(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 -Drug Synthesis Database

【结构式】

【分子编号】10296

【品名】(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

【CA登记号】109838-85-9

【分子式】C₉H₁₆N₂O₂

【分子量】184.23832

【元素组成】C 58.67% H 8.75% N 15.21% O 17.37%

与该中间体有关的原料药合成路线共 5 条

合成路线1 合成路线2 合成路线3 合成路线4 合成路线5

合成路线1

该中间体在本合成路线中的序号：(XIII)

The synthesis of intermediate (XXI) has been performed as follows: The condensation of 4-fluoro-3-nitrobenzyl bromide (XII) with the chiral dihydropyrazine (XIII) by means of BuLi and CuCN gives the chiral adduct (XIV), which is treated with TFA to yield the 4-fluoro-3-nitro-D- phenylalanine (XV). The N-protection of (XV) with Teoc-Cl gives the N-protected phenylalanine (XVI), which is condensed with the already described intermediate (XI) by means of PyBop to yield the amide (XVII). The oxidation of the primary OH group of (XVII) with DMP and NaClO2 affords the carboxylic acid (XVIII), which is cyclized to the cyclic amide (XIX). The cleavage of he protecting groups of (XIX) with HCl, followed by selective N-protection with Boc2O, provides primary carbinol (XX), which is finally oxidized with DMP and NaClO2 to give the desired carboxylic acid intermediate (XXI).

参考文献中间体

合成目标

【1】 Boger, D.L.; et al.; First and second generation total synthesis of the teicoplanin aglycon. J Am Chem Soc 2001, 123, 9, 1862.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XI)	47037	tert-butyl (1R)-1-[3-(3-[(1S)-1-amino-2-[(2-methoxyethoxy)methoxy]ethyl]-5-methoxyphenoxy)-4-methoxyphenyl]-2-hydroxyethylcarbamate		C₂₇H₄₀N₂O₉	详情	详情
(XII)	47038	4-(bromomethyl)-1-fluoro-2-nitrobenzene		C₇H₅BrFNO₂	详情	详情
(XIII)	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
(XIV)	47039	(2R,5S)-2-(4-fluoro-3-nitrobenzyl)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine; (3R,6S)-3-(4-fluoro-3-nitrobenzyl)-6-isopropyl-5-methoxy-3,6-dihydro-2-pyrazinyl methyl ether		C₁₆H₂₀FN₃O₄	详情	详情
(XV)	47040	(2R)-2-amino-3-(4-fluoro-3-nitrophenyl)propionic acid		C₉H₉FN₂O₄	详情	详情
(XVI)	47041	(2R)-3-(4-fluoro-3-nitrophenyl)-2-([[2-(trimethylsilyl)ethoxy]carbonyl]amino)propionic acid		C₁₅H₂₁FN₂O₆Si	详情	详情
(XVII)	47042	2-(trimethylsilyl)ethyl (1R,4S)-4-[3-(5-[(1R)-1-[(tert-butoxycarbonyl)amino]-2-hydroxyethyl]-2-methoxyphenoxy)-5-methoxyphenyl]-1-(4-fluoro-3-nitrobenzyl)-2-oxo-6,8,11-trioxa-3-azadodec-1-ylcarbamate		C₄₂H₅₉FN₄O₁₄Si	详情	详情
(XVIII)	47043	(2R)-2-[(tert-butoxycarbonyl)amino]-2-[3-[3-((1S,4R)-4-(4-fluoro-3-nitrobenzyl)-1-[[(2-methoxyethoxy)methoxy]methyl]-10,10-dimethyl-3,6-dioxo-7-oxa-2,5-diaza-10-silaundec-1-yl)-5-methoxyphenoxy]-4-methoxyphenyl]ethanoic acid		C₄₂H₅₇FN₄O₁₅Si	详情	详情
(XIX)	47044	tert-butyl (8S,11R,14R)-11-(4-fluoro-3-nitrobenzyl)-5,18-dimethoxy-8-[[(2-methoxyethoxy)methoxy]methyl]-10,13-dioxo-2-oxa-9,12-diazatricyclo[13.3.1.1(3,7)]icosa-1(19),3(20),4,6,15,17-hexaen-14-ylcarbamate		C₃₆H₄₃FN₄O₁₂	详情	详情
(XX)	47045	tert-butyl (8S,11R,14R)-11-(4-fluoro-3-nitrobenzyl)-8-(hydroxymethyl)-5,18-dimethoxy-10,13-dioxo-2-oxa-9,12-diazatricyclo[13.3.1.1(3,7)]icosa-1(19),3(20),4,6,15,17-hexaen-14-ylcarbamate		C₃₂H₃₅FN₄O₁₀	详情	详情
(XXI)	47046	(8S,11R,14R)-14-[(tert-butoxycarbonyl)amino]-11-(4-fluoro-3-nitrobenzyl)-5,18-dimethoxy-10,13-dioxo-2-oxa-9,12-diazatricyclo[13.3.1.1(3,7)]icosa-1(19),3(20),4,6,15,17-hexaene-8-carboxylic acid		C₃₂H₃₃FN₄O₁₁	详情	详情

