4,4,4-Trifluorobutyric acid -Drug Synthesis Database

【结构式】

【分子编号】14781

【品名】4,4,4-Trifluorobutyric acid

【CA登记号】406-93-9

【分子式】C₄H₅F₃O₂

【分子量】142.0777096

【元素组成】C 33.82% H 3.55% F 40.12% O 22.52%

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 synthesis of the key chiral amine component (VII) is outlined: Conversion of 4,4,4-trifluorobutyric acid (XI) to the corresponding acid chloride and subsequent reaction with the anion derived from the Evans oxazolidinone (XII) yielded the acyloxazolidinone (XIII). Treatment of (XIII) with a strong base such as sodium hexamethyldisilazide and alkylation of the resultant enolate with iodomethane at -35 C afforded a mixture of the diastereomeric acyloxazolidinones (XIV). The desired diastereomer was obtained by crystallization of the crude product. Reductive cleavage of the chiral auxiliary gave the enantiomerically pure alcohol (XV), which was converted in two steps to the desired enantiomerically pure amine hydrochloride (VII). Alternative routes to the amine, such as resolution of racemic 4,4,4-trifluoro-2-methylbutyric acid followed by amide formation and reduction to (VII) could also be utilized.

参考文献中间体

合成目标

【1】 Bernstein, P.R.; Jacobs, R.T.; ZD 3523. Drugs Fut 1995, 20, 12, 1233.
【2】 Jacobs, R.T.; Yee, Y.K.; Bernstein, P.R.; Brewster, A.G.; Sependa, G.J. (AstraZeneca plc); A process for the preparation of 2(R)-methyl-4,4,4-trifluorobutylamine, intermediates and a process for the preparation of a derivative thereof. EP 0489548 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	12376	Phthalimide; 1H-Isoindole-1,3(2H)-dione; Isoindole-1,3-dione;Phthalic dicarboximide;Phenylimide;Isoindole-1,3-dione	85-41-6	C₈H₅NO₂	详情	详情
(XI)	14781	4,4,4-Trifluorobutyric acid	406-93-9	C₄H₅F₃O₂	详情	详情
(XII)	14782	[(4R,5S)-4-Methyl-2-oxo-5-phenyl-1,3-oxazolidin-3-yl]lithium		C₁₀H₁₀LiNO₂	详情	详情
(XIII)	14783	(4R,5S)-4-Methyl-5-phenyl-3-(4,4,4-trifluorobutanoyl)-1,3-oxazolan-2-one		C₁₄H₁₄F₃NO₃	详情	详情
(XIV)	14784	(4R,5S)-4-methyl-5-phenyl-3-[(2R)-4,4,4-trifluoro-2-methylbutyl]-1,3-oxazolan-2-one		C₁₅H₁₈F₃NO₂	详情	详情
(XV)	14785	(2R)-4,4,4-trifluoro-2-methyl-1-butanol	107103-95-7	C₅H₉F₃O	详情	详情
(XVI)	14786	2-[(2R)-4,4,4-trifluoro-2-methylbutyl]-1H-isoindole-1,3(2H)-dione		C₁₃H₁₂F₃NO₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VII)

Amine (III) was synthesized from 2,2-dimethylcyclopentanone (I) by treatment with tosylmethyl isocyanide, followed by reduction of the resultant nitrile (II) with LiAlH4. Condensation of 4-cyanobenzoic acid (IV) with amine (III) produced the corresponding amide (V). Subsequent addition of hydroxylamine to the cyano group of (V) gave rise to the hydroxyamidine (VI). The target oxadiazole derivative was then obtained by condensation of (VI) with 4,4,4-trifluorobutyric acid (VII), followed by cyclization under basic conditions. Separation of the enantiomers was carried out by chiral preparative HPLC.

参考文献中间体

合成目标

【1】 LLoyd, J.; et al.; Design and synthesis of 4-substituted benzamides as potent, selective, and orally bioavailable IKS blockers. J Med Chem 2001, 44, 23, 3764.
【2】 Poss, M.A.; Lloyd, J.; Rovnyak, G.C.; Caulfield, T.J.; Atwal, K.S.; Stein, P.D.; Ahmad, S. (Bristol-Myers Squibb Co.); Benzoic acid derivs. and related cpds. as antiarrhythmic agents. WO 9837068 .

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)	43358	2,2-dimethylcyclopentanone		C₇H₁₂O	详情	详情
(II)	43359	2,2-dimethylcyclopentanecarbonitrile		C₈H₁₃N	详情	详情
(III)	43360	(2,2-dimethylcyclopentyl)methylamine; (2,2-dimethylcyclopentyl)methanamine		C₈H₁₇N	详情	详情
(IV)	36897	4-cyanobenzoic acid；4-Carboxybenzonitrile;p-Carboxybenzonitrile	619-65-8	C₈H₅NO₂	详情	详情
(V)	52509	4-cyano-N-[(2,2-dimethylcyclopentyl)methyl]benzamide		C₁₆H₂₀N₂O	详情	详情
(VI)	52510	4-[amino(hydroxyimino)methyl]-N-[(2,2-dimethylcyclopentyl)methyl]benzamide		C₁₆H₂₃N₃O₂	详情	详情
(VII)	14781	4,4,4-Trifluorobutyric acid	406-93-9	C₄H₅F₃O₂	详情	详情

Extended Information