2-chloro-4-nitrobenzoyl chloride -Drug Synthesis Database

【结构式】

【分子编号】26674

【品名】2-chloro-4-nitrobenzoyl chloride

【CA登记号】7073-36-1

【分子式】C₇H₃Cl₂NO₃

【分子量】220.01116

【元素组成】C 38.21% H 1.37% Cl 32.23% N 6.37% O 21.82%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(III)

The reductocyclization of 1-(2-nitrobenzyl)pyrrole-2-carbaldehyde (I) gives the pyrrolobenzodiazepine (II), which is acylated with 2-chloro-4-nitrobenzoyl chloride (III) giving the expected 10-benzoyl derivative (IV). The reduction of the nitro group of (IV) with H2 over Pd/C or with SnCl2 yields the corresponding 4-amino derivative (V), which is finally acylated with 5-fluoro-2-methylbenzoyl chloride.

参考文献中间体

合成目标

【1】 Albright, J.D.; Delos Santos, E.G.; Reich, M.F.; et al.; 5-Fluoro-2-methyl-N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)-3-chlorophenyl]benzamide (VPA-985): An orally active arginine vasopressin antagonist with selectivity for V2 receptors. J Med Chem 1998, 41, 14, 2442.
【2】 Albright, J.D.; Reich, M.F.; Sum, F.-W.; Delos Santos, E.G. (American Cyanamid Co.); Tricyclic diazepine vasopressin antagonists and oxytocin antagonists. CA 2128956; EP 0636625; JP 1995157486; US 5516774 .
【3】 Albright, J.D.; Sum, F.-W.; Delos Santos, E.G.; Reich, M.F. (American Cyanamid Co.); Tricyclic diazepine vasopressin antagonists and oxytocin antagonists. US 5736540 .
【4】 Reich, M.F.; Delos Santos, E.G.; Sum, F.-W.; Albright, J.D. (American Cyanamid Co.); Tricyclic diazepine vasopressin antagonists and oxytocin antagonists. US 5733905 .

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)	21083	1-(2-nitrobenzyl)-1H-pyrrole-2-carbaldehyde; N-(2-Nitrobenzyl)pyrrole-2-carboxaldehyde	22162-51-2	C₁₂H₁₀N₂O₃	详情	详情
(II)	21084	10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine	22162-53-4	C₁₂H₁₂N₂	详情	详情
(III)	26674	2-chloro-4-nitrobenzoyl chloride	7073-36-1	C₇H₃Cl₂NO₃	详情	详情
(IV)	26675	(2-chloro-4-nitrophenyl)[5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-yl]methanone		C₁₉H₁₄ClN₃O₃	详情	详情
(V)	26676	(4-amino-2-chlorophenyl)[5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-yl]methanone		C₁₉H₁₆ClN₃O	详情	详情
(VI)	26677	5-fluoro-2-methylbenzoyl chloride		C₈H₆ClFO	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VI)

Tetrahydrobenzothiophene-4-one (I) was treated with hydroxylamine to afford oxime (IIa-b) as a mixture of syn and anti isomers, which were condensed with tosyl chloride yielding the oxime O-tosylate (IIIa-b). Beckmann rearrangement of (IIIa-b) in the presence of KOAc gave rise to lactam (IV), and subsequent reduction with borane provided thienoazepine (V). Condensation of (V) with 2-chloro-4-nitrobenzoyl chloride (VI) gave amide (VII). A 7-oxo group was introduced by oxidation of (VII) with KMnO4 in acetone-water. The resulting ketone (VIII) was treated with Bredereck’s reagent to afford the dimethylaminomethylene ketone (IX). Cyclization of (IX) with hydrazine produced the tricyclic compound (X). The nitro group of (X) was then reduced to amine (XI) using stannous chloride. Coupling of (XI) with 2-biphenylcarbonyl chloride (XII) furnished the diacylated derivative (XIII). Finally, selective monodeacylation of(XIII) with NaOH yielded the title compound.

