N-(tert-butyl)-5-propyl-2-thiophenecarboxamide -Drug Synthesis Database

【结构式】

【分子编号】16967

【品名】N-(tert-butyl)-5-propyl-2-thiophenecarboxamide

【CA登记号】

【分子式】C₁₂H₁₉NOS

【分子量】225.355

【元素组成】C 63.96% H 8.5% N 6.22% O 7.1% S 14.23%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(I)

The reaction of 4-benzoyloxycyclohexanone (I) with pyrrolidine (II) by means of p-toluenesulfonic acid in refluxing benzene gives the corresponding enamine (III), which is cyclized with acrylamide (IV) in refluxing dioxane yielding the mixture of hexahydroquinolones (V) and (VI). Benzylation of this mixture with benzylbromide (A) and NaH in THF affords the mixture of N-benzylquinolones (VII) and (VIII), which is reduced with LiAlH4 to the mixture of N-benzylhexahydroquinolines (IX) and (X). The reduction of this mixture with sodium cyanoborohydride in THF affords trans-1-benzyl-6-hydroxydecahydro quinoline (XI), which by reaction with BN in CH2Cl2 is converted to trans-1-cyano-6-hydroxydecahydro quinoline (XII). Oxidation of (XII) with CrO3/pyridine in CH2Cl2 gives the corresponding quinolone (XIII), which by reaction with dimethylformamide dimethyl acetal (XIV) in refluxing benzene is converted to 1-cyano-6-oxo-7-(dimethylaminomethylene)decahydroquinoline (XV). The cyclization of (XV) with hydrazine in refluxing methanol affords 5-cyano-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]quinoline (XVI), which by a reductive cleavage with Zn and acetic acid gives 4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]quinoline (XVII). Finally, this compound is alkylated with propionaldehyde (B) and sodium cyanoborohydride in methanol.

参考文献中间体

合成目标

【1】 Bach, N.; Kornfeld, E.C. (Eli Lilly and Company); Prolactin inhibiting octahydropyrazolo[3,4-g]quinolines. DD 148517; EP 0013787; ES 482087; FR 2446820; FR 2446821; FR 2446822; GB 2040915; GB 2092579; US 4198415 .
【2】 Serradell, M.N.; Castaner, J.; Castaner, R.M.; Mannhold, R.; Quinpirole Hydrochloride. Drugs Fut 1987, 12, 6, 558.

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)	12912	1-(Bromomethyl)benzene; Alpha-bromotoluene	100-39-0	C₇H₇Br	详情	详情
(B)	15966	propionaldehyde	123-38-6	C₃H₆O	详情	详情
(I)	16967	N-(tert-butyl)-5-propyl-2-thiophenecarboxamide		C₁₂H₁₉NOS	详情	详情
(II)	11376	Pyrrolidine	123-75-1	C₄H₉N	详情	详情
(III)	28829	4-(1-pyrrolidinyl)-3-cyclohexen-1-yl benzoate		C₁₇H₂₁NO₂	详情	详情
(IV)	10851	Acrylamide	79-06-1	C₃H₅NO	详情	详情
(V)	28830	2-oxo-1,2,3,4,5,6,7,8-octahydro-6-quinolinyl benzoate		C₁₆H₁₇NO₃	详情	详情
(VI)	28831	2-oxo-1,2,3,4,4a,5,6,7-octahydro-6-quinolinyl benzoate		C₁₆H₁₇NO₃	详情	详情
(VII)	28832	1-benzyl-2-oxo-1,2,3,4,5,6,7,8-octahydro-6-quinolinyl benzoate		C₂₃H₂₃NO₃	详情	详情
(VIII)	28833	1-benzyl-2-oxo-1,2,3,4,4a,5,6,7-octahydro-6-quinolinyl benzoate		C₂₃H₂₃NO₃	详情	详情
(IX)	28834	1-benzyl-6-hydroxy-3,4,5,6,7,8-hexahydro-2(1H)-quinolinone		C₁₆H₁₉NO₂	详情	详情
(X)	28835	1-benzyl-6-hydroxy-3,4,4a,5,6,7-hexahydro-2(1H)-quinolinone		C₁₆H₁₉NO₂	详情	详情
(XI)	28836	(4aR,8aR)-1-benzyldecahydro-6-quinolinol		C₁₆H₂₃NO	详情	详情
(XII)	28837	(4aR,8aR)-1-cyanodecahydro-6-quinolinol		C₁₀H₁₆N₂O	详情	详情
(XIII)	28838	(4aR,8aR)-1-cyanooctahydro-6(2H)-quinolinone		C₁₀H₁₄N₂O	详情	详情
(XIV)	11984	N-(Dimethoxymethyl)-N,N-dimethylamine;dimethylformamide dimethylacetal;1,1-dimethoxy-N,N-dimethylmethanamine； Dimethoxy-N,N-dimethylmethanamine; N,N-Dimethylformamide dimethyl acetal	4637-24-5	C₅H₁₃NO₂	详情	详情
(XV)	28839	(4aR,8aR)-1-cyano-7-[(Z)-(dimethylamino)methylidene]octahydro-6-quinolinone		C₁₃H₁₉N₃O	详情	详情
(XVI)	28840	(4aR,8aR)-5-cyano-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]quinoline		C₁₁H₁₄N₄	详情	详情
(XVII)	28841	(4aR,8aR)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]quinoline		C₁₀H₁₅N₃	详情	详情

