【结 构 式】 |
【分子编号】17319 【品名】1-bromo-3-methoxypropane; 3-bromopropyl methyl ether 【CA登记号】 |
【 分 子 式 】C4H9BrO 【 分 子 量 】153.01886 【元素组成】C 31.4% H 5.93% Br 52.22% O 10.46% |
合成路线1
该中间体在本合成路线中的序号:(XX)2) The reaction of 3-acetyl-2,5-dichlorothiophene (XIV) with benzyl chloride and thiourea in ethanol/water gives 3-acetyl-2-(benzylsulfanyl)-5-chlorothiophene (XV), which is treated with Cl2 gas in ethyl acetate yielding the expected sulfenyl chloride (XVI). The oxidation of (XVI) with H2O2/sodium tungstate and treatment with ammonia affords 3-acetyl-5-chlorothiophene-2-sulfonamide (XVII), which is brominated with pyridinium bromide perbromide (IV) giving the corresponding bromoacetyl derivative (XVIII). The reductive cyclization of (XVIII) with (+)-CDPB in THF affords the bicyclic 4(S)-hydroxy derivative (XIX), which is condensed with 3-methoxypropyl bromide (XX) by means of K2CO3 in DMSO giving 6-chloro-4(S)-hydroxy-2-(3-methoxypropyl)-3,4-dihydro-2H-thieno[3,2-e] [1,2]thiazine (XXI). The sulfonation of (XXI) with BuLi, SO2 and hydroxylamine-O-sulfonic acid as before yields the sulfonamide (XIII), already obtained, which is finally treated with trimethyl ortoacetate and ethylamine in refluxing acetonitrile.
【1】 Graul, A.; Wroblewski, T.; Castañer, J.; Brinzolamide. Drugs Fut 1998, 23, 4, 365. |
【2】 Dean, W.D.; Deason, M.E.; Sproull, S.J.; Conrow, R.E.; DuPriest, M.T.; Zinke, P.W.; Dantanarayama, A.P.; Enantioselective synthesis of brinzolamide (AL-4862), a new topical carbonic anhydrase inhibitor. The "DCAT route" to thiophenesulfonamides. Org Process Res Dev 1999, 3, 2, 114. |
【3】 Dean, W.D.; Zinke, P.W.; Sproull, S.J.; Deason, M.E.; Conrow, R.E.; Dantanarayana, A.P. (Alcon Laboratories, Inc.); Preparation of carbonic anhydrase inhibitors. CA 2114877 . |
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) | 17303 | pyridinium | C5H6N | 详情 | 详情 | |
(XIII) | 17312 | (4S)-4-hydroxy-2-(3-methoxypropyl)-1,1-dioxo-1,2,3,4-tetrahydro-2H-thieno[3,2-e][1,2]thiazine-6-sulfonamide | 154127-42-1 | C10H16N2O6S3 | 详情 | 详情 |
(XIV) | 17313 | 3-Acetyl-2,5-dichlorothiophene; 1-(2,5-dichloro-3-thienyl)-1-ethanone | 36157-40-1 | C6H4Cl2OS | 详情 | 详情 |
(XV) | 17314 | 1-[5-chloro-2-[(4-methylphenyl)sulfanyl]-3-thienyl]-1-ethanone | 160982-09-2 | C13H11ClOS2 | 详情 | 详情 |
(XVI) | 17315 | 3-acetyl-5-chloro-2-thiophenesulfenyl chloride | C6H4Cl2OS2 | 详情 | 详情 | |
(XVII) | 17316 | 3-acetyl-5-chloro-2-thiophenesulfonamide | C6H6ClNO3S2 | 详情 | 详情 | |
(XVIII) | 17317 | 3-(2-bromoacetyl)-5-chloro-2-thiophenesulfonamide | 160982-11-6 | C6H5BrClNO3S2 | 详情 | 详情 |
(XIX) | 17318 | (4S)-6-chloro-4-hydroxy-3,4-dihydro-2H-thieno[3,2-e][1,2]thiazine-1,1(2H)-dione | 160982-16-1 | C6H6ClNO3S2 | 详情 | 详情 |
(XX) | 17319 | 1-bromo-3-methoxypropane; 3-bromopropyl methyl ether | C4H9BrO | 详情 | 详情 | |
(XXI) | 17320 | (4S)-6-chloro-4-hydroxy-2-(3-methoxypropyl)-3,4-dihydro-2H-thieno[3,2-e][1,2]thiazine-1,1(2H)-dione | C10H14ClNO4S2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号:(II)Alkylation of 3-hydroxy-4-methoxybenzyl alcohol (I) with 1-bromo-3-methoxypropane (II) gives ether (III). Subsequent conversion of benzyl alcohol (III) into bromide (IV) is carried out using bromotrimetylsilane. The chiral isovaleryloxazolidinone (V) is alkylated with bromide (IV) by means of LiHMDS to afford (VI), which is hydrolyzed to the (S)-2-aryl-2-isopropylpropionic acid (VII) by means of lithium peroxide. The reduction of acid (VII) to the corresponding alcohol with NaBH4/I2 reagent, followed by treatment with PPh3 and NBS, provides bromide (VIII). Alkylation of the chiral dimethoxydihydropyrazin (IX) with bromide (VIII) produces (X). Further hydrolysis of the pyrazine ring of (X) with HCl, followed by Boc protection of the resulting (S,S)-amino ester, yields compound (XI). Reduction of the ester group of (XI) with DIBAL gives aldehyde (XII). This compound is condensed with the Grignard reagent (XIII) to afford the diastereomeric mixture of amino alcohols (XIV). Treatment of mixture (XIV) with 2,2-dimethoxypropane (XV) and TsOH produces a mixture of oxazolidines, from which the required (S,S,S)-isomer (XVI) is isolated by flash chromatography. Hydrogenolitic deprotection of the benzyl ether of (XVI) gives alcohol (XVII).
