Halazepam, Sch-12041, Paxipam, -Drug Synthesis Database

【结构式】

【药物名称】Halazepam, Sch-12041, Paxipam

【化学名称】7-Chloro-5-phenyl-1-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one

【CA登记号】23092-17-3

【分子式】C₁₇H₁₂ClF₃N₂O

【分子量】352.74619

【开发单位】Schering-Plough (Originator)

【药理作用】Anxiolytics, PSYCHOPHARMACOLOGIC DRUGS, Benzodiazepines, GABA(A) BZ Site Receptor Agonists

合成路线1 合成路线2 合成路线3 合成路线4 合成路线5

合成路线1

1) The alkylation of 2-amino-5-chlorobenzophenone (I) with 2,2,2-trifluoroethyl trichloromethansulfonate (II) in refluxing xylene gives the N-trifluoroethyl derivative (III), which is then cyclized with glycine ethyl ester (A) in refluxing pyridine. 2) Compound (III) can also be bromoacetylated with bromoacetyl bromide (B) in refluxing benzene yielding the N-bromoacetyl compound (IV), which is then cyclized with ammonia in CHCl3. 3) By alkylation of 7-chloro-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one (IX) with NaOMe and 2,2,2-trifluoroethyl iodide in MeOH.

参考文献中间体

【1】 Topliss, J.G.; 2-Polyfluoroweralkyl benzophenones. US 3641147 .
【2】 Topliss, J.G.; 1-Polyhalogenoalkyl-2-oxo-1,3-dihydro-2H-14-benzodiazepines. US 3429874 .
【3】 Topliss, J.G.; Verfahren zur Herstellung von neuen 1,4-benzodiazepinen bzw. ihren 4-Oxyden. CH 505842; DE 1793682; FR 1518382; GB 1179125 .
【4】 Castaner, J.; Thorpe, P.; Halazepam. Drugs Fut 1978, 3, 2, 109.
【5】 Topliss, J.G.; Steinman, M.; Alekel, R.; Wong, Y.S.; York, E.E.; 1-Polyfluoroalkylbenzodiazepines. J Med Chem 1973, 16, 12, 1354-60.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	18806	1,1,1-trifluoro-2-iodoethane	353-83-3	C₂H₂F₃I	详情	详情
(A)	10309	ethyl 2-aminoacetate; Glycine ethyl ester	459-73-4	C₄H₉NO₂	详情	详情
(B)	14005	2-Bromoacetyl bromide; Bromoacetyl bromide	598-21-0	C₂H₂Br₂O	详情	详情
(I)	10279	(2-Amino-5-chlorophenyl)(phenyl)methanone; 2-Amino-5-chlorobenzophenone	719-59-5	C₁₃H₁₀ClNO	详情	详情
(II)	33474	2,2,2-Trifluoroethyl trichloromethanesulfonate; 2,2,2-Trifluoroethyl trichloromethylsulfonate	23199-56-6	C₃H₂Cl₃F₃O₃S	详情	详情
(III)	33848	[5-chloro-2-[(2,2,2-trifluoroethyl)amino]phenyl](phenyl)methanone		C₁₅H₁₁ClF₃NO	详情	详情
(IV)	33849	N-(2-benzoyl-4-chlorophenyl)-2-bromo-N-(2,2,2-trifluoroethyl)acetamide		C₁₇H₁₂BrClF₃NO₂	详情	详情
(IX)	10281	7-Chloro-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one; 1,4-benzdiazepin-2-one-5-phenyl-7-chloro	1088-11-5	C₁₅H₁₁ClN₂O	详情	详情

合成路线2

N-trifluoroethyl derivative (III) can also be obtained by alkylation of (X) with (II) in refluxing xylene giving 4-chloro-N-(2,2,2-trifluoroethyl)aniline (XV), followed by a Friedel-Crafts reaction with benzoyl chloride by means of AlCl3.

参考文献中间体

【1】 Topliss, J.G.; 1-Polyhalogenoalkyl-2-oxo-1,3-dihydro-2H-14-benzodiazepines. US 3429874 .
【2】 Topliss, J.G.; 2-Polyfluoroweralkyl benzophenones. US 3641147 .

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)	33474	2,2,2-Trifluoroethyl trichloromethanesulfonate; 2,2,2-Trifluoroethyl trichloromethylsulfonate	23199-56-6	C₃H₂Cl₃F₃O₃S	详情	详情
(III)	33848	[5-chloro-2-[(2,2,2-trifluoroethyl)amino]phenyl](phenyl)methanone		C₁₅H₁₁ClF₃NO	详情	详情
(X)	12034	4-Chlorophenylamine; 4-Chloroaniline; p-Chloroaniline	106-47-8	C₆H₆ClN	详情	详情
(XV)	33475	N-(4-chlorophenyl)-N-(2,2,2-trifluoroethyl)amine; 4-chloro-N-(2,2,2-trifluoroethyl)aniline		C₈H₇ClF₃N	详情	详情

合成路线3

N-bromoacetyl compound (IV) can also be obtained by bromoacetylation of (XV) with bromoacetyl bromide (B) in refluxing benzene affording 4-chloro-N-bromoacetyl-N-(2,2,2-trifluoroethyl)aniline (XVI), followed by a Friedel-Crafts reaction with benzoyl chloride by means of AlCl3.

