2,2,2-Trifluoroethyl trichloromethanesulfonate; 2,2,2-Trifluoroethyl trichloromethylsulfonate -Drug Synthesis Database

【结构式】

【分子编号】33474

【品名】2,2,2-Trifluoroethyl trichloromethanesulfonate; 2,2,2-Trifluoroethyl trichloromethylsulfonate

【CA登记号】23199-56-6

【分子式】C₃H₂Cl₃F₃O₃S

【分子量】281.4663896

【元素组成】C 12.8% H 0.72% Cl 37.79% F 20.25% O 17.05% S 11.39%

与该中间体有关的原料药合成路线共 5 条

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

该中间体在本合成路线中的序号：(A)

The alkylation of 2-amino-5-chloro-2'-fluorobenzophenone (II) with 2,2,2-trifluoroethyl trichloromethylsulfonate (A) gives 2-(2,2,2-trifluoroethylamino)-5-chloro-2'-fluorobenzophenone (III), which is bromoacetylated with bromoacetyl chloride (B) in refluxing benzene yielding the bromoacetanilide (IV).This compound is cyclized with NH3 in chloroform affording 7-chloro-1-(2,2,2-trifluoroethyl)-1,3-dihydro-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one (I), which by reaction with P2S5 in refluxing dioxane gives the target compound.

参考文献中间体

合成目标

【1】 Steinman, M.; Benzodiazepines and the process for their manufacture. DE 2138773; ES 393953; FR 2102114; GB 1345938 .
【2】 Steinman, M.; 1-Polyfluoroalkyl-1,4-benzodiazepin-2-thiones for effecting tranquilization, sedation and treating colvulsions. US 3920818 .
【3】 Castaner, J.; Thorpe, P.; Quazepam. Drugs Fut 1978, 3, 2, 139.
【4】 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
(B)	27903	2-Bromoacetyl chloride	22118-09-8	C₂H₂BrClO	详情	详情
(A)	33474	2,2,2-Trifluoroethyl trichloromethanesulfonate; 2,2,2-Trifluoroethyl trichloromethylsulfonate	23199-56-6	C₃H₂Cl₃F₃O₃S	详情	详情
(I)	33471	7-Chloro-5-(2-fluorophenyl)-1-(2,2,2-trifluoroethyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one		C₁₇H₁₁ClF₄N₂O	详情	详情
(II)	32281	2-Amino-5-chloro-2'-fluorobenzophenone; (2-Amino-5-chlorophenyl)(2-fluorophenyl)methanone	784-38-3	C₁₃H₉ClFNO	详情	详情
(III)	33472	[5-Chloro-2-[(2,2,2-trifluoroethyl)amino]phenyl](2-fluorophenyl)methanone; 2-(2,2,2-Trifluoroethylamino)-5-chloro-2'-fluorobenzophenone		C₁₅H₁₀ClF₄NO	详情	详情
(IV)	33473	2-bromo-N-[4-chloro-2-(2-fluorobenzoyl)phenyl]-N-(2,2,2-trifluoroethyl)acetamide		C₁₇H₁₁BrClF₄NO₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(A)

The alkylation of p-chloroaniline (V) as before yields N-(2,2,2-trifluoroethyl)aniline (VI), which is then condensed with aziridine (C) affording the substituted aniline (VII). The benzoylation of (VII) with 2-fluorobenzoyl chloride (D) yields the amide (VIII), which is cyclized with P2O5 in refluxing POCl3 giving 7-chloro-(2,2,2-trifluoroethyl)-1,3-dihydro-2H-5-(2-fluorophenyl)-1,4-benzodiazepine (IX). This compound is oxidized with RuO4 in CCl4 to give 7-chloro-1-(2,2,2-trifluoroethyl)-1,3-dihydro-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one (I), which by reaction with P2S5 in refluxing dioxane gives the target compound.