【1】 Mealy, N.E.; Castañer, R.M.; Silvestre, J.S.; Castañer, J.; Aliskiren Fumarate. Drugs Fut 2001, 26, 12, 1139. |
【2】 Rigollier, P.; Stutz, S.; Goeschke, R.; Yamaguchi, Y.; Maibaum, J.; Wood, J.; Structural modification of the P2' position of 2,7-dialkyl substituted 5(S)-amino-4(S)-hydroxy-8-phenyl-octane-carboxamides: Discovery of a potent non-peptide renin inhibitor active after once daily dosing in marmosets. 15th European Federation for Medicinal Chemistry International Symposium on Medicinal Chemistry (Sept 6 1998, Edinburgh) 1998, Abst P.230. |
【3】 Göschke, R.; Maibaum, J.K.; Schilling, W.; Stutz, S.; Rigollier, P.; Yamaguchi, Y.; Cohen, N.C.; Herold, P. (Novartis AG); Delta-amino-gamma-hydroxy-omega-aryl alkanoic acid amides with enzyme especially renin inhibiting activities. EP 0678500; EP 0678503; JP 1996053434; JP 1996081430; US 5559111; US 5627182; US 5646143 . |
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) | 28115 | 5-(hydroxymethyl)-2-methoxyphenol | 4383-06-6 | C8H10O3 | 详情 | 详情 |
(II) | 17319 | 1-bromo-3-methoxypropane; 3-bromopropyl methyl ether | C4H9BrO | 详情 | 详情 | |
(III) | 28116 | [4-methoxy-3-(3-methoxypropoxy)phenyl]methanol | 172900-74-2 | C12H18O4 | 详情 | 详情 |
(IV) | 28117 | 3-[5-(bromomethyl)-2-methoxyphenoxy]propyl methyl ether | 172900-73-1 | C12H17BrO3 | 详情 | 详情 |
(V) | 28131 | (4S)-4-benzyl-3-(3-methylbutanoyl)-1,3-oxazolidin-2-one | C15H19NO3 | 详情 | 详情 | |
(VI) | 28118 | (4S)-4-benzyl-3-[(2R)-2-[4-methoxy-3-(3-methoxypropoxy)benzyl]-3-methylbutanoyl]-1,3-oxazolidin-2-one | C27H35NO6 | 详情 | 详情 | |
(VII) | 28119 | (2R)-2-[4-methoxy-3-(3-methoxypropoxy)benzyl]-3-methylbutyric acid | C17H26O5 | 详情 | 详情 | |
(VIII) | 28120 | 3-[5-[(2R)-2-(bromomethyl)-3-methylbutyl]-2-methoxyphenoxy]propyl methyl ether | 172900-69-5 | C17H27BrO3 | 详情 | 详情 |
(IX) | 10296 | (R)-2,5-Dihydro-3,6-dimethoxy-2-isopropylpyrazine; (3R)-3-Isopropyl-5-methoxy-3,6-dihydro-2-pyrazinyl methyl ether; (2R)-2-Isopropyl-3,6-dimethoxy-2,5-dihydropyrazine | 109838-85-9 | C9H16N2O2 | 详情 | 详情 |
(X) | 28121 | (2R,5S)-2-isopropyl-3,6-dimethoxy-5-[(2S)-2-[4-methoxy-3-(3-methoxypropoxy)benzyl]-3-methylbutyl]-2,5-dihydropyrazine | C26H42N2O5 | 详情 | 详情 | |
(XI) | 28122 | methyl (2S,4S)-2-[(tert-butoxycarbonyl)amino]-4-[4-methoxy-3-(3-methoxypropoxy)benzyl]-5-methylhexanoate | C25H41NO7 | 详情 | 详情 | |
(XII) | 28123 | tert-butyl (1S,3S)-1-formyl-3-[4-methoxy-3-(3-methoxypropoxy)benzyl]-4-methylpentylcarbamate | C24H39NO6 | 详情 | 详情 | |
(XIII) | 28124 | [(2S)-2-[(benzyloxy)methyl]-3-methylbutyl](bromo)magnesium | C13H19BrMgO | 详情 | 详情 | |
(XIV) | 28125 | tert-butyl (1S,4S)-4-[(benzyloxy)methyl]-2-hydroxy-1-[(2S)-2-[4-methoxy-3-(3-methoxypropoxy)benzyl]-3-methylbutyl]-5-methylhexylcarbamate | C37H59NO7 | 详情 | 详情 | |
(XV) | 10722 | 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane | 77-76-9 | C5H12O2 | 详情 | 详情 |
(XVI) | 28126 | tert-butyl (4S,5S)-5-[(2S)-2-[(benzyloxy)methyl]-3-methylbutyl]-4-[(2S)-2-[4-methoxy-3-(3-methoxypropoxy)benzyl]-3-methylbutyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate | C40H63NO7 | 详情 | 详情 | |
(XVII) | 28127 | tert-butyl (4S,5S)-5-[(2S)-2-(hydroxymethyl)-3-methylbutyl]-4-[(2S)-2-[4-methoxy-3-(3-methoxypropoxy)benzyl]-3-methylbutyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate | C33H57NO7 | 详情 | 详情 |