-Drug Synthesis Database

【结构式】

【药物名称】

【化学名称】4-[1-(Furo[3,2-c]pyridin-2-yl)-1-methylethyl]-1-[2(S)-hydroxy-4(R)-[N-[3(S)-hydroxy-3,4-dihydro-2H-1-benzopyran-4(S)-yl]carbamoyl]-5-phenylpentyl]-N-(2,2,2-trifluoroethyl)piperazine-2(S)-carboxamide

【CA登记号】342598-35-0

【分子式】C₃₈H₄₄F₃N₅O₆

【分子量】723.79948

【开发单位】Merck & Co. (Originator)

【药理作用】AIDS Medicines, Anti-HIV Agents, ANTIINFECTIVE THERAPY, HIV Protease Inhibitors

合成路线1 合成路线2 合成路线3

合成路线1

(S)-Piperazine-2-carboxylic acid (I) was sequentially protected as the 4-Boc derivative (II) and then as the 1-Alloc-4-Boc-piperazine (III). After conversion of (III) to benzyl ester (IV), its N-Boc group was selectively removed by treatment with trifluoroacetic acid. The resultant 4-deprotected piperazine (V) was then alkylated with 3-chloro-3-methyl-1-butyne (VI) yielding (VII). Copper-promoted coupling of 4-hydroxy-3,5-diiodopyridine (IX) prepared by halogenation of 4-hydroxypyridine (VIII) with N-iodosuccinimide with the propargyl piperazine (VII) gave rise to the furo[3,2-c]pyridine derivative (X). The N-Alloc protecting group was then replaced by the N-Boc group to yield (XII) via palladium catalyzed deprotection of (X), followed by treatment of the resultant piperazine (XI) with Boc2O. Simultaneous hydrogenolysis of the benzyl ester and the iodo substituent of (XII) led to acid (XIII). After coupling of (XIII) with 2,2,2-trifluoroethylamine, acidic cleavage of the N-Boc group furnished the piperazine-2-carboxamide (XIV).

参考文献中间体

【1】 gamma-Hydroxy-2-(fluoroalkylaminocarbonyl)-1-piperazinepentanamides as HIV protease inhibitors. EP 1242426; WO 0138332 .

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)	16266	(2S)-hexahydro-2-pyrazinecarboxylic acid; (S)-Piperazine-2-carboxylic acid		C₅H₁₀N₂O₂	详情	详情
(II)	51591	(2R)-4-(tert-butoxycarbonyl)-2-piperazinecarboxylic acid		C₁₀H₁₈N₂O₄	详情	详情
(III)	56252	(2S)-1-[(allyloxy)carbonyl]-4-(tert-butoxycarbonyl)-2-piperazinecarboxylic acid		C₁₄H₂₂N₂O₆	详情	详情
(IV)	56253	1-allyl 2-benzyl 4-(tert-butyl) (2S)-1,2,4-piperazinetricarboxylate		C₂₁H₂₈N₂O₆	详情	详情
(V)	56254	1-allyl 2-benzyl (2S)-1,2-piperazinedicarboxylate		C₁₆H₂₀N₂O₄	详情	详情
(VI)	22416	3-chloro-3-methyl-1-butyne	1111-97-3	C₅H₇Cl	详情	详情
(VII)	56255	1-allyl 2-benzyl (2S)-4-(1,1-dimethyl-2-propynyl)-1,2-piperazinedicarboxylate		C₂₁H₂₆N₂O₄	详情	详情
(VIII)	56256	4-Hydroxypyridine; 4-Pyridinol; 4(1H)-Pyridone; 4-Pyridol; 4-Pyridone; gamma-Pyridone	626-64-2	C₅H₅NO	详情	详情
(IX)	56257	3,5-diiodo-4-pyridinol		C₅H₃I₂NO	详情	详情
(X)	56258	1-allyl 2-benzyl (2S)-4-[1-(7-iodofuro[3,2-c]pyridin-2-yl)-1-methylethyl]-1,2-piperazinedicarboxylate		C₂₆H₂₈IN₃O₅	详情	详情
(XI)	56259	benzyl (2S)-4-[1-(7-iodofuro[3,2-c]pyridin-2-yl)-1-methylethyl]-2-piperazinecarboxylate		C₂₂H₂₄IN₃O₃	详情	详情
(XII)	56260	2-benzyl 1-(tert-butyl) (2S)-4-[1-(7-iodofuro[3,2-c]pyridin-2-yl)-1-methylethyl]-1,2-piperazinedicarboxylate		C₂₇H₃₂IN₃O₅	详情	详情
(XIII)	56261	(2S)-1-(tert-butoxycarbonyl)-4-(1-furo[3,2-c]pyridin-2-yl-1-methylethyl)-2-piperazinecarboxylic acid		C₂₀H₂₇N₃O₅	详情	详情
(XIV)	56262	(2S)-4-(1-furo[3,2-c]pyridin-2-yl-1-methylethyl)-N-(2,2,2-trifluoroethyl)-2-piperazinecarboxamide		C₁₇H₂₁F₃N₄O₂	详情	详情