参考文献中间体

合成目标

【1】 Mazandarani, H.; Coupet, J.; Dusza, J.P:; Chan, P.S.; Ru, X.; Delos Santos, E.G.; Albright, J.D.; The synthesis and vasopressin (AVP) antagonist activity of a novel series of N-aroyl-2,4,5,6-tetrahydropyrazolo[3,4-d]thieno[3,2-b]azepines. Bioorg Med Chem Lett 2000, 10, 8, 695.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(IIa)	41567	(Z)-6,7-dihydro-1-benzothiophen-4(5H)-one oxime		C₈H₉NOS	详情	详情
(IIb)	41568	(E)-6,7-dihydro-1-benzothiophen-4(5H)-one oxime		C₈H₉NOS	详情	详情
(IIIa)	41569	(Z)-4-([[(4-methylphenyl)sulfonyl]oxy]imino)-6,7-dihydro-1-benzothiophene		C₁₅H₁₅NO₃S₂	详情	详情
(IIIb)	41570	(E)-4-([[(4-methylphenyl)sulfonyl]oxy]imino)-4,5,6,7-tetrahydro-1-benzothiophene		C₁₅H₁₅NO₃S₂	详情	详情
(I)	11045	6,7-Dihydro-1-benzothiophen-4(5H)-one; 4-Keto-4,5,6,7-tetrahydrothianaphthene; Tetrahydrobenzo(b)thiophene-4-one	13414-95-4	C₈H₈OS	详情	详情
(IV)	41571	4,6,7,8-tetrahydro-5H-thieno[3,2-b]azepin-5-one		C₈H₉NOS	详情	详情
(V)	41572	5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepine	180340-57-2	C₈H₁₁NS	详情	详情
(VI)	26674	2-chloro-4-nitrobenzoyl chloride	7073-36-1	C₇H₃Cl₂NO₃	详情	详情
(VII)	41573	(2-chloro-4-nitrophenyl)(5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepin-4-yl)methanone		C₁₅H₁₃ClN₂O₃S	详情	详情
(VIII)	41574	4-(2-chloro-4-nitrobenzoyl)-4,5,6,7-tetrahydro-8H-thieno[3,2-b]azepin-8-one		C₁₅H₁₁ClN₂O₄S	详情	详情
(IX)	41575	4-(2-chloro-4-nitrobenzoyl)-7-[(E)-(dimethylamino)methylidene]-4,5,6,7-tetrahydro-8H-thieno[3,2-b]azepin-8-one		C₁₈H₁₆ClN₃O₄S	详情	详情
(X)	41576	(2-chloro-4-nitrophenyl)[4,5-dihydropyrazolo[3,4-d]thieno[3,2-b]azepin-6(2H)-yl]methanone		C₁₆H₁₁ClN₄O₃S	详情	详情
(XI)	41577	(4-amino-2-chlorophenyl)[4,5-dihydropyrazolo[3,4-d]thieno[3,2-b]azepin-6(2H)-yl]methanone		C₁₆H₁₃ClN₄OS	详情	详情
(XII)	18506	[1,1'-biphenyl]-2-carbonyl chloride		C₁₃H₉ClO	详情	详情
(XIII)	41578	N-(4-[[2-([1,1'-biphenyl]-2-ylcarbonyl)-4,5-dihydropyrazolo[3,4-d]thieno[3,2-b]azepin-6(2H)-yl]carbonyl]-3-chlorophenyl)[1,1'-biphenyl]-2-carboxamide		C₄₂H₂₉ClN₄O₃S	详情	详情

合成路线3

该中间体在本合成路线中的序号：(VII)