参考文献中间体

【1】 Topliss, J.G.; 2-Polyfluoroweralkyl benzophenones. US 3641147 .
【2】 Topliss, J.G.; 1-Polyhalogenoalkyl-2-oxo-1,3-dihydro-2H-14-benzodiazepines. US 3429874 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(D)	10463	Benzoyl chloride	98-88-4	C₇H₅ClO	详情	详情
(B)	14005	2-Bromoacetyl bromide; Bromoacetyl bromide	598-21-0	C₂H₂Br₂O	详情	详情
(IV)	33849	N-(2-benzoyl-4-chlorophenyl)-2-bromo-N-(2,2,2-trifluoroethyl)acetamide		C₁₇H₁₂BrClF₃NO₂	详情	详情
(XV)	33475	N-(4-chlorophenyl)-N-(2,2,2-trifluoroethyl)amine; 4-chloro-N-(2,2,2-trifluoroethyl)aniline		C₈H₇ClF₃N	详情	详情
(XVI)	33852	2-bromo-N-(4-chlorophenyl)-N-(2,2,2-trifluoroethyl)acetamide		C₁₀H₈BrClF₃NO	详情	详情

合成路线4

The starting benzophenone (I) can also be obtained in several different ways: a) By a Friedel-Crafts reaction of p-chloroaniline (X) and benzoyl chloride (D). b) By reaction of 5-chloroanthranilic acid (XI) with acetic anhydride to the bicyclic compound (XII), which is then submitted to a Grignard reaction with phenylmagnesium bromide (E). c) By oxidation of 2,3-diphenyl-5-chloroindole (XIII) with CrO3 to the N-benzoylbenzophenone (XIV), followed by debenzoylation with NaOH.

参考文献中间体

【1】 Topliss, J.G.; 1-Polyhalogenoalkyl-2-oxo-1,3-dihydro-2H-14-benzodiazepines. US 3429874 .
【2】 Topliss, J.G.; 2-Polyfluoroweralkyl benzophenones. US 3641147 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(D)	10463	Benzoyl chloride	98-88-4	C₇H₅ClO	详情	详情
(E)	17616	bromo(phenyl)magnesium; Phenyl Magnesium Bromide	100-58-3	C₆H₅BrMg	详情	详情
(I)	10279	(2-Amino-5-chlorophenyl)(phenyl)methanone; 2-Amino-5-chlorobenzophenone	719-59-5	C₁₃H₁₀ClNO	详情	详情
(X)	12034	4-Chlorophenylamine; 4-Chloroaniline; p-Chloroaniline	106-47-8	C₆H₆ClN	详情	详情
(XI)	10285	2-Amino-5-chlorobenzoic acid	635-21-2	C₇H₆ClNO₂	详情	详情
(XII)	33853	6-chloro-2-methyl-4H-3,1-benzoxazin-4-one		C₉H₆ClNO₂	详情	详情
(XIII)	33854	5-chloro-2,3-diphenyl-1H-indole		C₂₀H₁₄ClN	详情	详情
(XIV)	33855	N-(2-benzoyl-4-chlorophenyl)benzamide		C₂₀H₁₄ClNO₂	详情	详情

合成路线5

The reaction of 4-chloro-N-(2,2,2-trifluoroethyl)aniline (V) with ethyleneimine (C) by means of AlCl3 in benzene affords the N-(2-aminoethyl) compound (VI), which is benzoylated with benzoyl chloride (D) as usual yielding the benzamide (VII). Compound (VII) is cyclized with P2O5 in POCl3 giving 7-chloro-1,2-dihydro-5-phenyl-1-(2,2,2-trifluoroethyl)-3H-1,4-benzodiazepine (VIII), which is finally oxidized with RuO4.

参考文献中间体

【1】 Topliss, J.G.; Steinman, M.; Alekel, R.; Wong, Y.S.; York, E.E.; 1-Polyfluoroalkylbenzodiazepines. J Med Chem 1973, 16, 12, 1354-60.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(D)	10463	Benzoyl chloride	98-88-4	C₇H₅ClO	详情	详情
(V)	33475	N-(4-chlorophenyl)-N-(2,2,2-trifluoroethyl)amine; 4-chloro-N-(2,2,2-trifluoroethyl)aniline		C₈H₇ClF₃N	详情	详情
(VI)	33476	N(1)-(4-chlorophenyl)-N(1)-(2,2,2-trifluoroethyl)-1,2-ethanediamine; N-(2-aminoethyl)-N-(4-chlorophenyl)-N-(2,2,2-trifluoroethyl)amine		C₁₀H₁₂ClF₃N₂	详情	详情
(VII)	33850	N-[2-[4-chloro(2,2,2-trifluoroethyl)anilino]ethyl]benzamide		C₁₇H₁₆ClF₃N₂O	详情	详情
(VIII)	33851	7-chloro-5-phenyl-1-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-1,4-benzodiazepine		C₁₇H₁₄ClF₃N₂	详情	详情
(C)	10151	Ethyleneimine; Aziridine; Azirane	151-56-4	C₂H₅N	详情	详情

Extended Information