合成路线2

该中间体在本合成路线中的序号：(IVR)

2) The same reaction sequence of (I) and (IVr) yields intermediates (Vs), (VIs) and (VIIs), and finally (S)-OPC-12759.

参考文献中间体

合成目标

【1】 Morita, S.; Yamasaki, K.; Shimizu, T.; Uchida, M.; Otsubo, K.; Kanbe, T.; Synthesis and antiulcer activity of optical isomers of 2-(4-chlorobenzoy lamino)-3-[2(1H)-quinolinon-4-yl]propionic acid (rebamipide). Chem Pharm Bull 1991, 39, 11, 2906.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(IVR)	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
(VS)	10297	2-Chloro-4-[[(2S,5R)-5-isopropyl-3,6-dimethoxy-2,5-dihydro-2-pyrazinyl]methyl]quinoline; (3R,6S)-6-[(2-Chloro-4-quinolinyl)methyl]-3-isopropyl-5-methoxy-3,6-dihydro-2-pyrazinyl methyl ether		C₁₉H₂₂ClN₃O₂	详情	详情
(VIS)	10298	methyl (2S)-2-amino-3-(2-chloro-4-quinolinyl)propanoate		C₁₃H₁₃ClN₂O₂	详情	详情
(VIIS)	10299	(2S)-2-Amino-3-(2-oxo-1,2-dihydro-4-quinolinyl)propionic acid		C₁₂H₁₂N₂O₃	详情	详情
(II)	10289	4-(Bromomethyl)-2-chloroquinoline		C₁₀H₇BrClN	详情	详情
(III)	10290	2-Chloro-4-(chloromethyl)quinoline		C₁₀H₇Cl₂N	详情	详情
(VIII)	10295	p-Chlorobenzoyl chloride; 4-Chlorobenzoyl chloride	122-01-0	C₇H₄Cl₂O	详情	详情

合成路线3

该中间体在本合成路线中的序号：(IX)

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).

参考文献中间体

合成目标

【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

合成路线4

该中间体在本合成路线中的序号：(I)

参考文献中间体

合成目标

【1】 Kim D, Wang LP, Becoru M, et al. 2005. (2R)-4-Oxo-4-[3-(Trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl}l-(2,4,5-trifluorophenyl)butan-2-amine:a potent, orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. J Med Chem, 48(1):141～151

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(II)	66723	1-(bromomethyl)-2,4,5-trifluorobenzene		C₇H₄BrF₃	详情	详情
(I)	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
(III)	66724	(2S,5R)-2-isopropyl-3,6-dimethoxy-5-(2,4,5-trifluorobenzyl)-2,5-dihydropyrazine		C₁₆H₁₉F₃N₂O₂	详情	详情
(IV)	66725	(R)-methyl 2-amino-3-(2,4,5-trifluorophenyl)propanoate		C₁₀H₁₀F₃NO₂	详情	详情
(V)	66729	(R)-methyl 2-((tert-butoxycarbonyl)amino)-3-(2,4,5-trifluorophenyl)propanoate		C₁₅H₁₈F₃NO₄	详情	详情
(VI)	66728	(R)-2-((tert-butoxycarbonyl)amino)-3-(2,4,5-trifluorophenyl)propanoic acid		C₁₄H₁₆F₃NO₄	详情	详情
(VII)	66727	(R)-tert-butyl (4-diazo-3-oxo-1-(2,4,5-trifluorophenyl)butan-2-yl)carbamate		C₁₅H₁₆F₃N₃O₃	详情	详情
(VIII)	66726	(R)-3-((tert-butoxycarbonyl)amino)-4-(2,4,5-trifluorophenyl)butanoic acid		C₁₅H₁₈F₃NO₄	详情	详情
(IX)	24075	2-chloropyrazine	14508-49-7	C₄H₃ClN₂	详情	详情
(X)	66713	2-Hydrazinopyrazine	54608-52-5	C₄H₆N₄	详情	详情
(XI)	66730	2,2,2-trifluoro-N'-(pyrazin-2-yl)acetohydrazide 2,2,2-trifluoroacetate		C₆H₅F₃N₄O.C₂HF₃O₂	详情	详情
(XII)	66715	3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyrazine		C₆H₃F₃N₄	详情	详情
(XIII)	66731	3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine		C₆H₇F₃N₄	详情	详情
(XIV)	66732	(R)-tert-butyl (4-oxo-4-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-1-(2,4,5-trifluorophenyl)butan-2-yl)carbamate		C₂₁H₂₃F₆N₅O₃	详情	详情

