methyl (2S)-3-hydroxy-2-(tritylamino)propanoate -Drug Synthesis Database

【结构式】

【分子编号】31420

【品名】methyl (2S)-3-hydroxy-2-(tritylamino)propanoate

【CA登记号】

【分子式】C₂₃H₂₃NO₃

【分子量】361.44056

【元素组成】C 76.43% H 6.41% N 3.88% O 13.28%

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：(VIII)

The stereocontrolled reaction of 3-pentanone (I) with 2-methylpropionaldehyde (II) by means of (+)-bis(diisopinocampheyl)borane triflate and DIEA in THF, followed by silylation with Tes-Cl and imidazole gives the silylated heptenone (III), which is condensed with 3-benzyloxypropionaldehyde (IV) by means of chlorodicyclohexylborane yielding the diol (V). The protection of the hydroxy groups of (V) with 2,2-dimethoxypropane and camphorsulfonic acid (CSA) with simultaneous desilylation affords the isopropylidene ketal (VI), which is acylated with propionic anhydride and triethylamine giving the propionate (VII). The Claisen rearrangement of (VII) by means of LDA and TBDMS-Cl in HMPT yields the carboxylic acid (VIII), which by regio- and stereoselective hydroboration of its double bond with BH3, followed by oxidation with N-methylmorpholine N-oxide (NMO) and tetrapropylammonium perruthenate (TPAP) in dichloromethane affords the lactone (IX). The reaction of (IX) with Me2Al-NH2, followed by debenzylation with H2 over Pd/C provides the dihydroxyamide (X), which is oxidized with Dess-Martin periodinane (DMP) in dichloromethane giving the keto aldehyde (XI). The cyclization of (XI) with HF in acetonitrile yields the spiro carbaldehyde (XII), which is silylated with Tes-OTf in dichloromethane providing the silyl ether (XIII).

参考文献中间体

合成目标

【1】 Nicolaou, K.C.; et al.; Total synthesis of sanglifehrin A. Angew Chem. Int Ed Engl 1999, 38, 16, 2447.

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)	32415	Propione; Dimethylacetone; Diethyl ketone; 3-Pentanone	96-22-0	C₅H₁₀O	详情	详情
(II)	11387	2-Methylacrylaldehyde; Methacrylaldehyde	78-85-3	C₄H₆O	详情	详情
(III)	32416	(4R,5R)-4,6-dimethyl-5-[(triethylsilyl)oxy]-6-hepten-3-one		C₁₅H₃₀O₂Si	详情	详情
(IV)	14688	3-(benzyloxy)propanal		C₁₀H₁₂O₂	详情	详情
(V)	32417	(3S,4S,5S,6S,7R)-1-(benzyloxy)-4,6,8-trimethyl-7-[(triethylsilyl)oxy]-8-nonene-3,5-diol		C₂₅H₄₄O₄Si	详情	详情
(VI)	31418	[6-(benzyloxy)-2-(4-hydroxyphenyl)-1-benzothiophen-3-yl][3-methoxy-4-(1-pyrrolidinylmethyl)phenyl]methanone		C₃₄H₃₁NO₄S	详情	详情
(VII)	31419	4-[6-(benzyloxy)-3-[3-methoxy-4-(1-pyrrolidinylmethyl)benzyl]-1-benzothiophen-2-yl]phenol		C₃₄H₃₃NO₃S	详情	详情
(VIII)	31420	methyl (2S)-3-hydroxy-2-(tritylamino)propanoate		C₂₃H₂₃NO₃	详情	详情
(IX)	32421	(3S,5S,6S)-6-((1S)-1-[(4S,5R,6S)-6-[2-(benzyloxy)ethyl]-2,2,5-trimethyl-1,3-dioxan-4-yl]ethyl)-3-ethyl-5-methyltetrahydro-2H-pyran-2-one		C₂₆H₄₀O₅	详情	详情
(X)	32422	(2S,4S,5S,6R)-2-ethyl-5-hydroxy-6-[(4R,5R,6S)-6-(2-hydroxyethyl)-2,2,5-trimethyl-1,3-dioxan-4-yl]-4-methylheptanamide		C₁₉H₃₇NO₅	详情	详情
(XI)	32423	(2S,4S,6S)-2-ethyl-4-methyl-5-oxo-6-[(4S,5R,6S)-2,2,5-trimethyl-6-(2-oxoethyl)-1,3-dioxan-4-yl]heptanamide		C₁₉H₃₃NO₅	详情	详情
(XII)	32424	2-[(2S,3R,4S,5S,6R,9S,11S)-9-ethyl-4-hydroxy-3,5,11-trimethyl-8-oxo-1-oxa-7-azaspiro[5.5]undec-2-yl]acetaldehyde		C₁₆H₂₇NO₄	详情	详情
(XIII)	32425	2-[(2S,3S,4S,5S,6R,9S,11S)-9-ethyl-3,5,11-trimethyl-8-oxo-4-[(triethylsilyl)oxy]-1-oxa-7-azaspiro[5.5]undec-2-yl]acetaldehyde		C₂₂H₄₁NO₄Si	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XV)

Subsequent Mitsunobu condensation of (XIV) with N-trityl-L-serine methyl ester (XV) in the presence of DEAD and PPh3 produced the serine ether (XVI). Deprotection of the trityl group of (XVI) by means of trifluoroacetic acid and triethylsilane, followed by transfer hydrogenolysis of the benzyl ether with ammonium formate and Pd/C provided the deprotected intermediate (XVII). Finally, reduction of the ester group of (XVII) with LiAlH4 yielded the title compound.

参考文献中间体

合成目标

【1】 Antithrombotic diamines. EP 0863755; US 6025382; WO 9725033 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XIV)	31419	4-[6-(benzyloxy)-3-[3-methoxy-4-(1-pyrrolidinylmethyl)benzyl]-1-benzothiophen-2-yl]phenol	C₃₄H₃₃NO₃S	详情	详情
(XV)	31420	methyl (2S)-3-hydroxy-2-(tritylamino)propanoate	C₂₃H₂₃NO₃	详情	详情
(XVI)	31421	methyl (2S)-3-(4-[6-(benzyloxy)-3-[3-methoxy-4-(1-pyrrolidinylmethyl)benzyl]-1-benzothiophen-2-yl]phenoxy)-2-(tritylamino)propanoate	C₅₇H₅₄N₂O₅S	详情	详情
(XVII)	31422	(2S)-3-amino-2-[(phenylsulfonyl)amino]propionic acid	C₉H₁₂N₂O₄S	详情	详情

Extended Information