合成路线2

该中间体在本合成路线中的序号：(IV)

ABT-431 can be obtained by two related ways: 1) The reduction of 6,7-dimethoxy-1-tetralone (I) with NaBH4 in ethanol followed by dehydration with p-toluenesulfonic acid in refluxing toluene gives 6,7-dimethoxy-1,2-dihydronaphthalene (II), which is nitrated with tetranitromethane and pyridine in acetone yielding 6,7-dimethoxy-3-nitro-1,2-dihydronaphthalene (III). The condensation of (III) with N-tert-butyl-5-propylthiophene-2-carboxamide (IV) by means of butyllithium in THF affords the trans racemic (V), which is reduced with Zn/HCl to the corresponding amine (VI). The reaction of (VI) with 10% H2SO4 in refluxing methanol gives a mixture of the decarboxylated compound (VII) and the cyclization compound (VIII). The enantiomeric separation of (VIII) by chiral chromatography in a Chiracel(TM) OD column affords the (5aR,11bS)-enantiomer, which is demethylated with BBr3 in dichloromethane to the chiral diol (IX), and finally acetylated with acetyl chloride in trifluoroacetic acid and treated with ethereal HCl. 2) The condensation of (III) with 5-allyl-N-tert-butylthiophene-2-carboxamide (X) by means of butyllithium in THF affords the trans racemic (XI), which by successive treatments with Zn/HCl, hydrogenation with H2 over Pd/C, p-toluenesulfonic acid in refluxing toluene and finally with BH3 in THF, is converted into the previously reported tetracyclic racemic compound (VIII). N-tert-Butyl-5-propylthiophene-2-carboxamide (IV) has been obtained by condensation of 2-propylthiophene (XII) with tert-butyl isocyanate (XIII) by means of butyllithium in THF.

参考文献中间体

合成目标

【1】 Merlos, M.; Graul, A.; Castañer, J.; ABT-431. Drugs Fut 1997, 22, 8, 821.
【2】 Michaelides, M.R.; Hong, Y.; DiDomenico, S. Jr.; Bayburt, E.K.; Asin, K.E.; Britton, D.R.; Lin, C.W.; Shiosaki; Substituted hexahydrobenzo[f]thieno[c]quinolines as dopamine D1-selective agonists: Synthesis and biological evaluation in vitro and in vivo. J Med Chem 1997, 40, 11, 1585-99.
【3】 Michaelides, M.R.; Hong, Y.; DiDomenico, S. Jr.; Asin, K.E.; Britton, D.R.; Lin, C.W.; Williams, M.; Shiosaki, K.; (5aR,11bS)-4,5,5a,6,7,11b-Hexahydro-2-propyl-3-thia-5-azacyclopent-1-ena[c]phenanthrene-9,10-diol(A-86929): A potent and selective dopamine D1 agonist. J Med Chem 1995, 38, 18, 3445-7.
【4】 Michaelides, M.R.; Hong, Y. (Abbott Laboratories Inc.); Tetracyclic cpds. as dopamine agonists. EP 0690863; JP 1996508487; US 5597832; WO 9422858 .