合成路线5

该中间体在本合成路线中的序号：(II)

参考文献中间体

合成目标

【1】 Lindsay KB. Skrydstrup T. 2006. Formal total synthesisi of the potent renin inhibitory aliskiren: Application of a Sml-promoted acyl-like radical coupling. J Org Chem, 71(13): 4766～4777

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XI)	67001	benzyl (1-(4-(2-hydroxypropan-2-yl)-5-oxotetrahydrofuran-2-yl)-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-4-methylpentyl)carbamate		C₃₃H₄₇NO₈	详情	详情
(I)	28120	3-[5-[(2R)-2-(bromomethyl)-3-methylbutyl]-2-methoxyphenoxy]propyl methyl ether	172900-69-5	C₁₇H₂₇BrO₃	详情	详情
(II)	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
(III)	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
(IV)	66995	(2R,4R)-methyl 2-amino-4-(4-methoxy-3-(3-methoxypropoxy)benzyl)-5-methylhexanoate		C₂₀H₃₃NO₅	详情	详情
(V)	66996	methyl 2-(((benzyloxy)carbonyl)amino)-4-(4-methoxy-3-(3-methoxypropoxy)benzyl)-5-methylhexanoate		C₂₈H₃₉NO₇	详情	详情
(VI)	66997	2-(((benzyloxy)carbonyl)amino)-4-(4-methoxy-3-(3-methoxypropoxy)benzyl)-5-methylhexanoic acid		C₂₇H₃₇NO₇	详情	详情
(VII)	27936	4-Mercaptopyridine; 4-pyridinethiol	4556-23-4	C₅H₅NS	详情	详情
(VIII)	66998			C₃₂H₄₀N₂O₆S	详情	详情
(IX)	66999	methyl 5-(((benzyloxy)carbonyl)amino)-7-(4-methoxy-3-(3-methoxypropoxy)benzyl)-8-methyl-4-oxononanoate		C₃₁H₄₃NO₈	详情	详情
(X)	67000	benzyl (3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-4-methyl-1-(5-oxotetrahydrofuran-2-yl)pentyl)carbamate		C₃₀H₄₁NO₇	详情	详情
(XII)	67002	benzyl (3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-4-methyl-1-(5-oxo-4-(prop-1-en-2-yl)tetrahydrofuran-2-yl)pentyl)carbamate		C₃₃H₄₅NO₇	详情	详情
(XIII)	67003	5-(1-amino-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-4-methylpentyl)-3-isopropyldihydrofuran-2(3H)-one		C₂₅H₄₁NO₅	详情	详情
(XIV)	67004	tert-butyl (1-(4-isopropyl-5-oxotetrahydrofuran-2-yl)-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-4-methylpentyl)carbamate		C₃₀H₄₉NO₇	详情	详情
(XV)	28129	3-amino-2,2-dimethylpropanamide	324763-51-1	C₅H₁₂N₂O	详情	详情
(XVI)	67005	tert-butyl (8-((3-amino-2,2-dimethyl-3-oxopropyl)carbamoyl)-6-hydroxy-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-2,9-dimethyldecan-5-yl)carbamate		C₃₅H₆₁N₃O₈	详情	详情

Extended Information