Acylation of methyl 4-amino-2-chlorobenzoate (I) with 5-fluoro-2-methylbenzoyl chloride (II) in the presence of Et3N gives amide (III), which is then hydrolyzed at the ester group using NaOH in boiling H2O/EtOH to yield 2-chloro-4-(5-fluoro-2-methylbenzamido)benzoic acid (IV). Finally, after chlorination of acid (IV) with SOCl2 at reflux, the resulting acid chloride (V) is condensed with 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (VI) by means of DIEA in CH2Cl2 .
In a related method, acylation of benzodiazepine (VI) with 2-chloro-4-nitrobenzoyl chloride (VII) by means of Et3N in CH2Cl2 provides the nitrobenzamide (VIII), which is reduced to the corresponding 4-amino derivative (IX) using either H2 or hydrazine in the presence of Pd/C in EtOH or by means of SnCl2. Finally, amine (IX) is acylated with 5-fluoro-2-methylbenzoyl chloride (II) using Et3N in CH2Cl2 .
The tricyclic intermediate (VI) is prepared by alkylation of pyrrole-2-carbaldehyde (X) with 2-nitrobenzyl bromide (XI) by means of NaH in DMF to afford 1-(2-nitrobenzyl)pyrrole-2-carbaldehyde (XII), which undergoes reductocyclization to the pyrrolobenzodiazepine (VI) upon catalytic hydrogenation over Pd/C in EtOH/EtOAc .

参考文献中间体

合成目标

【1】 Albright, J.D., Reich, M.F., Delos Santos, E.G. et al. 5-Fluoro-2-methyl-N-[4-(5H-pyrrolo [2,1-c]-[1, 4]benzodiazepin-10(11H)-ylcarbonyl)-3-hlorophenyl] benzamide (VPA-985): An orally active arginine vasopressin antagonist with selectivity for V2 receptors. J Med Chem 1998, 41(14): 2442-4.
【2】 Albright, J.D., Reich, M.F., Sum, F.-W., Delos Santos, E.G. (Wyeth, LLC). Tricyclic diazepine vasopressin antagonists and oxytocin antagonists. CA 2128956, EP 0636625, JP 1995157486, US 5516774.
【3】 Sum, F.-W., Albright, J.D., Delos Santos, E.G., Reich, M.F. (Wyeth, LLC). Tricyclic diazepine vasopressin antagonists and oxytocin antagonists. US 5733905.
【4】 Reich, M.F., Sum, F.-W., Delos Santos, E.G., Albright, J.D. (Wyeth, LLC). Tricyclic diazepine vasopressin antagonists and oxytocin antagonists. US 5736540.
【5】 Reich, M.F., Sum, F.-W., Albright, J.D., Delos Santos, E.G. (Wyeth, LLC). Tricyclic diazepine vasopressin antagonists and oxytocin antagonists. US 5624923.

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)	26678	methyl 4-amino-2-chlorobenzoate		C₈H₈ClNO₂	详情	详情
(II)	26677	5-fluoro-2-methylbenzoyl chloride		C₈H₆ClFO	详情	详情
(III)	26679	methyl 2-chloro-4-[(5-fluoro-2-methylbenzoyl)amino]benzoate		C₁₆H₁₃ClFNO₃	详情	详情
(IV)	26680	2-chloro-4-[(5-fluoro-2-methylbenzoyl)amino]benzoic acid		C₁₅H₁₁ClFNO₃	详情	详情
(V)	26681	2-chloro-4-[(5-fluoro-2-methylbenzoyl)amino]benzoyl chloride		C₁₅H₁₀Cl₂FNO₂	详情	详情
(VI)	21084	10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine	22162-53-4	C₁₂H₁₂N₂	详情	详情
(VII)	26674	2-chloro-4-nitrobenzoyl chloride	7073-36-1	C₇H₃Cl₂NO₃	详情	详情
(VIII)	26675	(2-chloro-4-nitrophenyl)[5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-yl]methanone		C₁₉H₁₄ClN₃O₃	详情	详情
(IX)	26676	(4-amino-2-chlorophenyl)[5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-yl]methanone		C₁₉H₁₆ClN₃O	详情	详情
(X)	21081	Pyrrole-2-carbaldehyde; 1H-pyrrole-2-carbaldehyde	1003-29-8	C₅H₅NO	详情	详情
(XI)	21082	1-(bromomethyl)-2-nitrobenzene；2-Nitrobenzyl bromide;alpha-Bromo-2-nitrotoluene	3958-60-9	C₇H₆BrNO₂	详情	详情
(XII)	21083	1-(2-nitrobenzyl)-1H-pyrrole-2-carbaldehyde; N-(2-Nitrobenzyl)pyrrole-2-carboxaldehyde	22162-51-2	C₁₂H₁₀N₂O₃	详情	详情

Extended Information