group of (VIII) was then reduced with borane-dimethyl sulfide complex to the cyclic amine (IX). Methyl ether cleavage in (IX) to produce phenol (X) was then achieved by heating with pyridine hydrochloride (1). Phenol (X) was converted to the aryl triflate (XI) by treatment with trifluoromethanesulfonic anhydride. Displacement of the triflate group of (XI) with zinc cyanide in the presence of Pd catalyst furnished nitrile (XII). Partial hydrolysis of the nitrile (XII) under basic conditions produced the corresponding racemic amide. The title dextro-enantiomer was then isolated by preparative chiral HPLC.
| 【2】 Millan, M.; Lejeune, F.; Peglion, J.-L.; Harmange, J.-C. (ADIR et Cie.); Disubstd. trans-3,4,4a,5,6,10b-hexahydro-2H-napht(1,2-b)-1,4-oxazines, process for their preparation and pharmaceutical compsns. containing them. CA 2246482; EP 0899267; FR 2767825; JP 1999130759; US 6025356 . |
| 【1】 Peglion, J.-L.; et al.; Discovery of S32504. A preferential agonist at dopamine D3 vs. D2 receptors possessing antiparkinsonian and antidepressant properties. 222nd ACS Natl Meet (Aug 26 2001, Chicago) 2001, Abst MEDI 208. |
| 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) | 21385 | 7-methoxy-3,4-dihydro-1(2H)-naphthalenone | 6836-19-7 | C11H12O2 | 详情 | 详情 |
| (II) | 21386 | 7-methoxy-3,4-dihydro-1,2-naphthalenedione 2-oxime | C11H11NO3 | 详情 | 详情 | |
| (III) | 21387 | N-(7-methoxy-1-oxo-1,2,3,4-tetrahydro-2-naphthalenyl)propanamide | C14H17NO3 | 详情 | 详情 | |
| (IV) | 21388 | N-[(1R,2R)-1-hydroxy-7-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl]propanamide | C14H19NO3 | 详情 | 详情 | |
| (V) | 21389 | (1R,2R)-7-methoxy-2-(propylamino)-1,2,3,4-tetrahydro-1-naphthalenol | C14H21NO2 | 详情 | 详情 | |
| (VI) | 11296 | 2-Chloroacetyl chloride; Chloroacetic chloride | 79-04-9 | C2H2Cl2O | 详情 | 详情 |
| (VII) | 21403 | 2-chloro-N-[(1R,2R)-1-hydroxy-7-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl]-N-propylacetamide | C16H22ClNO3 | 详情 | 详情 | |
| (VIII) | 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 | |
| (IX) | 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 | |
| (X) | 51579 | (4aR,10bR)-4-propyl-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazin-9-ol | C15H21NO2 | 详情 | 详情 | |
| (XI) | 51580 | (4aR,10bR)-4-propyl-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazin-9-yl trifluoromethanesulfonate | C16H20F3NO4S | 详情 | 详情 | |
| (XII) | 51581 | (4aR,10bR)-4-propyl-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazine-9-carbonitrile | C16H20N2O | 详情 | 详情 |