参考文献中间体

合成目标

【1】 Steinman, M.; Benzodiazepines and the process for their manufacture. DE 2138773; ES 393953; FR 2102114; GB 1345938 .
【2】 Steinman, M.; 1-Polyfluoroalkyl-1,4-benzodiazepin-2-thiones for effecting tranquilization, sedation and treating colvulsions. US 3920818 .
【3】 Castaner, J.; Thorpe, P.; Quazepam. Drugs Fut 1978, 3, 2, 139.
【4】 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)	19551	2-Fluorobenzoyl chloride	393-52-2	C₇H₄ClFO	详情	详情
(A)	33474	2,2,2-Trifluoroethyl trichloromethanesulfonate; 2,2,2-Trifluoroethyl trichloromethylsulfonate	23199-56-6	C₃H₂Cl₃F₃O₃S	详情	详情
(I)	33471	7-Chloro-5-(2-fluorophenyl)-1-(2,2,2-trifluoroethyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one		C₁₇H₁₁ClF₄N₂O	详情	详情
(V)	12034	4-Chlorophenylamine; 4-Chloroaniline; p-Chloroaniline	106-47-8	C₆H₆ClN	详情	详情
(VI)	33475	N-(4-chlorophenyl)-N-(2,2,2-trifluoroethyl)amine; 4-chloro-N-(2,2,2-trifluoroethyl)aniline		C₈H₇ClF₃N	详情	详情
(VII)	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
(VIII)	33477	N-[2-[4-chloro(2,2,2-trifluoroethyl)anilino]ethyl]-2-fluorobenzamide		C₁₇H₁₅ClF₄N₂O	详情	详情
(IX)	33478	7-chloro-5-(2-fluorophenyl)-1-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-1,4-benzodiazepine; 7-chloro-(2,2,2-trifluoroethyl)-1,3-dihydro-2H-5-(2-fluorophenyl)-1,4-benzodiazepine		C₁₇H₁₃ClF₄N₂	详情	详情
(C)	10151	Ethyleneimine; Aziridine; Azirane	151-56-4	C₂H₅N	详情	详情

合成路线3

该中间体在本合成路线中的序号：(II)

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

合成目标

【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4

该中间体在本合成路线中的序号：(II)

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

合成目标

【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5

该中间体在本合成路线中的序号：(XXIII)

The aminoazepinone building block (III) can be prepared as follows. 2,4-Dimethoxybenzylamine (XIII) is alkylated with 2,3-dibromopropene (XIV) in the presence of Et3N to yield amine (XV), which is condensed with 2(R)-(benzyloxycarbonylamino)-4-pentenoic acid (XVI) by means of EDC in CH2Cl2 giving amide (XVII). Subsequent coupling of vinyl bromide (XVII) with 2,3-difluorophenylboronic acid (XVIII) in the presence of 1,1’-bis(diphenylphosphino)ferrocenedichloropalladium(II)· CH2Cl2 and Na2CO3 in DMF gives (XIX). Ring-closing olefin metathesis in diene (XIX) utilizing a second-generation Grubbs catalyst generates the azepinone derivative (XX), from which the dimethoxybenzyl group is removed by means of trifluoroacetic acid in CH2Cl2 to provide compound (XXI). Hydrogenation of olefin (XXI) and simultaneous Cbz group cleavage in the presence of Pd/C and Boc2O leads to the Boc-protected aminoperhydroazepinone (XXII). After alkylation of lactam (XXII) with the 2,2,2-trifluoroethyl sulfonate (XXIII) and NaH in DMF, the N-Boc group is removed using trifluoroacetic acid to furnish the target amine (III) (1). Scheme 2.

参考文献中间体

合成目标

【1】 Burgey, C.S., Deng, Z.J., Williams, T.M., Paone, D.V., Shaw, A.W., Nguyen, D.N. (Merck & Co., Inc.). CGRP receptor antagonists. EP 1638969, JP 2006523697, US 2004229861, US 6953790, WO 2004092166, WO 2004092168.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(III)	65556	(3R,6S)-3-Amino-6-(2,3-difluorophenyl)hexahydro-2-oxo-1-(2,2,2-trifluoroethyl)-1H-azepine		C₁₄H₁₅F₅N₂O	详情	详情
(XIII)	32115	(2,4-dimethoxyphenyl)methanamine; 2,4-dimethoxybenzylamine	20781-21-9	C₉H₁₃NO₂	详情	详情
(XIV)	21748	2,3-dibromo-1-propene	513-31-5	C₃H₄Br₂	详情	详情
(XV)	65562			C₁₂H₁₆BrNO₂	详情	详情
(XVI)	65563	Cbz-alpha-Allyl-L-Gly; N-ALPHA-CARBOBENZOXY-L-ALPHA-ALLYL-GLYCINE; CBZ-(S)-2-AMINO-4-PENTENOIC ACID; (S)-2-CBZ-AMINO-4-PENTENOIC ACID	78553-51-2	C₁₃H₁₅NO₄	详情	详情
(XVII)	65564			C₂₅H₂₉BrN₂O₅	详情	详情
(XVIII)	65565	2,3-Difluorophenylboronic acid; 2,3-Difluorobenzeneboronic acid	121219-16-7	C₆H₅BF₂O₂	详情	详情
(XIX)	65566			C₃₁H₃₃F₂N₂O₅	详情	详情
(XX)	65567			C₂₉H₂₈F₂N₂O₅	详情	详情
(XXI)	65568			C₂₀H₁₈F₂N₂O₃	详情	详情
(XXII)	65569			C₁₇H₂₁F₂N₂O₃	详情	详情
(XXIII)	33474	2,2,2-Trifluoroethyl trichloromethanesulfonate; 2,2,2-Trifluoroethyl trichloromethylsulfonate	23199-56-6	C₃H₂Cl₃F₃O₃S	详情	详情

Extended Information