合成路线2

Bromochromanone (XVI) was prepared by bromination of 4-chromanone (XV). Subsequent reduction of (XVI) with NaBH4 provided bromohydrin (XVII). Ritter reaction of (XVII) with acetonitrile and sulfuric acid, followed by acidic hydrolysis, led to racemic cis-3-bromo-4-chromanol, which was then resolved by means of (S)-(+)-mandelic acid. The desired (S,S)-isomer (XVIII) was coupled with hydrocinnamic acid (XIX) giving amide (XX). After protection of hydroxy amide (XX) as the acetonide (XXI), the lithium enolate of amide (XXI) was alkylated with allyl bromide (XXII) to furnish the (S)-2-benzyl-4-pentenamide (XXIII) as the main diastereoisomer. Halogenation of (XXIII) with N-iodosuccinimide in H2O-EtOAc afforded iodohydrin (XXIV), which was cyclized to epoxide (XXV) in the presence of NaOMe.

参考文献中间体

【1】 gamma-Hydroxy-2-(fluoroalkylaminocarbonyl)-1-piperazinepentanamides as HIV protease inhibitors. EP 1242426; WO 0138332 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XV)	14461	2,3-Dihydro-4H-chromen-4-one; 4-Chromanone	491-37-2	C₉H₈O₂	详情	详情
(XVI)	56263	3-bromo-2,3-dihydro-4H-chromen-4-one		C₉H₇BrO₂	详情	详情
(XVII)	56264	3-bromo-4-chromanol		C₉H₉BrO₂	详情	详情
(XVIII)	56265	(3S,4S)-4-amino-3,4-dihydro-2H-chromen-3-ol		C₉H₁₁NO₂	详情	详情
(XIX)	49181	Hydrocinnamic acid; 3-Phenylpropionic acid; Benzylacetic acid	501-52-0	C₉H₁₀O₂	详情	详情
(XX)	56266	N-[(3S,4S)-3-hydroxy-3,4-dihydro-2H-chromen-4-yl]-3-phenylpropanamide		C₁₈H₁₉NO₃	详情	详情
(XXI)	56267	1-[(3aS,9bS)-2,2-dimethyl-3a,9b-dihydro-2H-chromeno[4,3-d][1,3]oxazol-1(4H)-yl]-3-phenyl-1-propanone		C₂₁H₂₃NO₃	详情	详情
(XXII)	11463	3-Bromo-1-propene; 3-Bromopropene；allyl bromide	106-95-6	C₃H₅Br	详情	详情
(XXIII)	56268	(2S)-1-[(3aS,9bS)-2,2-dimethyl-3a,9b-dihydro-2H-chromeno[4,3-d][1,3]oxazol-1(4H)-yl]-2-benzyl-4-penten-1-one		C₂₄H₂₇NO₃	详情	详情
(XXIV)	56269	(2R,4S)-1-[(3aS,9bS)-2,2-dimethyl-3a,9b-dihydro-2H-chromeno[4,3-d][1,3]oxazol-1(4H)-yl]-2-benzyl-4-hydroxy-5-iodo-1-pentanone		C₂₄H₂₈INO₄	详情	详情
(XXV)	56270	(2R)-1-[(3aS,9bS)-2,2-dimethyl-3a,9b-dihydro-2H-chromeno[4,3-d][1,3]oxazol-1(4H)-yl]-2-benzyl-3-[(2S)oxiranyl]-1-propanone		C₂₄H₂₇NO₄	详情	详情

合成路线3

Ring opening of epoxide (XXV) with piperazine (XIV) in refluxing isopropanol provided the amino alcohol adduct (XXVI). The title compound was then obtained by acetonide group hydrolysis in (XXVI) in the presence of methanolic HCl.

参考文献中间体

【1】 gamma-Hydroxy-2-(fluoroalkylaminocarbonyl)-1-piperazinepentanamides as HIV protease inhibitors. EP 1242426; WO 0138332 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XIV)	56262	(2S)-4-(1-furo[3,2-c]pyridin-2-yl-1-methylethyl)-N-(2,2,2-trifluoroethyl)-2-piperazinecarboxamide	C₁₇H₂₁F₃N₄O₂	详情	详情
(XXV)	56270	(2R)-1-[(3aS,9bS)-2,2-dimethyl-3a,9b-dihydro-2H-chromeno[4,3-d][1,3]oxazol-1(4H)-yl]-2-benzyl-3-[(2S)oxiranyl]-1-propanone	C₂₄H₂₇NO₄	详情	详情
(XXVI)	56271	Fmoc-(R)-3-amino-3-phenylpropionic acid	C₂₄H₂₁NO₄	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)