3-bromo-1,1,1-trifluoroacetone -Drug Synthesis Database

【结构式】

【分子编号】39909

【品名】3-bromo-1,1,1-trifluoroacetone

【CA登记号】431-35-6

【分子式】C₃H₂BrF₃O

【分子量】190.9474896

【元素组成】C 18.87% H 1.06% Br 41.85% F 29.85% O 8.38%

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：(XI)

The cyclization of trifluoroacetylmethylpyridinium bromide (I) with 3-(4-trifluoromethylbenzoyl)acrylic acid (II) by means of ammonium acetate in refluxing methanol gives 2-trifluoromethyl-6-(4-trifluoromethylphenyl)isonicotinic acid (III), which by condensation with 2-bromopyridine (IV) by means of butyllithium in ethyl ether yields 2-trifluoromethyl-6-(4-trifluoromethylphenyl)4-pyridyl-2'-pyridyl ketone (V). Finally, this compound is reduced with H2 over Pt in aqueous concentrated HCl. The starting products are prepared as follows: 1) The acrylic acid (II) is obtained by condensation of maleic anhydride (VI) with 4-trifluoromethylphenylmagnesium bromide (VII) by means of ZnCl2 in refluxing ethyl ether. An alternative method is the condensation of 4-trifluoromethylacetophenone (VIII) with glyoxylic acid (IX) by means of triethylamine at 135 C. 2) The pyridinium salt (I) is prepared by bromination of 1,1,1-trifluoroacetone (X) giving 1,1,1-trifluoro-3-bromoacetone (XI), which is then condensed with pyridine.

参考文献中间体

合成目标

【1】 La Montagne, M.P.; et al.; Antimalarials. 6. Synthesis, antimalarial activity and configurations of rracemic alpha-(2-piperidyl)-4-pyridinemethanols. J Med Chem 1974, 17, 5, 219-523.
【2】 Ash, A.B.; et al. (Department of the Army); 2-Substituted phenyl-6-trifluoromethyl-4-pyridylcarbinolamines. US 3940404 .
【3】 Ash, A.B.; et al. (Department of the Army); 2-Aryl-6-trifluoromethyl-4-pyridylcarbinolamine antimalarials. US 3953463 .
【4】 Ash, A.B.; et al. (Department of the Army); 2-Aryl-6-trifluoromethyl-4-pyridylcarbinolamine antimalarials. US 3886167 .
【5】 Castaner, J.; Roberts, P.J.; WR-180,409. Drugs Fut 1978, 3, 9, 694.

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)	39908	1-(3,3,3-trifluoro-2-oxopropyl)pyridinium bromide		C₈H₇BrF₃NO	详情	详情
(II)	39906	(E)-4-oxo-4-[4-(trifluoromethyl)phenyl]-2-butenoic acid		C₁₁H₇F₃O₃	详情	详情
(III)	39910	2-(trifluoromethyl)-6-[4-(trifluoromethyl)phenyl]isonicotinic acid		C₁₄H₇F₆NO₂	详情	详情
(IV)	29052	2-Bromopyridine；α-bromopyridine;α-bromoazine	109-04-6	C₅H₄BrN	详情	详情
(V)	39911	2-pyridinyl[2-(trifluoromethyl)-6-[4-(trifluoromethyl)phenyl]-4-pyridinyl]methanone		C₁₉H₁₀F₆N₂O	详情	详情
(VI)	11182	2,5-Furandione; Maleic anhydride	108-31-6	C₄H₂O₃	详情	详情
(VII)	39311	bromo[4-(trifluoromethyl)phenyl]magnesium		C₇H₄BrF₃Mg	详情	详情
(VIII)	39907	1-[4-(trifluoromethyl)phenyl]-1-ethanone	709-63-7	C₉H₇F₃O	详情	详情
(IX)	15618	2-Oxoacetic acid; Glyoxylic Acid	298-12-4	C₂H₂O₃	详情	详情
(X)	35449	1,1,1-trifluoroacetone	421-50-1	C₃H₃F₃O	详情	详情
(XI)	39909	3-bromo-1,1,1-trifluoroacetone	431-35-6	C₃H₂BrF₃O	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VII)

The chiral (R)-(+)-epoxide (X) was synthesized by asymmetric reduction of 3-bromotrifluoroacetone (VII) using (+)-B-chlorodiisopinocampheylborane (VIII), followed by intramolecular cyclization of the resulting (R)-bromohydrin (VIII) in aqueous NaOH. Finally, reaction of amine (IV) with the chiral epoxide (X) furnished the desired enantiomer.

参考文献中间体

合成目标

【1】 Durley, R.C.; et al.; Chiral N,N-disubstituted trifluoro-3-amino-2-propanols are potent inhibitors of cholesteryl ester transfer protein. J Med Chem 2002, 45, 18, 3891.
【2】 Grapperhaus, M.L.; Hickory, B.S.; Sikorski, J.A.; Wang, L.J.; Massa, M.A.; Mischke, D.A.; Honda, D.D.; New simple class of potent cholesteryl ester transfer protein inhibitors. 220th ACS Natl Meet (Aug 20 2000, Washington DC) 2000, Abst MEDI 283.
【3】 Durley, R.C.; et al.; Discovery of chiral N,N-disubstituted trifluoro-3-amino-2-propanols as potent inhibitors of cholesteryl ester transfer protein. J Med Chem 2000, 43, 24, 4575.
【4】 Vernier, W.F.; Wang, L.; Mischke, D.A.; Hamme, A.T.; Promo, M.A.; Sikorski, J.A.; Spangler, D.P.; Grapperhaus, M.L.; Massa, M.A.; Durley, R.C.; Reinhard, E.J.; Fobian, Y.M.; Hickory, B.S.; Tollefson, M.B.; Norton, M.B.; Rueppel, M.L. (Pharmacia Corp.); (R)-Chiral halogenated 1-substd.amino-(n+1)-alkanols useful for inhibiting cholesteryl ester transfer protein activity. WO 0018721; WO 0018724 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(IV)	45687	N-(3-phenoxyphenyl)-N-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]amine; 3-phenoxy-N-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]aniline		C₂₁H₁₇F₄NO₂	详情	详情
(VII)	39909	3-bromo-1,1,1-trifluoroacetone	431-35-6	C₃H₂BrF₃O	详情	详情
(VIII)	45693	chloro[(1R,2R,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl][(1S,2S,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]borane		C₂₀H₃₄BCl	详情	详情
(IX)	45694	(2S)-3-bromo-1,1,1-trifluoro-2-propanol	88378-50-1	C₃H₄BrF₃O	详情	详情
(X)	45689	(2R)-2-(trifluoromethyl)oxirane		C₃H₃F₃O	详情	详情

Extended Information