BMS-363131, -Drug Synthesis Database

【结构式】

【药物名称】BMS-363131

【化学名称】3(R)-(1-Amidinopiperidin-3(R)-ylmethyl)-4-oxo-1-[4-(6-phenylhexanoyl)piperazin-1-ylcarbonyl]azetidine-2(S)-carboxylic acid

【CA登记号】253177-55-8 (stereoisomer), 253175-00-7 (stereoisomer, monoHCl)

【分子式】C₂₈H₄₀N₆O₅

【分子量】540.6682

【开发单位】Bristol-Myers Squibb (Originator)

【药理作用】Antiallergy/Antiasthmatic Drugs, Asthma Therapy, RESPIRATORY DRUGS, Tryptase Inhibitors

合成路线1 合成路线2

合成路线1

Ethyl nipecotate (I) was protected as the N-Boc derivative (II) and subsequently reduced to alcohol (III) by means of LiAlH4. Conversion of alcohol (III) into iodide (IV) was achieved by treatment with iodine and triphenylphosphine. The dianion of the chiral azetidinecarboxylic acid (V) was alkylated with iodide (IV) to furnish adduct (VI) as a diastereomeric mixture that was desilylated to (VII) using tetrabutylammonium fluoride. Benzyl ester (VIII) was then obtained by reaction of carboxylic acid (VII) with benzyl bromide and NaHCO3.

参考文献中间体

【1】 Treuner, U.; Kronenthal, D.R.; Xu, Z.; Seiler, S.; Slusarchyk, W.A.; Bisacchi, G.; Randazzo, M.E.; Sutton, J.C.; Shi, Z.; Zahler, R.; Schwinden, M.D. (Bristol-Myers Squibb Co.); Amidino and guanidino azetidinone tryptase inhibitors. WO 9967215 .

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)	25693	ethyl 3-piperidinecarboxylate	5006-62-2	C₈H₁₅NO₂	详情	详情
(II)	26186	1-(tert-butyl) 3-ethyl 1,3-piperidinedicarboxylate		C₁₃H₂₃NO₄	详情	详情
(III)	51124	tert-butyl 3-(hydroxymethyl)-1-piperidinecarboxylate		C₁₁H₂₁NO₃	详情	详情
(IV)	51120	tert-butyl 3-(iodomethyl)-1-piperidinecarboxylate		C₁₁H₂₀INO₂	详情	详情
(V)	51121	(2S,3R)-3-[[1-(tert-butoxycarbonyl)-3-piperidinyl]methyl]-1-[tert-butyl(dimethyl)silyl]-4-oxo-2-azetidinecarboxylic acid		C₂₁H₃₈N₂O₅Si	详情	详情
(VI)	49426	(2S)-1-[tert-butyl(dimethyl)silyl]-4-oxo-2-azetidinecarboxylic acid		C₁₀H₁₉NO₃Si	详情	详情
(VII)	51122	(2S,3R)-3-[[1-(tert-butoxycarbonyl)-3-piperidinyl]methyl]-4-oxo-2-azetidinecarboxylic acid		C₁₅H₂₄N₂O₅	详情	详情
(VIII)	51123	tert-butyl 3-([(2S,3R)-2-[(benzyloxy)carbonyl]-4-oxoazetidinyl]methyl)-1-piperidinecarboxylate		C₂₂H₃₀N₂O₅	详情	详情

合成路线2

Coupling of 6-phenylhexanoic acid (X) with N-Boc-piperazine (IX) to give (XI), followed by acid deprotection of the Boc group of (XI), provided (6-phenylhexanoyl)piperazine (XII). This was converted to the carbamoyl chloride (XIII) upon treatment with phosgene. The condensation of carbamoyl chloride (XIII) with azetidinone (VIII) gave rise to the urea derivative (XIV). After acid cleavage of the Boc protecting group of (XIV), the resulting piperidine (XV) was condensed with N,N'-dicarbobenzoxy-S-methylisothiourea (XVI) in the presence of HgCl2, yielding the protected guanidine (XVII). This was finally deprotected by catalytic hydrogenolysis over Pd/C.

参考文献中间体

【1】 Treuner, U.; Kronenthal, D.R.; Xu, Z.; Seiler, S.; Slusarchyk, W.A.; Bisacchi, G.; Randazzo, M.E.; Sutton, J.C.; Shi, Z.; Zahler, R.; Schwinden, M.D. (Bristol-Myers Squibb Co.); Amidino and guanidino azetidinone tryptase inhibitors. WO 9967215 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VIII)	51123	tert-butyl 3-([(2S,3R)-2-[(benzyloxy)carbonyl]-4-oxoazetidinyl]methyl)-1-piperidinecarboxylate		C₂₂H₃₀N₂O₅	详情	详情
(IX)	13225	N-tert-Butoxycarbonyl piperazine; tert-butyl 1-piperazinecarboxylate;tert-butyl piperazine-1-carboxylate	143238-38-4	C₉H₁₈N₂O₂	详情	详情
(X)	51125	6-Phenylcaproic acid; 6-Phenylhexanoic acid; Benzenehexanoic acid	5581-75-9	C₁₂H₁₆O₂	详情	详情
(XI)	51126	tert-butyl 4-(6-phenylhexanoyl)-1-piperazinecarboxylate		C₂₁H₃₂N₂O₃	详情	详情
(XII)	51127	6-phenyl-1-(1-piperazinyl)-1-hexanone		C₁₆H₂₄N₂O	详情	详情
(XIII)	51128	4-(6-phenylhexanoyl)-1-piperazinecarbonyl chloride		C₁₇H₂₃ClN₂O₂	详情	详情
(XIV)	51129	tert-butyl 3-[((2S,3R)-2-[(benzyloxy)carbonyl]-4-oxo-1-[[4-(6-phenylhexanoyl)-1-piperazinyl]carbonyl]azetidinyl)methyl]-1-piperidinecarboxylate		C₃₉H₅₂N₄O₇	详情	详情
(XV)	51130	benzyl (2S,3R)-4-oxo-1-[[4-(6-phenylhexanoyl)-1-piperazinyl]carbonyl]-3-(3-piperidinylmethyl)-2-azetidinecarboxylate		C₃₄H₄₄N₄O₅	详情	详情
(XVI)	32861	benzyl (E)-[[(benzyloxy)carbonyl]amino](methylsulfanyl)methylidenecarbamate		C₁₈H₁₈N₂O₄S	详情	详情
(XVII)	51131	benzyl (2S,3R)-3-[[1-([[(benzyloxy)carbonyl]amino][[(benzyloxy)carbonyl]imino]methyl)-3-piperidinyl]methyl]-4-oxo-1-[[4-(6-phenylhexanoyl)-1-piperazinyl]carbonyl]-2-azetidinecarboxylate		C₅₁H₅₈N₆O₉	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)