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-(VIII)	16971	(rac)-(5aR,11bS)-10-methoxy-2-propyl-4,5,5a,6,7,11b-hexahydrobenzo[f]thieno[2,3-c]quinolin-9-yl methyl ether; (rac)-(5aR,11bS)-9,10-dimethoxy-2-propyl-4,5,5a,6,7,11b-hexahydrobenzo[f]thieno[2,3-c]quinoline		C₂₀H₂₅NO₂S	详情	详情
(I)	16964	6,7-dimethoxy-1-tetralone; 6,7-dimethoxy-3,4-dihydro-1(2H)-naphthalenone	13575-75-2	C₁₂H₁₄O₃	详情	详情
(II)	16965	3-methoxy-5,6-dihydro-2-naphthalenyl methyl ether; 6,7-dimethoxy-1,2-dihydronaphthalene		C₁₂H₁₄O₂	详情	详情
(III)	16966	3-methoxy-6-nitro-7,8-dihydro-2-naphthalenyl methyl ether; 6,7-dimethoxy-3-nitro-1,2-dihydronaphthalene		C₁₂H₁₃NO₄	详情	详情
(IV)	16967	N-(tert-butyl)-5-propyl-2-thiophenecarboxamide		C₁₂H₁₉NOS	详情	详情
(V)	16968	N-(tert-butyl)-3-[(1S,2R)-6,7-dimethoxy-2-nitro-1,2,3,4-tetrahydro-1-naphthalenyl]-5-propyl-2-thiophenecarboxamide		C₂₄H₃₂N₂O₅S	详情	详情
(VI)	16969	3-[(1S,2R)-2-amino-6,7-dimethoxy-1,2,3,4-tetrahydro-1-naphthalenyl]-N-(tert-butyl)-5-propyl-2-thiophenecarboxamide		C₂₄H₃₄N₂O₃S	详情	详情
(VII)	16970	(1S,2R)-6,7-dimethoxy-1-(5-propyl-3-thienyl)-1,2,3,4-tetrahydro-2-naphthalenylamine; (1S,2R)-6,7-dimethoxy-1-(5-propyl-3-thienyl)-1,2,3,4-tetrahydro-2-naphthalenamine		C₁₉H₂₅NO₂S	详情	详情
(VIII)	65064	(5aR,11bS)-9,10-dimethoxy-2-propyl-4,5,5a,6,7,11b-hexahydrobenzo[f]thieno[2,3-c]quinoline; (5aR,11bS)-10-methoxy-2-propyl-4,5,5a,6,7,11b-hexahydrobenzo[f]thieno[2,3-c]quinolin-9-yl methyl ether		C₂₀H₂₅NO₂S	详情	详情
(IX)	16972	(5aR,11bS)-2-propyl-4,5,5a,6,7,11b-hexahydrobenzo[f]thieno[2,3-c]quinoline-9,10-diol		C₁₈H₂₁NO₂S	详情	详情
(X)	16973	5-allyl-N-(tert-butyl)-2-thiophenecarboxamide		C₁₂H₁₇NOS	详情	详情
(XI)	16974	5-allyl-N-(tert-butyl)-3-[(1S,2R)-6,7-dimethoxy-2-nitro-1,2,3,4-tetrahydro-1-naphthalenyl]-2-thiophenecarboxamide		C₂₄H₃₀N₂O₅S	详情	详情
(XII)	16975	2-propylthiophene; Thiophene, 2-propyl-	1551-27-5	C₇H₁₀S	详情	详情
(XIII)	16976	tert-butylisocyanate; tert-butyl isocyanate; 2-isocyanato-2-methylpropane	1609-86-5	C₅H₉NO	详情	详情

Extended Information